AU2007200261A1 - Chemokine receptor antagonists and methods of use thereof - Google Patents

Description

P/00/0 II Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT

(ORIGINAL)

Name of Applicants: Millennium Pharmaceuticals, Inc. of 75 Sidney Street, Cambridge, Massachusetts 02139, United States of America and Kyowa Hakko Kogyo Co., Ltd. of 6-1 Ohtemachi 1-chome, Chiyoda-ku, Tokyo 100, Japan Actual Inventors: ELDER, Amy NAKASATO, Yoshisuke; GHOSH, Shomir; HARRIMAN, Geraldine, MATTIA, Karen, OHSHIMA, Etsuo; CARSON, Kenneth, and LULY, Jay, R.

Address for Service: Invention Title: DAVIES COLLISON CAVE, Patent Trademark Attorneys, of 1 Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM "Chemokine receptor antagonists and methods of use thereof" The following statement is a full description of this invention, including the best method of performing it known to us:- CHEMOKINE RECEPTOR ANTAGONISTS AND METHODS OF USE THEREFOR RELATED APPLICATION This application is a divisional of Australian Patent Application No. 2002352772, the entire content of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION Chemoattractant cytokines or chemokines are a family ofproinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes and lymphocytes. They can be released by many kinds of tissue cells after activation.

Continuous release of chemokines at sites of inflammation mediates the ongoing migration of effector cells in chronic inflammation. The chemokines characterized to date are related in primary structure. They share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family is divided into two main branches, designated as the C-X-C chemokines (a-chemokines), and the C-C chemokines (P-chemokines), in which the first two conserved cysteines are separated by an intervening residue, or adjacent respectively (Baggiolini, M. and Dahinden, C. Immunology Today, 15:127-133 (1994)).

The C-X-C chemokines include a number of potent chemoattractants and activators ofneutrophils, such as interleukin 8 PF4 and neutrophil-activating peptide-2 (NAP-2). The C-C chemokines include RANTES (Regulated on Activation, Normal T Expressed and Secreted), the macrophage inflammatory proteins la and 13 (MIP-la and MIP-1p), eotaxin and human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3), which have been characterized as chemoattractants and activators of monocytes or lymphocytes but do not appear to be chemoattractants for neutrophils. Chemokines, such as RANTES and MIP-l a, have been implicated in a wide range of human acute and chronic inflammatory diseases including respiratory diseases, such as asthma and allergic disorders.

The chemokine receptors are members of a superfamily of G protein-coupled receptors (GPCR) which share structural features that reflect a common mechanism of action of signal transduction (Gerard, C. and Gerard, Annu Rev. Immunol., 12:775-808 (1994); Gerard, C. and Gerard, N. Curr. Opin. Immunol., 6:140-145 (1994)). Conserved features include seven hydrophobic domains spanning the plasma membrane, which are connected by hydrophilic extracellular and intracellular loops. The majority of the primary sequence homology occurs in the hydrophobic transmembrane regions with the hydrophilic regions being more diverse. The first receptor for the C-C chemokines that was cloned and expressed binds the chemokines MIP-la and RANTES. Accordingly, this MIP-la/RANTES receptor was designated C-C chemokine receptor 1 (also referred to as CCR-1; Neote, et al., Cell, 72:415-425 (1993); Horuk, R. et al., WO 94/11504, Mvay 26, 1994; Gao, et al., J. Exp. Med., 177:1421-1427 (1993)). Three receptors have been characterized which bind and/or signal in response to RANTES: CCR3 mediates binding and signaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath et al., J. Exp. Med., 183:2437 (1996)), CCR4 binds chemolcines including RANTES, MIP-la, and MCP-1 (Power, et al., J. Biol. Chem., 270:19495 (1995)), and CCR5 binds chemokines including MIP-la, RANTES, and MIP-1P (Samson, et al., Biochem. 35: 3362-3367 (1996)). RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of T-cells. The responses of these different cells may not all be mediated by the same receptor, and it is possible that the receptors CCRI, CCR4 and CCR5 will show some selectivity in receptor distribution and function between leukocyte types, as has already been shown for CCR3 (Ponath et In particular, the ability of RANTES to induce the directed migration of monocytes and a memory population of circulating T-cells (Schall, T. et al., Nature, 347:669-71 (1990)) suggests this chemokine and its receptor(s) may play a critical role in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrates of T cells and monocytes.

Many existing drugs have been developed as antagonists of the receptors for biogenic amines, for example, as antagonists of the dopamine and histamine receptors. No successful antagonists have yet been developed to the receptors for the larger proteins such as chemokines and C5a. Small molecule antagonists of the interaction between C-C chemokine receptors and their ligands, including RANTES and MIP-la, would provide compounds useful for inhibiting harmful inflammatory processes "triggered" by receptor ligand interaction, as well as valuable tools for the investigation ofreceptor-ligand interactions.

SUMMARY OF THE INVENTION It has now been found that a class of small organic molecules are antagonists of chemokine receptor function and can inhibit leukocyte activation and/or recruitment.

An antagonist of chemokine receptor function is a molecule which can inhibit the binding and/or activation of one or more chemokines, including C-C chemokines such as RANTES, MIP-la, MCP-2, MCP-3 and MCP-4 to one or more chemokine receptors on leukocytes and/or other cell types. As a consequence, processes and cellular responses mediated by chemokine receptors can be inhibited with these 0 0 -4- 0 small organic molecules. Based on this discovery, a method of treating a disease associated with aberrant leukocyte recruitment and/or activation is disclosed as well as a method of treating a disease mediated by chemokine receptor function. The cN method comprises administering to a subject in need an effective amount of a

O

S 5 compound or small organic molecule which is an antagonist of chemokine receptor function. Compounds or small organic molecules which have been identified as antagonists of chemokine receptor function are discussed in detail hereinbelow, and can be used for the manufacture of a medicament for treating or for preventing a disease associated with aberrant leukocyte recruitment and/or activation. In one aspect, the compound has the formula:

R

70 71

(CH

2

M

Z=rS R 72

R

73 or a physiologically acceptable salt thereof, wherein Z, n, M, R 7 0

R

7 1

R

7 2 and R 73 are as described herein.

The invention also relates to the disclosed compounds and small organic molecules for use in treating or preventing a disease associated with aberrant leukocyte recruitment and/or activation. The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier. The invention further relates to novel compounds which can be used to treat an individual with a disease associated with aberrant leukocyte recruitment and/or activation and methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic showing the preparation of the compounds represented by Structural Formula Figure 2 is a schematic showing the preparation of the compounds represented by Compound (VI-b).

Figure 3 is a schematic showing the preparation of the compounds represented by Structural Formula (I) Figure 4 is a schematic showing the preparation of the compounds represented by Structural Formula wherein Z is represented by Structural Formula (III) and wherein Ring A and/or Ring B in Z is substituted with R 40 Figure 5 is a schematic showing the preparation of the compounds represented by Structural Formula wherein Z is represented by Structural Formula (II) and wherein Ring A and/or Ring B in Z is substituted with 2

),-COOR

20 2 0

-(O)U-(CH

2 2

R

2 2 or 2 0 Figures 6A-6Z show the structures of exemplary compounds of the present invention.

Figure 7 shows the preparation of compounds represented by Structural Formula where in Z is represented by Structural Formulas (111) and wherein Ring A or Ring B in Z is substituted with R 40 Figure 8A is a schematic showing the preparation of 4-(4-chlorophenyl)-4fluoropiperidine.

Figure 8B is a schematic showing the preparation of 4-4-azido-4-(4chlorophenyl)piperidine.

Figure 8C is a schematic showing the preparation of 4-(4-chlorophenyl)-4methylpiperidine.

Figure 9A is a schematic showing the preparation of compounds represented by Structural Formulas (VII) and (VIII) wherein R' is an amine.

Figure 9B is a schematic showing the preparation of compounds represented by Structural Formulas (VIII) and (VIII) wherein R' is an alkylamine.

Figure 9C is a schematic showing the preparation of 2-(4-chlorophenyl)- c-- S-6methyl)ethylamine.

Figure 9D is a schematic showing the preparation of 3-(4-chlorophenyl)-3chloro- 1 -hydroxypropane.

Figure 9E is a schematic showing the preparation of 3-(4-chlorophenyl)-

-N-

O

N 5 methylaminopropane.

Figure 10A is a schematic showing the preparation of 3-(4-chlorophenyl)-3- Shydroxyl-3-methyl- 1 -N-methylaminopropane.

Figure 10B is a schematic showing the preparation-of 1-(4-chlorobenzoyl)-1,3propylenediamine.

Figure 10C is a schematic showing three procedures for the preparation of compounds represented by Structural Formulas (VIII), (IX) and (XI) wherein Z is represented by Structural Formula and wherein Ring A or Ring B in Z is substituted with R 4 0 In Figure 10C, R 4 0 is represented by 2

NR

21

R

2 2 u is one, t is zero.

Figure 10D is a schematic showing the preparation of 4-(4-chlorophenyl)-4pyridine.

Figures 11A- 11T show the structures of exemplary compounds of the present invention.

Figure 12 is a schematic showing preparation of compounds of formula (VIc).

Figure 13 is a schematic showing preparation of compounds of formula (VIe).

Figure 14 is a schematic showing a procedure for the preparation of Examples 434 and 435.

Figure 15 is a schematic showing a procedure for the preparation of Examples 436-438.

Figure 16 is a schematic showing a procedure for the preparation of compounds of formula Figure 17 is a schematic showing a procedure for the preparation of Examples 441 and 442.

Figure 18 is a schematic showing a procedure for the preparation of Example 443.

Figure 19 is a schematic showing a procedure for the preparation of Examples 315, 455, 338 and 446.

Figures 20-28 show the structures of exemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to small molecule compounds which are modulators of chemokine receptor function. In a preferred embodiment, the small molecule compounds are antagonists of chemokine receptor function. Accordingly, processes or cellular responses mediated by the binding of a chemokine to a receptor can be inhibited (reduced or prevented, in whole or in part), including leukocyte migration, integrin activation, transient increases in the concentration ofintracellular free calcium and/or granule release ofproinflammatory mediators.

The invention further relates to a method of treatment, including prophylactic and therapeutic treatments, of a disease associated with aberrant leukocyte recruitment and/or activation or mediated by chemokines or chemokine receptor function, including chronic inflammatory disorders characterized by the presence of RANTES, MIP-1 a, MCP-2, MCP-3 and/or MCP-4 responsive T cells, monocytes and/or eosinophils, including but not limited to diseases such as arthritis g., rheumatoid arthritis), atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus type 1 diabetes mellitus), psoriasis, multiple sclerosis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, rejection of transplanted organs and tissues acute allograft rejection, chronic allograft rejection), graft versus host disease, as well as allergies and asthma. Other diseases associated with aberrant leukocyte recruitment and/or activation which can be treated (including prophylactic treatments) with the methods disclosed herein are inflammatory diseases associated with Human Immunodeficiency Virus (HIV) infection, AIDS associated encephaliti s, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulo nephritis. The method comprises administering to the subject in need of treatment an effective amount of a compound one or more compounds) which inhibits chemokine receptor function, inhibits the binding of a chemokine to leukocytes and/or other cell types, and/or which inhibits leukocyte migration to, and/or activation at, sites of inflammation.

The invention further relates to methods of antagonizing a chemokine receptor, such as CCR1, in a mammal comprising administering to the mammal a compound as described herein.

According to the method, chemokine-mediated chemotaxis and/or activation of pro-inflammatory cells bearing receptors for chemokines can be inhibited. As used herein, "pro-inflammatory cells" includes but is not limited to leukocytes, since chemokine receptors can be expressed on other cell types, such as neurons and epithelial cells.

While not wishing to be bound by any particular theory or mechanism, it is believed that compounds of the invention are antagonists of the chemokine receptor CCR1, and that therapeutic benefits derived from the method of the invention are the result of antagonism of CCR1 function. Thus, the method and compounds of the invention can be used to treat a medical condition involving cells which express CCR1 on their surface and which respond to signals transduced through CCR1, as well as the specific conditions recited above.

In one embodiment, the antagonist of chemokine receptor function is represented by Structural Formula

M

(GIr- N M -9c

(I)

and physiologically acceptable salts thereof.

C

Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to one, two or Smore aromatic rings, wherein each ring in Z is independently substituted or unsubstituted.

Sn is an integer, such as an integer from one to four. Preferably, n is one, two or three. More preferably n is two. In alternative embodiments, other aliphatic or aromatic spacer groups can be employed for M is >NR 2 or >CR'R 2 M is preferably >C(OH)R 2 R' is -OH, -N 3 a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -O-(aliphatic group), -O-(substituted aliphatic group), -SH, -S-(aliphatic group), -S-(substituted aliphatic group), -OC(O)-(aliphatic group), -O-C(O)-(substituted aliphatic group), -C(O)O-(aliphatic group), -C(O)O-(substituted aliphatic group), -COOH, -CN, -CO-NR 3

R

4

-NRR

4 or R can be a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M. R' is preferably -H or -OH.

R

2 is -OH, a halogen, an acyl group, a substituted acyl group, -NR 5

R

6 an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, -O-(substituted or unsubstituted aromatic group), -O-(substituted or unsubstituted aliphatic group) or -C(O)-(substituted or unsubstituted aromatic group) or -C(O)-(substituted or unsubstituted aliphatic group). R 2 is preferably an aromatic group or a substituted aromatic group.

R

3

R

4

R

5 and R 6 are independently an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

R' and R 2

R

3 and R 4 or R 5 and R 6 taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

In embodiments where M is >CR'R' and R' is a covalent bond between the carbon atom at M and an adjacent carbon atom in the ring which contains M, the antagonist of chemokine function can be represented by Structural Formula (Ia).

2 (cH 2 -N C- R z n (la) Z, n and R 2 are as described in Structural Formula In one embodiment, Z is a tricyclic ring system comprising two carbocyclic aromatic groups fused to a five, six, seven or eight membered cycloalkyl group or to a non-aromatic heterocyclic ring. In one example, Z is represented by Structural Formula (IT):

CB

(II)

The phenyl rings in Structural Formula labeled with an and are referred to herein as "Ring A" and "Ring respectively. The central ring, labeled with a is referred to as "Ring C" and can be, for example, a five, six, seven or eight membered non-aromatic carbocyclic ring a cycloheptane or cyclooctane ring) or a non-aromatic heterocyclic ring. When Ring C is a non-aromatic heterocyclic ring, it can contain one or two heteroatoms such as nitrogen, sulfur or oxygen. In particular embodiments, Ring c is When Z is represented by Structural Formula the tricyclic ring system can be connected to the remainder of the molecule by a covalent double bond between a carbon atom in Ring C and the carbon atom which, as depicted in Structural Formula is bonded to Z.

Ring A and/or Ring B in Structural Formula (II) can be unsubstituted.

Alternatively, Ring A and/or Ring B can have one or more substituents. Suitable substituents are as described hereinbelow. In one example, Ring A or Ring B is substituted with 2

),-C(O)OR

2 0 2 0 2

R

22 or 2

),-NHC(O)O-R

2 0 u is zero or one.

t is an integer, such as an integer from zero to three, and the methylene group

(CH

2 can be substituted, as described herein for aliphatic groups, or unsubstituted.

R

2 0

R

21 or R 2 2 are independently an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R 2 and R 2 2 taken together with the nitrogen atom to which they are bonded, can form a non-aromatic heterocyclic ring.

Ring C optionally contains one or more substituents, as described hereinbelow. Examples of suitable tricyclic ring systems, Z, are provided by Structural Formula i A C B Ring A and Ring B in Structural Formula are as described for Structural -12- Formula (UI).

X, is a bond, -CH 2

-CH

2

-CH

2

-CH

2

-S-CH

2 -,-0-CH 2 -C11 2

-NR,-CH

2

-CH

2

-SO-CH

2

-CH

2

-S(O)

2

-CH

2

-GH

2 -S(0) 2

-CH=CH-,

-NR,-G0- or -CO-NRc-. Preferably X, is -CH 2

-CH

2

-CH

2

-CH

2 -NRc-COor k~ is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

In one example, R, is -(CH 2

),-COOR

30

-(CH

2 5 32

R

2 or

-(CH

2 5

-NHC(O)-O-R

0 wherein s is an integer, such as an integer from one to three;

R"

0 R" and R" 2 are independently an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, and R" 2 taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.

Other examples of suitable tricyclic ring systems for Z include benzodiazepines, benzooxazepines, benzooxazines, phenothiazines and groups represented by the following structural formnulas:

SS

In other embodiments, Z is a tricyclic ring system comprising two aromatic groups fused to a seven or eight membered cycloalkyl group or to a non-aromatic heterocyclic ring, wherein at least one of the aromatic groups is a heteroaryl group.

In one example, Z is represented by Structural Formula (IV):

(NV)

A C B Ring A in Structural Formula (IV) can be a substituted or unsubstituted heteroaryl group. Ring B in Structural Formula (IV) can be a substituted or unsubstituted aromatic group, a heteroaryl group or carbocyclic aryl group.

Suitable substituents are as described hereinbelow. In one example, Ring A and/or Ring B is substituted with 2 0 2 0 2 2

'R

2 2 or 2 0 as described above. u, t,

R

20

R

21 and R 22 are as described above. X, and R c can be as described above for Structural Formula (MI).

In another embodiment of the present invention Z is represented by Structural Formula wherein Ring A is a pyridyl group and Ring B is an aromatic or heteroaromatic group. In one example, Z is represented by Structural Formula (IVa): S(IVa).

In this embodiment Ring A and Ring B are independently substituted or unsubstituted, and Ring B is preferably a phenyl group. X, and R, can be as C described above for Structural Formula In another embodiment, both Ring A and Ring B are pyridyl groups, and Z is represented by Structural Formula (IVb): N N (IVb) Ring A and Ring B can be independently substituted or unsubstituted as described above in Structural Formula and X, can be as described above for Structural Formula (III).

In preferred embodiments, Z is represented by Structural Formula

(V)

Ring A and Ring B can be independently substituted or unsubstituted as described above in Structural Formula and X, can be as described above for Structural Formula (III).

In particularly preferred embodiments, Ring B in Structural Formula is substituted para to the carbon atom of Ring B which is bonded to X, of Ring C, and Z is represented by Structural Formula (VI):

R

4 0 IAi C B N X,

(VI)

X, can be as described above in Structural Formula Preferably X, is

-CH

2 or -CH 2

R

40 is a substituent as described herein for aromatic groups. In one embodiment, R 40 is -OH, -COOH, a halogen, -NO 2 an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR"R 2

-CONR

2 4

R

2 5

-C(=NR

0

)NR

2 1

R

22 -Q-(aliphatic group), -Q-(substituted aliphatic group), -O-(aliphatic group), -O-(substituted aliphatic group), -O-(aromatic group), -O-(substituted aromatic group), an electron withdrawing group, 2 1

-C(O)OR

2 0 2

),-OC(O)R

2 0 2 2

'R

22 or 2 )t-NHC(O)O-R 2 0 Q, R 20

R

2 1

R

22

R

4

R

25

R

6 0 u and t are as described herein.

Preferably R 40 is an aliphatic group, substituted aliphatic group, -O-(aliphatic group) or -O-(substituted aliphatic group). In certain embodiments, R 40 is an -0alkyl, such as -O-CH 3 -O-C2H,, -O-C 3 H, or -O-C 4

H

9 In another embodiment, R 40 can be represented by -(O),-(CH2),-C(O)-NR2R22, wherein u is one, t is zero, and R 2 and R 2 2 are as described herein. In this -16embodiment, R 2 and R 2 2 can each independently be a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, or R 2 and R 22 taken together with the nitrogen atom to which they are bonded form a substituted or unsubstituted nonaromatic heterocyclic ring pyrrolidine, piperidine, morpholine).

In another embodiment, R 4 0 can be represented by 2

R

2 wherein u is zero, t is one to about three, and R 2 1 and R 22 are as described herein.

In another embodiment, R 4 0 can be represented by 2 1

R

22 wherein both u and t are zero, and R 21 and R 22 are as described herein.

In another embodiment, R 4 0 is an aliphatic group methyl, ethyl, propyl) that is substituted with -NR2 4

R

2 1 or -CONR 4

R

25 wherein R 2 4 and R 2 5 are as described herein. For example, R 4 0 can be represented by

NR

2 eR 25 Of 4

R

2 or O O In another embodiment, R 4 0 is -O-C(O)-NR 1

R

26 wherein R 2 is as described herein, R 2 6 can be an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C(O)-O-(substituted or unsubstituted aliphatic group), -C(O)-0-(substituted or unsubstituted aromatic group), -S(O) 2 -(substituted or unsubstituted aliphatic group), -S(0) 2 -(substituted or unsubstituted aromatic group) or R 21 and R 26 taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

In additional embodiments, R 40 can be -S(0)2-NR 2 1

R

2 2 or -N-C(O)-NR 2

R

2 2 wherein R 21 and R 22 are as described herein.

In a preferred embodiment, the chemokine receptor antagonist can be represented by Structural Formula I wherein n is three, M is C(OH)R 2

R

2 is a phenyl group or a halophenyl group 4-chlorophenyl) and Z is represented by Structural Formula (VI) wherein X, is -CH 2 In one example of this embodiment, R 4 0 can be -O-(substituted aliphatic group), such as InOH p In particularly preferred embodiments, RO 40 is I 0

OH

In other preferred embodiments, R 40 is a substituted aliphatic group, a substituted aromatic group, -O-substituted aliphatic group or -O-substituted aromatic group. Preferably the aliphatic or aromatic moiety of the substituted aliphatic group, substituted aromatic group, -O-substituted aliphatic group or -O-substituted aromatic group bears a substituent selected from the group consisting of-OH, -COOR -18- -Q-aliphatic group or -Q-aromatic group substituent. Q is as described herein.

Preferably, Q is For example, R 40 can be a linear, branched or cyclic aliphatic group that contains 1 to 6 carbon atoms, such as a C,-C 6 alkyl group, a C2-C 6 alkenyl, C 2

-C

6 alkynyl, that is substituted with -OH, -COOH, -C(0)O-(Ci-C6 aliphatic) or -C(O)O-(aromatic).

In another embodiment, the antagonist of chemokine activity can be represented by Structural Formula (VII): N

M

n 4 /Mq

(VII)

and physiologically acceptable salts thereof.

n is as described in Structural Formula Z is as described herein, preferably as described in Structural Formula or (VI).

M is >NR 2

>CR'R

2 or -CH 2

-CR'R

2 R' and R 2 are as described in Structural Formula q' is an integer, such as an integer from zero to about three, and q 2 is an integer from zero to about one. The ring containing M can be substituted or unsubstituted.

Thus, the antagonist of chemokine function can be represent by, for example, Structural Formulas (VIla)-(Vllk): -19-

IND

(Vlia) (CF2-nTWN (VIIc) (cp,7N I (VJ~b) (Vild) (c P r,-N \/M (Vfle) Z~ (CFI-nT 0 N R1 (CFHT7nN (\'Ilf (Vil) (cii2T-, N' z=Is0 R 2 (cM -n a Z=gj- 1

.R

(VE~h) (ii (ViTi) 0 0 R2

NR

(cg--N N-R 2 (c-N S(vnj) (VIIk) 0 and physiologically acceptable salts thereof, wherein Z, n and M are as described in Structural Formula (VII), and the ring which contains M is substituted or unsubstituted. The ring containing M can have one or more suitable substituents which are the same or different. Suitable substituents for the ring which contains M and other nonaromatic heterocyclic rings are as described herein. For example, the ring containing M can be substituted with a methyl, ethyl, propyl, butyl or oxo group.

When the ring containing M is substituted, the compound can be represented by Sturctural Formula (VII1): R77 R 70 R76 R 7

(CH

2 )7N M

R

72

(VIII)

R

74

R

7 3 or physiologically acceptable salt thereof.

R0, R 7 1

R

7 1

R

7 2 R74, R 75

R

76 and R 77 are independently -OH, -N 3 a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -O-(aliphatic group), -O-(substituted aliphatic group), -SH, -S-(aliphatic group), -S-(substituted aliphatic group), -OC(O)-(aliphatic group), -O-C(O)-(substituted aliphatic group), -C(O)O-(aliphatic group), -C(O)O-(substituted aliphatic group), -COOH, -CN, -CO-NRR 4 -NRRR, an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, -O-(substituted or unsubstituted aromatic group), or any two of R 7 0

R

71

R

7 2

R

73

R

7 4

R

7 5

R

76 and R 77 taken together with the atoms to which they are bonded form a three to eight membered ring.

n is as described in Structural Formula Z is as described herein, preferably as described in Structural Formula or M is as described in Structural Formula (VII). Preferably, M is >NR 2 or >CR'R 2 In certain embodiments R 7 4

R

75

R

76 and R" are In other embodiments,

R

74

R

75

R

76 and R 77 are and at least one of R 7 0

R

7 1

R

72 and R 73 is an aliphatic group or a substituted aliphatic group. Preferred aliphatic groups at R 7 0

R

7 1

R

7 2

R

73

R

74

R

75

R

76 and R 77 are C 1 alkyl, preferred substititued aliphatic groups are are alkyl substituted with -OH, 2

-C(O)OR

20 or -O-(aliphatic group) wherein t is zero to three, u is zero or one, and R 2 0 is alkyl. In more particular embodiments, the compound has the formula of Structural Formula VIII wherein

R

7 0

R

73

R

74

R

7 5

R

76 and R 7 7 are and at least one of R 71 and R 72 is -CH 3 In a preferred embodiment, the chemokine receptor antagonist is represented by Structural Formula VIII wherein n is two; M is >C(OH)R 2

R

2 is a halophenyl group 4-chlorophenyl);

R

7 2

R

73

R

7 4

R

75

R

76 and R 7 7 are -H and R 70 and R 71 are independently alkyl or substituted alkyl; or R 7 0

R

7 1

R

74

R

75

R

7 6 and R 77 are -H and R 7 2 and

R

73 are independently alkyl or substituted alkyl; and Z is represented by Structural Formula (VI) wherein X, is When R 72 and R 73 are each -CH 3 the compounds of this preferred embodiment can have the formula: R2 Ho Yi

(XII)

m" -22or a physiologically acceptable salt thereof, wherein R 2 is 4-halophenyl. Preferably R 2 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl.

0 Preferred groups at R" are as described herein. Particularly preferred at R 4 0 are aliphatic 0 N groups alkyl) and substituted aliphatic groups.

t"- 0 In a particularly preferred embodiment, the compound is the (S)-enantiomer of the 0 N compound of Formula (XII) and has the structure:

R

2

N

R

4 0 N -O (XIII) or a physiologically acceptable salt thereof, wherein R 2 is 4-halophenyl.

Particularly preferred compounds of the invention have the structure of Formula XIII wherein R 2 is 4-chlorophenyl and R 4 0 is selected from the group consisting of: 0 0 O- .OH, \NH OH NH,

OH

,O NH 2 ,O0 0 O, OH

H

OH and ON OH 0 I In another embodiment, the compound is represented by Structural Formula VIIi: -23- Z c- a' n -Rn

R

2 or a physiologically acceptable salt thereof, wherein n, R' and R 2 are as described in Structural Formula and Z is as described in Structural Formula or (VI).

In a certain embodiments, Z is represented by Structural Formula (VI) wherein X, is -CH 2 n is two, R' is -H and R 2 is -NR'R. Preferably, compounds of these embodiments have the structure:

R

6 N O or a physiologically acceptable salt thereof, wherein R 5 and R 6 are as described in Structural Formula I, and preferred groups at R 40 are as described herein.

In particular embodiments, R' is aliphatic group C 1

-C

6 alkyl) or substituted aliphatic group, and R 6 is benzyl or substituted benzyl; or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring. In more particular embodiments, R 5 is C,-C 6 alkyl and R 6 is halo-substituted benzyl. In a preferred embodiment, R' is ethyl and R 6 is chloro-substituted benzyl 4-chlorobenzyl).

The nitrogen atom in the ring containing M can be a tertiary nitrogen as depicted in Structural Formula or the nitrogen atom can be quatemized with a suitable substituent, such as a C, to about C 6 or a C, to about C 3 substituted or unsubstituted aliphatic group. Compounds which comprise a quaternary nitrogen atom can also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.

The antagonist of chemokine function can be represented by Structural Formula (VII) wherein the heterocyclic ring containing M is substituted with a suitable bivalent group which is bonded to two atoms that are in the ring, thereby forming a bicyclic moiety. Suitable bivalent groups include, for example, substituted or unsubstituted bivalent aliphatic groups, such as a alkylene group.

The antagonist of chemokine receptor function can comprise a variety of bicyclic moieties. In one embodiment, the antagonist of chemokine receptor function can be represented by Structural Formula (VIl):

(CH

2 I- N M (vnI) and physiologically acceptable salts thereof.

M is >NR 2

>CR'R

2

-O-CR'R

2 or -CH 2 Preferably, M is >NR 2 or >CR'R 2 R' and R 2 are as described in Structural Formula and n and Z are as described in structural Formula (VII).

In another embodiment, the antagonist of chemokine receptor function is represented by Structural Formula (IX):

(CH

2 )--NRs 5

RS

Z'

(IX)

and physiologically acceptable salts thereof.

Z is as described herein, preferably as described in Structural Formula or

(VI).

n is an integer, such as an integer from one to about four. Preferably, n is one, two or three. More preferably n is two. In alternative embodiments, other aliphatic or aromatic spacer groups can be employed for (CH 2

R

5 and R 5 are each independently an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -NR'R 4 an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group or a covalent bond between the nitrogen atom an adjacent carbon atom.

R

3 and R 4 are independently an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

R

3 and R 4 taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

In a preferred embodiment R 5 0 is a substituted aliphatic group, such as a substituted C, to about C,2 alkyl group, and R 5 is -H or a substituted or unsubstituted aliphatic group. More preferably, RS' is a substituted linear or branched C 2 to about C 7 aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom, such as nitrogen, oxygen or sulfur, and R 5 is -H or a linear or branched C, to about C 6 or a C, to about C 3 aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom. R 5 0 and R 51 can be substituted with one or more suitable substituents, as described herein, preferably an aromatic group phenyl, 4-halophenyl). For example, R 5 0 can be selected from the group consisting of:

IND

-26- HO K 0 C1 The activity of chemokine receptor antagonists represented by Structural Formula IX can be affected by the character of the nitrogen atom to which R 5 0 and

R

5 1 are bonded. It is believed that compounds in which said nitrogen atom is basic can have potent chemokine receptor antagonist activity. It is known that the basicity of a nitrogen atom can be decreased when the nitrogen atom is bonded to a carbonyl group, sulfonyl group or a sulfinyl group. Therefore, it is preferred that neither R 5 0 nor R 5 comprise a carbonyl group, sulfonyl group or sulfinyl group that is directly bonded to the nitrogen atom.

In another aspect, the antagonist of chemokine receptor function is represented by Structural Formula x (CH2) N M

(X)

and physiologically acceptable salts thereof.

Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to one, two or more aromatic rings, wherein each ring in Z is independently substituted or unsubstituted. Preferably, Z is as described in Structural Formula (VI).

n is an integer, such as an integer from one to about four. Preferably, n is one, two or three. More preferably n is two. In alternative embodiments, other aliphatic or aromatic spacer groups can be employed for M is >NR 2 or >CR 2

R

2 is -OH, an acyl group, a substituted acyl group, -NRR 6 an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, -O-(substituted or unsubstituted aromatic group) or -O-(substituted or unsubstituted aliphatic group). R 2 is preferably an aromatic group or a substituted aromatic group.

R and R 6 are independently an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

R

5 and R 6 taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

X- is a physiologically acceptable anion. Preferably, X is Cl or Br'.

The chemokine receptor antagonist described herein can be prepared and administered as active compounds or as prodrugs. Generally, prodrugs are analogues of pharmaceutical agents which can undergo chemical conversion by metabolic processes to become fully active. For example, A prodrug of the invention can be prepared by selecting appropriate groups for R 4 In one embodiment, a prodrug can be represented by Structural Formula (XI):

OH

N

(XI)

wherein, R 4 0 is Q-substituted aliphatic group, and the aliphatic group is substituted with 2

),-C(O)OR

2 0 wherein Q is u is one, t is zero and R 20 is a cyclic aliphatic group. For example, when the substituted aliphatic group i s a substituted ethyl group, R 4 0 can be represented by: 0-1 0 0 0 Such a prodrug can be converted to an active chemokine receptor antagonist represented by Structural Formula XI, wherein R 40 is -COOH.

Another embodiment of the present invention includes novel compounds employed in these methods.

The compounds disclosed herein can be obtained as E- and Z-configurational isomers. It is expressly pointed out that the invention includes compounds of the Econfiguration and the Z-configuration around the double bond connecting Ring C of Z to the remainder of the molecule, and a method of treating a subject with compounds of the E-configuration, the Z-configuration, and mixtures thereof.

Accordingly, in the structural formulas presented herein, the symbol: is used to represent both the E-configuration and the Z-configuration. Preferably Ring A and the alkylene chain bonded to Ring C are in the cis configuration. For example, the compounds can have the configuration of: (CHJn A C B N

X

It is understood that one configuration can have greater activity than another.

The desired configuration can be determined by screening for activity, employing the methods described herein.

Additionally, certain compounds of the invention may be obtained as different stereoisomers diastereomers and enantiomers). The compounds of the invention can be prepared as racemates or as substantially pure stereoisomers. The stereoisomers of the invention and (R)-enantiomers) can be prepared using any suitable method. For example, the enantiomers can be resolved from the racemate using chiral chromatography or recrystallization. Preferably, the stereoisomers and/or (R)-enantiomers) are prepared by stereospecific synthesis as described herein.

The optical configuration of the stereoisomers of the invention are assigned using the method of Cahn-Ingold-Prelog. (See, J. March, "Advanced Organic Chemistry," 4 h Edition, Wiley Interscience, New York, pp.

10 9 1 11 (1992).) 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. Sterioisomers can be separated and isolated using any suitable method, such as chromatography. Again, it is understood that one sterioisomer may be more active than another. The desired isomer determined by screening.

Also included in the present invention are physiologically acceptable salts of the compounds represented by Structural Formulas through (XIII). Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium, ammonium, calcium and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharmna. Sci., 66:1 (1977).) As used herein, aliphatic groups include straight chained, branched or cyclic

C

1

-C

2 0 hydrocarbons which are completely saturated or which contain one or more units of unsaturation. Preferred aliphatic groups are C, to about Co hydrocarbons.

-31- More preferred are C, to about C, or C 1 to about C 3 hydrocarbons. One or more carbon atoms in an aliphatic group can be replaced with a heteroatom, such as nitrogen, oxygen or sulfur. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic CI-C 20 alkyl, alkenyl or alkynyl groups.

An arninoalkyl group is an alkyl group substituted with -NR 4 R 2 1 R 24 and R 2 1 are as described herein. Preferably the alkyl moiety comprises one to about twelve, more preferably one to about six carbon atoms. The alkyl moiety of an aminoalcyl group can' be unsubstituted or substituted as described herein for aliphatic groups.

Examples of suitable aminoalkyl groups include aminomethyl, 2-aminoethyl, 3 -amninopropyl, 4-aminobutyl, dim ethyl aminoethyl, di ethylaminomethyl, methylaminohexyl, amninoethylenyl and the like.

Aromatic groups include carbocyclic aromatic groups such as phenyl, I1-naphthyl, 2-naphthyl, I -anthracyl and 2-anthracyl, and heterocyclic aromatic or heteroaryl groups such as N-imidazolyl, 2-irnidazolyl, 4-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyr-rolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyriniidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazoly], 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. Where these rings are fused, for example, to Ring C, the stated point of attachment can be either of the two fused bonds.

Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings.

Examples include tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, I -isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, and the like. Also included within the scope of the term "aromatic group", as it is used herein, is a group in which one or more carbocycli c aromatic rings and/or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, for example, benzocyclopentane, beazocyclohexane.

Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered and/or fused to another ring, such as a on aromatic ring. Examples include 1 ,3-dioxolan-2-yl, 3-1 H-benzimidazol-2-one, 3-1 -alkyl-benzimidazol-2-one, 3-1 -methyl-benzimidazol- 2-one, 2-tetrahydrofuranyl, 3 -tetrahydrofuranyl, 2-tetrahyrothiophenyl, 3 -tetrahyrothi ophenyl, 2-morpholino, 3 -morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1 -piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted di azolonyl, 1 -phthalimidyl, 1-3- alkyl -phthalimidyl, benzox ane, benzopyrol i dine, benzopiperidin e, benzoxol ane, benzothiolane, benzothiane, tetrahydrofuran-2-one-3-yl, 2,5 -dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl, 2-oxo-3H-l ,2,3,5-oxathiadiazol-4-yl, 0 0 0 0 s O O I 0 0 0 00 00 >H O NH*W NIs C1 .01 -and Suitable substituents on an aliphatic group, aromatic group (carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, a halogen (chloride, bromide, fluoride, iodide), azido, COO, C0NR 2 4

R

2 5

-NR

2 4

R

25

-O()NR

2 4

R

2 5

S()NR

24 R 2 5

-OH

-33- -S (O) 2

NH

2 guanidino, ureido, ox alo, anidino, -C(&NR 0 )NRR R 2 2 ,NiRO,

-(O)U-(CH

2 )L-NIHC(O)O-R 20 -Q-(aliphatic group),-Q-(substituted aliphati c group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group),

-Q-(CH

2 )p-(substituted or unsubstituted aromatic group) p is an integer from 1 -Q-(non-aromatic heterocyclic group) or -Q-(CH,)P-(non-aromatic heterocyclic group).

R"

0 and R 2 are independently an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromifc heterocyclic group, -NHC(O)-O-(aliphatic group), -NIIC(O)-O-(aromatic group) or -NHC(O)-O-(non-aromatic heterocyclic group) and wherein R 2 1 and R 22 taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

R"

0 is a -OH, an aromatic group or a substituted aromatic group..

1 5 t is an integer from zero to about three, and the methylene group, -(Cl- 2 1 can be substituted, as described herein for aliphatic groups, or unsubstituted.

u is zero or one.

Q IS -S(O) 2

-OS(O)

2

-NI-C(O)O-,

-NTI-C(O)-NH-, -S(O)2NH-, -NHS(O) 2 -N(R 2 -C(NR21hNH-NI-,

-NH-NHC(NR

23

-NR

24 or -NR 2 1S(0) 2 R 2 1 is an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group.

R"

4 and R 2 are independently -OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic gi~oup or R 2 and R 2 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring.

A substituted non-aromatic heterocyclic ring, beazyl goup or aromatic group can also have an aromatic group, an aliphatic or substituted aliphatic group, as a substituent. When a non-aromatic ring (carbocyclic or heterocyclic) or an aromatic -34ring (carbocyclic aromatic or heteroaryl) is substituted with another ring, the two rings can be fused. A substituted aliphatic group can also have an oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group as a substituent. A substituted nonaromatic heterocyclic ring can also have =NH or =N(aliphatic, aromatic or substituted aromatic group) as a substituent. A substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or substituted benzyl group can have more than one substituent, which can be the same or different.

Acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.

Suitable electron withdrawing groups include, for example, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -CH=NH, -CN, -NO, and halogens. In the structural formulas depicted herein, the single or double bond by which a chemical group or moiety is connected to the remainder of the molecule or compound is indicated by the following symbol: For example, the corresponding symbol in Structural Formulas (11I) and (IV) indicates the double bond by which the central ring of the tricyclic ring system is connected to the remainder of the molecule represented by Structural Formula A "subject" is preferably a bird or mammal, such as a human, but can also be an animal in need of veterinary treatment, domestic animals dogs, cats, and the like), farm animals cows, sheep, fowl, pigs, horses, and the like) and laboratory animals rats, mice, guinea pigs, and the like).

An "effective amount" of a compound is an amount which results in the inhibition of one or more processes mediated by the binding of a chemokine to a receptor in a subject with a disease associated with aberrant leukocyte recruitment and/or activation. Examples of such processes include leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca 2 and granule release of proinflammatory mediators. Alternatively, an "effective amount" of a compound is a quantity 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 a disease associated with aberrant leukocyte recruitment and/or activation.

The amount of compound administered to the individual will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Typically, an effective amount of the compound can range from about 0.1 mg per day to about 100 mg per day for an adult. Preferably, the dosage ranges from about 1 mg per day to about 100 mg per day. An antagonist of chemokine receptor function can also be administered in combination with one or more additional therapeutic agents, e.g. theophylline, p-adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents cyclosporin A, FK-506, prednisone, methylprednisolone), hormones adrenocorticotropic hormone (ACTH)), cytokines interferons IFNP-la, IFNP-lb)) and the like.

The compound can be administered by any suitable route, including, for example, orally in capsules, suspensions or tablets or by parenteral administration.

Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. The compound can also be administered orally dietary), transdermally, topically, by inhalation intrabronchial, intranasal, oral inhalation or intranasal drops), or rectally, depending on the disease or condition to be treated. Oral or parenteral administration are preferred modes of administration.

The compound can be administered to the individual in conjunction with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for treatment of HIV infection, inflarmmatory disease, or the other diseases discussed above. Formulation of a compound to be administered will vary -36ct N according to the route of administration selected solution, emulsion, capsule).

Suitable carriers may contain inert ingredients which do not interact with the N compound. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing 'I 5 Company, Easton, PA. Suitable carriers for parenteral administration include, for 0 example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer'slactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, el al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).

The quantity of active ingredient (one or more compounds of the invention) in the composition can range from about 0.1% to about 99.9% by weight. Preferably the quantity of active ingredient is about 10% to about 90%, or about 20% to about by weight. A unit dose preparation can contain fiom 1 mg to about 1000 mg active ingredient, preferably about 10 mg to about 100 mg active ingredient. The composition can, if desired, also contain other compatible therapeutic agents, such as theophylline, p-adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents cyclosporin A, FK-506, prednisone, methylprednisolone), hormones adrenocorticotropic honrone (ACTH)), cytokines interferons IFNP-la, IFNP-lb)) and the like.

In one embodiment, the pharmaceutical composition comprises the enantiomer of a compound of the invention a compound of Structural Formula (XIE)) and a physiologically acceptable carrier or excipient. For example, in one embodiment, the composition comprises (S)-4-(4-Chlro-phenyl)-l- 1hydroxy-l-methyl-ethyl)- 11H-10-oxa-l-aza-dibenzo[a,d]cyclohepten-5-ylidene]propyl}-3,3-dimethyl-piperidin- 4 -ol and a physiologically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises the (S)-enantiomer of a compound of the invention a compound of Structural Formula (XlII)) and is substantially free of the corresponding (R)-enantiorner (contains at least about 98% or at least about 99% enantiomeric excess of(S)enantiomer). In another embodiments, the composition comprises the (S)-enantiomer of a compound of the invention a compound of Structural Formula the corresponding (R)-enantiomer and a physiologically acceptable carrier or excipient.

In a more particular embodiment, the composition comprises a racemic compound of Structural Formula for example, racemic-4-(4-Chloro-phenyl)-l-{3-[7-(lhydroxy- 1 -methyl-ethyl)- 11H-10-oxa- propyl}-3,3-dimethyl-piperidin-4-ol In other embodiments, the ratio enantiomer:(R)-enantiomer in the compositions is at least about 2:1 or about 5:1 or about 10:1 or about 20:1 or about 50:1.

The activity of compounds of the present invention can be assessed using suitable assays, such as receptor binding assays and chemotaxis assays. For example, as described in the Exemplification Section, small molecule antagonists ofRANTES and MIP-I a binding have been identified utilizing THP-1 cells which bind RANTES and chemotax in response to RANTES and MIP-la as a model for leukocyte chemotaxis. Specifically, a high through-put receptor binding assay, which monitors 2 I-RANTES and 2 1-MIP-la binding to THP-1 cell membranes, was used to identify small molecule antagonists which block binding of RANTES and MIP-la.

Compounds of the present invention can also be identified by'virtue of their ability to inhibit the activation steps triggered by binding of a chemokine to its receptor, such as chemotaxis, integrin activation and granule mediator release. They can also be identified by virtue of their ability to block RANTES and MIP-1 a mediated T-cell, peripheral blood mononuclear cell, and eosinophil chemotactic response.

The compounds disclosed herein can be prepared accordingly to the schemes shown in Figures 1 5 and 7. The schemes are described in greater detail below.

Figure 1 shows the preparation of compounds represented by Structural .Formula L' is PPh 3 C1, PPh 3 Br, PPhI or (EtO) 2

L

2 is a suitable leaving group such as halogen, p-toluene sulfonate, mesylate, alkoxy, and phenoxy; Pg is a suitable protecting group such as tetrahydropyranyl; and the other symbols are as defined above.

In Step 1 of Figure 1, a Wittig reaction is carried out in a solvent such as -38ether, or tetrahydrofuran (THF) in the presence of a base such as sodium hydride, n-butyl lithium or lithium diisopropylamide (LDA) at O'C up to the reflux temperature for the solvent used for 5 minutes to 72 h. Compounds represented by Formula II in Figure 1 can be prepared by methods disclosed in JP 61/152673, U.S.

Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, the entire teachings of which are incorporated herein by reference.

In Step 2 of Figure 1, deprotection is carried out with an acid in a solvent such as methanol at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h. Alternatively, a compound of represented by Formula V in Figure 1 can be prepared directly from step 1 without isolating an intermediate.

The reaction mixture obtained after the work up of the reaction described in step 1 can be dissolved in the solvent and reacted with .the acid.

In Step 3 of Figure 1, the hydroxy group can be converted to a leaving group by known methods. Compounds represented by Formula VI in Figure 1 can be prepared by methods disclosed in J. Med. Chem., 1992 (35) 2074-2084 and JP 61/152673.

In Step 4 of Figure 1, an alkylation reaction is carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 2 shows the preparation of compounds represented by Compound In Step 1 of Figure 2, a Grignard reaction may be carried out in a solvent such as ether, or tetrahydrofuran (THF) at 0°C up to the reflux temperature for the solvent used for 5 minuets to 72 h. Compound VII is available commercially.

In Step 2 of Figure 2, bromination may be carried out with brominate agents such as hydrobromic acid, bromotrimethylsilane or boron tribromide-methyl sulfide complex in a solvent such as acetic acid, dichloromethane or dichloroethane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 3 shows the preparation of compounds represented by Structural Formula In Figure 3, a reductive amination may be carried out with reducing regents such as sodium cyanoborohydride, sodium acetoxyborohydride or sodium borohydride in a solvent such as methanol, ethanol, tetrahydrofuran (THF), dichloromethane or dichloroethane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 4 shows the preparation of compounds represented by Structural Formula where in Z is represented by Structural Formulas (III) and wherein Ring A and/or Ring B in Z is substituted with R 4 0 In Figure 4, the alkylation reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 5 is a schematic showing the preparation of the compounds represented by Structural Formula wherein Z is represented by Structural Formulas (III) and wherein Ring A and/or Ring B in Z is substituted with 2

-COOR

2 0 2 0 2 2

'R

22 or 2 0 In Figure 5, the hydrolysis reaction may be carried out in a mixture of aqueous alkali metal hydroxide solution and a solvent such as methanol, ethanol, tetrahydrofuran (THF) or dioxane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h. The acylation reaction can be carried out using dicyclohexylcarbodiimide (DCC) or (l-ethyl-3-(3dimethylaminopropyl)carbodiimide (DEC) in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF) or methylene chloride in the presence of a base such as pyridine or triethylamine (when necessary) at temperatures of 0 to 1 00'C for minutes to 72 h.

Figure 7 shows the preparation of compounds represented by Structural Formula wherein Z is represented by Structural Formulas (fl) and wherein Ring A or Ring B in Z is substituted with R 40

L

4 is a suitable leaving group such as halogen or trifluoromethylsulfonate. In Figure 7, a palladium coupling reaction such M as Stille coupling, Suzuki coupling, Heck reaction, or carboxylation using carbon monoxide may be carried out using a palladium catalyst such as Stetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, and palladium acetate in a solvent such as tetrahydrofuran (THF), 1,4-dioxane, S 5 toluene, dimethylformamide (DMF), or dimethylsufoxide (DMSO) in the presence rof additive (when necessary) such as triphenylphosphine, 1,1'bis(diphenylphosphino)ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride, or lithium chloride at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 10C shows three procedures for the preparation of compounds represented by Structural Formulas (VII) and wherein Z is represented by Structural Formula (III) and wherein Ring A or Ring B in Z is substituted with R 4 0 In Figure 10C, R 4 0 is represented by 2 )t-C(O)-NR 2 1

R

2 2 u is one, t is zero. In Figure 1 OC a compound containing a phenol can be reacted with a carbonate equivalent, such as a carbamoyl chloride (method an isocyanate (method B) or an acylimidazole (method in the presence of a base such as sodium hydroxide, potassium carbonate or sodium carbonate in a solvent such as dimethylformamide or tetrahydrofuran, at a temperature from 0°C to reflux temperature for a period of about 5 minutes to about 72 hours.

Compounds represented by Structural Formula wherein Z is represented by Structural Formulas (II) or X is -CO-NR,- and R, is -(CH 2

),-COOR

3 0

-(CH

2 3

R"

2 or -(CH 2

),-NHC(O)-O-R

3 0 can be prepared by suitable modification of the scheme shown in Figure 1-5 and 7. One modification utilizes the starting material shown in Figure 1, wherein X is -CO-NH-. The amide is then alkylated with L 3

-(CH

2

),-COOR

3 0 wherein L is a suitable leaving group, using the alkylation procedures described above. The remainder of the synthesis is as described in Figures 1 5 and 7.

Figure 12 shows the preparation of compounds of formula The Friedel-Crafts acylation can be carried out using an acid chloride in the presence of a Lewis acid, such as aluminum trichloride or titanium tetrachloride, in a solvent such -41c as dichloromethane, dichloroethane, nitrobenzene or carbon disulfide. The acylation reaction can be run at a temperature of about room temperature up to the reflux temperature of the chosen solvent, and for a period of about 5 minutes to about 72 hours.

Figure 13 shows the preparation of compounds of formula In Step 1 Sof Figure 13, a chlorosulfonylation can be carried out using chlorosulfonic acid in a solvent, such as dichloromethane, or in the absence of a solvent at a temperature of about 0°C to about 60 0 C for a period of about 5 minutes to about 72 hours. In Step 2 of Figure 12, a coupling reaction can be carried out using an amine in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, acetone, ethanol, THF or DMF. The reaction can be carried out at a temperature of about room temperature up to the reflux temperature of the selected solvent, and for a period of about 5 minutes to about 72 hours.

Although Figures 1 5, 7, 12 and 13 show the preparation of compounds in which Rings A and B are phenyl rings, analogous compounds with heteroaryl groups for Rings A and B can be prepared by using starting materials with heteroaryl groups in the corresponding positions. These starting materials can be prepared according to methods disclosed in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION

Example 1: 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene- 5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,1 dibenzo[a,d]cycloheptene (described in JP 48-030064)(200mg) in DMF (1Oml) were added chlorophenyl)-4-hydroxypiperidine (230mg), potassium carbonate (360mg), and potassium iodide (50mg). The mixture was stirred at 70'C for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer -42was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to give the titled compound (250mg). 1 H-NMR (CDCl 3 d: 1.65-2.11(5H,m), 2.32-3.10(8H,m), 3.22-3.67(4H,m), 5.87(1H,t), 7.03-7.44(12H,m). MS m/z: 444(M+1).

Example 2: 4-(4-Chlorophenyl)-l -dihydrodibenz[b,ejoxepin-l 1yli dene)propyl]piperidin- 4 -ol The titled compound was prepared by following the procedure of Example 1, but replacing bromopropylidene)-10,11 with 11-(3-bromopropylidene)-6,11-dihydrodibenz[b,e] oxepine. 'H-NMR (CDCI 3 d: 1.61-2.16(5H,m), 2.37-2.80(8H,m), 5.22(2H,brs), 5.70(0.6xH,t), 6.03(0.4x1H,t), 6.73-6.90(2H,m), 7.09-7.45(10OH,m). MS m/z: 446(M+1) Example 3: Membrane Preparations for Chemokine Binding and Binding Assays Membranes were prepared from THP-1 cells (ATCC #TB202). Cells were harvested by centrifugation, washed twice with PBS (phosphate-buffered saline), and the cell pellets were frozen at -70 to -85 0 C. The frozen pellet was thawed in icecold lysis buffer consisting of 5 mM HEPES (N-2-hydroxyethylpiperazine-N'- 2 ethane-sulfonic acid) pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), 4g/ml each aprotinin, leupeptin, and chymostatin (protease inhibitors), and 100 g/ml PMSF (phenyl methane sulfonyl fluoride also a protease inhibitor), at a concentration of 1 to 5 x 10' cells/mi. This procedure results in cell lysis. The suspension was mixed well to resuspend all of the frozen cell pellet. Nuclei and cell debris were removed by centrifugation of 400 x g for 10 minutes at 4 0 C. The supernatant was transferred to a fresh tube and the membrane fragments were collected by centrifugation at 25,000 x g for 30 minutes at 4cC. The supernatant was aspirated and the pellet was resuspended in freezing buffer consisting of 10 mM HEPES pH 7.5, 300 mM sucrose, 1I g/ml each aprotinin, leupeptin, and chymostatin, and 10 .g/ml PMSF (approximately 0.1 ml per each 10' cells). All clumps were resolved using a minihomogenizer, and the total protein concentration was determined using a protein assay kit (Bio-Rad, Hercules, CA, cat #500-0002).

The membrane solution was then aliquoted and frozen at -70 to -85 0 C until needed.

Binding Assays utilized the membranes described above. Membrane protein (2 to pg total membrane protein) was incubated with 0.1 to 0.2 nM 12 5 1-labeled RANTES *or MIP-l a with or without unlabeled competitor (RANTES or MIP-la) or various concentrations of compounds. The binding reactions were performed in 60 to 100 ILl of a binding buffer consisting of 10 mM HEPES pH 7.2, 1 mM CaCl2, 5 mM MgCl2, and 0.5% BSA (bovine serum albumin), for 60 min at room temperature.

The binding reactions were terminated by harvesting the membranes by rapid filtration through glass fiber filters (GF/B or GF/C, Packard) which were presoaked in 0.3% polyethyleneimine. The filters were rinsed with approximately 600 p.1 of binding buffer containing 0.5 M NaC1, dried, and the amount of bound radioactivity was determined by scintillation counting in a Topcount beta-plate counter.

The activities of test compounds are reported in the Table below as IC 5 s values or the inhibitor concentration required for 50% inhibition of specific binding in receptor binding assays using 2 I-RANTES or 2 'I-MIP-la as ligand and THP-1 cell membranes. Specific binding is defined as the total binding minus the non-specific binding; non-specific binding is the amount ofcpm still detected in the presence of excess unlabeled Rantes or MIP-la.

Table BIOLOGICAL DATA Example IC50 Example IC50 Example IC50 Example (PM) (4M) J(jM) 1 <1 38 <1 63 <10 114 <1 2 <1 39 <10 64 <1 117 <1 8 <1 40 <1 65 <1 118 <1 12 <1 41 <1 66 <1000 120 <1 17 <10 42 <1 67 <1 122 <1 18 <1 43 <10 68 <10 123 <1 19 <1 44 <1 69 <1 128 <1 21 <1 45 <1 71 <1 130 <1 22 <1 46 <1 72 <10 131 <1 23 <1 47 <1 73 <10 132 <1 24 <10 48 <1 74 <1000 133 <1 <1 49 <1 75 <10 134 <1 26 <1 51 <1 76 <10 135 <1 27 <1 52 <1 77 <1 138 <1 28 <1 53 <1 78 <1 139 <1 29 <1 54 <1 79 <1 140 <1 55 <1 83 <1000 141 <1 31 <1 56 <1 85 <1 142 32 <1 57 <10 86 >10 143 <1 33 <1 59 <1 89 >10 144 <1 34 <1 60 <1 90 <1 145 <1 61 <10 91 <1 146 36 <1 62 <10 111 <1 Table Example 1050 Example [1C50 1 Exampl 1150 JExample 150 W 1 M (pM 147 <10 180 <1 212 282 <z1 148 <10 181 <1 215 <1 283 <1 149 <1000 182 <1 216 <1 284 <1 150 <10 183 <1 218 <1 285 <1 151 <1 184 <10 242 <1 286 <1 152 <1 185 <1000 248 10 287 <1 153 <1 186 <1 249 <1 288 <1 154 <1 187 <1 262 <1 289 <1 155 <1 188 >10 263 <1 290 <1 158 <1 190 >10 264 <1 291 <1 159 <119] >10 265 <1 292 <1 160 <1 192 >10 266 <1 306 <1 161 <10 193) <1 267 <1 422 <1 162 <1 194 <1 268 <1 423 <1 163 <1 195 <10 269 <1 424 <1 166 <10 197 <1 270 <1 425 <1 167 >1 198 <1 271 <1 426 <1 168 1 199 <1 272 <1 427 <1 172 <1 200 <1 273 <1 428 <1 173 <1 201 <1 277 <1 429 <1 174 <1 203 <1 278 <1 430 <1 175 <1 204 <1 279 <1 431 <1 176 <1 205 <1 280 <1 432 <1 178 <1 211 <1 281 <1 Table Example Example JICoJ Example 1C50 [Example 456 <1 479 <1 502 <1 525 457 <1 480 <1 503 <1 526 <1 459 <10 481 <1 504 <1 527 <1 459 <10 482 <1 505 <1 528 460 <1 483-1 <1 506 <1 529 483-2 461 <10 484 <1 507 <1 530 462 <10 485 <1 508 <1 531 <1 463 <10 486 <1 509 <1 532 <2 464 <1 487 <1 510 <1 533 465 <1 488 <1 511 <1 534 <1 466 <50 489 <10 512 <1 535 467 <1 490 <1 513) <1 536 <1 468 <1 491 <1 514 <1 537 <1 469 <1 492 <10 515 <1 538 470 <1 493 <10 516 <1 539 471 <1 494 <1 517 <1 540 472 <1 495 <1 1518 <1 541 473 <1 496 <10 519 <1 542 474 <1 497 <10 520 <1 543 475 <1 498 <10 521 <1 544 476 <1 499 <10 522 <1 545 477 <10 500 <10 523 <1 546 <1 478 <10 501 <10 524 <1 547 <1 -47- Table__ Example [IC5 0 1Example IC50 Ex ample fIC50 Example (W)ML (g~m) 548 <10 554 <1 560 <10 566 549 <1 555 <1 561 <10 567 <1 550 <1 556 <1 562 <10 568 <1 551 <1 557 <1 563 <10 569 <1 552 <1 558 <10 564 <10 570 553 1<1 1559 1<1 1565 <10 571 Example 8: 4-(4-Chlorophenyl)- 1 11 -dihydro-dibenz[b,e]thiepin- I1Iylidene)propyl]piperidin-4-ol Step 1 I1I -(3-Bromopropylideiie)-6, 11 -dihydrodibenz[b,e]thiepine was prepared by following the procedure of example 45, step 1 and 2, but replacing 5,11 -dihydro-7methoxypyrido[2,3-c][1 ]benzoxepin-5-one with 6,11 -dihydrodibenz[b,e~thiepin-1 I one.

'H-NMR (CDCI 3 5: 2.50-2.64(2H,rn), 3.36-3.47(3H,m), 4.99(lIH,d), 5.94(I H,t), 6.98-7.31 (8H,m).

Step 2 The titled compound was prepared by following the procedure of example step 3 but replacing 5-(3-bromopropylidene)-l 0,11 -dihydro-SHdibenzo~a,d]cycloheptene with the product of step 1.

'H-NMR (CDCI 3 5: 1.65-1.80(3H,m), 1.95-2.70(1OH,m), 3.35(1H,d), 4.998(IH,d), 5.96(IH,t), 7.09-7.43(12H,m).

MS mlz: 462(M+1) Example 12: 1 -Benzyl-6, 11 -dihydro-6-oxo-5H-dibenz[b,e]azepin- 11Iylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-oI -48- To a solution 4-(4-chlorophenyl)- 1 11 dibenz[b,e] azepin- I1 -ylidene)propyl]piperidin-4-ol hydrochloride (Example 39)(300nig) in DMF were added sodium hydride (60% in oil, 200mg), benzyl bromide 1 5mI) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (I180mg).

'H-NN4R (CDCI 3 5: 1.62-1.67(2H,m), l.99-2.20(3H,m), 2.33-2.65(8H,m), 5.1 0(1H,d), 5.75(IH,d), 5.94(lH,t), 7.1 l-7.42(16H,m), 7.91(IH,dd).

MS mlz: 549(M+1) Example 17: 1 -[3-(5-Carboxymethyl-6,1 1-dihydro-6-oxo-5H-dibenz[b,e]azepin- 11ylidene)propyl] -4-(4-chlorophenyl)-piperi din-4-ol 4-(4-Chlorophenyl)-l1-[3-(6, 11 -dihydro-5-ethioxycarbonylmethyl-6-oxo dibcnz[b,elazepin-1 1-ylidene)propylj]piperidin-4-ol (Example I 8)(1 .0g) was solved in IM hydrogen chloride in diethyl ether and stirred at room temperature for 24 hours. Aqueous sodium hydroxide and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound (250mg).

'H-NMvR (DMSO-d 6 5: 1.44-1.61 2.07-2.1 7(IH,m), 2.35-3.01 (9H,rm), 4.28(IH,d), 4.59(lI-,d), 5.83(1 7.1 8-7.71(12H,rn).

MS m/z: 517(M+l) Example 18: 4-(4-Chlorophenyl)- 11 -dihydro-5-ethoxycarbonymetyl-6-oxo- 5H-dibenz[b,e]azepin-l 1-ylidene)propyl~jpiperidin-4-ol The titled compound was prepared by following the procedure of example 1, but replacing 5-(3-brornopropylidene)-1 0, 11 -dihydro-5H-dibenzo[ad]cycloheptene with 11 -bromopropyli dene)-5-ethoxycarbonymetyl-6-oxo-5H-dibenz[b,e]aztpine.

.49- 'H-NMR (CDCl 3 1.30(3H,t), 1.64-1.69(2H,m), 1.97-2.10(3H,m), 2.38- 2.71 4.27(2H,q), 4.32(IH,d), 4.84(1H,d), 5.88(1H,t), 7.16-7.45(1 IH,m), 7.88(1 H,dd).

MS mlz: 545(M+1) Example 19: 4-(4-Chlorophenyl)- 11 -dihydro-5-methyl-6-oxo-5Hdibenzb,e]azepin- 11 -ylidene)propy]]piperidin-4-ol The titled compound was prepared by following the procedure of Example 1, but replacing 5-(3-bromopropylidene)- 10,11 -dihydro-5H- dibenzo[a,d]cycloheptene with 11 -(3-bromopropylidene)-5-methyl-6-oxo-5H-dibenz[b,e]azepin.

'H-NM7R (CDCI 3 5: 1.58-2.06(5H,ni), 2.39-2.75(8H,m), 3.53(3H,s), 5.84(1 H,t), 7.10-7.44(l1 7.85-7.89(1H,rn). MS mlz: 473(M+]).

Example 21: 4-(4-Chlorophenyl)- I-[3-(5H-dibenzo[ad]cycloheptene-5ylidene)propyl]piperid in-4-ol The titled compound was prepared by following the procedure of examrple 1, but replacing 5-(3-bromopropyl idene)- 10,1 with 5 -bromopropy i den 5H -dibenzo cycl ohepten e.

'H-NN4R (CDCI 3 6: 1.58-1.63(2H,m), 2.00-2.05(2H,m), 2.26-2.46(6H,m), 2.62- 2.66 5.55(1 6.85(2H,s), 7.24-7.40(12H,m).

MS m/z: 442 1).

Example 22: 4-(4-Chlorophenyl)- 1 11 -dihydro-2m ethoxycarbonyl dib enz[b, e)ox epin- I11 -ylidene)propyl ]pi peri din -4-olI The titled compound was prepared by following the procedure of example 1, but replacing 5-(3-bromopropylidene)- 10,11 -dihydro-5H-dibenzota,d]cyclohep tene with 11 -(3-bromopropylidene)-6, 1-dihydro-2-methioxycarbonyldibenz[b,eloxepine.

'H-NMR (CDCl 3 6:1.65-1 2.01-2.13(3H,m), 2.41 3.85(31{, S.40(2H,brs), 5.73(0.6xlH,t), 6.09(0.4xIH,t), 6.76(0.6xlH,d), 6.82(0.4x1 HA), 7.21 -7.43(8H,m), 7.73(1H,dd), 7.87(0.6xlH,d), 7.97(0.4xlH,d).

MS mlz: 504 Example 23: 1 -[3-(2-Butoxycarbonyl-6,1 1i-dihydrodibenz[b,e]oxepin-I 1yli dene)propyl] -4-(4-chlorophenyl )piperidin-4-ol The titled compound was prepared by following the procedure of example 1, but replacing 5 -bromopropyli dene)- 10,1 1-dihydro-5H-dibenzo~a,d]cycloheptene with I11 -(3-bromopropylidene)-2-butoxy-6, I1 -dihydrodibenz[b,e~oxepine.

'H-NMR (ODCd 3 8: O.96(3H,t), l.53(2H,q), 1.70-1.77(3H,m), 2.02-2.14(3H-,ni), 2.39-2.78(5H,m), 4.27(2H,t), 5.27(2H,brs), 5.75(0.8xlH,t), 6.1 0(0.2xlH,t), 6.78(IH,d), 7.27-7.43(SH,m), 7.76(1H,dd), 7.89(0.8x lH,d), 7.98(.2xlH,d).

MS mlz: 546 Example 24: 1 -[3-(2-Carboxyl-6, 11 -dihydrodibenz[b,e)oxepin- I11 -ylidene)propyl)-4- (4-chlorophenyl)piperidin-4-ol To a solution of 4-(4-Chlorophenyl)- I 11 -dihydro-2methoxycarbonyldibenz[b,e] oxepin- 11 -yl idene)propyl] pip eridin-4-o] (Ex ampl e 22)(1 00mg) in ethanol (3m1) were added 15% sodiuin hydroxide aqueous solution (0.6m1) and the mixture was heated to reflux for 12 hours. The solvent was distilled off under reduced pressure. Water and ethy] acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound 1 H-NMR (CD 3 OD) 8: 1.73-1 .79(2H,rn), 2.14-2.1 9(2H,m), 2.80-2.93(3H,m), 3.02- 3.1 1 3.24-3.29(2H,m), 5,.25(2H,brs), 5.61(0.7xlH,t), 6.05(0.3xlH,t), 6.72(lI-,d),7.22-7.40(8H,m), 7.52-7.65(1Hm), 7.75(0.7xlH,d), 7.80(0.3x1 H,d).

MS ml/z: 490 Examiple 25: 4-(4-Chlorophenyl)- 11 -dihydro-2dimethyl aminocarbonyldibenz[b,e] ox epin- 1-ylidene)propyl~piperidin-4-ol The titled compound was prepared by following the procedure of example 1, but replacing 5-(3-bTomopropylidene)- 10,11 -dihydro-5H-dibenzo[a,d~cycloheptefle with 11 -(3-bromopropylidene)-2-dimethylaminocarbonyl-6,1 I1dihydrodibenz[b,e~oxepine.

H-NM.R (CDCI 3 8: l.62-1.67(2H,m), 2.00-2.12(2H,m), 2.37-2.47(8H,m), 2.89(6H, 5.25(2H,brs), 5.68(0.7xlH,t), 6.03 (0.3x11-,t), 6.71(0.3xlT-,d), 6.78(0.7xlH,d), 7.13=7.40 (1OH,m).

MS m/z: 517 Example 26: 4-(4-Chlorophenyl)- -dihydro-2hydroxym ethyl dibenzb,e) ox epin-1 I 1-ylidene)propyl]piperi din-4-ol To a solution of (4-chlorophenyl)- -[3-(6,11ldihydromethoxycarbonyldibenzjb,e]oxepin- 11 -ylidene)propyljpiperidin-4-o] (1 10mg) in TI-F (8m1) were added lithium aluminum hydride (1.OM, 0.42rn1) dropwise at 0 and the mixture was stirred at room temperature for 1 hour. Aqueous sodium hydroxide (IM) was added to the reaction mixture to stir for 30 minutes, then ethyl acetate and brine was added to the mixture. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (10:1) to give the titled compound 'H-NMR (CDCI 3 5: 1.61-1 .66(2H,ni), I .98-2.03(2H,m), 2.39-2.48(3H,m), 2.57-2.79 4.52(21-,s), 5.20(2H,brs), 5.66(0.8xlIH,t), 6.01 (0.2x I 6.67(0.2x I 6.79(0.8xlH,d), 7.06(]H,dd), 7.1S-7.37(9H,m).

MS m/z: 476 Example 27: 4-(4-Chlorophenyl)- 1 11 -dihydro-2-(1 -hydroxy- 1 methyl)ethyldibenzlb,e]oxepin- 1-ylidene)propyl]piperi din-4-ol To a solution of 4-(4-chlorophenyl)- 1 11 -dihydro-2methoxycarbonyldibenz[b,e]oxepin-I I -ylidene)propyl~piperidin-4-ol (60mg) in THE -52- (6m1) were added methylmagnesium chloride (10OM, 0.16m1) dropwise-at 0 and the mixture was stirred at room temperature for 2 hour, the reaction mixture was quenched by saturated amnrmonium aqueous, then ethyl acetate and water was added to the mixture. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (95:5) to give the titled compound 'H-NMR (CDCI 3 5: 1.54(0.7x6H,s), I .62(0.3x6H,s), 1.63-1.70(2H,m), 2.03- 27.1 0(3H,m), 2.38-2.49 2.62-2.82(4H,m), 5. 17(2H,brs), 5.68(0.7x1 H,t), 6.05(0.3x 1H,t), 6.75(0.3x lH,d), 6.83(0.7x1 7.1 8-7.43(1 OH,m).

MS rnlz: 504 Example 28: 4-(4-Chlorophenyl)-1- [3 -(2-cyano-6, 11 -dihydrodibenzllb,e~oxepin-1iiyl idene)propyllp.iperidin-4-ol The titled compound was prepared by following the procedure of example 1, but replacing 5-(3-bromopropylidene)- 10,11 -dihydro-SH-dibenzo [a,d]cycloheptene with 1 1-(3-brornopropyliden e)-2-cyano-6,1 I-dihydrodibenz[b,e] ox epine.

'H-NMR (CDCl 3 5: l.67-l.72(2H,m), 2.02-2.13(2H,m), 2.37-2.77 (SH,irn), 5.35 (2H,brs), 5.75(O.7x 1H,t), 6.07(0.3xlH,t), 6.78(0.3x lH,d), 6.82(0.7xlH,d), 7.25- 1 (1OH,m).

MS rnlz: 471 Example 29: 1 .[3-(2-Aniinomethyl-6,1 1 dihydrodibenz1Ib,e]oxepin- 1-.

ylidene)propyl] -4-(4-chlorophenyl)piperi din-4-ol To a solution of 4-(4-chlorophenyl)-l -[3-(2-cyano-6, 1Idihydrodibenz[b,e]oxepin- 11 -ylidene)propyl]piperidin-4-ol (3 80mg) in EtOH (2Ornl) were added Raney nickel (50%.slurry in water, 60 nmg), and the mixture was hydrogenated at 15 psi for 2 hours. The mixture was filtered through the cfelite and distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol-aqueous ammonium -53- (95:5: 1) to give the titled compound (130mg).

'H--NMIR (CDCI 3 5: l.76-1.94(3H,m), 2.18-2.34(2H,m), 2.85-3.l0(8H,m), 3 .88(2H,s), 5.30(2H,brs), 5.59(lH~t), 6.78(IH,d), 7. 13-7.40(1OH,m).

MIS mlz: 475 Example 30: 4-(4-Chlorophenyl)- 11 -dihydro-2-nitrodibenz[b,e]oxePin.11ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 1, but replacing 5-(3-bromopropylidene)- 10,1 1-dihydro-5H-dibenzo[a,d]CYClohePtene with I1-(3 -bromopropylidene)-6, 1 -dihydro-2-nitorodibenz[b,ej oxepine.

'H-NMiR 6:1.62-1 .67(2H,m), 1.80-2. 12(3H,m), 2.28-2.78(8H,m), 5.05(O.3x2H,brs), 5.40(0.7x2H,brs), S.90(0.7x lH,t), 6.1 7(O.3x lH,t), 6 8 2 (0.

3 x 1H,d), 6.92(0.7xlH), 7.28-7.41 7.82(lH,dd), 8.15(0.7x IH,d), 8.22(0.3x1Hf,d).

MIS m/z: 491 (M 1).

Example 31: 1 -(2-Amiino-6, 11 -dihydrodibenzb,e]oxepin- 11 -ylidene)propyl-4- (4-chlorophenyl)piperidin-4-ol To a solution of 4-(4-chlorophenyl)- I I -dihydro-2ni trodibenz[b,e~oxepin- 1-ylidene)propyi]piperidin-4-ol (120mg) in EtOH (1 Sm!) were added tin (HI) chloride (1 90mng), and the mixture was heated to reflux for I hour. The solvent was distilled off under reduced pressure. To the residue was added ethyl acetate and sodium aqueous to neutralize. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with di chlorom eth an e-m ethanol (95:5) to give the titled compound 'H-NMR (DMSO-d 6 6: 1.54-1.60(2H,m), I .85-2.00(2H,m), 2.30-2.80(SH,rri), 3.88(2H,s).5.07(2H,brs), 5.66(1H,t), 6.41 -6.46(2H,m), 6.59(1 7 24 7 4 9 (SH,m).

MS mliz: 461 -54- Example 32: 4-(4-Chlorophenyl)- 1 -[3-(6,11i -dihydro-2-hydroxydibenz[b,e]oxepin- 11 -ylidene)propyl]piperidin-4-ol Step 1 11 -Bromopropylidene)-6,1 I -dihydro-2-hydroxydibenz[b,eloxepine was prepared by following the procedure of example 45, step 1 and 2, but replacing 5,11 dihydro,-7-methoxypyridol2,3-c][ I ]benzoxepin-5-one with 6,11 -dihydro-2hydroxydibenz[b,e]oxepin-1 1-one.

'H-NMR (CDCl 3 5: 2.69(2H,q), 3.39 5.20(2H,brs), 5,92(lH,t), 6.50- 6.81(4H,rn), 7.1 7-7.37(4H,m).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-bromopropylidene)- 10,11 dibenzo[a,d]cycloheptene with the product of step 1.

'H-NMR (CDC] 3 6: 1.60-i .75(3H,m), 1.95-2.1 0(2H,m), 2.35-2.80(SH,m), 5.1 0(2H,brs), 5.93(lH,t), 6.56(2H,brs), 6.71 (11-,brs), 7.11 -7.35(8H,m).

MS mlz: 462(M+l) Example 33: 4-(4-Chlorophenyl)- 1 11 -dihydro-2-methoxydibenz[b,e] oxepin- 11 -ylidene)propyl]piperidin-4-ol Step 1 11 -(3-Bromopropylidene)-6,1 1-dihydro-2-methoxydibenz[b,e]oxepine was prepared by following the procedure of example 45, step 1 and 2, but replac-ing 5,11 dihydro-7-methoxypyrido[2,3 [1 ]benzox epin-5 -one with 6,1 1 -dihyclro-2methoxydibenz[b,e~oxepin- I11 -one.

'H-NMvR (CDCl 3 6: 2.74(2H-,q), 3.43 3.77(3H,s), 5.10(2H,brs), 6.02(lIH,t), 6.70-6.83(3H,m), 7.21-7.38(4H,m).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-bromopropylidene)- 10,11 dibenzo[a,d]cycloheptene with the product of step 1.

'H-NMR (CDCl 3 8: 1.59-1 .65(2H,m), 1.95-2.66(1 1 3.75(3H,s), 5.1I 0(2H,brs), 6.03(1 6.69(2H,brs), 6.82(1 H,brs), 7.20-7.40(8H,m).

MS mlz: 476(M+1) Example 34: 4-(4-Chlorophenyl)- 11 -dihydro-2-ethoxydibeniz[b,e]ox epil-I Iyli dene)propyl]piperidin-4-ol To a solution of 4-(4-chlorophenyl)-1 -dihydro-2hydroxydibenz[b,e]oxepin- I I -ylidene)propyl]piperidin-4-ol (Example 32)(200rng) 1 0 in DMF (Smi) were added sodium hydride (60% in oil, 25mg), ethyl iodide (0.052m1) and the mixture was stirred at room temperature for I hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane 1) to give the titled compound (1 'H-NMR (CDCl 3 8: 1.37(3H,t), I.60-1.65(2H,m), 1.95-2.08(3H,m), 2.28-7 3.96(2H,q), 5. 15(2H,brs), 6.02(1 6.68(2H-,brs), 6.82(1 H,brs), 7.19-7.42 (8H,m).

MS m/z: 490(M+l) Example 35: 1-[3-(3-Bromo-6,l l-dihydrodibenzrb,e]oxepin-l l-ylidene)pro~pyl]-4- (4-chloroplienyl)piperidin-4-ol Step I 3-Bromo-I 1-(3-bromopropylidene)-6,1 1-dihydrodibenz[b,e)oxepine was prepared by following the procedure of example 45, step I and 2, but replacing 5,1 1dihydro-7-metboxypyrido[2,3-c] 1 ]benizoxepin-5 -one with 3-bromo-6,1 Idihydrodibenz[b,e~oxepin-11 -one.

'H-NMR (GDCl 3 5: 2.74(2H,q), 3.43 3.77(3H,s), 5.10(2H,brs), 6.02(1 H,t), 6.70-6.83(3H,m), 7.2 1-7.38(4H,m).

-56- Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-bromopropylidene)-l10,1 dibenzo[a,dllcycloheptene with the product of step 1.

'H-NMvR (CDCl 3 8: l.63-1.70(3H,m), l.96-2.10(2H,m), 2.32-2.69(8H,m), 5.20(2H,brs), 6.00(1 6.92-7.00(2H,m), 7.11-7.1 4(1H,rn), 7.24-7.42(8}{,r).

MS mlz: 524, 526(M+1) Example 36: 4-(4-Chlorophenyl)-1- 1-dihydrodibenz[b,e]oxepin- 11ylidene)propyl] -4-methoxypipendine To a solution of 4-(4-chlorophenyl)- 1-dihydro-2methoxydibenz[b,e]oxepin- I1I -ylidene)propyl]piperidin-4-ol (Example 2)(400mg) in DMF (5mi) were added sodium hydride (60% in oil, 50mg), methyl iodide (0.07m]) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane 1) to give the titled comipound (1 00mg).

'H-NMR (CDCl 3 8: 1.90-2.04(4H,m), 2. 34-2.62(SH,m), 2.93 5 .25(21-{,brs), 6.04(IH,t), 6.75-6.91 7.09-7.37(9H,m).

MS m/z: 460(M+l) Example 37: 4-Acetoxy-4-(4-chlorophenyl)- 11 .diydiodibenz[b,e]o x epin- 11 -yl idene)propyl]piperi dine To a solution of 4-(4-chlorophenyl)- 1 11 -dihydro-2methoxydibenz[b,eJoxepin-I I -ylidene)propyl~lpiperidin-4-ol (Example 2)(200mg) in dichioromethane were added acetyl chloride (0.06m1), triethylamine 19m1) and the mixture was stirred at room temperature for I hour. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organlic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residuiewas purified by silica gel chromatography eluting with ethyl acetate-hexane to give the titled compound (190mg).

'H-NMR (CDCl 3 5: 1.98-2.85(12H,m), 2.02(3H,s), 2.93(3H,s), 5.23(2H,brs), 6.01 6.73-6.90(3H,m), 7.11 -7.40(9H,m).

MS rnlz: 488(M+1) Example 38: 1 -[3-(8-Bromo-4, 10-dihydrothienol3,2-c][lI benzoxepin- yli dene)propyl]piperidin-4-(4-chlorophenyl)-4-ol Step I 8-Bromo-1I -(3-bromopropylidene)-4, 10-dihydrothieno[3,2-c] [1]benzox epine was prepared by following the procedure of example 45, step I and 2, but replacing 11 -dihydro-7-rnethioxypyrido[2,3-c] [1I ]benzoxepin-5-one with 4,10dihydrothi eno[3 1 ]benzoxepin- I 0-one.

'H-NMR (CDCI 3 5: 2.84(2H,q), 3.45(2H,t), 5.10(2H,s), 6.11 6.65(l1-,d), 7.03-7.08(2H-,m), 7.38-7.43(2Hi,r).

Step 2 The titled compound was prepared by following the procedure of examnple step 3, but replacing 5-(3-bromopropylidene)-10,1 dibenzo[a,d~cycloheptene with the product of step 1.

'H-NMR (CDCl 3 5: 1.66-1 .75(3H,m), 2.03-2.1 6(2H,mi), 2.40-2.86(SH,M), 5.09(0.7x2H-,s),5.I 4(0.3x2H,s), 5.90(0.3x1 6.1 0(0.7xlH,t), 6.64(0.7xl]H,d), 6.75(0.3x I 6.90(0.3x I1H,d), 7.03-7.09(2H,m), 7.21 -7.45(6H,m).

MS mlz: 532(M+1) Example 39: 4-(4-Chlorophenyl)- 1 11 -dihydro-6-oxo-5H-dibenzb,e] azepin- 11 -ylidene)propyl]piperidin-4-ol Step 1 -58- 11 -(3-Bromopropylidene)-6, 1-dihydro-6-oxo-5H-dibeflz[b,e] azepine was prepared by following the procedure of example 45, step 1 and 2, but replacing 5,11 -dihydro- 7-methoxypyrido[2,3-c] [I ]benzoxepin-5-one with 6,11 dibenz~b,e]azepin-6, 1 1-dione.

'H-NMR (ODCd 3 8: 2.70-2.92(2H,m), 3.45 5.92(IH,t), 7.08-7.58(7H,m), 8.05(IH,dd), 9.00(1H,brs).

Step 2 T he titled compound was prepared by following the procedure of example step 3, but replacing 5 -bromopropylidene)- 10, 11 dibenzolla,d]cycloheptene with the product of step 1.

'H-NMNR (CDCI 3 8: 1.61-1 .66(2H,m), I .97-2.20(3H,m), 2.35-2.68(8H,m), 5.80(1 7.03-7.53(11 8.02(IH,dd), 9.27(IH,brs). MS 459(M+1) Example 40: 4-(4-Chl orophenyl)- 11 -dihydro-5-ethyl-6-oxo-5Hdibenz[b,e] azepin-I 1i-ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 12, but replacing benzy] bromide with ethyl iodide.

'H-NMR (CDCd 3 5: 1.19-1 .28(3H,m), 1 .63-1 .69(2H,m), 1.99-2.1 6(3H,m), 2.37- 2.70(8H,m), 3.77-3.85(1H,m), 4.40-4.48(1H,m), 5.85(1H,t), 7.12-7.45(1 1J{1,m), 7.85(1 H,dd).

MS m/z: 487(M+1) Example 41: 1 -[3-(5-n-Butyl-6,l 1.dihydro-6-oxo-5H-dibenz[b,e]azepin-1 1ylidene)propyl]-4-(4-chloroph enyl)-piperidin-4-ol The titled compound was prepared by following the procedure of examp le 12, but replacing benzyl bromide with n-butyl iodide.

'H-NMR (CDCI 3 5: 0.90-0.98(3H,m), 1 .25-2.20(9H,m), 2.40-2.87(8H,m), 3.62- 3.72(lH,m), 4.52-4.64(1H,m), 5.85(IH,t), 7.16-7.45(1 1H,m), 7.88(lH,dd).

MS mlz: 515(M+l) -59- Example 42: 4-(4-Chlorophenyl)- 1 11 -dihydro-S-(3-hydroxypropyl)-6-oxo- I11 -ylidene)propyllpiperidin- 4 -ol To a solution 4-(4-chlorophenyl)- 11 dibenzlib,e]azepin- 1 -ylidene)propy]]pipenidin-4-ol hydrochloride (Example 39)(500mg) in DMF were added sodium hydride (60% in oil, 200mg), 2-(3bromopropoxy)tetrahydro-2H-pyrafl (0.5ml) and the mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was solved in IM hydrogen chloride in diehyl ether and stirred at room temperature for 1 hour.

Aqueous sodium bicarbonate and ethyl acetate were added to the reaction nriixrure, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (250mg).

'H-NMNR (CDCl 3 6: 1.25-2.87(1 5H,m), 3.51-3.56(2H,m), 3.76-3.82(IH,m), 4.81- 4.87(1 5.86(IH,t), 7.1 6-7.45(1 lH,m), 7.82(lH,dd).

MS jnfz: 517(M+1) Example 43: 1 -[3-(5-tert-Butoxycarbonymethyl-6, I1 -dihydro-6-oxo-SHdibenz[b,e] azepin-I 1 -ylidene)propyl]-4-(4-chlorophcnyl)-piperidii-4-ol The titled compound was prepared by following the procedure of examp le 12, but replacing benzyl bromide with tert-butyl bromoacetate.

1 H-NMR (CDCI 3 8: 1.50(9H,s), l.65-1.70(2H,m), l.95-2.10(3H,m), 2.42- 2.75(8H,m), 4.24(lH,d), 4.75(1 5.88(1 7.16-7.46(11 7.90(1I,dd).

MS mlz: 573(M+1) Example 44: 4-(4-Chlorophenyl)- 1-dihydro-7-hydroxy [1 ]benzoxcepino[2,3 b]pyri din- 5 ylidene)pT-opyllpiperidil-4-ol Step I To a solution of the product of example 45, step 1 (4.3g) in dichioroethane (100m.1) was added boron tribromide-methyl sulfide complex (19.3 g) and the mixture was heated to refiux for 3 hour. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatogaphy eluting with ethyl acetate-hexane to give 5-(3-bromopropylidene)-5, 1-dihydro-7-hydroxy [I )benzoxepino[ 2 3 b]pyridine (3.2g).

'H-NMR (CDC] 3 8: 2.72(2H,q), 3.45(2H,t), 5.28(2H,brs), 6.03(lIH,t), 6.66- 6.80(3H,m), 7.26(lH,dd), 7.58(lH,dd), 8.51 (IH,dd).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-bromopropylidetie)-5,1 l-dihydro-7-methoxy [I benzoxcepin o[2,3 pYrldinle with the product of step 1.

'H-NMR (DMSO-d 6 8: 1.46-1.51 1 .74-1 .85(2H,m), 2.29-2.51 (8H,rn), 5.1 5(21-,brs), 6.07(lH,t), 6.6 1-6.70(3H,m), 7.33-7.48(5H,m), 7.73( 1H,dd), 8.47(1H,dd), 9.06(lH,s).

MS ml/z: 463(M+1) Ex ample 45: 4-(4-Chlorophenyl)- 1-[3-(5,11 -dihydro-7-methoxy[ I]benzoxepinol 2 3 b~pyri din- 5 yli den e)propyl ]piperi din 4 -ol Step I To a solution of 5,1 1-dihydro-7-methoxy [1 ]benzoxepino[2,3 -b]pyrldifl- 5 -one (5.0g) in TI-F (50m]) was added L.IM cyclopropylmagnesium bromide THE solution (25m1) at 0 0 C. The reaction mixture was warmed to room* temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated -61aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hcxane to give 5-cyclopropyl-5,1 1-dihydro-7methoxy[1 ]benzoxepino[2,3-b]pyridin-5-ol Step 2 To a solution of the product of step 1 (4.3g) in acetic acid (30ml) was added 48% aqueous HBr (25ml) at 10*C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to give 5-(3-bromopropylidene)-5,11-dihydro-7-methoxy [1]benzoxepino[2,3b]pyridine (5.6g).

'H-NMR (CDC13) 8: 2.74(2H,q), 3.46(2H,t), 3.78(3H,s), 5.25(2H,brs), 6.07(1H,t), 6.72-6.82(3H,m), 7.21-7.42(5H,m), 7.56(1H,dd), 8.45(1H,dd).

Step 3 To a solution the product of step 2 (1.1 g) in DMF (15ml) were added 4-(4chlorophenyl)-4-hydroxypiperidine (0.81g) and potassium carbonate (0.53g) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and iashed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (0.86g) and minor one (0.05g).

Major isomer 'H-NMR (CDCI 3 5: 1.64-1.69(2H,m), 1.91-2.08(3H,m), 2.34-2.69(8H,m), 3.77(3H,s), 5.25(2H,brs), 6.07(IH,t), 6.72-6.82(3H,m), 7.21-7.42(5H,m), 7.56(lH,dd), 8.45(lH,dd).

MS ml/z: 477(M+1) Minor isomer IH-NMR (CDC1 3 d: 1.65-1 .79(3H,m), 2.01-2.1 3(2H,m), 2.35-2.76(8H,m), 3 .76(3H,s), 5.22(2H,brs), 5.95(1H,t), 6.72-6.80(2H,m), 7.06( lH,d), 7.1 6(1H,dd), 7.28(2H,d), 7.42(2H,d), 7.66(lH,dd), 8.39(IH,dd).

MS rnliz: 477(M+1) Example 46: 4-(4-Ghlorophenyl)- 1-dihydro-7-ethoxy [I ]benzoxepino[2,3b ]pyidin- 5-ylidene)propyl~piperi din- 4-ol The titled compound was prepared by following the procedure of example 34, but rep lacing 4-(4-chlorophenyl)- dihydro-2-hydroxydibenz[b,e]oxepifl-l 1 ylidene)propyl]piperidin-4-ol with 4-(4-chlorophenyl)- I -dihydro-7hydroxy[ I ]ben zox epino [2,3 -b]pyri di n-5 -yli den e)propyl ]pip eri din 4 -olI (example 44).

'1--NMR (CDCI 3 8: 1.38(3H,t), l.67-l.72(3H,rn), 2.05-2.16(2H,m), 2.40- 2.80(8H,m), 3.99(2H,q), 5.26(2H,brs), 6.05(1 6.71 -6.82(3H,m), 7.23- 7.43(5H,m), 7.57( IH,dd), 8.47(11-,dd).

MS mlz: 491(M+l) Example 47: 4-(4-Chlorophenyl)- 1 -dihydro-7i sopropoxy[ I benzoxepino[2,3-b]pyndmn-5-yli dene)propyflpiperi din-4-oI The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with isopropyl bromide.

'H-NMR (CDCI 3 8: 1.30(6H,d), 1.60-1.70(3H,m), 1.99-2.09(2H,m), 2.33- 2.69(8H,m), 4.37-4.48(1H,m), 5.26(2H,brs), 6.06(lH,t), 6.73-6.82(3H,m), 7.21- 7.43(5H,m), 7.55(IH,dd), 8.47(IH,dd).

MS 505(M+1) Example 48: 4-(4-Chloropheflyl)-l1-[3-(5, 1-dihydro-7- -63ethoxycarbonylm ethyl oxy[ I ]benzoxepino[2,3-b]pyridil-5-ylidele)propyl]piPeridifl- 4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with ethyl bromoacetate.

'H-NMR (CDCl 3 5: 1.28(3H,t), 1.63-l.68(2H,m), 1.97-2.02(3H,m), 2.33- 2 .68(8H,m), 4.24(2H,q), 4.55(2H,s), 5.26(2H,brs), 6.06(1 6.73-6.88(3H,m), 7.2l-7.42(5H,m), 7.55(IH,dd), 8.44(1H,dd). MS mlz: 549(M+1) Example 49: 4-(4-Chlorophenyl)-l1-[3 -(7-cyanomethyloxy-5,l1 dihydro[ I J benzox epi no[ 2,3 pyri din -5-ylidee)propyl~pipel dil- 4 -oJ The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with bromoacetonitrile.

'T--NMR (CDCl 3 8: 1 .62-1 I .94-2.06(2H,m), 2.2 l(lH,brs), 2.34- -2.66(8H,m), 4.70(211,s), 5.26(2H,brs), 6.10(1lH,t), 6.80(2H,brs), 6.92(l H,brs), 7.22- 7.41(5H,m), 7.56(]H,dd), 8.44(IH,dd).

1 5 MS m/z: 502(M+l) Example 50: 1 .[3-(7-(2-Acetoxyethiyl)oxy-5, 1 1-dihydro [I ]benzoxepino[2,3b]pyridin-5-yldene)propyl]-4-(4-chlorophelyl)pipeldi- 4 -oI The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 2-bromoethyl acetate.

'H-NMR (CDCl 3 8: 1.65-1.72(3H,rn), l.97-2.09(5H,m), 2.37-2.70(8H,m), 4.11- 4.1 4(2H,rn), 4.37-4.41 5.25(2H,brs), 6.07(1 6.75-6.84(3Hjn), 7.23- 7.43(5H-,m), 7.56(IH,dd), 8.47(IH,dd).

MS m/z: 549(M+l) Example 51: 4-(4-Chlorophenyl)- ,11 -dihydro-7-(2hydroxyethyl)oxy[ I ]b enzox epino[2,3-blpyri din-5 -ylidene)propyl]piperi din- 4-al To a solution of I -[3-(7-(2-acetoxyethyl)oxy-5,1 1-dihydro[ I]benzoxepin o[2,3- -ylidene)propyl] -4-(4-chlorophenyl)piperidin-4-ol (Example 50) (140mg) -64in ethanol (5rmi) were added 15% sodiun hydroxide aqueous solution (2m1) and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10: 1) to give the titled compound (I120mg).

'H-NMR 8: l.64-1.69(2H,m), 1.98-2.l0(3H,m), 2.36-2.79(8H,m), 3.89- 3 .94(2H,m), 3.99-4.04(2H,m), 5 .24(2H,brs), 6.04( 1H,t), 6.71-6. 84(3H,m), 7.23- 7.41 7.54(lH,dd), 8.43(IH,dd).

MS mliz: 507(M+1) Example 52: 4-(4-Chlorophenyl)- 1 -(5,11 -dihydro-7-(2morpholinoethyl)oxy[ I ]benzoxepino[2,3-b]pyri din- 5 -yidefle)propyl]pipefldifl 4 -ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 4-(2-chloroethyl)morpholine hydrochloride.

'H--NMR (CDCI 3 5: 1.62-1 .67(2H,m), 1 .95-2.08(2H,m), 2.20-2.67( 13H,m), 2.74(2H,t), 3.67-3.71 4.04(2H,t), 5.23(2H,brs), 6.05(1 6.73-6.52(3H,m), 7.20-7.41 7.53(IH,dd), 8.42(IH,dd).

MS mlz: 576(M+1) Example 53: 4-(4-Chlorophenyl)- 11 -dihydro [I ]benzoxepino[2,3-b] pyri din- -ylidene)propyl] piperidin-4-ol Step I 5-(3-Bromopropylidene)-5, I1 -dihydro [I ]benzoxepino[2,3-b]pyridine was prepared by following the procedure of example 45, step I and 2, but replaping 5,1 1-dihydro- 7-methoxy[lI benzoxepino[2,3-b]pyridin-5-one with 5,11 dihydro[ I ]benzox epino [2,3 -b]pyridifl-5 -one.

'H-NMR (ODCd 3 2.71(2H,q), 3.46(2H,t), 5.33(2H,brs), 6.04(lH,t), 7.01 7.1 7(3H-,rn), 7.29(lH,dd), 7.56(IH,dd), 8.53(1 H,dd).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-bromopropylidene)-5,l1 -dihydro-7-methoxy benzox.epino (2,3 -b]pyri dine with the product of step 1.

'H-NMR (CDCl 3 8: 1.66-1.71 2.Q0-2.20(3H,m), 2.36-2.69(8H,m);, 5.34(2H,brs), 6.l0(lH,t), 6.83-6.96(3H,m), 7.1 7-7.44(6H,m), 7.60(1H,dd), 8.46(IH,dd).

MS mlz: 447(M+l) Example 54: 1 -[3-(8-Bromo-5,1 I -dihydro[ 1 ]benizoxepino[2,3-b]pyridin-5ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol Step I 8-Bromo-5-(3-bromopropylidene)-5, 11 -dihydro[ I ]benzoxepinojl2,3-b]pyridine was prepared by following the procedure of example 45, step 1 and 2, but replacing 5,11 -dibydro-7-methoxy[ 1 ]benzoxepinof[2,3 -b~pyridin- 5-one with 8-bronio- 5,11I dihydro[1I]benzoxepino[2,3' 'H-NMR (CDC1 3 8: 2.75(2H,q), 3.50(2H,t), 5.38(2H,brs), 6.08(IH,t), 6.85- 6.98(2H,m), 7.1 S-7.35(3H,m), 7.59(1 H,dd), 8.54(]H,dd).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5-(3-broniopropylidene)-5,1 I1-dihydro-7methoxy[ 1]benzoxepino [2,3-b]pyri dine with the product of step 1.

'H-NIVR (CDCI 3 8: 1.64-l.69(2H,m), 1.90-2.07(3H,m), 2.30-2.67(SH,m), 5.30(2H,b-rs), 6.08(1H,t), 7.00-7.07(2H,m), 7.1 3(IH,d), 7.25-7.42(5}H,m), 7.56(1H,dd), 8.47(lH,dd).

MSm/z:525,527(M+l) Example 55: 4-(4-Chlorophenyl)- I-113-( 0, 1-dihydro- 10-oxo-5H-pyrido[2, 3c] [2]berizazepin-5 -ylidene)propyllpiperidin-4-ol c-I -66- Step 1 5-(3 -Bromopropyli dene)- 10,1 1-dihydro- 10-oxo-5H-pyrido[2,3 [2]benzazepine was prepared by following the procedure of example 45, step 1 and 2, but replacing cI5,11 -dihydro- 7 -rethox y[ 1] benzox epino [2,3 -b]pyridin- 5-one with 10,11 -dihydro- 5H -pyrido[2,3-c][2]benzazepin-5,1I0-dione.

'H-NNM (CDCl 3 8: 2.75-2.90(21H,m), 3.45 5.92(1H,t), 7.04-7.70(5H,m), 8.1 0(1H,dd), 8.48(lH,dd), 1 0.00(IH,brs).

Step 2 The titled compound was prepared by following the procedure of example step 3, but replacing 5 -(3-bromopropylidene)- 10,1 11 dibenzo[a,d]cycloheptcne with the product of step 1.

'I--NMR (CDCl3) 8: 1.64-l.69(3H,rn), 2.00-2.12(2H,m), 2.35-2.70(8H,m), 5.82(1 H,t, '.08(1H,dd), 7.23-7.62(8H,m), 8.04(lH,dd), 8.32(1 H,dd), 8.76(1 H,brs).

MS mlz: 460(MI1) Example 56: 4-(4-Chlorophenyl)- 0,l1-dihydro-1 1 -m ethyl-i pyrido[2,3-c] [2]benzazepin-5-ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 36, but replacing of 4-(4-chlorophenyl)- I 1-dihydro-2-methoxydibenzb,e~oxepin- I1ylidene)propyl]piperidin-4-ol with 5-(3-bromopropylidene)-l 0, 11 -dihydro-I 1 -oxo- 5H-pyrido[2,3-c]i2]benzazepine.

'H-NMR (CDC1 3 8: 1.64-1.70(3H,m), 2..00-2.10(2H,m), 2.4 1-2.69(8H,m), 3.62(3H,s), 5.82(iH,t), 7.07(1H,dd), 7.25-7.54(81-,m), 7.91(1 H,dd), 8.34(1N,dd).

MS nilz: 474(M+1) Example 57: 4-(4-Chlorophenyl)- I-[3-(S,11 -dihydro-7-methoxy[I1]benzoxepino[2,3b~pyridin-5-ylidene)ethyl]piperidin-4-oI Step 1 To a solution of methyltriphenyiphosphonium, bromide (2.2g) in THE (20m]) was added 1.6M n-butyl lithium hexane solution (2.9m1) at 0 C for 30 minutes. To the reaction mixture cooled to O'C was added 5,11-dihydro-7methoxy[l ]benzoxepino[2,3-b]pyridin-5-one (1.0g) dropwise as THF solution and the mixture was warmed to room temperature, and stirred for 3 hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure.

The residue was purified by silica gel chromatography eluting with ethyl acetatehexane to give 5,11 -dihydro-7-methoxy-5-methylenepyrido[2,3c][l]benzoxepine (0.14g).

Step 2 To a solution of DMF (0.54ml) was added phosphorus oxychloride (0.41ml) at 0°C for 10 minutes. To the reaction mixture was added the product of step 1 (210mg) in carbontetrachloride (5ml) and the mixture was heated to reflux for hours. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to give 1 -dihydro-7-methoxy[ ]benzoxepino[2,3b]pyridin-5-ylidene)acetaldehyde (130mg).

'H-NMR (CDCl 3 5: 3.77(0.7x3H,s),3.79(0.3x3H, 5.31(2H,s), 6.46(0.7x1H,d), 6.52(0.3xlH,d), 6.78-7.40(4H,m), 7.68(0.3xlH,dd), 7.78(0.7x1H,dd), 8.55(0.7x H,dd), 8.64(0.3xlH,dd), 9.62(0.3xlH,d), 9.79(0.7xlH,d).

Step 3 The titled compound was prepared by following the procedure of example 58, step 2, but replacing of 3-(5,11-dihydro-7-methoxy[ ]benzoxepino[2,3-b]pyridin-5ylidene)propanaldehyde with product of step 2.

'H-NMR (CDCl 3 5: 1.64-1.82(2H,m), 1.92-2.22(3H,m), 2.43-2.58(2H,m), 2.79- -68- 3 .45(6H,m), 3.68(0.3x3H,s), 3.70(0.7x3H,s), 5.24(2H,brs), 6.1 8(0.7xlH,t), 6.21 (0.3x1 6.72-7.42(8H,m), 7.78(0.3xlH,dd), 7.85(0.7xlH,dd), 8.42(0.7xlH,dd), 8.46(0.3xlIH,dd).

MS ml/z: 463(M+1).

Example 58: 4-(4-Chlorophenyl)- 11-.dihydro-7-methoxy[lI benzoxepino [2,3 b )pyridin-5 -ylid ene)butyl )pip eri din-4-ol Step 1 ,11 -Dihydro-7-methoxy[l1]benzoxepino[2,3-b]pyridin-5ylidene)propenaldehyde was prepared by following the procedure of example 57, step 2, but replacing 5,11 -dihydro-7-methoxy-5-methylene[ 1 ]benzoxepino[2,3b]pyridine with 5,11 -dihydro-7-methoxy-5-(propyl- I -ene) [1I ]benzoxepino[2,3b~pyridine (by-product of example 45, step 3).

'H-NMvR (CDCI 3 8: 3.7_8(0.3x3H,s), 3.8O(0.7x3H,s), -5.32(2H,brs), 6.34- 6.39(1 6.72-7.38 7.58(0.7x1 H,dd), 7.77(0.3x 1H,dd), 8.49(0.3 x H,ddJ, 8.60(0.7x1I H,dd), 9.51](0.7x IH,d), 9.54(0.3xl1H,d).

Step 2 To a solution of the product of step 1 (90mg) in dichioromethane (6ml) were added sodium tri acetoxyborohydride (170mg), 4-(4-chlorophenyl)-4hydroxypiperidine (70mg) and acetic acid (0.02m1) and the mixture stirred at room temperature for 24 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (95:5) to give 4-(4-chlorophenyl)- I 11 -dihydro-7methoxy[ 1 ]benzoxepino[2,3-b]pyridifl-5-ylidele)buten-2-yl]piperidi- 4 -oI 110Omg).

'H-NMR (CDCl 3 8:1.68-1 .73(2H,m), 2.04-2.1 6(2H,m), 2.43-2.72(3H,m), 2.77- 2.81 3.08-3.1 3(2H,m), 3.73(0.3x3H,s), 3.77(0.7x11,s), 5.20(2H,brs), 5.98- 6.05(1H,m), 6.23-7.43(lOH,m), 7.58(0.7xlH,dd), 7.65(0.3x 1H,dd), -69- 8.37(0.3xlH,dd), 8.45(0.7xlH,dd).

MS mlz: 489(M+l).

Step 3 To a solution of the product of step 2 (8mg) in ethanol (2rn1) were added 10% Pd- C (2mg) was stirred under hydrogen (under a balloon) at room temperature for I hour. The mixture was filtered through the celite and distilled off under reduced pressure to give the titled compound (6mg).

'H-NMR (CDC1 3 8: l.68-3.00(15H,m), 3.77(3H,s), 5.18-5.35(2H,m), 5.94(O.4H,t, isomer), 6.06(0.6H,t, Z isomer), 6.65-6.88(3H,m), 7.05-7.73(6H,m), 8.30- 8.56(lH,m).

MS ml/z: 491(M+1) Example 59: 1 1 1-Dihydro-7-methoxy[l1 benzoxepino[2,3-b~pynidin-5yli1den e)propyl lpiperidin-4-pheiiyl-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypip eri dine with 4-phenyl-4hydroxypiperi dine.

'H-NTvIR (CDC1 3 6: 1.68-1 .73(2H,m), 2.02-2.1 5(3H,m), 2.38-2.72(8H-,m), 3 .77(3H,s), 5.26(2H,brs), 6.08(1 6.72-6.83(31-i,m), 7.21 -7.36(4H,rn), 7.46- 7.49(2H,m), 7.58(IH,dd), S.46(LH,dd).

MS mn/z: 443 Example 60: 4-(4-Broniophenyl)- 1i-dihydro-7methoxy[ 1 ]benzox epino [2,3 pyri din -5-yli dene)propyl]piperi din-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypipendine with 4-(4bromophenyl)-4-hydroxypiperi dine.

'H-NMR (CDCl 3 6: l.65-l.69(2H~m), 2.O0-2.I0(3H,m), 2.37-2.71(8H,m), 3.76(3H,s), 5.24(2H-,brs), 6.70-6.82(3H,m), 7.24(lH,dd), 7.38 (214,d), 7.44(2H-,s), 7.52(1H,dd), 8.44(IH,dd).

MS mlz: 521,523 Example 61: 1 11 -Dihydro-7-methoxy[l1]benzoxepino[2,3-b~pyridifl- ylidene)propyl]pipeidil-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypipefl dine with 4hydroxypiperidine.

'1{-NMR (CDCl 3 6: 1.43-I .60(2H,m), 1.80-1 .98(2H,m), 2.00-2.1 8(3H,m), 2.34- 2.48 2.63-2.76(2H,rn), 3.64-3.73(lH,m), 3.70(3H,s), 5.35(2H,brs), 6.06(1H,t), 6.74-6.84(3H,m), 7.25( lH,dd), 7.60(1H,dd), 8.50(lH,dd).

MS mlz: 367 Example 62: 4-Benzyl- ,1 1-dihydro-7-methoxy[l1]benzoxepino[2,3-b]pyndifl- -ylidene)propyl]piperidifl- 4 -ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidifle with 4-benzyl-4hydrox ypiperi dine.

'H-NMR (CDC1 3 6: 1.42-1 .57(3H,m), 1.62-1 .75(2H,m), 2.22-2.70(8H,rn), 2.79(2H,s), 3.80(3H-,s), 5.25(2H,brs), 6.08(1 6.73-6.84(3H,m), 7.18- 7.24(6H,m), 7.57(1 H,dd), 8.50(l1-,dd).

MS m/z: 457 Example 63: 4-Cyano- 1 11 -dihydro-7-methoxy[ 1 ]benzoxepino[2,3-b] pyridin- -yl idene)propyl] -4-phenylpiperi dinle The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl orophenyl)-4-hydroxypiperi dinle with 4-cyanio-4phenylpiperidine.

'H--NMTR (CDCI 3 8: 1.97-2 .06(4H,m), 2.37-2.60(6H,m), 2. 85-2.90(2H,m), 3 .79(3H,s), 5.27(2H,brs), 6.08(1H,t), 6.72-6.84(3H,m), 7.24-7.58(7H,m),.

-71- 8.49(1 H,dd).

MS mlz: 452 Example 64: 1 11 -Dihydro- 7-rnethox y[ 1 ]benzox epino[2,3 pyri din-5 ylidene)propyl] -4-phenylpiperidine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4phenylpip eri dine.

'H-NMP. (CDCI3) 8: 1.73-1.79(4H,ni), 1.96-2.03(2H,m), 2.37-2.52(5H,m), 2.86- 2.94(2H,m), 3.77(3H,s), 5.26(2H,brs). 6.08(]H,t),.6.72-6.83(3H,m), 7.17- 7.31(6H,m), 7.56 (1IH,dd), 8.49(1H,dd).

MS m/z 426 Example 65: 4-(4-Chlorophenyl)-1-43 -(5,11 -dihydro-7-methoxy[I1]benzoxepino The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl orophenyl)-4-hydrox ypip eri dine with 4-(4chlorophenyl)piperidine.

'H-NMR (CDC1 3 8: 1.68-1 .74(4H,m), I .96-2.03(2H,m), 2.36-2.48(5H,rn),2.89.

2.94(21-,m), 3.77(3H,s), 5.27(2H,brs), 6.07(1 6.73-6.83(3H,m), 7.10- 7.27(5K,m), 7.5 7(1 H,dd), 8.48(IH,dd).

MS m/z: 461 Example 66: 1 -Dihydro- 7-m ethoxy[ 1 ]benzox epino [2,3 -b]pyri din -5 yl i dene)propyl ]-4-piperi dinop iperi dine The titled compound was prepared by following the procedure of examp le step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4piperidinopiperidine.

'H-NMR (CDC1 3 6: 1.40-2.00(1 2H,m), 2.15-2 .60(9H,m), 2.80-2.92(2H,m), 3.80(3H,s), 5 .28(2H,brs), 6;05(IH,t), 6.75-6.86(3H,m), 7.30(1H,dd), 7.55(l I{,dd), 8.46(1H,dd).

MS mlz 434 Example 67: 1 -Dihydro-7-methoxy[ I benzoxepino[2,3-b]pyridin-5ylidene)propyl]-4-(2-keto- 1 -benzimidazolinyl)piperidine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlo rophenyl)-4-hydroxypiperidine with 4-(2-keto- Ibenzimidazolinyl)piperidine.

'H-NMR (CDCl 3 5: 1.75-i .79(2H,m), 2.03-2. 15(2H,m), 2.38-2.52(6H,m), 2.93- 2.98 3.78(3H,s), 4.30-4.38(1H,m), 5.30(2H,brs), 6.10(1 6.73- 6.84(3H,m), 7.01-7.03(3H,m), 7.21 -7.28(2H,m), 7.59(1H,dd), 8.48(lH,dd).

MS m/z: 483 Example 68: 1 1-Dihydro-7-methoxy[l1]benzoxepino[2,3 -b]pyridin- yl idene)propylj -4-(2-keto-3 -methyl- I -benzimidazolinyl)piperi dine The titled compound was prepared by following the procedure of example 36, but replacing of 4-(4-chlorophenyl)- 1 -dihydro-2-methoxydibenzlb,e] oxepin-I 11ylidene)propyl]piperidin-4-ol with 1 1-dihydro-7methoxy[ I ]benzox ep ino [2,3 -b]pyri din- 5-yl idene)propyl] -keto-1I benzimidazolinyl)piperidine.

'H-NMR (CDCI 3 6: 1 .72-1.76(2H,m), 2.09-2.14(2H,rn), 2.23-2.54(6H,m), 2.91 2.96 3.38(3H,s), 3.77(3H,s), 4.30-4.37(1 5.27(2H,brs), 6.08(1LH,t), 6.71 -6.83 6.93-7.06(3H,m), 7.23-7.60(2H,m), 8.08(l H,dd), 8.48(1 H,dd).

MS ml/z: 497 Example 69: -Dihydro-7-metboxy[ I]benzoxepino[2,3-b]pyridin-5 ylidene)propyl]-lI-phenyl-1I,3,8-triazaspiro[4,5]decan-4-one The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with I1-pheny]-l ,3,8tri azaspiro[4,5]decan-4-one.

-73- 'H-NMvR (CDCI 3 1.65-1 .70(2H,m), 2.36-2.41 2.53-2.79(gH,m), 3.76(3H, 4.70(2H,s), 5.25(2H,brs), 6.10(1 6.71 -6.88(6H,rn), 7.21 -7.27(3H,rn), 7.58- 7.61(2H,m), 8.48(lH,dd).

MS mlz: 497 Example 70: 4-Anilino-4-carbanmyl-1-[3-(5,1 1-dihydro-7m ethox y[ I ]benzox ep ino [2,3-b]pyridin-5 -ylidefle)propyl )pip endinle The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypip eri dine with 4-ani lino-4carbaniylpiperidine.

'H-NMR (CDCI 3 d: 1.85-1 .90(2H,ni), 2.03-2.08(2H,m), 2. 19-2.46(6H,m), 2.62- 2.67(2H,m), 3.75(3H,s), 3.97(lH,brs), 5.27(2H,brs), 5.53(1H,brs), 6.03(1H,t), 6.60(2H,d), 6.70-6.85(4H,m), 7.1 2-7.25(4H,m), 7.53(IH,dd), 8 .46(1H,dd).

MS m/z 48 5 (M+lI).

Example 71: 1 -(4-Chlorophenyl)-4[3-(5, 1-dliydro-7-methoxy[ I]benzoxepino[2,3b]pyri din- 5-yl i den e)propyl] piperazin e The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 1-(4chl orophenyl)piperazine.

'H-NMR (CDCI 3 8: 2.36-2.53(g1-,m), 3.07-3.09(4H,m), 3.76(3H,s), 5.26(ZIH,brs), 6.08(1 6.72-6.81 7.1 6-7.28(3H,m), 7.56(lH~dd), 8.49(1 H,dd).

MS mlz: 462 (M4-I).

Example 72: I -Dihydro-7-methoxy[ I]benzoxepino(2,3-b]pyridin- ylidene)propyl]-4-(2-pyrimidyl)piperazifle The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with I pyrimidyl)piperazine.

'H-NMR (CDCI 3 5: 2.37-2.53(8H,m), 3.74-3.83(7H,m), 5.27(2H, brs), 6.08(IH,t), -74- 6.45(IH,t), 6.72-6.83(3H,m), 7.25(1H,dd), 7.56(1H,dd), 8.27(2H,d), 8.49(1lH,dd).

MS mlz: 430 1).

Example 73: 1 -Cyclohexyl-4-[3-(5,l1 -dihydro-7-methoxy[lI]benzoxepino[2,3b]pyri din- The titled compound was prepared by following the procedure of example N ~step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 1 cyclohexylpiperazine.

'H-NMR (CDC1 3 5: 1.12-l.27(6H,m), 1.74-1.86(6H,m), 2.18-2.52 (1 1H,rn), 3 .76(3H,s), 5.26(2H,brs), 6.04(IH,t), 6.74-6.81 7.23 (1H,dd), 7.55( IH,dd), 8.48(LH,dd).

MIS mlz: 434 1).

Example 74: 1 11-Dihydro-7-methoxy[1 ]benzoxepino[2,3-bllpyridin-5ylidene)propyl]-4-(2-furoyl)pperazifle The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl orophenyl)-4-hydrox ypiperi dine with 1 furoyl)piperazine.

'H-NMR (CDCl3) 8: 2 .34-2.48(8H,m), 3.71-3 .74(7H,s), 5 .24(2H,brs), 6.05 (1 H,t), 6.42(1H,dd), 6.70-6.80(3H,m), 6.93(1H,d), 7.23(IH,dd), 7.42(lH,d), 7.53( lH,dd), 8.46(IH,dd).

M S mz: 446 Example 4-(3-Chlorophenyl)- 1 11 -dihydro-7-methoxy[ I ]benzoxepino[2,3-blpyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with 4-(3 -chlorophenyl)-4-hydroxypiperi dine.

'H-NMR (GDCl 3 5: 1.61-1 .75(2H,m), 1.98(1 H,brs), 1 .99(2H,dt), 2.25(31{,s), 2.30- 2.76(8H,m), 3.73(3H,s), 5.22(2H,brs), 5.95(0.1H,t, E isomer), 6.04(0.9H,t, Z isomer), 6.71 -6.89(3H,m), 6.95(1 H,dd), 7.1 5-7.20(0.3H,m, E isomer),7.2 1- 7.3 5(2.7H,m, Z isomer), 7.53(0.9H,dd, Z isomer), 7.65 1H,dd, E isomer), 8.35(0.1H,dd, E isomer), 8.45(0.9H,dd, Z isomer).

MS mlz: 477(M+1) Example 76: 4-(2-Chlorophenyl)- 1 11 -dihydro-7-methoxy[ I ]benzoxepino[2,3-b]pyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4- (4-ch lorophenyl)-4-hydroxypipeH dine with 4-(2-chl orophenyl)-4-hydroxypiperidine.

'H-NMR (CDCI 3 5: l.98-2.08(2H,m), 2.24(2H,dt), 2.38-2.78(9H,m), 3.77(3H,s), 5.27(2H,brs), 6.08(1 6.82-6.75(3H,mn), 7.28-7.1 9(3H,m), 7.33(1 H,dd), 7.49(1H,dd), 7.58(1H,dd), 8.40(0.1H,dd, Z isomer), 8.47(0.9H,dd, E isomer).

MS mlz: 477(M+1) Example 77: I-Dihydro-7-methoxy,[ 1]benzoxepino[2,3-b~pyridin-5-ylidene)propyl]-4- (4-fluorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl oroplienyl)-4-hydroxypiperi dine with 4-(4-fluorophenyl)-4-hydroxypiperidine.

'H-NMR (CDC13) 8: 1.58-1 .72(2H,rn), 2.04(21-,dt), 2.22-2.78(9H,m), 3.75(3H,s), .26(2H,brs), 6.09(1H,t), 6:,70-6.88(3H,m), 7.O0(2H,dd), 7.23(1H,dd), 7.42(2H,dd), 7.56(IH,dd), 8.41(1H,dd).

MS m/z:461(M+1) Example 78: 1 -Dihydro-7-rnethoxy[ I benzoxepino[2,3-b]pyridin-5-ylidene)propyl] =4- (p-tolyl)piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(p-tolyl)-4-hydrox ypiperi dine.

'H-NMR (CDCl 3 5: 1.65-1.78(2H,m), 2.02(2H,dt), 2.3 l(3H,s), 2.24-2.75(9H,ni), 3 .75(3H,s), 5.25(2H,brs), 6.07(lH,t), 6.72-6.84(3H,m), 7.1 3(2H,d), 7.23(1 H,dd), 7.56(1H,dd), 8.43(IH,dd).

MS m/z: 457(M+1) Example 79: 4-(3,4-Dichlorophenyl)- 1-[3- (5,1 1-dihydro-7-methoxy[l1]benzoxepino[2,3-b]pyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi e with 4-(3 ),4-di ch] orophenyl)-4-hydroxypiperi dine.

'l-NMR (CDCL 3 d: 1.58-1.72(2H,rn), 1.84(IH,brs), 2.02(2H,td), 2.32-2.72 3.76(3H,s), 5.27(2H,brs), 5.95(0.1IH,t, E isomer), 6.07(0.9H,t, Z isomer), 6.72-6.85 7.1 2-7.20(O.2H,m, E isomer), 7.21-7.32(0.1 SH,m, Z isomer), 7.32- 7.45(IH,m), 7.52-7.56(2H,m), 8.37(0.9H,dd, E siomer), 8.45(0. 1H,dd, Z isomer).

MS m/z: 512(M+1) Example 83: 4-(5-Chloropyridin-2-yl)-l1-[3-(5, 11 -dihydro-7-rnethoxy[l1]berizoxepino[2,3 -b]pyridi ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine w ith 4-(5 -chloropyri din-2-yl)-4-hydroxypiperi dine.

'H-NMR (CDCI 3 8: l.77-1.82(2H,m), 2.36-2.94(1 1H,m), 3.77(3H-,brs), 5.26(2H,brS), 6.07(IH,t), 6.76-6.84(3H,m), 7.26(lH,dd), 7.57(IH,dd), 8.49- 7.48(IH,d), 8.42-8.53(3H,m).

MS mlz: 478(M+1) Example 4-(5-Chloro-2-keto- 1 -benzimidazolinyl)- 1 11 -dihydro-7-methoxy[ 1 ]benzoxepi no[2,3 -b]pyridin- 5-yli dene)propyl]pip eri dine The titled compound was prepared by following the procedure of examiple step 3, but replacing 4-(4-chloropheny])-4-hiydroxypiperidine with 4-(5-chloro-2-keto- 1 -benzimi dazolinyl)piperi dine.

'H-NMR (CDCl3) 5: 1.68-1. 72(2H,m), 2.03-2.60(8H,m), 2.90-3 .02(2H,m), 3.78(3H,s), 4.32-4.21(1H,m), 5.29(2H,brs), 5.95(O.lH,t, E sionier), 6.08(O.9H,t, Z isomer), 6.70-6.92(3H,m), 7.02(IH,dd), 7.08-7.20(1H,m), 7.26(IH,dd), 7.58(0.9H,dd, Z isomer), 7.70(0.IH,dd, E isomer), 8.42(0.l1H,dd, E isomer), 8.48(O.9H,dd, Z isomer), l0.5(IH,s). (NHl is not observed in the spectrum) MS rn/z: 517(M+1) Example 86: 4-(p-Chloroanilino)- 1-dihydro-7-methoxy I ]benzoxepino(2,3-b]pyridi ylidene)propyl]pipeidine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(p-chloroanilino)piperi dine.

'H-NMR (CDC 3 6: l.20-1.54(2H-,rn), 1.85-2.20(4H,m), 2.24- 2.60(4H,m), 2.73(2H,m), 3.1 8(1H,rn), 3.77(3H,s), S.27(2H,brs), 6.06(1H,t), 6.47(2H,m), 6.68-6.90(3H,m), 7.07(21-,m), 7.24(IH,dd), 7.57(1 8.48( lHdd).

NH- signal was not observed.

MS mlz: 476(M+1) Example 89: 1 -Dihydro-7-methoxy[ 1 ]benzox epino [2,3 -b]pyri din- 5-yli dene)prop yl] 4-(p-tosyl)piperazine The titled compound was prepared by following the procedure of example 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidifle with I -(p-tosyl)piperazine.

'H-NMvR (GDCI 3 2.20-2.54(1 1H,m), 2.82-3.1 0(4H,m), 3.73(3H,s), 5. 16(2H,brs), 6.00(1H,t), 6.66-6.85(3H,m), 7.2 1(1H,dd), 7.3 1(2H,m), 7.5 1(1H,dd), 7.61(2H,m), 8.45(lH,dd).

MS ml/z: 506(M+1) Example [3-(5,11 -Dihydro-7-methoxy[ I ]benzoxepino[2,3-b~pyridin-5yli dene)propyl] spiro[isobenzofuran- 1(3H),4'-piperidinej The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with spirojisobenzofuran- I (3lH,4'-pipen dine]I.

'H-NMR (CDCI 3 5& l.62-1.82(2H-,m),- 1.92(2H,dt), 2.25-2.85(SH,m), 3.76(3H,s), .03(2H,s), 5 .30(2H,brs), 6.11 (1 HAt), 6.68-6.90(3H,m), 7.02-7.34(5H,m), 7.58(IH,dd), 8.48(lH,dd).

MS mlz: 455(M+1) Examnple 91: -Chloro 1- [3 -(5,11 -dihydro-7 -methoxy[ I )benzox epino (2,3 -blpyri din-5 ylidene)propyl] spirollisobenzofuran- 1(3H),4'-piperidine] The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with -chlorospiro [isobenzofiuran- 1 (3H),4'-piperidine].

lH-NMR (CDCI 3 8: 1.69-1 .74(2H,m), 1.81-1 .93(2H,m), 2.30-2.44(4H,m), 2.52-2.63(2H,m), 2.7 1-2.75(2H,m), 3.79(3H,s), 5.00(2H,s), 5.28(2H,brs), 6.09(IH,t), 6.73-6.84(3H,m), 7.03(1H,d), 7.17-7.28(3H,rn), 7.58(lH,dd), 8.49(1H,dd).

MS mlz: 489(M+l) -79- Example I111: 4-(4-Chlorophenyl)-lI-[3-(5 ,1 1-dihydro[ I ]benzothiepinojl2,3-b~pyridin-5ylidene)propyl~piperidin-4-ol The titled compound was prepared by following the Procedure of example 45, but replacing 5,11 -di hydro-7-methox y[ 1 ]benzoxepi no[2,3 -b]pyridin-5 -one with 5,11 -d ihydro[ I ]benzoth-i epino [2,3 -b]pyri din-5 -one.

1H-NMR (CDCI 3 d: I .66-1.78(3H,m), 2.04-2.65(IOH,m), 3.66(1H,brd), 5.05(1 H,brd), 6.03(1H,t), 7.04-7.46(1 OH,m), 8.44(11-,dd).

MS m/z: 463(M+1) Example 114: 4-(4-Chloropheinyl)- 11 -dihydro-8-methoxy[ 1]benzoxepino[2,3-b]pyridin-S yl idene)propyl ]piperidin-4-oI The titled compound was prepared by following the procedure of example 45, but replacing 5,11 -dihydro-7-methoxy[ I ]benzoxepino[2,3-b]pyridin-5-one with 5,11 -dihydro-8-rnethoxy[ 1 ]benzoxepino[2,3 I H-NMR (CDCI 3 d: 1 .66-1 .70(3H,m), 1 .98-2.09(2H,m), 2 .34-2.70(8H,ni);- 3 .75(3H,s), 5.32(2H,brs), 6.02(1H,t), 6.39(1 6.51 (1H,dd), 7.1 9-7.44(6]H,m), 7.57(IH,dd), 8.49(1 H,dd).

MS mlz: 477(M+1) Example 115: 4-(4-Chlorophenyl)- I -dihydro- 7-m ethyl[ 1 )benzox epino [2,3 -b]pyri din-5 yli dene)propyl]piperi din-4-ol The titled compound was prepared by following the procedure of examp le 45, but replacing 5,11 -dihydro-7-methoxy[ 1 ]benzoxepino[2,3-b~pyridin-5 -one withi 5,1 1 -d ihydro-7-methyl [I ]benzox epiio [2,3 -b]pyri din-5 -one.

IH-NMR (CDCl 3 6: 1.50(lH,brs), 1.66-1.70(2H,m), 1.98-2.10(2H,m), 2.28(3H,s), 2.34-2.42(4H,m), 2.52-2.57(2H,m), 2.66-2.70(2E,m), 5.30(2H,brs), 6.08(1 H,t), 6.76(1H,d), 6.97(1H,dd), 7.09( 1H,d), 7.24-7.44(5H,m), 7.5 7(lH,dd), 8.49( lH,dd).

MS mlz: 461(M+1) Example 117: 1 -[3-(7-Chloro-5,1l -dihydro[ I]benzoxepino[2,3-b]pyridin-5-ylidene)propylj -4- (4-chlorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of e xample 45, but replacing 5,11 -dihydro-7-methoxy[ I ]benzoxepino[2,3-b~pyridin-5-one with 7-chloro-5, 1-dihydro[ I ]benzoxepino[2,3-b]pyridin-5-one.

I{-NMR (CDC1 3 8:1.66-1.71 2.00-2.1 0(2H,m), 2.36-2.44(4H,m), 2.52-2.57(2H,m), 2.66-2.70(2H,m), S.32(2H,brs), 6.13(1H,t), 6.78(lH,d), 7.1 1(lH,dd), 7.26-7.44(5H,m), 7.58(IH,dd), 8.51(IH,dd).

MS m/z: 481 1) Example 118: 1 -[3-(7-Carboxy-5, I 1 -dihydro[I1 benzoxepino[2,3-b]pyridin-5-ylidene)propyl]- 4 (4-chlorophenyl)piperidin-4-ol Amixture of the product of example 169 (500 mg) potassium acetate (330 mg), pall adi um(ll) di acetate (10 mg), 1,1 '-bis(diph enylphosphino)ferrocene (93 mng), in.

dimethylsulfoxide (10 ml) was purged with carbon monoxide for 5 minutes and stirred under a carbon monoxide balloon at 60'C for 3 hours. Water was added to the reaction mixture, the precipitation was filtered. The solid were- dissolved with ethyl acetate and dilute sodi um hydroxide solution. The aqueous layer Was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the* titled compound (250 mg).

I H-NMR (DMSO-d 6 8: 1 .45-1.55(2Hm), 1.75-1 .85(2H,rn), 2.36-2.62(8H,rn), .42(2H,brs), 6.21 6.90(IH,d), 7 4 O-7.52(5H,m), 7. 75( IH,dd), 7.83(1 H,dd), 7.95(LH,d), 8.56(1H,dd).

MS m/z: 491(M+1) Example 120: 4-(4-Chlorophenyl)- I-[3-(7-carboxymiethyl-5,11 -dihydro[ I]benzoxepino[2 ,3bjpyri din -5 -yli1dene)propyl]piperi din-4-o I To a solution of product of Example 290 (3.7g) in methanol acetic acid (6m1), and water (37m1) were added sodium periodate (1.7g) in water (I 5ml) at O'C, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added amidosulfuric acid (1 .2g) and sodium chlorite (0.89g) in water (I OmI), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was distilled off under reduced pressure into half volume. The residue was neutralized with 1N sodium hydroxide. The precipitation was filtered and washed with wvater to give the titled compound (2.6g).

'H-NMR (DMSO-d 6 8: 1.45-1 .50(2H,m), 1.73-1 .82(2H,m), 2.24-2.50(8H,m), 3.50(2H,s), 4.84( lH,brs), 5.24(2H,brs), 6.13(1 6.74(1 H,d), 7.06(l H,dd), 7.21](1H,d), 7.33-7.48(51-i,m), 7.74(lH,dd), 8.50(IH,dd).

Example 122: 4-(4-Chilorophenyl)-1I-[3-(7-dimethylamiinocarbonylrnethiyl-5,1

I-

dihydro[ 1]benzoxepino[2,3-b)pyridi-5-ylidene)propyl]pipendin4-o The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 120.

H-NMR (CDCI 3 5: 1.65-1.70(2H,rn), l.95-2.06(2H,m), 2.31 -2.66(9H,m), 2.93(3H,s), 3.00(3H,s), 3.61 5.29(2H,brs), 6.09( 6.78(1H,d), 7.00(1H,dd), 7.20-7.43(6H,m), 7.56(1I-,dd), 8.42(1IH,dd).

MS mlz: 532(M+1) -82- Example 123: 1 -[3-(7-(2-Carboxy)ethyl-S ,1 1 -dihydro[ I ]benzoxepinoll2,3-b~pyridin-5ylidene)propyl) -4-(4-chlorophenyl)-piperidin-4-oI (71 The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 288.

H-NMR (DMSO-d 6 6: 1.44-1.49(2H,m), 1.70-1.82(2H,m), 2.22-2.48(l 0H,m), 2.75(2H,t), 4.82(lIH,brs), 5.23(2H,brs), 6. 14(l1H,t), 6.71 (1IH,d), 7.04(1H,dd), 7.17(lH,d), 7.33-7.48(5H,m), 7.72(IH,dd), 8.49(1H,dd).

MSM/Z: 519(M+1) Example 128: 4-(4.Chlorophenyl)- 1 11 -dihydro-7-propoxy[ I ]benzoxepino[2,3-b]pyridin-5yli dene)propyl]piperid in-4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with propyl iodide.

I H-NMR.(CDCI 3 6: 1 .03(3H,t), 1.65-1 .70(2H,m), 1 .78(2H,q), 1.98-2.09(3 2.3 7-2.45(4H,m), 2.51-2. 56(2H,m), 2.66-2.70(2H,m), 3.8 8(2H,t), 5 .26(2H,brs), 6.08(lH,t), 6.72-6.84(3H,m), 7.23-7.43(5H,m), 7.58(IH,dd), 8.43(1H,dd).

MS m/z: 505(M+1) Example 130: 4-(4-ChlIorophenyl)- 1 [3-(7-cyclopropylm ethyl oxy- 5,11 -di hydro 1I )benzox epino [2,3 b]pyri din-S -ylidene)propyl]piperi din-4-oI The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with cyclopropylmethyl bromide.

'H-NMR (CDCI 3 6: 0.3 1-0.37(2H,m), 0.60-0.67(2H,m), 1.2 1-l.28(1H,m), 1.66-1 .72(3B,m), 2.01-2.1 1(2H,m), 2.37-2.7 1(8H,m), 3 .77(2H,d), 5.27(2H,brs), 6.08(IH,t), 6.73-6.86(3H,m), 7.23-7.44(5H,m), 7.58(IH,dd), 8.47(IH,dd).

MS m/fz: 517(M+l) Example 131: 4-(4-Chlorophenyl)- 1-dihydro-7-(2-dimetylaminoethyl)oxy)[I1]benzoxepino [2,3 -b]pyri din -5 -yli dene)propyl]pip eri din-4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 2-(dimethylaxnino)ethyl chloride hydrochloride.

'H-NM4R (CDCl 3 8: 1.71-1 .76(2H,m), 2.12-2.21 2.38(6H,s), 2.40-2.79(1 1H,m), 4.07(2H,t), 5 .28(2H,brs), 6.07(1I-,t), 6.74-6.86(3H,m), 7.27-7.46(5H,m), 7.59(1H,dd), 8.49(1 H,dd).

MS mlz: 534(N4+1) Example 132: 4-(4-Chlorophenyl)- 1 [3-(5,11 -dihydro- 7 -(tetra.7ol-5-yl)methyloxy)[ 1 ]benzoxepino[ 2,3-b]pyridin-5-ylidene)propyl]piperidin-4-oI Step I 4-(4-Chlorophenyl)- 1-dihydro-7-(2-triphenylxnethyltetrazol-5-yl)m ethyloxy 1 5 I benzoxepiino[2,3-b]pyridin-5-ylidenie)propyl]piperidin-4-o was prepared by following the procedure of example 46, but replacing ethyl iodide with (2 -triphenylmethyl tetrazol-5-yl)mnethyl chloride.

H-NMR (CDCl 3 8: 1.64-1 .70(3H,m), 2.02-2.1 5(2H,m), 2.35-2.71 (8H,m),5.29(2H,brs), 5.33(2H,s), 6.03(IH,t), 6.77(IH,d), 6.83(1 H,dd), 6.96(1H,d), 7.04-7.08(6H,m), 7.23-7.45(14H,m), 7.54(1H,dd), 8.50(1H,dd).

Step 2 A solution of the product of-step 1 (530 mg) in acetone (2.5 ml), acetic acid ml) and water (2.5 ml) was stirred at 55'C for 30 minutes. The reaction mixture was distilled off under reduced pressure. The residue was washed with methanol to give the titled compound (280 mg).

'H-NMR(DMSO-d 6 8: 1.69-1 .74(2H,m), 1 .99-2.09(2H,m), 2.95-3. 14(8H,m), 5.1 8(2H,brs), 5.20(2H,s), 6.1 4(IH,t), 6.76(1H,d), 6.93(1 H,dd), 7.04(IH,d), 7.39-7.48(5H-,m), 7.78(LH,dd), 8.52(1H,dd).

MS mlz: 545(M+1) Example 133: 1- [3-(7-Carboxymethyloxy-5,ll -dihydro[ 1 ]benzox epino[2,3-b]pyridin-5 -ylidene)pro pyl) -4-(4-chlorophenyl)piperidin-4-ol To a solution of product of example 48 (3.0 g) in methanol (50 ml) was added iN sodium hydroxide solution (8 ml) and the mixture stirred at room temperature for 1 hour. The reaction mixture was distilled off under reduced pressure. The residuc was dissolved with water and neutralized with IN hydrochloric acid. The precipitation was filtered and washed with water to give the titled compound (2.6 g).

'H-NMR (DMSO-d 6 8: 1.48-1.53(2H,m), 1.76-1.88(2H,m), 2.392'2 60(8H,-m), 4.60(2H,s), 5.l8(2H,brs), 6.16(1H,t), 6.72-6.84(3H,m), 7.34-7.48(5H-,m), 7.73(]H,dd), 8.50(1H,dd).

MS ml/z: 521(M+1) Example 134: 4-(4-Chlorophenyl)-1 -dihydro-7dimethylamninocarbonylmethyloxy[ I ]beiizoxepino[2,3-b]pyri din- 5-ylid ene)propyl )pi peridin-4-ol To a solution of product of example 1333 (420 mg) in dimethylformamide (17 ml) were added I -hydroxybenz.otriazol hydrate (250 mng), I -(3-dimethylaminopropy])-3ethyicarbodiimide hydrochloride (310 mg), dimethylamine hydrochloride (270 mg) and triethylamine (0.45 ml), and the mixture stirred at room temperature for 12 hours. Water and chloroform were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodiumn chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give the titled compound (380 mg).

'H-NMvR (CDCI 3 8: 1.67-1.71 1.95-2.11 (3H,rn), 2.37-2.71 (8H,mr), 2.97(3H,s), 3.08(3H,s), 4.64(2H,s), 5.27(2H,brs), 6.09(1H,t), 6.74-6.82(2H,rn), 6.93(IH,d), 7.24-7.44(5H,m), 7.58(1H,dd), 8.47(IH,dd).

MS rn~z: 548(M+l) Example 135: 4-(4-Chlorophenyl)- 1-[3 1-dihydro-7-morpholinocarbonylmnethylo xy[ 1 ]benzox e pino[2 ,3-bllpyridin-5-ylidene)propyl]piperidin.4-ol The titled compound was prepared by following the procedure of example 134, but replacing dimethylamine hydrochloride with morpholine.

'H-NMR (CDCI 3 5: 1.67-1 .71(2H,m), 1 .87(IH,brs), 2.00-2.11 (2H,m), 2.38-2.71 3.61 -3.68(8H,m), 4.65(2H,s), 5.27(2H,brs), 6.09(1H,t), 6.74-6.83(2H,m), 6.90(1I-,d), 7.25-7.44(5H,n,), 7.58(1 H,dd), 8.48(1H,dd).

MS mlz: 590(M+1) Example 13 8: 4-(4-Chlorophenyl)- 1 -dihydro-7-( I -ethoxycarbonyl- 1 m ethyl ethyl)ox y[ 1 ]benzoxep in o[2,3 -b ]pyri din 5-yli dene)propyl] piperidin-4 -ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with ethyl 2-bromoisobutylate.

'1--NMR (CDC1 3 6: 1 I .56(6H,s), 1.63-1 .71(3H,m), 2.01-2.1 0(2H,m), 2.35-2.70(8H-,m), 4.24(2H,q), 5.28(2H,brs), 6.05(1H,t), 6.67-6.75(2H,m), 6.87(1 7.24-7.44(5H,m), 7.56(l H,dd), 8.49(1H,dd).

MS mlz: 577(M+l) Example 139: 1 1-Carboxy- I-rnethylethyl)oxy-5, 11 -dihydro[l1]benzoxepino[2,3-b]pyri ylidene)propyl]-4-(4-chlorophenyl)piperdin-4-oI The titled compound was prepared by following the procedure of examipl e 133, but replacing product of example 48 with product of example 138.* 'H-NMR (DMSO-d 6 5: 1.45-1 .52(8H,rn), 1.79-1 .85(2H,m), 2.28-2.53(8H,m), 5.1 9(21-,brs),'6.07( 1H,t), 6.69-6.73(2H,m), 6.85(1H,d), 7.33-7.47(5H,m), 7.71(]H,dd), 8.48(1H,dd).

MS mlz: 549(M+l) Example 140: 1 1 -Dihydro-7-m ethoxy[ I ]benzoxep ino[2,3 -b ]pyri din -5 -y i dene)prop yl -4- -86- (4-methoxyphenyl)piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypipenfldinle with 4- N (4-methoxyphenyl)-4-hydroxypiperidifle.

'H-NMR (GDC 3 5: 1.62-1.75(2H,m), 2.08(2H,dt), 2.41-2.76(9H,m), 3.77(3H,s), 3.78(3H,s), 5.26(2H,brs), 6.06(lH,t), 6.75-6.871 7.23(1H,dd), 7.38(2H,d), 7.57(lH,dd), MS mlz: 473QvI) Example 141: 4-(4-Cyanophenyl)- 1 11 -dihydro- 7-m ethoxy[ 1 benzox epino [2,3 -b]pyri din-5 ylidene)propyl~Ipipenidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl~orophenyl)-4-hydroxypiperidifle with cyanophcen yD-4-hydroxyp ip eri dine.

'H-NMvR (CDCl 3 5: l.58-l.70(2H,m), 2.03(2H,t), 2.3 1-2.64(7H,m), 2.65- 2.78(2H,m), 3.75(3H,s), 5.26(2H,brs), 5.95(0.1H,t, E isomer), 6.05(0.9H,t, Z isomer), 6.70-6.80(3H,m), 7.22(1H,dd), 7.54-7.68(5H,m), 8.31(0.1 H,dd, E iosmer), 8.39(0.9H,dd, Z~ isomer).

MS mlz:468(M+1) Example 142: 1 -Dihydro-7-methoxy[ I ]benzoxepino[2,3-bljpyridin-5-ylidene)propyl]-4- (4-hydroxyphenyi)pipeidin-4-oI T'he titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydrox ypiperi dine with 4-(4-hydroxyphenyl)-4-hydrox ypip eridine.

'HFlvfR (CDCI 3 5: 1.76-1 .88(2H,m). 2.08-2.22(2H,m), 2.45-2.95(9H,m), 3.76(3H,s), 5.28(2H,brs), 5.95(0.3H,t, E isomer), 6.04(O.7H,t, Z iosmer), 6.69- 6.72(3H,m), 6.90(2H,d), 7.20-7.30(3H,m), 7.56(0.7H,dd, Z isomer), 7.67(0- 3H,dd, E -87isomer), 8.46(0.7H,dd, Z isomer), 8.47(0.3H,dd, E isomer). OH signal was not observed.

MS m/z: 473(M+1) Example 143: 1 -Dihydro-7-methoxy[ 1 ]benzoxepino[2,3-b]pyridin-5-ylidene)propyl] -4- (4-flu oro-3-methylphenyl)piperidin-4-oI The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypip eri dine with 4-(4-fluoro-3 -methylphenyl)-4-hydroxypiperidine.

'H-NMR (CDC1 3 6: 1.62-1.75(2H,m), 2.05(1H,brs), 2.09(2H,dt), 2.25(3H,s), 2.30- 2.76(8H,m), 3.76(3H,s), 5.26(2H, brs), 5.96(0.1IH,t, E isomer), 6.07(0.9H,t, Z isomer), 6.75-6.89(3H,m), 6.93(1H,t), 7.1 1-7.20(0.3H,rn, E isomer), 7.21- 7.35(0.24H,m, Z isomer), 7.56(0.9H,dd, E isomer), 7.67(0.1H, dd, E isomer), 8.38(0.I1H,dd, E isomer), 8.45(0.9H,dd, Z isomer).

MS mlz: 475(M+1) Example 144: 4-(3 ,4-difluorophenyl)- 1 11 -dihiydro-7-rnethoxy[ I ]benzoxepino[2,3-b]pyridinyli den e)propyl]pip eri din-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chl orophenyl)-4-hydrox ypiperidine with 4-(3 ,4-di flu oroph enyl)-4-hydroxyp iperi dine.

'H-NMIR (CDC] 3 6: 1.58-1.72(2H,m), 1.96(2H,dt), 2*33-2.71(SH,m), 3.73(3H,s), 5.23(2H,brs), 5.94(0.IH,t, E isomer), 6.04(0.9H,t, Z isomer), 8.38-8.36(0.9H,m, Z isomrer), 6.68-6.79(3H,m), 6.98-7.38(4H,m), 7.50-7.62(O.9H,m, Z isomer), 7.63- 7.68(0.lIH,m, E isomer), 8.29-8.32(0.I1H,m, E isomer), 8.32-8.44(0.9H,m, Z isomner).

OH signal was not observed.

MS nt/z: 479(M+1) -88- Example 145: 4-(4-Chloro-3 -trifuluorornethyiphenyl)- 1-[3 1-dihydro-7-methoxy[ I benzoxepin o[(2,3 -b ]pyri din- 5-ylidene)propyl]pip erdin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chloroph enyl)-4-hydrox ypiperi dine with 4-(4-chloro-3 -trifl uoromethiylphenyl)-4-hydroxypiperidine.

'H-MR (CDCI 3 6: 1.62-l.74(2H,m), 2.10(2H,dt), 2.35-2.8O(8H,m), 2.42(1H, brs), 3.76(3H,s), 5.26(2H,brs), 6.07(0.9H,t, Z isomer), 6.03(Q.lH,t, E isomer), 6.82- 6.71(3H,m), 7.24(lH,dd), 7.43(lH,d), 7.56(l.8H,dd, Z isomer), 7.65(0.2H~dd, E isomer) 7.83(1H,d), 8.36(0.1 H,dd, E isomer), 8.44(0.9H,dd, Z iosmer), MS m/z: 545(M+l) Example 146: 4-(3,5 -di chi orophen yi)- 1 -[3-(5,11I -dihydro- 7-niethoxy[ I]benzoxepinol2,3 ylidene)propyl~piperidin-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(3,5-dichlorophenyl)-4-hydroxypiperidiine.

'H-NMR (CDCI 3 6: 1.58-2.22(5H,ni), 2.38-2.77(8H,m), 3.76(3H,s), 5.26(2H,brs), 5.92(0.L1H,t, E isomer), 6.07(0.9H,t, Z isomer), 6.83-6.71(3H,m), 7.19-7.42 (4H,m), 7.56(0.9H,dd, Z isomer), 7.68(0.1H,dd, E isomer), 8.38(0.I1H,dd, E isomer), 8.45(O.9H,dd, Z isomer).

MS mlz: 512(M+l) Example 147: 1 -Dihydro-7-methoxy[l 1 ]benzox epino [2,3 -b~pyri din- 5-ylidene)propyl 4 (2-pyridyl)piperi din-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chloropheinyl)-4-hydroxypiperidine with -89- 4-(2-pyridyl)-4-hydroxypiperidine 'H-NMvR (CDCI 3 d: 1.54-1.65(2H,m), 2.06(2H,dt), 2.07(IH,brs), 2.35- 2.62(7H,m), 2.73-2.87(2H,m), 3.78(3H,s), 5.28(2H, brs), 6.08(1H,t), 6.72- 6.85(3H,in), 7.1 4-7.29(2H,m), 7.57(IH,d), 7.70(IH,dd), 8.48(2H,dd).

MS mlz: 444(M+1) Example 148: I 11-Dihydro-7-methoxy[I1 benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4- (3 -pyiidyl)piperi din-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chloroph en yl)-4-hydroxypip eri dine with 4-(3 -pyri dyl)-4-hydrox ypiperi dine.

'H-NMvR (CDC] 3 6: 1.65-1 .78(2H,m), 2.08(2H,dt), 2.37-2.88(7H,m), 2.63- 2.79(2H-,m), 3.78(3H,s), 5.28(2H, brs), 6.02(0.IH,t, E isomer), 6.07(O.9H,t, Z isomer), 6.70-6.84(3H,m), 7.22-7.32(3H,m), 7.56(1H,dd), 7.77( 1H,dd), 8.46(0.9H,d), 8.57(0. 1H,dd, E isomer), 8.73(1H,dd).

MS m/z: 444(M+1) Example 149: 1 -(5,11 -Dihydro-7-methoxy[ 1 ]benzoxepinoll2,3-blpyridin-5-ylidene)propyl]-4- (4-pyridyl)piperi din-4-oI The titled compound was prepared by following the procedure of example step 3, but replacing 4- (4-chl orophenyl)-4-hydroxypip eri dine with 4-(4-pyridyl)-4-hydrox ypiperi dine.

'H-NM4R (CDCI 3 6: 1 .5 8-1 .72(2H,m), 2.03(2H,dt), 2.34-2.89(8H,m), 2.96(1 H,brs), 3.76(3H,s), 5.25(2H, brs), 6.06(lH,t), 6.72-6.83(3H,m), 7.24(1H,dd), 7.37(2H,dd), 7.56(IH,dd), 8.45(1H,dd), 8.48(2H,dd).

MS rnlz: 444(M+1) Example 150: 1- 1-Dihyclro-7-rnethoxy[lI]benzoxepino[2,3-b]Pyr din-S -ylidene)propyl]-4- (4-tni fluoromethylphenyl)piperi din-4-ol The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chloroph enyl)-4-hydrox ypip eridinle with 4-(4-tnifluoromethylphenyl)-4-hydroxypiperidile.

'H-NMR (CDCI3) 5: 1.64-1.75(2H,m), 2.01(1H, brs), 2.16(2H-,dt), 2.38- 2. 86(8H,m), 3 .76(3H,s), 5 .26(2H,brs), 6.04( LH,t), 6.72-6. 84(3H,m), 7.23(1 H,dd), 7.56(5H,m), 8.42(lH,dd).

MS m.z: 511 (M+1) Example 15 1: 4-(4-Chloropheny])- 1-[3 -(5,11 -dihydro-7-hydroxy[ I ]benzoxepino [2,3 -b]pyri ylidene)propyl )piperi dine The titled compound was prepared by following the procedure of example 44, step 2, b ut replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with 4-(4-chlorophenyl)piperidine.

'H-NMR (CDCl 3 8: 1.62-1.92(4H,m), 1.94-2.18(2H,m), 2.28-2.64(SH,m), 2.99(2H,m), 5.25(2H,brs), 6.00(IH,t), 6.60-6.82(3H,m), 7.02-7.36(5H,m), 7.50(IH,dd), 8.47(IH,dd). OH signal was not observed.

MS rnlz: 447(M+1) Example 152: 4-(4-Chlorophenyl)- I-[3-(5,1l -dihydro-7- ethoxy[ I]benzox epino[2,3-b~pyridin-5 ylidene)propyl]piperidine The titled compound was prepared by following the procedure of example 46, but replacing the product of example 44 with the product of example 151.

'H-MR (CDCl 3 5: 1.40(3H,t), 1.52-2.14(6H,in), 2.30-2.57(5H,m), 2 94 2 4.00(2H,q), 5.28(2H,brs), 6.07(IH,t), 6.68-6.86(3H,m), 7.05-7.36(5H,m), 7.58(lH,m), 8.49(lH,m).

MS mlz: 475(M+I) Example 153: 4-(4-Chlorophenyl)-1- [3 -(5,11 -dihydro-7-ethoxycarbonylmethyloxy[l1 benzoxep mo[ 2,3 pyri din- 5-yliden e)propyl ]piperi dine The titled compound was prepared by following the procedure of example 48, but replacing the product of example 44 with the product of example 15 1.

2.28-2.55(5H,m), 2.91 4.27(2H,q), 4.5 8(2H,s), 5 .28(2H,brs), 6.09(1 H,t), 6.68-6.95(3H,m), 7.07-7.32(5H,m), 7.58(1H,dd), 8.49(1H,dd).

MS 533(M+1) Example 154: 1 -[3-(7-(Carboxymethyloxy-5 ,11I -d ihydro[ I ]benzox epino [2,3 -bl pyri din- 5-ylid ene)pr opyfl-4-(4-chlorophenyl)piperidine The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 153.

'H-NMR (CD 3 OD) 8: 1. 82-2.1 7(4H,m), 2.69(2H,m), 2.86(l 3.07(2H-,rn), 3.30(2H,m), 3.57(2H,m), 4.5 7(2H,s), 5.21 (2H,brs), 6.10(1 6.70-7.04(3 B,m), 7.16-7.38(4H,m), 7.44(IH,m), 7.77(1H,m), 8.47(1H,ni). COOH signal was not observed.

MS 505(M+1) Example 155: 4-(4-Chlorophenyl)- I1 -di hydro-7 -dim ethyl amin ocarbonylm ethyl ox y[ I ]benz ox epino [2,3 -b ]pyridin -5 -yI idene)propyl ]pip eri dine The titled compound was prepared by following the procedure of exanip le 134, but replacing the product of example 133 with the product of example 154.

'H-NMR (CDCl 3 6: 1.58-1.92(4H,m), 2.04(2H,m), 2.30-2.68(51{,m), 2.93(2H,m), 2 .98(3H,s), 3 .08(3H,s), 4.65(2H,s), 5 .28(2H,brs), 6.07(1 6.70-6.98(3H, ii), 7.08-7.36(5H,m), 7.60(1H,m), 8.50(1H,rn).

MS mlz: 532(M+l) Example 156: 1 -(7-(2-Acetoxyethyl)oxy-5,1 1-dihydro[ I]benzoxepino[2,3 -b]pyridin-5 ylJ dene)propyl]piperi dine The titled compound was prepared by following the procedure of example but replacing the product of example 44 with the product of example 15 1.

'H-NMR (CDCl 3 8: 1.55-1 .88(4H,m), 1 .90-2.32(2H,m), 2.1 0(3H,s), 2.28- 2 .60(5H,m), 2.82-3 .02(2H,m), 4.1 4(2H,dd), 4.41 (2H,dd), 5 .29(2H,brs), 6.08(1 H,t), 6.72-6.90(3H,m), 7.1 8-7.34(5H,m), 7.57(1H,m), 8.50(1H,m).

MS mlz: 533(M+1) Example 157: 4-(4-Ch] orophenyl)- 1-[3 1-dihydro-7-(2-hydroxyethyl)oxy[l1]benzoxepino [2,3-b The titled compound was prepared by following the procedure of example 5 1, but replacing the product of example 50 with the product of example 156.

'H-NMR (CD3OD) l.66-l.98(4H,ni), 2.40-2.73(5H,m), 2.82-2.94(2H,rn), 3 .22(2H,m), 3 .84(2H,dd), 4.01 (2H,dd), 5.23(2H,brs), 6.1 3(lH,t), 6.64-6.98(3H,m), 7.13-7.34(4H,m), 7.45(1H,m), 7.77(IH,rn), 8.47(lH,m). OH signal was not observed.

MS m.l/z: 491(M+1) Example 158: 4- Chlorophenyl)- 1 (3 -(5,11 -dihydro-7-( I -ethoxycarbonyl -I -m ethyl ethyl) ox y[ I lb enzoxepino[2 ,3-bjpyri The titled compound was prepared by following the procedure of example 138, but replacing the product of example 44 with the product of example 151.

'H-NMR (CDC 3 d: 1.28(3H,t), l.

5 6 (611,s), 1.56-1.85(4H,m), l.97(2H,dt), 2.28- 2.55(5H,m), 2.93(2H,rn), 4.24(2H,q), 5.28(2H,brs), 6.04(lH,t), 6.62-6.95(3H,m), 7.07-7.32(5H,m), 7.57(1I-,dd), 9.50(lH,dd).

MS nilz: 561(M+l) Example 159: -Carboxy-l-methylethyl)oxy-5,11 dihydro[ I ]benzoxepino[2,3-b]pyridin-5 -ylidene)propyl]-4- (4-chlorophenyl)piperidine The titled compound was prepared by following the procedure of example 133, but replacing the product of example'48 with the product of example 158.

'H-NNMf (CD 3 OD) d: 1.50(6H,s), l.82-2.18(4H,ni),. 2.70(2H,m), 2.87(1H,m), 3.12(2H,m), 3.30(2H,m), 3.60(2H,in), 5.25(2H,brs), 6.07(lH,t), 6.67-7.04(311,m), 7.16-7.38(4H,m), 7.58(1IR,r), 7.96(IH,m), 8.52(1H,m). COON signal was not observed.

MS m/z: 533(M+1) Example 160: I -[3-(8-Brorno-5,1 1-dihydro[l1jbenizoxepino[2,3-b]pyridini-5 -ylidene)propyl]-4- (4 -chl oroph enyl)piperi dine The titled compound was prepared by following the procedure of example but replacing the product of example 45, step 2 with the product of example 54, step 'H-NMR (CDC1 3 d: 1.50-1.86(4H,m), 1.98(2H,m), 2.26-2.60(5H,m), 2.88(2H,m), 5.30(2H,brs), 6.09(IH,t), 6.96-7.36(8H,rn), 7.57(1H,dd), 8.51(1 H,dd).

MS m/z: 509, 511(M+1) Example]161: I -[3)-(8-Carboxy-5,1 1-dihydro[ I]benzoxepino[2,3-b]pyridin-5 -ylidene)propyl] -4- (4-chlorophenyl)piperidine To a solution of I -[3-(8-Bromo-5,1 1I-dihydro[I1 benzoxepino[2,3-b] pyridin- 5-ylidene)propyl]-4-(4-chlorophenyl)piperidine (Example 160) (130 mg) in ml) was added 1.6M n-butyllithium hexane solution (0.17 ml) at -78'C. After stirring 10 minutes at the same temperature, CO 2 (dry-ice) was added to the mixture.

After being warmed to ambient temperature, the mixture was stirred for 30 Tminutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluted with dichioromethane -methanol 1) to give the titled compound IH-NMIR (CD 3 OD) 8: 1.55-1.95(4H,m), 2.17(2H,dt), 2.32-2.78(5H,m), 3.00(2H,m), 5.30(2H,brs), 6.19(IH,t), 7.08-7.54(8H,m), 7.76(1H,dd), 8.45(1H,dd). COOH signal was not observed.

MS mlz: 475(M+1) Example 162: 1 -[3-(7-Bromo-5,1 1-dihydro[l1]benzoxepino[2,3-bjpyridin-5-ylidene)propyl] -4- (4-chlorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of example but replacing 5,11 -dihydro-7-rnethoxy[ I ]benzoxepino[2,3-b]pyridin-5-one with I1 -dihydro[ I ]benizoxepinoll2,3-b]pyridin-5-one.

I H-NMR (CDCl 3 5: 1.60-1.71 I .98-2.09(2H,m), 2.34-2.69(SH,m), .32(2H,brs), 6.1 3(1H,t), 6.73(IH,d), 7.22-7.44(7H,m), 7.57(I,dd), 8.52( 1H,dd).

MIS mlz: 525, 527(M+1) Example 163: 4-(4-Chlorophenyl)- 11 -dihydro-7ethyl [1 ]b enzox epino 2,3 pyri din- 5-yli dene)propyl] piperi din-4-ol The titled compound was prepared by following the procedure of example but replacing 5,1 1 -dihydro-7-methoxy[ 1 ]benzoxepino [2,3-b]pyridin-5 -one 'with 5,11 -dihydro-7-ethyl[ 1 ]benzoxepino[2,3 -b]pyridin- IH-NMR (CDCI 3 d: 1 .23(3H,t), 1 .52(1H,brs), 1.66-1.71 1 .98-2.06(2H,m), 2.35-2.70(1 IH,m), 5.31 (2H,brs), 6.09(IH,t), 6.79(1H,d), 7.01 (1H,dd), 7.1 1(1H,d), 7.25-7.44(5H,m), 7.58(lH,dd), 8.49(IH,dd).

MS mlz: 475(M+1) Example 164: 4-(4-Chloropbenyl)- 1 -[3-(5,11i -dihydro-8vinyl I)b enzoxepino [2,3 -b~pyri din- 5-yl idene)propyl ]piperi din-4-o I The titled compound was prepared by following the procedure of example but replacing 5,11 -dihydro-7-methoxy[I I benzox epino[2,3 -b]pyridin- 5-one with 5,11 -dihydro-S -vinyl[ 1 )benzoxepino [2,3 -b]pyri din-5 -one.

IH-NM11R (CDC1 3 d: 1.66-1 .71(3H,m), 2.00-2. 10(2H,ni), 2.36-2.70(8H,m), 5.22(2H,d), 5.3-4(2H,brs), 5.70(1 6.1 1(IH,t), 6.61 6.89(1H,d), 6.99(1H,dd), 7.24-7.44(6H,m), 7:58(IH,dd), S.49(IH,dd).

MS mlz: 473(M+1) Example 165: 4-(4-Chlorophenyl)- 11 -dihydro-8-ethyl[l1 benzoxepino[2,3-b]pyridin-5ylidene)propyl]piperidin-4-ol A mixture of the product of example 164 (100 mg) and Pd-C (20 mg) in ethanol(2 ml) stirred under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with chloroformn-methianol (15: 1) to give the titled compound (50 mgy).

1 H-NMR (CDClI) 1 .22(3H,t), 1.55-1 .77(3H,m), 2.00-2.1 3(2H,m), 2.33-2.74(1 OH,m), 5.32(21-,brs), 6.07(IH,t), 6.70(IH,d), 6.78(1H,dd), 7. 19-7.44(6H,ni), 7.57(1 H,dd), 8.49(I,dd).

MIS mlz: 475(M+1) Example 166: 4-(4-Chlorophenyl)-l1-[3-(5, 1-dihydro-9-methoxy[ 1]benzoxepino[2,3-b]pyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of examplIe but replacing 5,1 1 -dihydro-7-methoxy[ I ]benzoxepino[2,3-b]pyridin-5-one 'With 5,11 -di hydro -9-rnethoxy[ 1 ]b enzox epino pyri din- 1 H-NMR (CDC1 3 5: 1.65-1.70(2H,m), 1.95-2.06(2H,m), 2.15 (1H,brs), 2.37-2.67(8H,m), 3.83(3H,s), 5.43(21{,brs), 6.09(1H,t), 6.79-6.91 (3H,m), 7 .22-7.43(SH,m), 7.57(1-IH,dd), 8.44(1I-I,dd).

MS mlz: 477(M+1) -96- Example 167: 4-(4-Chlorophenyl)-lI-[3-(5 ,1 1-dihydro[l1 benzox epino[4,3-c]pyridin-5ylidene)propyl]piperidin-4-o] The titled compound was prepared by following the procedure of example but replacing 5,1 1-dihydro-7-methoxy[1I]b enzoxepino [2,3 -b]pyridin- 5-one with 5,11- dihydro[1I]benzoxepino [4,3 -c]pyridiri-5 -one.

1H-NMR (CDCl 3 6: 1.67-1.71 1 .97-2.08(2H,m), 2.16(1 H,s), 2.40-2.69(8H,m), 5. 16(2H,brs), 6.14(1H,t), 6.80(1H,dd), 6.91-6.97(IH,ni), 7.13-7. 19(JH,m), 7.26-7.44(6H,ni), 7.50-8.54(2H,m).

MS m/z: 447(M+1) Example 168: 4-(4-Chlorophenyl)- 1-dihydro[l1jbenzoxepinojj4,3-d]pyrimidin-5yl ideiie)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example but replacing 5,11 -dihydTo-7-methoxy[ 1 ]benzoxepino[2,3-b]pyridin-5-one with 5,11 dihydro[ I ]benzoxepino[4,3-d]pyrimidin-5 -one.

I H-NM\R (CDCI 3 5: 1.68-1.72(2H,m), 1.90(lH,brs), 2.06-2.19(2H,m), 2.41 -2.78(8H,m), 5.20(2H,s), 6.1 2(IH,t), 7. 14-7.45(8H,ni), 8.72(1H,s), 8.9 7(1 H,s).

MS mlz: 448(M+l) Example 169: 4-(4-Chlorophenyl)- 1-dihydro-7-trifluoromethanesulfonyloxy( I]b enzoxepi no[2,3-b]pyridin-5-yli dene)propyl]piperidin-4-oI To a solution of product of example 44 (1.0 g) in pyridine (10 ml) was added tr-ifluoromethanesulfonic acid anhydride (0.55 ml) at 0 0 C, and the mixture was stirred at room temperature for 1 hour. Water and diethyl ether were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel -97chromatography eluting with ethyl acetate-methanol (10: 1) to give the titled compound (1.1 g).

11--NMR (CDCI 3 6: 1.56(l H,brs), I.66-1.71(2H,M), I .97-2.09(2H,m), 2.35-2.69(8H,m), 5.35(2H,brs) 6.1 5(1H,t), 6.88(lH,d), 7.05(lH,dd), 7.2 1-7.44(6H,m), 7.60(1H,dd), 8.54(1H,dd).

MIS mlz: 595(M+1) Example 170: I -[3-(7-Allyl-5, 1-dihydro[I1]benzoxepino[2,3-b)pyridin-5-ylidene)propylj -4- (4-chioroph enyl)piperidin-4-ol A mixture of the product of example 169 (240 mg), allyltributyltin (0.19 ml), dichlorobis(triphenyiphosphine)palladium(I1) (30 mg) and lithium chloride (76 mg), in dimethylformamide (3 ml) was heated under argon at 120*C for 2 hours. Aqueous ammonium fluoride solution and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with chloroform-methanol (10: 1) to give the titled compound (180 mg).

1 H-NMR (CDCI3)) 5: 1.62-1.72(3H,m), 2.03-2.1 1(2H,m), 2.39-2.73(81-,m), 3.31 5.04-5.11 5.29(2H,brs), 5.87-6.02(lH,m), 6.06(1 H,t), 6.77(1 6.99(IH,dd), 7. 10(1IH,d), 7.23-7.43(5H,ni), 7.57(l H,dd), 8.40(l 11,dd).

Example 171: 1 -(7-(2-t-Butoxycarboxy)ethenyl- 5,11 -dihydro[ I]benzoxepino[2,3-b]pyridin-5-yI idene)propyl] -4-(4-chilorophenyl)piperidin-4-ol A mixture of the product of example 169 (1.7 t-butyl acrylate (0.85 nal), triethylamine (2.5 ml), 1,1'-bis(diphenylphosphino)ferrocene (250 mg) and palladium(11) diacetate (33 mg) in dimethylformrnide (3 ml) was heated uaider argon at 90'C for 24 hours. Water ethyl acetate were added to the reaction rrixture, the organic layer was separated and washed with saturated aqueous sodium chloride, -98and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (30:1) to give the titled compound (780 mg).

1 H-NMvR (CDCI 3 5: 1 .45(9H,s), 1.63-1.71 1.98-2.1 0(2H,m), 2.35-2.72(8H,m), 5.35(2H,brs), 6. 15(1H,t), 6.26(1H,d), 6.83(1H,d), 7.22-7.44(7H,m), 7.53(1H~d), 7.58(1H,dd), 8.52(1H,dd).

Example 172: I -[3-(7-(2-Carboxy)ethenyl-5,1 I -dihydro [I benzox epino[2,3 -b]pyri din- 5-yl id ene)pr opylj -4-(4-chlorophenyl)piperidin-4-ol The product of example 171 (330 mg) was dissolved with 4N hydrochloric acid 1,4-dioxane solution (4 and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Water was added to the residue, and neutralized with sodium hydroxide solution. The precipitation was filtered to give the titled compound (190 mg).

1 H-NMR (DMSO-d 6 6: 1.45-1 .52(2H,m), I .72-I .84(2H,m), 2.25-2.58(8H,rn), 5.25(2H,brs), 6.28(IH,t), 6,43(1H,d), 6.82(1H,d), 7.34-7.60(8H,m), 7.75(IH,dd), 8.52(1 I-,dd).

Example 173: 4-(4-Chloropheny])- 1-dihydro-7-propargyloxy[lI benzoxepino[2,3-b]pyridi ylidene)propyl]piperidin-4-ol The ti tled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with propargyl chloride.

1H-NMR (CDC1 3 6: 1.66-1.71 (2H,rn), I..79(1H,brs), 1.99-2.1 0(2H,m), 2.35-2.71 4.66(2H,d), 5.28(2H,brs), 6. 10(1H,t), 6.80-6.93(3H,m), 7.24-7.46(5H, 7.59(lH,dd), 8.48(lH,dd).

MS ni/z: 501(M+l) -99- Example 174: 4-(4-Chloropheriyl)- I-[3-(7-cyclopentoxy-5,1 1-dihydro[ I]benzoxepino[2,3 -b]pyridi yli den e)propyllpiperi din-4-oI1 The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with cyclopentyl bromide.

1I--NMR (CDCl 3 6: 1.54-2.1 8(13H,m), 2.41 -2.72(8H,m), 4.66-4.73(IH,m), .27(2H,brs), 6.08(1H,t), 6.70-6.87(3H,m), 7.23-7.44(5H,m), 7.58(1H,dd), 8.49(LH,dd).

MS m/z: 531(M+l) Example 175: 4-(4-Chlorophenyl)- I-[3-(5,11 -dihydro-7-(2-methoxyethyl)oxy)[ I]benzoxepino[2,3b]pyri din-5-ylidene)propylllptperidi n-4-ol Thc titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 2-methoxyethyl chloride.

I1H-NM R (CDCI 3 6: 1.66-l.75(3H,m), 2.00-2.1 l(2H,m), 2.36-2.71 (SH,m), 3 .45(3H,s), 3.71 -3.75(2H,m), 4.07-4.11 (2H,rn), 5.27(2H,brs), 6.09(lH,t), 6.75-6.91 7.23-7.44(5H,rn), 7.57(1H,dd), 8.48(1 H,dd).

MS m/z: 521(M+1) Example 176: 4-(4-Ghlorophenyl)- 1 dirnethyaminocarbonyl- 1 -m ethyl) ethylox y- 5,11 -dihydrof 1] benzoxep ino6[2,3 pyridin- 5-ylidene)propyfl]pip eidin-4-ol The titled compound was prepared by following the procedure of examnple 134, but replacing the product of example 133 with the product of example 139.

1 H-NMR (ODCd 3 6: 1.59(6H,s), 1.67-1.72(2H,m), I.99-2.09(2H,m), 2.36-2.70(9H,m), 2.96(3H,s), 3.2 5.25(2H,brs), 6.02(IH,t), 6.60-6.77(3H,m), 7.24-7.44(5H,m), 7.58(1 H,dd), 8.44(l H,dd).

MS m/z: 576(M+1) -100- Example 177: 4-(4-Chlorophenyl)- ,1 1-dihydro-7-( I-ethoxycarbonylethyl)oxy[ I]benzoxepin o[2,3 -blpyridin-5-yli dene)propyllpiperidin-4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with ethyl 2-bromopropionate.

1H-NMvR (CDCl 3 5: 1.25(3H,t), 1.59(3H,d), 1.65-1.70(2H,m), 1.98-2.08(2H,m), I.35-2.68(SH,m), 2.80(IH,brs), 4.21 4.68(1H,q), 5.24(2H,brs), 6.07(1I-,t), 6.68-6.79(2H,m), 6.88( 1H,d), 7.22-7.44(5H,m), 7.56( IH,dd), 8.40(1H,dd).

Example 178: 1 I-Carboxyetlhyl)oxy-5, 11 -dihydro[I1]benzoxepino[2,3-b]pyridin-5 -ylidene)p ropyl] -4-(4-chlorophenyl)piperidin-4-oI The titled compound was prepared by following the procedure of example 133, but replacing product of example 48 with product of example 177.

IH-NNM (DMSO-d 6 5: 1.46(3H,d), l.58-1.63(2H,m), 1.98-2.06(2H,rn), 2.41 -2.45(2H,m), 2.72-2. 86(6H,m), 4.74(lH,q), 5.1 8(2TH,brs), 6.1 1(11-,t), 6.73(2H,s), 6.84(1 7.36-7.47(5H,m), 7.73(IH,dd), 8.50(lH,dd).

MS mlz: 535(M+l) Example 179: 4-(4-Chlorophenyl)- 1-dihydro-7-(lI-ethoxycarbonyl)cyclobutoxy[ 1 ]benzoxe pinoj[2,3-blpyridin-5- ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with ethyl 2-bromo cyclobutanecarbox yl ate.

I H-NMR (CDCI 3 5: 1.19(3H,t), 1.67-1.71(2H,m), 1.92-2.1 2.33-2.77(12H,m), 4.2 1(2F1,q), 5.25(2H,brs), 6.05(IH,t), 6.47(IH,dd), 6.70(1H,d), 6.73(1 7.23-7.44(5H,m), 7.55(1 H,dd), 8.44(1H,dd).

Example 180: I I-Carboxy)cyclbutoxy-5, 1I -dihydro[I1 ]benzox epino[2,3 -b]pyridin- 5 -yli den -101e)propyl]-4-(4-chlorophenyl)pi peni din-4-ol The titled compound was prepared by following the procedure of example 133, but replacing product of example 48 with product of example 179.

1 H-NMR (DMSO-d 6 6: 1.60-1 .65(2H,m), 1 .86-2.08(4H,rn), 2.24-2.90( 12H,m), 5.1 7(2H,brs), 6.05(1 6.50(1H,dd), 6.66(1H,d), 6.73(IF{,d), 7.3 7-7.48(5H,ni), 7.74(IH,dd), 8.5 1(I{,dd).

MS m/z: 561 1) Example 181: 1 3 7 -Carbamnoylrnethyloxy-5, 1I -dihydro[ 1 ]benzoxepino[2 ,3-bjpyridin-5 -ylidene) propyl]-4.(4-chlorophenyl)pipeiidin-4-o The titled compound was prepared by following the procedure of example 134, but replacing dimethylamine hydrochloride with ammonium hydroxide.

I H-NMvIR (CDCI 3 6: 1.66-1.71 1 .98-2.09(2H,m), 2.2 1 (1 H,brs), 2.3 8-2.70(8H,m), 4.45(2H,s), 5.2 8(2H,brs), 6.09(1 6.11 1H,brs), 6.5 8(1 H,brs), 1 5 6 7 4- 6 7.24-7.44(5H,m), 7.58(IH,dd), 8.47(IH,dd).

MS 520(M+1) Example 182: 4-(4-Chlorophenyl)- 1 1] -di hydro- 7 -methyl ani nocarbonylniethyl oxy[ 1 ]benzox epino[2 3 -b]pyridin-5-ylidene)propyflpipeidin4-o The titled compound was prepared by following the procedure of example 134, but replacing dimethylarnine hydrochloride with methylamine.

I H-NMvR (CDC 3 6: 1.67-1 .72(2H,m), 1.99-2.1 0(2H,m), 2.36-2.70(9H,m), 2.89(3H,d), 4.45(2H,s), 5.28(2H,brs), 6.08( lH,t), 6.66(1 H,brs), 6 73 -6.84(3-i,m), 7.25-7.45(5H,m), 7.58(1H,dd), 8.47(1H,dd).

MS mlz: 534(M+1) Example 183: 1 11 -Dihydro-7-methoxy[ I 1benzoxepino(2,3-bpyidin5ylidene)prop yl]-4-(4 -102- -hydroxyphenyl)piperidine The titled compound was prepared by following the procedure of examnple step 3, but replacing 4-(4-chloroph enyl)-4-hydrox ypip eri dine with 4-(4-hydroxyphenyl)piperidine.

1IH-NMR (CDCL3) 5: 1.52-1.88(4H,m), 2.01(2H,dt), 2.28-2.60(5H,m), 2.93(2H,m), 3.79(3H,s), 5.268(2H,brs), 6.08(1H,t), 6.68-6.88(3H,m), 7.05-7.36(5H,m), 7.58(1H,dd), 8.50(1H,dd).

MS mlz: 461(M+1) Example 184: 1 -Dihydro-7-methoxy[ 1 ]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4- (2-hydroxyphenyl)piperidine The titled compound was prepared by following the procedure of example step. 3, but replacing 4-(4-chlorophcnyl)-4-hydroxypi penidine with 4-(2-hydrox yphenyl)pip eri dine.

'H-NMR (CDCI 3 6: 1.78-1 .92(4H,m), 2. 12-2.25(2H,m), 2.32-2.70(4H,m), 2.80- 2.97(1 3.01 -3 .1I 5(2H,m), 3.77(3H,s), 3.78(1 H,brs), 5.28(2H,brs), 6.03 (1I-I,t), 6.74-6.86(4H,m), 7.05(1 H,dd), 7.11 (IH,dd), 7.23-7.28(2H,m), 7.56(1H,dd), 8.48(IH,dd), OH signal was not observed.

MS mlz: 443(M+1) Example 185: 4-(7-Chloro-1 ,2-benzisoxazol-3-yl)-1 1-dihydro-7-rnethoxy[ 1]benzo:xepino[2 ,3-b~pyri din 5-yli dene)propyll piperidi ne.

The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chloropheniyl)*-4-hydroxypiperi dine with 4-(7-chloro- 1,2-benizisoxazol-3-yl) piperidine. This tetrahydropyri dine was prepared by the same method described in J. Med Chem. 28:761-769 (1985).

'H-NMR (CDC1 3 6:1. 94-2.20(6H-,m), 2.3 0-2 .60(4H,m), 2.86-3.1 4(3H,m), 3.79(3H,s), 5.29(2H,brs), 6. 10(IH,t), 6.70-6.88(3H,m), 7.22(IH,t), 7.27(1 1-1,dd), -103- 7.50(IH,dd), 7.57-7.68(211,m), 8.49(1H,dd).

Example 186: 4-(7-Chloroindol-3-yI)- 1 11 -dihydro-7-methoxy[ 1 ]benzoxepino[2,3-b]pyridinylid ene)propyl ]piperi dine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(7-chloroindol-3-yl)piperi dine. This piperidine was prepared by the same method described in J Med. Chem. 36:4006-4014 (1993) and following hydrogenation described in Example 58, step 3.

'H-NMR(CDC

3 5: 1.66-1 .88(2H,m), I .92-2.22(4H,m), 2.32-2.63(4H,m), 2.78(1 2.97(2H,m), 3.79(3H,s), 5.29(2H,brs), 6.09(IH,t), 6.70-6.87(3 H,m), 6.97-7.07(2H,m), 7.1 2-7.30(2H,rn), 7.52(1H,m), 7.59(1H,dd), 8.45(1H,brs), 8.50(IH,dd).

Example 187: 4-Azido-4-(4-chlorophenyl)-l1-[3 1-dihydro-7-miethoxy[ I]benzoxepino [2,3-b]py ri din-S -yl i dene)propyl]piperi dine Step 1 4-azi do-4-(4-chlIorophenyl)piperi dine Fig. 8b To a cold (0 0 C) solution of!1 (3.0 g, 14 mmol) in anhydrous dioxane (15 mL) under an inert atmosphere was added NaN 3 (1.0 g, 15.4 mmol) followed by the slo~w dropwise addition of and BF 3 *0Et (4.4 rnL, 35 mnmol). The reaction was stirred at 0'C for 3 hrs; and was quenched at 0 0 C by the slow careful addition of saturated aqueous NaH-C0 3 to basicity. The organic layer was separated and dried over Na 2

SO

4 The reaction mixture was purified via silica gel flash chromatography eluting a 2 g 1:3 mixture of azidopiperidine 2 and olefin 3 with 2% MeOHC 2 C1 2 The mixture was taken directly on to the next reaction.

Step 2 The titled compound was prepared by then following the procedure of exarnple -104step 3, with the above reaction mixture (thereby replacing 4-(4-chlorophenyl)-4-hydroxypipefldifle with 4-azido-4-(4-chlorophenyl)piperidine)), but limiting the amount of bromide to 0.25 equivalents.

'H-NMiR (CDCL 3 8: 1.88(2H,rn), 2.55-2.85(4H,m), 3.O0-3.30(6H,m). 3.75(3H,s), 5.1 9(2H,brs), 5.97(1H,t), 6.68-6.65(3H,m), 7.20-7.46(5H,m), 7.63(1H,dd), 8.35(1H,dd).

MS mlz: 477(M+1 .N 2

+H

2 Example 188: Methyl 1 -dihydro-7 -methoxy[ I ]benzox ep ino [2,3 -blpyri dinl-5 -yl idene)propyl] 4-phenylpiperidi-4-caboxylate The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophien yl)-4-hydroxypiperi dine with methyl 4 -phenylpip eri din-4-carb oxylate.

'H-NMIR (CDCI 3 8: 1.82-2.1 5(4H,m), 2.28-2.60(6H,m), 2.78-2.82(2H,m), 3.62(3H,s), 3.68(3H-,s), 5.26(2H,brs), 5.95(0.1IH,t, E isomer), 6.05(.9H,t,Z isomer), 6.82-6.70(3H,m), 7.33-7.22(6H,m), 7.65(0. IH,dd, Z isomer), 7.55 (0.9H,dd, Z isomer), 8.39(0.1H,dd, E isomer), 8.48(0.9H,dd, Z isomer).

MS nilz: 485(M+1) Example 189: 1 -(5,11 -Dihydro-7-methoxy[I1]benzoxepino[2,3-b]pyridin-5-ylidene)propylJ- 4-phenylpip eridin-4-carboxylic acid The titled compound was prepared by following the procedure of excample 133, but replacing product of example 48 with product of example- 188.

'H-NMR (CD 3 OD) 8: 2.16-2.23(2H,rn), 2.69-2.91(4H,m), 3.00-3.16(2H,rr), 3.37- 3.25(2H,m), 3.68-3.73(2H,m), 3.76(3H,s), 5.34(2H,brs), 6.24(lH,t), 6.70- 7.04(3H,rn), 7.26-7.55(51{,m), 7.79-7.89(lH,m), 8.21-8.34(lH,m), 8.56- 4105- 8.62(0.1 8.63-8.77(0.9H,m), MS mlz: 471(M+1) Example 190: 1 -(2.Clilorophenylsulfonyl)-4-[3-(5, I I -Dihydro-7-methoxy[ I ]benzoxepino [2,3-b]py The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with I -(2-chlorophenylsulfonyl)piperazine.

H-NMR (CDC1 3 6: 2.20-2.58(8H,m), 3.12-3.38(4H,m), 3.76(3H,s), 5.22(2H,brs), 6.03(IH,t), 6.64-6.90(3H,m), 7.23(1 H,dd), 7.32-7.60(4H,m), 8.01 (1H,dd), 8.48(1 H,dd).

MS m/z: 526(M±1) Example 191: I -(3-Chilorophienylsulfonyl)-4-[3-(5, 1 -Dihydro-7-inethoxy[ I ]benzoxepino [2 ,3-blpy ridin-5 -ylidene)propyl]piperazine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-clhlorophenyl)-4-hydroxypiperi dine with 1 -(3-chlorophienylsulfonyl)piperazine.

'H -NMR (CDCI 3 6: 2.20-2.60(81-,m), 2.82-3.12(4H,rn), 3.76(3H,s), 5.18(2H~brs), 6.00(1 6.64-6.90(3H,m), 7.23(1H,dd), 7.42-7.78(5H,ni), 8.48(lH,dd).

MS mlz: 526(M-I1) Examiple 192: 1 -(4-Chloropheniylsul fonyl)-4-[3-(S,1 I -Dliydro-7-methoxy[ 1 jbenzoxepino [2,3-b]py -ylidene)propyl]piperazine The titled compound was prepared by following the procedure of examplIe step 3, but replacing 4 4 -chlorophenyl)-4-hydroxypiperi dinie with I -(4-chlorophenylsulfonyl)piperazine.

-106- 'H-N'MR (CDC1 3 5: 2.20-2.56(8H,m), 2.82-3.10(4H,rn), 3.76(3H,s), 5.18(211,brs), 5.99(1H,t), 6.62-6.92(3H,m), 7.23(1H,dd), 7.42-7.78(5H,m), 8.48(1H,dd).

MS mlz: 526(M+1) Example 193: 4-(4-Chlorophenyl)- 1-[3 -(5,11 -dihydro-7-hydroxy[I1]benzoxepino[2,3-b]pyridifl-5-y lidene)propyl]- 1,2,3 ,6-tetrahydropyri dine The titled compound was prepared by following the procedure of example 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with 4-(4-chlorophenyl)- 1,2,3 ,6-tetrahydropyri dine.

'H-NMvR (CDCI 3 d: 2.3 7-2.72(8H,m), 3 .07(2H,m), 5 .25(2H,brs), 6.00( IH,rn), 6.07(1 6.60-6.78(3H,m), 7.1 8-7.47(5H,m), 7.56(1 H,dd), 8.50(1H,dd). OH! signal was not observed.

MS mlz: 445(M+l) Example 194: 4-(4-Chlorophenyl)-1 -dihydro-7-methoxy[ 1 Jbenzoxepino[2,3-b]pyridifl-5-y lidene)propyl]- 1,2,3,6-tetrahydropyri dine The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hyclroxypiperi dine with 4-(4-chlorophenyl)- 1,2,3,6-tetrahydropyri dine.

'H-NMR (CDCI 3 5: 2.37-2.72(8H,m), 3.06(2H,m), 3.78(3H,s), 5.27(2H,brs), .99(IH,m), 6.10(1 6.72-6.90(3H,m), 7.20-7.44(5H,m), 7.60(1 H,dd), 8.50(lH,dd).

MS mlz: 459(M+1) Example 195: 4-(7-Chloroindol- 3-yl)-1 11 -dihydro-7-methoxy[I1]benzoxepino[2,3-b]pyridin-5ylidene)propyl)- I ,2,3,6-tetrahydropyri dine.

-107- The titled compound was prepared by following the procedure of example step 3, but replacing 4-(4-chlorophenyl)-4-hydrox ypiperi dine with 4-(7-chloroindol]- 3-yI)- 1,2,3,6-tetrahydropyri dine. This piperidin e was prepared by the same method described in J Med Chemn. 36:4006-4014 (1993).

'H-NMR (CDC] 3 6: 2.37-2.76(8H,m), 3.14(2H,m), 3.78(3H,s), 5.29(2F{,brs), 6.02- 6.23(2H,m), 6.67-6.90(3H,m), 7.05(1 H,dd), 7. 12-7.33(3H,m), 7.60(IH,dd), 7.77(IH,m), 8.50(IH,dd), 9.06(1H,br s).

Example 196: -Chioro- I I-dihydro- 7-hydroxy[ 1 ]b enzox epino [2,3 -b]pyri din yli den e)propy) )spiro [isob enzofuran- 1 (3 H),4'-pip eridin e) The titled compound was prepared by following the procedure of example 44, step 2, but rep] acing4-(4-chlorophenyl)-4-hydroxypiperid ine with -chl orospiro [i sobenzo firan- 1 (3 H),4'-piperi dine].

I H-NMR (CDCI 3 5: 1.66-1.71 1.79-1.91 2.26-2.73(8H,m), 4.99(2H,s), 5.22(2H,brs), 6.07(IH,t), 6.63-6.70(2H,ni), 6.76(IH,d), 7.06(lH,d), 7. 19- 7. 3 2(3 7.60(1 H,dd), 8.47(lIH,dd), 8.63 (1H,s).

MS n~z: 475(M+1) Example 197: 1 11 -dihydro-7-(2-methoxyethyl)oxy[ 1 ]benzoxepino[2,3-bl pyridinyli dene)propyl] spiro[isobenzofuran- I (3H),4'-piperidine] The titled compound was prepared by following the procedure of examplIe 175, but replacing the product of example 44 with the product of example 196.

1 H-NMIR (CDCI1 3 5: 1.69-1 .74(2H,m), 1.83-1 .94(2H,m), 2.3 1-2.76(8H,m), 3 .45(3H,s), 3.72-3 .75(2H,m), 4.08-4.11 (2H,rn), 5 .00(2H,s), 5 .28(2H,brs), 6.09(1H,t), 6.74-6.82(2H,m), 6.89(1H,d), 7.04(1I-,d), 7. 17-7.28(3H,m), 7.57(1H,dd), 8.49(IH,dd).

MS mlz: 531(M+1) -108- Example 198: N 4-(4-Chlorophenyl)- 1 -[3-(7-dimethylaminocarbonyl- 5,1 1-dihydro[l1]benzoxepino[2,3-bjpyridim-5-ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 118.

I1H-NMiR (CDCl 3 5: 1.65-1.70(2H,m), 1.99-2.09(3H,m), 2.32-2.69(8H,m), 2.1 7(3H,s), 5.35(2H,brs), 6.1 5(lH,t), 6.82(1H,d), 7.1 9(1H,dd), 7.28-7.46(6H,m), 7.58(IH,dd), 8.49(IH,dd).

Example 199: 4-(4-Chl orophenyl)- 1-hydrox y-2-methyl)propyl)oxy-5,1 Idihydro[ I ]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol To a solution of product of example 138 (500 mg) in methanol (5 ml) was added sodium borohydride (330 mg), and the mixture was heated to reflux for 1 hour. The mixture was distilled off under reduced pressure. Water and ethyl acetate were 1 5 added to the residue, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with chloroformn-methanol (10: 1) to give the titled compound (440 mg).

1H-NMR (CDCI 3 5: l.26(611,s), 1.66-1 .70(2H,m), I .79(1H.brs), 2.00-2.08 (2H,m), 2.37-2.70(9H,m), 3.58(2H,s), S.30(2H,brs), 6.05(IH,t), 6.75-6.84(2H,m), 6.91 (1 7.26-7.44(SH-,m), 7.58(1 H,dd), 8.49(1H,dd).

MS m/z: 535(M+1) Example 200: 4-(4-Chlorophenyl)- 3-(7 -m ethyl -2-hydroxy)propyl)oxy- 5,11di hydro[I 1 benzoxepino [2,3 -b]pyri din- 5-yli dene)propyl ]piperidin-4-o I To a solution of product of example 48 (500 mg) in tetrahydrofuran (5 was added 0.95M methylmagnesium bromide tetrahydrofuran solution (3.8 ml) at 0 0

C,

-109and the mixture was stirred at room temperature for 20 minutes. Aqueous ammoniurn chloride solution and ethyl acetate were added to the mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with chl oroform-m ethanol (10: 1) to give the titled compound (360 mg).

I H-NMR (CDCl 3 8: 1 .34(6H,s), 1 .5 8(1H,brs), 1.66-1 .7 l(2H,m), 1 .99-2.1 0(21,rn), 2.25(1H,brs), 2.36-2.71 3.77(2H,s), 5.28(2H,brs), 6.09(IH,t), 6.74-6.86(3H,m), 7.24-7.44(5H,rn), 7.57(1H,dd), 8.49(1H,dd).

MS mfz: 535(M+l) Example 203: 4-(4-Chlorophenyl)-l1-[3-(7-(2-ethoxy)ethyloxy)-5, 1I -dihydro[ 1 ]benzoxepino [2,3b]pyri din- 5-ylidene)propyl ]pipen* difl- 4 -ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 2-ethoxyethyl bromide.

I H-NMR (CDCl 3 8: 1 .24(3H,t), 1 .66-1 .75(3H,m), 2.00-2.1 1(2H,m), 2.36-2.71(8H,rn), 3.59(2H,qJ, 3.7 l-.75(2H,m), 4.07-4.1 l(2H,m), 5.27(2H,brs), 6.09(1 6.75-6.91(3H,rn), 7.23- 7.44(5H,ni), 7.57(1 H,dd), 8.48(1 H,dd).

MSrn~z: 535(M+l) Example 205: 4-(4-Chlorophenyl)-1 ,l1 -dihydro-7-(l dihiydroxy)propyloxy)[I1]benzox epino[2,3-b]pyridin-5-ylidene)propylllpiperidil- 4 -ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with glycidol.

H-NM4R (CDCI 3 8: 1.66-1.75(2H,m), 2.00-2.l1(2H,m), 2.36-2.7 l(SH,m), 3.62-3. 76(2H,m), 3 .94-4.02(4H,ni), 4.21 (2H,brs), 5 .27(21-L,brs), 6.09(lH,t), 6.76-6.86(3H,m), 7.23-7.44(5H,m), 7.57(1H,dd), 8.48(1 1-,dd).

MS m/z: 537(M+1) Example 211: 1 -Carbamoyl- 1 -methyl)ethyloxy-5, 1-dihydro[ I ]benzoxepino[2,3 b]pyri din -5 -yl defle)propyl] -4-(4-chlorophenyl)pipe din- 4 -ol The titled compound was prepared by following the procedure of example 176, c-i but replacing dimethylamine hydrochloride with ammonium hydroxide.

I

H-NMR (CDCl 3 8: 1.50(6H,s), 1.67-1 .72(2H,m), 1.96-2 .09(3H,m), 2.36- 2.70(8H,m), 5.30(2H-,brs), 5.70(1H,brs), 6.05(1H,t), 6.75-6.90(4H,m), 7.25- 7.44(5H,m), 7.58(1H,dd), 8.49(IH,dd).

MS mlz: 548(M-Il) Example 212: 4-(4-Chlorophenyl)-l 1-dihydro-7-(l1-methylaminocarbonyl- 1methyl)ethyloxy[ I ]benzox epinolj2,3 -blpyridin-5 -ylidene)propyl~piperidin- 4 -oI The titled compound was prepared by following the procedure of example 176, 1 5 but replacing dimethylamnine hydrochloride with methylamnine.

H-NM (CDCI 3 8: 1.47(6H,s), 1.67-1 .72(2H,m), 1 .96-2.09(2H,m), 2.20(1 H,brs), 2 .36-2.70(SH,ni), 2.87(3H,d), 5 .29(2H-,brs), 6.04(IH,t), 6.72-6.86(4H,m), 7.27-7.44(5H,m), 7.58(1H,dd), 8.47(IH,dd).

MS mlz: 562(M+1) Example 215: 4-(4-Chlorophenyl)-l I [3-(7-(2-dimethylainfocarboxy)ethelyl-5,1 11dihydro[ I ]b enzox epino [2,3 -b~pyi din-5 -yl iden e)propyl ]piperi dil- 4 -ol .The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 172.

1 H-NMR (CDCI3) 8: 1.63-l.71(3H,m), l.98-2.10(2H,ni), 2.35-2.72(8H,m), 3.07(3H,s), 3.1 7(3H,s), 5.36(2H,brs), 6. 16(lH,t), 6.76(lE-I,d), 6.84(lH,d), 7.28-7.45(7H,m),

-III-

7.59-7.65(2H,m), 8.52(1H,dd).

MS m/z: 544(M+l) Example 218: 1 -[3-(7-(2-Carbamoyl)ethyl-5,1 1-dihiydro[I1]benzoxepino[2,3-b]pyridin-5yli1den e)propyl] -4-(4-chloroph enyl)-p iperi di n-4-o The titled compound was prepared by following the procedure of example 18 1, but replacing the product of example 133 with the product of example 123.

1 H-NMR (GDCI 3 6: 1.65-1.90(3H,m), 2.l0-2.22(2H,m), 2.40-2.80(1 OH,m), 2.91 5.31 -5.46(4H,m), 6.1 1(1H,t), 6.78(1H,d), 7.01(1 H,dd), 7.1 6(lH,d), 7.28-7.46(5H,m), 7.57(1H,dd), 8.49(1H,dd).

M,,S m/z: 518(M+1) Example 234: 1 I -Dihydro-7-rnethoxy[I1]benzoxepino[2,3-bjpyridin-5yl idine)propyl]-4-(indol--3yl)-pipendine The titled compound was prepared by following the procedure of example 45, step 3, but replacing 4-(4-ch lorophenyl)-4-hydroxypiperi dine with 4-(Indol1-3 -yl)-piperi dine. This piperidine was prepared by the same method described in J led Chin. 36:4006-4014 (1993) and follow hydrogenationi described in Example 58, step 3.

'H-NMR(CDC1 3 d: 1.65-1.93(2H,rn), 1.94-2.28(4H,m), 2.34-2.70(4H,in), 2. 8 1(1 2.96(2H,mn), 3.78(3H,s), 5.28(2H,brs), 6.09(1 6 7

O-

7 4 2 (sl-i,r), 7.53-7.72(2H,ni), S.28(1H,brs), 8.49(IH,rn).

Example 23 5: 1 -Dihydro-7-methoxy[1 ]benzoxepino[2,3-b]pyridin-5ylidine)propyl]-4-(indol-3-yl)- 1, 2 ,3,6-tetrahydropyridine.

The titled compound was prepared by following the procedure of example 45, step 3, but replacing 4-(4-chl orophenyl)-4-hydroxypiperi dine with -112- 4-(indol-3-yl)-1,2,3,6-tetrahydropyridine. This piperidine was prepared by the same method described in J Med. Chem. 36:4006-40 14 (1993).

'H-NMR (GDCI 3 d: 2.35-2.77(8H-,m), 3.06-3.26(2H,m), 3.78(3H,s), 5.29(2H,brs), 6.05-6.22(2H,m), 6.70-6.8 8(3H,m), 7.07-7.3 8(5H,m), 7.60(l H,dd), 7.87(l H,m), 8.42(IH,brs), 8.50(IH,m).

Example 236: 4-(4-Chlorophenyl)- l-[3-(5,l1 -dihydro-7-(3- (ethoxycarbonyl)propyloxy[ 1 ]benzox ipino[(2,3 -b ]pyri din- 5-yli dine)propyl] piperidin e The titled compound was prepared by, following the procedure of example 153, but replacing ethyl bi-omoacetate with ethyl 4-bromobutyrate.

'H-NMR (CDCL 3 5: l.26(3H,t), l.56-l.85(4H,m), 2.0l(2H,dt), 2.09(2H,quint), 2.30-2.60(7H,m), 2.93(2H,m), 3.98(2H,t), 4.15(2H,q), 5.28(2H,brs), 6.07(1H,t), 6.68-6.86(3H,m), 7.07.7.33(5H,m),7.58(lH,dd), 8.50(IH,dd).

MS m/z:561(M+1) 1 5 Example 237: 1 -[3'-(7-(3-Carboxypropyl)oxy-5,1 1-dihydro-[1 ]benzoxepino)[2,3)b] pyridin-5-ylidi ne)propyl] -4-(4-chloropheflyl)-piperi dine The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 236.

'H-NMJR (CD 3 OD) 5: 1 .92-2.20(6H,rn), 2.48(2H,t), 2.70-3.02(3H,m), 3.06- 3 .45(4H4,n), 3.66(2H,m), 4.01 5 .48(2H,brs), 6.36(1 6. 85(2H,s), 7.00(lH,s), 7.20-7.40(4H,m), 8.1 1(IH,dd), 8.64(1H,d), 8.81 COOH- signal was not observed.

MS mlz: 533(M+1) Example 242: 4-(4-Chlorophenyl)- 1 11 -dihydro-7-( 1 -hydroxy- 1 methyl)ethyl[ I ]benzoxepino[2,3 -bl~pyridin-5 -yliden e)propyl ]piperi din-4-ol The titled compound was prepared by following the procedure of example 200, but replacing the product of example 48 with the product of example 273.

-113-

I

1.93-2.21 (2H,rn), 2.28-2.73(8H,m), 5.32(2H,brs), 6.1 3(IH,t), 6.82(lH,d), 7.20- 7.50(7H,m), 7.59(1 H,dd), 8.50(1 H,dd) MS ml/z: 505(M+l) Example 243: 1 I-Carboxy-l1-methyl)ethyl-5, 11 -dihydro[ I]benzoxepino [2,3-b]pyridi~n-5ylidene)propyl] -4(4-chlorophenyl)piperi din-4-oI Step 1 To a solution of Example 363, step 2 (2.4 g)in toluene (30 ml) was added DIIBAL (1 mollL toluene solution, 9.2 ml) at -78 0 C, and the mixture stirred at 0 0 C for I hour, and at room temperature for 30 minutes. The reaction mixture was added saturated aqueous ammonium chloride. 1 N aqueous hydrochloric acid, sat-urated sodium chloride and ethyl acetate were added to the mixture, the organic layer Was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to give 5-(3-bromopropylidene)-5, 1 I1-dihydro-7-(l -hydroxy-1Imethy])ethyl [I ]benzoxepino[2m30b]pyri dine (2.0 g).

'H-NUvR (CDCI 3 5:I.45(H,s), 2.75(2H,q), 3.47(1H,t), 5.33(2H, brs), 6.04(l H,t), 6.87(1IH, 7.09-7.14(2H, in), 7.30(11-, dd), 7.57(lH, dd), 8.53(IH, dd), 9.46(1 H,s).

Step 2 5-(3-bromopropylidene)-7-( I-carboxy-l1-methyl)ethyl-5, 11 -dihydro[l1]benzoxepino [2,3-b]pyridine was prepared by following the procedure of Example 382, step 2, but replacing the product of Example 382, step 1 with the product of step I above.

Step 3 -114- The titled compound was prepared by following the procedure of example 44, step 2, but replacing the product of example 44, step 1 with the product of step 2.

(DMSO-d6) 8:1.46(6H, 1.63-1.84(2H, in), 2.17-2.37(4H, in), 2.37- 2.53(4H, mn), 3.20-3.43(2H, in), 4.83(IH, 5.23(2H, brs), 6.13(1K, 6.76(1K, d), 7.16(IH, dd), 7.25(1K, 7.35(2H, 7.42-7.48(3H, mn), 7.76(1H, dd), 8.50(1K, dd). MS m/z:533(M+1) Example 248: 1 -Dihydro-7-methoxy[l1 benzoxepino[2,3-b~pyridin-5yl idine)propyl]-6-methylspiro[4K-3 ,1 -benzoxazine-4,4'-piperidine] -2(1 H)-one The titled compound was prepared by following the procedure of example 45, step 3, but replacing 4-(4-ch lorophenyl)-4-hydroxypiperi dine with 6methiylspiro[4K-3 -benzoxazine-4,4'-pipendin)-2( 1H)-one.

'H-NMR (CDCI 3 5: 1.99-2.06(2H,m), 2.29(3K,s), 2.32-2.69(IOH,m), 3.77(3)H,s), .27(2H,brs), 6.09(l 6.69-6.83(4H,in), 6.94(IH,s), 7.02(1H,d), 7.25(1 H,dd), 7.55(1H,dd), 8.48(lH,dd), 8.56(IH,s).

MSmni/z: 498(M+1) Example 249: 5-(4-Chlorophenyl)- 1 ,11 -dihydro-7methioxy[ I]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4,6-diox azacane.

-(4-Chlorophenyl)- 1 -dihydro-7-methoxy[ I ]benzoxepino[2,3-b]pyridifl-5yli)den e)propyl] -4,6-di azacyclooctylamine Stepl 5-(3-(N,N'-Bis(2-hydroxyethyl)amino)propyli dene)-5,1 I -dihydro-7methoxy[ I ]benzoxepino[2,3-b]pyridine was prepared by following the procedure of example 45, step 3, but replacing 4-(4-chloroph enyl)-4-hydroxypiperidina with diethanolamine.

H-NMR (CD 3 OD) 8: 2.46(2K,m), 2.84(4H,t), 2.98(2H,m), 3.67(4H,t), 3.7 5(3H-,s), 5.20(2H,brs), 6.16(IH,t), 6.68-6.80(2H-,m), 6.87(1H,d), 7.46(IH,dd), 7.81 (IH,dd), 8.45(lH,dd).

-115- Step2 To a mixture of product of step 1 (78mg) and 4-chlorobenzaldehyde dimethyl acetal (0.lml) in 1,2-dichloroethane (60ml) was added p-toluenesulfonic acid monohydrate (5mg) at room temperature, and the mixture was stirred at reflux for 12 hours. Dichloromethane and saturated aqueous sodium bicarbonate was added to the cooled reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with dichloromethane-methanol (20:1) to give the titled compound 1 H-NMR (CDC1l) 8: 2.35(2H,m), 2.64-2.94(6H, m), 3.52-3.68(2H, 3.78(3H,s), 3.72-3.90(2H,m), 5.27(2H,brs), 5.66(1H,s), 6.08(1H,t), 6.68-6.88(3H,m), 7.18-7.46(5H,m), 7.58(1H,dd), 8.50(1H,dd).

Example 252: Step 1 To a cold stirred solution of 4-oxohomopiperidine*HCI (0.6 g, 4.05 rnmol),

KCO

3 (0.615 g, 4.46 mmol) in anhydrous THF (10 mL) will be ethyl chloroformate (0.44 mL, 4.05 mmol) dropwise. The reaction was warmed to RT for 2 hrs then quenched with H 2 0, extracted with EtOAc, and the organic layer dried over Na 2

SO

4 Pure l-ethylcarbonyl-4-oxohomopiperidine will be isolated via silica gel flash chromatography Step 2 To a cold stirred solution of 1-ethylcarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 mL) under argon can be added dropwise l.o mM 4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 1Ommol). The reaction can be warmed to RT for 2 hrs then quenched with saturated aqueous NH,C] mL). The reaction mixture can then be extracted with EtOAc (2 X 50 mL), the organic layers combined and dried over NaSO. Pure 1-ethoxycarbonyl-4-(4chlorophenyl)-4-hydroxyhoflopeperidifle (2.1 g, 96%) can be isolated via silica gel flash chromatography eluting with 50% ETOAc/hexane.

4-(4-chlorophenyl)-4-hydroxyhomopiperi dinle can be prepared by reacting I1etoyabnl4(-hoohnl--yrxhmpprdn with a nucleophiIi c hydroxide equivalent such as LiOH in a solvent such as THF, methanol or ethanol.

Removal of the solvent can afford 4-(4-chlorophenyl )-4-hydroxyhomopep eridine.

Step 4 The compound was prepared by following the procedure for Example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypeperi dinle with 4-(4-chlorophenyl hydroxyhomopeperidine.

Examples 253 and 254: Step I To a stirred solution of 4- oxohornopiperidine* HCl (1.2 g, 8.05 mmol), NaGH (0.68 g, 16.9 mmnol) in t-BuOHIH 2 10 mL) was added t-butyldicarbonate (1.93 m.L, 8.9 mmol) drop-wise. The reaction was stirred at RT overnight, extracted with EtOAc (2 X 10 mnL) and the organic layer separated. The organic layer was dried over Na 2

SO

4 and concentrated under vacuo. Pure 1 -t-butoxycarbonyl-4oxohomopiperidifle (1.42 g, 84%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 'H NMR CDCI 3 5: 44 (9H1, 1.72-1.84 (2H, in), 2.60-2.65 (4H, in), 3.55-3.61 (4H, mn).

Step 2 To a cold (0 0 C) stirred solution of 1 -t-butoxycarbonyl-4-oxohomopiperidifle (1.42 g, 6.07 inmol) in anhydrous THYF (5 0 m.L) under argon was added dropwise 1. .0 M 4chiorophenylnagnesium bromide in diethyl ether (10 inL, 10 inmol). The reaction was warmed to RT for 2 his then quenched with sat'd aqueous NHCI (5 mL). The reaction mixture was extracted with EtOAc (2 X 50 mL), the organic layers combined and dried over Na 2

SO

4 Pure I -t-butoxycarbonyl-4-(4-chloropheflyl)- 4 hydroxyhoinopiperidine (2.1 g, 96%) was isolated via silica gel flash c-I -117chromatography eluting with 50% EtOAc/hexane. 'H NMR CDCI 3 5 1.43 (9H,s), 1.61-2.22 (6H, in), 3.21-303 1 (2H, in), 3.48-3.82 (2H, mn).

Step 3 N- To a stirred solution of I -t-butoxycarboniyl-4-(4-chloropheny])-4ydroxyhomopiperi dine (2.1 g) at RT in CHC 2 (48 mL) was added TEA (2.0 MrL).

The reaction was stirred at RT for 2 hrs. Excess solvent and TFA was removed affording 2.0 g (92% yield) 1: 1 mixture of 3-(4-chlorophenyl)-2,3dehydrohomopiperidine and 3 -(4-chlorophenyl)-3 ,4-dehydrohomopiperidine. 'H NMR (MeOD, isomer A) 6 2.01-2.11 (2H, m, 2.60-2.71 (2H, mn, 2.8 1-2.92 (2H, mn, 2.83 -3.05 (2H, mn, 3.66-3.92 (4H, m, 6.16-6.21 (1LH, t, H NMvR (MeOD, isomer B) 3.44-3.56 (2H, m, 3.88-3.97 (2H, in, 6.01-6.12 (111 t, 7.32-7.44 (IH, t, 4).

Step 4 The compounds can bez prepared by following the procedure for Example 44 but replacing 4-(4-chlorophenyl)-4-hydroxypip eri dine with 3-(4-chlorophenyl)-3,4dehydrohornopi peri di ne and 3-(4-chlorophenyl)-4,5-dehydrohomopiperidine.

Example 255: 1 -(4-Chlorophenyl)-4-[3-(5,1 I -dihydro-7-hydroxy[ I )benzoxepino[2,3-b]pYridin-s..

ylidene)propyl] piperazinone The titled compound was prepared by following the procedure of example 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with 1-(4chlorophenyl)piperazinone.

1 H-NMR (DMSO-d 6 5: 2.30-2.34(2H,mn), 2,49-2.57(2H,m), 2.68(2H,Q, 3..O6(2H,s), 3.58(2H,t), 5,12(2H,hrs), 6.06(2H,t), 6.57-6.69(3H,m), 7.35-7.71 7.72(lH,dd), 8.48(1H,dd).

Example 256: 1 -(4-Chlorophenyl)-4-[3-(S, 1-dihydro-7-hydroxy[ 1 ]benzoxepino[2,3-b]pyridn-5yl idene)p ropy] ]homopi perazdine -118- The titled compound was prepared by following the procedure of example 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydoxypiperidifle with 1-(4chlorophenyl)homopiperazdine.

H-NMIR (CDCI 3 6: 1 .89(2H,brs), 2.27-2.35(2H,m), 2.5 1-2.70(6H,m), 3.37-3.53(4H,rn), S.23(2H,brs), 5.98(1H,t), 6.48-6.74(6H,m), 7.05-7.26(2H,m), 7.52(IH,dd), 8.45(1H,dd).

MS m/z: 462(M+1) Example 260: 3-(4-Chlorophenyl)-8-[3-(5, 1-dihydro-7-hydroxy[ I ]benzoxepino[2,3-b]pyridifl-5ylidene)propyl]-8-azabicyclo[ 3 .2.1 ]octan-3-ol The titled compound was prepared by following the procedure of example 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dinle with 3-(4chilorophenyl)-8 -azabicyclo[ 3 2 1l]octan-3 -ol

H-NMR(CDCI

3 5:1.65-2.1 0(4H,m), 2.1 3.32(2H,bs), 3.78(31-I,s), 5.24(2H,bs), 6.10(1 H,dd), 6.70-6.90(3H,m), 7.15-7.3 1(311,r), 7.45(bd,2H), 7.64(dd,1I-) 8 .46(dd, 1 H) MIS mlz: 503(M+1) Example 261: 1 '-(4-Chlorophenyl)- 1 -dihydro-7 -hydrox y[ I] benzox epino[2,3 -b]pyri dinl- ylidene)propyl] spiro[5-chloro-1I,3-benzodioxole-2,4'-piperidine] The titled compound was prepared by following the procedure of example 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperi dine with spiro[5-chloro- 1,3 benzodiox ole-2,4'-piperi dine] (Journal of/Medicinal Chemistry. 1995, 38, 2009- 2017).

1 H-NMvR(DMSO-d 6 6: 1.78-2.02(4H1, in), 2.18-2.63(8H, in), 4.97-5.27(2H-, brs), 6.06(111, 6.58-6.67(3H, in), 6.79-6.87(2H, in), 6.99(IH, 7.42(1 H, dd), 7.72(lH, dd), 8.49(IH, dd), 9.07(IH, -119s).

Example 262: I -Carbamoyl1-methyl)ethyloxy-5, 1-dihydro[lI]benzoxepino[2,3 b]pyri din -5 -ylidene)propyl] -4-(4-chloroph enyl)-4-hydroxy- 1 -methylpiperidinium iodide To a solution of the productof example 211 (330mg) and in acetonitrile (1.2m1) was added iodomethane (0.07ml), and the reaction mixture was stirred at room temperature for 2 hours. The precipitation was filtered and washed with acetonitrile to give the titled compound (250mg).

H-NIMR (DMSO-d 6 5: I.39(6H,s), 1.65-l.8S(2H,m), 2.20-2.64(4H,m), 3.09(3H,s), 3.30-3.65(6H,m), 5.20(2H,m), 5.61(1H,s), 6.01(1 H,t), 6.75-6.92(3H,m), 7.27(1H,s), 7.38-7.64(6H,m), 7.83(lH,dd), 8.56(IH,dd) MS mlz: 562[(M-D+] Example 263: 4-(4-Chlorophenyl)- 1 3 -di ethyl aminocarbonylm ethyloxy- 5,11 dihydro[ I ]benzox epi no [2,3 -blpyridin- 5-yli den e)propyl ]pip eridin-4-ol The titled compound was prepared by following the procedure of example 134,* but replacing dimethylamine hydrochloride with di ethylarnine.

1 H-NMR (CDCI 3 6: 1.67-i .72(2H,m), 1.99-2.1 0(2H,m), 2.362.7(9Hm),2.8(3Hd),4.45(2H-,s), 5.28(2H,brs), 6.08(1I-,t), 6.66(I,brs), 6.73-6.84(3H,m), 7.25-7.45(5H,rn), 7;58(IH,dd), 8.47(1H,dd).

MS mlz: 534(M+l) Example 268: 4-(4-Chlorophenyl)- 11 -dihydro-7methylaminocarbonyl [1]benzoxepino[2,3blpyr-idin-5-ylidene)propyl]piperidin-4-oI -120- The titled compound was prepared by following the procedure of example 198, but replacing dimethylamine hydrochloride with methylamnine.

'H-NN4R (DMSO-d6) 8: 1.75-1.80(2H, mn), 2.38-2.50(2H, mn), 2.63-2.73(2H, mn), 2.78(3H,d), 3.17-3.50(6H, in), 5.38(2H, brs), 6.36(IH, 6.87(lIH, 7.41 7.50(4H, in), 7.55-7.99(4H, mn), 8.48-8.50(1H, in), 8.6 1(1W, dd).

MS inlz: 504(M+1) Example 269: 1 -43-(7-Carbamoyl-5, 1-dihydro[ 1 benzoxepinojl2,3-b]pyridin-5-ylidene)propyl]-4- (4-chlorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of example 198, but replacing dirnethylamine hydrochloride with ammonium hydroxide.

H-NMR (CDCl 3 5: 1.67-1 .79(2H,m), 2.01-2.1 0(2H,m), 2.1 7-2.71.(8H,m), 5.38(2H,brs), 6.2] 6.85(1H,d), 7.27-7.57(9H,m), 7.90(lI-l,dd), 8.50(lIH,dd).

MSin/z: 490(M+l) Example 270: 4-(4-Chlorophenyl)- 1 -(3-(7-diethylaminocarbonyl-5, 11dihydro 1 ]benzox epino pyri din- 5-yli dele)propyllpi fdin 4 -olI The titled compound was prepared by following the procedure of example 198, but replacing dimethylamine hydrochloride with diethylamine.

MS ni/z: 546(M+1) Example 273: 4-(4-Chlorophenyl)-l1-[3-(5,1 1-dihydro-7-(methoxycarbonyl[l] benzoxepino[2,3b ]pyri din-5 -ylidene)pT)pyI] pip eridin -4-ol A mixture of the product of example 169 (15.0g), palladium(II) diacetate (170mg), 1 ,3-bis(diphenylphosphiflo)propane (310mg), and triethylamrine in methanol (I Q0mi) and dimethylfornainide (I 50in1) was purged with carbon -121monoxide for 5 minutes and stirred under a carbon monoxide balloon at 70-C for 8 hours. The reaction mixture was evaporated under reduced pressure. The residue was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate methanol 10: 1) to give the titled compound(1 3.l1g).

'H-NMR(CDC

3 5: 1.45-1.80 1.90-2.15 (2H,ni), 2.28-2.48 (4H,rn), 2.50-2.75 (4H,rn), 3.89(3H,s), 5.25-5.50(2H,m), 6.20(lH,dd), 6.85(1H,d), 7.20-7.37(3H-,m), 7.42(21-,d), 7.58(1H,d), 7.80(lH,dd), 8.01 (IH,dd), 8.52(IH,dd) MS mlz: 505(MvI) Example 274: 4-(4-Chlorophenyl)- 1-dihydro.7-hydroxymethyl[ I ]benzoxepiino[2 .3b]pyridin-5-yldene)propyl]piperidin-4-oI To an ice-cooled solution of the product of example 273 (2.0g) in tetrahydrofuran (1 O0ml) was added lithium aluminum hydride (3 00mg), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction mixture was cooled to 0 0 C, water (0.3m1), 1 5% sodium hydroxide aqueous solution and water were added. The reaction mixture was filtered, and the filtrate was dried over magnesium sulfate. The solvent was evaporated under reduced pressuire and the residue was purified by silica gel columrn chromatography (chloroform: methanol 28% ammnonia in water 100 5 1) to give the titled compound 0l.6g).

'H-NMIR (CDCI 3 6: 1.55-1.71 1 .95-2.25(2H,m), 2.34-2.70(8H,m), 4.62(2H,s), 5.20-5.45(2H,brs), 6.1 6.84(1H,d), 7.1 6(IH,dd), 7.23- 7.43(6H,m), 7.58(IH,dd), 8.5 1(IH,dd) MS mlz: 477(M+1) Example 275: 4-(4-Chlorophenyl)- 1 -dihydro-7-(1 -propyl amino)m ethyl -122- [1 ]benzoxepino[2,3 -b~pyri din- 5-ylidene)propyl ]pip eridin-4-ol To a solution of the product of example 314 (300mg) and I1-propylarnine (0.26m1) in tetrahydrofuran (6 ml) was added acetic acid (0.36m1), and the reaction mixture was stirred at 60*C for 30 minutes. Then the reaction mixture was added sodium triacetoxyborohydride (670mg) at 0 0 C and stirred for 1.5 hours at room temperature. Sodium bicarbonate, water, and chloroform were added to the reaction mixture. The organic layer was extracted, and dried over potassium carbonate, and evaporated under reduced pressure. The residue was recrystallized with ethyl acetate to give titled compound (130mg).

'H-NMvIR (CDC]3) 6: 0.92(3H,t), 1.49-l.70(6H,m), 1.98(2H,m), 2.34-2.42(4H,m), l-2.70(6H,m), 3.71 5.32(2H,brs), 6. 12(l 6.8 1(1IH,d), 7.11 (1 H,dd), 7.25-7.45(6H,m), 7.57(1H,dd), 8.49( lH,dd).

MS mlz: 518(M-s-) Example 276: 4-(4-Chlorophenyl)- 1 11 -dihydro-7-(3-hydroxy- 1 propyl am in o)methyl[ 1 ]benzoxepino[2,3-b]pyridin-5-ylidene)propyl~piperi din-4-ol The titled compound was prepared by following the procedure of Example 275, but replacing I -propylamine with 3-amino-]I -propano].

MS mlz:534(M+I) Example 277: 4-(4-Chlorophenyl)- 1-dihydro-7-( 1-piperidino)methyl[ I ]benzox epino[2 ,3b]pyridin- 5-ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 275, but replacing I1-propylamine with piperidine.

MS ml~z: 544(M+l) Example 278: 4-(4-Chlorophenyl)-i 1-[3-(5,l1 1-dihydro-7-(4c-I -123morpho lino)m ethyl I benzoxepino[2,3 -b]pyridin-5 -ylidene)propyl]piperidin-4-ol N The titled compound was prepared by following the procedure of example 275, but replacing. I -propylamine with morpholine.

IND MS mlz: 546(M+1) Example 279: 4-(4-Chlorophenyl)- 1 11 -dihydro-7-(1 -pyrroli dino)m ethyl [I ]b enzox epino [2,3 -blpyidin- 5-ylidene)propyl] piperi din-4-ol The titled compound was prepared by following the procedure of Example 275, but replacing I1-propylamine with 4-aminobutyric acid.

H-NMR (CDCl 3 5: 1.70-1.75(2H,m), 1.98(2H,m), 2.1 2-2.23(2H,m), 2.40-2.86(1 OH,m), 3.27(2H,t), 4.36(2H,s), 5.29(2H,brs), 6.07(lH,t), 6.80(IH,d), 7.04(IH,dd), 7.19(lH,d), 7.28-7.32(3H,m), 7.50(IH,t), 7.61(lH,dd), 8.51 (1H,dd).

MS m/z: 544(M+1) Example 280: 4-(4-Chlorophenyl)- I -dihydro-7-(2-hiydroxy)erhlyl[lI]benzoxepi no [2,3bipyri din-5-ylidene)propyl] piperidin-4-ol The titled compound was prepared by following the procedure of example 273, but replacing the product of example with the product of example 274.

H-NMR (CDCI 3 5: l.60-1.70(4H,m), 2.0l-2.12(2H,m), 2.3 7-2.70(SH,rn), 2.81 3.84(2H,t), 5.31 (2H,brs), 6.09(l 6.81 I,d), 7.03(IH,dd), 7.15(IH,d), 7.26-7.43(5H,m), 7.57(1H,dd), 8.49(1H,dd).

MS m/z: 491(M+1) Example 28 1: I -[3-(7-Carbarnoylmethyl-5,1 1-dihydro[ 1 ]benzoxepino[2,3-b]pyridin-5yli dene)propyl] 4-(4-chl orophenyl)-piperidin-4-o I -124- The titled compound was prepared by following the procedure of example 122, but replacing dirnethylamine hydrochloride with ammnoniumn hydroxide.

H-NMiR (CDC1 3 6: l.65-1.70(2H,m), 1.98-2.06(2H,m), 2.27-2.70(9H,m), 3.46(2H,s), 5.30(2H,brs), 5.74(1H,brs), 6.04(lH,brs), 6.09(lH,t), 6.79(11-,d), 7.02(1H,dd), 7.18-7.41 (6H,ni), 7.54(1H,dd), 8.43(1H,dd).

MS mlz: 504(M+1) Example 288: 4-(4-Chlorophenyl)- 1 -[3-(7-(2-ethoxycarboxy)ethy]-5,11Idihydro[ 1 ]benzoxepino[2,3blpyridin-5-ylidele)propyI]piperidifl- 4 -ol The titled compound was prepared by following the procedure of example 165, but replacing the product of example 164 with the product of example 31-0.

H-NMR (CDCI 3 8: 1 .23(3H,t), 1.63-1.71 (3H,m), 1.98-2.1 O(2H,m), 2.3 5-2.7 1(1 OH,m), 2.89(2H,t), 4.1 3(2H,q), 5.3 1(2H,brs), 6.08(IH,t), 6.78(IH,d), 7.00(IH,dd), 7.12(IH,d), 7.26-7.44(5H,m), 7.57(IH,dd), 8.49(lH,dd).

MIS mlz: 548(M+l) Examiple 289: 4-(4-Chlorophenyl)- I -[3-(7-(l1-(3-hydroxy)propyl)-5, 1-dihydro[ I]benzoxepino[2,3b]pyridin-5-ylidene)propyl]piperidin-4-oI The titled compound was prepared by following the procedure of example 133, but replacing the product of examiple 48 with the product of example 288.

H-NMR (DMSO-d 6 5: 1.45-1 .50(2H,m), 1.66-1 .80(4H,m), 2.26-2.57(1 OH,m), 3.41 4.46(IH,t), 4.83(lH,s), 5.23(2H,brs), 6.14( 1H,t), 6.71(lH,d), 7.01(IH,dd), 7.13(1H,d), 7.34-7.48(5H,m), 7.72(1H,dd), 8.49(IH,dd).

MS rn/z: 505(M+1) Example 290: c-I -125- 4-(4-Chlorophenyl)-* 11 -dihydro-7-(2,3dihydroxy)propyl I1 ]benzoxepino [2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol To a solution of product of example 170 (6.9g) in tetrahydrofuran (70ml) and c-i water (14m1) were added N-methylmorpholine oxide(1.7g) and osmium tetraoxide at 0 0 C, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the mixture, the aqueous layer was separated. Chloroformn-isopropanol 1) was added to the aqueous layer, the organic layer was extracted, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give the titled compound 'H-NMR (CDCI 3 6: 1.65-1.73(2H,m), 1.95-2.l0(2H,m), 2.30-2.75(1 3H,m), 3.45-3.50(IH,rn), 3.60-3.65(1H,m), 3.83-3.90(1H,m), 5.28(2H,brs), 6.06(lH,t), 6.84(IH,d), 7.03(l H,dd), 7.15(]Ii,d), 7.26-7.43(5H,m), 7.57(IH,dd), 8.49(IH,dd).

MS 521(M+1) Example 291: 4-(4-Chlorophenyl)- I -d ihydro-7-phenyl[ I] benzo xepino [2,3-b]pyri din-5 yl idene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 170, but replacing allyltributyltin with phenyltri butyltin.

'H-NMIR (CDCI3) 6: 1.84-1..92(2H, in), 2.85-3.40(l10H, in), 5.33(2H, brs), 6.05(I,t), 6.95(lH, 7.30-7.58(12H, mn), 7.63-7.66(l1H, mn), 8.56-8.58(l11i, m) MS m/z: 523(M-t-) Example 292: 4-(4-Chlorophenyl)- 1 41-dihydro[I1]benzoxepino[2,3-b]Pyridin-5ylidene)propyl)piperidin-4-ol The titled compound was prepared by following the procedure of example 170, but replacing allyltributyltin with ethyl (2-furyl)tributyl tin.

I

H-NMvR (CDCI 3 6: 1.70-1.80(3H,m), 1.97-2.16(2H,m), -126- 2.3-2.8(8H,m), 5.36(211,m), 6. 19(1H,t), 6.45(1H,dd), 6.55(1H,d), 6.87(1H,d), 7.20- 7.50(7H,m), 7.60-7.65(2H,m), 8.52(1H,dd) MIS mlz: 5l3(M+1) Example 293: 4-(4-Ghlorophenyl)- 1-[3 -(7-ethoxycarbonylamino-5,1 I dihydro[l1]benzoxepino[2,3 -b]pyridin-5 -ylidine)propyl]piperidin-4-ol A mixture of product of example 118 (490mg) and diphenyiphosphonic; azide (0.28m]) was stirred at 1 I0 0 C for 30minutes. After the mixture was cooled, and triethylamine 14m1) and ethanol (5mi) were added, and the mixture was heated to reflux for 8 hours. The reaction mixture was diluted with ethyl acetate and filterd through Celite. The filtrate was washed with saturated aqueous sodium bic-arbonate, and dried over magnesium sulfate. The solvent,waS removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform methanol 10 1) to give the titled compound (2 I H-NMR (CDC1 3 8 1.31 1.65-1 .70(2H,m), 2.01 -2.09(2H,m), 2.36-2.70(8H,m), 4.21 5 .30(2H,brs), 6.1 3(IH,t),.

6.46(IH,brs), 6.80(1H,d), 7.02(IH,dd), 7.28-7.50(6H,m), 7.57(IH,dd). 8.50(IH,dd).

MS rnlz: 534(M-tH) Example 294: I -[Bis(ethoxycarbonylmetyl)miethoxy-5, I1 -dihydro[ I]benzoxepliio[2,3-b)pyridin-5yl i den e)propyl] -4-(4-chlorophenyl)-piperidin -4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with diethyl bromomnaloriate.

H-NMR (CDCI 3 8: 1.30(3H,t), 1.66-l.71(2H,m), I .98-2.09(2H,m), 2.35-2.69(9H,m), 4.30(2H,q), 5.14(IH,s), 5.26(2H,brs), 6.1 0(1H,t), 6.78(2H,d), 7.00(lH,t), 7.26-7.45(5H-,m), 7.57(1H,dd), 8.43(IH,dd).

MS mlz: 621(M+1) -127- Example 295: I1-[l, 1-Bis(ethoxycarbonylmetyl)ethyloxy-5,1 1-dihydro[ 1 ]beazoxepino[2,3 -ylidene)propyl]-4-(4-chloropherlY)-PiPeridil- 4 -oI The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with diethyl 2-bromo-2-methylnialonate.

H-NMR (ODCd 3 6: 1 .27(6H,t), 1 .65-1 .70(5H,m), 1 .99-2.08(3H,m), 2.31 -2.69(8H,m), 4. 28(4H,q), 5 .27(211,brs), 6.06(1 H,t), 6.72(IH,d), 6.80(IH,dd), 7.00( lH,d), 7.27-7.45(5H,mr), 7.56(1H,dd), 8.46(1H,dd).

Example 296: 4-(4-Chlorophenyl)-l1-[3-(5, 11 -dihydro-7-(2-hydroxy- 1hydrox ym eth yl)ethyl oxyl 1 ]benzoxepino 2,3 -b]pyridin- 5-ylidene)propyl ]pip eri difl- 4 ol *The titled compound was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of example 294.

1 H-NMvIR (CDC] 3 6: 1.70-l.75(2H,rn), 2.10-2.80(l lH,rn), 3.90(4H,d), 4.36(IH,quint), 5.28(2H;brs), 6.13(1 6.71 -6.87(2H-,rn), 7.00(IH,d), 7.29- 7.45(5H,m), 7.58(11-,dd), 8.51(IH,dd).

MS mlz: 537cM+1) Example 297: 1 I-Bis(hydroxymetyl)ethyloxy-5, 1-dihydro I ]benzoxepino[l2,3-bjpyridin-5yli dene)propylj -4-(4-chlorophenyl) -pip eri din- 4 -ol The titled compound was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of example 295.

H-NMVIR (CDCd 3 5: l.09(3H,s), 1.66-l.71(2H,m), 1.90-2-.l0(3H,m), 2.37-2.75(SH,m), 3.72-3.82(4H,m), 5.29(2H,brs), 6.05(lyi-,t), 6.77(lH,d), 6.88(IH,dd), 7.03(lH,d), 7.26,.7.43(511,m), 7.56(1H,dd), 8.48(LH,dd).

MS m/z: 551(M+1) -128- Example 299: 4-(4-Chlorophenyl)-l ethoxycarbonylpropyl)oxy[ 1 ]benzoxepino [2,3 -b]pyridin-5-yli dene)propyl]piperi din- 4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with ethyl 4-broinobutyrate.

'K-NMR (CDCl 3 8: 1.24(3H, 1.65-1.69(2K, in), 1.96-2.12(4K, in), 2.26- 2.67(l OK,m), 3.96(2H, 4.12(2K, 5.24(2H, brs), 6.08(1H, 6.70-6.83(3K, mn), 7.21-7.59(6K,m), 8.39(1H, dd).

Example 300: I -[3-(7-(3-Carboxy-l1-propyl)oxy-5,l I-dihydro[ 1 ]benzoxepiino[2,3-b]pyri din-5 ylidene)propyl]piperidi n-4-ol The. titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 299.

'H-NMiR (DMSO-d6) 5: 1.41-1.95(2K, mn), 1.41-1 .95(4H, in), 2.20-2.72(1 OK, mn), 3.95(2H,t), 5.1 8(2K, brs), 6.1 7(IH, 6.72-6.84(3H, in), 7.36-7.48(5H, mn), 7.77(1K, dd), 8.50(1K, dd).

MS ink: 549(M+1) Example 30 1: 4-(4-Chlorophenyl)- 11 -dihydro-7-(4methoxycarbonylphenyl)inethoxy[ I ]benzoxepino[2,3-bjlpyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with methyl 4-broinoiethylbenzoate.

'H-NMvR (ODCd 3 8: 1.66-1.70(2H, in), 1.93-2.09(3K, mn), 2.37-2.70(8K, mn), 3.91(3K,s), 5.09(2K, 5.27(2K, bins), 6.06(1K, 6.80-6.91(3H, in), 7.24-7.60(8H, mn), 8.0 1-8.07(2H, in), 8.47(1K, dd).

-129- Example 302: 1 -[3-(7-(4-Carboxypheny)methoxy-5, 1 -dihydro[I1 ]benzox epino 2,3-b]pyri din-5 yli dene)propyl ]-4-(4-chlorophenyl)piperidin-4-Ol The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 301.

'I-I-NMR (DMSO-d6) 6: 1.44-1.49(2H, in), 1.67-1.87(2H-, in), 2.26-2.56(8H, in), 4.85(IH,brs), 5.15-5.25(4H, mn), 6.17(lH, 6.72-6.95(3H, mn), 7.30-7.75(SH, mn), 7.92-7.99(2H, in), 8.48(IH, dd).

MS m/z: 597(M+1) Example 303: 4-(4-Chlorophenyl)- 1-j13-(5, 1I -dihydro-7-(( 1hydroxymethyl)cyclopropyl)methoxy[ I ]benzoxepinojl2,3-b]pyridin-5yli dene)propyllpiperi din-4-o 1 Step 1 1 1-Bcnzoyloxyinethy])cyclopropyl) methioxy-5,11 -dihydro [I ]benzox epino [2,3-b]pyridin-5 .ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol was prepared by following the procedure of example 46, but replacing ethyl iodide with (1benzoyl ox ymethyl)cyclopropylmethyl methanesulfonate.

1 'H-NMiR (CDC1 3 6: 0.70-0.81(4H, 1.65-1.70(3H, mn), 1.98-2.07(2H, in), 2.35- 2.70(8H,in), 3.9 1(2H, 4.39(2H, 5.25(2H, brs), 6.06(1H, 6.72-6.84(3H-, mn), 7.23-7.59(9H, mn), 8.02-8.06(2H, in), 8.48(lH, dd).

Step 2 The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of step 1.

'H-NMvR (CDC' 13) 5:0.62(4H,s), 1.67-l.72(2H,m), 1,96-2.06(2H,m), 2.34- 2.69(8H-,in), 3.39(1 H,brs), 3.91 3.91 5.26(2H,brs, 6.09(1H,t), 6.72- 6.86(3H,M), 7.27-7.60(6H,m), 8.48(IH,dd).

MS mlz: 547(M+1) C-I -130- Example 305: 1 ,11 -dihydro-7-(2-hydroxyethyl)aminocarbofl[ I ]benzoxepino[2,3-b]pyridin- -ylidene)propyl] -4-(4-chlorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of example 198, but replacing dimethylamine hydrochloride with 2-hydroxyehylamine.

H-NMR (CDCd 3 5: 1.65-1.70(2H,m), 2.03-2.06(2H,m), 2.21(IH,d), 2.32- 2.68(8H,m), 3.63(2H,dt), 3.83(2H,t), 5.37(2H,brs), 6.l8(1H,t), 6.67(IH,brs), 7.25- 7.54(7H-,m), 7.86(1H,dd), 8,50(1H,dd).

MIS m/z: 534(M+1) Example 306: 4-(4-Chlorophenyl)- 1 11 -dihydro-7-( 1cyclohexyloxycarboniyloxy)ethyloxycarbonyl[ I ]benzoxepino[2,3-bjlpyridin-5ylidcne)propyllpiperidin-4-ol dihydrochloride To a solution of product of example 118 (1.1lg) in dimethylformamide (1 5m1) were added sodium iodide(0.1 7g), potassium carbonate (0.38 g) and cyclohexyl 1chioroethyl carbonate Antibiotics, 1987, 40, 81.) (0.57g) at room temperature.

The mixture was stirred at 7000 for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate methanol =100 The obtained oil was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl acetate solution (0.8ml) was added. The precipitation was filtered to give the titled coinpouLnd (0.96g).

'H-NMvR (DMSO-d 6 8: 1.22-1.47(6H,m), 1 .58(3H,d), 1 .63-1.8 1(6H,m), 2.38-3.30(1OH,m), 4.07-4.59(1H,m), 5.8O(2H,brs), 6.28( I-1,t), 6.87(IH, 6.97(1H,d), 7.40-7.49(4H,rn), 7.64(IH,dd), 7.79(LH,dd), 7.96(1 H,d), 8.03(lH,dd), 8.65(1H,dd), I 1.07(IH,brs).

MS ml1z: 661 [(M-2HCI)+lI] -131- Example 307: 4-(4-Chlorophenyl)- 1 11 -dihydro-7( 1ethoxycarbonyloxy)ethyloxycarbonyl[ 1 ]benzoxepino[2,3-bjpyridin-5ylidene)propyl]piperidin-4-ol The titled compound was prepared by following the procedure of Example 307, but replacing cyclohexyl 1-chioroethyl carbonate with ethyl 1-chloroethyl carbonate.

MS mlz: 607(M+1) Example 308: 4-(4-Chl orophenyl)- 1-dihydro-7-(5-hydroxyfuran-2-yl)[I1]benzoxepino[2,3b]pyridin-S-ylidene)propyl]piperidin-4.ol Step 1 4-(4-Chlorophenyl)- I 1-dihydro-7-(5 -formylfuran-2-yl)[l1]benzoxepino[2,3b] pyri din-5 -yli dene)propyl]p ipei di n-4-o I was prepared by following the procedure of example 170, but replacing allyltributyltin with (5 -formnylfuran-2 -yl)trib utyl tin.

IH-NMR (CDC 13) 8: 1.40-1 .80(2H,m), 1.89-2.1 2(2H,m), 2.20-2.75(8H,m), 5.28(2H,brs), 6.1 6.69(IH,d), 6.84(IH,d), 7.22-7.55(SH,m), 7.76(1 H,d), 8. 42(I H, dd), 9.5 2(1 H, s).

Step 2 The titled compound was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of step 1.

MS ni/z: 543(M+l) Example 309:.

1 -[3-(7-(5-Carboxyfiiran-2-yl)-5,1 1-dihydro[l1]benzoxepino[2,3-bjpyridin-5ylidene)propyl] -4-(4-chlorophenyl)piperidin-4-oI The titled compound was prepared by following the procedure of Example 382, step 2, butreplacing the product of Example 382, step 1 with the product of exarriple 307, step 1.

MS mlz: 557(M+I) -132- Example 310: 4-(4-Chloropheriyl)- 1 [3-(7-(2-ethoxycarboxy)ethelA-5,1lIdihydro [1 benzoxepino[2,3-b]pyridi.5yidele)propyl]piperidifl 4 -oI The titled compound was prepared by following the procedure of example 171, but replacing t-butyl acrylate with ethyl acrylate.

'H-NMR (CDCI 3 5:-1.33(3H,t), 1.63-1.71 (3H,m), 1 .98-2.10(21-,m), 2.35-2.72(8H,m), 4.25(2H,q), 5.36(2H,brs), 6.1 0(LH,t), 6.33(IH,d), 6.85(1 7.22-7.44(7H,m), 7.58-7.65(2H,m), 8.53(1H,dd).

Example 311: 4-(4-Chlorophenyl)- 1 -[3-(7-(l1-(2-ethyl-2-hydroxy)butyl)oxy-5, I1dihydro I1 ]benzoxepino[2,3-b]pyridin-5-yldele)propyfl~pperdil- 4 -o The titled compound was prepared by following the procedure of example 200, but replacing ethylmagnesium bromide with methylmagnesium bromide.

H-NMR (CDCI 3 6: 0.93(6H,t), i.60-1.70(6H,m), 1.95-2.lO(3H,m), 2.36- 2.70(8H,m), 3.79(2H,s), 5.28(211,brs), 6.09(IH,t), 6.77-6.86(3H,m), 7.24-7.43(5H,m), 7.57(lH,dd), 8.47(1 H,dd).

MS ml/z: 563(M+1) Example 312: 4-(4-ChlIorophenyl)- 1 (-2-23-i ty hdoybtloy51I dihydro[ I benoxep ino [2,3-b)p yridin- 5-yli defe)propyl]piper difl 4 -ol The titled compound was prepared by following the procedure of example 200, but replacing the product of example 48 with the product of example 138.

H-NMIR (ODCd 3 8: 1.22(611,s), 1.32(6H,s), 1.66-1.71(2H,m), 1.99-2.l0(2]H,rn), 2.35-2. 85(9H,rn), 3 .77(2H,s), 5 .28(2H,brs), 6. 04( 1H,t), 6.74-6 .89(3H,m), 7.26-7.43(5H,m), 7.57(lH,dd), 8.44(lH,dd).

MS mlz: 563(M+1) -133- Example 313: 4-(4-Chlorophenyl)- 1-dihydro-7-(2-oxopropyl)oxy[ 1]benzoxepino [2,3 b] pyridin- 5-yli den e)propljp iperidin-4-o] The titled compound was prepared by following the procedure of example 146, but replacing ethyl iodide with chioracetone.

I H-NMIR (CDCI 3 5: 1.62-1.71(3H,m), l.99-2.10(2H,m), 2.27(3H,s), 2.35- 2.70(8H,m), 4.5 l(2H,s), 5.28(2H,brs), 6.08(1H,t), 6.70-6.84(3H,m), 7.25- 7.32(3H,m), 7.41 -7.44(2H,m), 7.58(lH,dd), 8.50(lH,dd).

MS m/z: 519(M+l) Example 314: 4-(4-Chlorophenyl)-lI-[3-(7-formnyl-5,1 1-dihydro[I1]benzoxepino[2,3-b]pyri ylidene)propyl~piperidin-4-ol To a solution of the product of example 274(1.Og) in methylene chloride(200nil) was added rnanganese(IV) oxide(3.Og), and the suspension was stir-red at amibient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was evaporated under reduced pressure to give the titled cornpound(930mg).

I

H-NMR (CDCI 3 5: 1.71-1 .80(3H,m), I .98-2.09(2H,m), 2.35-2.43(4H,m), 2.53- 2.69(4H,m), 5.30(2H,brs), 6.24(1 6.95(liH,d), 7.27-7.44(5H,m), 7.61 (1 .H,dd), 7.67(]H,dd), 7.85(1H,d), 8.54(IH,dd), 9.88(1H,s).

Example 315: I -[3-(7-Acetyl-5,1 1-dihydro[ I]benzoxepino[2,3-b]pyridin-5-yli'dene)propyl]-4-(4chlorophenyl)piperidin-4-ol Step I To a solution of example 53, step 1 (7.2g) in dichloromethane (70 ml) was added aluminum chloride (9.1 g) and acetyl chloride (3.2 ml), and the mixture stirred at 0 0 C for 10 minutes. The reaction mixture was poured into ice. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated -134aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The Residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane to give 7-acetyl-5-(3- 1-dihydrof I]benzoxepino[2,3-bjpyridine (7.9 g).

1 H-NMvR (ODCd 3 6:2.57(3H,s), 2.77(2H,m), 3.49(2H,t), 5.40(2H, brs), 6.1 6(IH,t),6.88(lH,d), 8.33(IH,dd), 7.58(IH,dd), 7.77(1H,dd), 7.96(1H,d), 8.56(lH,dd).

Step 2 The titled compound was prepared by following the procedure of example 44, step 2,but replacing the product of example 44, step I with the product of step 1.

'H-NMR (CDCI 3 8: 1.52-1 .79(2H,m), 1.93-2.11 2.27-2.49(4H,m), 2.49- 2.60(5H,m), 2.60-2.73(2H,rn), 5.40(2H,brs), 6.22(1H,t),6.87(IH,d), 7.29- 7.34(3H,rn), 7.42(2H,d), 7.59(IH,dd), 7.75(1 H,dd), 7.96(1H,d), 8.53(1 H,dd).

MS mlz: 489(M+1) Example 316: To a stirred solution of phenol containing the product of Example 44 mmol) and K 2 C0 3 (1.5 mmol) in THF (10 mL) at RT was added N, Ndimethylcarbamoylchloride (1.2 mmol). The reaction was stirred at reflux for 24 hrs.

Excess solvent was removed and pure compound was isolated via silica gel chromatography eluting with 5% MeOHICH 2 Cl 2 MS nilz: 535) Example 317: To a stirred solution of phenol containing the product of Example 44 mmol) and K 2 C0 3 (1.5 mmol) in TI-F (10 miL) at RT was added morpholinocarbamoylchloride (1.2 mmol). The reaction was stirred at reflux for 24 h rs. Excess solvent was removed and pure compound was isolated via silica gel chromatography eluting with 5% MeOH-/C{ 2

C

2 MS mlz: 577) Example 318: -135- To a stirred solution of phenol containing the product of Example 44 mmol) in DMF at RT was added NaH (1.5 mmol) followed by the addition of Nisopropylisocyanate (1.5 mmol). The reaction was heated to 60 0 C for 6 hrs. The reaction was quenched with 1.5 equivalents of H 2 0 and excess DMF was removed under reduced pressure. Residue was charged on a silica gel column and eluted off with 5% MeOH/CH 2 Cl,. MS m/z: (M+548) Example 319: To a stirred solution of phenol containing the product of Example 44 mmol) and K,CO 3 (1.5 mmol) in THF (10 mL) at RT was added N-methyl-Nphenylcarbamoylchloride.(1.2-mmol). The reaction was stirred at reflux for 24 hrs.

Excess solvent was removed and pure compound was isolated via silica gel chromatography eluting with 5% MeOH/CH 2 CIl. MS m/z: 597) Example 320: To a stirred solution of phenol containing the product of Example 44 mmol) in DMF at RT was added NaH (1.5 mmol) followed by the addition of Nrnmol). The reaction was heated to 60 0 C for 6 lhs. The reaction was quenched with 1.5 equivalents of HO and excess DMF was removed under reduced pressure. Residue was charged on a silica gel column and eluted off with 5% MeOH/CHCl,. MS rn/z: 583) Example 321: To a stirred solution of phenol containing the product of Example 44 mmol) in DMF at RT was added NaH (1.5 mmol) followed by the addition of N-(3mmol). The reaction was heated to 60 0 C for 6 hrs. The reaction was quenched with 1.5 equivalents of H 2 0 and excess DMF was removed under reduced pressure. Residue was charged on a silica gel column and eluted off with 5% MeOH/CHCI 2 MS m/z: 584) -136- Example 322: To a stirred solution of phenol containing the product of Example 44 mmol) and KCO 3 (1.5 mmol) in THF (10 mL) at RT was added pyrolidinylcarbamoylchloride (1.2 mmol). The reaction was stirred at reflux for 24 hrs. Excess solvent was removed and pure compound was isolated via silica gel chromatography eluting with 5% MeOH/CH 2

CI

2 MS m/z: 560) Example 323: The compound was prepared by following the procedure for example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(4chlorophenyl)-4-cyanopiperidine. MS m/z: 486).

Example 324: To a cold stirred solution of Example 323 (0.50 g, 0.104 mmol) in anhydrous THF (5 mL) was added lithium aluminum hydride (8 mg, 0.21 mmol).

The reaction was stirred at RT for 2 hrs. The reaction was then quenched by the careful addition of HO0 (0.21 mL), 15% aqueous KOH (0.21 mL), then H 2 O (0.21 mL). The organic layer was separated and dried over Na 2 SO The compound was purified via silica gel flash chromatography eluting with 10% methanol/methylene chloride. MS m/z: 490).

Example 325: The compound can be obtained by the reduction of the azido functionality of Example 187 with a reducing agent, such as triphenyl phoshine, lithium aluminum hydride, sodium borohydride, in a solvent such as tetrahydrofuran or diethyl ether in reaction temperature ranges from 0°C to reflux with a reaction time between minutes and 72 hours.

-137- Example 326: The compound was prepared by following the procedure for example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(4chlorophenyl)-4-methylpiperidine provide in Example 329, steps 1-3. MS m/z: (M+ 475) Example 328: Step 1 N-benzyl-4-(4-chlorophenyl)-4-hydroxypiperidine: Fig. 8a To a stirred solution of commercially available 4-(4-chlorophenyl)-4hydroxypiperidine (10 g, 47 mmol., 1) in anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K 2

CO

3 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into

CH

2 CI, (100 mL) washed with H 2 0 (2 X 50 mL). Organic layer separated, dried over NaSO, and charged on a silica gel flash column. Eluting off with 2% MeOH/CH 2

CI

2 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+ 303) Step 2 N-benzyl-4-(4-chlorophenyl)-4-fluoropiperidine: Fig. 8a To a cold (-78 0 C) solution of 2 (10 g, 33 mmol) in CHCI 2 (20 mL) was slowly added DAST (diethylaminosulfur trifluoride, 5.3 mL, 39.8 mmol) under an inert atmosphere. The reaction was stirred at -78 0 C for an additional 45 min. The reaction was quenched at -78°C by the slow addition of enough saturated aqueous sodium bicarbonate solution to afford a pH This reaction resulted a quantitative conversion of the starting material to a 1:1 mixture of fluoropipendine 3 and 4-(4chlorophenyl)tetrahydropyridine 4. The mixture of 3 and 4 (3.5 g, mixture, yield) was purified via silica gel flash chromatography, eluting with 2% MeOH/CH 2 CIl. This mixture proved to be inseparable by silica gel flash chromatography. In order to separate out the desired product, the mixture of 3 and 4 were subjected to osmium tetroxide oxidation.

-138- To a stirred solution of the mixture of 3 and 4 (1.8 g) in acetone/HO (5:1, mL) was added a catalytic amount of OsO, in isopropanol (2.5 mol 1 mL) and N-methylmorpholine-N-oxide (0.69 g, 6.56 mmol). The reaction was stirred at RT overnight. The reaction was then evaporated to dryness, brought up into CH 2 C1, and washed with NaHSO3. This reaction resulted in the dihydroxylation of the undesired 4 to 5 and the clean separation of the desired fluoropiperidine 3 (1.0 g, yield) from the byproduct by silica gel flash chromatography eluting with 2% MeOH/CH 2 Cl. MS m/z: (M+306) Step 3 4-(4-chlorophenyl)-4-fluoropiperidine: Fig. 8a To a cold solution of 3 (1.07 g, 3.5 mmol) in 1,2-dichloroethane was added 1,1-chloroethylchloroformate (0.45 mL, 4.2 mmol). The reaction was then heated to reflux for 2 hrs. Excess solvent was removed and the residue was brought up into 5 mL methanol. The mixture was refluxed for 2 hrs and excess methanol was removed under reduced pressure. Precipitation of the hydrochloride salt of 6 by the addition of CH,Cl,/hexane followed by filtration resulted in the quantitative isolation of the desired crystalline product 6 0.70 MS m/z: (M+215) Step 4 The compound was prepared by following the procedure for example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(4-chlorophenyl)-4fluoropiperidine. MS m/z: 466).

-139- N lExample 329: Step 1 N-benzyl-4-methylpiperidine: Fig. 8c To a cold stirred solution of 1.4 M methyllithium in TI-IF (39 m.L, 54 rnrnol) under an inert atmosphere was added N-benzy]-4-ox opiperi dine 5.1 g, 27 mnmol). The reaction was stirred at -78'C for 2hrs. The reaction was quenched by the slow addition of saturated aqueous NI-1 4 C1, the organic layer was separated and dried over Na 2

SO

4 Pure methylpiperi dine was isolated via silica gel flash chromatography eluting with 5% MeOH/CH 2

C

2 MS mlz: (M+206) Step 2 N-b enzyl (4-chl oroph enyl)-4- methyl p Iperi din Fig. 8c To a flask containing chlorobenzene (10 rnL, excess) and methylpiperidine (0.42 g-,2.06 rnniol, 2) was added aluminum trichloride (1.65 rnL, 12.4 mrol). The reaction was heated to reflux for 24 hrs. Excess chlorobenzene was remnoved under 1 5 reduced pressure and pure 3 was obtained via silica gel flash chromatographay elutng wth IN EtOAcih ex ane. MS ml/z: 300) Step 3 4 4 -chlorophenyl])-4-i-nethv lipiperidinie: Fig. Sc To a cold (0 0 C) solution of AN-benzyl)-4-(4-chlor-ophenyt)4-metlhvlpipi-idine (0.41 g, 1.4 rnmol) in CH,CI, was 1.1 equivalent of Il-chlorocthiylchlorcofori-nate.

The reaction was then heated to reflux for 2 hrs. Excess solvent was removed and the residue was brought up into methanol. The mixture was refluxed for 2 hi-s and excess methanol was removed under reduced pressure. Precipitation of the hydrochloride salt 4 by the addition of Cf{ 2

C]

2 followed by filtration resulted in the quantitative isolation of the desired crystalline product 4 (100%, 0.34 M S mlz: 210) Step 4 The compound was prepared by following the procedure for ex ampl1e 44, step 2, but replacing 4 4 -chlorophenyl)-4-hydroxypiperidine with 4-(4chlorophenyl)-4-methylpiperidine. MS rn/z: 461) Example 330: The compound was prepared by following the procedure for example 199, but replacing the resultant compound of example 44 with the resultant compound of Example 329. MS m/z: 533) Example 331: Step 1 A mixture of epichlorohydrin (5.92 g, 64 mmol) and benzhydrylamine (11.7 g, 64 mmol) in MeOH (120 mL) was stirred under the protection of argon at room temperature for 48 hours. The mixture was then stirred at 50 0 C for 72 hours. The reaction mixture was then stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and HO0. The aqueous layer was extracted with EtOAc (200 mL x dried over MgSO, and concentrated in vacuo. Chromatographic purification on silica gel (CH,Cl,/MeOH 95/5) provided 10.0 g of 1-benzhydril-3-hydroxyazetidine. m/z 240 (m+1) Step 2 A mixture 1 -benzhydril-3-hydroxyazetidine (2.6 g, 11 mmol) and palladium hydroxide on active carbon (0.26 g, w/w 20%) in EtOH (40 mL) was shaken in hydrogenation parr under 60 psi for 24 hours. The reaction mixture was filtered through celite and concentrated under vacuum. Concentration in vacuo provided 0.75 3-hydroxyazetidine. 'H NMR (250 MHz, CD30D) 3.81-3.92 (2H, m), 4.14-4.25 (2H, 4.61-4.69 (1H, m).

Step 3 The compound 1-[3-(5,11 -dihydro-7-(methoxy[ l]benzoxepino[2,3b]pyridin-5-ylidene)propyl]azetidin-3-ol was prepared by following the procedure for example 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 3-hydroxyazetidine. m/z 339 Step 4 To a mixture of morpholine N-oxide (0.028 g, 0.244 mmol), crushed -141molecular sieves (0.066 g) and PrN"RO 4 (0.01 gy, 0.024 minol) in CI- 2 C1 2 was; added the 1 11 *-dihydro- 7 -(methoxy[ 1 ]benzox epino [2,3 -b]pyri dini-5 ylidene)propyl]azetidin-3-oI (0.055 g, 0. 16 mmol) under the protection of argon.

The mixture was stirring over night at room temperature. The reaction mixture was filtered off through celite and concentrated under vacuum. Chromatographic purification on silica gel (CH 2

CI

2 /MeOH 95/5 to 9/1) provided 0.033 g 1-[3-(5,11Idihydro-7 -(methoxy[ I ]benzoxepino[2,3-b]pyri din- 5-ylidene)propyll azetid in -3 -one( of the desired product. ml/z 337 (rn+l) Step To a solution ofI 1-dihydro-7-(methoxy[ I]benzoxepilno[2-,3 h pyridin- 5-ylid ene)propyl Iazeti din- 3-one (0.06 0.18 rnmol) in THY (8 niiL) was added dropwi~se a solution of 4-chiorophenyl magnesium bromide in diethyl ether GM, 0.27 rnL) under the the protection of argon at 0 0 C. The reaction was stirred at room temperature for 1.5 hours and quenched by the addition of saturated aqueous N~rHOH (4 niL). The aqueous layer was extracted with EtOAc (10 mL x 2), dried over M6SO4 and concentrated in vacuo. Chromatographic purification on silic gel (CHICI,/MeOI- 95/5) provided 0.048 g 3-(4-chloropheny)-1 1di hyd ro-7-(methoxy[ 1 ]benzox.-pino[2,3 -b~pyri din- 5-y',Iiden -)propyl] azetidi -ie (51%) m/z 449 Example 332: Step I tert-Butyl 3 -(4-chlorobenzoyl)> 1 -(2-aminoethyl) carbarnate: Fig. IlOb tert-Butyl N'-(2-aminoethyl) carbamnate 0.50 g g, 3 12 mmol) was added to the mixture of 4-chlorobenzoic acid chloride (0.547 g, 3.12 mmol) and Et 3 N (1.74 mL, 12.5 mmol) in CH 2

CI

2 (20 mL) under the protection of argon. Stirring at room temperature for 2 hours. The reaction mixture was diluted with H 2 0 (25 nmIZ), extracted with CH 2

CI

2 (50 mL x dried over MgSO, and concentrated in -vacuo.

Chromatographic purification on silica gel (CH,.C1 2 /MeOH 95/5) to provi3de 0.86 -142g 93%) of the desired product ter-t-Butyl 3-(4-chlorobenzoyl)-1 -(2-aminoethyl) carbamnate. MS mlz: 299).

Step 2 1 -(4.chlorobenzoyl)-1I,2-ethylenediamine: Fig. Trifluoroacetic acid (7.5 mnL) was added to the solution of tert-Butyl 3-(4chl orobenzoyl) 1-(2 -aminoethyl)carb am ate 0.86 g, 2.89 mmnol) in CH,C1 2 mnL) at O'C. Stirring at roomn temperature for 30 minutes. Concentration in vacuo provided 0.88 g of the desired product 1-(4-chlorobenzoyl)-1,2ethylenediarnine MIS mi/z: 199).

Step 3 The compound was prepared by following the procedure for example step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidiine with l-(4chiloroben-zoyDl-1,3)-propyleflediamine. NIS rn/z: 465).

Example 333: Step I 2-(4-Chlorophenyl)-1 -bromoethylene: Fig. 9c To a solution of AlC 3 (1.96 g,14.7 mmol) in-anhydrous C1lCl, (50 mL), Borane-te7-t-butyl amnine complex (2.57 g, 29.6 mrnol) was added at 0'C -ander aroon protection, stirred for.10 minutes and clear solution was formed. 4-Chlorophenacyl bromide 1.11 g, 4.91 mmol) in CH,C 2 (5 mL) was added to the resulte-d mixture at O'C The reaction was stirred for 1.5 hours and then quenched by the addition of 0.1 N HC1 (25 rnL). The mixture was extracted with EtOAc (80 mL x d-ried over MgSO4 and concentrated in v'acuo. Chromatographic purification on silica gel (Hexane/E-tOAc 1) provided 0.85 g of 2-(4-chlorophenyl)-l bromoethylene MIS rnlz: 219).

Step 2 2 -(4-chl orophenyl)- I ethyl) ethyl am ine: Fig. 9c A mixture of 2-(4-chlorophenyl)-lI-bromoethylene 1.02 g, 4.62 rnmol), EtOH (3 niL) and H 2 NMe in H 2 0 (6 mL, 40%,Aw/w) was heated at 135 0 0 C over -143niight. The mixture was cooled down to room temperature. The maixture was extracted with Et,0 (5mL x dried over MgSO 4 and concentrated in vacuo.

Chromatographic purification on silica gel (CH 2 Cl 2 /MeOH/NHO 4 H 9/1 1) provided 0.61 g 2-(4-chlorophenyl)-1-(N-methyl)ethylamine MS rnl/z: (M+ 170).

Step 3 The compound was prepared by following the procedure for example step 3, but replacing 4-(4-chilorophenyl)-4-hydroxypip eri dine with 2-(4chlorophenvi)- 1-(N-niethyl)ethiyl amine. MS mlz: 451).

Example 334: Step I 3-(4-chlorophenyl)- I .Anethiylaminopropane: Fig. 9e A mixture of 3-(4-chlorophenyl)-l -bromoropane 0.70 gy, 3.73 niol), EtOH (3 mnL) and H.N4e in H~O (6 mnL, w/wA) was heated at 135 0 0

C

overnigaht. The mIixtUre was then cooled down to room temperature. The mnixture was extracted with EtO (5 mnL x dried over MgSO, and concentrated ini vacuo.

Chrorniatographic punhfication on silica gel (CHCI,/M\eQH/NHOH 9/1/0. 1) proided 0.5 g; of 3 4 -chlorophenyl)---ehyannpopare() vSmz I 89).

Step 2 The compound was prepared by following the procedure for example step 3, but replacing 4 4 -chlorophenyl)-4-hyfdroxypiperidine with 3-(4chlorophenyl)- I -N-methylaminopropane. MS rnlz: 450).

Example 335: Step I 3-(4-chlorophenyl)-3-chloro-lI-hydroxypropane: Fig. 9d To 3,4'-Dichloropropylphenone (0.52 g, 2.53 namol) in anhydrous N~eOH mL) at 0 0 C under the protection of argon, NaBH 4 (0.23 g, 3.03 mmol) vvas -144added to the solution by several portions. The reaction was stirred under the same condition for 15 minutes. The mixture was warmed up to room temperature, stirred an additional 30 minutes, then concentration in vacuo. The residue was partitioned between EtOAc and H 2 0. The aqueous layer was re-extracted with EtOAc (30 mL x dried over MgSO, and concentrated in~vacuo. Chromatographic purification on silica gel (H-exane/EtOAc provided 0.52 g of 3-(4-chlorophfenyl)-3chioro-lI-hydroxypropane. MS mlz: (M+s205).

Step 2 The compound was prepared by following the procedure for example 1 0 step 3, but replacing 4-(4-chilorophenyl)-4-hydroXylpiperi dine with 3-(4chlorophenyl])-3-chloro-I -hydroxypropane. MS ml/z: (M%1 48 1).

Examiple 336: Stcp 1 3-(4-chloroph-enyl)-3)-hydroxy-3--mcthiyl- I -chioropropane: Fig. I Ga To 3,4'-Dichiloropropylphenone 1.10 g, 5.40 nimol) in anhydrolas THY at 0 0 C under the protection of argon, was added MeMRBr (2.50 miL, 7.35 n-ol) dropwise at 0 0 C. The reaction was stirred at room temperature for an additional hour. The reaction was quenched by adding. saturated aqueous NE- 4 C1. The reaction was then extracted with Et.,O (60 mnL x dried over M6S0, and conceIntrated in vacuo. Chromatographic purification on silica gel (HexaneiEtOAc 10/1), provide.d g of 3)-(4-chilorophienvl)-3I-hydroxy-3-methyl-l-bromoropane MS Step 2 3:-(4-chloroph enyl)-3 -hydroxyl-3'-methyl-lI-N-rnethylIaminopropane: Fig. 1 0a A mixture of 3 ,3,3-(4-Chlorophienyl)-hydroxylm ethyl- I -brornoropa-rie (2, 1.04 g, 4.74 rnmol), EtOH (5 rnL) and H 2 NMe in H 2 0 (10 mnL, 40% w/w) Xv'as heated at 135 0 0 C for 3 hours. The mixture was cooled down to room temperature.

The mixture was extracted with EtO (5mL x dried over MgSO, and concentrated in vauco. Chromatographic purification on silica gel -145-

(CH

2

C]

2 /MeOH/NI1 2 0H provided 1.0 1 g 3-(4-chlorophenyl)-3-hydroxyl- 3-methyl-1I-N-m ethyl aminoprop ane, MS mlz: 214).

Step 3 The compound was prepared by following the procedure for example step 3, but replacing 4-(4-chlorophienyl)-4-hydroxypiperI dine with 3-(4chlIorophenyl)- 3 -hydrox yl-3 -m ethyl -I -N-nieth ylaminopropan e. MS rn/z: 480).

Example 345: Using the procedure of Example 45, but replacing 5,1 1-di'hydro-7m ethox y[ I ]b enzox ep ino[2,3 -b]pyidin-S5-one with 1-azaxanthone, giv'es the desired compound.

Example 346: Using the procedure of Example 45, but replacing 5,1 11 -di hydro-7methoxy[l ]benzox epino[2,3-b] pyridin- 5-on e with I -4-azafluorene, gives the desired compound.

Example 347: Using the procedure of Example 45, but replacing 5,11 -dihvEho-7imethioxy,[ I]benizox pio'2,S-b'TvidN-5-one with 7-amino- I -az-ax anthone. gives thc desired compound.

Example 348: Using the procedure of Example 45, but replacing 5,11 -dihydro-7mnethox y[ I ]b en-zox epi1no [2,3-b]pyri din-5 -one with 4,5-diazafluorene, gives the desired compound.

Example 349: Using the procedure of Example 45, but replacing 5,1 1-dihydro-7methoxy[ I]benzox epino [2,3-blpyri din-5-one with I -aza-7-nitroxanthone, gives the -146desired compound.

IND Example 350: 3-(4-chlorophenyl)- 1 11 -dihydro-7-(metboxy[ I ]benzoxepino[2,3-b]pyridin-5ylidene)propyl]pyrrolidine SteplI ~-KIA mixture of 1 -benzyl.3-pyrrolidinone (10.0 g, 57 mmol), di-tert-butyl dicarbonate (13.7 g, 63 mmol) and palladium on active carbon (2.5 g, w/w 20%) in MeOI- was shaken in a Parr hydrogenation vessel (50 psi H 2 for 48 hours. The reaction mixture was filtered through celite and concentrated in vacuo.

Chromatographic purification on silica gel (Hexane/EtOAc 1/1) provided 6.21 g 1-e-butoxycarbonyl-3-pyrrolidinone 'H NMR (250 Mliz, CDCI3) 8: 1.46 2.5 7 (2H, t, J1= 7.8 Hz), 3.71-3.75 (4H, m) Step 2 To a stirred solution of I -:-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmnol) in THiF (10 mL) was added 4-chiorophenyl magnesiumn bromide (1.0 M, 5.2 mL) under the protection of argon at 0 0 C. The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NI-1 4 0 (8 mL). The aqueous layer was extracted with EtOAc (50 mL x dried over MgSO, and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc 3/1) provided 0.57 g 1-t-butoxycarbonyl-3-(4-chlorophenyl)-3hydroxypyrrolidine m/z 298 (m+l) Step 3 To a stirred solution of 1 -i-butoxycarbonyl-3-(4-chlorophenyl)-3hydroxypyrrolidine (0.335 g, 1.28 mmol) in CH 2

CI

2 8 mL) was added trifluoroacetic acid (2 mL) at O 0 C slowly. The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. This provided 0.355 g 3-(4chlorophenyl)-3 -hydroxypyrrolidine (100%) the desired product. m/z 198 (m+l1) Step 4 The titled compound was prepared by following the procedure for example -147- 44 but replacing 4-(4-chlorophenyl)-4-hydroxypiperidifle with 3 -(4-chlorophenyl)-3 hydr oxypyrrolidine. mn/z 432 1).

Example 35 1: Step I 4-(4-chl orophenyl)-4-p yridine: Fig To a solution of 4-bromopyridine 1.94 g, mmol), 4-chiorophenylboronic acid 1.56 g, mmnol) and K 2 C0 3 (2.76 g, 2.0 equiv) in ethanol/toluene was added Pd(PPh 3 3 The reaction was refluxed for I hr, cooled back down to RT and quenched with H 2 0 (15 mL). The reaction mixture was extracted with EtOAc and the organic layer was dried over Na 2

SO

4 Pure 4-(4chlorophenyl)-4-pyri dine 2 (1 .3g, 68% yield) was isolated after silica gel flash column purification eluting with 50% EtOAc/hexane. MS mlz: 19 1).

Step 2 T he titled compound was prepared by following the procedure for example step 3, but replacing 4-(4-chlorophenyl)-4-hycdroxypiperidine with 4-(4chlorophenyl)-4-pyridine. MS mlz: (M+456).

Example 352: The compound was prepared by following the procedure for example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with 4-(4-chlorophenyl)-4pyridine. MS mlz: (M+442).

Example 353: 5-2N-4(-hoohnl4-yrxycoey)Nmtyetyiee-, ,I dihydro-7-rnethoxy[I )bcnzoxepino[2,3-bjpyridine The compound was prepared by the procedure of Example 57, step 3, but replacing 4-(4-clhlorophenyl)-4-hydroxypiperidine with 4-(4-N-methyl.(4chlorophenyl)-4-hydroxycyclohexylamin. The starting material can be prepared according to methods disclosed in Journal of Medicinal Chemistry, Vol. 15, No. 12, -148pp. 1239-1243 (1972).

Example 354: 1 -[3-(7-(4-Carboxyphenoxy)-5 ,11I -dihydro 1 Jbenzox.epino [2,3 -b ]pyri din-5 yJ idene)propylj -4-(4-chlorophenyl )piperidin-4-ol Step I 4-(4-Chlorophenyl)- 143 1-dihydro-7-(4ethoxycarbonylphenoxy) [I ]benzoxepino[2,3-bjpyri din-5-ylidene)propyl ]pi peridin- 4-ol was prepared by following the procedure of example 46, but replacing ethyl iodide wih ethy' 4-fluoroberizoate 'H-NMN'R (CDC] 3 5: 1 .36(3H,t), I .65-2.07(4H,i-), 2.32-2.63(8H,m), 4.34(2 q),5 .33(2H,brs), 6.07( 1H,t). 6.8S-7.1I0(5H,m), 7.27-7.51 8( 1H,dd), 7.97-8.00(2H,m), 8.49(I H, dd).

Stcp 2 The titled compound wvas prepared by following the procedure of ex ample.

1 337 but replacing the product of example 48 with the product of step 1.

'H-'.NrMR (DMSO-d6) 8: 1.44-1.49(2H, in), 1.67-1.87(2H~m), 2.26- ').56(SH,rn),4.S5(IH,brs), 5.29(2H,brs), 6.17(1 6.88-7.09(5H~m), 7.33- 7.48(5H,m), 7.75(1H,dd), 7.89-7.93(2H,m), 8.52(1H,dd).

MS m/fz: 582(M) Example 355: 4-(4-Chlorophenyl)- I -dihydro-7-(2- (hydroxyirmin o)propyl)ox y[ 1 ]benzox epin o[2 ,3 pyri din- 5-yli den e)propyl ]p ipei din 4-ol To a solution of the product of example 313 (300mg) in ethanol (3j-rri1) was added hydroxylammonium chloride (80mg) at room temperature, and the mixture -149was stirred for 1 hour. The precipitation was filtered and washed with ethanol to give the titled compound (300mg).

IND'H-NlvR (DMSO-d6) 8:1.75-1 .80(2H,m). 2.23-2.42(2H,m), 2.53(3H,s)3. 16- 3.48(8H,m), 4.54(2H,s), 5.19(2H,brs), 5.57(1H,s), 6.14(IH,t), 6.76- 6 9 8(3H,m),7.41-7.48(SH,m), 7.79(1H,dd), 6.53(1I-,dd), l0.93(IH,s).

Example 356: I 3 7 -(?2-Carboxy-2-nmethl )II -propyl)oxy-5,1 l-dihydro[ I]benzoxepIno[2,3.

b~yidn5-l1dnepoy]--4cloohnlppeii -4-olI Step I 4 4 -Chlorophenyl)- 1 -dihydro-7-(2?-ethoxycarbonyl..x rnethylproyl)oxy,)[l bez.eio2,- ~ii-5yleepop pprdi-4-al was prepared by following the procedure of exam-ple 46, but replacing ethyl iodide with ethyl 2 -bronio-l1, 1-dimethyl propionate.

'H-NMR (CDCl 3 6: 1.31(61{s), l.

6 7 -1.72(2H,rn), l.

9 6-2.15(2H,m), 2.39- 2.78(8H,rn), 3.93(2H,s), 5.2 7(2H, brs), 6.09(1Hjt), 6 7 0-6.83(3H~m), 7 2 3-7.59(.6Hrni), 8.46(lH,dd).

Step 2 The titled comipound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of step 1.

'H-NMR (DMSO-d6) 5: 1.46-1 .50(2H,ni), 1.74-1 22)- 2 .38(8H,rn),3.92(2H,s), 4.58(1H,brs), 5.1 9(2H,brs), 6.1 8(IH,t), 6.71 6 .83(31-Lr), 7 3 3-7.48(5H,m), 7.72(1H,dd), 8.49(1I-,dd).

MS mnlz: 514(M±1) Example 357: 4-(4-Chlorophenyl)- 1 -(5,11 -dihydro-7-(- (hydroxyimino)propyl)[ I ]benizoxepino [2,3-b]pyidin-5 -ylidene)propyl ]pipe ri din-4 ol -150- The titled compound was prepared by following the procedure of Example 354, but replacingthe product of example 313 with the product of example 315.

'H-NMvR (DMSO-d6) 8: 1.39-1 .54(2H,m), 1.64-1 .86(2H,m), 2. 13(3H,s), 2.19- 2).36(4H,m), 2.36-2.52(4H,m), 4.83(1H,s), 5.28(2H,brs), 6.20(lH,t), 6.80(11-,d),7.35(2H,d), 7.43-7.49(4H,m), 7.58(1 7.76(IH,d), 8.5 l(11,dd), 1 l.04(IH,s).

MS mlz: 504(M+l) Example 358: 4-(4-Chlorophenl)-l1-[3-(5,11I-dihydro-7-propionylf 1 benzoxepino[I2,3-b yli dene)p ropy]l]p ip en'dif- 4 -ol The titled compound wvas prepared by following the procedure of ex ample but replacing acetyl chloride wAith propionyl chloride.

'H-NMR (CDCl 3 5:1 .22(3H,t), 1.63-1 .77(2H,m), 1 97-2.1 3(2H.rn), 2.25- 1.48(4H,m), 2.48-2.60(2H,m). 2.60-2.73(2H,m), 2.96(2?H.q), 5.41 (2'H,brs), 6.21 (1H,t),6.S6(lH,d), 7.30-7.34(3H,rn), 7.43(2H~d), 7.59(lH,d), 7.75(VH,dd), 7.9 7(IH. 8. d).

IMS rn/z: 503(M+1*) Example 359: 4-(4-Chloropheflyl 1 -dihydro-7-isobutyry[1 ]beinzoxepino[2,3)-b)pyrldin-5ylidene)propyl]pIperi dIn-4-ol The titled compound was prepared by following the procedure of example 315, but replacing acetyl chloride with isobutyryl chloride.

I H-NMR (CD CL) I .21-1.33(2H,m), 1 .76-2.0O(2H,rn), 2.46-3.47(8H, mn), 3 .53(IH,rn), 5.47(2H,brs), 6.09(IH,t), 6.69( lH,d), 7.32-7.45(6H,m), 7.64(lH,d),?.79(1H,dd), 7.94(I,d), 8.57(IH,d).

MS mlz: 517(M+1) Example 360: -151- 4-(4-Chlorophenyl)- 1 -(j7-cyclopropylacetyl -5,1 1 -dihydro[ 1 ]berzoxepino[2,3blpyi-idin-5-ylidene)propyljpipenidin-4-oI The titled compound was prepared by following the procedure of Example 315, but replacing acetyl chloride with cyclopropylacetyl chloride.

'H-NMR (CDCI 3 5: 0.98-1.05(2H,m), l.20-l.24(2H,m), 1.58-l.70(2H,m), 1.99- Cl 2.09(2H,m), 2.34-2.55(4H,m), 2.58-2.68(5H,m), 5.40(2H,brs), 6.23(1 H,t), 6.89(1H,d), 7.30-7.34(3H,m), 7.43(2H,d), 7.59(IH,dd), 7.86(lH,dd), 8.00(1H,d), 3(1 H, dd).

MSmrnz: 515(M±1) Example 361: I -[3-(7-(3-Carboxypropiony I l-dliydro[ I]benzoxepino[2.3-b pyrdn-5 ),-den e)propyl (4-chl orophe-nvl)pi per)idIn -4-o I Step I 4-(4-Chlorophenyl)- I-[3-(5,l1 I-dihydro-7-(3niethox ycarbony lproponyl)[1 ]benzoxepino[2,3-b]pid'in-5-yli'dene)pip-eridin-4-ol was prepared by following the procedure of Example 3 15, but replacing acelv) chloride wvith mnethyl succinyl chloride.

'H-NMR (CDCIJ) 6: 1 .57-1 .77(4H,rn), 1.94-2. 14(4H,rn), 2.27-2.61 (6Hmr) 2.61- 2.73(2H~m), 3.67(3H,s), 4.70(l 5.30(2H,brs), 6.1 6.83(l H,d), 7.14(1 7.29-7.32(4H~m), 7.42(2H,d), 7.58(IH,d), 8.50(1 H,d).

Step 2 The titled compound was prepared by following the procedure of Ex ample 13' 3, but replacing the product of example 48 with the product of step 1.

'H-NMR (DMSO-d6) 6: l.37-1.57(2H,.m), l.63-1.86(2H,m), 2.13-2.37(4H, rn), 2.45- 2.63(4H,m), 3.17-3.28(4H, in), 4.85(1B,brs), 5.36(2H,brs), 6.30(lH, 6.91 (1H-, d),7.35(2H,d), 7.46-7.50(3H,m), 7.78-7.83(2H,in), 7.95(IH, 8.53(IH,dd).

MS m/z: 547(M+l) -152- Example 362: 4-(4-Chlorophenyl)- ,1 -dihydro-7-(l -ethyl-I 0 hydroxy)propyl[ I]benzoxepino[2-,3-bjpyridil-5-ylidele)propyI]pipenldil- 4 -ol N The titled compound was prepared by flowing the procedure of example 242, but replacing methylmagnesium bromide w ith ethylmagnesium bromide.

'H-NMR (CDCI 3 8: O.79(61-,t), l.65-2.04(9H,m), 2.35-2.66(8H, in), 5.37(2H, brs),6.09(1H,t), 6.81(lH,d), 7.10(1K, dd), 7.26-7.5] (6H, mn), 7.59(IH, dd), 8.49(1H, dd).

MS m/z: 533(M+1) Example 363: 4-(4-Chloropheny])-l-{3-(7-( 1-cyanio- I-methyl)ethyl-5, I dihydro[ 1 ]benzoxepinoI2,3-blpyridin-5-Ylid-ne)propyl]piperidil- 4 -ol Step I -bromopropyli1derle)-7 -hydroxy-lI -m ethyl) ethyl -5,1 1dihydro[I1]benzoxepino[2,3)-blpyn'difle was prepared by followving the procedure of Example 200, but replacing the product of example 48 with the product of example 315, stepi.

'H-NMNR (CDCI,) 5: 1.58(6H, 2.74(2H, 3.47(2H,t), brs), 6.09(IH, 6.82(11-, 7.25-7.31(2H, in), 7.45(1K, 7.57(1K, dd), 8.52(1K, dd).

Step 2 To a solution of the product of step 1 (3.8 g) in dichlorornethane (40 nil) was added trimethylsilyl cyanide (4.1 mil) and boron trifluoride diethyl etherate (2.5 ml) at 0 0 C, and the mixture stirred at room temperature for 10 minutes. The re-action mixture was poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent w~as distilled off under reduced pressure. The residue was purified by silica gelchromatography eluting with ethyl acetate-hexane to give 5-(3- -153brornopropylidene)-7-(- 1 -cyano- 1 -methyl)ethyl-5,l I-dihydro[ 1 ]benzoxepino[ 2 3 b]pyridine (3.4 g).

'H-NMR (CDCI 3 5: 1.58(61{,s), 2.76(21-,m), 3.48(2H,t), 5.34(2H,brs), 6.09(1 Ht),6.87(1 7.22(1 H,dd), 7.32(IH,dd), 7.42(IH,d), 7.58(IH,dd), 8.55(IH,dd).

Step 3 The titled compound was prepared by following the procedure of example 44, step 2,but replacing the product of example 44, step 1 with the product of step 2.

'Hq-NMIR (CDCI 3 8: 1 .5S(6H,s), 1.60-1.70(2H,m), 1.93-2.1 2(2H~m), 21.30- 2.47(4H,m), 2.50-2.74(4H, in), 5.31(2H,brs, 6.15(IH,t), 6.86(IH, 7.19(1H,dd), 7.28-7.3)2(3H,mi), 7.41-7.43 (3H,mi), 7.61(lH,d), S.53(1H. dd).

MS mlaz: 514(N4+1I) Example 364: 4-(4-Chilorophtinyl)- 11 -d'lihydro I ]benzoxcpino[2,3D-b]pyridin-5ylidene)propylpiperidin-4-ol The titled compound wvas prepared by following the procedure of e>I ample 44, step 2,but replacingo the product of example 441, step 1 with 5-(3bromropropyli den e)-7-cyano-5 ,1l 1-cihydro[ 1 ]be~nzoxepirio[2,3-bjpyriidinef.

l-l-NM,4R (CDCL 3 5: 1.62-1.75(2H, 1.98-2.09(2H, in), 2.36-2.69(8H, ri-), MS inlz: 472(M+l) Example 365: 4-(4-Chlorophenyl)- I-[3-(5,l1 -dihydro-7-(tetrazo]-5-y)[l benzoxepino[2,3 -yl idene)propyl]piperidin-4-ol To a solution of the product of Example 364 (1 .0g) in DMF (10 mi) -were added sodium azide (0.69a) and ammnonium chloride (0.56g) and the mixtur-e stirred at 100 0 C for 36 hour. Water was added to the reaction mixture, and the precipitate was filtered and washed with ethanol to give the titled compound (800mg).

-154- 'H-NMR (DMSO-d6) 5:1.66-1.71 (2H, mn), 1.91-2.01 (2H, in), 2,86-3.09(8H, m),5.33(2H, brs), 6.22(111, 6.91(IH, 7.39-7.51(5H1, mn), 7.79-7.84(211, mn), 8.03(1H,d), 8.55(1H, dd).

MS mlz: 515cM+1) Example 366: 4-(4-Chlorophenyl)-1-[3-(5,l I -dihydro-7- (hydrox yiminom ethyl)[i I lbenzoxepino12, 3 b1pyri din- 5 -y iden e)prop yl] pip edin- 4 -ol The titled-comipound was p repared by followving the procedure of E-Xample 357, but replacing the productof example 315, step 2 with the product of example 314.

dd), MSni/z: 490(N1+1) Example 367: I -(4-Chlorophe-nyl)-4-[ 3 I -dihydro-7-(1 -hydroxy-l meth)yl)ethyl[ I 1benzoxepIno[2.3-bjpyrI din-l>ylidele)propyflpiperazine The titled compound was prepared by following the procedure of example 7 1, but replacing the product of example 45, step 2 with the product of Ex ample 363, step 1.

'H-NMNR (CDCl 3 5:1.58(6H1, 2.31-2.63(SH, in), 3.02-3.20(4H, mn), 5.32(2H1, brs),6.12(IH, 6.79-6.83(3H, mn), 7.17-7.31(6H, in), 7.45(IH, 7.59(1141, dd), S. 5 1(1H,dd).

MS mliz: 490(M+l) Example 368: 4-(4-Chlorophelyl)- I-13-(5,1 I -dihydro-7-sulfarnoyl[lIlbenzoxepinoll2,3-b -155ylidene)propyflpipeldil- 4 -oI Step 1 To the product of example 53, step 1 (5.4g) was added chiorosulfonic acid and the mixture stirred at O'C for 1 hour. The reaction mixture was poured to ice, and ethyl acetate was added to the mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dr-ied with magnesium sulfate. The solvent was distilled off under reduced pressure. To the residue were added THF (250m1) and ammonlium hydroxide (30m1) and the mixture stirred at -room temperature for 10 minutes. Ethyl acetate and water were added to the mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with maznesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate -he),.ane 1) to give 5-(3-brorropropylideIne>S,1 I dihydro-7-sulfanoy l b 3bnzo -pnoI 2 3 'H-NM.NR (CDCI 3 a: 2.70-2.75(2H, 3.48(2H, 5.39-5.49(4H, in), 6.16(1 H, t),6.88(IH~d), 7.25-7.34(2Hm), 7.53(1H, dd), 7.68(IH, dd), 7.93(IH, 8 .53(lH, dd).

Step 2 The titled compound was prepared by following the procedure of ex. ample 44, step 2,but replacing the product of example 44, step I wvith the product of step I.

'H-NrvIR (DMSO-d6) 8: 1.65-1 mn), 1.98-2.07(2H, in), 2.35-2.64(8E-, rn),4.9S(2H, brs), 5.39(2H, brs), 6.22(lH, 6.92(IH, d) 7.26-7.43(5H, in), 7.55- 7.69(2H, in), 7.91(1H, 8.53(IH, dd).

MS in/z: 526(M+l) Example 369: 1 [-3-(7-(2-Amiflothiazol- 4 Ii -dihydro[1 I berizox ep inoII2,3-blpyr* din ylidene)propyfl1-4-(4-chlorophenyDpiperidin 4 -oI -156- S tep 1 7 -bromoacety]-5-(3-bromopropylidene)-5, I 1-dihydro[ I ]benzoxepino[2,3b]pyridine was prepared by following the procedure of example 315, step 1, but replacing acetyl chloride with bronmoacetyl chloride.

'H-NTMR (ODCd 3 5: 2.77(2H, in), 3.50(2H, mn), 4.40(2H, 5.45(2H, brs), 6.17(l1H, t),6.90(IH, 7.35(lh, dd), 7.60(lH, dd), 7.79(IH, dd), 8.01(1H, 8.57(1H, dd).

Step 2 To a solution of the product of step 1(1.1I g) in ethanol (I]I ml) was added thiourea (I193mg) at room temperature, and the- mixture stirred at 70'C for minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodiurnbicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium Chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting, with ethyl acetate to Sgive 7 2 aniinothiazo 1 -brom opropyl ]den 511 dihvdro[ 1 ]benzox ep ino[2,3 -b)pyidine (749 ig).

'H-NNR 5: 2.74(2H, in), 3.47(2'H, t),5.02(2H, bTs),5..3 9(2H, brs), 6.16(I H, t),6.62(IHHI 6.85(1H, 7.30(1H, dd), 7.54-7.57(2H, 7.77(I1H, d), 8_53(1lH, dd).

Step 3 The titled compound was prepared by following the procedure of example 44, step 2, but replacing the product of example 44, step 1 with the product of step 'H-NMR (CDC 3 8: 1.57-1.70(2H, in), 1.83-2.13(2H, in), 2.30-2.46(4H, 2.46- 2.60(2H, in), 2.60-2.73(2H, 5.02(2H, 5.3 7(2H, brs), 6.20(l1K, 6.6 1 (1KH, s),6.85(1IH, 7.27-7.32(3K, mn), 7.42(2H, 7.50-7.58(2H-, in), 7.76(1K, d), 0(1 H, dd).

NIS iz: 545(M+1) -157- Example 370: I -[3-(7-(3-Carboxy-lI-hydroxy)propyl-5 1 -dihydro[I 1 benizoxepinoll2,3-b]pyridin-5ylid ene)propyl] -4-(4-chlorophenyl)pipendin-4-ol Step 1 4-(4-Chlorophenyl)- 11 -dihydTo-7-(3-methioxycarbony- 1hydrox y)propyl [I Ijbenzoxep ino[2,3 -b~pyridi-5 -yli denle)propyllpiperidin- 4 ol was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of Example 361, step 1.

2.73(2H, mn), 3.67(3H, 4.70(IH, 5.30(2H, brs), 6.1 1(1K, 6.83(lH, d), ,.14(lHtd), 7.29-7.32(4H, mn), 7.42(2K,d), 7.58(1H, 8.50(1K, d).

Step 2 The titled compound wvas prepared by following the procedure of examp!e 133, but replacing the product of example 48 with the product step 1.

2.19-2.82(6K, in), 3.24-3.53(4K, in), 4.49(IH, 5.03(IH. brs), 5.20(2H-, b-rs), 6.13(lIH, t),6.76(1 H, 7.12(1IH, dd), 7.27(l1H, 7.3 7.43-7.48(3H, in), 7.76(1K, d), 8.3 2(1 H, S.51 (1K, dd).

IMS ni1z: 549(M-'l) Example 371: 4-(4-Chlorophenyl)-1-[3-(5,l 1-dihydro-7-(2fi uoroethylamino)carbonyriethYloxy[ 1]benzoxepino[2,3 ylidene)propylpiperidin- 4 -ol The titled compound was prepared by following the procedure of example 134, but replacing diniethylamine hydrochloride with 2-fluoroethylamine.

'H-NM.R (CDCI 3 8: 1.62-1.71(3K, 1.98-2.10(2K, in), 2.36-2.71(8H, nia), 3.63(1K, 3.73(1K, 4.46(1K, 4.49(2K, 4.63(H, 5.29(.2K, brs), 6.10(1K, 6.75-6.96(4H, mn), 7.28-7.44(5K, mn), 7.60(lH, dd), 8.51(1K, d<l).

-158- MS mlz: 566(M+1) E~xample 3 72: 4-(4-Chlorophenyl)- 1 ,1 1 dihydro-7-(N-methylsulfamoyl)[l ]benzoxepino [2,3 b] p yi din-S 5 yli dene)propyllp ip eridif- 4 -ol The titled compound was prepared by following the procedure of Example 368, but replacing ammnonium hydroxide with methylamifle.

'H--NMIR

(CDCI

3 8: 1.57-1 .70(3H, mn), 1 .93-2.08(2H, mn), 2.34-2.73(l III, 4.33(IH, 5.36(2H, brs), 6.21(lH, 6.91(IH, 7.2-9-7.45(6H, in), 7.5 8- 7.65(2H, mn), 7.83(IH, dd), 9.53(lH, dd).

M Smr/z: 540(M+l1) Example 373: 4-(4-ChloropheflyI-l-[3-(5,1 l-dihydro-7-(N,Ndiniethylsulfafoyl)[l ]benzoxepiflo[2,3-bp fdi-5-l yidene)propy ]piper din- 4 -ol The titled compound was prepared by followig the procedure of Example 3 68, but replacing armmoniumn hydroxide with diinethylamine.

'H-N4R

(CDCI

3 6: 1.-,75-1.75(3H, mn), 1.96-2.07(2H, mn), 2.35-2.67(SH, i) 2.71(6H, 5.51 brs), 6.19(l H, 6.92(lIH, 7.29-7.73(SH, iin) 53(l1H, dd).

MS ml/z: 554(M-il) Example 374: 1 43 1 Carboxy-2-hydroxyethy)oxy-SIl -dihydro[I1 benzoxepino[ 2 3 -b]pyndin- -yli dene)propyfl]-4(4-chloinophenylpipeidin- 4 -oI Step I 4-(4-Chlorophefll-[3-(5 ,l I-dihydro-7-(1 -ethoxycarboxy,- 2 h ydroxyethyo~x y[ I Ibenzox epino[2,3 -blpyidin-l5 yli dele)propyl1p ipedin 4 ol was -prepared by following the procedure of example 199, but replacing the product of example 138 with the product of example 294.

1 H-NN4R (CDCI 3 68: 1.65-1.70(2H, in), 2.01-2.1 1(2H, mn), 2.35-2.70(gH, ri), -159- 3.76(3H, 3.97-4.08(2H, in), 4.71(IH, 5.25(lH, brs) 6.02(I, t) 6.70-6.91(3H, in), 7.23-7.56(6H-, in), 8.44(1H, dd).

Step 2 The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of Step 1.

'H-NMR (DMSO-d6) 6: 1.51-1.56(2H, in), 1.86-1.94(2H, mn), 2.33-2.67(8H, mn), 3.65-3.82(2H, mn), 4.58(1H, 5.17(2H, brs), 6.10(1H, 6.71-6.89(3H, in), 7.34- 7.47(5H, in), 7.72(l H, dd), 8.48(lIH, dd).

MS mlz: 5 5 1(M,1 Example 375: "-(4-Chlorophenyl)- 1 1 -dihyvdro-7-ure'dom-thy,[lI]be)nzoxeplio[2,3 'bjpvridini-5-yilidene)propyllpipe-ridifl-4-ol To a solution of the product of example 314 (800 mg) in acetic acid (20 ml) were added urea (2 g) and triinethylsilyl chloride (0.24 ml) at room temperature, and the mixture stirred for 2 hours. Sodium borohydride was added to the reaction mixture at room temperature, and the mixture was stirred for I hour. The solvent wvas distilled off under reduced pressure, and, chloroform, 2-propano! and N' :ater wvere added. The oreanlc layer was extr-acted, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting wvithi clhlorofor--methano]-ainnonium hydroxide (100: 10: 1) to give the titled compound (250 ig).

'H-NMiR (CDCI 3 6: 1 .62-2.04(5H, mn), 2.35-2.69(SH, mn), 4.26(2H, 4.4-0(2H, s), 4.48(IH, 5.32(2H, brs), 6.12(IH, 6.80(lH, 7.07(lH, dd), 7.23-7.5 8(7H, mn), 8.49(1 H, dd).

MS m/z: 519(M+1) Example 376: 4-(4-Chlorophenyl)- 1-dihydro-7-methylthi o[ I]benzoxepino[2,3-b ]pyridin- 4 -ol -160- The titled compound was prepared by following the procedure of example 44, step 2, but replacing the product of example 44, step I with 5-(3- 1I -dihydro-7-methylthio[ 1 ]benzoxepino[2,3 -b~pyri dine.

'H-NM4R (CDCI 3 8: 1.53-1.70(3H, 1.98-2.16(2H, in), 2.17(3H, 2.34- 2.70(SK, in), 5.32(2H, brs), 6.12(1K, 6.81(lH, 7.11-7.44(7H, mn), 7.57(1H, dd), 8.50(1K, ad).

MS mlz: 493(M+1) Example 377: 4-<4-Chlorophcflyl)- 1-f3 1-dihydro-7 -(2-furanon-3 N1)oxy[lI]benzoxepino[2,3]b]pyr1dif-5Ylidene)proPYllipidin~o The titled compound was prepared by following the procedure of example 46, but replacing ethyl iodide with 3-broinotetrahydro-2-franofl.

'H-NMR

(CDCI

3 6:1.65-1.70(2H, mn), 1.97-2.1 3(214, mn), 2.25-2.73(lIOH, mn), 4.25- 4.53(2K, mn), 4.82(1 H, 5.27(2H, brs), 6.09(l H, 6.73-6.91(2H, 7.03(1H, d), 7.22-7.590H1, mn), 8.4-3(114, dd).

MS rn/z: 547(.M-Il) Example 378: 4-(4t-Chloropheflyl)- 1 11 -dihydro-7-(Nmethoxycarb onyl mthyl sulfam ~oyl)[ I ]benzoxepino[2,3-b]pyrIdifl%yli1 den e)propyl]pipe~din-4-ol The titled compound was prepared by following the procedure of E-xam-ple 368, but replacing ammnonium hydroxide with glycine methyl ester hydrochloride.

'K-NMR (CDCI 3 6: 1.66-1.74(3K, mn), 1.97-2.15(2H, i-ri), 2.37-2.80(8K, i) 3.63(3K, 3.78(2H, s) 5.40(2K, brs), 6.22(1H, 6.92(1K, 7.28-7.45(5K, in), 7.62(2K, dd), 7.83(1K, 8.53(lH, dd).

MS nilZ: 598(M+l) Examrple 379: -161- 1 -[3-(7-(N-Carboxymethylsulfamoyl-5,1 I -dihydro [I ]benzox epino 2,3 -b]pyri din- yli1den e)propyl] chioroph en yl)piperi d in-4-ol The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of Example 378.

'H-NM:R(DMSO-d6) 6: 1.60-1.65(2H, in), 2.16-2.25(2H, 2.43-3.03(8H,rm), 3.45(2H, 5.33(2H, Urs), 6.39(1H, 6.94(1H, 7.41-7.*57(6H, in), 7.83(IH, dd), 8.00(1K, 8.54(1H, dd).

Example 380: 4-(4-Chlorophenyl)-1- 1-dihydro-7-(2--furanion- 5-yl)[I1]benzoxepino [2,3 b]pyri din-5.yl*idene)propyl~Ipiperidin-4-o1 The titled compound was prepared by following the procedure of example 249, step 2,bu eplacing the product of example 249, step 1 with the product of Example 370, step 1.

2.78(6H, in), 5.33(2H, brs), 5.46( H, 6.12(1H, 6.86(l H, 7.09(1H, dd), 7.27-7.-'2(4H, in), 7.42(2H, 7.58(l dd), 8.5 1 (IH, dd).

MS nlz: 53 1(M+l1) Ex ample 381: 1 -[3-(7-Amiino-5,I I -dihydro[ I ]benzoxepino[2,3-b]pyrTidi n-5-yli dene)propyl chloroplienyl)piperidin-4-ol To a solution of the produce of example 293 in ethanol (1301rr'1) was added 5N sodium hydroxide solution (1O0ml) and the mixture stirred at 90'C for 1 hour. The reaction mixture was distilled off under reduced pressure. The residue was dissolved with water and neutralized with IN hydrochloric acid. Ethyl acetate was added to the mixture, the organ +ic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate to giv'e the title-d compound 'H-NN4R (CDCI 3 6: 1.62-1.72(2K, in), 1.96-2.08(2H, in), 2.27-2.72(8H, rri), -162- 3.48(2H, brs), 5.23(2H1, brs), 6.01 (11H, 6.49-6.73(3H1, in), 7.18-7.59(6H1, in), 8.49(111, dd).

MS mlz: 462(M+1) Example 3S2: 1 -[3-(7-(2-Carboxyphenyl)-5,1 1 -dihydrof I ]beiizoxepino[2,3' -b~pyri din-5 yli dene)propyl] -4-(4-chlorophenyl)pipendin-4-ol Step I 4-(4-Chlorophenyl)- I-dihydro-7-(2-formylphenyl)[l ]benzoxepino[ 2 ,3bjpyn din-5-ylidene)propyl] piper-idini-4-ol was prepared by following the sir-nil ar procedure of exampl e 170, but replacing alivitributyltin with 2-formyihenylboronic acid.

1 H-NMR (CDCl 3 8: 1.65-1.91 (3H, in), 1.99-2.04(2H, in), 2.37-2.65(8I-, in), 5.39(2H, brs), 6.1 5(1H, tQ, 6.95(1H, 7.19-7.65(IOH, in), 7.97-8.05(,2H, ni), 2(1 H, dd), 10. 03 (1 H, s).

Step 2 To a solution of the product of step 1 (270mg) in acetic acid (2.2 nil) and water (0.5in1) were added ai-nidosulfuric acid (67mg) and sodium chlorite (6Smg-) InI water 1 mil), and the mixture was stirred at room tempe ,rature for 15 minutes. The reaction mixture was distilled off under reduced pressure into half volume. The residue was neutralized with IN sodium hydroxide. The precipitation was filtered and washed with water to give the titled compound I-I-NN'R (DMSO-d6) 6: 1.41-1 .57(2H, in), 1.74-1 .92(2H, 2.21 -2.58(8141, m), 5.32(21, brs), 6.20(lH, 6.82(111, 7.15(111, dd), 7.31-7.78(1111, in), S. 52(IH, dd).

MS in/z: 567(M+1) Example 3 83: 4-(4-Chlorophenyl)- I ,11 -dihydro-7-(N-(2,2,2trifluorocthyl)sulfamoyl)[I1]benzoxepino[2,3 -b]pyridin-5 -ylideine)propyllpiperidin- -163- 4-ol The titled compound was prepared by following the procedure of Example 368, but replacing ammonium hydroxide with 2,2,2-trifluoroethylamine hydrochloride.

'H-NMR (CDCl 3 8:1.64-1 .77(2H, in), 1.97-2.1 8(2H, mn), 2.35-2.80(8H, in), 3.63(2K, 5.41](2H, brs), 6.21(IH, 6.91(1H, 7.22-7.65(7H, mn), 7.84(1K, d), 7(1H, dd).

MS mlz: 608(M+1) Example 384: 4-(4-Chlorophenyl) -3 -(5,11i -dihydro-7-m ethyl sul fonyll 1 lb enzoxepino 3hlpyri din yl idene)propyl] piperid in-4-o I The *titled compound was prepared by following the. procedure of Example 44, ste-p 2, but replacing the product of Example 44, step I w ith 5-(3bromopropylidene)-5,1 1-dihvdro-7-niety~sulfonyl[ I ]bcnzox epino[2,3 -bjpyri dine.

1 H-NMR (CDC 3 5: 1.54-1.71(3H, in), 1.99-2.08(2K?, in), 2.34-2.68(SH, in), 3.04(3K, 5.43(2H, brs), 6.24(1K, t4 6.97(1K, 7.2-2-7.70(7H, mn), 7.S(lH, d), S. 5 5(1H, dd).

MS m/z: 525(M+1) Example 385: 4-(4-Chlorophenyl)- 1 -[3-(5,11I -dihydro-7-ureido[ I lbenzoxepino[2,3-blpyri ylidene)propyl]pipeidin- 4 -ol Step I 4-(4-Chlorophenyl)- 1 ,11 -dihydro-7pheoxycarboniylamino[ I benzoxepino12,3-b]pyridiin-5 -ylidene)propyllpiperidin- 4 -ol The titled compound was prepared by following the procedure of Example 293 but replacing ethanol with phenol.

'H-NMAR (CDCI 3 6: 1 .62-1 .68(2H, mn), 1.96-2.08(2K, in), 2.35-2.65(8H, rai), 5.28(2H, brs), 6. 10(1KH, 6.78(l H, in), 7.08-7.40(6H, in), 7.52(1K, dd), 7. 62(1KH, -164- 8.44(IH, dd).

MS m/z: 582(M+1) Step 2 To a solution of the product of Step 1 (300mg) in DMF (3m1) was added ammoniumn hydroxi de (1 .5m1) and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The ridue was purified by silica gel chromatography eluting with (chloroformn methanol =10 to give the titled compound (140mg).

'H-NMR (DMSO-d6) 5: 1.45-1.50(2H1, mn), 1.72-1.88(2H1, in), 2.28-2.51 (SH, mn), 4. S2(I H, 5.19(lIH, brs), 5.74(2H, brs), 6.09(11H, 6.69(l H, 7.12(lIH, dd), 7.32-7.48(6H, 7.74(lH, dd), 8.37(IH, 8.50(IH, dd).

MVS rn/z: 505(M+1) Example 38 6 4-(4-Chlorophenyl)- I 1i-dihydro-7-( 1morpholinocarboflylalinloI ]benzox epino [2.3-b~pyTidifl% yl idele)propy Ip ipen din- 4-ol The titled comnpound was prepared by following the procedure of Example 385, step 2, but replacing amnmonium hydroxide with morpholine 'H-N4R (CDC 3 6: 1.62-1.67(2H, in), 1.95-2. 16(2H, mn), 2.28-2.64(81, in), 33.41(4H1, 3.69(4H, 5.?26(2H, brs), 6.08(IH, 6.69-6.76(211, 6.98(111, dd), 7.21-7.51(7H1, mn), 8.42(1H, dd).

MS in/z: 575(Mi-1) Example 387: 4-(4-Chlorophe)l~1-[3 -(5,11I -dihydro-7-(3-(2ethox y)carbonyiethyl)urei do[ I ]b erzoxepi no [2,3 -b~pyridinl- ylidene)propyl]pipefldin- 4 -ol -165- The titled compound was prepared by following the procedure of Example 3 85, step 2, but replacing ammionium hydroxide with beta-alanine ethyl ester hydrochloride.

'H-NMR (CDCI 3 6: 1.1 8-1 .39(3H, 1.62-1.66(2H-, in), 1.92-2.01 (2H, in), 2.21- 2.62(l OH, in), 3.47-3.50(2H, in), 4.08(2H, 5.22(2H, brs), 5.98-6.03(2H, in), 6.68-6.92(2H-, mn), 7.15-7.42(7H-, in), 7.62(1K, 8.36(1K, dd).

MS mlz: 605(M+1) Exam~ple 388: arboxy-1-methy)e-thenvl-5,11I -dihydro[llbenizoxepino[2,3b]pyri din- 5 -),1]dene)propyl] -4-(4-chl oroph enyl)pipendin-4- ol Step I 4-(4-Chlorophenyl)- I -[3-(7-(E)-(2-ethoxycarboxy- I -methN l)ethenyl1-5,1 I1dihydro[ I 3benzox epi;no [2,3 -b]pyridin- 5 -YIId en e)propyl ]pi peridin-4-o I was prepared by following the. procedure of Example 411, but replacing ethyl cyanoforrnate with ethyl (triimethylsilyl)acetate.

'H-NMNR (CDCI 3 b: 1.30(3'K, 1.67-1.72(3H, in), 1.98-2.05(2H, 2.42- 2.67(1 1K, mn), 4.23(2H, 5.3)6(2K?, brs), 6.14-6.19(2H1, mn), 6.85(IH, 7.20- 7.61(SH, mn), 8.52(IH, dd).

Step?2 The titled compound was prepared by following the procedure of Example 133, but replacing the product of Example 48 with the product of step 1.

'H-NMR (DN4SO-d6) 6: 1.50-1.55(2H-, mn), 1. 87-1.99(2H, in), 2.34-2.61 (11 1-1, in), 5.29(2H, brs), 6.12(IH, 6.31(1H, 6.83(1H, 7.35-7.49(7H, 7.76(111, dd), 8.52(IH, dd).

MS ml/z: 530(NM±1) Example 389: 4-(4-Chlorophenyl).1 l-dihydro-7-oxalo[1 ]benzoxepino(2,3-b]pyridlin-5ylidene)propyllpiperidin-4-ol -166- The titled compound was prepared by following the procedure of Example 361, but replacing methyl succinyl chloride with methyl oxalyl chloride.

'H-NMR (DMSO-d6) 6: 1.66-1.86(2H, in), 2.08-2.34(2H; mn), 2.46-2.77(2H, mn), 3.00-3.68(6H, in), 5.10(2H, brs), 5.53(1H, 6.15(111, 6.89(IH, 7.34- 7.49(5H, in), 7.68(111, dd), 7.75(lH, dd), 7.87(1H, 8.53(IH, dd).

MS mlz: 519(M+1) Example 390: 1I3(-3-2Crox ty~ued-, I -dihydro[ I ]benzoxepino[2,3-b]pyridinflS \vIdefe)propy4(4-chlorophenyl)piperidin 4 -o The titled conmpound was prepared by following the procedure of Example 133 but replacing the product of Examiple 48 with the product of Example 3 87.

'H--NMR (DMSO-d6) 6: 1.45-1.55(2H1, rn). 1.72-1.85(2H, inO.H249 1, in), 3.29(2H1, 4.8S(lH, 5.19(2H, brs), 6.06-6.14(2H, mn), 6.69(111, 7.07(lH,_ dd), 7.33-7.48(6H1, rn), 7.73(1H, dd), 8.43(IH, 8.49(IH, dd).

MIS rnlz: 577(M-1) Examiple 391: 1-[ 4 3-(7-('3)(2-Hydro\,y)ethyl)ureidO,5 I -dih\ydro[ I ]benzoxepinotl2,3-b]PYri yi i dene)propyll-4-(4-chlorophe1ny)p iperdin 4 -ol The titled comnpound was prepared by following the procedure of ample 385, step 2, but replacing ammionium hydroxide with 2-arninoethanol.

'H-NMR (DM4SO-d6) 6: 1.45-1.51(2H, in), 1.72-1 .94(2H, mn), 2.24-2.51(8E4, i), 3.11-3.46(4H, in), 4,71(111, 4.83(111, 5.19(2H, brs), 6.08(111, 6.69(IH, d), 7.08(111, ad), 7.3-3-71.49(6H, mn), 7.73(1H, ad), 8.41(1H, s) 8.50(111, dd).

MS mlz: 549(M+1) Example 392: 1- [3 11 -Dihydro-7-(1 -hydroxy- I -inethyl)ethyl [1 ]benzox epino[2,3 -blpyri din- ylidene)pTOPYl) -4-(2-keto-I -imi dazolinyl)pip eri dine -16 7- The titled compound was prepared by following the procedure of Example 67, but replacing the product of Example 45, step 2 with the product of Example 363, step 1.

'H-NMR (CDCI 3 6: 1.59(6H, 1.71-1.87(2H, in), 2.01-2.18(2H, 2.28- 2.61(6H, in), 2.86-3.00(2H, in), 4.32(lH, mn), 5.36(2H, brs), 6.15(1H, 6.84(IH, 7.02-7.07(3H, in), 7.24-7.31(')H, mn), 7.47(lH, 7.60(IH, dd), 8.5l(IH, dd), 8.9 7(l H, s).

MS MlZ: 511 1) Example 393: 4-(4-Chlorophecnyl)- I-[3-(7-(E)-(2-ethoxycarboxy-2-methyl)e.thenyl-5,1l1-' dilhydro[ 1 ]bei-zoxcpino[2..3 -b]pyri din- 5-yli dene)propyl ]piperidifl-4-ol To a solution of sodium hydride (60%/c in oil, 100 rng) in TI-I (6 nil) wvere.

added triethyl 2-ph~osphonopropionate (0.3 nil) and the product of Examnple 314 (300 mg) at 0 0 C, and the mixture wvas stirred at room temperature for 30 minutes.

Water and ethyl acetate were added to the reaction mixture. The organic. layer was extracted, and the solvent was distilled off under reduced pressure. Th~e residue was purified by silica gel chr-omato graphy, eluing wvith chloroform-methanol (3 0: 1) to Lri\,e the titled compound (3 10 m) 'H-NNIR (CDCI 3 5: l.5S.-l.71(3H, in), 1.98-2.15(5H, mn), 2.37- 2.70(8H, iii), 5.3 7(2H, brs), 6.14(lH, 6.86(l1-H, 7.25-7.44(714I, rn) 7.58-7.63(2WH mn), 8.52(lIH, dd).

MS m/z: 559(M-4-) Example 394: I -[3-(7-(E)-(2-Carboxy-2-methyl)etheinyl-5 ,1 1-dihydro[ I]benzoxepino[2,3v b~pyridin-5 -ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol The titled compound was prepared by following the procedure of E-xample 133, but replacing the product of Example 48 with the product of step 1.

'H-NMR (DMSO-d6) 6: 1.62-1.67(2H, in), 1.91 -2.05(5H, mn), 2.50-2.94(81H, in), -168- 5.28(2H, brs), 6.23(IH, 6.87(1K, 7.34-7.55(8H, mn), 7.79(1H, dd), 8.54(lH, dd).

MS rnz: 531(M+1) Example 395: 1 -[3-(7-(5-Carboxy-1 -pentyl)oxy-5,1 I -dihydro[I1]benzoxepino[2,3-blpyridifl-5yl idene)propyl] -4-(4-chloropheny1)pipefldif-4-ol Step 1 4-(4-Chlorophenyl)- 1-[3-(7-(5-ethoxycar-bonyl -1-pentyl)oxy-5,1Idihydrot I benzoxepiflo[2,3 -b~pyridin-5-yIidene)propyl1piperidil- 4 -ol was prepared by following, the procedure of Example 46, but replacing ethyl iodide with ethyl 6bromohex anoate.

2.67(1IOH, mn), 3.87(2H-, 4.16(2H, 5.23(2H, brs), 6.09(IH, 6.67-6.S1(3)H, 7.2 1-7.63(6H, in), 8.16(11K, dd).

Step 2 The titled compound was prepared by following the procedure of Example 133, but replacing the product of Example 48 with the product of step 1.

1 1--NMNR (DMSO-d6) 6: 1.41-1.95(l OH, in), 2.20-2.72(l01O1, in), 3.92(2K), t), 5.18(211, brs), 6.17(1H, 6.7 2-6.84(3H, in), 7.36-7.48(5H, in), 7.77(1K, dd), 8.50(I H, dd).

MS mlz: 577(M4+l) Example 396: 1 -(2-Carboxy)ethyl)aninocabony1-l1-methyl)ethyloxy[ I benzoxepino[ 2 3 b~pyri din- 5 -ylidene)propyl] (4-chlorophenyl)pipeidil-4-ol Step I 4-(4-Chlorophenyl)-l1-[3-(7-( I-(2-ethoxycarbonyl)ethy1)afilocarbofll1i-nethyl)ethyloxy[ I ]benzoxepiflo[2,3 -blpyr-idin- 5-yl idefle)propyl1pipen* dif- 4 -ol was prepared by following the procedure of Example 176, but replacing dirnethylamnine -169hydrochloride with beta-al an~ine ethyl ester hydrochloride.

'H-NMR (CDCl 3 6: 1.42(3H, 1.62-1.67(2H, 1.95-2.10(3H, in), 2.3$- 2.59(1OH, mn), 3.5 1-3.53(2H, mn), 4.00(2H, 5.23(2H, brs), 6.00(lH, 6.68- 6.81(3H, in), 7.24-7.56(6H, rn), 8.39(IH, dd).

Step 2 The title compound was prepared by following the procedure of Example 133, but replacing the product of Example 48 with the product of step 1.

'H-NMR (DMSO-dG) 6: 1.3 7(6H, 1.41-1.52(2H, in), l.79-1.87(?H, 2.28- 2.4 1(1lOH, in), 3.3 3(2H, 5.21(2H, brs), 6.12(lIH, 6.70-6.87(3H, In), 7. 34- 7.48(5E-, in), 7.74(11-, dd), 8.08(IH, 8.50(lH, dd).

'MS rn/v 620(M+]) Examiple 397: 4-(4-Chlorophenyl)- 1 11 -d",Ihvdro-7-(tiazoline-2,4-dione-5ylidene)rnethyl[ I ]benzoxepino[2,3-b]pyridin-5-yliden-)propyllpipeidin-4-ol To a solution of the product of Example 314 (590 mg) in eflhanol (6 mil) were added 2,4-ihiazolinedione (440 mg) and piperidine (0.36 ml), and the mixtuare was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, -and, chloroform, 2-propanol and water wvere added. The organic laver wvas extracted, and the solv'ent was distilled off uinder reduced pressure. The res idue was purified by silica gel chromatography eluting with chloroformn-methanol 1) to giv e the titled compound (5 10 mng).

'H-.NMR (DMSO-d6) 6: 1 .61-1 .66(2H, mi), 1.97-2.1 2(2H, in), 2.79-2.99(SFI, in), 5.21(2H, brs), 6.25(1IH, 6.90(I H, 7.34-7.52(7H, mn), 7.81l(1H, dd), 8.-54(IH, dd).

MS m/z: 574(M+1) Example 398: 4-(4-Chlorophenyl)- 1-[3 I -dihydro-7-rnethanesulforianido[ I]benzoxep, ino[2,3b]pyridin-5-ylidenc)propyllpiperidin-4-oI -170- The titled compound was prepared by following the procedure of Example 402, but replacing trifluoromethanesulfonuC acid anhydride with methanesulfofly chloride.

'H-NMR

(CDCI

3 6: 1.64-1.69(2H, mn), 1.89-2.05(2H1, 2.24-2.77(SH, in), 2.95(3H, 5.29(2H,brs), 6.10(IH, 6.84(1H, 7.06(111, dd), 7.18-7.40(6H1, m), 7.56(111, dd), 8.42(111, dd).

MS m/z: 540(M+1) Example 399: 4-(4-ChlOrophell)- 1 -dihydro-7-(3penylureido)sulfofly)Il ]benzox epino 3b pyridin -li d -ne)ProPyllpiperi din 4 -ol The titled compound was prepared by following the procedure of Example 320, but replacing compound of Example 44, step 2 with compound of Example 368, step 2.

'H-NMR (DMSO-db) 6: 1.65-1 1.95-2.05(2H1, mn), 2.89-3.06(8H1, m), 5.31(2H1, brs), 6.14(lIH, 6.74-6.95(-'H, in), 7.08-7.12(2H1, mn), 7.3 7-7.64(SH, mn), 7.S0-7.84(214, mn), 8.44(111, 8.54(IH, dd).

MS 645(\M+1) Example 400: 4-(4-Chl orophienyl)- 1 )-(7-(3-cyclolhexviureido)sulfonylS5,1l dihydro[ 1 lbenzoxe-pino[ 2 -bipyridin- 5-ylidene)propyl~pipenldil- 4 -ol The titled compound was prepared by following the procedure of Example 399, but replacing phenyl isocyanate with cyclohexyl isocyanate.

'E4-N4R (DMSO-d6) 6: 1.07-1.81(14H1, in),2.23-2.58(811, in), 3.22-3.35(1 H, in), 4.91 (IH, 5.3)8(2H1, brs), 6.17-6.29(2H1, in), 6.96(111, 7.34-7.51(5H1, in), 7.62- 7.84(3H1, mn), 8.53(111, ad).

MS ml/z: 651(h4+1) -171- Example 401: 4-(4-Chlorophenyl)-l 1-dihydro-7-(3propyl urei do)sul fon yl benizox epino [2,3-b]pyri din- 5-yli dene)propyl ]piperi din-4-olI The titled compound was prepared by following the procedure of Example 399, but replacing phieryl isocyanate with propyl isocyanate.

'H-NMvRP (DMSIO-d6) 6: 0.74(3H, 1.25-1.53(4H, in), 1.8l-1.91(2H, in), 2.33- 2.59(IOH, mn), 2.89(2H, 4.92(IH, 5.35(2H, brs), 6.20(]H, 6.44(lH, brs), 6.96(IH, 7.-34-7.51(5H, mn), 7.64(IH, dd), 7.78-7.85(2H, in), 8.54(IH, dd).

MS m/z: 611 (M+1) Examnple 402: 4-(4-Chlorophenyl)-l I 1-dihydro-7trifluoromcthariesulfonamido[ I ]benzoxepIno[2.3)-b]pyridin-5yli ldcne)pr-opylI]piperidin-4-oI The title compound was prepared by following the procedure of Exain1ple 1 5 1 69, but replacing the product of Example 44, step 2 with the product of Ex ample 381.

1 H-NMNR (DMSO-d6) 6: 1.75-1 .80(2H, in), -1.02-2.07(2H, in), 2.49-2.54(2HI, ri), 3. in), 5.15(2H-, brs), 5.52(IH. 5.97(l H, 6.58(1H, 6.S0(IH, dd), 6.96(l H, 7.43--7.47(3H-, mn), dd), 8.51 (1H. dd).

2 0 IMS m/z: 59')(.N+1 -172- Example 403: 1 -[3-(7-(3-carboxy)propylS ,1 1-dihydro[iI lbenzoxepiflol2,3-b]pyndin-5 ylidene)propYl] -4-(4-chloropheflyl)piperidin- 4 -oI Step 1 To a solution of the product of Example 361, step 1 (820 mg) in TFA nil) was added triethyl silane (0.92 ml) at 0 0 C, and the mixture stirred at room temperature for 4 hour. The solvent was distilled off under reduced pressure. The residue was poured into saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodiumn chloride, and dried with mnagnesiunm sulfate. The solvent -was distilled off under reduced pressure. Thc rcsidue was purified by silica gel chromatography eluting with ethyl acetate-hexafle to give 4-(4-ChlorophenyD) 1 I-dliydro-7-(3-methoxycarbonyl)prop)'U[l ]benzoxepino[2,3.-b~py"IIdIfl-5 ylidene)propyl]pipenldin 4 ol (636 rng).

'H-NMR

(CDCY

3 6: 1.93(2H, in), 2.34(2H, 2.59(2H, 2.74(2H, 3.47(2H, t), 3.67(3K, 5.33(2H, brs), 6.05('iH, 6.7S(IH, 7.00(!H, dd), 7.09(1K, d), 7.29(1K, dd), 7.57(1H, dcl), 8.52(1K, dd.).

Step 2 The titled compound was prepared by followking the procedure of Example 133, but replacing the product of Example 48 with the product of step 1.

'H-NMR (DMSO-d6) 5: 1.3 7-1.57(2K', mn), 1.63-1 .87(4H, 2.1 0-2.36(611, in), 2.36-2.61(6H, in), 4.83(1H, brs), 5 .24(2H, brs), 6.14(1 H, 6.72(1K, 7.00(1K, dcl), 7.12(lH, 7.35(2H, 7.41-7.48(3K), in), 7.73(1K, dd), 8.49(1K, dd).

MSmlz: 533(M1\+1) Example 404: 1 -(7-BenzoYl sulfamroyl-5,ll -dibydro[t Jbenzox epino[2,3"-b]pyridin-Syljdene)propyl]>4(4chlorophen\ l)pipefldin-4-ol The titled compound was prepared by following the procedure of lExample 399, but replacing pheniyl isocyaflate with beaizoyl chloride.

-173- MS rnlz: 630(M+1) Example 405: 4-(4-Chlorophenyl)- 1-[3 -(5,11I -dihydro-7-(2,5-dihydro-5 -oxo-4H- 1,2,4-oxadi azol-3yl)methyl ox y[ 1 ]b enzox epino [j2,3 -b]p yri din -5 -yli dene)propyl] piperidin-4-ol To a solution of the product of Example 407 (1.7 g) in DMF (20 ml) was added 2-ethyihexyl chloroforrnate (0.62 ml) and the mixture was stirred at 0 0 C for 1 hour. Chloroform and water were added to the reaction mixture. The organic layer was extracted, and the solvent was distilled off under reduced pressure. The residue was puriied by silica gel chr-onatogaphy eluting With chl]oroforM-methanol (30:1) 1 0 and dissolved in xylene (50 ml). The solution was heated to reflux for 4 hoturs. The solvent was distilled off under reduced pressure. The residue was reslurried with ethanol to the titled comn'ound (490 mig).

1 H-NM-\,R (DMSO-d6) 6: 1.60-1.65(2H, in), 1.91-1.99(2H, 2.41-2.52(211I, i), 2.70-2,89(614, in), 4.90(2H1, 5.19(21-i, brs), 6.16(l H, 6.75-7.05(')H, mn), 7.37- 7.48(5H, in), 7.75(lH, dd), S.52(IH, dd).

MS m/z: 5 61 I1 Example 406: 4-(4I-Chlorophenyl)-lI-[3-(5, I1 -dihy\.dro-7-(2,5-dliydro-5-oxo-4H- 1,2-,4-oxad iazol-3- 1]benzoxepino[2,3'-blpyri'din-5-yldelle)propVylprldii-4-ol The titled compound was prepared by following the procedure of EK ample 405, but replacing the product of Example 407 with the product of Examplfe 408.

'H-NMR (DMSO-d6) 6: 1.58-1.63(2H, in), 1.87-1.96(2H, mn), 2.40-2.51(2a-, in), 1.63-2.85(6H, 5.14(2H1, brs), 6.23(IH, 6.92(11-, 7.36-7.62(6H, in), 7.77- 7.81(2H1, in), 8.54(IH, dd).

M S mlz: 5 31 (M+1) Example 407: 4-(4-Chlorophenyl)- 1-[3-(7-hydroxyamidinomethoxy-5,1 I- -17 4dihydrolil ]benzoxepilo 2,3 blPYridin y11 dene)propyl 3pipefl din 4 ol The titled compound was prepared by following the procedure of Example 355, but replacing, the product of Example 313 with the product of Example 49.

'H-NMR (DMSO-d6) 6:1.45-1.50(2H, in), 1.70-1.82(2H, in), 2.27-2.51(8K, in), 4.37(2H, 4.83(l1K, 5.20(1K, brs), 5.57(2H, brs), 6.17(1K, 6.72-6.94(3H, mn), 7.33-7.48(5H, in), 7.72(1K, dd), 8.49(1H, dd), 9.26(1K, s).

NISm/z: 535(Nl±l) Example 408: 4-(4-ChlorophelYl)- 1 [3)-(7-hydroxvainidilo- 5,11 -dihydro[Ilbenzoxeplol 2 ,3 blpyn'din-5-ylidcne)prop ,~lpifdin- 4 -oI The titled compound was prepared by following the procedure of Example 355, but replacing the product of Example 313 with the product of Example 364.

'H-N'MIvR (DMSO-d6) 6: 1.45-1 .50(2H, 1.73-1 .81(2H, in), 2.28-2.51(8F1, m), 4.83(1H, 5.79(2H, brs), 6.23(IH, 6.8 1(IH, 7.33-7.49(6H, in), 7.63- 7.7 6(2 H, mn), S. 5 1(1 H, d 9.4 8(1KH, s).

MIS ini/z 505(M+l) Example 409: 4-(4-Chlorophenyl)-l1 1 -dihy)dro-7-(2-oxo-3H I ,2,3,5,-oxathiadiazol- 4 yl)inethyl oxy[ benzox epiflo[2,3 blP yridin-5 yl 1den )prop>l pipe-ri din4o 1 To a solution of the product of Example 407 (700 mng) in TI-F (20 n-il) were added pyridine (0.21 ml) and thionyl chloride (0.1 ml) at 0 0 C, and the mixture was stirred at 0 0 C for I hour and the mixture was stirred at room temperature for minutes. \Water, chloroform~ and 2-propanol were added to the reaction mixture.

The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with chloroform-mnethanlol 1) to give the titled compound (170 mng).

MS inlz: 581(M+1) -175- Example 410: 4-(4-Chlorophenyl)-1-[3-(5,11 -dihydro-7-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3yl)methyloxy[ 1 ]benzox epino[2,3 -b]pyri din-5-ylidene)propyl]piperidin-4-ol To a solution of the product of Example 407 (700 mg) in THF (20 ml) was added thiocarbonyldiimidazole (280 mg) and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was extracted, and the solvent was distilled off under reduced pressure. To the residue were added THF ml) and boron trifluoride diethyl etherate (0.8 ml), and the mixture was stirred at room temperature for 1 hour. Chloroform, 2-propanol and water were added to the reaction mixture. The organic layer was extracted, and the solvent was distilled off under reduced pressure. The residue was reslurried with acetone to the titled compound (180 mg).

MS m/z: 577(M+1) Example 411: 4-(4-Chlorophenyl)- 1-[3-(5,11 -dihydro-7-ethoxycarbonylacetyl[ 1]benzoxepino[2,3bjpyridin-5-ylidene)propyl]piperidin-4-ol To a solution of the product of Example 315 (250 mg) in THF (3.0 rnl) was added LDA (0.51 mol/L THF-hexane solution, 3.0 ml) at -78°C, and the mixture stirred at room iemperature for 20 minutes. The reaction mixture was cooled to 78C again, and added ethyl cyanoformate (76 pl), stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and aqueous sodium chloride were added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with chloroform-methanol (10:1) to give the titled compound (280 mg).

'H-NMR (CDC1 3 6: 1.26(3H, 1.67-1.85(2H, 1.93-2.13(2H, 2.28- 2.47(4H, 2.47-2.60(2H, 2.60-2.76(2H, 3.94(2H, 4.21(2H, q), -176- 5.60(2H, brs), 6.22(1H, 6. 98(1 H, 7.29-7.34(3H, in), 7.43 (2H, 7.59 (1 H, d), 7.7 1(IH, dd), 7.97(1K, 8.53(lK, d).

MS rnlz: 561(M+1) Example 412: 4-(4.-fluoropheflyl)- ,1 -dihydr0-7-hyd0xy[ I ]benzox epirlo[2,3 b] pyridin-l5 ylidene) propyllpipendile- 4 -ol To a solution of 5-(3-brornoPropylidefle)-5,l 1-dihydro-7-hydroxy- [1lbenzoxepiflo[2, 3 pYridine (2.59 g) in DMF (10 ml) was added 4-(4- F luorophen l.4-hydrox yp iPeri dine (1.02 o) and triethylamifle (835 The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in i'acuo. The residue was Purified by silica gel chromatography (87:10:3 ethyl acetate: methanol: triethylarnifle) to yield 0.9 g of the title compound. 'H-NMNR (DMS0) d: 1.64-1.69 (2H, in), 1.74-1.85 (2H, in), 2.27-2.52 (8H, in), 4.81 (IH, 5.1 6 (2H, brs), 6.08 (1 H, 6.62-6.71 (3H, mn), 7.12 (2H, 7.40-7.51 (314, rn), 7.72 (IH, dd), 8.48 (I H, dd), 9.09 (1IH, s).

ESI-MS in/z: 447 (M +i 1).

Example 413: 4-(4-fluoropheflyl)- 1-[3 -(5,11I -dihydro-7-carboxy[ Ilbenzoxepilol 2 3-b~pTi din-S ylide.ne)propyl] piperidine- 4 -ol The titled compound was prepared by following the procedure of example 118S, but replacing the compound of Example 169 with the trifDate derived firomn compound 412.

'H-NMvIP (MeOD) 8:1.79-1.85 (2H, in), 2.25-2.40 (2H, mn), 2.57-2.70 (2H, in), 3.06- 3.35 (7H, rn), 5.06-5.81 (2H, brs), 6.23 (1WH, 6.77 (1 H, 7.00-7.11 (2H, in), 7.37-7.56 (3H, in), 7.65-7.80 (2H, in), 8.01 (1H, 8.48 dd).

MS ml/z: 475 -177- Example 414: 4-(4-fluorophenyl)- 1 11 -dihydro-7-( 1 -hydroxy- I -methylethyl)- [1 ]benzoxepino [2 ,3 -b]pyri din-5 -ylidene)propyl]pperi dinle-4-ol The titled compound was prepared by following the procedure of Example 27, but starting with the methyl ester of the compound of Example 413.

'H-NMR (CDCI 3 8: 1.57-2.14 (12H,m), 2.34-2.45 (411,m), 2.50-2.61 (2H,rn), 2.63- 2.78 5.22-5.43 brs), 6.14 6.95-7.10 7.25-7.35 92H,m), 7.40-7.60 8.50 (1IH,.dd).

MS ml/z: 489 Example 415: 4-(4-Chlorophenyl)- 1 11 -dihydro-7-diethylcarbamocyl-( I ]benzoxepino[* 2 ,3propy]]piperidine-4-o] The titled compound w,%as prepared by following the procedure of Example 3 16, but replacing dimethylamine wi th diethylamine.

'H-NMNR (CDCI 3 5: 1.18-1.30 (6H, in), 1.65 (2H, 1.80 (11H, 2.05 (2H. dt), 2.30-2.45 (4H, 2.50 2.60-2.70 (2H, in), 3.35-3.50 (4H, mn), 5.30 (2H, brs), 6.15 (.114, 6.83 (IH, 6.90 dd), 7.10 (1W, dd), 7.23-7.35 (311, 7.40 (2TH. 7.5 6 (1 H, d 8. 50 (1IH, d MIS m/z: 563 Example 416: 4-(4-Chlorophenyl)-1 1-dihydro-7-phenylsulfonylcarbamoyl- [I ]benizoxepinol2,3 -b]pyridin-5-ylidene) p3ropyl]piperidine-4-ol To a solution of the compound of Example 44 (0.511 g, 1. 1 mmol) in dry THIF (20 mL) was added sodium hydride (60% in mineral oil, 48 mg, 1.2 riuno 1 and the slurry heated at 40'C under argon with stirring for 20 minutes.

Phenylsulfonylisocyanate (160 1 1.2 rnmol) wvas added and the mixture wxas stirred for 14 hours. The solvent was then removed by rotary evaporation to g-ive the crude product. The solid material was washed twice with 20 mL CH 2

CI

2 and -178then twice with 20 mL MeoK: CH 2

CI

2 to give the title compound (274 mg).

MS m/z:64 7 Example 417: 4-(4-Chloropheflyl)-I ,11 -dihydro-7-imiethoxycarbonyl-carbanoyl- [1 ]benzoxeponolI2,3-b]pyndin5-ylidene) propyljlpiperidine- 4 -ol To a solution of the compound of Example 44 (0.2 14 g, 0.46 mmol) in dry THY (5m-L) was added sodium hydride (60% in mineral oil, 28 mg, 0.7 mmcol), and the slurry heated at 50'C under argon with stirring for 20 minutes. Methyl isocyanatoforrnate (56 pl, 0.7 nimol) wa's added and the mixture was stirred for 14 hours. The solvent was then removed by rotary evaporation to give the crude p roduct. The residue was purified by silica gel chromatography eluting with a dichloromethale/2.O Mv amrmonia in mnethaniol gradient (0 to 4% MeOH over 1 hour) to glive the title compound (102 mg).

'K-INMR (CDCl 3 8: 1.60-1.65 (2H, 1.80 (1K, 2.05 (2H, dt), 2.30-2.45 (4H, mn), 2.50 (2141, 2.60-2-.70 (2H, 3.35 (3H, 5.30 (2H, brs), 6.15 (IH, t),6.83 (1H, 6.90 (1H, dd), 7.10 (IH, dd), 7.23-7.35 in), 7.40 (2H, 7.56 (11K, dd), 8.50 (IH4, dd).

MIS m/z: 565 Example 418: 4-(4-Chloropheflyl)- 1-[3 1-dlihydro-7-(R-3-ethoxycarbol-lpiperidine- 1 -yl)carbamoyl-I1]benizoxepiflo[2,3bp Tidin-5-yl idene) propyl]piperidine- 4 -o I Step 1: R-ethyl nip ecotate-L-tartrate (1.53 g) was freebased with aqueous sodium hydroxide and ethyl acetate. The organic layers were evaporated, and the resulting am-ine was redissolved in THE (10 mL) and treated with carbonyl-diimidazole 81 The resulting solution was stirred at room temperature for 23 hours, concentrated ini vacuo, and redissolved in acetonitrile (5 mL). This solution was treated with methyl iodide (0.347 mL) and stirred for 18 hours at room temperature.

-179- Step 2: The compound of Example 44 (0.7 g) was suspended in THE (25 mL) and treated with sodium hydride (0.036 g) and stirred at room temperature for one hour.

The resulting anion was added to the imidazolium salt prepared in Step 1, and the solution was heated to reflux for 18 hr. The crude material was then loaded on silica gel and purified by silica gel chromatography (87:1 0:3 ethyl acetate:methanol:triethyl amInne) to yield 0.278 g of the title compound.

'H-NM (DMSO) 5: 1.11-1.21 (3H, in), 1.45-2.0 (8H, in), 2.15-2.40 (6H, rn), 3.05- 3.15 (2H, in), 3.31 (2H, in), 3.95-4.15 (3H,im), 5.31 (2H, brs), 6.14 (1 H. 6.78 (1lH, 6.92 (1 H, dd), 7.05 (1lH, 7.33 (2H, 7.42-7.47 (3H, mn), 7.72 IH, dd); 8. 50 (1 H, dd).

ESI-M4S iz: C-46 (M 1).

Example 419: 4-(4-Chlorophenyl)-l1-[S-(5,l 1-dihydro-7-(R-3-ethoxycarbonyl-pilperidine-1 -yl carbamnoyl-[ 1 ]beinzoxepino[2,3-bjpyrdin-5-ylidene) propyl]piperidine-4-ol The compound of Example 41 S (0.195 was dissolved in THF (1 mL) and treated with aqueous Ilithiumn hydroxide (0.0084 g) and stirred at room tempe-rature for 1 8 hours. The resulting solution was concentrated in vacuo, and the residue was puifIied by chrom~atography on a reverse-phase solid-phase-extraction colunin, eluting. with water-acetonitrile, 0.1 formic acid, to yield 0. 153 g of the title compound.

'H-NMR (DIMS0) 8: 1.55-2.25 (8H, rn) 2.30-2.80 (10H, in), 3.22 (lH, in), 4.15- 4.35 (2H, mn), 5.41 (2H, brs), 6.35 (1H, 6.98 (1H, 7.13 (lH, dd), 7.25 (IH, d), 7.54 (2H, 7.64 (3H, mn), 7.90 (IH, dd), 8.50 (1K, 8.70 (IK, dd).

ESJ-MS m/z: 618 (M 1).

Example 420: 4-(4-Chlorophenyl)-1- [3-(5,11I -di hydro-7 ethoxycarbonyl -pip erid ine- l-yI)carbamoyl- [1]benzox epino 2 3 -blpyri'din-5-ylidene) propyl]pipen'dine-4-ol -iso- The titled compound was prepared by following the procedure of Example 418, but replacing R-ethyl nip ecotat-L-tatate with ethyl isonipecotate.

'K-NMvIR (CDCl3 5: 1.25 (3K, 1.60-1.80 (4H, in), 1.90-2.05 (4H, in), 2.25-2.65 in), 2.90-3.15 (2H, mn), 4.05-4.25 mn), 5.30 (2H, brs), 6.15 (lH, 6.75- 6.90 (PK, mn), 7.05 (lH, 7.20-7.40 in), 7.40 (214, 7.56 dd), 8.45 (11-, dd).

MS in/z: 647 Example 421: 4-(4-Chloropheflyl)-l dihydro-7-(4-carboxy-pipeidine-1-yl)--carbai-noyl- [1 lbenzoxepiflo [2,S-bpyridin-5y1idefle) propyllpipefldifle- 4 -ol A solution of the compound of Example 420 (91 mg, 0. 14 nimol) ini Me4OH mL) was treated with a 0.4 M solution of lithium hydroxide (5 inL, 2 -irnol) and stirred for 3 hours. After addition of 5 mL of 0.4 N..HCl, the solvent was remioved under reduced pressure to give the crude product. The residue was purified3 using silica gel chromiatograPhy eluting with a di chloron ethafle:m ethanol gradient (0 to 0% MAeOR over I hour) to Pve the title compound (48S mg).

IH-N\MR (MieOD) OE:1.60-1.65 (2H, m) 2.10-2.70 (1 OH, mn), 5.30 brs), 6.15 (1HK, 6.80-6.90 (2K, 7.20-7.50 (6H, 7.62 (1KH, dd), 8.48 (1H, dd).

MIS mlz: 6 l 9 Ex ampl e 422: 4 -Chl o rophen yl) I [3 (5,11 -d jhy dro-7 -(S3Cthoxyc arb o n yl pI perdne -I yl) carbam-oyl-[ I benzoxepino[2,3bp)Tidfln 5-ylidene) propyllpiperi die4o

I

The titled compound was prepared by following the procedure of E-xample 418, but replacing R-ethyl nip ecotate-L-tartrate with ethyl (S)-nipecotate-D -tartrate.

'K-NMR (CDCl 3 8: 1.25 (3H, 1.30-1.70 (5H, mn), 1 .94-2.05 (3H, in), 2.25-2.65 (I IK, mn), 3D.05-3.15 (IlH, in), 4.05-4.25 (4K, in), 5.30 (2H, brs), 6.15 (lii, 6.75- 6.90 (2H, in), 7.05 (1 H, 7.20-7.40 (3H, in), 7.40 (2K, 7.56 (IH, dd), 8.45 (1I-H, dd).

-181- MS m/z: 647 Example 423: 4-(4-Chlorophenyl)- 1 -dihydro- 7-ethoxycarbonyl-[ I ]benzoxepino[2,3 propyljpiperidine--4-ol The compound of.Example 169 (0.166 g) was dissolved in DMF (I rnL) and treated with palladiumn (I1) acetate (0.007 1, 3 -bi s-diphenylphosphinopro pane (0.012 triethylamine (0.1 mL) and ethanol (I rnL), and stirred at 60'C for 18 hours under a CO balloon. The resulting- solution was quenched with water, extracted with ethyl acetate, concentrated in vacuo, and purified by silica gel chromatography (87:1 0:3 ethyl acetate:mcthanol: tri ethyl am ine). The residue was further purified by chromatography on a reverse-phase solid -phas e-ex tract) il colunm, eluting with water-acetonitrile, 0. 1%/0 formic acid, to yild 0. 114 g of the title compound.

'H-NTvN. (DMSO) 6: 1.28 (3H, 1.40-1.55 (2H, nm), 1.71-1.85 2.20-2.160 (6H, mn), 3.22 (2H, 4.28 (2H, 5.00-5.60 (2H, brs), 6.21 (1lH, t),6.92 (lIH, d), 7.4 0- 7.8 0 (SH, mn), 8.5 0 (1IH, d).

ESI-MS in/z: 519 (M I).

Example 424: 4-(4-Chloropheny])-1 1-dih~ldro- 7 -(ethoxycarbonvtlrnethyl)-oxy-carboniyl- [1 benzox epino [2,3-blpyri din- 5 yli]dene-) propyl]piperidine-4-ol The procedure of Example 423 was followed, but replacing ethanol wvith ethyl -glyoxylate to yield 0.041 g of the title compound.

'H-NMR (DMS0) 5: 1.10-1.30 (3H, mn), 1.35-1.55 (2H, in), 1.60-1.85 (211, mn), 2.20-2.60 (6H, in), 3.32 (2H, mn), 4.05-4.25 (2H, mn), 4.87 (2H, 5.00-5.60 (2H, brs), 6.21 (lIH, 6.92 7.2-7.90 (8H, in), 8.50 (IH, d).

ESI-MS mlz: 577 (M I).

Example 425: -182- 4-(4-Chlorophelyl)-l1-[3-(5 ,1 I -dihyldro-7-cyclohexyloxyearbonyl- [I ]benzox ep ilo[ 2 3 -b~pyri din- 5 -yli den e) propyflpiperidile- 4 -Ol The procedure of Examnple 423 was followed, but replacing ethanol with cyclohexaflol to yield 0.050 g of the title compound.

'1-l-NMR (MeOD) 5: 1.30-2.20 (14H, mn), 2.53-2.60 in), 2.95-3.32 in), 5.00 (lH, in), 5.00-5.60 (2H, brs), 6.28 (IH, 6.92 7.40-7.55 (8H, mn), 7.95 (2H, mn), 8.05 (1K, 8.50 (2H, mn).

ESI-MS mlz: 573 (M 1).

Example 426: 1 0 4-(4-ChlorophenylY-I-[3-(5, 1l-dihydro-7-( I -propoxy)carbonl-[l benzoxepinot 2 3 bjpyri din-5-Y lidefle) propyflpiperidiflno To a solution of the compound of Example 118 (109 mg, 0.22 inmol1) in dry, DMF (5 inL) was added potassium carbonate (91 mag followed by propyl iodide (24 4L, 0.66 miol). The mixture was heated to 55'C for 14 hours. The mixture wa,,s 1 5 diluted with ethyl acetate (200 rrL), wvashed twice with wlater (200 inL) and then wilth brine (100 mnL), and dried with sodium sulfate. The., gnc solvent was removed under reduced pressure and tlhe residue subjected to silica gnel chromatography using a dichloromfethafle :methanol gradient (0 to 5% MeOK over hour) to give the title compound (103 mg) 'H-NMR (CDCI 3 6: 1.06 (3H, 1.50-2.10 (414, in), 2.14-2.25 (2H, mn), 2.3 1-2.75 (101OH, mn), 4.28 (2H, 6.15 (11-H, 6.S 3 (1K, 7.24-7.3 8 mn), 7.42 (211, d), 7.59 (1KH, dd), 7.7 8 (1KH, dd), 8.00 (11-H, 8.50 (1IH, dd).

MS m/z: 533 Example 427: 4-(4-Chlorophenyl)-l ,l 1 -dihydro-7-(l -butoxy)carbol-[ I benzoxepiflo[ 2 3 propyllpipeidine- 4 -ol The procedure of Example 423 was followed, but replacing ethanol with nbutanol to yield 0.065 g of the title compound.

-183- 'H-NMR (MeOD) 6: 0.85-0.91 (3H, in), 1.25-1.45 (2H, mn),1.55-1.70 (2H, rn), 1.70-1.85 (2H, in), 2.10-2.28 in), 2.53-2.60 (2H, in), 3.15-3.38 (6H, 4.12- 4.21 5.00-5.60 brs), 6.10 (IH, 6.76 (IH, 7.22-7.40 (3H,mi), 7.71 (LH, mn), 7.95 (IH, mn), 8.05 (IH, 8.30 (1H, 8.41 (IH, in).

ESI-MS rnlz: 547 (M 1).

Example 428: 4-(4-Chlorophcnyl)- 1-dihydro-7-(2-propoxy)carboinyl-[ I]benzox epino[2,3bipyri din-S-yli dene) propyl]piperidine-4-ol The titled compound was prepared by following the procedure of Example 1 0 425, but repitacing propyl -Iodide with 2-bro'iriopropane.

H -NN'ER (C D CI 3 8: 1.3 0-2.10 (8 H, 2.14 -2.2 5 (2 H, mn), 2. 31I- 2.7 5 (10OH, in), *5.15 -5.6 0 (2 H, mn), 6.15 (1lH, 6.S83 (I H, 7.2 4 -7.3 8 (3 H,nm) 7.4 4 H, 7. 59 (I H. dd), 7.80 (1IH, dd). 8.02 IHd), 8.50 (11-I. dd).

MS in/z: 533 E-,aiple 429: *4-(4-Chlorophenyl)- 1 11 -dlihydro-7-cyclope.ntyll-oxyicarbonyl- [1 jb-.nzoxepIno[2,3 -b]pyrIin-5-:Id ene.) propyl]pipen idine-4-ol The titled compound was prepared by following the procedure of Example 426, but replacing propyl iodide with cyvclopenityl boimilde.

'H-NNT4R (MeOD) 6: 1.231-1.33 (1H, in), 1.50-2.04 (10H, mn), 2.27-2.41 (2H, mn), 2.70-2.90 (2H, mn), 3.30-3.62 (5H, 5.21-5.85 (3H, in), 6.15 (1IR, 6.85 (111i, d), 7.38 (2H, 7.42 (2H, 7.60-7.82 (2H, mn), 8.04 (11-H, 8.61 (1 H, dd).

MS inlz:559 Example 430: 4-(4-Chlorophenyl)- I 1-dihydro-7-(2-mor-pholinoethyl- 1 -yl)-oxycarbonyl- [I ]benzoxepinol2,3 -b~pyridin-5 -ylidene) propyl ]pip eri dine-4-ol The titled compound was prepared by following the procedure of Example -184- 426, bi~t replacing propyl iodide with 2-morpholifloethyl chloride.

'H-NMR

(CDC

3 5: 1.62-1.70 (2H, m) 1.90-2.13 (2H,mr),2.30-2.80 (14 H, rn) 3.62-3.75 (4H, in), 4.41 (2H, 5.11-5.62 (2H, brs), 6.19 6.83 (lIH, 7.23- 7.38 (3KH, in), 7.42 7.59 (1K, dd), 7.78 (1H, dd), 8.00 (1K, 8.50 (1K, dd).

MS m/z: 604 Ex ampl e 4 31: 4-(4-Chloropheflyl) 1 1 dihydro-7-(2, -diethyamifloethyl- 1 yl)-oxycarbofl- [1 ]benzox epino[ 2 3 -b]pyridin-5 -ylidene) propyllpiperdine- 4 -ol The titled compound was prepared by following the procedure of Ex ample 426, b~ut replacing propyl iodide with 2-(N,N-di ethyl amio)ethyl chloride.

'l--NMR (CDC1 3 6: 1.06 (6H, 1.62-1.71 (2H, mn), 1.93-2.10 (2H, in), 2.30-2.75 (12H, in), 2.85 (2H, 4.38 (21-4, 5.20-5.58 (2K, brs), 6.15 (1K, 6.S3 (lH, d), 7.24-7.38 (3H, in), 7.42 (2H, 7.59 (1H, dd), 7.78 (1K, dd), 8.00 (IH, 8.50 (I dd).

MSmiiz: 590 Example _432: 4-(4-Cnlorophelyl)- 1-[3 -(5,11 -dihiydro-7 -2.2-dim ethylpropioflyl -oxYviietllyD)ox ycarbonyl-( I )~benzoxepilo[2,3 -b1pyridiInS -ylidene) propyl]piperIdin.-- 4 ol The procedure of Examnple 426 was followed, but replacing with chloroinethyl pivalate to yield 0.36 g of the title compound.

'H-N-MR

(CDCI

3 8: 1.18 (9H, 1.58-1.72 (2H, ma), P.85-2.85 (10H, mn), 5.-00-5.60 brs), 5.94 (2H, 6.17 (1 H, 6.82 (1IH, 7.22-7.42 (5K, mn), 7.56 (1IH, dd), 7.80 (IH, dd), 7.99 (1K, 8.05 (lH, 8.46 (IH, dd).

ESI-MS n-t t z: 605 (M I).

Example 433: 4-(4-Chlorophelyl)- ,1 1 dihydro-7-(2-hydroxyethyl I -yl)-oxycarboriyl- [1 benzoxepilo[ 2 3 -blpyridifl-5-ylidefle) propyll pip eri difle- 4 -ol -185- The procedure of Example 423 was followed, but replacing ethanol wvith ethylene glycol to Yield 0.076 g of the title compound.

'H-NMR (MeOD) 8: 1.80-2.00 (414, in), 2.25-2.35 (2H, in), 2.55-2.65 (2H, mn), 3.15-3.45 (5H, in), 3.75 (2H, dd), 4.24 (2H, dd), 5.00-5.60 (2H, brs), 6.10 t), 6.76 (lH, 7.18-7.42 (5H, mn), 7.71 (2H, in), 7.99 (111, mn), 8.05 (IH, 8.30 (IH, 8.41 (1IH, mn).

ESI-MS inlz: 535 (M 1).

Example 434: {3-[4-(4-Chloro-phe nyl)-4-hydroxy-3-methy1-ppel dinl- I-yl]-propylidene 1-5,11Idihydaro- 10-ox a-I -aza-dibenzo[ a,d]cycloh-epten-7-ol Stop 1: 3-\ethyl-4-oxo-piperidine--1 -carboxylic acid tert-butyl ester In a Parr shaker flask, I -benzyl-3-methyl-4-piperidone (19 g, 93 nuimbI), ditert-butyl dicarbonate (27g, 121 miol) and palladium hydroxidc (2.6 0) weN(-re suspended in methanol (75 rnL) and then purged wvith argon. The reaction mnixture was then purged with hydrogen and placed on a Parr shaker apparatus for about 16 hours at about 44 psi of hydrogen. The catalyst wxas filtered over celite and wkashed wi'-th methanol. The crude product was chromatographed on silica gel, elutiing, with EtOAc /hexane to give a white crystalline solid.

1 H-NMVR (CDCI 3 0.97 1.45 (9H, 2.37-2.53 (3H, 2.80 (1H, bins), 3.16-3.26 01H, 4.11-4.18 (2H,mr).

ESI-MIS mlz: 15 8 [M CH=C(.CH 3 )2 I] Step 2: 4-(4-Chl oro-ph en yl)-4 -h ydro xy-3 -m ethyl -pip eri din e- I -carboxyl ic acid tertbutyl ester To 4-chlorophenyl magnesium bromide (49 mL, 49 minol, I M in diethyl ether) at about 0 'C under argon, was added 3 -Methyl-4-oxo-piperi dine- Icarboxylic acid tert-butyl ester (7 g, 32.8 mmrol) in THfF (50 mL) over a per-iod of about I hour. The reaction was allowed to warm to room temperature and stirred -186overnight. The reaction was quenched with saturated ainmonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over sodium sulfate. The solv'ent was evaporated and the crude residue was recrystallized in EtOAc to give a white solid.

'H-NN4R

(CDCI

3 8: 0.58 (3H, 1.45 (9H1, 1.50-1.69 (2H, in), 1.76-2.13 (211, in), 2.80 (1 H, 3. 10 (11-H, 3.96 (2H1, brs), 7.29 (4H, mn).

ESI-NIS rn/z: 252 [M CH=C(CH) 2 H0+ 11.

Step 3: 4- (4-Chl oro-ph enyl)- 3 -mnethyl1-p iperid if- 4 o I To a solution of 4-(4-Chloro-pheflyl)-4hydroxy-3 -methiyl-piperidin e-l carboxvlic acid tert-butyl ester (1 .5 g, 4.6 ininol) in dichlorornethafle (40 nIL) at about 000 w?,as added tri fluoroacetic acid (10 The solution was stirred for about 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was neutralized with saturated sodium bicarbonate, and Washed with bne- and dried over rna--nesium sulfate. The solvent was rernoved to give a yellow solid. No purification was needed.

H-NN!vM (CDCI,) 6: 0.65 (3H, 1.85 (IH, d)j, 2.52 (21)H, in), 3.05 (IR, 3.27 (111, dd3, 3.34 (2H, 7.40 (4H, in).

ESI-MS nilz: 240 [M I~ 123 4 -(4-Chi oro-phenyl)-4-hydroxy- 3 -rnethyl-piperi din- I -yfl-propylidefl e} -5,11 dihiydro- 10-oxa-lI aza-dibenzo~a,dcycohepten 7 -o To a solution of 4-4Cioopeil--ehlpprdn4o (1.0 g, 4.6 rnmiol) in DMF (10 ruL) with triethylamine (1.75 m-L, 12.54 rnmrol), was added 5-(3- Bronlo-propylidene)-5,11 -dihydro-1I0-oxa-l1 aza-dibenzo~a,dcyclohepten-7>oI (1.38 g, 4.18 inmol) drop wise for over a period of about 1.5 hours at about 50 IC The reaction was stirred overnight at about 50 The reaction -was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromnatography (87:10:3 ethyl acetate: methanol: tri ethylaine) to yield a brown solid of the title compound.

-1S7- 'H-NMR (CDC1 3 8: 0.53 (3H, 1.60-1.69 (21H, mn), 2.07-2.30 (3H, in), 2.34-2.51 (3H4, 2.56-2.75 (3H, in), 2.76-2.87 (1H, in), 2.98-3.11 (IH, mn), 5.25 (2H, brs), 6.12 (1H, 6.64-6.79 (3H, 7.20-7.40 (5H, rn), 7.53 (114, 8.50 (1IH, d).

ESI-MS ml/z: 477 [M 1].

Example 435: Trifluoro-inethanesulfoflic acid 5- {3-(4-(4-chloro-phenyl)-4-hydroxy-3-fethylpiperidin- I -yl]-propylidene} -5,1 1 -dihydro-1 0-oxa- 1 -aza-dibenzo[a,d]cyclohepten- 7yl ester The title compound was prepared according to the procedure of Exaxrnple 1 0 1 69 and obtained as.a brown solid.

'H-INMR (CDC1 3 8: 0.55 (3H4, 1.55-1.6S (2H, mn), 1.92-2.18 (2H, in), 2.24-2.69 (7-1 Hn), 5.3 6 (21-H, brs), 6.15 I H, 6.8 8 (114, 7.0 5 (11H, d 7.19 3 (6H4, in1), 7.6 0 (1 H, 8.5 4 (11H, d).

ESI-MS mlz: 609 [M I).

Examnple 436: 3 [4-(4-Chl oro-phe.nyl)-4-hydroxy- 3 -methvl-pi1pen'difl- I -vll -propy'Ident- 1 -5,11dihy/dro- I 0-oxa- 1 -aza-dibel-izoa,d]cvclohieptene--7-carboxylic acid methyl e-ster The title compound A.as p-epared according to the procedure of Exarnple 423 arnd obtained as a brown solid (formnate salt).

1 H-NMR (CDC] 3 6: 0.62 (31H, 1.75 (114, 2.41-2.71 (514, in), 2.90-3.14 (4H, mn), 3.27 (1H, 3.89 (3H4, 5.00-5.70 (2H, brs), 6.08 (114, 6.86 (1IH, di), 7.26- 7.3 9 (5 H, in), 7.5 9 (11H, 7.8 3 (1 H, 7.9 8 (1 h, 8.3 4 (114, 8.5 6 (11-a, ESI-MS mlz: 519 [M 1].

Example 437: 4-(4-Chloro-phenyl)-1- I-hydroxy- 1-methyl-ethyl)-I11H-I 0-oxa-lI-azadib enzo cycloh eptenl-5 -ylI dene] -propyl} 3-m ethyl -p lpenidif-4-ol -188 The title compound was prepared according to the procedure of Example 27.

The racemic compound was resolved using preparative chiral KPLC (ChiralPak

AD,

X 250 mm, isocrati elution with 10% ethanol:90% hexane, 15 mL/min., 17- minute run time). The more active enantiorrer eluted first, at 17 minutes. The less active enantiomer eluted second, at 23 minutes. white solid (formate salt).

'H-NN{R

(CDCI

3 6: 0.61 (3H1, 1.57 1.76 (1H, 2.43-2.72 (5H, in), 2.91-3.12 (411, mn), 3.25 (1H1, 5.04-5.46 (2H1, brs), 6.01 (1H, 6.82 (IH, d), 7.22-7.37 (5H, in), 7.46 (IH, 7.55 (111, 8.30-8.40 (1 H, brs), 8.52 (11-H, d).

ESI-MS rnlz: 519 [M 11.

Example 4 3 8: 3-4(-I]T-hnl--~drx\--nty-ieldn -yl]-propylidene 1dihydro- I 0-oxa-l -za-dibenzo[a,d~cyClohCptee7-carbox),lic acid The title compound was prepared according to the procedure of Example I1.8 and obtained as a brown solid (form ate salt).

'H-WIR

(CDCO

3 8: 0.49 (3H, 1.63 (IH, 2.29-2.43 (2H, in), 2.4-5-2.63 (3H, in), 2.7S-3.18 (5H1, rn), 4.K2-5.85 (2H, brs), 6.13 1H, t),6.67 (111, 7.19-7.3 1 in), 7.5 5 (11-H, 7.6 7 (1IH, 7.8S7 (1 h, 8.19 s) t 8.40 (1 H, d).

ESI-MS inlz: 505 [1\4 1].

Example 439: 5- .3 [4-(4-Chloro-phelyl)-4-hivdroxy-J ,5 -dirnethyl-piperidin- 1-y13-propyl id ene} 5,11 -dihydro-1I0-oxa-l1-aza-dibenzo ~a,d~cyclolhepten-7-ol Step 1: 1 -Benzyl-3 ,5-diinethy1-piperidifl-4-ofle To 1-benzy1-3-rnethylh4-pipefidone (2.0 g, 9.8 mmol) in THE at about -78 *C under argon, was added Lithium diisopropylainide (7.35 mL, 14.7 Mmol, 2 M in heptanelTllF/ethylbelzene). After stirring for about I hour at about -78 'C, iodomethane (0.73 mL, 11.8 nmol) was added. The reaction mixture was stirred for about 1 hour at about -78 *C then warmed to room temperature. Stirring was Ct -189continued overnight at room temperature. The reaction was quenched with saturated amnmonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate.

The crude product was chromatogaphed on silica gel, eluting with EtOAc /hexane 10) to give a yellow oil of the title compound.

'H-NMR (CDCl 3 6: 0.96 (614, 2.04 (2H, 2.62-2.78 (2H, in), 3.12-3.1 7 (2H, 3.59 (2H, 7.23-7.38 (5H, i).

ESI-MS 218 [M I].

Step 2: 3,5 -Dimethiyl -4-oxo-pipe ridine-l1-carbox yli c acid tert-butyl ester The title compound was prepared accordM,-g to the procedure of Ex ample 434, step I and obtained as a white crystalline solid.

H-NMR (CDCI 3 :1.02 (6H, 1.5 (9H, 2.47-2.75 in), 4.25-4.54 (2H, bins).

ESI-MS 172 [M CH=C(CH 3 )2 1 Step 3: 4-(4I-Chloro-ph-envl)-4-hydrox y-3 ,5-di rn ethyl-piperi dine- Il-carboxyli1c acid tert-butyl ester The title comipound was pzepar-.d according to the procedure of Example 434, step 2 and obtained as a white solid.

*'H-NMR (CDCI 3 6: 0.57 (6H, 1.49 (9H, 1.98-2.08 (2H, mn), 2.71-2.98 (214, in), 3.79-4.10 (211, in), 7.29-7.36 inn).

ESI-MS rn/z: 266 CH-=C(CH 3 2 H.,O I].

Step 4: 4- Chl oro-ph enyl) -3 ,5 -dim ethyl-pipei din-4 -ol The title compound was prepared according to the procedure of Example 434, step 3 and obtained as a light yellow solid.

'H-NMR (CDCI 3 8: 0.54 (6H, 1.97-2.11 (4H, in), 2.75 2.88 (2H, d), 7.27-7.32 (4H, rn).

-190- ESI-AS in/z: 240 [M I11I 3 4 -(4-Ch~oro-pheflyl)-4hydroxy- 3 ,5 -dimethyl-piperidifl- 1 -ylj -propylidefle 5,1 1 -dihydro- 10-oxa-1 -aza-dibenzo cycloheptefl- 7 -ol The title compound was prepared according to the procedure of Example 434, and obtained as a yellow solid.

1 H-NNMR (CDCl3 8: 0.58 (6H1, 2.50-2.80 (6H1, mn), 2.94-3.06 (2H, in), 3. 17 (211, 5.14-5.29 (211, brs), 5.87 (111, 6.75-6.90 (2H, in), 7.10-7.45 (6H1, in), 8.44 (I H, S. 52 (1 H, s).

ESI-MSminz: 491 [M I1 Example 440: 4-(4-Chloro-pheflyl)-l {3-117-(1 -hydroxy-1 -methyl-ethyl)- 1 I dibenzolia,dl cyclolheptefl-5 -yli dene]-propyl -3 ,5-direthyl-piperidifl- 4 -oI The title- compound was prepared according to the procedure of Example 439 but usinig -5()Brnopoyld-e- 1 -dihydro-l 0-oxa-l1-azadibenzo[a,d]cycloeptn7llpropan- 2 ol, and was obtained as a white solid (forinate salt).

'H-NN4R (CDCl 3 6& 0.59 (61-1, 1.58 (6H, 2.49-2.74 (6H, ill) 2.97-3.10 (2H1, mn), 3.16 5.20-5.45 (2H1, brs), 6.06 (1 H, 6.S3 (1IH, 7.12-7.43 in), 7.4 9 (1 H, 7.6 0 (1 H, 8.3 8 (1 H, 8. 54 (11H, in).

ESI-MS rnlz: 533 [M I].

Examples 441 and 442: 4-(4-Chloro-phenyl)-l -hydroxy-1 -methyl-ethYl)- I1IH-1 0-oxCa-l -azadibenzo[a,dllcycl ohepten-5 -ylidene]-propyl 3-methyl-piperidifl- 4 -ol and 4-(4-Chloro-pheflyl)-l 3-1i7-( 1-hydroxy- I -iethyl-ethyl)- IiH-I 0-oxa- I- 4-nethyl-piperidifl-3-oI -191- Step 1: 4-(4-Chloro-phenyl)-3 ,6-dihydro-2H-pyri dine- I -carboxylic acid ter-t-butyl ester To a solution of di-tert-butyl-dicarbonate 3.27 g, 15.0 mmnol) in CH 2 CI, mnL) was added 4-(4-chlorophenyl)- 1 ,2,3,6-tetrahydropiperidine hydrochloride( 3.02 g, 13.1 mmol) and triethylamine (3.6 mL, 20 mi-nol). The solution was stirred at about room temperature for about 15 hours. Gas evolution was observed. The reaction was quenched with aqueous amm~onium chloride, extracted with CIH 2

CI

2 and the organic layers were evaporated in vacuo. The residue was purified by plug filtration through silica gel to y ield the title compound as a colorless oil.

'H-NMR (CDCL 3 d: .1.50 (9H, 2.46 (2H, br 3.62 (2H, br 4.05 (2H, br s), 6. 0] (1H, br 7 .2 5 (4H, s).

Step 2: 6-(4"-Chloro-phienyl)-7-oxa-3-aza-bic~lclo[4. 1.0]heptane-3'-carboxyli c acid te-rt-butyl ester To a solution of 4-(4-Chloro-plheiyl)-3,6-dihydro-2H-pyrI dinle- I -carboxylic acid tert-butyl ester 3.8 g, 13 rnrol) in CH 2

CI

2 (50 rrL) was added 3chloroperbenzoic acid .8 g, 17.0 mnmol) and iriethylarnirie (3.6 mL, 20 rirnol).

The solution was stirred at -room temperature for about 4 hours. A-white precipitate was observed. The reaction was quenched with aqueous sodiurn bicarbonate, extracted w\.ith CI-,C1 2 and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35g SiO,, grad i ent elution fronm 100% hexane to 100% ethyl acetate) to yield the title compoand as a colorless oil.

'H-NN4R (CDCL 3 8: 1.50 (9H, 2.15 (1H, mn), 3.15 (2H, in), 3.6-4.2 (411, in), 7.31 (4H, s).

Step 3: 4-(4-Chloro-phelyl)-4-hydroxy-3-methyI -Piperidinle- I -carboxyli c acid tertbutyl ester and 4-(4-Chloro-phenyl)-3 -hydroxy-4-nethyl-pipeldine-l1-carb oxylic acid tert-butyl ester -192- A suspension of copper(I) iodide (0.38 g, 2 mmol) in THE (20 mL) was cooled to about 4"C, and treated with methylmagnesium bromide (6 rnL of 3M solution in diethyl ether, 18 mmol). To the cooled suspension of cuprate was added N ~6-(4-Chloropheyl)7oxa-3abicyclo[4. l .0heptane-3-carboxylic acid tert-butyl ester 1.9 g, 6.1 nmnol) in THE (5 mL). The solution was stir-red and allowed to warm to about room temperature for about 4 hours. The reaction was quenched with aqueous ammoniumr chlori de, extracted with ethyl acetate, and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35g SiO 2 gradient elution from 100% hexane to 50% ethyl acetate) to yield a mixture of the title compounds as a white foam. This mixture was carried on to the next step.

Stp4 ynthesis of 4 4 -Chloro-phefylme li eln 4 o an 4(-Chlorophenyl)-4-rnethyb-Piperidin-3 -ol The BOC-protected amino-alcohol mixture 0.8 c.2.5 rnmol) was dissolved in 4MN HiClfDioxafle (5 mL, 20 rnmol). The solution was stirred at room tem-perature for about I hour. The solvent was removed in v'acuo. The residue was quenched with aqueous sodium hydroxide, extracted with ethyl acetate., and the organ-ic layers were dried over sodium sulfate and evapo~ated in vacuc to Nyield the title compound as a brown solid.

ESI-MIS mlz: 226 (M 208 The mixture was carried on to the next step without further purification.

4-(4-Chloro-phel)l t3-[7-(l -hydroxy-lI-rnethyl-ethyl)-l I H-I 0-oxa-1 -az a- 6 jbefzo d]cycl oh eptefl 5 yl 1den ej propyl} -3 -m ethyl -piperi difl-4-ol and 4-(4 -Chloro -phenyl)- I 3 -hydroxy- I -methyl- ethyl)-I 1 H-I 0-oxa- 1- -4-methyl-pipenldifl- 3 -oI To a solution of the amino alcohol mixture (0.53 a, 2.3 mmol) in isopropanol (10 mL) was added 2,6-lutidine (0.23 mL, 2.0 mmol) and catalytic 193potassium iodide. This mixture was heated to about 80'C, and treated with 1-dihydro- 10-oxa-l1-aza-dibenzo[a,d~cyclohepten- 7 -yllpropan-2-ol 0.37 g, 1.0 mmol), added in portions over about 2 hours. The solution was then stirred at about 80'C for about ani additional 2 hours. The reaction was concentrated in vacuo, then purified by flash chromatography on silica gel SiO 2 gradient elution from 100% ethyl acetate to 87% ethyl rnethanol:3% triethylamine) to yield the title compounds.

The faster eluting isomer: 4-(4-Chloro-phenyl)- 1- -hydroxy- 1-methyl-ethyl)- I IH-1 0 -ox a- I -aza-dib enzo[ a,d] cyc Ioh epten- 5-yl dene] -propyl} -3 -niethy'l -Dipcri-din- 1 0 4-ol, a brown semisolid. 'H-NMR (CDCL 3 a: 0. 70 (3 H, d, J =7.2 Hz), 1. .53 (6H, 1.92 (3 H, 2.2 8-2.69 (SH, in), 5.3 0 (2H, br 6.15 (1IH, t, J 1.4 Hz 6.79 (2H, d, J S.4 Hz), 7.18-7.45 mn), 7.59 (IH, d, J 8 Hz), 8.45 (IH, in). ESI- MS m.z: 519(M 1).

The slower eluting isomer: 4-(4-Chiloro-phenyl)-1 -hydroxy- 1-methylethyl)-, a browAn semisolid. 'H-NMR (CDCL 3 8: 1.16 (3H, 1.55 (6H, 2.28- 2.69 (5H, 3.86 (111, br 5.30 (2H, br 6.07 (IH, t, J 1.4 Hz), 6.79 (2H) d, I1 =8.4 Hz), 7.18-7.45 (7H, in), 8.45 (IH, in). ESI-MAS rn/z:. 519(M 1).

Example 443: 4-(4-Chloro-phenyl)- 1- -hydroxy- I -mn ethyl -ethyl)- I1H-I 0-oxa- I -az adiberizo[a,d]cyclohepten-5-ylidene] -propyl 3,3 -dimethyl-piperidin-4-ol Step 1: 1 -Benzyl-3 ,3-dimethyl-piper-idin-4-one To a solution of 1-Benzyl-3-mietlhyl-piperidin-4-one (2.03 g, 10 mraiol) in THEF (10 niL) was added potassium t-Butoxide .1 g, 10 inmol) and methyl iodide( 0.62 niL, 10 mmol). The solution was then stirred at room temperature for about 72 hours. The reaction was quenched with brine and extracted with ethyl a cetate.

The combined organic layers were concentrated in vacuo, then purified by flash -194chromatography on silica gel (35g SiO 2 gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.

'H-NMvR

(CDCL

3 a: 1.12 (6H, 2.41 (211, 2.52 (2H1, in), 2.73 (2H, in), 3.56 (2H, 7.20-7.40 in). ESI-MS im/z: 218 (M4 1).

Step 2: 3,3 -Diinethyl-4-ox o-piperidine-l1-carboxyhic acid tert-butyl ester To a solution of I-B enzyl3,3 dim ethylpipeidin 4 one 2.48 g, 11 inmol) in ethanol (100 inL) was added di-tert-butyl dicarbonate (2.18, 10 mrnol) and palladium hydroxide 0.10 The suspension was then shaken under a hydrogen atmosphere (40 PSI.) at roonm temperature for about an additional 12 hours. The reaction was filtered through celite and evaporated in vacuo to yield the title compound as a white solid.

'H-'NMR

(CDCL

3 a: 1.12 (6H, br 1.48 (9H, 2.45-2.80 (3H, mn), 3.12 (IH, in), 3.42 (1lH, br 3.70 in).

Step 3: 4-4Clr-hnl--yr> -i ty-ielie -carboxylic acid tert-butyl ester To an ice-cool d-solution 3, -3D imeth %l14-oo-piperi dine-I -carb ox 'l ic acid tert-butyl ester (1 .6 g, 7.2 tiiol) in THF (20 mQL was added 4chlorophenyvirnagnesium bromide (1 M1 in ether, 15 rnL, 15 mmol). The solution was allowed to warm to about room temperature, then stirred at room temperature for about 22 hours. The reaction was quenched with aqueous ammionium chloride and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35g SiO 2 gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.

'H-NMP.

(CDCL

3 a: 1.12 1.50 (1111, mn), 2.60 (11H, in), 3.20 (2H1, mn), 3.56 (I H, in), 4.20 (1H, in), 7.20-7.40 (4H, in). ESI-MS m/z: 218 (M 1).

Step 4: 4 (4-Chl oro-phenyl> 3,3dim ethylpip eidin 4 -ol -195- 4-(4-Chloro-pheny])-4-hydroxy-3 ,3 -dimethyl-piperi dine- I -carboxyli c acid tert-butyl ester (0.25 g, 0.73 mmol) was dissolved in 4M HClIDioxane (2 ml, 8 mmol). The solution was stirred at room temperature for about 4 hours. The solvent was removed in vacua. The residue was quenched with aqueous sodium hydroxide, extracted with ethyl acetate, and the organic layers were dried over sodium sulfate and evaporated in vacuo to yield the title compound as a yellow solid. The mixture was carried on to the next step 'Without further purification.

4-(4-Chloro-phenyl)- I -hydroxy- I -methyl-ethyl)-l 1H- 1 0-oxa-l -aza- 1-3,3 -dirnethyl-piperidin-4-ol To a s olution of the amino alcohol mixture (0.17 g, 0.Trnmol) in isopropanol rnL) was added 2,6-lutidine (0.23 mL, 2.0 mimol) and catalytic potassiurim iodide.

This mixture was heated to about S0 0 C, and treated with 2-[5-(3-Brornopropylidene)-5,1 1-dihydro- 10-oxa-lI-aza-dibernzo[a,d]cyclohepten-7-\'l]-propan-2-oI 19 g, 0.5 mrn 01), added in portions over about 2 hours. The solution was then stirred at about 80'C for an additional 2 hours. The reaction was concentrated in vacuo, then purified by flash chromatography on silica gel (l Og SiO 2 gradi ent el ution from 100% ethyl acetate to 87% ethyl acetate:]10% methanol:3% triethylamine) to yield the ti-tle compound as a brown semisolid.

'H-NTNR (CDCL 3 a: 0.7S (3H, 0.90 (3H, 1.45 (2H, mn), 1 .53 (614, 2.28- 2.80 (9H, in), 5.30 br 6.15 (lIH, t, J 1.4 Hz 6.79 (2H1, d, J1 8.4 liz), 7.18-7.45 (7H, rn), 7.59 (IH, d, J 8 Hz), 8.45 (IH, mn). IESI-MS m/z: 533 (M 1).

Example 456 4-(4-Chloro-phenyl)-lI- {3 -hydroxy-1 -methyl-ethyl)-1 lU-i 0-oxa-l-a~adibenzo- [a,d]cyclohepten-5-ylidene]-propyl -piperidine-4-carbonitriie Step I: Bis-(2-ch~oroethyl)-carbamic acid tert-butyl ester To a solution of bis-(2-chloroethyl)-amine hydrochloride 7 .12a, 4D mumol) in dichioromethane (65m1) was added N, N-disopropyl ethyl amine (34.8m], 200 -196mmol) and catalytic amount of 4-dimethylaminopyridine, followed by portionwise addition of di-tert-butyl dicarbonate (8.72g, 40 mmol). The solution was stirred at room temperature for 72 hours. The reaction mixture was concentrated and triturated with ether (70 ml). The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate to give the title compound (2.02 g, 21%).

'H-NMR (CDC13) 1.5 (9H, 3.5-3.6 (8H, m).

Step 2: 4-(4-Chloro-phenyl)-4-cyano-piperidine-l-carboxylic acid tert-butyl ester To 1.26 g (8.37 mmol) 4-chloro-benzylcyanide was added bis-(2chloroethyl)-carbamic acid tert-butyl ester (2.02 g, 8.37 mmol) in 25 ml N, Ndimethylfonnamide. The resulting mixture was stirred and cooled in an ice bath, then sodium hydride 60 suspension in mineral oil) (1.1 g, 42 mmol) was added portionwise. The reaction was brought to room temperature and then heated in an oil bath at 60 OC for 16 hours. The reaction mixture was quenched by addition of ice water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed rwice with water, once with brine, dried with magnesium sulfate and concentrated in vacuo. The residual brown oil was purified by silica gel chromatography eluting with hexane-ethyl acetate to give the title cormpound (1.44 g, 54%).

'H-NMR (CDC13) 5: 1.5 (9H, 1.8-2.0 (2H, 2.1 (2H, 3.2 (2H, 4.3 (2H, brs), 7.4 (4H, m).

MS m/z: 221 (M+1-100) Step 3: 4-(4-Chloro-phenyl)-piperdine-4-carbonitrile To a chilled solution of 4-(4-chloro-phenyl)-4-cyano-piperidine-l carboxylic acid tert-butyl ester (315 mg, Immol) in 5 ml dichloromethane was added 1 ml trifluoroacetic acid. The reaction was stirred at 0 °C for 3 hours, then concentrated under vacuum. The resulting oil was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate. The aqueous wa.shings -19 7were extracted three times with dichioromethane. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum to yield the title compound (180 mg, 82%).

'H-NMR (CDC1 3 6: 1.9-2.1 (4H, in), 3.0-3.2 (4H, in), 7.3-7.5 (4H, mn).

MS mlz: 221 (M+1) Step 4 To a suspension of 4-(4-chloro-phenyl)-piperdine-4-carbon trile (IS80 mg, 0.8 rnmol) in acetonitrile/water was added potassium carbonate (221 rrig, 1.6 rrnol), followed by -(3)-bronmo-propylidene)- ,I I1 -dihydro- 10-oxa-] -azadibenzoladcycohepten-7-ylIl-propan-2--ol (150 mg, 0.4 mnrol). The 'reaction Mixture was stirred at room temperature for 48 hours and then concentrated in v'acuo. The resulting residue was treated with water and extracted with eth-yl acetate.

Solvent was evaporated from the combined dried (1\ 4 0) organic extracts, and the residue was purified by column chroi-natog-raph)y on silica gel using hexane-ethyl acetate to afford the title compound.

'H-NNIR (CDCI 3 5: 1.5 (6H, 1 .8-2.0 (4H, mn), 2.4 (4H, mn), 2.55 in), 2.8 (2H, 53 brs), 6.1 (1H, 6.S (IH, 7.27-7.4 (7Hi, in), 7.5 8.5 (1H, d) inl/z: 5 14 (M\4+I) Example 457 1 -(4-(4-Chlor-o-phenyl)-i -hydroxyl-1-methyl-ethyl)-]Il-I 10-ox -azadibenzo [a,d~cycl ohepten-5 -ylidene]-propyl)}-piperi din-4-yl)-ethanone Step 1: 1 -[4-(4-Chloro-phenyl)-piperidin-4-yl]-ethanone To a dry round bottom flask was added via syringe 10 ml methyl inmagnesium bromide in toluene/tetrahydrofuran (75:25, 1.4 The flask was cooled i an ice bath under a stream of nitrogen. A solution of 4-(4-Chloro-pheny])-4-cyanQ:piperi dine-1I-carboxyl ic; acid tert-butyl ester (357 mg, 1.11 minol) in 4 ml -198tetrahydrofuran was added dxopwise to the flask over 20 minutes and the resulting mixture was stirred at 0 'C for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was quenched by slowly pouring 150 ml saturated aqueous ammoniumn chloride and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The yellow residue was purified by reverse phase 1{PLC to get the formate salt of the title compound (106 mg, MS m/z: 23S (M+l) Step 2 To a suspension of I-4(-hoopey)ppr di 4y] ehnn in actitie/water was added potassium carbonate (221 rng, 1.6 mmol), followed by 2-[5-(3)-bromo-propylIdefle)-5, 1I -dihydro-l 0-oxa-]I -azadibenzo[a,d]cyclohepteil7Y l]-propan.

2 -oI (150 mg, 0.4 mmol). The reaction mixture wvas stirred at roomn temperature for 48 hours and then concentratedl in vacuo. The resulting residue wvas treated with water and extracted with ethyl acetate. Solvent was evaporate from the comnbine-d dried (MgSO,) Organic e~<tracts.

P uinfi cation on, silica Qel chromatography using dichloromethane-mfethano 1 (9.5:0.5) afforded the title compound.

'H-,NMt\R

(CDCI

3 6: 1.3 (2H, in), 1.5 (6H, 1.9 (3H, ]2.5 (1IOH, in), 5.3 (2H, brs), 5.9 (1lH, 6.8 (11-H, 7.3 (6Hi, mn), 7.4 (1IH, 7.6 (1 H. 8.5 (1 H, d) MIS rnlz: 531 (M+l) Example 458 4-(4-Chloro-pel)>-I I-hydroxy-l1-methyl-ethyl)-I11H-I 0-oxa- I-azadibenzodl4]cyclohepten- 5-ylidene] -propyl) -piperi dine-4-carboxylic acid mnethyl ester Step 1: 4 -(4-Chl oro-pheflyl) -pip endine- 1 ,4-di carb oxylic acid mono-tert-butyl ester -199- To a Solution of 44 -chl oroph enyl-4cyno-piperiidine I -carboxyli c acid N Sodium hydroxide. The resulting solution was warmed to reflux for 48 hours, cooled to room temperature, poured into 1 N aqueous hydrochloric acid, and extracted into ethyl acetate. The organic extracts were washed with brine, dried over magnesium~ sulfate, and concentrated in vacuo. Recovered orange oil wvas purified by silica gel chromatography, eluting with dichloromethane-methanol to give the title compound (1.0 g, 86%).

MS ml/z: 338 (M-1) Se 2 -4Cllr-hey)pieiie-,-iaroyi acid Il-tert-butyl ester 4mnethyl ester To a stirred 4 4 -clorole,xiern,4-diarox..,acd on..rt huryl Z ese (8I -g m in methanol (5 rnl)-benizene- (17.5 ml) was added ml(tir et ylill~i o 1 2. M Souion in hexanes) at room temperature.

1 5 The mixture was stirred for 16 hours at room temperature and concentrated in VacZ4o. The residual yellow oil was purified by silica g2el Chromatogr-aphy el utingc wAith hexane-ethvl acetate 1) to gi%,e the Corresponding, ester (780 mng, 88%/l).

'H-NMR

(CDCI

3 6: 1.5 (9H, 2.8-2.9 (2H, ni), 2.5 3.0 (2H, 3.7 (3H, s), (2H, 7.4 (4H1, in).

MS m/z: 354 Ste 3:4-(-Choropheyl)P]Penidne.4-carboxylIic acid methyl ester The title compound was prepared by following the procedure of Example 6, Step 3, but rep lacing 4 4 -chloro-phenyl)4cyao-ppriin- -carboxyuIc acid tert-butyl ester with 4-4clr-hnl- lpr in-1 4 -dicarboxylic acid 1 zer-tbutyl ester 4 -i-ethyl ester.

iJ144tIR~

(CDCI

3 6: 1.9 2.55 2.9 3.25 (2H, 3.8 (3H, s), 7.2 (41H, m) MS 254 (M I) -200- St p4To a suspension of 4 4 -chlOrO-phenyl)>piperidine 4carboxylic acid m ethyl.

ester in acetonitrile/Water was added potassium carbonate (221 mg, 1 .6 mmrol), followed by 2 -[5-(3-bromo-propylidefle)-5,1 1 -dihydro- I 0-oxa-1 -azadibenzo[ad1Cccohepten7ylV-popanol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with waler and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO 4 organic extracts.

Purification on silica gel chromatography using dichioremethale-m~ethanol afforded the tiitle compound.

'H-NMNR (CDC13 6: 1.5 (6H, 1.8-2.0 (4H, mn), 2.1 (2H, in), 2.4-2.5 (7K, iii), 2.6 (214, in), 5.3 (2H, brs), 6.1 (1 H, 6.8 (IH, 7.3 (6H, rn), 7.4 (11-H, 7.6 (1IH, d) MS 547 (NM+1) Example 4 5 9 4-(4-Chl oro-phenyl)- I J 3 7-(l -hydroxy- I -methyl -ethyl)- I1 H-I 0-oxa-1 -aza- -dibenzo a,d] cvcloheptefi- 5-Nil ideriel -propyl) -piperidine-4-carboxylic acid To a solution 4-(4-Chloro-phefil)l- -hydro>;y-l-mrethyl-etlhyl)-I

IH-

I 0-oxa- -piperidine-4-carbox li c acid methyl ester (1 10 0.2 rnmol) in methanol (5 ml) was added 1 ml I N aqueous sodium hydroxide. The resulting solution was wanned to 50 'C for 1 6 hours, cooled to room temperature, and concentrated under a stream of nitrogen.

The residue was purified by reverse phase HPLC to get the formate salt of the title compound (96 rmg. 'H-NMR (CDC1 3 5: 1.5 (6K1, 1.8-1.9 (2H, in), 2.4 (4H, in), 2.55 (2H, mn),2.

6 2 .8 (4H, 5.3 (2H, brs), 5.9 (1K, 6.8 (1K, 7.27-7.4 (7H, in), 7.5 (IH,mn), (IH, d) MS ilz: 533 -201- E~xample 460 4 -(4-Chloro-phenyl)-1- (3-j17-( 1-hydroxy- I -methyl -ethyl)-] IlH- 10-oxa- 1-azadibenzo[a,djcyclohepten-5syldeney-propyl)-pein-4croycaidnle StepI: 4Carbmoyl4-(4chloo-phnyl-piperidine-4carboxylic acid r-ide Stept1: .To a solution of 4 4 -chloro-phenyl).4-cyano-piperi dine- I -carboxyli c acid tert-butyl ester (500 mg, 1 .56 minol) in ethanol (15 nil) was added 2 ml 10 N aqueous sodium hydroxide. The resulting solution was warmed to-reflux for 2 hours, cooled to room tembperature, poured into 1 N aqueous hydrochloric acid, and 1 0 extracted into ethyl acetate. The organic extracts were washed withi brine, dried over magnesium sulfate, and concentrated in vacuc. Recovered yellow oil was purnfied by siic p chromatography, eluting with dichloromethiane-i -t!ao to give the title compound (306 mng, MS rn/z: 339 (M+I) Step 2: 4 4 -Chloro-phen\vl).piperidine4carboxylic acid amide The title compound was prep ared by followingr the procedure of Example 456, step 3, but reptacing 4 4 -chloropenyl4c\vanopiperi dinel carbox lijc acid tert-butyl ester with 4 -carban oyl chloro-ph envl)-p iperi dine- 1 -carboxy I Ic acid tert-butyl ester.

MS ml/z: 239 (M+l) Step 3 The title compound was prepared by following the procedure of Example 456, step 4 but replacing 4-4clr-hnl-iprie4croirl with 4-(4chloro-phenyl).piperidine-4-caboxylic acid aride. Purification on silica -el chromatography using d ichlorornethane.m ethanol afforded the title co)mpound.

'H-NMR

(CDCI

3 5: 1.5 (611I, 1.8-2.0 (6H, in), 2.3-2.6 in), 5.3 (214, bins), 6.1 (lI H, 6.8 (1 H, 7.3 (6H, m),7.4 (I1-H, 7.5 (1 8.5 (1IH, d) -202- MS rnlz: 532 (m+l) Example 4 6 1 -1ylprpldn)5

I

t{3 4 4 -Chloro-phefl14hydoxyrnethylpip eridin l-rpl dn}-,1 dihydro-1 0-ox a- I- aza-dibelzo[a,dl1cyclohepten- 7 -yl)-propafl- 2 -0l Step 1: 4 4 -Chloro-phenlD4-hy&oxymethyl-pipen dine- -carboxylic acid tertbutyl ester To a chilled solution of 4 4 -chloro-phenyl)-p iperi dine1,4-dicarbox yl acid 1 -tert-butyl. ester 4-methyl ester (700 mg, I .98mrnol) in 6 ml ether was added dropwise 2rnl lithium alumini'um hydride 1I\ solution in ether. The reaction was stirred at 0 'C for 3 hours, then water (100 ml) was slowly added. The resulting gel was filtered and the aqueous filtrate was extracted three times with ether. The combined organic layers were dried with magneium, sulfate and concentrated under \!aculn.Recvered oil was purified by silica gelI chomatography, eluting with hexane-ethv'l acetate to give the title compound (297 nig, 46%).

'H-trM\R (CDCI3 5: 1.5 1.7-IS (2H, mn), 2.1 3.0 mn), 3.5 (2H, 3.7 (2H, 7.4 (4H, in) MS miz: 324 (M-1) Step 2: [4-(4-Chl OrO-phenyl)-Piperi di1T4 ylmethanol The title compound was prepared by following the procedure of Example 456, step 3, but replacing 4 4 -choro-phenyl)4cyano-piperidine- I -carboxylic acid tert-butyl ester with 4-(4-chloro-pheflyl>4-hydro xyniethyl -piperi dine- I -c arboxyli c acid fe,-t-butyl ester.

MS mlz:. 224 (M-1) Step 3 The title compound was prepared by following the procedure of Example 456, step 4, but replacing 4 4 -chloro-phnyl)piperdine4carbonitrile with -203chioro-phenyl )-piperidiri-4-yl]-methanol. Purification on silica gel chromatography using di chl orometh an e-mnethanol afforded the title compound.

'H-.NMR (CDC1 3 5:1.5 (6H, 2.0 (2H, in), 2.2-2.3 (4H, m) 2.4 (2H, in), 2.55 (2H, mn), 2.8 (2H1, 3.5 (2H1, 5.3 (2H, brs), 6.0 (1 H, 6.8 (1H, 7.27-7.4 (7H, in), 7.5 (1IH,d), 8.5 (1lH, d) MS in/z: 517 (M-1) Example 462 (3 4-(4-chl oro-ph enyl)-4-(I -h ydrox y-ethyl)-piperi din -I -yl]-propylidene}1 5,1 1-dilhydro-1 0-oxa-l1-aza-di~b.nzo[a,dlcyclohepten-7-yl])-propan-2-o To a chilled solution of I -(4-(4-Chiloro-phienyrl)- 1- -ydroxy"- Imiethyl-ethyl)-I11 N-I0-oxa-] -aza-dibenizo[a,d]cyclohepten-5-ylidenel]-prop\'l} -Ierd in-4y)ehnn 7 n,01 nn in 5 ml methanol was added sodium borohydride (20 mng, 0.53 mrnol). The reaction mixture was stirred at 0 'C for 4 hours, then concentrateld down unde-r a strecam of nitrogen. The residue was purifled by reverse phase HPLC to get the forinate salt of the title compound (39 mg-, 56%).

1H-NMR (CDC1 3 3:0.8S (4H, 1. 5 2. 1-2.7 (101OH, 3.1 (2H. 11), 5.3 (2H, brs), 5.95 (1 H, 6.8 (1 H, 7.27-7.41 (7H, rn), 7.5 (1IH,d), 8.5 d) MAS rn/z: 533 (M+1) Example 463 {3-[4-(4-Chloro-pheniyl)-4-( I-hydroxy- I -mnethyl -ethyl)-piperidin-lI -yI] propyli dene} -5,11 -dihvdro- I 0-oxa- I -aza-dibenzo[a,d]cyclohepten-7-yl1)-pr-opan-2-ol Step 1: 4- Acetyl -4-(4-chl oro-phenyl)-pip eri dine-lI-carbox yl Ic acid tert-buty] ester To a chilled solution of I -1 4 -(4-chloro-phenyl)-piperidin-4-yl].ethanone, (540 mg, 1 .98 nol) in dichlorornethane (1 Oml) was added triethylarnine (0.6 ml, 3.82 mumol), followed by portionwise addition of di-tert-buryl dicarbonate (470 mng, 1 .98 mmnol). The solution was stirred at room temperature for 16 hours. The -204reaction mixture was concentrated down, quenched with 1 N aqueous hydrochloric acid, and extracted into dichloromethane. The organic extracts were washed with Ssaturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, Sand concentrated in vacuo. Recovered oil was purified by silica gel chromatography, eluting with hexane-ethyl acetate to give the title compound N (445 mg, 67%).

'H-NMR (CDC13) 8: 1.5 (9H, 1.9 (5H, 2.3-2.4 (2H, 3.1 (2H, 3.7-3.8 (2H, 7.4 (4H, m) MS m/z: 338 (M+1) Step 2: 4-(4-Chloro-phenyl)- 4 -(l-hydroxy--methyl-ethyl)-pipeidine-l-carboxylic acid tert-butyl ester To a dry round bottom flask was added via syringe 16 ml methyl magnesium bromide in toluene/tetrahydrofuran (75:25, 1.4 The flask was cooled in an ice bath under a stream of nitrogen. A solution 4 -acetyl-4-(4-chloro-phenyl)-pipen dine- 1 -carboxylic acid iert-butyl ester (337 mg, 1.02 mnol) in 5 ml tetrahydrofuran was added dropwise to the flask over 20 minutes and the resulting mixture was stirred at 0 °C for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was quenched by slow addition of 150 ml saturated aqueous ammnonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The yellow residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate togive the title compound (242 mg, 67%).

'H-NMR (CDC13) 1.1 (6H, 1.4 (9H, 1.8-1.9 (2H, 2.3-2.4 (2H, 2.6 (2H, 3.9 (2H, 7.3 (4H, m) MS m/z: 354 (M+l) Step 3: 2 -[4-(4-Chloro-phenyl)-piperidin- 4 -yl]-propan- 2 -ol The title compound was prepared by following the procedure of Ex ample -205- 456, step 3, but replacing 4-(4-chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester with 4-(4-chloro-phenyl)-4-( I-hydroxy-l1-methyl-ethyl)-pip eridine- 1-carboxylic acid tert-butyl ester.

MS m/z: 254 QvI+1) Step 4 The title compound was prepared by following the procedure of Example 456, step 4, but replacing 4-(4-chloro-phenyl)-piperdine-4-carbonitrile with chiloro-ph enyl)-piperi din-4-yl ]-propan-2 -ol. Purification on silica gel chromatolgraphy usingc. dichloromethiane-methanol afforded the title compownd.

H-NMNR (CDCI 3 8: 1.1 (6H, 1.5 (6H4, 1.8 (2H, 2.3-2.6 (1 OH, 5. 3 (2 H, brs), 5.95 (1IN, 6.8 (1IH, 7.27-7.4 (7H, 7.5 (1IH,d), 8.5 (1 H, d) MS mlz: 547 (M+1) Example 464 4-(4-Chloro-phenylarnino)- I 1 -hydroxy-1 -methyl-ethyl)-l 11H-I 0-ox a- I -aza- 1 5 dibenzo[ad]cyclohieptein--yldene]-propyl -piperidine-4-carbonitriie Step 1: 1 -3 eazyl-4-(4-c hl oro -ph env]arnino)-piperi dine-4-carboi 1trilIe To a solution of I -Benzy'l-piperidin-4-one (2.68g, 14.2Oinmol) in acetic acid (13m1, o1acial) was added 4-Chloro-phenylaniine, (1,99g, 15.6mmol). The reaction wvas cooled in a cool temperature water bath. Trim ethylsilylcyani de (I .89rn1i, 14.2OmmoI) wvas added slowly. The reaction mixture was allowcd to warn,3 to room temperature and stir overnight under N 2 The reaction was cooled to 0 0

C.

Concentrated ammonium hydroxide (Il5ml) was added slowly. Next added was cold water. The pH of the mixture was The mixture was extracted three times with methylene chloride, and the organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Ether was added to the residue, and the white solid was filtered off and dried under high vacuum to give the titled compound (3.73 g, 8 1%) -206- 'H-NMR (CDCI 3 8: 1.90-2.01(2H,t), 2.3-2.4(2H,m), 2.45-2.55(2H,t), 2.81- N 2.93(2H,m), 3.61(2H,s), 3.68(1H,s) 6.87(1H,s), 6.90(1H,s) 7.2-7.38(7H,m).

MS m/z: 326 Step 2: 4-(4-Chloro-phenylamino)-piperindine-4-carbontrile To I -Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile (163mg, 0.5002mmol) in dichloroethane (5ml) was added 1-chloroethyl chloroformate (651, 0.600mmol). The mixture was heated to reflux and stirred under N 2 After 1 hour minutes, an additional 86ul (0.800mmol) of the chloroformate was added to the reaction and stirred for an additional 2 hours at reflux. After cooling to room temperature the reaction was concentrated under reduced pressure. To this residue was added methanol (5ml) and the reaction was heated at reflux for 2 hours. Next, the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was removed and sodium hydroxide (iN) was added to the aqueous layer until pHz9. The aqueous layer was extracted with ethyl acetate 2 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (S4mg, 71%).

'H-NMR 5: 1.66-1.68(1H,d), 1.70-1.75(2H,d), 2 77-2 2.87- 3.12(414,m), 3.61(1H,bs), 6.53-7.27(4H,m) MS m/z: 236 Step 3 The title compound was prepared by dissolving 2-[5-(3-Bromo-propylidene)- 5,11-dihydro-10-oxa- -aza-dibenzo[a,d]cyclohepten- 7 -yl]-propan- 2 -ol (106.7mg, 0.285mmol) in water (4ml) and acetonitrile (Iml). To this was added potassium carbonate (82.7mg, 0.599mmol) and 4-(4-Chloro-phenylamino)-piperidine- 4 carbonitrile (84.0mg, 0.356mmol). The reaction was heated to 50 0C and stirred overnight. The next day the reaction was allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was washed twice with -207water, dried over mag~nesiumn sulfate, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to give the title compound (1 1.5mg, 8% yield, 88%pure by LC/MS).

'H-NMR(CDCl 3 5: 1 .52(6H,bs), 2.2-2.8(1 2H, in), 3.4(lH,b), 5.1 6-5.36(2H,b), 6.00-6. 10(1H,m), 6.75-6.80(2H,m), 6.95-7.55(7H,m), 8.45-8.76(1I{,x) MS m/z: 529 (M 1).

Example 465 4-(4-Chloro-phenylarniino)- 1- I -h ydrox y- I -methyl -ethyl)- I1 H- 10-ox -azadiben~zo cyclohepten-5 .ylidene] -propyl} -piperidine-4-carboxylic acid methyl ester Step 1: 1 -B enizvl-4-(4-chl oro-ph en yl amin o)-pip enidine-4-carbox yli c acid aicl1e To I -Benzyl-4-(4-chloro-phenylanmino)-piperidine-4-car-bonitrile (1 97 g, was added concentrated sulfuric acid The reaction stirred at room temperature as an orange homogeneous solution. After 24 hours the reaction was cooled to 0CC and very slowly poured into concentrated ammioniuni hydroxide in ice-. The precipitate was filtered and washed with water to give a white solid (202mgo, 'H-NrMR(CDCl 3 6: 1.S7-l.92(2H,bd), 2.06-2.14 (2H,t) 2.27-238(214,m), 2.70- 2.78(2Hi,bd), 3.50(2Hs), 3.05(1H,s), 5.42-5.44(1 H.bs), 6.55-6.57(2H,d), 6. 76- 6.82( lH,bs), 7.10-7.1 5(2H,d), 7.24-7.31 MS m/z: 344 Step 2: 1 -B enzyl-4-(4 -chl oro -phenylam ino) -pip eri din e-4-carbox yl c acid methyl ester To a solution of I -Benzyl-4-(4-chloro-phenylamino)-piperidine-4-c arboxylic acid amide 19g 3.46mmol) in methanol (1lOmi) in a sealed tube was added toluene sulfonic acid (2.33g, 12.11mnnol). The reaction was heated to 120'C, and stirred at that temaperature behind a blast shield for 5 days. The reaction was then -208allowed to cool to room temperature at which time it was worked up by diluting with water, then by adding concentrated ammtonium hydroxide until the plHzS. The mixture was extracted three times with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The yellow oil was used crude (744mg, 1 H-NMR(CDCI3 OE: 1 .93-2.03(2H,bd), 2.1 9-2.28(2H,dt), 2.32-2.48(2H,m), 2.55- 2.64(2HJ,m), 3.51(2H,.5), 3.68(3H,s), 3.85 (IH,s) 6.47-6.51(2H,bd), 7.07- 7.1 0(21-,bd), 7.21-7.35(5H,m) NIS rnlz: 359(M±1) Step 3: 4-(4-Chloro-phel amnino) p i penidine-4-carbox yli c acid methyl ester The titled compound was prepared by following the procedure of Ex ample 464, step 2, b ut replacing I -Benzyl-4-(4-chilorophenylamiiio-piperidine- 4 carboni trile with I -Benzyl-4-(4-chloro-phenyl am ino)-piperidine-4-carbox yli c acid methyl ester. This compound was also purified on a sep-pak silica column eluted with 2% 10% M\eOH/CH 2

CI:.

1 1--NMR(CDCl 3 5: 1.92-1 .99(21{bd), 2.11 2.73-3.03(41-,m), 3 3 .94(tH,s), 6.50-6.53(2'H,bd), 7.09-7.1 2(2R,bd) IMS m'z: 2)69(Ml+l) Step 4 The titled compound was prepared by following the procedure of Ex amiple 464, step 3, but replacing 4 4 -clorophenylamifo)piperiine4carboritrile with 4- 4 -Chloro-pherlylamfino)-piperidine4carboxylic acid methyl ester. The residue was puified by reverse phase L-IPLG to give the title compound (62mg, 32%).

'H-NN4R(CDC 3 6: 1 .58(611,s) 2.09-2.20(2{,rn), 2.3 6-2.47(2F1,mf), 2.51 2.60(2H,rn), 2.85-3.02(6H, in), 3.69(3 5.19-5.41 (3 H,bs), 6.01-6.06(114,t), 6.51 6.54(2H,d), 6.82-6.84(IH,d), 7.10-7.1 3(2H,d), 7.24-7.34(2H,m), 7.43-7.44( IH,d), 7.55-7.58(1I-,d), 8.26(1H,s), 8.53-8.55(lH,dd) MS mlz: 562 (M) -209- Examiple 466 4 -(4-Chloro-ph enyl amino)- 1 f{3-[7-(lI-hydroxy- 1 -methyl-ethyl)- 1H-I 0-oxa- 1 -azadibenzo [ad]cyclohepten-5-ylidene] -propyl)}-piperidine-4-carboxylic acid amide Step 1: 4-( 4 -Chloro-phenylamino)-piperidine-4-carboxylic acid amide The titled compound was prepared by following the procedure of Ex ample 464, step 2, but replacing 1 Benzyl- 4 4 -chloro-ph enyl amino) -pip eri dine-4carbonitrile with 1 -Benzyl-4-(4-chloro-phenyl amino)-piperidine-4-carbox ylic acid arnide.

'H-NMR(CDC

3 6: 1 .82-1 .92(2H,bd), 2.1 0-2.37(3H,m), 2.69-2.79(2!H,m), 2.89- 1 0 3.03'(2H.m), 5.42-5.46(IH,bs), 6.47-6.59(2H,m), 6.76-6.82 IH,bs), 7.08;.

7. 15(2H,bd).

MIS rn/z: 254 (N+1) Step 2 The titled compound was prepared by following the procedure of Example 1 5 464, step 3, but replacing 4 4 -chilorophecnylamino)-piperdin--4-carbonitri1 e with 4- 4 -Chloro-phienv Ianiin o)-pipeid ine-4 -c arbox ylic acid amnide. The sample \,as puiied using, rceverse phase IIPLC to give the title compound (25mgv,

'H-\.M\R(CDC

3 5: 1.53-1 .55(7HF,s), I .97-2.07(2H,ni), 2.40-2.61 2.67- 2.76(31-,m), 2.86-2.96(2H.m), 5.20-,;.38(2H,bs), 6.04-6.09(1 HA), 6.51 -6.54(2H,bd).

6.77-6.80(l1H,bd), 7.08-7.11 (2H,bd), 7.1 9-7.29(214,m), 7.42-7.43(l H,bd), 7.51 7.55(1IH,dd), 8.1 S(IH,bs), 8.48-S.5O(lIH,dd) MS rnlz: 547 (M) Example 467 2 Q3-[4-(4-Chloro-phenyl)-4-fluoro-pipe-ridin- I -yl] -propyl i dene) -5,11 -dihydro- 1 0-oxa- 1 -aza-dibenzo[a,dlcyclohepten-7-y)-propan-2-oI Step I -210- To a cooled (0 solution of hydrogen fluoride (65 70 in pyridine (4 mL) was added 4 -(4-chloro-phenyl)-piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0 "C for 15 min and then warmed to rt and stirred lh. The mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with methylene chloride (100 mL; ADD SOLVENT AND EXTRACT SLOWLY AND WITH

CAUTION).

Excess hydrogen fluoride was neutralized with solid sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with a methylene chloride to methylene chloride/methanol/ammonium hydroxide gradient to give 4-(4-Chloro-phenyl)-4-fuoro-piperdine (260 g, 52 'I--NMR (CDCl1, 300 MHz) 5: 2.98 3.14 4 1.87 2.10 4 7.33 7.36 4 H).

"'F-NMR (CDC1 3 282 MHz) d: -160.40 -160.20 MS m/z: 214 (M 1).

Step 2 To a solution of the product of Step 1 (252 mg, 1.18 mmol) in isopropyl alcohol (5 nL) was added 2,6-lutidine (197 mg, 214 uL, 1.84 mmol) and potassium iodide (few mg). The resulting suspension was warmed to 80 Solid Bromo-propylidene)-5,1 1-dihydro- 0-oxa-1 aza-dibenzo[a,d]cyclohepten- 7 -yl]propan- 2 -ol (221 mg, 0.591 mminol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80 The mixture was concentrated and the resulting residue purified by silica gel chromatography (methylene chloride to methylene/methanol 95:5 gradient) to afford the title compound (160 mg, 54 'H-NMR

(CDC

3 1, 300 MHz) 5: 1.57 1.66 8 1.88 1.97 3 2.31 2.46 4 2.52 2.62 2 2.67 2.76 2 5.20 5.45 (br s, 2 H), 6.14, 1 6.83 1 7.22 7.37 6 7.45 1 7.59 (dd, 1 8.51 (dd, 1 H).

-211- 1 9 F-NMR (CDCl 3 282 MHz) 5:-160.30 160.50 MS m/z: 507 (M 1).

Example 468 4-(4-Chloro-phenyl)-4-fluoro- 1- -hydroxy- 1 -methyl-ethyl)- 1H- 10- oxa- 1aza-dibenzo[a,d] cyclohepten-5 -ylid ene] -propyl -piperidin-3-o] Step I To a solution of 4-(4-chloro-phenyl)-3 ,4-dihydroxy-piperidine- I -carboxylic acid tert-butyl ester (1.213 g, 3.34 mrnol) in methylene chloride (30 mL) at -78 'C wvas added diethylamino sulfur trifluoride (DAST, 3 The resulting solution was 1 0 stirred at -78 *C 4h. Methanol (20 mL) was added to quench excess DAST and the mixture was allowed to remain at -78 'C 5 min before warm-ing- to rt. The mixture wvas concentrated and purified by silica gel chromatography (80 hexanes 20 ethyl acetate gradient) to afford 4 -(4'-chloro-phenyl)-4-fluoro-piperidin-3- 01 (262 mg, 24%) 1 5 'H-\MR (CDCb3. 300 MHz) 6: 1 .48 9 1 .84 (br dd, I 2.50 (dddd, I H), 3.15 (br dd, I 3.38 I 3.76 1 4.04 4.36 (rn, 2 7.33 -7.44 (in, 4 H).

9 F-N7\IR 282 MI~z)8: 159.90 Step 2 4-(4-Chloro-phenyl)-4-fluoro-p iperi din-.3-ol was prepared as in step 3 of Example 502, substituting 4-(4-chloro-phenyl)-4-fluoro-3 -hydroxy-piperidi me- 1carboxylic acid tert-butyl ester for 4 -(4-chlIoro-phenyl) -4-hydrox y-3,3 -dimePthyl piperidine-l-carboxylic acid tert-butyl ester. Following isolation from the crude mixture, the free amine was used immediately without further purification 'H-NMTR (CDCI 3 300 MaiFz). 4 -(4-Chloro-phenyl)-4-fluoro-piperidin-3-oI appears as the major constituent of a mixture of compounds.

MS mlz: 230 (M 1; major peak in chromatogram).

.212- Step 3 The titled compound was prepared as in step 5 of Example 502, substitutinlg 4 4 -choro-phefylY-4fluoropipeidin 3 oI for S -4-(4-chloro-phenyl)- 3 ,3 -dimethylpiperidini- 4 -0l.

1 H-NMP- (CDCI3 300 MHz) 8: 1.59 6 1.74 -1.96 (in, 2 2.31. 2.75 (in, 8 2.80 (br d, I 3.06 1 3.67 (br d, I 5.20 5.45 (br s, 2 6.11

I

6.84 1 7.22 7.36 (mn, 4 7.39 7.47 (i,3 7.57 I 8.56 (dd, I H).

1 9 F-NMR (CDCI 3 282 MHz) -158.30 MS m/z:523 (M

I.

Example 4 6 9 (3-[-4Ci r-hnl--luoo')-- ty ppndn -yll-propylidei1ie) -5,1 1dihydro- 10-oxa-1 I aza-dibenizo a,dlcyclohieptef--lDpropai 2 -oI Step 1 4-(4-Chl oro-phen),l).4fluoro-3-eth),lpiperidin- was prepared following the procedure in Step 1 in Example- 4 6 7 re-placing 4 4 -chiloro-plefll-piperidin- 4 ol with 4-(4-Chl oro-ph enyl)- 3 -m ethyl -piperi din-4-ol. IH-NMR (CDCI 3 300 MHz) 5: 0.67 3 1.91 2.26 2 2.84 I H), 3.02 (dd, I 3.06 3.21 (mn, 2 3.33 (br s, 2 7.27 2 7.34 2 H).

"F-NM-R (CDCl 3 2 82 MHz) 5: 180.60 (ddd).

M Sm z:2 2 8

I.

Step 2 The titled compound was prepared following the procedure step 2 of Example 467, replacing 4 4 -chloro-phefylY14fluoropiperfldine with 4-(4-chlorophenyl)- 4 -fluoro3-methylIpiperidine.

213- 'H-NMR (CDC1 3 300 MHz) 6: 0.63 3 1.58 6 1.76 1.96 2 H), 2.09 2.52 6 2.55 2.88 4 5.18 5.50 (br s, 2 6.12 1 6.83 1 7.22 7.36 6 7.46 (dd, 1 7.59 1 8.51 1 H).

MS m/z: 521 (M 1).

Example 470 4-(4-Chloro-phenyl)-1- 3-[7-(1-hydroxy-1 -methyl-ethyl)- 11H-10-oxa-I -azadibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperidine-3,4-diol Step 1 To a suspension of 4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (2 g, 8.73 nunol) in methylene chloride (50 rnL) was added triethylamine (1.42 g, 1.95 mL, 14.0 mol). The resulting mixture was cooled to 0 "C and di-tert-butyl-dicarbonate (2.19.g, 10.0 mmol) was added in a single portion.

After 10 min at 0 the mixture was warmed to rt and stirred 90 min. The contents of the flask were poured into 250 mL methylene chloride and washed with 1 N hydrochloric acid/brine saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated and the resulting oil filtered through a plug of silica with methylene chloride elution, to afford 2.88g (>100 of 4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1carboxylic acid tert-butyl ester.

'H-NMR (CDC13, 300 MHz) 6: 1.49 9 2.45 2.52 2 3.63 2 H), 4.07 2 6.02 (br s, 1 7.29 4 H).

Step 2 The product of step 1 (2.88 g, approx. 8.7 mmol) was dissolved in 15 mL of a 5:1 acetone:water solution. Osmium tetroxide (2.5 in tert-butyl alcohol, 1 mL) was added followed by 4-methyl morpholine N-oxide (1.13 g, 9.65 mmol). The mixture was stirred at rt 16 h. Saturated aqueous sodium bisulfite (5 mL) -was added and the acetone was removed under reduced pressure. The resulting aqueous phase -214was extracted with methylene chloride and the extracts washed with an aliquot of saturated aqueous sodium bisulfite, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The extracts were then dried over magnesium sulfate, filtered and concentrated to afford an oil which was purified by silica gel chromatography (100 methylene chloride to 90:10 methylene chloride:methanol gradient). 4-(4-Chloro-phenyl)-3,4-dihydroxy-piperidine-l-carboxylic acid tertbutyl ester was afforded as an oil (2.64 g, 83 2 steps).

'H-NMR (CDC13, 300 MHz) 6: 1.44 9 1.62 (br d, 1 1.82 (br s, 2 2.69 (br s, 1 2.99 (br t, 1 3.12 (br s, 1 3.90 4.30 3 7.33 2 7.41 2 H).

Step 3 The product of step 2 (500 mg, 1.37 mmol) was dissolved in methylene chloride (10 mL) and the resulting solution cooled to 0 Trifiuoroacetic acid (3 mL) was slowly added and the reaction was allowed to stir at 0 'C for 2 h, before concentration under reduced pressure. The trifluoroacetate salt was dissolved in tetrahydrofuran and excess triethylamine was added. Solids generated were removed by suction filtration and the supernatant solution was concentrated to afford 4-(4-chloro-phenyl)-piperidine- 3 ,4-diol.

'H-N MR (CDOD, 300 MHz) 1.91 (ddd, 1 2.13 (ddd, 1 3.12 3.28 4 4.08 (dd, 1 7.37 (ddd, 2 7.51 (ddd, 2 H).

Step 4 The titled compound was prepared following the procedure in step 2 of Example 467, but replacing 4-(4-Chloro-phenyl)-4-fluoro-piperidine with 4-(4- Chloro-phenyl)-piperidine- 3 ,4-diol.

'H-NMR (CD 3 OD, 300 MHz) 5: 1.51 6 1.80 (br d, 1 2.03 -2.11 1 2.56 2 2.68 3.12 6 4.00 (dd, 1 5.00 5.50 (br s, 2 6.17 1 6.76 2 7.27 (dd, 1 7.33 (ddd, 2 7.44 7.49 4 7.80 (dd, 1 8.48 (dd, I H).

-215- MS rnl1z: 521 (M 1).

IND Example 471 Chloro -phen yl)-3 -ethyl-I 1- {3 1 -hydroxy- 1 -m ethyl -ethyl)- I1 H-I 0-oxa-lI-aza- -ylidene] -propyl)}-piperidiin-4-ol Step I A solution of' 4 -oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g 25.1 rnmol), py-rollidine (5 mnL) and p-toluenesulfonic acid (25 rng) in benzene (100 m.L) was heated at reflux for 16 h with azeotropic distill-ation of water. The resulting enamine solution was cooled to rt and concentrated. The crude nanine was dissolved in acetonittile (50 rnL); iodoethane (4.67 g, 30.1 nunoL) was added and the mixture was heated at 1 00 'C for 0.5 h, cooled to rt and concentrated. The mixture was dissolved in ethyl acetate (200 mL), washed with I N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The extract was dri ed over magnesium sulfate, filtered and concentrated. The crude compound was purified by silica gel chromatography (80 hexanes 20 ethyl acetate) to afford 3-ethyl-4oxo-piperidinc-lI -carboxylic acid tcrt-butyl ester (680 mg).

'h-NMR (CDCI 3 300 MHz) 5: 0.95 S3 1.26 1.42 (iii, I 1,50 9 H), 1 .69 1 .85 (in, 1 2.30 (br s, I 2.43 2 2.90 4.36 (mn, 4 H).

Step2 4-(4-Chloro-ph enyl)-3 -ethyl -4-hydrox y-pipen di ne- I -carboxylic acid tentbutyl ester was prepared following the procedure in step 2 of Example 502, substituting 3-ethyl-4-oxo-piperidi'ne-l-carboxylic acid tert-butyl ester for 3,3diniethyl-4-oxo-pipei dine- 1 -carboxylic acid tert-butyl ester.

'H-NMR (CDCl 3 300 M~z) 8: 0.80 3 0.91 1.13 (in, 2 1.18 1 .28 (in, 1 1.48 9 1.57 -1.64 (br d, 1 1.75 -1.91 (in, 2 2.79 I 3.14 (ddd, I 4.02 (bn d, I 4.19 (br d, 1 7.28 7.37 (in, 4 H).

-2 16- Step 3 4 -(4-Chloro-pheflyl)3ethyl-piperidin- 4 -oI was prepared according to the procedure of step 3 in Example 502, substituting 4-(4-chloro-phenyl)-3-ethyl- 4 hydroxy-pip eri dinle-I caboxyli c acid tert-butyl ester for 4-(4-chloro-pheflyl)- 4 hydroxy- 3,3 -dim ethyl -pip eridinle- I -carbox yl i c, acid tert-butyl ester.

'H4-NMR (CDCl 3 300 MHz) 5: 0.75 3 0. 88 1.17 (in, 2 1.26 1 H), 1.65 (br d, 2 1.83 2.02 (in, 2 2.75 1 2.95 -3.21 (mn, 3 7.32 2 7.40 2 H).

MS mn/z: 240 (M I).

Step 4 The titled compound was prepared following the procedure in step 5 of Example 502, substituting 4-(4-chloro-phenyl)-3ethyl-piPeridin- 4 -ol for 4-(4chloro-phenyl)- 3 3 -dinethy)I-piperidil- 4 -ol.

H-MR (CDCI 5 300 M.Hz) 8: 0.70 3 0.81 1.11 (mn, 3 1.56 1 .64 (mn, 7 1.77 -2.09 (mn, 4 2.23 -2.86 (mn, 7 5.00 -5.60 (mn, 2 6.13 I H), 6.83 I 7.23 7.47 (mn, 6 7.46 I 7.59 (dd, I 8.49 (dd, I H).

MS rn/z: 533 (M 1).

Example 472 5-Chloro-1 -hydro xy- 1 -methl -ethyl) -I 1 H-I0-oxa-l -aza-dibenzo[ a,d]cyclohepten-5--Ildene]-propyl} -spiro j3-oxo- 1,3 -dihydroisobenzofural- 1,4' piperidine] Step I To a suspension of 2-bromo-5-chlorobelzoic acid (1.5 g, 6.4 mmol) in methylene chloride (15 rnL) at room temperature was added oxalyl chloride (969 mg, 666 .tL, 7.64 inmol) and 2 drops of dimethylforinamide; bubbling commenced and the mixture ultimately became homogenous. The mixture was stirred at room temperature for 7 hours and concentrated. The resulting acid chloride residue was -217dissolved in methylene chloride (15 mL). Triethylamine (325 mg, 450 3.2 mmol) was added, followed by 2-amino-2-methyl-l-propanol (627 mg, 672 L, 7.04 rnmol) and the reaction was allowed to stir at rt 3h. The mixture was poured into 1 N hydrochloric acid (50 mL), extracted with methylene chloride (2 x 75 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered and concentrated and dried in vacuo.

The crude amide residue was dissolved in methylene chloride (15 mL) and thionyl chloride (1.29 g, 794 iL, 10.9 mmol) was added. Stirring at room temperature was carried out for 4 h after which the mixture was poured into saturated sodium bicarbonate (50 mL). The pH was adjusted to 9 by the addition of solid sodium bicarbonate and further basified by the addition of several milliliters of aqueous sodium hydroxide (5 The biphasic mixture was extracted with methylene chloride (150 50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the crude residue which was purified by silica gel chromatography (80 hexanes 20 ethyl acetate gradient) to yield 2-(2-bromo-5-chloro-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (1 .15 g, 62 'H-NMR (CDC1 3 300 MHz) 5: 1.42 6 4.14 2 7.25 (dd, 1 7.55m (d, 1 7.67 1 H).

Step 2 To a cold 78 solution of the product of step 1 (1.09 g, 4.63 mrnol) in anhydrous tetrahydrofuran (10 mL) was added a solution ofn-butyllithium (1.6 M in hexanes, 2.89 mL, 4.63 mmol) and the contents of the reaction were allowed to react for 0.5 h. A solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (922 mg, 4.63 mmol) in tetrahydrofuran (10 mL) was added and the combined contents stirred for 2 h at -78 Reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL), followed by warming to rt. The biphasic mixture was extracted with ethyl acetate (150 mL); washed with water and brine; dried over magnesium sulfate; filtered and concentrated. 4-[4-Chloro-2-(4,4-dimethyl-4,5- -218dihydro-oxazol2-yl)phenyl4hydoxy-pipeidine -carboxylic acid tert-butyl ester was isolated (412 me., 22 following silica gel chromatography (80 O/6 hexanesI ethyl acetate).

Cl 'IH-NMR (0D01 3 300 MI-lz, mixture; spectrum of major component:) 5: 1.36 6 1.50 91-H), 1.66 2 1.96 (dd, 2 3.19 (br d, 2 3.42 2 4.24 C1 (br s, 2 7.16 I 7.45 (dd, I 7.71 (br s,1 IH).

MS mlz: 409 (M 1).

Step 3 To a solution of the product of step 21(200 mg, 0.49 mmol) in tetrahydrofurafl (5 mL) was added water (5 mL) and oxalic acid (300 mg). Stir at rt for about 4 days. The solids were separated and dissolved in ethyl acetate (50 mL); the resulting solution was washed with saturated aqueous sodium bicarbonate and brine. The extracts were dried over mnagniesiuml sulfate; filtered and concentrated.

The 5 -chloro spi ro[ 3 -oxo- 1,3 -di'hydrol sob efzoftaral-l 1,4'-piperidin e] 1 -carboxylic acid tert-butyl ester thus afforded (100mg, 61 was used without further purification.

'H-NMNR

(CDCI

3 300 M-Ir) 5: 1.49 9 1.67 2 2.04 (ddd, 2 3.24 (dd, 2 4.21 (br s, 2 7.32 IW), 7.-64 (dd, 11H), 7.85 I H).

M\1S rniz: 238 (N4 I 100).

Step 4 3 -oxo-1,3-dihydroisobelzofurafl-1I,4'-piperidin-e] was prepared according to the procedure In step 3 of Example 502, using chlorospi-ol3-oxo-l ,3-dihydroisobenzofurafl 1,4' -piperidine1-l1-carboxyli c acid tertbutyl ester instead of 4-(4-choro-phenyl4hydroxy- 3 ,3-dimethyl-piperidifle- I carboxylic acid tert-butyl ester.

I H-NMvR (CDC1 3 300 MH-1) 8: 1.71 2 2.09 -2.22 (in, 2 3.13 3.28 (mn, 4 7.37 I 7.64 (dd, I 7.84 1 H).

MS in/z: 238 (M I).

-219- Step ri The titled compound was prepared according to the procedure in step 2 of Example 467, substituting 5-chlorospiro[3 -oxo- I ,3-dihydroisobenzofuran- 1,4'piperidine] for 4-(4-chloro-phenyl)-4-fl uoro-piperidine.

'H-NMNR (CDC1 3 300 MJ-{z) 5: 1.58 6 1.64 2 2.04 -2.15 (in, 3 H), 2.33 2.50 (in, 3 2.57 2 2.76 2 5.20 5.50 (br s, 2 6.12 1 6.81 I 7.22 7.34 (in, 3 7.45 2 7.55 7.63 (in, 2 7.81 (d, 1 8.48 (dd, I H).

Example 473 4-(4-Chloro-phenyl)- 1- -hydroxy-l1-metIhyl-e thyl)-l I H-i0-oxa- I -azadiben zo ad]cycl oh epten- 5-yl Id enel-propyl -4-inethoxy-3-m ethyl -p Iper] din -3 -ol Step I To a suspension of 4-(4I-chloro-phenylI)- 1,2,3,6-tetrahvdro-pvrI dine hydrochloride (5 g, 21.8 nuriol) In methylene chloride (100 mL) was added -triethylamine (3.6 g, 4.9 inL, 35 mnrnl). The resulting solution was cooled to 0 *C in an ice-water bath. Di-tert-butyl-dicarbon ate (5.4 g,25 nmiol) was added and the resulting, reaction wvas allowed to warm to rt and stir over night. The mixture was poured into 100 rnL of a 1: 1 1 N HC]:brine solution and diluted with methylIene chloride (300 mL). The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to afford 4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine- 1-carbo-xylic acid tert-butyl ester (6.68 g, 93 as a colorless oil, which was used without further purification.

'H-NMIR (CDCl 3 300 MlHz) 8: 1.48 9 2.45 2.55 (mn, 2 3.63 2 H), 4.07 2 6.03 (br s, I 7.29 (mn, 4 H).

Step 2 -220- To a cooled (0 solution of 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine- S1-carboxylic acid tert-butyl ester (7.10 g, approx. 24.1 mmol) in methylene chloride S(150 mL) was added a solution of 3-chloroperbenzoic acid (75 8.34 g, 36.2 rnmmol) in methylene chloride (120 mL) over 40 min. The mixture was warmed to rt and allowed to stir over night (16 The solution was washed twice with a halfsaturated aqueous solution of sodium bisfulfite to destroy excess oxidant. The mixture was then twice washed with half-saturated aqueous potassium carbonate, and brine. The extracts were dried over magnesium sulfate, filtered and concentrated to afford a crude oil which was purified by silica gel chromatography (100 hexanes 80 hexanes 20 ethyl acetate gradient) to afford pure 6-(4-Chlorophenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (5.34 g, 71 as a clear, colorless oil which solidified on standing.

'H-NMR (CDClI, 300 MHz) 5: 1.48 9 2.06 2.22 1 2.42 (ddd, 1 H), 3.08 3.23 2 3.57 4.19 3 7.26 7.36 4 H).

Step 3 To a solution of 6-(4-Chloro-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane- 3 carboxylic acid tert-butyl ester (2.4 g, 7.8 mmol) in methanol (100 mL)was added acatalytic amount of p-toluenesulfonic acid (ca. 50 mg). The resulting solution was heated at reflux 24h, cooled and concentrated. The crude residue was purified by silica gel chromatography (100 hexanes 80 hexanes/20 ethyl acetate gradient) to afford 4 4 -chloro-phenyl)-3-hydroxy-4-methoxy-piperidine- carboxylic acid tert-butyl ester (2.05 g, 77 note the diol moiety has the transorientation.

'H-NMR (CDC13, 300 MHz) 8: 1.47 9 1.95 1 2.37 (ddd, 1 2.97 (s, 3 3.47 1 3.67 (br s, 1 3.98 4.17 3 7.29 7.42 4 H).

Step 4 A solution of 4-(4-chloro-phenyl)-3-hydroxy-4-methoxy-piperidine-lcarboxylic acid tert-butyl ester (2.05 g, 6.0 mmol) in methylene chloride (75 mL) -221was cooled to 0 Dess-Martin periodinane (3.30 g, 7.8 mrnol) was added, followed by water (200 uL) and the reaction allowed to stir at rt 2 h. The reaction was quenched by the addition of a solution consisting of equal parts saturated Saqueous sodium thiosulfate and saturated aqueous sodium bicarbonate; the resulting reaction was stirred until the mixture formed two homogenous phases. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to afford recovered starting material (1.17 g, 57 and 4-(4chloro-phenyl)-4-methoxy-3-oxo-piperidine- -carboxylic acid tert-butyl ester (540 mg, 27 (62 brsm)).

'H-NMR (CDC13, 300 MHz) 5: 1.43 9 2.16 2.40 2 3.12 3 H), 3.55 (ddd, 1 3.80 (br s, 1 3.96 1 4.34 (br s, 1 7.23 7.40 4

H).

Step To a solution of 4 4 -chloro-phenyl)-4-methoxy-3-oxo-piperidine carboxylic acid tert-butyLester (470 mg, 1.38 rnmol) in anhydrous tetrahydrofuran mL) at 0 "C was added methylmagnesiunibromide (1.4 M in diethyl ether, 2.96 mL, 4.15 mmol) and the resulting mixture was stirred at that temperature for 3 h.

Excess organomagnesium was quenched by the addition of saturated aqueous anunonium chloride and the reaction was allowed to warm to rt. To the biphasic mixture was added water and ethyl acetate. The phases were separated and the organic phase washed with brine, dried over magnesium sulfate, filtered, dried and concentrated to afford a crude residue which was purified by silica gel chromatography (100 methylene chloride- 97.5 methylene chloride 2.5 methanol gradient) to afford pure 4 4 -chloro-phenyl)-3-hydroxy-4-methoxy-3methyl-piperidine-1-carboxylic acid tert-butyl ester (269 mg, 58 'H-NMR (CDCI 3 300 MHz) 6: 0.97 3 1.50 9 1.81 1 2.59 (ddd, -222- 1 2.96 (br t, 1 3.11 3 3.31 3 3.72 3.88 1 7.27 7.37 4 H).

Step 6 4-(4-Chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine- 1 -carboxylic acid tert-butyl ester (260 mg, 0.74 mmol) was dissolved in methylene chloride mL) and the resulting solution was cooled to 0 Trifluoroacetic acid (1 rnL) was added and the mixture was stirred 2h. Solvents were then removed under reduced pressure and the residue dissolved in ethyl acetate. Water and 6 N aqueous sodium hydroxide were added until the pH 10. The organic phase was washed with brine and dried over magnesium sulfate, filtered and concentrated to afford 4-(4-chlorophenyl)-4-methoxy-3-methyl-piperidin-3-ol.

'H-NMR (CDC13, 300 MHz) 8: 0.94 3 1.91 1 2.65 2.81 (mn, 2 H), 2.94 (ddd, 1 3.13 3 3.25 1 3.30 1 7.37 4 H).

MS m/z: 256 (M 1).

Step 7 To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-methyl-pipendin-3-ol (206 mg, 1.24 mmol) in acetonitrile/water 20 mL) was added potassium carbonate (171 mg, 1.24 mnmol) followed by 2-[5-(3-bromo-propylidene)-5,11- -aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (417 m, 1.12 mmol). The mixture was stirred at rt 40h and concentrated. The product residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (100 methylene chloride methylene chloride 10 methanol gradient) to afford the titled compound (232 mg, 35 as an off-white solid.

'H-NMR (CDC1 3 300 MHz) 5: 0.83 3 1.57 6 1.76 1.94 2 H), 2.20 1 2.29 -2.72 7 3.06 3 3.39 (br s, I 5.19 5.54 (br s, 2 -223- 6.12 1 6.82 1 7.21 7.34 (in, 6 7.46 1 7.58 I H), 8.51 1 H).

MS m/z: 549 (Mv 1).

Example 474 4-(4-Chloro-phenyl)- 1- 1-hydroxy-l1-methyl-ethyl)-I 11H-i 0-oxa-l1-azadib enzo [a,d jcycl ohep ten- 5-yi dene] -propyl -4-methox y-piperi din-3 -o I Step I 4(4-Chl oro-ph enyl)-4-inethox y-piperi din- 3-ol was prepared following the procedure in Step 6 of Example 473, replacing 4-(4-chloro-phenyl)-3-hydroxy-4m-ethoxy,-3-me-thyl-pipe-ridine-1-carboxylic acid tert-butyl 'ester with 4t-(4-chloroph enyl)-3 ,-hydroxy,-4-methoxy-piperid inc-I -carboxyli c acid tert-butyl ester.

MS mlz: 242 (M 1).

St.p The titled compound was prepared following the procedure of Step 7 in Example 473, replacing 4-(4-chloro-phieny1])-4-ni ethoxy-3-mcthy1I-piperidirn-3-o

I

with the product of Step 1 in Example 474.

H--NMIR 300 Mvflz) 6: 1.58 6 1.63 1.82 (in, S) 1.95 I H), 'Z221 2.7 8 (mn, 8 24.91 3 3.63 (br s, 1 5.3 2 (br s, 2 6.11 I H), 6.81 I 7.21 737 (mn, 6 7.44 1 7.5 7 (dd, I 8.51 (dd, I H).

MSnm/z: 535 (M I).

Example 475 (3 Chl OrO-phenyl) dim ethoxy-pipeidin- I -y1l-propylidene) -5,11dihydro- 1 0-oxa-l1-aza-dibenzo~a,d~cvclohepten-7-yl)-propan-2-oI Step I -224- The product of Step 3 in Example 473 (259 mg, 0.76 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 Sodium hydride (60 dispersion in mineral oil, 46 mg, 1.15 mmol) was added in a single portion and the mixture stirred min. Methyl iodide was added and the mixture was warmed to rt and stirred 48 h.

Excess base was quenched by the addition of saturated aq. NHC1 and water. The biphasic mixture was extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (hexanes 80 hexanes/20 ethyl acetate gradient) to afford 4-(4-chloro-phenyl)-3, 4 dimethoxy-piperidine-1-carboxylic acid tert-butyl ester (191 mg, 71%).

'H-NMR (CDC1,, 300 MHz) 6: 1.47 9 1.90 1 2.31 (ddd, 1 IH), 2.91 3.38 9 3.93 4.37 (br m, 2 7.24 7.37 4 H).

Step 2 4-(4-Chloro-phenyl)- 3 ,4-dimethoxy-piperidine was prepared follow ing the procedure in Step 6 of Example 473, substituting the product of Step 1 for 4-(4- Chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-l -carboxylic acid tertbutyl ester.

'H-NMR (CD.OD, 300 MHz) 5: 1.96 1 2.27 (dddd, 1 2.71 3.03 9 3.04 3.15 2 7.30 7.41 4 H).

MS m/z: 256 (M 1).

Step 3 The titled compound was prepared following the procedure in Step 7 of Example 473, substituting the product of Step 2 for 4-(4-chloro-phenyl)-4-rethoxy- 3-methyl-piperidin- 3 -ol.

'H-NMR (CDC1 3 300 MHz) 8: 1.58 6 1.67 (br s, 2 1.77 1 1.91 (d, 1 2.18 2.31 1 2.33 -2.47 2 2.48 2.62 2 2.65 2.75 1 2.83 2.90 4 2.92 3 3.07 (br s, I 5.06 5.57 (br s, 2 H), -2 C]6. 10 1 6.8 2 I 7.22 7.3 5 (in, 6 H)D, 7.44 1 7.59 1 HI), 8.5 0

IH).

IND MS mlz: 549 (M 1).

Example 476 3 -Azido-4-(4-chloro-phenyl)-1- {3 -hydroxy-l1-mnethyl-ethyl)-l 11H- 10- oxa- 1aza-dibenzo[a, d] cyclohepten-5-ylidene} -propyl }-piperidin-4-ol Step 1: 4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyidine-1 -carboxylic. acid tert-butyl ester To a solution of di'-tert-butyl-dicarbonate (9.96 g, 45.6 rnmol) in CH-lCb, (5 00 rnL) was added 4-(4-chlorophenv])- 1,2,3 ,6-tetrahydrop 7i dine hydrochloride (10.00 g,43.5 mmol) and triethylanine (12.42 rn.L, 89 rnmo]). The solution was stirred at ii for 4h. Gas evolution was observed. The reaction was quenched with IN HGl and extractedwith CHCl, and the organic layers were collected togyether, dried over N4oSO 4 and evaporated in vacuc. The residue was purified to yield the title compound as a colorless oil. 'H-NM4R (CDCl 3 6: 1.50 (9H, 2.46 br 3.62 (2H, br 4.05 (214, br 6.01 (IH, br 7.25 (4H, s).

Step2: 6-(4-Chiloro-phienyl)-7-oxa-3-aza-bicvclo[4. 1.0]heptanie-3-carboxylic acid tert-butvl ester To a solution of 4-(4-chloro-phenyl)-3 dihydro-21-!-pyri dine- 1 -carboxylic acid tert-butyl ester 4.0 g, 13.6 mmol) in CH 2

CI

2 (136 mnL) cooled to 0 0 C. 3- Chiloroperbenzoic acid (4.07 g,20.4 mnmol) was dissolved in CH 2 C1 2 and added portion wise ovrer 45 min. A white precipitate was observed. The solution was allowed to stir at room temperature for 14h. The reaction was washed with 1 x NaSO 3 1 x 10% Na 2

C

3 1 x brine and dried over Mg 2

SO

4 filtered and evaporated 2 5 in vacuo. The residue was purified by Biotage flash system (90% hexane/ 10% ethyl acetate to 80% hexane/20% ethyl acetate to yield the title compound as a colorless oil (2.75 'H-NMiR(CDC1 3 8: 1.50 (9H4, 2.15 (1 H, in), 3.15 (2H, in), -226- 3.6-4.2 (4H, mn), 7.31 (4H, s).

Step 3: 4-Azido-4-(4-chloro-phelyl)- 3 -hydroxy-piperidil-I-carboxylic acid tertbutyl ester and 3 aid--4cloopey)4hyrxyppr ie -carboxyli c acid tert-butyl ester To a solution of 6-(4-chloro-phenyl)-7-oxa- 3 -aza-bicyclo[ 4 .l .Olheptafle-3carboxylic acid tert-butyl ester (0.960g, 3.1 inmol) in 3lmL of DMSO was added sodium azide (0.970g, 14.9 mnmol). The solution was allowed to heat at I 0 C for 24 h and cooled to room temperature. The reaction was washed with water, dried over Mg 2

SO

4 filtered and evaporated in vacuo. The residue was purified by Biotagle flash system (90% hexane/10% ethyl acetate to 80% hexane/2 0 ethyl acetate to hexane/3 0 ethyl acetate to y Ield two compounds. The faster eluting isomer 4-azido-4-(4-chloroplenyl)- 3 -hvdroxy,-piperdiflI-carboxylic acid* tert-butyl ester (0.01 'H--NMR

(CDCI

3 5: 1.46(s, 9H), 1.93(d, III), 2.51(dt, IH), 3.10(bt, IH), 3.34(d, 3.80(bs, 11H), 4.09(m, 2141), 7.41 The slower eluting isomer 3 -azido- 4 4 -chloro-phel)l4-hydioxy-pipeidile-l-carbox ylic acid tert-butyl ester (0.361g5, 33%) 'H-NrNMR

(CDCI

3 5: 1.43(s, 9H), 1.57(m, 2.40(t, 2.93(m, 1H), 3.1 I(t, IH), 3.50(s, 3.56(d, lH), 4.07(m.,2H), 7.3 3(d, 2H), 7.40 2d-).

Step 4 The Boc-protected azido-alcohol (0.184 g, 0.5 mr-nol) was dissolved in

CH

2

CI

2 (2 mL) and cooled to O'C arnd TFA (0.790 mL) was added. The solution was allowed to stir at 0 0 C for I h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO3 and CHCI 2 The aqueous solution was extracted (3x) and then washed with brine and dried over Na 2

SO

4 The residue was carried onto the next step without further purification.

Step To a solution of the azido piperidine 142 g, 0.56 ninol) in isopropaflol -227- (5.6 mL) was added 2,6-1utidine (0.066 miL, 0.8 mrnol) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with 2-[5-(3-Bromopropylidene)-5,1 1-dihydro- 10-oxa-lI-aza-dibenzo[a, d~cyclohepten-7.yl]-propan-2-ol (0.025 g, 0.O67mmol), added in portions over 2h. The solution was then stirred at 80 'C for an additional 14 h. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (75% EtOAc/25% Hexane to 1 00% ethyl acetate) to yield the title compound (0.135 g, 'H-NMNR (CDCI 3 8 1 .56(6H, s), 1.65(d, 1H), 1.85(s, 1H), 2.13(s, 1H), 2'.36-2.94(m, 8H), 3.51(s, 1H), 5.24(bs, 2H), 6.16(t, IH), 6.80(d, 1H), 7.21-7.45(m, 7H), 7.58(d, 1H), 8.44(d, IH). ESI-MS m/z: 546(M retention time 1.55.

Example 4*77 4-Azido-4-(4,-chiloro-plienyl)- I- 1-hvdroxy,-1-miethyl-ethyl)- 1 0- oxa-1 aza-dibenzoi-a.d]cyclohe pten-5 -ylidenie, -propyl -piperidiin-3-ol Step 1 The Boc-protected azido-alcohol (Example 476, step (0.050 g, 0 .2 mrnol) was dissolved in CH 2 CI, (2 miL) and cooled to 0 0 C and TEA (0.2 rnL) was added.

The solution was allowed to stir at 0 0 C for I h. The solvent was evaporate-d in vacuc and the residue was partitioned between NaI-C0 3 and CH,C1 2 The aqueous solution was extracted (3x) and then washed with brine and dried over Na, SO 4 The residue was carried onto the next step without further purification.

Step 2 To a solution of the azido piperidine (0.025 g, 0. 1 mrnol) in isopropanol (1 .0 rnL) was added 2,6-lutidine (0.012 mL, 0. 1 rnmol) and catalytic potassium iodide.

This mixture was heated to 80 0 C, and treated with 2-[5-(3-Bromo-propylidiene)- 5,11 -dihydro-1I0-oxa-lI-aza-dibenzo/a, d] cyclohepten- 7-yIJ -prop an-2-olI 0 .025 g, 0.O67mmol), added in portions over 2h. The solution was then stirred at 8 O'C for anl additional 14 h. The reaction was concentrated in vacuo, then purified by Biotage -228flash chromatography (100% ethyl acetate) to yield the title compound (0.0 13 g, 'H-NMR (CDCl 3 8 1.56 6H), 1.65 IH), 1.85 1KH), 2.13 111), 1.36-2.94 (in, 8H1), 3.51 111), 5.24 (bs, 2H), 6.16 111), 6.80 1H), 6.93 (d, lH), 7.2 1-7.46 (in, 8H), 7.58 1H), 8.42 1H). ESI-MS mlz: 546(M 1), retention time 1.71.

Example 478 N-[4-(4-Chloro-phelyl)-4-hydroxy- 1- {3-[7-(hydroxyl- I -methyl-ethyl)-l 111--I0-oxa- I -aza-dibenzolia, d]cycloheptefl-5-ylideflel-propyl}f -piperidin-3-yl)-propionlarilde Step 1: 3-,m'o4(-llr-leyl--yrx-ie-die -carboxyli c acid tert- 1 0 butyl ester 'da o -clr-hev dhyrx- ie i I-carboxylic aci d tertbutyl ester (0.67 g, 0.2 mmnol) was dissolved in Et 2 O (2 rnL) and cooled to OTC and LiAIH, (0.280 mL, 0.23mmrol) was added. The solution was allowved to warm to room temperature and stir for 2h. A white precipitate fornned. The reaction mixture was quenched with water and extracted with EtO The organic layers were -collected together, dried over MgSO, and evaporated in vacuo to gIve the amino -alcohol which was used directly in the next reaction.

Step 2: 4-(4_Chloro-phenyl)-4-hydroxy 3 -propi onylamino-pipen dine- 1 -carboxyli c acid tert-butyl ester 3-Aio4(-hoope) )4l)doyppndn--carboxylic acid tertbutyl ester (0.116 g5, 0.35 minol) was dissolved in CH 2

CI

2 Propionyl chloride 0.034 mL, 0.39 rnmol) and triethylamine (0.109 mL, 0.78 inmol) were added and the solution was stirred for 24 h at room temperature. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (30% ethyl acetate/70% hexane to 50% ethyl acetate/50%hexane) to yield the title compound (0.133 g, 'H-NMR (CDCI 3 8 0.87 3H), 1.44 9H1), 1.78-1.95 (mn, 3H), 2.20 (dt, 1H), 3.24 IH), 3.50 1K), 3.90 1K), 4.08 2H), 4.28 1H), -229- 5.48 (bd, lH), 7.26 2H), 7.37 2H). ESI-MS mn/z: 383 (M retention time 2.21.I Step 3 The Boc-protected 3-N-acyl-alcohol (0.180 g, 0.47 mmol) was dissolved in

CH

2

CI

2 (5 mL) and cooled to 0 0 C and TFA (2 mnL) was added. The solution was allowed to stir at 00 C for I h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO 3 and CH 2

CI

2 The aqueous solution was extracted (3x) and then washed with brine and dried over Na,S0 4 The residue was carried onto the next step without further purification.

Step 4 To a solution of the N-[4-(4-clor-o-phe nyl)-4-hiydroxy -piperidin-3 -yl]propionarnide (0.133 g1, 0.47 rnniol) in isopropanol (5.0 inL) was added 6-lutidine (0.055 rnL, 0.47 mnmol) and catalytic potassium iodide. This mixture was heated to S0 and treated with 2--[5-(3-Bronmo-propylidcne)-5,i I -dihydro- I 0-oxa- 1 -azadibenzo[a,d'jcyclohiepte-n-7-yl]-propani-2'-oI 0.176 g, .35mirnol), added in portions over 2h. Thle solution was then stirred at 80'C for anl additional 14 h. Thle reaction was concentrated in 'v'ccuo, then purified by HPLC (acetonitrile&,O/Form.nic acid) to yield the title compound as a white foninate salt (0.085 g, 'H-NMNR (CDC 3 5 0.780 3H), 1.55 6H), 1.90 (in, 2.60 (mn, 2H), 2.92-3.28 (in, 61-i), 4.50 (d, 11-1), 5.26 (bs, 2H), 6.00 IlH), 6.8S2 I 7.22-7.3 7 (in, 7.44 I1-H), 7.5 6 1H), 8.20 lH), 8.34 IH), 8.47 IH). ESI-MS m/z: 576(M 1), retention time 1.43.

Example 479 Tr-ans-4-(4-Chloro-phenyl)-4-hydroxy-1- -hydroxyl- I-methyl-ethyl)-I 11H- oxa-1 -aza-dibenzo[a, d]cyclohepte n-5-ylidene]-propyl} -piper-idin-3-carboni i tri le -230- Step 1: Cis and trans -4(-hoopey)3can--yrx-ielie carboxylic acid tert-butyl ester Acetone cyanohydrin 0.917 mL, 10 mmol) was added to THF (22 mL) and cooled to 0 0 C. To the solution was added lithium hydride 0.077 g, 9.7 m~rnol) in several portions over 20 min. and then stirred at room temperature for 1 h. 6-(4- Chloro-phenyl)-7-oxa-3-aza-bicyclo[ 4 .l .Ojheptane-3-carboxylic acid tert-butyl ester (1.00 ,3.2 mrnol) dissolved in THIF (10 rnL) was added to the above solution and heated to reflux for 7 1/2 h. The reaction was diluted with H,O and extracted (3x).

The reaction was washed with water, dried over Mg 2

SO

4 filtered and evaporated in vacuo. The residue was purified by Biotage flash system (90% hexane/10 0 /o ethyl acetate to 80% hexane/20% ethyl acetate to 70% hexanel30% ethyl acetate to yield Two compounds. The faster el uting isomer cis-4-(4-chloro-phenvI)-3-cyaflo- 4 hydroxy-piperdiiie-I-carboxylic acid tert-butyl ester (0.210g-, 19%) 'H-NNIR (CDCl 3 5 1.35 9H), 1.59-1.86 (mn, 2H), 2.83-3.30 (in, 3.88 (bs, 2H), 4.16 (ri, lH), 7.23 2H), 7.333 2H).

The second eluting isomer was the trans -4-(4-chloro-phenyl)-3-cyano- 4 hyvdroxyl-pipefldifle-l-carboxylic acid tert-butyl ester (0.560g, 51%).'H-NIVIR

(CDCI

3 8 1.43 9H), 1.70 11H), 2.47 (dt; 1H), 2.76 (bs3-2H), 3.10-3.54 (mn, 4.18 (in, 2H), 7.31 2H), 7.44 2H).

Step 2 Trans -4-(4-chloro-ph enylI)-3 -cyano-4-hydrox y-pip~eridine-I -carbo xylic acid tert-butyl ester (0.210 g, 0.62 inmol) was dissolved in CI- 2 C1 2 (5 mL) and c-ooled to 0 0 C and TFA (1.0 mL) was added. The solution was allowed to stir at 00 C for I h.

The solvent was evaporated in vacuo and the residue was partitioned between NaHCO 3 and CH 2 Cl 2 The aqueous solution was extracted (3x) and then wvashed with brine and dried over Na 2

SO

4 The residue was carried onto the next step without further purification.

-23 1- Step 3 To a solution of the trans-3-cyano-4-hydroxypiperidine 137 ca" 0.58 nmol) in isopropanol (5.7 mL) was added 2,6-lutidine (0.067 m.L, 0.58 mmnol) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with (3-Brorno-propylidene)-5 ,1 1-dihydro-1I0-oxa-lI-aza-dibenzo[a, djcyclohepten-7-yl)propan-2-ol (0.108 g, 0.29mmol), added in portions over 2h. The solution was then stirred at 80 'C for an additional 14 h. The reaction was concentrated in vacuo, then purified by Biotage flash. chromatography (50% ethyl acetate/S 0% hexane to ethyl acetate! 25% hexane to 100% ethyl acetate) to yield the title compound 1 0 (0.040Pg, 'H-NN{RM (CDCI 3 6 1.50 6H), 1.63 1H), 1 .78 I 2.08 2.35 (in, 21-1), 2.5 1-3.03 (in, 3.48 5.29 (bs, 2H), 6.42 1H), 6.7 9 I 7.15 IlH), 7.2 8 (in, I 7.3 7 2H), 7.5 0 2H), 7.5 5 IlH), 7.58 I 8.46 I ESI-MS mlz: 5' retention time 1.50.

Example 480 Cis-4"-(4-Chloro-plienyl)-4-hydroxy,-- 13-[7-(l -hydroxyl-lI -m ethyl -ethyl)- 1 1 H-I 0oxa- I -aza-dibenzo[a~d]cyclohepten-5-ylidene-propyl}f -piperidin-3-carbonitrile Step-I Cis-4-(4-chl oro-plhenylI)-3-cyano-4-hydroxy-piperdine. 1-carbox yli c ;acid tertbutyl ester (0.2 10 g, 0.62 mmnol) was dissolved in CH 2

CI

2 (3 rnL) and cooledl to 0 0

C

and TEA (I mQL was added. The solution was allowed to stir at 00 C for 1 The solvent wvas evaporated in vacuo and the residue was partitioned between NaHCO 3 and CH 2

,C]

2 The aqueous solution was extracted (3x) and then washed withi brine anid dried over Na.SO,. The residue was carried onto the next step without further purification.

Step 2 To a solution of the cis- 3-cyano-4-hydrox ypiperi dine 125 g, 0.53 rnrnol) in isopropanol (5.8 mL) was added 2,6-lutidene (0.061 mL, 0.53 mrnol) and -232catalytic potassium iodide. This mixture was heated to 80 and treated with (3_-Bromo-propylidene)-5,1 1-dihydro- 10-oxa- I -aza-dibenzoja, d]cyclohepten-7-yl propan-2-oI 0. 100 0.26mmol), added in portions over 2h. The solution was then stirred at 80'C for an additional 14 h. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate! 50% hexane to ethyl acetate! 25% hexane to 100% ethyl acetate) to yield the title compound (0.050 g, 'I--NMR (CDCl 3 5 1.53 1.57(s, 6H), 1.74 IH), 1.89 lH), 2.35-2.68(m, 7H), 2.88 l 3.11 1H), 5.30 (bs, 2H), 6.1 1 111), 6.82 (d, lH), 7.23-7.45 (in, 7H), 7.57 1H), 8.48 I1H). ESI-MS m/z: 530.2(M 1), retention time 1.58.

Example 481 4-(4-Chl oro-phenyl)-4-hydrox/- I 34 7-(hydroxyl- 1 -m ethyl-ethyl)- I1 H-I 0-ox a-I aza-dibenzo[a, d] cyclohepten-5 -Nili denel-propyl) 3-methy]-piperidine-3-carbox)'liC acid methyl ester Step 1: 4-Oxo-piperidinC-,3-dicarboxylic acid I1-tert-bury] ester 3-methyl ester To a solution of di-tert-butyl-di carbonate (3.08 gl, 14.1 nuno]) in CHCl, (134 miL) was added methyl-4-oxo-3)-piperdifle carboxylate HCl (2.6 g, 13.4 rnrnol) and triethylamine (3.84 mL, 27.5 mrniol). The solution was stirred at rt for 12h. Gas evolution was observed. The reaction was quenched with IN iC] and extracted with CH 2 CI: and the organic layers were collected together, dried over Mg4SO, and evaporated in vacuo. The residue was purified to yield the title compound as a colorless oil. 'H-NM (CDCI 3 6: 1.46 9H), 2.36 2H), 3.55 2H), 3.77 (s, 4H), 4.04 2H).

Step 2: 3-Methyl-4-oxo-pipen'dirle- 1,3-dicarboxylic acid- I -ter-t-butyl ester 3-methyl ester 4-Oxo-piperidifle-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester( 2.00g, 6.8 inmol) was dissolved in tetrahydrofuran and cooled to 0 To the -233solution was added NaH (0.300 g, 12.5 mmol) portionwise over lh. H 2 was evolved during the addition. The reaction was allowed to stir for 30 minutes at 0 'C

IND

Cq and then methyl iodide (0.422 mL, 6.8 mmol) was added and allowed to stir at room

O

Stemperature for 13 h. The reaction was quenched with ice water and concentrated down. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with EIOAc the organics were collected together dried over MgSO 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/ 90% hexane to yield the title compound (1.1 g, 52 (CDCl 3 8 1.29 3H), 1.47 9H), 2.47 (dt, 1H), 2.76 (rn, 1H), 3.07 1H), 3.33 (dt, 1lH), 3.71 3H), 4.11 1H}, 4.50 1H).

Step 3: 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperdine-1,3-dicarboxylic acid 1tcrt-butyl ester 3-nmethyl ester 3-Methyl-4-oxo-piperdine-i,3-dicarboxylic acid-l -ert-butyl ester 3-methyl ester (1.1 g, 4.07 mmol) was dissolved in tetrahydrofuran and cooled to 0 To the solution was added 4-chlorophenyl magnesium bromide (12.2 mL, 12.2 nrunol) dropwise over -1/2 h and then stirred at 0 "C for lh. The reaction was quenched with saturated solution ofNH,C] and extracted with ethyl acetate The organics were collected, dried over MgaSO, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/ 90% hexane to 20% ethyl acetate/80% hexane) to yield the title compound (1.1 g, 70 (CDC13): 8 1.17 3H), 1.44 9H), 1.55 (m 1.96 1H)3.00 1H), 3.37 2H), 3.53 3H), 3.91 2H), 4.07 IH), 7.27 2H), 7.43 2H). ES1-MS m/z: 384.1 (M retention time 2.95.

Step 4 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine- 1,3-dicarboxyli c acid 1 tert-butyl ester 3-methyl ester (1.1 g, 2.87 mmol) was dissolved in CH2Cl 2 (35 mL) and cooled to 0°C and TFA (8 mL) was added dropwise. The solution was allowed to stir at 0 C for 1 h. The solvent was evaporated in vacuo and the residue wvas -234partitioned between IN NaOH and CH 2 I The aqueous solution was extracted (3x) and then washed with brine and dried over NaS,S0. The residue was carried onto the next step without further purification.

Step To a solution of 4-(4-chloro-phenyl)-4-hydroxy-3-nlethyl-pipefldifle- 3 carboxylie acid methyl ester (0.71 g, 2.5 mrnol) in acetonitrile/water (25 mL) was added K 2 C0 3 (1.40g, 10.0 mrno]) and 2-[5-(3-bromo-propylidene)-5,l 1dihydro-l O -oxa- 1 -aza-dibenzo[a,dl cyclohepten-7-yl]-propan-2-ol 0.937 g, mmo]). The soltition was allowed to stir at robin temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/HO, extracted -xN'ith EtOAc The organics were collected together dried over Mgy,S0 4 filtered and evaporated in vacuo, then purified by Biotaz-. flash chromatography (501% ethyl acetate! 50% hexane to 75% ethyl acetate! 25% hexane to 100% ethyl acetate) to yield the title compound (0.835 a, 58 %).'H-NMNR (CDCI 3 1.30 3H), 1 .57 (s, 6H), 1.76 IM), 2.24-2.53 (in, 7H1), 2.65 111), 2.86 2H), 3.44 5.30 (bs, 211), 6.16 1H), 6.82 1H), 7.26 (mn, 4H), 7.45 111), 7.53 11-1). 7.58 11-4), 8.49 ESI-MS-rn/z: 577 (M retention time 1.50.

Example 482 4-(4-Chloro-plhenyl)- 3-hydrox rnetl,- I- {3-[7-(hydrox yl-l -methyl-ethyl])- 1 I oxa-l1 aza-dibenzo[a,dflcycloheptcn-5-ylidene]-propyl} -3-nethyl-piperidine-4-ol 4-(4-Chl oro -phenylI)-4-hydrox y- I1- {3 [7-(hydroxyl- 1 -m ethyl -ethyl) -1 1 IH- oxa-l1-aza-dibenzo[a, d]cyclohepten-5-ylidenie]-propyl }-3-methyl-pipeidine-3carboxylic acid methyl ester (0.250 g, 0.43 rnol) was dissolved In tetrahydrofuran and cooled to 000. To the solution was added LiAI- 4 (1.3 mL, 1.3 minol) dlxopwise and the reaction was allowed to stir at 0'C for 3h. The reaction was quenched with ice water slowly anid diluted with ethyl acetate. The reaction mixture was allowed to stir at room temperature for 45 min. to break up any aluminum complexes. The Ct -235organics were separated and the aqueous layer was extracted (2x) more. All of the organrics were collected, dried Over MgS0 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate! 50% hexane to ethyl acetate! 25% hexane) to yield the title compound 103 g, 43 %).'H-NMR (CDC1 3 8 0.53 3H), 1.55 6H), 1.62 (mn, 1K), 2.40 2H), 2.55 3H), 2.72-2.86 (in, 4H), 3.19 (dd, lH), 3.24 1H), 3.41 1H), 5.33 (bs, 2H), 6.17 (t, IlH), 6.44 (bs, lH), 6.79 lH), 7.17 7.26-7.59 (in, 7H), 8.50 IlH). ESI- MS mlz: 549 (M retention time 1.39.

Example 483-1, Example 483-2 1 0 Racernic 4-(4-Chl oro-phenyl)-3 -hydroxym ethyl {3-[7-(hydroxyl- 1 -methylcthyl)-l I-1 0-ox a- I -aza-dibeznzo[a, dcyclohe-pteni-5ylidel-propyl}; -3-m ethylpiperdine-14-ol was resolved using a ChiraiPak AD column eluting with 5/'5/90 miethanol/ethanal/hexane. Peak One is the more active enantiomer, Example 483-i.

Peak Two is the less active enantiomer, Example 483-2.

Examnple 484 4 4 -Chloro-phien-yl)-3-e.thoxyiinethyl- 3[7-(-hydroxy- I-imethiv]-ethyl)-I I1-10oxa-] -aza-dibenzo[adcvclohepten-53ldenepropyl}3: nethipiperidii-4-o Step 1 To a solution of 4-4clr-h y)4hdo)-3hdoxiehl3iiehl piperidine- I-carboxylic acid-iert-butyl ester (0.270 g, 0. 76 mrnol) in TI-F 8 rnL was added NaH (0.075 g, 1 .9 mxnol) and stirred for 20 min at room temperature.

Ethyl iodide (0.066 mL, 0.83 mminol) was added and the solution was heated to for Ilh. The reaction was quenched with water and extracted with ethyl acetate (3x).

The organics were collected together dried over Mg 2 SO., filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate! hexane to 20% ethyl acetate! 80% hexane to 30% ethyl acetate! 70% hexante) to -236yield the title compound (0.110 g, 37 (CDCI 3 0.7 9 3 1.10 (t, 3H), 1.26 1Hi), 1.45 9H), 1.84 1H), 2.74 (in, 2H), 2.98 1Hi), 3.18 (in, 3.28 3.97 2H), 7.26-7.39 (in, 4H).

Step 2 4-(4-Chloro -phenyl) -3 -eth oxym ethyl-4-hydroxy- 3 -rnethyl -pipenfldin e- 1 carboxylic acid-lert-butyl ester (0.052 g,0. 14 rnnmol) was dissolved in CH 2

CI

2 (3 rnL) and cooled to 0 0 C and TFA (1 mnL) was added. The solution was allowed to stir at 00 C for I h. The solvent was evaporated in vacuo and used directly in the next reaction.

Step 3 To a so]lution of 4 -(4,-chlIoro-phenyl)- 3 -eth oxym ethyl -3 -methyl -pip ellidin-4ol (-0.038gy, 0.13 mmol) In acetonitrile/water (1.3 rnL) wAas added KCO 3 (0.075g, 0.53 mmol) and 2-[5-(3-broimo-propylidene)-5,1 I -dihydro- lO-oxa- I -azadibenzo~a,djcyclohep ten- 7-yl ]-propan-2-ol (0.050c,, 0.13 inniol). The solution \vas allovwed to stir at room temperature for 48 h. The reaction -was concentratcd and partitioned betvmeen EfOAc/.PLO, extracted wivth -EtOAc The organics were collected, dried over M6SO, filtered and evaporated in vacuo, then purifiedj by Biotage flash chiroinato graph y (75% ethyl acetate! 25% hexane) to yield the title compound in 65% yield. 'H-NMR (CDCI 3 5 0.81 3 0. 98 3 1.-5 8 (s, 6H), 1.84 1H), 2.31-2.49 5H), 2.58 IH), 2).67 1H), 2.77 3.26 21H), 3.65 2H), 5.33 (bs, 2H), 6.16 lH), 6.82 1H), 7.22-7.36 7H), 7.45 1H), 7.60 1H). ESI-MS rnfz: 577 (M retention time 1.58.

Example 485 (4-(4-Chloro-phenyl)-4-hydoxy-1- {3 1-hydrox y- 1 -methyl-ethyl)-I I1H- 1 0-ox a-iaza-d ibenzo d] cyclohepte1- 5 -yli dene] -propyl -3 -methyl -pip eridin- 3-ylrn eth ox y)acetic acid ethyl ester -237- Step I To a solution of 4-(4-chloro-ph en yD-4-hydrox y-3 -h ydrox ym ethyl -3 -m ethyl piperi dine-1I-carboxylic acid-tert-butyl ester (0.080 g, 0.22 nunol) in TEF (2.2 mL) was added NaH (0.031 g, 0.78 rnmol) and stirred for 20 min at room temperature.

Ethyl bromnoacetate (0.027 mnL, 0.30 mmol) was added and the solution was heated to 50'C for lh. The reaction was quenched with water and extracted with ethyl acetate The organics were collected together dried over MgS0 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/ 90% hexane to 20% ethyl acetate! 80% hexane) to yield the ethyl ester (0.050,g,-50 'H-NMR (CDCI 3 0.85 (bs, 3H), 1.22 3H), 1.45 9H), 1.66 (s, lh), 2.64-3.39 (i 6H), 3.96 2H), 4. 12 7.26-7.3 8 (in, 4H).

Step 21 4-(4-Chloro-phienyl )-3I-ethioxycarbonyhn ethoxyni ethy]1-4-hydrox %1-3 -n ethylpiperidine-1 -carboxylic acid-ier!-but\'l ester (0.060 g, 0.14 inol) was dissolved in CH,C1, (3 inL) and cooled to 0 0 C and TFA (1 mnL) was added. The solution was allowed to stir at O'C for 1 h. The solvent was evaporated in 1'acuc. and used directly in the next reaction.

Step 3 To a solution of 4-(4ch Ioro-phenyl)-4-hydrox y- 3 -methyl -p iperi din- 3 ylmnethoxy] -acetic acid ethyl ester 0.046g, 0.13 nmnol) in acelonitrile/water (8:2) (1.3 rnL) was added K 2 C0 3 (0.075g, 0.53 rnmol) and 2 -[5-(3-bromo-propyl:Idene)- 5,1 l-dihvdro-1 0-oxa-l1-aza-dilbenizo[a,d]cyclohiepten-7-yl]-propan')o] (0.0 51g& 0.13 rnrnol). The solution was allowed to stir at room temperature for 48 h. Tile reaction was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over Ma 2

O

4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate! 25% hexane) to yield the title compound in 54% yield. 'H-NMR (ODC 3 0.86 3H),l 1.16 1.57 6H), 1.78 I1H), 2.37 1H), 2.46-2.71 (i, -238- 2.81 1H), 3.80 2H), 3.97 2H4), 4.06 211), 5.30 (bs, 2H), 6.18 (t, 1H), 6,82 1H), 7.22 (dd, 1H), 7.26-7.36 (in, 7H), 7.47 IH), 7.60 11-).

ESI-MS 635 (M retention time 1.62.

Example 486 4-(4-Chloro-phenyl)- 3-(2 -di ethyl aino -ethoxym ethyl)-4-h ydrox y- 3 -m ethyl piperidine-I1-carboxylic acid-tert-butyl ester Step 1 To a solution of 4-(4-chloro-phenylI)-4-hydroxy-3 -hydroxymethyl-3 -methylpiperidine-1 -carboxylic acid-ter-t-butyl ester (0.071 g, 0.15 niol) in THF 1.5 niL) was added NaH (0.016 g,0.3 9 rnmol) and stirred for 20 min at roomn temperature. 2- Bromno-N,N-diethyletbylamnMe lTBr (0.044 rnL, 0.1 7rnmol) was added and the solution was heated to 50'C for Ilh. The reaction was quenched with water and extracted with ethyl acetate The or~anics wvere collected, dried over Mg-SO 4 filtered and evaporated in vacuo, then purified by Biotage flash chirornatography 1 5 (10% ethyl acetate/ 90% hexane to 201!/ ethyl acetate! 80% hexane) to ield the diethylarnilne (0.0355 g).

Step 2 4-(4-Chloro-phenyl)-3)-(2-d jethyl amino-ethoxymethl,)-4-hydr-oxy-3 -methylpiperidine-1-carboxylic acid-zert-butyl ester (0.035 g, 0.62 mimol) was dissolved in

CH

2 CII(3 QrL) and cooled to 0 0 C and TFA (1 mL) was added. The solution was allowed to stir at 00 C for I h. The solvent was evaporated in vacuo and used directly in the next reaction.

Step 3 To a solution of 4-(4-chloro-phenyl)-3-(2-di ethylamino-ethoxymnethyl)-3methyl-piperidin-4-ol in acetonitrile/water (3.2 miL) was added K 2 C0 3 and 2- [5-(3-bromo-propyli dene)-5,1l -dihiydro- 10-oxa-lI-aza-dibenzo[a,d]cyclohep ten- 7 -239yl]-propan-2-ol. The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H' 2 0, extracted with EtOAc The organics were collected, dried over MgSO,, filtered and N evaporated in vacuo, then purified by Biotage flash chromatography rmethanol/ 95% methylene chloride to 10% methanol] 90% methylene chloride to 150/o ri methanol/85% methylene chloride) to yield the title compound. 'H-NMiR (CDC 3 0.50 3H), 0.97 6H), 1.52 6H), 2'.40-".66 (mn, 12H), 3.16-3.30 (in, 6 5.32 (bs, 2H), 6.06 lH), 6.80 IH), 7.20 (dd, IH), 7.29 (dd, IH), 7.29-7.31 (mn,614), 7.58 2H), 8.51 IN). 8 ESI-MS n-i/z: 648 (M retention time 1.19.

Example 487 4 -[(4-Chloro-benzyl)ethyl-amnino]-pipeh'din- )I l-propvlid-ene)-5,1 I- I-az-a-dibe-nzo[a, d]cyclohepten-7-y]J,-propan--ol) Step 1: 4- (4-Ch loro-benzyl amino)-piperi dine- I carboxyl ic acid tert-butyl ster 4-Arnino-1 -N-Boc piperidine (1.80g, 8.9 mirnol) was dissolved in CH,CII and 4-chlorobenzylIbromide (1.84.o, 8.9 minol) and iriethylamnine m.L, 8.9 mmol) were added. The soluition was allowed to- stir for 1 4h at room teinp--ratUre and evaporated in v'acuo and partitioned between ether! I N NaCH. The aqueous layer was removed and the ether was washed with brine and dried over MgSO0, filtered and evaporated in vacuo, then purified by Biotage flash chromatography methanol] 95% methylene chloride) to yield the title compound (0.800 27

(CDC

3 6 1.26 IH), 1.44 1.83 2H), 2.63 IH), 2.78 2H), 3.46 2H), 3.78 2H), 4.00 (bs, 2H), 7.26 (bs, ESI-MS 325.1 (M retention time 1.86.

Step 2 (4-ChI oro-benzyl)-ethyl-arniino]-pipen'dine-lI-carboxyli c acid ierl-bixtyl ester (0.500g, 1.4 mm-ol) dissolved in 4M H-ClfDioxane (100 mL). The solution was -240stirred at rt for Ilh. The solvent was removed in vacuo and the mixture was carried N on to the next step without further purification as the hydrochloride salt.

r-Step 3: (4-Chloro-b enzyl)-ethyl-piperdifl-4-yl-alrife 4-(4-Chloro-benzylamiflo)-piperidine-l-carboxylic acid rcrt-butyl ester was dissolved in CHCI, and acetaldehyde (0.678-, 3.2 mimol), Na(OAc)BH (0.163g, 3.7 inmrol) and I drop of AcOH was added. The solution was stirred in a sealed vessel for 10 h. The reaction mixture was washed with IN NaOH, brine and dried over Mg 2 S 04, filtered and evaporated in vacuc, then purified by Biotage flash chromatography (15% ethyl acetate! 85% hexane) to yield the title compound (0.350 g 4 Step 4 To a solution of (4-chloro-bcnzyl)-Cth),l-piPefldini-4-yl-ainle hydr-ochloride (0.200 g, 0.83 mmol) in acetonitrile/water (S mL) was added K 2 C0 3 (0.476g7 3.4 mrnol) and 2-[5-(3)-bronmo-propyldefle)-5,1 I -dihydro- I 0-oxa- I -azadibenzo[a,d]cycloheptefl-7Y l]-propan- 2 -ol (0 'S 2g,7.5mmol). The solution was allowed to stir at room tempe.rature for 48 h. The reaction was concentrated and partitioned bem,-een EtOAc/H,0, extracted with EtOAC The organics were collected, dried over M\gSO,, filtered and evaporated in vacuc, then purified by Biotage flash chromatography (5 methanol! 95 methylene- chloride to methanol! 90% nmethylene chloride) to yield the title compound (0.240 g, 60 NMR (CDCI 3 5 0.988 3H), 1.57 6H), 1.67 2H), 1.85 2.3 2-2.46 (in, 5H), 2.51 2H), 2.84 2H), 3.47 2H), 3.56 2H), 5.29 (bs, 6.07 (t, I 6.80 1H), 7.21-7.2 8 (mn, 6H), 7.42 I1H), 7.56 I 8.48 1 ESI- MS 546 (M retention time 1.87.

Example 488 1- -Hydroxy- I-methyl-ethyl)- 1 IH-1I0-oxa- I -aza-dibenzo[a,dlcycl ylidene] -propyl) -4-phenyl-piperidifl- 4 -oI -241- To a solution of the 4-phenyl -pip eri din-4-ol (0.212 g, 1.2 nunol) in isopropanol was added 2,6-lutidine (0.240 miL, 2.1 rmol) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with 2-[5-(3-Brorno- I1 -dihydro- I 0-oxa- I-aza-dibenzo[ a,d]cyclohepten-7-yl]-propan-2-oI (0.224 g, 0.6mrnol), added in portions over 1 h. The solution was then stirred at 'C for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% rnethanol/85%/c methylene chloride) to yield the title compound 140 g, 'H-NNR (CDCO 3 5 1.12 3H), 1.57(s, 6H), 2.67-2S0 (mn, 4H), 1.95-2.11 (mn, 2.34-2.41 (in, 2H), 2.43 -2.54 (in, 2H), 2.88 2H).

3.22 2H), 3.43 (mn, 1IH), 5.2 8 (bs, 2H), 6.12 I 6.60 21H), 6.80 l H), 7.13 2H), 7.21-7.30 2H), 7.45 IH), 7.56 1H), 8.48 (dd, 1H). ESJ-MS M/2: 534 (M retention time 2.47.

Example 489 4-(2-ChloTo-phenyl)- I1- -hydroxy- 1 -methiyl-ethyl)- I lH- I 0-oxa- I -aza dibtnzo[a.dcvclohepten-5 -ylidene]-propyl} -piperi din-4-ol Step 1 To a I -bronio-2-chloro-berizene (0.97 mL, 8.3 inol) in ether was added mnagnesium (0.238 gy, 9.8 irnol) and catalytic iodide at room temperature for 2h.

This mixture was cooled to 0 and treated with 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.5 g, 7.5 mmol) dissolved in ether 8 mL) and added to the reaction mixture slowly. The reaction was heated to reflux for lh. The reaction wvas quenched with ammonium chloride and the aqueous phase extracted with ethyl acetate. The organics were combined and dried over MgSO 4 filtered and evaporated in vacuo. The residue was purified by Isco flash system hexane/25% ethyl acetate) to yield the alcohol (0.600 g, 38%).

Step 2 -242- 4-(2-Chloro-phenyl)-4-hydroxy-piperi dine-i -carboxyli c acid tert-b utyl ester 600 g, 1.9 mnmol) was dissolved in CHC1 2 (19 mL) and cooled to OTC and TFA (4 mnL) was added, The solution was allowed to stir at 0 0 C for I h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO 3 and CH 2

CI,.

The aqueous solution Wa extracted (3x) and then washed with brine and dried over NaSO 4 The residue was carried onto the next step without further purification.

Step 3 To a solution of the 4-(2-chloro-phenyl)-piperidin-4-ol (0.210 g, 1. 0 mnmol) in isopropanol was added 2,6-lutidine (0.31 mL, 2.7 mnmo]) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with 2-f 5.-(3-Bromo- 1 -dihydro-I 1 -oxa- I -aza-diberizo[a,d]cyclohiept-en-7-yfl-propan-2-ol (0.287 g, 0.77 rnol), added in portions over 1 h. The solution wa~s then stirred at 'C for an additional 14 h. The reaction was concentrated in v'acuo, [lhen purified by Isco flash chromatography (15% methanol!85% methylene chloride) to yeld the title compound (0.200 g, 1 1--NMR (CDCI 3 8 1.55 6H), 1.70 2H), 2.10-2.30 (in, 2.36-2.54 (mn, 2H), 2.57-2.92 (mn, 6H), 5.30 (bs, 2H), 6. 16 (t, I 6.77 1lH), 7. 16-7.36 (in, 5H), 7.48 2H), 7.5S 1IH), 8.37 (dd, 1 ES!- MS m/z: 505 (M retention time1.8- Example 490 4-(4-Chloro-2-methylI-phenyl)- 1 -hydroxy,-l-methyl-ethyl)-I IH-1 0-oxa- 1aza-dibenzo[a,d4cyclohepten- 5-ylidene]-propyl -piperidin-4-ol Step 1 To 4-chloro-2-inethylphenylmagnesium bromide (15 mnL, 7.5 nmol) in ether cooled to 0 'C was added 4-oxo-pip eri dine-lI-carboxylic acid tert-butyl este-r (1 .0 g, 2 5 5.0 mmol) over 30 min. The resulting solution was heated to reflux. for lh. The reaction was quenched with ammronium chloride and the aqueous phase extracted with ethyl acetate. The organics were combined and dried Over MgSO 4 filtered and -243evaporated in vacuo. The residue was purified by Isco flash system ethyl acetate) to yield the alcohol (0.534 g, 33%).

Step 2 4 -(4-Chloro-2-methyl-phenyl)-4-hydroxy-piperidine-lI-carboxylic acid tert.

buty] ester (0.5 34 g, 1.6 rnmol) was dissolved in CH 2 CI, (16 mL) and cooled to OTC and TFA (3 m.L) was added. The solution was allowed to stir at 00 C for I h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO 3 and CH 2 C12. The aqueous solution was extracted (3x) and then washed with brine and dried over Na 2 SO,. The residue was carried onto the next step wvithout. further 1 0 purification.

Step 3 To a solution of the 4 I-(4-chloro-2-rncthyl-phe-nyl)-piperidin-4-ol 160 g 0.71 m-mol) in isopropan-ol was added 2,6-lutidine (0.24 mL, 2.1 i-nnol) andl catalytic potassium iodide. This mixture was heated to S0 0 C, and treated w,,ith (3 -Bronio-propyl iden 1-dihydro- 10-oxa-l1-aza-dibeinzo[a,d]cvclohepten-7-vil]propan-2-ol (0.22] g, 0.59 rnol), added in portions over I l. The solution- was then stii-red at 80 'C for an additional 14 h. The reaction was concentrated vacuo, then purified by Isco flash chrornatography (15% rnethanol/85% methylencchloride) to yield the title compound (0.130 g, 'H-NMNR (CDC 3 5 15 s 6H), 1.92 2H), 2.30 2H), 2.49 3H), 2.48-2.63 (in, 2H), 2.74-3.11 (mn, 6H), 3.40 I 5.2 1 (bs, 2H), 6.09 I FF), 6.7 5 I 7.06 I 7.08 I H), 7.20(d, 2H), 7.22-7.36 (mn, 1H), 7.57 8.36 (dd, I ESI-MS mlz: 519 (M +I retention time 1.61.

Example 491 4-(3,4-Dichloro-phenyl)- I 1-hydroxy- 1-methyl-ethyl)- 11H- 1 0-oxa- 1. -azadibenzo[a, d]cyclohepten-5 -ylidene]-propyl -piperidin-4-ol -244- Step 1 To 3,4-dichlorophenylmagnesium bromide (7.5 mL, 7.5 mmol) in ether cooled to 0°C was added 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, mmol) over 30 min. The resulting solution was heated to reflux for h. The reaction was quenched with ammonium chloride and the aqueous phase extracted with ethyl acetate. The organics were combined and dried over MgSO 4 filtered and evaporated in vacuo. The residue was purified by Isco flash system ethyl acetate) to yield the alcohol (0.630 g, 36%).

Step-2 4-(3,4-Dichloro-phenyl)-4-hydroxy-piperidine- 1 -carboxylic acid tert-butyl ester (0.630 g, 1.8 mmol) was dissolved in CH,CI, and cooled to 0°C and TFA (3 mL) was added. The solution was allowed to stir at 0° C for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaI-CO and CHC1 2 The aqueous solution was extracted (3x) and then washed with brine and dried over Na2SO,. The residue was carried onto the next step without further purification.

Step 3 To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol 140 g, 0.57 mmol) in isopropanol was added 2,6-lutidine (0.23 mL, 2.0 mmol) and catalytic potassium iodide. This mixture was heated to 80 0 C, and treated with (3-Bromo-propylidene)-5,1 1-dihydro-10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]propan-2-ol (0.213 g, 0.57 mmol), added in portions over 1 h. The solution was then stirred at 80 OC for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.110 g, 'H-NMR (CDClI): 61 .55 (s, 6H), 1.70 2H), 2.10 -2.30 2H), 2.45 2H), 2.57-2.92 6H), 5.30 (bs, 2H), 6.16 1H), 6.77 1H), 7.16-7.40 4H), 7.08 1H), 7.57 2H), 8.36 (dd, 1H). ESI-MS m/z: 539 (M retention time 1.72.

-245- Example 492 4-(4-Chloro-3 -nitro-phenyl)-1- 1-hydroxy-l1-methyl-ethyl)- 11H-i 0-oxa-lI-azad ib enzo cycl ohepten- 5-y idene] -propyl) -pip eri din-4-olI Step 1 To fuming nitric acid (20 mL) was added 4 -(4-chloro-phienyl)-piperidin-4-ol at 0 'C and stirred for 5 min. The solution was carefially neutralized with Na,C0 and Filtered. The resulting solid was trituated with water and then filtered to give a yellow solid. The solid was dissolved in sat NaHCO 3 and extrated with ethyl acetate The organics were collected together dried over Mg 2 SOll filtered and evaporated in vacuo to give the 4-chloro-3-nitro compound (L I g, 18%).

Step 2 To a solution of the 4 -(4-Chloro-3-itro-phenyl)-piperidiin-4-oI (0.295 1.2 imnol) in isopropanol was added 2,6-lutidine (0.2 25 iinL, 2.1 mmcl) and catalytic potassium iodide. This mixture was he ated to 80'C. and treated with Bromo-prop)yldene)-5l I 1-dihy)dro-1I0-oxa- I-aza-diben7zo~a. lcyclohepten-7-yl]propan-2-ol (0.224 a, 0.6 mniol), added in portions over I h. The solution .,vas then stirred at 80 'C for an additional .14 h. The reaction was concentrated in v-czio, then purified b)y Isco flash chromatography (1 methanol/85% methylene chloride) to yield the title compound (0.100 g, 305/). 'H-NMR (CDCI 3 8 1.53 6H), 1.70 (d, 1.81-2. 18 4H), 2.3-2.44 (mn, 4H), 2.56 2H), 2.69 2H), 5.32 (bs, 2H), 6.16 IH), 6.81 IH), 7.28 2H), 7.48 2H) 7.58 2H), 8.06 l1H). ESI- MS rnlz: 550 (M retention time 1.51 Example 493 2 4 -[(4-Chloro-phenyl)-ethyl -amino] -piperidin- I -yl -prop)yli dene)-5, 1 1dihydro-1I0-ox a-I -aza-dibenzo[a,d]cyclohepten-7-yl] -propan-2-oI Step I -246- 4-Amino-piperidine--carboxylic acid tert-butyl ester 58 g, 7.9 mrimol) and acetaldehyde (0.417g, 9.48 mmol) were mixed with sodium triacetoxy borohydride (3.35, 15.8 mmol) in dichioroethane containing acetic acid and the resultingy mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH 2 C1 2 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (10% methanol/90% methylene chioride/ammoniumn hydroxide) to yield the tert-butyl ester (0.71 g, 39%).

Step 2 4-Eth\'lamino-piperi dine- I -carboxylic acid tert-butyl ester (0.694T g, 3.04 nunol) and I -Brorno-4 -chloro -benzene 582, 3.04 rnol) was dissolved in toluene along with sodium t-butoxide (0.41, 4.26 mmol), Pd 2 (dba) 3 (0.055 g, 0.061 ilmol) and BINAP (0.037 g, 0.061 mmol). The solution was heated to 70 'C for 2 days and then filtered and the reaction was concentrated in vacuo, then purified by Isco flash chromatography (500/ ethyl acetate/ 50 hexane) to Yield the tert-butyl ester (0.25 S te p 3 4-(Ethyl -phenyl -amino) -pip endi ne- I -carboxylic acid tert-butyl ester (0.251 g) 1 .0 mmol) was dissolved in 4M HCI/Dioxane (1 0 rnLJ). The solution was stirred at ri for lh. The solvent was removed in vacuo and the mixture was carried on to the next step without far-ther purification as the hydrochloride salt.

Step 4 To a solution of the (4-chloro-phenyl)-ethyl-pipen'din-4-yl-alinfe 150 0% 0.63 mrnol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) arnd catalytic potassium iodide. This mnixture was heated to 80'C, and treated with 1-dihydro-1I0-oxa- I -aza-diberzo[a, d]cyclohepten-7-yl]propan-2-o] (0.221 g, 0.6 mmol), added in portions over I h. The solution was then -247stirred at 80 'C for an~ additional 14 h. The reaction was concentrated in vacuo, then purlfied-by Isco flash chromatography (15% methanoi/85% nmethylene chloride) to yield the title compound 108 g, 'H-NTMR (CDC1 3 8 1.12 3H), 1.57 (s, 6H), 2.67-2.80 (mn, 4H), 2.00 (in, 2H), 2.34-2.41 (in, 2H), 2.43-2.54 (mn, 2H), 2.88 2H), 3.22 2H), 3.37 -3.51 (mn, IH), 5.28 cbs, 6.12 IH), 6.60 2H), 6.80 IH), 7.13 2H), 7.21- 7.30 (in, 2H), 7.45 1H), 7.56 I 8.48 (dd, 1 ESI-MS m/z: 532 (M retention time 2.47.

Example 494 2 3 [4-(4-Chl oro-phenyl)-4-methox y-pip cridin- 1 -yl] -propyli1 dene) 1-5,1 1 dihy)dro-l 0-ox a-lI aza-dibeInzo[a,d~cyclohieptefl-7-yl)-propal- 2 -ol Step 1 4-(4"-Chloro-phelyl)-4-hiydroxy-Pipefl dine- I -carbox ylic acid tert-bu tyl ester (200 ing, 0.641 inmol) was added portionwise as a solid to a suspension of sodiumi hydride (0.01 8g, 0.770 mu-mol) in dirnethylformamide (6 m-L) at room temperature.

After 30 minutes, methyl iodide (0.109g, 60 uL, 0.770 minol) w7,as added an-d tile miixture was stir-red overnight. The mixture was poured into an equal volumne of water and extr"acted with ethyl acetate (2 X 10 mL). The ethyl acetate extracts were_ dried over magnesium sulfate, filtered, and concentrated in v'acuo to grive a tan oil.

The crude oil was purified by silica gel chromatography (hexane to 60:40 hexane/ethyl acetate gradient) to afford 4-(4-Chl oro-phenyl)-4-methoxy-pi peri dine- 1 -carboxylic acid tert-butyl ester as a clear oil (1 08 mrg, 52%).

'H-NM.NR (CDCI 3 300 lvfl-z) 8: 1.45 9H), I .80(td, 2H), 1.97 (bd, 2H), 2 .96 (s, 3H), 3.16 (td, 2H), 3.90 (bd, 2H), 7.36 4H) MS m/z: 326 (M 1) Step 2 4-4Clr-hnl--ehx-ielie I -carboxylic acid ter-t> utyl ester 108g% 0.33 1 mumol) was dissolved in methylene chloride (6inL) and coolIed in an -248ice bath. Trifluoroacetic acid (2 m.L) was added slowly dropwise. The mixture was stirred for 2 hr as it warmed to room temperature. The reaction mixture was concentrated in vacuo and then redissolved in mnethylene chloride and washed with saturated sodium bicarbonate (2 X 10 mL). The pooled aqueous layers were extracted with methylene chloride (2 x 10 The methylene chloride extracts were pooled, dried over magnesium sulfate, filtered and concentrated in i'acuo to g-iv~e 4- (4-Ch Ioro-phenyl)-4-m eth ox y-pi peridinle as a clear oil (72 mg, 97%).

'H-NMR (CDCI 3 300 MHz) 5: 1.92 (in, 4H), 2.98 3H), 3.07 (in, 4H), 4.50 (bs, I 7.3 0 4H-) MS ni/z: 226 (M +1) Step 3 4-(4-Chloro-phenyl)-4-nethoxy-piperidifle (0.0 72 g, 0.319 nmirol) %v'as dissolved in isopropanol (5 rnL) and 2,6-lutidine (0.034gD, 37 uL, 0.3.9iaol) was added. Catalytic iodine was also added. The resulting suspension was wani-neid to SO Solid 2-[5-(3-Bronrn-propylidefle)-5, 11 dilbeinzo[a..d]cyclohelptel-7-y.]-propafl- 2 -ol (0.060cg, 0. 160 mmol) -was added InI approximately equal portions over 2 h. Stirring wvas continued an additional 20 h at S0 The mrixture wvas concentrated and the resulting, residue purified by silica gel chromatography (ethyl acetate to 67/10/3 ethyl acetate/rnethanol/triethylamifle gradient) to afford the title compound (70 ing, 'H-NMR (CDCI 3 300 MHz) 8: 1.67 1.99-2.86 (in, 12H), 2.98 3H), 5.32 (brs, 2H), 6.16 INH), 6.81 I1H), 7.25-7.40 (in, 6H), 7.50 I 7.66 I H), 9 1KH) MSin~z: 519 (M +1) Example 495 3[-2-hoo-hnxy-ie id yI]-propylidene} -5,11 -dihydro- 1.0-ox a- 1 -aza-dibenzo~a,dlcyclohepte1- 7 -yl)-propan- 2 -oI -249- 4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1 .32 mL) and water 17 mL). To this Nrrmixture was added 2-f 5-(3-Bromo-propylidene)-5,1 1-dihydro-1 0-oxa-1-azadibenzo[a,d]cyclohepten-7-yl]-propan-2-oI (0.050Og, 0.134 rnm-ol) and potassium N- 5 carbonate (0.074gs, 0.536 mmol). The mixture was stirred at room temperat-ure for 24 hrs and then concentrated in x'acuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate 2 X 5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in v-acuo to afford an oil. The residue 1 0 was purified by silica gel chromatography (ethyl acetate to S7/l 0/3 ethyl ace tate/rnethanol/t-iehylamine gradient) to afford the title compound (46 mig, 'I1.NN4R (ODC1 3 300 MHz) 8: 1.58 6H), 1.7 -2.9 (in, 12H), 4.42 (br s, I H), 5.3 4 (br s, 2 6. 1 I 6.7 5 IlH), 6.8 8 2H), 6.9 -7.3 (mn, 4 7. 3 2 (s, I1H), 7.5 8 INH), 8. 55 I MS nilz: 5 06 (M4 1) 1 5 Example 496 (4-Chloro-phenyl)-(j -hydroxy- 1 -m ethyl -ethyl)- I IH- 1 0-oxa- I -azadibenzo[a,d] cyclIoh epten-5 -),I]dene] -propy}I -pi peri din-4-yl)-methanione The title compound was prepared by following the procedure of Exa..nple 494, Step 3, but replacing 4-(4 -Chloro-phienyl)-4-methoxy,-piper-idine wi th (4- Chi oro-pheniyl )-piperidin-4-yI-methanone.

'Il-NMR (CDCd 3 300 Mvl-z) 1.45 2.05 (in, 2H), 2.55 (in, 214), 2.7 1(m, 2H), 3.05 (in, 2H), 3.20 (mn, 2H), 3.61 (mn, 2H), 5.20 (in, 2H), 6.05 1H), 6.77 (d, 1Hi), 7.35 -7.60 (in, 6H), 7.82 8.35 (br s, 8.52 IN); MS 517 (lvi 1) Example 497 -250- (3 -[4-(4-tri flu oromethyl -phenoxy)-pip eri din- 1 -yl]-propylidene} -5,11 -dihydro- 1 0-ox a-I -aza-dibenzo cyclohepten- 7-yl)-propan-2-ol The title compound was prepared by following the procedure of Example 495, but replacing 4-(2-Chloro -phenoxy)-pip eri dine hydrochloride with 4-(4- Trifluorom ethyl -ph enox y) -pip eri dine.

'H-NN'fR (CDCl 3 300 Ml~z) 8: 1.62 6H), 2.15 (br d, 2H), 2.60 -3.15 (il, SH), 3.3 (br d, 2H), 4.74 11-1), 6.07 I1H), 6.84 I 6.91 2H), 7.10 7.24 (in, 7.40 1H), 7.55 (mn, 3H), 8.52 IH); MS imlz: 539 (M 1) Example 498 4-(4-Chloro-ben~zyl)-3-( 1- t3-[7-(1 -hydroxy-1 -methyl-ethyl)-1 1 H-I 0-oxa-l -aza- -pi'peridin-4-\'l)-oxazolidin-2--oine Step I 2-Arnino-3-(4-chloro-phenylI)-propan-l1-ol and 4-oxo-piperidlne-1 carboxylic acid tert-butyl ester were dissolved in 12 ml of mecthylene chloride.

Sodium triaceioxybor'ohydnhde (1.03 g,0.00487 mole) was added as a solid followed by catalytic acetic acid. The reaction was stirred overnight at room temperature.

The reaction was quenched by adding 12 rnl of IN sodium hydroxide. The intennediate alcohol was extracted into methylene chloride (3 x 1 2 mQL, thle oreanics were dried over magnesium sulfate, filtered and concentrated in vacuc to give the intermediate alcohol as a clear yellow oil (1 .1 g, This oil was carried on without additional characterization.

1-(4-Chloro-benzyl)-2-hydroxy-ehtylaniino]-piperidine-lI-carboxylic acid tert-butyl ester, the intermediate alcohol was dissolved in 15 mL of methylene chloride. Triethylamnine (0.423 g, .00418mo1, 583 uL 1.2 equiv) was added followed by portionwise addition of carbonyl diimidazole (0.68g, 0.00418 mnol, 1.2 equiv). The mixture was stirred at room temperature and then quenched with water mL). The organic layers were separated and the remaining aqueous layer was -251extracted with methylene chloride (3 x 15 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yello'w solid.

The crude oil was purifie.d by silica gel chromatography (methylene chloride to methanol in methylene chloride gradient) to afford 4-[4-(4-chloro-benzyl)-2-oxooxazolidin-3 -yi]-piperi dine-lI -carboxylic acid tert butyl ester as a white solid (1.1 g, 80 1 H-NM4R(CDCl 3 300 MI-z) 5: 1.40 9H), 1.70 10 4H), 2.75 (mn, 2H),\2.72 (td, IlH), 4.11 (m 3H), 4.15 (br t, 2H), 7.05 2H), 7.45 2H); MS nilz: 3 95 (M Step 2 4- [4-(4-ch-loro-btnzvI)-2 -oxo-oxazoli]din-S -yl -piperid ine- I -carboxylic acid *tei-t- butyl ester (0.9 g, ,0.002279 mole) was dissolved in methvlene chlori de (41 The solution was cooled to ice bath temperature and trifluoroacetic ac:id (14 rnL) was added and the reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to give the trifluoroacetate salt of the product as an'I. The salt wvas free based by adding saturated sodiumn bicarbonate (50 irnL) and extracting with methyl ene chloride (2 x 50 rnL). The organic layers were pooled, dried over magnesium sulfate, ffilterd and concentrated in vacuo to g'ive 4-(4chlIoro-benzyl)-3 -pip er Idn- 4-yl-ox azoli1din-2 -one as an off-white foam (560 ing,) 84%).

I1-NMR (CDCI 3 300 MHz) 8: 1.70 -2.15 (in, 4H), 2.60 -2.80 (in, 4H), 3 .05 3.30 2H), 3.55 (br s, IH), 3.71 (in, 1K), 3.87 (in, 2H), 7.01 2H), 7.23 (d, 2H); MS r-n/z: 295 (M 1) Step 3 The title compound was prepared by following the procedure of Example 495, but replacing 4-(2-Chloro-phenoxy)-piperidine hydrochloride with 4-(4-chlorob enx yl) -3 -pip eri din yl-ox azol i din-2-one.

-252- 'H-NMR (CDCI 3 300 MHz) 5: 1.60 6H), 1.97 3. 10 (mn, 14H), 3.75 (br s, 2H), 4.1 0 (br s, 2H), 5.9 8 I 6.80 I 7.00 7.20 (in, 8H), 7.40 I 7.62 (d, IH), 8.60 IF); MS m/z: 590 (M 1) Example 499 1- {4-(4-Chloro-phenyl)- 1-[3-(7-isopropenyl-I IH-I 0-oxa-lI-azadib enzo cyclohepten5 -yi dele)-popyl -pip erdin- 4 -yl} -ethanol The product of Example 457 (64 mg, 0.12 rnmol) was dissolved in anhydrous methanol~ (2.5 mL) and the resulting solution cooled to 0 Sodium borohydri'de (37 mng, I inrol,) was added portionwise over 5 h. The reaction was quenched with water and concentrated. The crude product residue 'was purified by reverse phase HPLC (water, acetonitrile, formic acid gradient) to afford the titled compound (note elimination of tertiary benzylic alcohol).

MS rn/z: 515 (nm I).

Example 500 ~(4-Chloro-benzyl)-.(l j 3 -hydrox y- I -:-methyl -ethyl) -I IH- I 0-oxa- I -aza- -dibenzo[ a,d]cycl oheptefl- 5 -yl idenel -propyl} -piperi din-4-yl)-ami1no] -acetic acid niethyl cstcr Step 1.

To a solution of 4-chlorobenzylarnifle (859 mg, 6.07 rmnol) in 1,2dichloroethane (20 rnL) was added t-butyl-4-oxo-piperidile-I -Carboxylate (1 .451 g 7.282 mmnol), acetic acid (400 uL), and sodium triacetoxyborohydride (1.800 g) 8.497 mmol). The mixture was stirred at rt under nitrogen for 2h, diluted w~ith ethyl acetate, washed thrice with saturated sodium bicarbonate solution and dried over magnesium sulfate. The extracts were filtered and concentrated to afford 4-(4chloro-benzylamino)piperidine-1-carbox),Iic acid tert-butyl ester (2.49 g, >100 -253as a yellow oil, which was of sufficient purity by H-NMR to use without further purification.

'H-NMR (CDC13, 300 MHz) 6: 1.44 9 1.56 1.70 (br s, 2 1.81 1.

(br d, 2 2.63 (dddd, 1 2.78 (dd, 2 3.72 1 3.78 1 4.00 (br s, 2 7.16 7.25 4 H).

MS m/z: 325 (M 1).

Step 2 To a solution of the product from step 1 (620 mg, 1.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (0.386 g, 532 uL, 3.82 nm ol) followed by methyl bromoacetate (0.584 g, 361 uL, 3.82 rmmol). The resulting mixture was heated at 55 'C for 2 d then rt for 3 days. The reaction was diluted with ethyl acetate, washed twice with water and once with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude 4-[(4-chloro-benzyl)methoxycarbonylmethyl-amino]-piperidine- -carboxylic acid tert-butyl ester (0.697 g, 92 was of sufficient purity to use without further purification.

'H-NMR (CDC1 3 300 MHz) 6: 1.44 9 1.78 1.95 2 2.60 2.83 2 3.3 4.2 12 7.24 7.36 4 H).

MS m/z: 397 (M 1).

Step 3 To a solution of the product of step 2 (0.270 g, 0.681 mmol) in methanol (6 mL) was added hydrogen chloride in dioxane (4.0 M, 340 uL, 1.36 mmol). After stirring at rt 3 h, an additional 1 mL aliquot of the HCI in dioxane solution was added and the mixture was allowed to stir at rt over night. The mixture was concentrated under reduced pressure to afford [(4-chloro-benzyl)-piperidin-4-ylamino]-acetic acid methyl ester which was used without further purification.

MS m/z: 297 (M 1).

Step 4 To a solution of the product of step 3 (0.251 g, 0.680 mmol) in acetonitrile -254- (4 mL) was added potassium carbonate (0.310 g, 2.24 mmol) in water (2 mL), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-I -azadibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (170 mg, 448 mmol). The resulting orange solution was stirred at rt 13 days. The mixture was diluted with ethyl acetate and washed with water and brine. The washed extracts were dried over magnesium sulfate, filtered and concentrated. Pure titled compound was afforded by silica gel chromatography of the crude material (methylene chloride 98/2 methylene chloride/methanol gradient); 107 mg, 41 'H-NMR (CDC13, 300 MHz) 5: 1.56 6 1.74 1.92 6 2.28 2.48 4 2.53 2.66 2 2.82 (br d, 2 3.30 2 3.63 3 3.77 2 H), 5.21 5.39 (br s, 2 6.07 1 6.80 1 7.21 7.32 (rn, 6 7.42 1 7.55 (dd, I 8.50 (dd, 1 H).

MS m/z: 590.

Example 501 [(4-Chloro-benzyl)-( {3-[7-(1-hydroxy- I-methyl-ethyl)- 1H-10-oxa-l-azadibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperidin-4-yl)-amino]-acetic acid To a solution of the product of step 4 in Example 500 (209 mg, 0.353 mmol) in dioxane (5mL) and water (2.5 mL) was added lithium hydroxide (59 mg, 1.41 rnnmol). The reaction was allowed to stir at rt 24 h, was concentrated and purified by reverse-phase HPLC (water, acetonitrile, formic acid gradient) to afford the titled compound (44 mg, 22 as a white solid.

'H-NMR (CDC13, 300 MHz) 8: 1.49 6 1.69 2 2.05 2 2.28 2.53 5 2.82 3 3.14 3.20 (4 4.06 2 5.18 5.36 (br d, 2 6.12 1 6.76 1 7.25 (dd, 1H), 7.32 7.40 2 7.45 7.51 (m, 4 7.78 (dd, 1 8.49 (dd, 1 H).

MS m/z: 576 (M 1).

-255- Example 502 S-4-(4-Chloro-phenyl)-1- {3-[7-(1-hydroxy-l -methyl-ethyl)- 11H-10-oxa-l-aza- IN dibenzo[a,d]cyclohepten-5-ylidene]-propyl} -3,3-dimethyl-piperidin-4-ol

O

Step 1 To a dry, 2L 2-neck, round-bottom flask equipped with a magnetic stirrer, a condenser, and a large 10 °C water bath was added 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (125 g, 628 mmol) and anhydrous tetrahydrofuran (1 To the resulting yellow solution was added methyl iodide (85 mL, 1365 mmol). Sodium tbutoxide (150g, 1560 mmol) was then added portionwise over 30 minutes. An exotherm was detected, especially at the beginning of the'addition. The reaction mixture did warm to a gentle reflux, the rate was controlled by the speed of addition of base. The mixture was stirred an additional 30 minutes. The solvent was removed in vacuo. The oily residue was treated with NH,Cl/water (500 mL), and extracted with ether (3 x 200 mL). The combined organics were washed with brine, dried over NaSO,, and filtered through a short plug of silica gel. The solvent was removed in vacuo, and the resulting yellow oil had started to ccrystallize. It was left under high vacuum overnight. The mixture was slurried in hexane (50-100 mL) and sonicated for one minute. The yellow solid was collected by filtration and washed with hexane (100 mL). The first crop of 3,3-dimethyl-4-oxo-piperidine-lcarboxylic acid tert-butyl ester yielded a yellow solid. (See, preparation of (37) in Vice, S. etal., J. Org. Chem., 66:2487-2492 (2001).) 'H-NMR (CDCl 3 300 MHz) 5: 1.13 6 1.49 9 2.49 2 3.43 (br s, 2 3.73 2 H).

Step 2 A 2-neck, 2-L round bottom flask was fitted with 2 125 mL dropping funnels and a stir bar. The assembly was flame-dried under dry nitrogen. The flask was charged with THF (700 mL) and 4-bromo-chlorobenzene (33.7 g, 176 mmol, The resulting solution was cooled to -78 "C in a dry ice/acetone bath. To one -256of the dropping funnels was added butyllithium (2.5 M in hexanes, 70 mL, 175 mmol, 2.5 eq) via canula. The butyllithium solution was slowly added to the cold THF solution over I h. Stirring continued for an additional 0.5 h affording a white suspension. A solution of 3,3-dimethyl-4-oxo-piperidine-l-carboxylic acid tertbutyl ester (16.0 g, 70.5 mmol, 1 cq.) in TITF (100 mL) was prepared and added to the reaction mixture via the second dropping funnel over 1.75 h. The resulting mixture was stirred at -78 'C for 2h, at which time reaction appears to be essentially complete by TLC analysis. Saturated aqueous NH 4 CI (150 mL) was added and the reaction was allowed to warm to rt. Water (150 mL) was added and the mixture extracted with ethyl acetate (2 1 The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The solid residue was triturated with ethyl acetate and filtered. The supematant was concentrated and triturated with ether. The resulting supematant was then triturated Swith ether/petroleum ether. The resulting solids were combined to afford 4-(4- Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidine-l-carboxylic acid tert-butyl ester (17.52 g, 51.6 mmol, 73 as an off-white solid.

'H-NMR (CDC13, 300 MHz) 8: 0.82 6 1.34 1.44 2 1.49 9 H), 2.67 (ddd, I 3.10 3.70 3 4.00 4.30 1H), 7.31 2 7.39 2

H).

Step 3 To a cooled (0 solution of the compound prepared in step 2 (10.42 g, 30.7 mmol) in methylene chloride (300 mL) was slowly added trifluoroacetic acid mL) over 1.25 h. The resulting yellow solution was stirred at 0 'C for an additional h. The mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate (1.2 washed with aqueous sodium hydroxide (1 N, 150 mL). The aqueous layer was extracted with additional ethyl acetate (200 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting solid residue was triturated with ether to afford 4- (4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol (6.94 g, 29.0 mmol, 94 as an off- -257white solid.

'H-NMR (CD30D, 300 MHz) 8: 0.73 3 0.85 3 1.42 (ddd, 1 2.36 1 2.61 (ddd, 1 2.91 (br dd, 1 3.08 3.19 2 7.26 7.32 2 7.44 7.50 2 H).

MS m/z: 240 (M 1).

Step 4 A visibly clean 5 L, 3-neck flask was fitted with an overhead stirrer and flushed with nitrogen for 20 min. 4-(4-Chloro-phenyl)-3,3-dimethyl-piperidin-4-ol (202g, 843 mmol), L-(+)-tartaric acid (114 g, 759 mmol) and 4040 mL of a 9:1 butanone:water mixture were added to the flask. The mixture was heated to reflux.

Water (202 mL) was added portionwise over 45 min (ratio ofbutanone to water: 6:1) to fully dissolve the solid mixture. Reflux was continued an additional 45 min, the heat source was then turned off and the flask allowed to cool slowly to rt overnight. Solids were removed under suction filtration and dried 3 d in vacuo to afford S-enantiomer (134.4 g, 41 as the tartrate salt.

The above salt was partitioned between 1 M NaOH and methylenc chloride (brine washed and sodium sulfate-dried) to afford the free base.

'H-NMR (CD 3 OD, 300 MHz 0.73 3 0.85 3 1.42 (ddd, 1 2.36 1 2.61 (ddd, 1 2.91 (br dd, 1 3.08 3.19 2 7.26 7.32 2 7.44 7.50 2 H).

MS m/z: 240 (M 1).

Step To a solution of the homochiral product of step 4 (2.40 g, 10 mmol) in acetonitrile (80 mL) and water (20 mL) was added potassium carbonate (1.39 g, mmol) followed by 2-[5-(3-bromo-propylidene)-5,1 I-dihydro- 10-oxa- -azadibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (2.49 g, 6.67 mmol). The biphasic mixture was stirred at rt 48 h. Acetonitrile was removed by rotary evaporation and the resulting slurry was partitioned between ethyl acetate and brine. The organic -258phase was dried over magnesium sulfate, filtered and concentrated to afford an oily solid which was purified by silica gel chromatography (methylene chloride 90/10 methylene chloride/methanol gradient) to afford the title compound as an off-white powder (2.63 g, 74 'H-NMR (CD 3 OD, 300 MHz) 6: 0.71 3 0.84 3 1.4 1.55 9 H), 2.18 2.81 9 5.15 5.40 (br s, 2 6.23 1 6.74 1 7.23 7.31 3 7.42 7.50 4 7.80 (dd, 1 8.47 (dd, 1 H).

MS m/z: 533 (M 1).

Example 503 R-4-(4-Chloro-phenyl)- (3-[7-(1-hydroxy- -methyl-ethyl)-11 H-10-oxa-I -azadibenzo[a,d]cycloh epten-5-ylidene]-propyl}-3,3-dimethyl-piperidin-4-ol Step 1 Racemic 4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol (0.500 g, 2.086 nmol) was dissolved in minimal hot isopropyl alcohol (ca. 5 mL). The hot solution was filtered through a plug of cotton and transferred to a solution of 0camphorsulfonic acid (0.484 g, 2.086 mmol) in isopropyl alcohol (ca. 3 mL). The mixture was stirred vigorously for several minutes, during which a thick precipitate forms, and allowed to cool to rt over 0.25 h. The solids were removed by suction filtration and dried in vacuo. The dried salt was dissolved in hot isopropyl alcohol (ca. 50 mL), filtered thorugh a cotton plug, and allowed to slowly cool to rt, undisturbed, overnight. The solids that formed on cooling (95 mg, 19 of theoretical) were removed by suction filtration and shown by analytical HPLC to be enantiomerically pure. The salt was suspended in ethyl acetate and neutralized with sodium hydroxide (1 The homogenous organic phase was washed with water and brine, dried over sodium sulfate, filtered and dried to afford R-4-(4-chlorophenyl)-3,3-dinmethyl-piperidin-4-ol.

-259- 'H-NMR (CD, OD, 300 MHz) 5: 0.73 3 0.85 3 1.42 (ddd, 1 2.36 1 2.61 (ddd, 1 2.91 (br dd, 1 3.08 3.19 (in, 2 7.26 -7.32 (in, 2 7.44 7.50 (mn, 2 H).

MS 240 (M I).

Step 2 The titled compound was prepared following the procedure in step 5 of Example 502, substituting S-4-(4-chloro-phenyl)-3,3 -dimethyl-piperidin-4-ol for R- 4-(4-chloro-phenvl)-3 ,3-dimelhyl-piperidin-4-ol.

1 H-NMR (CD 3 OD, 300 MIHz) 8: 0.71 3 0.84 3 1.4 1.55 (mn, 9 H), 2.18 -2.81 9H), 5.15 -5.40 (brs,2 6.23 I 6.74 1 7.23 -7.31 (mn, 3 7.42 7.50 (in, 4 7.80 (dd, 1 8.47 (dd, I H).

MS rn/z: 533 (M 1).

Example 504 S-I oro-ph enyl)-4-hydroxy-3 ,3 -di methyl -pip erd in -I -yl]propylidene If-5,1 1 -dihydro- I 0-oxa- I -aza-dibenzo cyclohepten-7-yl1)-etrhanolne To a soiution of S-4-(4-chloro-phenyl)-3,3-dim ethyl -piperdi n4-ol (1 80 Ing, 0.75 nol) in acetonitile/water was added potassium carbonate- (120 nmg, 0.86 rnmol), followed by 1 )-bromo-propylIdene)-5,1 I -dihydro-1 I0-oxa-1I -azadibenzo[a,d]cyclohepten-7-yl]-ethanone (214 mng, 0.6 inmol). The reaction mixture was stirred at 50 'C for 8 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporated from the combined dried (MgSO 4 organic extracts, and the residue was purified by column chromatography on silica gel using methylene chloride-mnethanol (96:4) to afford the title compound (217 mng, 70 'H-NMR (CDCI 3 6: 0.6-0.9 (6H, 1.2-1.6 (4K, mn), 2.2-2.4 (4H, mn), 2.55 (3H, s), 2.8 (2H, 5.3 (2H, brs), 6.25 (1H, 6.85 (1IH, 7.27-7.4 (6H, mn), 7.6-7. 8 (2H, rn), 8.0 8.5 (IH, d).

-260- MS m/z 517 (M 1).

Example 505 R- 1 3 -[4-(4-Chl oro-phen yl) -4-hydroxy-3 ,3 -dim ethyl -piperdin- Il-yl] propylidene) -5,1 1 -dihydro- I 0-oxa- I -aza-dibenzo [a,d~cyclohepten-7-yl)-ethanone To a solution of R-4-(4-chloro-plienyl)-3,3-dirnethyl-piperdin-4-ol (100 mg, 0.417 ninol) in acetonitrile/water was added potassium carbonate (5 7 mg, 0.413 mnmo1), fol lowed by I -[5-(3-bromo-propylidene)-5, I] -dihydro-] I0-oxa- 1 -azadibenzo~ja,dccycloheptei..7-yl]-ethanone (100 mg, 0.279n-mmol). The reaction mixture was stirred at 50 'C for 8 hours and then concentrated in vacuo. The resulting- residue was treated with water and extracted with ethyl acetate. Solvent was evaporated fro-m the combined dried (Mg-SO,) organic cxtracts, and the residue was purified by column chromnatography on silica gel using methylene chloridemethanol (96:4) to afford the titled compound (102 mng, 71%) 'H-NMR 8: 0.6-0.9 (6H, 1.2- 1.6 (4H, in), 2.2-2.4 mn), 2.5 5 (3H, s), 2.8 (2H, 5.3 (2H, brs), 6.25 (1 H, 6.85 (1IH, 7.27-7.4 (6H, in), 7.6- 7.S (2H, S.0 (4 8. 5 (lIH, d).

MS m~z: 517 1).

Example 506 Acetic acid 2-(5-3(3 -[4-(4-chiloro-phenyl)-4-hydroxy-3 ,3-dimethyl-piperi din- I -vflpropylidenel -5,1 1 -dihydro- 10-oxa-I -aza-dibenzo[a,djcyclohepten-7-yloxy)-ethyI ester To a solution of 5 (3 3-[4-(4-Chloro -phenyl)-4-hydroxy- 3,3 -dim ethyl piperi din- I -yll-propylidene) -5,11 -dihydro- I 0-oxa- I -aza-dibenzo[a,djjcyclohepten- 7 ol (64.5mg, 0.13Inimol) in NN-dimethyformamide (2.5m1l) was added sodium hydride (6 mg, 0. 15 8iniol), 60% dispersion in mineral oil, then acetic acid 2bromo-ethyl ester (17 il, 0.158mmol). The reaction stirred at room temperature -261overnight under a nitrogen atmosphere. The reaction was quenched the following day with water and diluted with ethyl acetate. The organic layer was washed twice with waler, then brine. After the organic~Jayer was dried over magnesium sulfate the solvent was distilled off under reduced pressure to give the title compound, 132mg (100%).

1 H-'NMR(CDC1 3 8:1.73-1 .90(4H,m), 2.07-2.90(4H,s), 2.29-2.79(6H,rn), 4.11 4. 14(2H,bt), 4.36-4.40(2H,bt), 5.23-5.30(2H,bs), 6.10-6.1 6.73-6.84(3H,ni), 7.24-7.39(1 OH,m), 7.56-7.59(1H,dd), 8.47-8.50(1H,dd).

MS mlz: 577 (M) Example 507 4-(4-Chloro-phenyl)-l {3-[7-(2-hydroxy-ethoxy)- IH-I 0-ox a-I -aza-dibenzo[a,d] cv~clohepten -5-ylidene]-propyl k -3 ,3 -dimecthyl -piperidin-4-ol To asolution of 75Sg(0.l3I4rnmol) Acetic acid 2-(5-,3-[4-(4-chlorophenyl)-4-hydrox y-3 3 -dimethyl -piperi din -I -yH]-propylidene} -5,11 -dihydro-l 0-oxa- 1 -aza-diberzo[a,d~cyclohepten-7.vloxv)-e-thyl ester (example 10) in ethanol ,was added a 15% sodium hydroxide in watcr solution. The reaction -was heated to reflux for 30 minutes, at which limne the LC/MTS showed it to be complete.

After cooling to room temperature the reaction was worked up by diluting A,.Ith ethyl acetate and washing with water and brine. The combined aqueous layers were back extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and the solvent was distilled under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (421g 0) 'H-NlM(CDC 3 0.821 0.975(3'H,s), 2.56-5.64(2H,bq), 2.68- 2. 74(1 H,bd), 2.80-3.08S(H,m), 3.30-3.38(14,bM), 3.62-3 .67(2H,t), 4.04-4.0 8(2H,t), 5.1 9-5.32(2H,bs), 5.94-6.00(1H,t), 6.79-6.87(4H,m), 7.26-7.40(4H,m) 7.56 7.60(lH,bd), 8.35-8.37(1-,s), 8.50-8.53(1I,dd) MS m/z: 535 (Mv) -262- Example 508 4-(4-Chloro-phenyl)- {3-[7-(2-methoxy-ethoxy)- 11H-1I0-oxa-l1-aza-dibenizo dene]-propyl} -3,3-dimethyl-pipe-idin-4-oI The titled compound was prepared by following the procedure of Example 506, but replacing acetic acid 2-bromo-ethyl ester with Il-Bromo-2-methoxy-ethane.

The residue was pur-ified by reverse phase HIPLC to give the title compound (27mg, 3

'H-NTMNR(CDCI

3 6: O.79-.085(3H,s), 0.95-1.03(3H,s), 2.55-3.12(SH,rn), 3.28- 3.45(2H,m), 3.4S(3H,bs), 3.70-3.78(2H,bs), 4.06-4.1 3(2H,bs), 5.18-5 .28(2H,bs),.

5.92-6.01 (1H,bt), 6.75-6.88(3-1,.m), 7.25-7.43(4H,m),-7.55-7.63(1I,bd), 8.48- 8.55(2H, bd) MS mhz: 549 (M) Example 509 5-{f3 -[4-(4-Chiloro..phenyl)-4-hydroxy-3 ,3 -dirnethyl-piperi din- I -propyl 1 d enc'. 5,11 -dihydro- 1 0-oxa- 1 -aza-dijbenzora,d]cyclohiepten-7-oI The titled compound was prepared-following the procedure in step 5 of Example 502, substituting 5-(3-bromo-propylidene)-5,1 1-dihydro-1I0-oxa- I -azadibenzo[a,d]cyclo-hepten-7-ol for -bromo-propylidene)-5,1 I -dihydro- oxa-1 -aza-dibenzo[a,d]- cyclohepten-7-ylJ-propan-2-ol and raceniic piperi dine for the S-piperidine.

'H-MR (CDCl 3 300 MHz) 8: 0.74 3 0.88 3 1.45 (in, I 2.20- 2.54 (mn, 7 2.66 -2.77 (mn, 2 5.27 (br s, 2 6.11 I 6.67 (dd, I H), 6.74 6.79 (mn, 2 7.25 -7.31 (in, 3 7.36 7.42 (mn, 2 7.59 I 8.50 (dd, 1 MS inlz: 491 (M 1).

Example 510 -263- (3 4 4 -Chl oro-ph en yl) -4-hydrox y- 3,3 -dimnethy pip eri din- 1 -y1] -prop yli dene} 5,1 1-dihydro- 1 0-oxa-lI-aza-dibenzo[a,d]cyclohepten-7-yloxy)2methyl-propionic IND acid ethyl ester To a cooled (0 solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3',3..

dimethyl-piperidin- 1-yl]-propylidene} -5,1 1-dihydro- 10-oxa- I -azadibenzo[a,d]cyclohepten-7-o] (250 mg, 0.51 mmol) in dim ethyl forrnanide (7 rnL) was added sodium hydride (60 dispersion in oil, 31 mg, 0.76 mnmol). The resulting mixture was stirred at 0 'C forlO min. Ethyl 2-brorno-2-methyl propionate (149 mg, 0.76 mmol) was added. Stirring at 0 *C was continued 10 min before the.

-mixture was warmed to rt and stirred 4h. The reaction was then partitioned between ethyl acetate and water; the aqueous phase was back-extracted with additional ethyl acetate. The combined organic phases were washe-d thrice with water, brine and dried ov'er magnesium sulfate, filtered and concentrated. The crude residue Was puriied by silica gel chromatographiy(methylene chlor-ide -95:5 xnethiylene chloridemethanol g-radient) to afford .he titled compound (233 mg, 76 'H-NMR (CDC1 3 300 MHz) 5: 0.74 3 0.87 3 1.27 3) 1.41 I 1. 50 (bn s, I 1. 55 6 2.18 2. 56 7 2.64 2.7 8 (mn, 2 4.2 4 2 Hi), 5.27 (br s, I 6.09 1 6.67 6.76 (mn, 2 6.87 I 7.25 7.31 2 7.37 -7.42 (in, 2 7.57 2 8.01 I 8.50 I MS iJz: 605 I).

Example 511 4-(4-Chloro-phenyl)-1 [7-(2-hydroxy- 1, 1 -dim ethyl-ethoxy)-1 I IH-10-oxa- I-azadibenzo[a,d] cyclohepten-5-ylidene]-propyl)}-3,3-dirnethyl-piperidin-4-oI To a cooled (0 solution of 3 -[4-(4-Chloro-phenyl)-4-hydroxy-3 ,3dimethyl-piperidin- I -yl]-propylidene} -5,1 1-dihydro- 10-oxa- I -azadibenzo cyclobepten- 7 -yloxy)-2-methylI-propionic acid ethyl ester (117 mng, 0. 193 nr-nol) in tetrahydrofuran (5 rnL) was added lithium aluminum hydride (I.0 M

O

-264solution in tetrahydrofuran, 0.39 mL, 0.39 mmol). The reaction was allowed to stir ,D at 0 'C for 2 h. Excess hydride was quenched by the addition of a saturated aqueous O potassium/sodium tartrate solution. The mixture was stirred at rt until two clear N phases formed. The mixture was diluted with ethyl acetate and shaken. The rlextracts were dried over magnesium sulfate, filtered and concentrated. The crude C residue was purified by silica gel chromatography (methylene chloride 90:10 methylene chloride/methanol gradient) to afford the titled compound (102 mg, 94 'H-NMR (CDCI1, 300 MHz) 8: 0.74 3 0.87 3 1.25 6 1.41 1 2.18 2.55 9 2.65 -2.79 2 3.58 2 5.20 5.40 (br s,2 H), 6.12 1 6.74 6.84 2 6.92 1 7.25 7.32 3 7.36 7.42 2 7.60 (dd, 1 8.51 (dd, 1 H).

MS m/z: 563 (M 1).

Example 512 {3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimehyl-piperidin--yl]-prop ylidene} 5,11 -dihydro- 10-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid To a solution of {3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl]-propylidene} -5,1 1-dihydro- 10-oxa-l -aza-dibenzo[a,d]cyclohlepten-7yloxy)-2-methy!-propionic acid ethyl ester (158 mg, 0.261 mmol) in methanol (3 mL) was added sodium hydroxide (1 N in water, 1 mL). Following a slight exotherm, the mixture clarified. An additional aliquot of sodium hydroxide (1 N, 1 mL) was added after 1 h and the mixture was allowed to stir an additional I h at rt.

The solvents were evaporated under reduced pressure and the residue dissolved in water (2.5 mL). The basic solution was neutralized (pH 7) with hydrochloric acid (1 N) and the titled compound was precipitated and collected by suction filtration (86 mg, 57 -265- 'H-NNM (CD 3 OD, 300 Mffz) 5: 0.80 3 0.91 3 1.47 6 1.72 I 2.56 -2.72 (mn, 2 2.83 -3.00 (in, 2 3.15 -3.24 (mn, 3 3.32 3.48 (in, 2 5.18 (br s, 2 6.04 I 6.69 -6.84 (in, 2 6.97 1 7.2 8- 7.3 7 (mn, 3 7.40 7.47 (mn, 2 7.67 (dd, I 8.42 (dd, 1 h).

MSni/z: 577 (M 1).

Example 513 {3 -[4-(4-Chloro-phenyl)-4-hydroxy-3 ,3 -dimethyl-piperidiri-1I-yll-propylidene}f 5,11 -di1hydro 1 O-oxa-1 -aza-dibenzo[a,d]cyclohepten-7.y] oxy)-2-rnethylpropionarnide 1 0 To a solution of {3 -[4-(4-Chiloro-phenyl)-4-hvdroxy-3 ,3-diniethyi)]piperidi-I1 -yfl-propylidene} -5,11 -dihvdro- 10 0--1 -aza-dibenzo[a,djcyclohiepten-7y'Ioxy)-2-methyll-propionic acid (72 ing, 0.125 minol) in diiethyl fonnamide (3 inL) was added 1 -(3'-diiniethylIaminopropyl,)-3-ethylcarbodiiinide hydrochloride (48 ng, 0.25 mmol), 1-hydroxybenzotriazole (34 nil-, 0.25 inmol), and ainmion urn hydroxide(1 70 pL, 0.50mrmol) and triethylainine (100 f.LL). Stir at rt4Ah h mixture was poured Into chloroform and w rashed with water. The organic phase wvas washed with additional water~and brine;, dried over magnesium sulfate, filtered and concentrated. The crude residue was purifie-d by silica gel chromatography (methylene chloride -90:10 iethyleie chloride./nethaniol gradient) to Yield the titled compound (22 mg, 31 1-I-NVW. (CDCI 3 300 Mvl-z)'8: 0.74 3 0.87 3 1.42 (br d, I 1.49 (s, 6 2.16 6- 2.61 (in, 7 2.63 2.78 2 5.20 -5.40 (br s, 2 5.5 0 (br s, I 6.1 1 1 6.68 6.82 (in, _3 6.91 (dd, I 7.26 7.33 (mn, 4 7.36 7.43 (in, 2 7.60 (dd, 1 8.51 (dd, I MS m/z: 576 (M Example 514 -266- {3-[4-(4-Chloro-phenyD)-4-hydroxy-3 ,3-dimethyl-piperidin- I -yl]-propylidene} 5,11 -dihydro- 1 0-oxa- I -aza-dibenzo [a,d~cyclohepten-7-yloxy)-acetic acid methyl ester [4-(4-Chloro-phenyl)-4-hydroxy-3 ,3 -dim ethyl-piperi din- Il-yl] propylidene} -5,1 1 -dihydro- 10-oxa-l1-aza-dibenzo[a,d]cyclohepten-7-ol (0.4 g, 0.814 rnmol) was dissolved in dimethyl forrnamide (10 mL). Sodium hydride (0.029 g, 1.22 rnrnol, 1.5 equiv; 48 mag of a 60% suspension in mineral oil) was added at room temperature and gas evolution was visible. Methyl bromnoacetate 187 g, 1. 22 mnmol, 116 uL) was added anid the mixture was stirred at room temperature. After stirring overniight at room temperature, the reaction was quenched with water rnL). The resulting suspension was extracted with ethyl acetate (3 x 10 rnL). The combined ethyl acetate extracts were dried over magnesium sulfate, filteredl and concentrated in vacuo to give an oil. The crude oil was puified by silica gel chromaatography (niethylene chloride to 1 0 methanol in methylene clori de 1 5 gradient) to afford the title compound as a whi te solid (222 mg, 48%).

'H--Nl\MR 300 MHz) 5: 0.7 3MH), 1.2 3H), 1.30 -1.70 3H), 2.6- 3.51 (in, 9 3.82 3H), 4.55 22H), 5.22 (br s, IH), 5.88 IN), 6.S5 (rn, 2H), .7.15 -733 (in, 6H), 7.62 8.43 iN); MS ni/z: 564 (M 1) Example 515 210 (5 {3 -[4-(4-Chloro-phenyl)-4-h vdro xy-3 ,3 -dimethyl-piperi din- I -yl]-propyl i dene} 5,1 1 -dihydro- 10-oxa- I -aza-dibenzo[a,d] cyclohepten-7-yloxy)-acetic acid {3-[4-(4-Chiloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin- l-yl] propylidene) -5,11 -dihydro- 1 0-oxa- I -aza-dibenzo~ja,d]cyclohepten-7-yloxy) -acetic acid methyl ester (0.060 g, 0.107 mrnol) was dissolved in methanol (1.5 mL-).

Sodium hydroxide (150 uL, IN stock solution) was added and the resulting mnixture was stirred at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to give a yellow oil. The oil was Ct -267suspended in water (2 mEL) and then washed with ethyl acetate (3 x 3 mEL). The aqueous layer was then acidified to pH 2 and extracted with ethyl acetate (3 x N rnmL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated *in vacuo to afford a white solid (55 mg, 94%).

'H-NMR (ODCd 3 300 MHz) 8: 0.8 3H), 0.92 3H), 1. 12 1.31 (in, 611), 2.68 (br d, 2H), 3.8 9 (in, 1 2.9 5 I 3.10 -3.3 6 (in, 2 4.4 5 IlH), 5.20 (br s, 2H), 5.98 6.81 (in, 2H), 6.96 1H), 7.40 2H), 7.40 (in, 3H), 7.83 (d, 1I), 8.44 IH); MS in/z: 550 (M 1) Example 516 1 0 2 -[4-(4-Chloro-pheniyl)-4-hydroxy-3 ,3 -dim iethyl -piperidin-lI-vfl]-i~oyiee 5,11 -di hydro- I 0-ox a- I -aza-dibenzo cyclohepten- 7-ylox y)-acetamid e The title compound was prepared by following the procedure of Example 514, but replacing methyl broinoacetate with broinoacetamide. This yielded 58 mag of the title compound after chromnato graph y 'I-INMR (CDCb3, 300 MHz) 0.5 (br s 0.78 2.90 (mn, 10 4.35 IH), 5.22 (br s, 2H), 5.74 (br s, lH), 6.11 (br s 1H), 6.55 (br s, lH), 6.82 (mn, 3H), 7.33 3 7.25 2H), 7.65, I 8.55 I1H); MS m/z: 549 (M 1) Example 517 4-(4-Chl oro-phenyl)- I {3-[7-(2-hydroxy-2-methiyl-propoxy)-I 11H- 10-ox a-I azadibenzo cyclohepten- 5-yl i den e] -propyl -3,3 -dimnethyl-piperidin-4-ol [4-(4-Chloro-phenyl)-4-hydroxy-3,3 -dimethyl-piperidin-1I-yl] propylidene} -5,1 1-dihydro-1I0-oxa- I-aza-dibenzo[a,d]cyclohepten-7-yloxy) -acetic acid methyl ester (52 mg, 0.0923 rnmole) was dissolved in tetrahydrofuran (2 mEL).

The resulting solution was cooled to ice bath temperatures and methylmagaiesium bromide (0.369 mmol, 264 uL of 1.4 M solution in toluene/tetrahydrofuran) was added dropwise. The reaction was stirred for 4 his at ice bath temperature and then -268warmed to room temperature overnight. Tetrahydrofaran was removed by concentration in v'acuo. The resulting solid was dissolved in ethyl acetate 10 mL) and washed with saturated ammionium chloride (10 mL). The ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil.

The crude oil was purified by silica gel chromatography (miethylene chloride to methanol in methylene chloride gradient) to afford the title compound as a white solid (40 mg, 77%) 1 H-NMR (CDCl 3 300 MI-z) 8: 0.92 6H), 1.34 6H), 1.62, (br s, 2H), 2.24 (in, 9H), 3.78 2H), 6.82 (in, 3H), 7.22 -7.41 (in, 7.62 8.52 1K); MS -lz: 564 (1\+l1) Example 518 3 'k 3 [4-(4-Chloro-ph enyl)-4-hydroxy-3,3 -d imethyl -piper]idin -I -yl] -propy3li dene} 5,11 -dihydro-1I0-oxa-1 -aza-dibenizo[ad]cyclohepten-7-yl)propane- 1,2-dial I -[3-(Allyl-I 11H-I 0-oxa-l1-aza-dibernzo[a,d]cyclohepten-5-ylidene.)-propyl]- 4-(4-chloro -phenyl)-')33-dim ethyl -piperi di n-4-ol (0.044g, 0.08 mmiol) was dissolved THF (2 mL) H,0 (0.5 rnL) and cooled to 0CC. To the solution was added 0504 (1.07 rnL-2.5% 0s0 4 in t-butanol) and stirred at room temperature for 4h. The reaction was diluted with sat. sodium bisulfite, the org~anics were removed dried over MgS0 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography methanol/ 95% mnethylene chloride to 7.5% methanol/92.5% methylene chloride to 15% methanol! 85% methylene chloride) to yield the title compound (0.025 g, 53 (CDCI 3 5 0.74 (ss 3H), 0.87 3H), 1.22 (d, I1H), 1.41 I 1.44 I 2.26-2.77 (mn, 9H), 3.5 3 IlE), 3.70 (dd, I 3.93 1K), 5.30 (bs, 2K), 6.14 1K), 6.79 111), 7.02 1K), 7.16 1H), 7.27 (d, 3H), 7.37 2H), 7.58 1K), 8.48 (dd, 1K). ESI-MS m/z: 515 (lv 1), retention time 1.72.

Example 519 -269ri 3 4 4 -Chloro-pheny1)-3-methyl-piperazi>-1 -yl] -propylidene} -5,11I -dihydro- I 0-oxa- I -aza-dibenzofa,d]cyclohepten-7-y1).propan-2-ol Step 1: 4 4 -Chloro-phenyl)-3-methyl-piperazinelcarboxylic acid tert-butyl ester Ni To a solution of 3 -Methyl-piperazine-l-carboxylic acid tert-butyl ester g, 5 mmol) and 4-bromochlorobeilzene 77g, 4 mmol) was added sodium tel-tbutoxide (0.96 g, 10 minol), palladium(ll) dibenzylideneacetone (Pd 2

DBA

3 0.09g, OInmmol), and BINAP (0.19g, 0.3 minol). The suspension was stirred at 120'C for hour s. The reaction was filtered through celite and evaporated in v'acuo. The residue was purified by silica gel chromatography (hexane-) ethyl acetate) to yield 0.84 g of-the title conmpound. 'H-NMR (CDC 3 5 1.00 (3H, rri), 1.74 (914, s), 3.10 (3H, mn), 3.30 (IH, in), 3.80 (214, in), 4. 10 (IH4, brs), 6.85 (214, 7.20 (2H, d).

Step2: 1 4 -Chloro-phe-nvl)-2-i-nethvl-piperazine 4-(4-Chloro-phenyl)-3 -methylI-piperazine- I -carboxylic acid tert-butyl ester (0.83 a, 0.68 mnol) was dissolved in HC/dioxane. (4M, 8 mL) and stirred for 2 hir at rt. The mixture wvas then evaporated in vacua, basified wvith aqueous sodium hyvdroxide (I M, 50 mL), and extracted with ethyl acetate (3X 100 rnL). The organic layers were evapc~rated and the crude residue used in the next step, (0.56g) brown oil) Step 3: t 3 4 4 -ChIOrO-phenyl)-3 -m ethyl -piperazin. I -ylI]-propyliderie j -5,11 dihydi-o- 10-ox a- 1 -aza-dibenzo[a,d]cvciohe-pten-7-yl-propan2oI A solution of 2 -[5-(3-Bromo-propylidene).5,l I -dihydro- I 0-oxa- 1 -azadibenzo[a,d]cyclohepten-7-yl]-propan-2.oI (0 2 0.64 mmol) in isopropan ol mL)vwas treated with I 4 -Chloro-phenyl)-2-methyl-piperazine (0.25g, 1.2 rnmol) and catalytic potassium iodide. The solution was stirred at 80'C for 5 hr, arnd evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-->S7:10:3 ethyl acetate/methanol/triethylamine) to yield 0.22 g of the title compound, 'H-NMR (CDCl 3 5: 1.00 (3H, in), 1.60 (6H, 2.20-2.70 (814, m), -270.

3.10 (2H, mn), 3.75 (1H, in), 5.30 (2H, brs), 6.12 (1H, 6.87(4H, 7.18-7.32 (3H, in), 7.45 (1H, 7.70 8.55 (1H, d).

ESI-MS mlz: 504 [M 1].

The freebase was conv'erted to the form ate salt with formic acidlmethanol.

CHN

passed, 0.4 formic acid.

Example 520 3 [6 -chiloro- 1 ,2 -dihydro-2 -ox o-spiro [4H- 3, 1 -benzox azin-4,4-piperi din] 1 -yl] propyiidene} -5,1 1-dihydro- 10-oxa- 1 aza-dibenzo[a,d~cycloheptel-7-yl)-propal- 2 -ol A solution of 6-chioro-1I,2-dihydro-2-oxo-spirof4H-3 ,1I-benzoxazin piperidine] (Made by the procedure of Bock, et a. GB2,355,465, 0.25a, 0. 7 rnrol) in isopropanol (5 mL) was treated with 2-[5-(3-Bronio-propyIhdefle)-5,l I1-dihydro- I 0-oxa-l -aza-dibcnzo[a..d]cvclohiePtefl- 7 -yl]Fpropan- 2 -ol (0.1 9g,0.50 rnol) andcatalytic potassium iodide. The solution was stirred at 80'C for 5 i, and evaporated i n vacuo. The residue was purified by reverse-phase preparativc HPLC to yield 0.029 g of the title compound, 'H-NM4R (CD 3 OD) 8: 1.50 (3 H, 2.18 (2H, brs), 2.95-3.1 (6H, in), 5.30 (2H, brs), 6.18 (1K, 6.79(IH, in). 6.92 (1H, mn), 7.12 (I H, in), 7.38 (211, 7.48 (2H, mn), 7.81 (2H, mn), 8.3 1 (1 H, S.5-5 (IH d).

ESI-MS mi/z: 546 [M I].

Example 521 2 t -2Cloop nl)4mehl- prdn -yll-propyl idenel -5,1 I -dhydroa- I aza-dibenzo d] cycloheptefl- 7 -yl) -prop an- 2 -ol Step 1: 1 -Bcnzyl-4-rnethyl-piperldifl- 4 -ol A solution of 1-benzyl-4-piperidone (4.9 mL, 26.5 minol) in anhydrous diethyl ether (50 mL) was cooled to -78'C and treated with methyllithium 1.4 M, 21 mL, 29 inol). This mixture was stir-red for 2.5 hr at -78 0 C, then quenched with aqueous brine, and extracted with ethyl acetate (3x 100 mL). The combined organics -27 1were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (CH 2 Cl.,-90:l 0:1 CHC1 2 /methanol/NH 4 OII) to yield g of the title compound, ESI-MS ni/z: 206 [M 1].

Step 2: 1 -B enzyl -chlIoro-phenyl)-4.m ethyl -piperid ine SAsolution of l-Benzyl-4-methyl-piperidin-4-ol (4.5 a, 22 nmol) in chiorobenzene (60 mL) was treated with anhydrous AIC 3 (15 g, 1 10 mmol). This mixture was stirred for 3 hr at reflux, then quenched into ice (250g), basified with sodium hydroxide, and extracted with ethyl acetate (3x 100 rL). The combined organics were dried over sodiumi sulfate and evaporated in vacuc. The resi due was purified by silica gel chromatography (CH,Cl 2 ->90:1 0 CH 2

CI

2 /methanol) to yield 0.59 g(10%) of the title compound, ESI-MS m/z: 300 [M I]1.

Step 3: 4-(2-Chloro-ph enyl)-4-methyl -pip eri dine A solution of 1I-benzyl-4-(2 -chi oro-phen yl)-4-methyl -pi peri dine (0.59 g, 1.95 nimol) in 1,2-dichloroethiane (10 mQL was treated with 1-chloroethyl chloroforrnate (0.28 mL, 2.6 nnol). This mixture was stir-red for 12 hr at reflux, then evaporated in vacuo. The residue was redissolved in methanol (10 mL) and heated to reflux for 1 hr, then evaporated in vacuo. The resulting brown solid (the hydrochloric salt) was washed with ethyl acetate, then freebased with ethyl acetate/sodium hydroxide to yield 0.30 g of the title compound, ESI-MS m/z: 246 [M 13.

Step 4: 2-(5 3 -[4-(2-Chloro-ph enyl)-4-m ethyl -piperi din- 1 -yl] -propyli1dene -5,11dihydro- I0-oxa-l1-aza-dibenzo[a,d~cyclohepten-7-y1)-propan-2-ol A solution of 4 -(2-Chloro-phenyl)-4-methyl-piperidine (0.29 g, 1.38 mmnoI) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,1 1-diliydro- I 0-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-oI 19g, 0.50 mmol) and catalytic potassium iodide. The solution was stin-ed at 80'C for 12 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate--> 87:10:3 ethyl acetate/methanolltriethylamine) to yield 0.062 g(25 0 of the -272title compound, 'H-NMIR(CDCI 3 a: 1. 10 (3H, 1.58 (6H, 1.78 (2H, in), 1.90 (1H, in), 2.10 (2H1, mn), 2.40 (8H, in), 5.30 (2H, bors), 6.18 (1H, 6.79(IH, in), 6.92 in), 7.19-7.39 (6H, in), 7.42 (IH, mn), 7.55 (111, in), 8.55 (11H, d).

ESI-MS m/z: 503 [M 13.

Example 522 4-(4-Chloro-phenyl)-1- {3-[7-(2-hydroxy-2-methyl-propoxy)- 11-1 0-oxa- 1 -azadibenzo [a,djcyclohepten-5-ylidene]-propyl)}-3-methyl-piperidin-4-ol Step 1: (5 {3 (4-Chloro-phenyl) -4-hydroxy-3 -methyl-pip eri din- 1 -yl]propylidene) -5,1 1-dihydro- 10-oxa- I-aza-dibenzo[a,d~cyclohepten-7-yloxy)-acetic acid methyl ester A solution of 5 t 3-[4-(4-Chl oro-ph enyl)-4-hydroxy-3 -inethyl -piperi din- I ylj]-propylidene} -5,1 1-dihydro-1I0-oxa-l1-aza-dibenizo[adjcyclohepten-7-ol (0.14 g, 0.28 inmol) in dim ethyl forrnamide (3 inL) was treated with sodium hydride (60% in ineral oil, 0.016 g, 0.4 minol) and methyl bromoacetate (0.038 mL, 0.4 n-mol).

The mixture was allowed to stir at rt for 2 hir, then quenched with aqueous brine, and extracted with ethyl acetate (RIO inL). The combi ned organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel 'chromatography (ethyl acetate-) 87:1 0:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g of the title compound, ESI- MS m/z: 549 [M+1I].

Step 2: 4-(4-Chloro-phenyl)-1- {3 -(2-hydroxy-2-methyl-propoxy)- 1H.-i 0-oxa-lI- -3-methyl-piperidin-4-ol A solution of (3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperi din- Iyl]-propylidene} 11 -dihydro- I 0-oxa- I -aza-dibenzo~ja,d]cyclohepten-7-ylox y)acetic acid methyl ester (0.07 g, 0. 13 mmxol) in TI-F (3 mL) was treated with nmethylmagnesium bromide (3M, 0.15 inL, 0.45 inunol). The solution was stirred at rt for 2 hr, and quenched with brine. The aqueous residue was extracted with ethyl acetate (3x1 0 mL), and the combined organics were evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-487:10:3 ethyl acetate/methanol/triethiylamine) to Yield 0.03 8 g of the title compound, IH- INDNvR (CDCI 3 a: 0.6 (3H, 1.37 (6H, 1.66 (2H, in), 1.99-2.80 (911, in), 3.78 (2H. 5.30 (2H, brs), 6.18 (1 H, 6.79-6.89 (3H, mn), 6.92 (1 H, mn), 7.25-7.45 (6H, mn), 7.5 5 (1 H, in), 8. 55 (1 H, d).

ESI-MS mlz: 549 [M 1] Example 523 4-(4-Chloro-phenyl)-1I 1 -hydrox y-lI -m ethyl -ethyl)-]I -oxy-l 11H-I 0-oxa-lI-aza- 1 0 dibenzo[a,d]cyclohepten-5-ylidenie)-propyI If -3,3-diinethyl-piperidin-4-ol Step 1: 1 -[5-(3-Bromo-propylidene)- I -oxy-5, 11 -dihydro- I 0-oxa- 1 -azadibenizo[a,d]cyclohepten-7-yl].cthaiioie A solution of I -(5-(3-Bror-no-propylidene)-5, 1I -dihydro- I 0-oxa- I -azadibenzofa,d]cyclohepten-7-yl]-ethanoine (1.5 g, 4.2 rmol) in CI-,CI, (10 mnL) was 1 5 treated with rn-cliloroperbenzoic acid 1 .2 g, 5.0 inmol). The mixture was allowed to stir at rt for 12 hr, then quenched with aqueous brine and extracted with CH,CI, (3030 inL). The combined organics were dried over sodium sulfate and evaporated in vacuo. The resulting brown foam, 1.5 g was carried on to the next step crude. ESI-MS rnlz: 374 [M I].

Step 2: 1 {3 -[4-(4-Chl oro-phenyl)-4 -hydroxy-3,3 -dim ethyl -p Iper]di n- I -yl]propylidene) I -oxy-5, 11 -dihydro- I 0-oxa-]I -aza-dibenzo[a,d]cyclohepten-7-yl)ethanone A solution of 1-[5-(3-Broino-propylidene)-1I -oxy-5,1 1 -dihydro- I 0-Oxa-1I aza-dibenzo[a,d~cyclohiepten-7-yl]-ethanone (1.4 g, 3.8 minol) In acetonitri le/water (12 mL/3 mL) was treated with 4-(4-Ch Ioro-phenyl) -3,3-dim ethyl -piper] di1n-4-o I co, 4.2 inmol) and potassium carbonate (I g, 7.6 iniol). The suspension was stirred at rt for 72 hr, and evaporated in vacuo. The residue was purified by silica -274gel chromatography (ethyl acetate-*87:10:3 ethyl acetate/m ethanol/tri ethyl am ine) to yield 1.2 g of the title compound, ESI-MS mh/z: 533 [M 1].

Step 3: 4-(4-Chloro-phenyl)- 1- 1-hydroxy-1I-methyl-ethyl)- 1 -oxy- I11--10oxa- I -aza-di benzo d] cyclohept en- 5-yl iden e] -propyl -3 ,3 -dirm ethyl-piperidin-4-ol A solution of 1 {3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethylpiperidin- I -yl]-propylidene} -1 -oxy-5,1 I -dihydro- 1 0-oxa- I -azadibenzo[ad]cyclohepten-7-yl)-eth anon e (0.43 g, 0.81 mmol) in TH-F (3 m.L) was treated with methylmagnesium bromide (1.4M, 0.74 mL, 1.0 rnmol). The solution was stirred at ri for 48 hi, and quenched with brine. The aqueous residue was extracted with ethyl acetate (3x 10 and the combined organics were evaporated in vcacuo. The residue was purified by silica gel chromatography (ethiyl acetate-) 87:10:3 ethyl acetate/miethanol/tniethylamine) to Yield 0. 10 g of the title compound, 'H-NMR (CDC 3 a: 0.6 (3H, 0.9 1 .55 (6H, 1 .99-2.80 (IlOH, in), 5.30 (2H, brs), 6.18 (1lH, bin), 6.89 (1H, in), 7.25-7.45 (7H, ni) 7.50 (1IH, 8.5 5 (1lH, d).

ESI-MS mlz: 549 [M I].

Example 524 f{3 -[(4-Chloro-benzyl)-ethyl-amino] -pyrroli din- Il-y]) -propylidene)-5,1 I dihydro- I 0-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-o (R)-Pyrrolidin-3-yl-carbamic acid tert-butyl ester (7.85 g, 42.1 mmol) was dissolved in methylene chloride at 0 0 C and triethylarnine (11.72 mL, 84.3 mm-ol) and ethyl chloroforrnate (8.06 inL, 84.3 mmol) were added. The solution was warnied to room temperature and stirred for 30 min, the reaction was washed with NaHCO 3 The organics were combined and dried over MgSO 4 filtered and evaporated in vacuo. The residue was purified by Isco flash system ethyl acetate) to yield the ester (7.73 g, 71%).

-275- Part 2: (R)-3-tert-Butoxycarbonylamino-pyrrolidine-l-carboxylic acid ethyl ester (7.73 g, 29.9 mmol) was dissolved in 4M HC/dioxane. The solution was stirred at rt for lh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Part 3: (R)-3-Amino-pyrrolidine-l-carboxylic acid ethyl ester and acetaldehyde (1.76 mL, 31.43 mmol) were mixed with sodium triacetoxyborohydride (9.54g, mmol) in dichloroethane 200 mL) containing acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH,Cl and washed with 1 N NaOH solution and brine and dried over magnesium sulfate. The reaction was concentrated in vacuo. The residue was used directly in the next reaction (4.0 g, 72%) Part 4: (R)-3-Ethylamino-pyrrolidine-1-carboxylic acid ethyl ester (1.00g, 5.4 mmol) was dissolved in acetonitrile (100mL) and potassium carbonate 3.7 g, 27 mmol), KI 0.050 mg) and 1-bromomethyl-4-chloro-benzene (1.1 g, 5.4 n-muol) were added. The solution was heated at 60 °C for 20 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by Isco flash system (75% hexane/25% ethyl acetate) to yield coupled product (0.410 g, 25 Part (R)-3-[(4-Chloro-benzyl)-ethyl-amino]-pyrrolidine carboxylic acid ethyl ester (4.00g, 1.29 mmol) was dissolved in 15 mL of ethanol and potassium hydroxide (1.5 g, 26.7 mmol) in water (8 mL) was added. The solution was heated to reflux for 14 h and the ethanol was removed in vacuo. The residue was partitioned between water and methylene chloride. The organics were removed and -276washed with sat'd solution of NaHCO 3 and brine, then dried over magnesium sulfate. The reaction was concentrated in vacuo (0.253 g, 82%).

Part 6: To a solution of the (R)-(4-chloro-benzyl)-ethyl-pyrrolidin-3.yl-amine (0.253 g, 1.06 mmnoI) in isopropanol was added 2,6-lutidine (0.225 g, nixno]) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with (3 -Bromo-propylidene)-5,1 1-dihydro- 10-oxa- I -aza-dibenzo~a, dlcyclohepteri-7-yl] propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80 'C for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanoll85% methylene chloride) to yield the title compound 100 g, 3 'H-NMR (MeOD): 5 0.94 3H), 1.40 (s, 6H), 1.88-2.01 (mn, 111), 2.02-2.18 IH), 2.42-2.67 (in, 4H), 3.03-3.36 (in, 7H), 3.56 IH), 3.72 IH), 5.16 (bs, 2H), 6.03 6.77 7.22-7.37 (i, 7.38-7.47 (in, 2H), 7.69 IH), 8.30 IH), 8.37 (dd, IH). ESI-MS ml/z: 534 (M retention timne 1.22.

Example 525 f 3-f 4 -Chloro-pheinyl)-ethyl-amino]-pyrrolidiin I -yl} -propylidene)-5, 11 d ihydro- I 0-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7-yl] -propan-2-oI Part 1: 3 -Ethyl amino-pyrro lid ine- I-carboxylic acid ethyl ester (2.0 g, 10. 8 mimol) and 1-brorno-4-chjoro-benzeiie (2.06 g, 10.8 nmmol) was dissolved in toluene along with sodium t-butoxide (1.45 g, 15.12 inmol), Pd 2 (dba), (0.195 g, 0.2 1 rurol) and BINAP 13 g, 0.21 mmol). The solution was heated to 100 'C for 2 days, then filtered, and the reaction was concentrated in vacuo, and then purified by Isco flash chromatography (50% ethyl acetate! 50 hexane) to yield the product (0.53 6 g, 17%).

-2 77- Part 2: 3 4 -Chl oro-phenyl) ethyl]-amino] pyro 1) dine I-carboxyli c acid ethyl ester (0.536g, 1.8 nimol) was dissolved in 15 m.L of ethanol and potassium hydroxide (2.05 g, 36.2 mrnol) in water (8 mL) was added. The solution was heated to reflux for 14 h and the ethanol was removed in vacuo. The residue was partitioned between water and methylene chloride. The organics were removed and washed with sat'd solution of NaHCO 3 and brine, then dried over magnesiu sulfate. The reaction was concentrated in vacuo (0.273 g, 67%).

Part 3: To a solution of the 4 -Chloro-phenyJ)-ethyl-pyrrolidin-3yl-aine (0.270 g, 1.2 mnmo1) in isopropanol was added 2,6-luuidine (0.20 g, 1.7 rnol) and catalytic potassiumn iodide. This mixture was heated to 80'C, and treated with (3-Brorno-propylidene)-5,1 1-dihydro-lO-oxa-]I -aza-dibenzo[a,alcyclohepten..7-y1> propan-2-o] 180 g, 0.48 rnol), added in portions over 1 h. The solution was then stirred at 80 TC for an additional 14 h. The reaction was concentrated in i'acuo, then purified by Isco flash chromatography (15% miethanol/85% methyl ene chloride) to yield the title compound 180 go 'H-NMNR (CDC 3 8 1 .08 (t, 3H), 1.54 6H), 1.6S-1.92 (in, 2H), 2.08-2.25 (mn, 2.36-2.92 (in, 7H), 3.26 (q, 42.8 I 5.29 (bs, 2H), 6.12 I 6.74 2H), 6.82 I 7.0 8 (d, 2H), 71.3-7.3] 7.44 IRH), 7.52 IH), 8.48 (dd, 1H). ESI-MS rn/z: 520 (M retention time 2.01.

Example 526 [3 4 -Chloro-b enzyl)-ethyl -amino]-methyl) -pyrroli din- I -yl)propylidene] 5,1 1 -dihydro- I 0-oxa- 1 -aza-di benzo[a,d] cyclohep ten7yl -prop an-2 -olI Part 1: 3 -Am inornethyl -pyrro Ii dine I-carboxylic acid tert-butyl ester 385 g, -278- 1.92 mmol) and 1-bromomethyl-4-chloro-benzene (0.395 g, 1.92 mmol) were dissolved in acetonitrile at 0 C (10 mL) and triethyl amine (0.793 mL, 5.76 nmmol) was added. The solution was allowed to warm to room temperature and stir overnight. The reaction was concentrated down and partitioned between IN NaOH and extracted with CH 2 CI The organics were collected together and dried over MgSO,, filtered and evaporated in vacuo. The residue was purified by Isco flash system (20% hexane/80% ethyl acetate) to yield the product (0.35 g, 57 Part 2: 3-[(4-Chloro-benzylamino)-methyl]-pyrrolidine- -carboxylic acid tertbutyl ester (0.35 g, 0.1 mmol) and acetaldehyde (0.15 mL, 0.15 mmol) were mixed with sodium triacetoxyborohydride (0.35 g, 0.15 mmol) in dichloroethane 15 mL) containing acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CHC1I and washed with 1 N NaOH solution and brine and dried over magnesium sulfate. The reaction was concentrated in vacuo. The residue was used directly in the next reaction (0.34 g, 100%) Part 3: 3- (4-Chloro-benzyl)-ethyl-amino]-methyl}-pyrrolidine- -carboxylic acid tert-butyl ester (0.34 g, 0.98 mmol) was dissolved in 4M HCl/dioxane. The solution was stirred at rt for lh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Part 4: To a solution of (4-Chloro-benzyl)-ethyl-pyrrolidin-3-ylmethyl-amine in acetonitrile/water (10 mL) was added K 2

CO

3 0.54g, 3.9 mmol) and bromo-propylidene)-5,1 1-dihydro-10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]propan-2-ol 0.368 g, 0.98 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between -279- EtOAc/H 2 0, extracted with EtOAc The organices were collected together dried over Mg2S0 4 filtered and evaporated in vcicuo, then purified by Isco flash chromatography methanol/ 95% methylene chloride! ammonium hydroxide) to yield the title compound (0.110 g, 33 'H-NMR (CDC 3 80.94 3H), 1.37 (in, IN), 1.48 6H), 1.76-2.15 (in, 4H), 2.22-2.68 (in, IOH), 3.41 iH), 3.52 IH), 5.28 (bs, 2H), 6.11 INH), 6.82 I 7.14-7.32 (in, 6H), 7.48 I 7.54 (d, I 8.5 1 (dd, 1IH). ESI-MS mlz: 548 (M retention time 1.02.

Example 527 3 -[(4-Chloro-benzyJ)-ethyl-amino]-pyirolidin-1 -yl) -prop ylidene)-5 ,1 I dihydro- I 0-oxa- 1 -aza-dibenzo[a, dlcycloheptene-7-carboxylic acid Part I: To a solution of 4 -Chloro-benzy)-ethyJ-pyrrolidi-3.y-amne (0.43 g, 1.8 mimo]) in acetonitrile/water was added K,C0 3 (0.99 g, 7.2 rnmo]) and I -[5-(3-Bromo-propylidene)-5, 1I -dihydro- 1 0-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7yl]-ethanone 0.65 g, 1.8 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over Mg 2 SO., filtered and evaporated in vacuc, then purified by Isco flash chromatography methanol/ 95% mnethylene chloride/ animoniuni hydroxide) to yield the ketone tricycle (0.683 g, 73 'H-NMR (MeOD): 5 0.96 3H), 1 .39 (dd, I 1.48 (dd, 1H), 1.84 IH), 1.81 (in, 1H), 1.94 (in, 1H), 2.33-2.47 (mn, 21-1), 2.53 3H), 2.58 -2.66 (in, 2H), 2.68-2.86 (in, 4H), 5.42 (bs, 2H), 6.24 111), 6.81 IH), 7.17-7.32 (in, 4H), 7.46 (dd, IH), 7.77 2H), 7.96 IN), 8.48 (d, 1H). ESI-MS in/z: 517 (M retention time 2.61.

Part 2: Bromine 13 iL, 2.5 mniol) was added dropwise to a solution of NaGH (0- 3 32g, 8.3 imol) in water (3 mL) at 10 The solution was cooled to 0 IC and -280- I Chl oro-benzyl)- ethyl-amino] -pyrroli din- l-yl) -propylidene)-5,1 1dihydro-1I0-oxa-l1-aza-dibenzo[a,djcyclohepten-7-yl]-ethanone (0.43 g, 0.83 mniol) dissolved in dioxane (8 m.L) was added to the solution dropwise. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was evaporated in vacuo and purified by HPLC. 'H-NMR (MeOD): 8 0.96 3H), 1.37 (mn, IH), 1.48 (in, IH), 1.95 1H), 1.94 (in, IH), 2.10 (in, 1H), 2.42-2.63 (in, 3H), 2.90 lH), 2.97 -3.23 (mn, 3H), 5.82 (bs, 2H), 6.26 6.65 IH), 7.13-7.31 (in, 4H), 7.39 1H), 7.61 IH), 7.67 1H), 7.86 1H), 8.37 IH). ESI-MS m/z: 519 (M retention time 1.91.

Example 528 2- f [2-(4-Chl oro-phenyl)-ethyl] -ethyl -amino I -pyrroli din- 1l-yl)propylidene]-5,1 1-dihydro-1I0-oxa- 1-aza-dibenzo[ad]cyclohepten-7-y} -propan-2-ol Part 1: To a solution of 3-amino-pyrrolidine-I -carboxylic acid tert-butyl ester (0.300g, 1.37 mmol) dissolved in dimethylformamide was added K 2 C0 3 0.567g, 4.11 inmol) and l-(2-bromo-ethyl)-4-chloro-benzene 0.30 g, 1.37 mmnol). The solution was heated to 6000 for 2 d and then concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over Mg 2

SO

4 filtered and evaporated in vacuo, then purified by Isco flash chromatography (60% ethyl acetate/40% hexane) to yield the intermediate compound (0.263 g, 59%) Part 2: 3 -[2-(4-Chloro-phenyl)-ethylarnino] -pyrroli dine- I -carboxylic acid tertbutyl ester (0.263 g, 0.81 mrnol) and acetaldehyde (0.068 mL, 1.2 inmol) were mixed with sodium triacetoxyborohydride (0.25 g, 1.2 mniol) in dichioroethane containing acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH 2

CI

2 and washed -28 1with 1 N NaOH solution and brine and dried over magnesium sulfate. The reaction was concentrated in vacuo. The residue was used directly in the next reaction (0.24 g, 85 Part 3: 2-(4-Chl oro-pheny1)-ethyl -ethyl-amino)} -pyrroli dine- 1 -carboxyli c acid tert-butyl ester (0.242 g) was dissolved in 4M HCI/dioxane. The solution was stirred at rt for I h. The solvent was removed in vacuc and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Part 4: To a solution of [2-(4-Chloro-pheny])-ethyljj-etliyl-pyrrolidin-3 -ylamine 100 g, 0.39 mmol) in acetonitrile/water (10 mL) was added K 2 C0 3 0.837 g, 6.06 rnmol) and 2-[5-(3-Bromo-propylidene)-5,l 1-dihydro-10-oxa-l-azadibenzo[a, d~cyclohepten-7-yl]-propan-2-oI (0.100 g, 0.26nmnol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAcIH 2 O, extracted with EtOAc The organcs were collected together dried over Mg 2

SO

4 flee n vprtdi vacuo, then purified by Isco flash chromatography methanol/ 95% methylene chloride! ammonium hydroxide) to yield the title compound (0.048 g, 33 'H- NMR (CDCI 3 6 1.06 3H), 1.52 6H), 1.58 (mn, 1H), 2.10 (in, IH), 2.20-2.78 (mn, 13H), 3.30(m, 1H), 5.28 (bs, 2H), 6.12 11-I), 6.80 IN), 7.06 2H), 7.14- 7.30 (in, 4H), 7.46 7.52 1H), 8.52 (dd, IlH). ESI-MS rn/z: 548 (M4 1), retention time 1.35 Example 529 {3-[3-(4-Chloro-benzyloxy)-pyrrolidin- 1-yl]-propylidene} -5,1 1-dihydro- 1 0-oxa- I -aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol -282- To a solution of -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester g, 2.67 mmol) in THF (10 mL) was added NaH (0.128g, 3.2 mmol) (60 dispersion in oil). The resulting solution was stirred for 5 min. and 1-bromomethyl- 4-chloro-benzene (0.658g, 3.2 mnol) dissolved in THF 5 mL) was added. The reaction mixture was stirred overnight. The reaction was quenched with water and extracted with ethyl acetate The organics were collected together dried over Mg 2

SO

4 filtered and evaporated in vacuo, then purified by Isco flash chromatography (15% ethyl acetate/ 85% hexane) to yield the intermediate compound (0.48 g, 58 Part 2: (S)-3-(4-Chloro-benzyloxy)-pyrrolidine- 1-carboxylic acid tert-butyl ester (0.48 g) was dissolved in 4M HCI/dioxane. The solution was stirred at rt for lh.

The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Part 3: To a solution of(S)- 3-(4-chloro-benzyloxy)-pyrrolidine (0.38 g, 1.54 mmol) in acetonitrile/water (10 mL) was added KCO 3 0.85 g, 6.15 mmol) and (3-bromo-propylidene)-5,11 -dihydro-10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]propan-2-ol 0.575 g, 1.54 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H 20 extracted with EtOAc The organics were collected together dried over MgSO., filtered and evaporated in vacuo, then purified by Isco flash chromatography methanol/ 95% methylene chloride/ ammonium hydroxide) to yield the title compound (0.112 g, 14 'H-NMR (CDCI'): 5 1.54 6H), 1.81 (m, 1H), 1.94-2.12 2H), 2.31 3H), 2.48-2.72 4H), 4.10 1H), 4.38 2H), 5.28 (bs, 2H), 6.12 1H), 6.84 1H), 7.16-7.30 6H), 7.48 1H), 7.56 (d, 1H), 8.52 (dd, 1H). ESI-MS m/z: 507 (M retention time 1.56.

-283- Example 530 1- -Hydroxy-1 -methyl-ethyl- 11H-10-oxa-1 ylidene]-propyl}-pyrrolidine-3-carboxylic acid 4-chloro-benzylamide 3-(4-Chloro-benzylcarbamoyl)-pyrrolidine-l-carboxylic acid tert-butyl ester To a solution of di-tert-butyl-dicarbonate (1.86 g, 8.5 mmol) in dioxane (100 mL) was added 3-pyrrolidine carboxylic acid (1.0 g, 8.5 mmol) and 1 N NaOH mL). The solution was stirred at rt for 12h. The reaction was concentrated down and partitioned between EtOAc/ IN HC1. The reaction was quenched with 1N HCI and extracted with EtOAc and the organic layers were collected together, dried over MgSO 4 and evaporated in vacuo. The residue was was used directly in the next reaction.

Step 2: Pyrrolidine-1,3-dicarboxylic acid 1.59g, 7.3 mmol) was dissolved in CHCIl and EDCI (2.53g, 13.2 mmol), HOBt (1.48g, 10.9 mmol) and 4chlorobenzylamine (0.97 mL, 8.05 mmol) was added. The solution was allowed to stir at room temperature for 1Oh and then washed IN NaOH IN HCI (lx) and brine The organic layers was dried over MgSO 4 and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/ 50% hexane) to yield the title compound (1.50 g, 62 (CDCI 3 6 1.43 9H), 2.07 2H), 2.85 (pentet, 1H), 3.30 1H), 3.49 1H), 3.55 2H), 4.38 2H), 6.16 (bs, 1H), 7.17 2H), 7.27 2H).

3-(4-Chloro-benzylcarbamoyl)-pyrrolidine- -carboxylic acid tert-butyl ester (0.707g, 2.07 mmol) was dissolved in 4M HCl/Dioxane (5 mL). The solution was stirred at rt for Ih. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

-284- To a solution of pyrrolidine-3 -carboxylic acid 4-chloro-benzylaxnide hydrochloride (0.2 g, 0.83 inmol) in acetonitrile/water (8 m.L) was added

K

2 C0 3 (0.476g, 3.4 mnmol) and 2-[5-(3-bromo-propylidene)-5,1 I1-dihydro-] I0-oxa-lIaza- dibenzo d] cycloh epten-7 -yl] -prop an-2 -ol 0.282 g, 0.83 nimol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc[H 2 0, extracted with EtOAc (3x).

The organics were collected together dried over Mg2SO,, filtered and evaporated in vacuc, then purified by Biotage flash chromatography methanol! methylene chloride to 10% methanol! 90% methylene chloride) to yield the title compound (0.240 g, 60 (CDCl 3 1.54 614), 1.93 (in, I1H), 2.12 (in, 214), 2.29- 2.82 (in, 1014), 4.26 (bs, 2H4), 5.26(BS, lh),.6.05 114), 6.79.(d, 114), 7.03 (di, 2H), 7.19-7.26 (in, 4H4), 7.42 IH), 7.51 114), 8.46 114). ESI-MS rnlz: 532.05 (M retention time 1.68.

Example 531 1- I-Hydroxy- 1-methyl-ethyl)-I 1 H- 10-oxa- I-aza-dibenzo[a, yl idenej -propyl -pyrrolIi din e-3 -carboxyli c acid (4-ch]oTo-phenyl)-ethyl -ami de 3 4 -Chloro-ph enyl)- ethyl -carbamoyl)] -pyrrolidine- 1 -carboxyl ic acid ieri-butyl ester To a solution of di-tert-butyl-dicarbonate 86 g, 8.5 mmol) in diox ane (100 mnL) was added 3-pyrrolidine carboxylic acid (1.0 g, 8.5 mmo]) and 1 N NaCH inL). The solution was stirred at rt for 12h. The reaction was concentrated down and partitioned between EtOAc! IN HCI. The reaction was quenched with IN HCI and extracted with EtOAc and the organic layers were collected together, dried over MgSO 4 and evaporated in vacuo. The residue was used directly iin the next reaction.

Step 2: PyrroIi dine- 1, 3-di carboxyli c acid 0.300g, 1.4 inmol) was dissolved in -285-

CH

2 Cl 2 and EDCI (0.477g, 2.4 mmol), HOBt (0.280g, 2.1 rnrol) and N-ethyl-4chloro aniline (0.236 g, 1.5 mnmol) was added. The solution was allowed to stir at room temperature for 24h and then washed I N NaGH (l I N HCI (I x) and brine (Ilx). The organic Jayers was dried over MgSO 4 and evaporated in vacuo, then purified by Biotage flash churmatography (30% ethyl acetate! 70% hexane to ethyl acetate! 60% hexane) to Yield the title compound 0.040 g, 8 %).'H-NNvIR (CDCl 3 8 1.08 3H), 1.41 1.78 (in, lH), 2.13 (in, IH), 2.76 (pentet, 1H), 3.10 1H), 3.36 (pentet, 2H), 3.50 IN), 3.73 (in, 2H), 7.09 2H), 7.42 (d, 2H).

3 (4-Chloro-phenyl)- ethyl -carbam oyl)] -pyrrol11din e- I -carboxylic acid tertbutyl ester (0.040 g, 0. 1 mmol) was dissolved in 4M HCI/Dioxane (2 inL). The solution was stirred at rt for Ilh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

To a solution of pyrrolidine-3-carboxylic acid (4-chloro-phenyl)-ethylamide hydrochloride (0.033 g, 0.11 mrnol) in acetonitrile/water (2 mL) was added K 2 G0 3 (0.125g, 0.89 nimol) and 2-[S-(3-bromo-propylidene)-5,l 1-dihydro- I10-oxa-l1-aza-d ibenzo [a,d]cyc lohepten-7-y ]-prop an-2-oI 0.042 g, 0. 11 nuinol).

The solution was allowed to stir at room temperature for 48 h. The reactioni was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc (3x).

The organics were collected together dried over Mg 2

SO

4 filtered and evaporated in vacuo, then purifi ed by Biotage flash chromatography (2 1/2% methanol/ 9 7 1/2% methylene chloride to 5% methanol! 95% mnethylene chloride) to yield the title compound (0.028 g, 46 %).'H-NMvR (CDCI 3 8 1.07 1.55 (6H, 1 .62 (mn, IH), 1.99 (in, 3H), 2.30 (pentet, 3H), 2.47-2.77 (in, 5H), 3.68 (in, 2H), 5.26 (bs, 2H), 6.09 111), 6.79 IN), 7.03 2H), 7.24 (mn, 2H), 7.37 2H), 7.42 (s, 1H), 7.52 lH), 8.47 IH). ESI-MS in/z: 546.04 (M retention time 1.44.

Example 532 -286- -Chioro- 1,3-dihydro-isoindol-2-yl)-pyrrolin- I -propylidene- 5,1 1-dihydro- 10-oxa- 1 -aza-dibenzo d] cyclohepten -7 -yl -prop an -2-ol 1,3-dioxo- 1,3-dihydro-isoindol-2-yl)-pyrrolidine-l1-carboxylic acid tert-butyl ester 4-Chlorophthalic acid monosodium (2.00g, 8.9 nmol) and PC], (5.61 g, 26.9 mmol) were added neat to a flask and heated to 180 'C (caution the initial mixture of the acid and PC], was very exothermic). The mixture was heated for 3h and then the suspension was diluted with toluene and filtered. The reaction was concentrated down and used without further purification.

Part 2: (R)-4-Chloro-phthaloyl dichloride (0.556g, 2.3 rnmol) and (R)-3-ainino-l-N- Boc-pyrrolidine (0.400g, 2.1 mmol) were dissolved in 21 mL of pyridine and heated to 80 'C for 2 1/2 h. The solution was diluted with water and extracted with EtOAc.

The organic were collected together and washed with IN HCI, IN NaOH, brine and 1 5 dried over Mg,S0 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5 methanol! 95 niethylene chlori de to 10% ethyl acetate/ hexane to 20% ethyl acetate/80% hexane) to yield the title compound (0.200 g, 26 %).'H-NMiR (CDCL 3 5 1.46 9H), 2.12 (in, 1H), 2.59 (pentet, 1H), 3.38 (quartet, 1H), 3.71 (in, 3H), 4.83 (pentet, 1H), 7.69 1H), 7.77 11H), 7.80 1H). ESI- MS ml/z: 351 (M retention time 2.73.

-ChlIoro- 1 ,3 -dihydro-isoindo I-2-yl)-pyrroli dine- I -carboxyli c acid ter-butyl ester 1,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-pyrrolidine- 1carboxylic acid tert-butyl ester (0.200g, 0.57 inmol) was dissolved in ether and cooled to 0 0 C and LiAlH 4 (2.85 mL, 2.8 rnmol) was added dropwise, followed by ALC1 3 (0.380~g, 2.8 mmol). The solution was allowed to stir at 0 0 C for 1 V 2 Ih and then slowly quenched with water and extracted with ethyl acetate The organic -287were collected together and dried over Mg 2

SO

4 filtered and evaporated in vacuc, to yield the title compound (0.076 g, 41 without further purification. ESI-MS mlz: 323 (M retention time 1.27.

1,3-dihydro-isoindol-2-yl)-pyrrolidine-lI-carboxylic acid ieri-butyl ester (0.076 g, 0.23 rrnol) was dissolved in 4M HCIlDioxane (2 mL).

The solution was stirred at rt for lh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Step 2: To a solution of (R)-5-chloro-2-pyrrolin-3-yl-2,3-dihydro-l1H-isoindole hydrochloride (0.052 g, 0.23 mnol) in acetonitrile/water (2 mL) was added KC0 3 (0.215g, 1.5 mmol) and 2-[5-(3-brorno-propylidene)-5,1 I1-dihydro-1 I0-oxa-1Iaza-dibenzo~a,d]cyclohepten-7-yl1-propan-2-oI 0.079 g, 0.21 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over Mg 2

SO

4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography methanol/ mnethylene chloride to 10% mnethanol/ 90% methylene chloride to methylene chloride) to yield the title compound (0.055 g,55 NMR (CDCI 3 0' 1 .55(s, 1 .77 (in, IH), 2.02 (in, 2H), 2.3 7(pentet, 3H), 2.42- 2.64 (in, 41-l), 2.81 I 3.17 (pentet, I 3.43 3Hf), 3.84 4M-1, 5.26 (bs, 2H), 6.11 I1-1), 6.79 1H), 7.08-7.28 (in, 5H), 7.43 IlH), 7.56 1H), 8.46 I ESI-MS nih: 516.02 (M retention time 1.26.

Example 533 1-(4-Chloro-benzyl)-1 {3-117-(1 -hydroxy- 1-methyl-ethyl)-I 1f- 10-ox a-I -azadibenzo(a, d]cyclohepten-5-ylidene]-propyl) -pyrrolidin-3-yl)urea -288- 1 -(4-Chi oro-benzyl)-1 -pyr-ro lidin-3-yl-urea -(4-Chloro-benzylamino)-pyrrolidine-l1-carboxylic acid tert-b utyl ester (0.690g, 2.2 mrnol) was dissolved in CHIC1 2 with a few drops of isopropanol and trimethylsilylisocyanate (0.365 mL, 2.6 mmol) were added. The solution was allowed to stir at room temperature for 1 2h, the reaction was concentrated down and used directly in the next reaction. ESI-MS m/z: 354 (M retention time 2.15.

Part 2: 1(4-Chloro-benzyl)-ureido]-pyrrolidine-l1-carboxylic acid tert-butyl ester (0.300 g, 0.84 mmol) was dissolved in 4M HCl/Dioxane (2 mL). The solution was stirred at rt for lb. The solvent was removed in vczcuo and the mixture was carred on to the next step without further purification as the hydrochloride salt- To a so]luti on of 1 -(4-Chioro-benzyl)- I -pyrrolidin-3-yl-urea (0.200g, 0.78 mmnol) in acetonitrile/water (8 mL) was added KC0 3 (0.449 g, 3.2 mmol) and 2-[j5-(3-bromo-propylidene)-5, 11 -dihydro- 1 0-oxa- I -aza- 1 5 dibenzo(a,d]cyclohepten-7-yl]-propan-2-ol 0.267 Ig, 0.71 mxnol). The so]lution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc The organics were collected together dried over Mg 2 SO,, filtered and evaporated in vacuo, then purified by Biotage flash chrmatography methanol! methylene chloride to 10% methanol! 90% methylene chloride) to yield the title compound (0.231 g, 60 1 H-NMR (CDC1 3 8 1.55 6H), 1.88 (pentet, I H), 2.01-2.28 (mn, 2.53 (pentet, 6H), 3.12 1H), 3.14 lH), 3.83 IH), 4.37 (s, 1H), 4.53 2H), 5.28 (bs, 2H), 6.18 IH), 6.78 IH), 7.11 (dd, 114), 7.16 (s, I 7.18-7.27 (mn, 4H), 7.49 lI 7.5 1 IlH), 8.47 (dd, ESI-MS mriz: 547.06 (M retention time 1.65.

Example 534 (R)-S-Chloro-4-( 1- 3 (7-(-hydroxy- I -methyl-ethyl)-l 11H-I 0-oxa-lI-aza-dibenzo[a, d] -289- -pyrrolidine-3-yl)- 1,3,4,5-tetrahydrobenzo[e][ 1,4]diazepin-2-one Step 1: 3-(4-Chloro-2-nitro-benzylamino)-pyrroli dine-I -carboxylic acid tert-buty] ester To a solution of 3-Amino-pyrrolidine-1-carboxylic acid tert-buty] ester (2 g, 10.7 mmol) in methanol (20 mL) was added 4-Chloro-2-nitro-benzaldehyde (1.98 g, 10.7 mrnol). The resultant solution was heated at 60 'C overnight. The reaction mixture was cooled to 0 'C and to it was added NaBH4 (629 mg, 10 rnmmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without further purification. LCMS (retention time 1.28, ES+; 356) Step 2: 4 -Chiloro-benzyl)-miethoxycarbonylmethyl-amino]-pyrrolidine- 1carboxylic acid tert-butyl ester To a solution of 3-(4-Chloro-2-nitro-benzylamino)-pyrrolidine- -carboxylic acid tert-butyl ester (3.8 g, 10.7 mmol) in DMF (40 mL) was added Bromo-acetic acid methyl ester (1.01 mnL, 10.7 mmol) and K 2

CO

3 (1.48 g, 10.7 mnrnol). The resultant suspension was stirred at 70 'C overnight. The reaction mixture was diluted with water and ethyl ether. The organic extract was dried over MgSO, filtered and concentrated to provide the desired product as an oil. The crude product was purified on SiO 2 and concentrated to provide the desired product as an oil (2 g, LCMS (retention time 3.03, ES+ 428) Step 3: 3-(8-Chloro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of 3-[(4-Chloro-2-nitro-benzyl)-methoxycarbonylmethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g, 2.4 mmol) in ethyl -290acetate (20 mL) was added 10% Pd/C. Hydrogenolysis of the reaction solution at rt under atmospheric pressure provided the desired product after 1.5 h. The reaction mixture was filtered through a pad of celite and concentrated. The crude product (662 mg, 1.7 mmol) was dissolved in DMF (5 mL) and to it was added 60% NaH (100 mg, 2.5 mmol). The resultant solution was stirred at rt overnight. The reaction was quenched with water and extracted with ethyl ether. The organic extract was dried over MgSO,, filtered and concentrated to get the crude product. Purification on SiO 2 provided the desired product. LCMS (retention time 1.89, ES+; 310) (R)-3-(8-Chloro-2-oxo-l,2,3,5-tetrahydro-benzo[e][ 1,4]diazepin-4yl)pyrrolidine-l-carboxylic acid tert-butyl ester (0.210 g, 0.57 mmol) was dissolved in 4M HCl/Dioxane (5.7 mL). The solution was stirred at rt for lh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as the hydrochloride salt.

Step 2: To a solution of (R)-8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydrobenzo[e][ ,4]diazepin-2-one (0.198 g, 0.58 mmol) in acetonitrile/water (5.8 mL) was added K 2 CO 0.655g, 4.6 mmol) and 2-[5-(3-bromo-propylidene)-5,1 1- -aza-dibenzo[a,d]cyclohepten-7-yl]-propan- 2 -ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over MgSO 4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography methanol/ 95% methylene chloride to 10% methanol 90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.077 g, 28 (CDCI,): 81.55 6H), 1.74 (septet, 1H), 2.01 (sextet, IH), 2.32-2.60 6H), 2.76 1H), 3.26 (pentet, 1H),.3.43 1H), 3.46 2H), 3.74 2H), 5.27 (bs, 2H), 6.12 1H), 6.78 1H), 6.96 1H), 7.06 (dd, 1H), 7.13 IH), 7.19- -291- 7.27 (mn, 2H), 7.44 LH), 7.55 (dd, 1H), 8.47 (dd, 1H), 8.49 1H). ESI-MS m/z: 559 (M retention time 1.24.

Example 535 (R)-8-Chloro- I-ethyl-4-( 1- 3 [7-(-hydroxy-1 -methyl-ethyl)- 1 11-1 0-oxa-l1-aza- *dibenzo[a, d] cyclohepten-5-ylidene]-propyl)}-pyrolidine-3-yl)- 1,3,4,5-tetrahydrobenzo[e][ 1,4]diazepin-2-one (R)-3-(8-Chloro-l1-ethyl-2-oxo- 1,2,3,5-tetrahydro-benzo[e][ 1,4]diazepin-4yl)pyrroli'dine- 1 -carboxylic acid tert-butyl ester (R)-3-(8-Chloro-2-oxo-1I,2,3,5 -tetrahydro-benzo[e] [1 ,4]diazepin-4yl)pyrrolidine-1I-carboxylic acid teri-butyl ester (0.25 8g, 0.70 rnrol) was di ssolved in TI-F (7mL) and cooled to 000. To the solution was added Nail (0.042g, inmol) and stirred for 15 min, followed by ethyl iodide (0.085 niL, 1 .0 mmol). The solution was allowed to warm to room temperature slowly and stir at room temperature for 14h. The reaction was quenched with water and extracted with EtOAc The organics were collected together dried over Mg,S0 4 filtered and evaporated in vacuc, then purified by Biotage flash chromatography (75% ethyl acetate! 25% ethyl acetate to 100% ethyl acetate) to Yield the title compound 130 g47 1 H-NIAR (CDCI 3 5 1.16 3H), 1.43 9H), 1.75 (sextet, IH), 2.18 (pentet, IH), 3.05 -3.9 (in, IH), 7.20 (in, ESI-MS mlz: 394 (M retention time 2.25.

3-(8 -Ch loro-1I -ethyl -2-ox o- 1 ,2,3,5 -tetrahydro-benzo[e] 1,4] diaz epin-4yI)pyi-rolidine-1-carboxylic acid teri-butyl ester 130 g, 0.32 minol) was dissolved in 4M HCI/Dioxane (3.2 mL). The solution was stirred at rt for Ilh. The solvent was removed in vacuo and the mixture was carried on to the next step without further purification as t he hydrochloride salt.

-292- Step 2: To asolution of -chi oro- 1 -ethyl -4-pyrro lidin-3 -yl- 1, 3,4,5 -tetrahydrobenzo~e][1,4]diazepin-2-one (0.121 g, 0.32 mmol) in acetonitrile/water (3.2 mL) was added K,C0 3 (0.368g, 2.6 mmol) and 2-[5-(3-brorno-propylidene)-5,1

I-

dihydro- 10-oxa- 1-aza-dibenzo[a,d]cyclohepten-7-yl]-propal-2-ol 0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H 2 0, extracted with EtOAc The organics were collected together dried over Mg 2 filtered and evaporated in vacuo, then purified by Biotage flash chromatography methanol! 95 methylene chloride to 10% methanol! 90% methylene chloride to methanol'85% methylene chloride) to yield the title compound (0.033 g, 21 (CDC1 3 61.17 3H), 1.55 6H), 1.73 (septet, 1H), 2.08 (in, 1H), 2.34(pentet, 2H), 2.43-2.61 (in, 4H), 2.85 I1H), 2.92 I1H), 3. 10 I 3.22 (in, 1H), 3.52 2H), 3.91 (septet, 2H), 5.29 (bs, 2H), 6.12 Ili), 6.79 (dd, 1H), 7.15 -7.28 (in, 5H), 7.44 IH), 7.56 H4), 8.47 IH). ESI-MS rn/z: 587 (M retention time 1 .37.

Example 536 (4-Chloro-b enzyl)-(l 13 -hydroxy- I1-methyl -ethyl)- I1H-1 0-oxa- I-azadib enzo[a,d] cyclohepten- 5-ylidene] -propyl }-pyrrolidin-3 amino]-acetic acid methyl ester Step 1: 3 -(4-Chloro-benzy amino)-pyrroli dine--carboxylic acid tert-butyl ester To a solution of 3 -Amnino-pyrroli1dine-1I-carbox ylic acid tert-butyl ester (2'g, 10.7 mrnol) in methanol (20 mL) was added 4-Chloro-benzaldehyde (1.5 g, 10.7 rnmol). The resultant solution was heated at 60 *C overnight. The reaction mixture was cooled to 0 *C and to it was added NaBH4 (629 mg; 10 mmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgS 04, filtered and concentrated to provide the crude product as an oil. The crude product was used in the -293subsequent reaction without further purification. LCMS (retention time 1.27, ES+ 311) Step 2: 3-[(4-Chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine- carboxylic acid tert-butyl ester To a solution of 3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 10.7 mmol) in DMF (40 mL) was added Bromo-acetic acid methyl ester (1.01 mL, 10.7 mmol) and K 2

CO

3 (1.48 g, 10.7 mmol). The resultant suspension was stirred at 70 'C overnight. The reaction mixture was diluted with water and ethyl ether. The organic extract was dried over MgSO 4 filtered and concentrated to provide the desired product as an oil. The crude product was purified on SiO, and concentrated to provide the desired product as an oil (3.5 g, LCMS (retention time 2.96, ES+ 383) Step 3: [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester 3-[(4-Chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine- carboxylic acid tert-butyl ester (3.5 g, 9.1 mmol) was dissolved in 4N HCI in dioxane (60 mL). The resultant solution was stirred for 2 h at rt then concentrated to provide the desired product as a white solid. LCMS (retention time 1.26, ES+ 283) Step 4: [(4-Chloro-benzyl)-(1 {3-[7-(1-hydroxy- 1-methyl-ethyl)- 1 H- 0-oxa- -azadibenzo[a,d]cyclohepten-5-ylidene]-propyl}-pyrrolidin-3-yl)-amino]-acetic acid methyl ester To a solution of [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 mL) was added 2,6-lutidine (186 uL, 1.6 mmol), and a catalytic amount of potassium iodide. The resultant solution was heated at 80 C and to it was added 2-[5-(3-Bromo-propylidene)-5,1 dihydro-10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (149 mg, 0.4 mmol) portionwise over 0.5 h. The reaction solution was heated overnight then -294partitioned between water and ethyl acetate. The product was purified on SiO 2 (ethyl acetate: Methanol: triethylamine 95 and isolated as a film. LGMS (retention time 1. 84, ES-t; 576); 'H NMR (CD 3 OD): 8 8.46 (1 7.76 (1IH, d), 7.45 (2H, mn), 7.23 (5H, in), 6.74 (1H, 6.15 (1H, in), 3.72 (2H, mn), 3.60 (4H, s), 3.30 (6H, in), 2.78 (4H, in), 2.42 (2H4, in), 2.05 (1K, in), 1.82 (114, in), 1.50 (6H, s).

Example 537 [(4-Chloro-benzyl)-(1- -hydroxy- 1-methyl-ethyl)-l 11H-i 0-oxa-l1-aza- -ylidene] -propyl I -pyrrolidin-3 -yl)-amino] -acetic acid Step 1: (4-Ch OrO -benzyl)-( I {3 -hydroxy- 1 -methyl -ethyl)- 1 I1H- I 0-ox a- 1 -azad ibenzo[ a,d] cycl oh eptel- 5 -yl denle] -propyl) -pyrro li din- 3-yI)- amino] -acetic acid To a solution of (4-Chloro-benzyl)-( 1- {3 7 -(1I -hydrox y- I -m ethyl -ethyl)- 11 H- I 0-ox a- 1 -aza-dibenzo [ad]cyclohepten-5-yl i den e] -propyl -pyrrol idin-3 -yD:ainino]-acetic acid methyl ester (116 mg, 0.2 mmol) in THF:H 2 0 1, 10 mL total volume) was added lithium hydroxide monohydrate (17 mng, 0.4 iniol). Th-e resultant solution was stirred at rt for 3 h. The reaction solution was quenchied with IN HCI and extracted with ethyl ether, dried over MgSO,, filtered and concentrated.

The final product was filtered through filter paper and re-concentrated. This product was submitted without further purification. LCMS (retention time 1.72, ES+ 562); 'H NMR (CD 3 OD): 5 8.48 (IH, 7.78 (1H, 7.48 (2H, in), 7.31 (5H, nm), 6.76 (IH, 6.15 (lH, 3.85 (2H, dd), 3.60 (2H, in), 3.30 (7H, in), 3.24 (1H, s), 3.18 (1K, mn), 3.06 (1K, in), 2.58 (IH, nm), 2.48 (1H, 2.06 (2H, in), 1.50 (6H, s).

Example 538 ,4-Dichloro-phenyl)-piperazir'-1-yl] -propyli dene) -5,1 1-dihydro- oxa-l1-aza-dibenzo [a,d)cyclohepten-7-yl)-propan-2-ol To a solution of 1-(3,4-dichloro-phenyl)-piperazine (0.14 g,0.601 n.-inol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, '0.802 rnniol) and catalytic potassium iodide. This mixture was heated to 80'C and treated with 2-[5-(3-broino- -295- I -dihydro-10-oxa-1-aza-dibenzo d] cyclohepten-7-yl]-propan-2ol (0.37 g, 1.0 mmol), added in three portions over 2h. The reaction was then stirred at 80 'C for 18 hours. The reaction was concentrated in vacuum, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5%methanol to 90% ethyl acetate/i 0% methanol) to yield the title compound as a white solid (0.15 g, 'H-NMR (MeOD) 6: 1.55 (6H, 2.35-2.65 (8H, nm), 3.15-3.25 (4H, 5.30 (2H, br 6.20 (1H, 6.82 (IH, dd), 7.23-7.55 7.59 (1H, 8.50 (1H, dd). ESI-MS m/z: 524 (M UV retention time: 1.66 mm.

Example 539 {3-[4-(4-Chloro-2-methyl-phenyl)-piperazin-1-yl]-propylidene}-5, 11-dihydro- -aza-dibenzo d] cyclohepten-7-yl)-propan- 2 -ol Step 1: 4-(4-Chloro-2-methyl-phenyl)-piperazine- 1 -carboxylic acid tert-butyl ester (0.82 g, 4 mmol) and tert-Butyl I -piperazine carboxylate (0.89 g, 2.32 mmnol) were added to a solution of tri-t-butyl phosphine (0.033 g, 4 mmol tris(dibenzylideneacetone) dipalladium(0) (0.075 g, 2.0 mmol and cesium carbonate (1.95g, 6.0 mmol) in toluene and heated to 80 OC overnight. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified on silica gel (gradient elution from ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound in yield. ESI-MS m/z: 311 (M UV retention time: 3.49 min.

Step 2: 1-(4-Chloro-2-methyl -phenyl)-piperazine A solution of 4-(4-chloro-2-methyl-phenyl)-piperazine- -carboxylic acid tert-butyl ester (0.26 g, 0.837 mmol) in dichloromethane cooled at 0 OC was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organics were separated -296and dried over sodium sulfate and concentrated. The product was used without further purification ESI-MS rnlz: 211 (M UV retention time: 1.25 min.

Step 3. 2 t{3 -[4-(4-Chloro-2-methyl -phelyl)-piperazifl- 1 -y -propyl iden e} -5,11 dihydro-1I0-oxa-l1 aza-dibenzo[a,d]cycloheptel- 7 -Yl)-propan- 2 -ol To a solution of 1 -(4-chloro-2-methyl-phel)-piperazifle 0. 13 g, 0.6 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mrnol) and catalytic potassium iodide. This mixture was heated to 80'C, and treated with ,1 1-dihydro- 1 0-oxa- I -aza-dibenzo[a,d] cyclohepten-7-yl]propan-2-ol 0. 15 g, 0.4 mrnol), added in portions over 2h. The solution was then stirred at 80 'C for an additional 12h. The reaction mixture was concentrated in i'acuo, then purified by flash chromatography on silica gel (gradient elution from ethyl acetate/5 %methanol to 90% ethyl acetate/I 0% methanol) to yield the title compound 11 g,54 'H-NMR (DMS0) 5: 1.45 (6H, 2.30-2.65 (811, in), 2.75-2.85 (4H, mn), 3.30 (3H, 5.30 (2H, br 6.20 (1H, 6.75 (1H, 7.00-7.47 (6H, mn), 7.80 (1 H, dd), 8.5 0 (1IH, dd). ESI-MS mlz: 5 04 (M UV reten tion time: 1 .65 min.

Example 540 -Chl oro-2 {3 7-(1I -hydroxy-1I -m ethyl -ethyl)-1I 1H-1 O -oxa- I-aza- -piperazin- I -yl)-benzonitrile Step 1: 4-(2-Cyano-phenyl)-pipeazile-l-carboxylic acid tert-butyl ester To a solution of 2-piperazin-1-yl-benzoflitrile (1.1 g, 5.87 mxnol) in dichloromethane (1 0 mL) was added di isopropyl ethyl amine (3.1 mL, 17.62 inmol) followed by di-tert-buty] -dicarbon ate (1.28g, 5.87 inmol) and reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in i'acuo dissolved in ethyl acetate and washed with saturated aqueous sodiuin bicarbonate solution. The aqueous layer was back extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate and -297concentrated in vacuo. The crude product was purified using a short plug of silica gel using hexane/ethyl acetate 'H-NMR (CDCL 3 8: 1.47 (9H, 3.12-3.16 (4H, 3.61-3.65 (4H, 6.90-7.05 (2H, 7.47-7.70 (2H, ESI-MS m/z: 288 UV retention time: 2.75 min.

Step 2 4-(4-Chloro-2-cyano-phenyl)-piperazine-l-carboxylic acid tert-butyl ester To a solution of 4-(2-cyano-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (7.1 g, 24.72 mmol) in acetonitrile (120 ml) was added N-chlorosuccinimide (3.96g, 29.66 mmol) and the resulting mixture was slowly heated to 80 0 C and stirred for 1.5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. The aqueous layer was back extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified using a short plug of silica gel using gradient elution from hexane/ether to hexane/ether to give thep-chloro isomer in 50% yield. 'H-NMR (CDCL 3 8: 1.48 (9H, 3.10-3.38 (4H, 3.60-3.70 (4H, 6.85-7.18 (1H, 7.40-7.60 (2H, ESI-MS m/z :322 UV retention time: 3.07 min.

Step 3: 5-Chloro-2-piperazin- -yl-benzonitrile A solution of 4-(4-chloro-2-cyano-phenyl)-piperazine-1-carboxylic acid tertbutyl ester (0.32 g, 1 mmol) in dichloromethane cooled at 0 °C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organic layers were separated and dried over sodium sulfate and concentrated in vacuo. The product used without further purification.

ESI-MS m/z 222 UV retention time: 1.05 min.

Step 4 5-Chloro-2-(4- {3-[7-(1-hydroxy-l-methyl-ethyl)- 11H-10-oxa-l- -298azadibenzo[a,d] cyclohepten-5 -ylidene] -propyl -piperazin- 1 -yl)-benzonitril e To a solution of 5-chloro-2-piperazifl-1-yl-benzoflitrile (0.22g, I mmol) in isopropanol (8 mL) was added 2,6-lutidine 16 niL, 1.33 mrumol) and catalytic potassium iodide. This mixture was heated to 80 'C and treated with bromo-propylidene)-5,l 1-dihydro-1I0-oxa-l1-aza-dibenzo[a,d] cyci ohepten-7 -yl)propan-2-ol 0.26 g, 0.67 mmo]) in portions over 2h. The solution was then stirred at 80 'C for an additional 18 h. The reaction mixture was concentrated in vacuc, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl to 90% ethyl acetate/l0% methanol) to yield the title compound (0.11 g, 54 'H-NMR (MeOD) 8: 1.40 (6H, 2.30-2.58 (8H, in), 3.00-3.15 mn), 5.20 (1K, hr 6.18 (1H, 6.70 (IH, dd), 7.18-7.84 (7H, in), 8.50 (11-H, dd). ESI-MS mlz: 515 (M UTV retention time: 1.75 min.

Example 541 -Chloro-2-(4- -hydroxy- 1-methyl-ethyl)- 1 IH- 10-oxa- 1-azadibenzo cyclohepten-5 -ylidene]-propyl) -piperazin-1I-yl)-benzoic acid methyl ester Step 1: 4-(2-Carboxy-4-chloro-phenyl)-piperazine I -carboxyli c acid tert-butyl ester To a solution of 4-(4-chloro-2-cyano-phenyl)-piperazine-l1-carboxylic acid tert-butyl ester (0.6 g, 1.86 mrnol) in methanol (4.0 mL) was added 1.0 N NaOH mL, 4.0 rnmol) and the resulting mixture was heated to reflux at 80 0 C for 36 h.

Additional 1.0 N NaOH (2.0 ml, 2.0 mmol) was added to the reaction mixture and refluxed further for 18 hrs. The reaction mixture was concentrated and acidified to pH 4.0- 5.0 using 1.0 N HCI and extracted with chloroform The corabined organics were dried over sodium sulfate, concentrated and dried in vacuo oNernight.

The product contained approximately 20% amide and was separated after esterification in the next step. ESI-MS inlz 341(M LTV retention time: 2.33 min.

-299- Step 2: 4-(4-Chloro-2-methoxycarbonyl-phenyl)-piperazine- 1 -carboxylic acid tertbutyl ester To a solution of 4 -(2-Garboxy-4-chloro-phenyl)-piperazine- I -carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in toluene: methanol 1) was added a trimethylsilyldiazomethane (2.0 M in hexanes) (1.05 mL, 2.07 mmol) and the resulting mixture was stirred at room temperature for I h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate 'H-NMR (CDCL)) 8: 1.45 (9H, 2.90-3.00 (4H, in), 3.50-3.60 in), 3.90 (3H, 6.90-7.00 (1H, 7.35-7.45 (114, dd), 7.80 (1H, ESI-MS m/z:355 (M UV retention time: 3.1Imin.

Step 3: 5-Chloro-2-piperazin-1I-yl-benzoi c acid methyl ester A solution of 4-(4-chloro-2-methoxycarbonyl-pheny)-piperazine- 1carboxylic acid tert-butyl ester (0.32 g, 0.92 inmol) in dichloromethane (5-0 mL) cooled at 0 'C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate.

The organics were separated and dried over sodium sulfate and concentrated i17 vacuc. The product used without any further purification. ESI-MS mlz: 25 5 (M UV retention time: 1. 14 min.

Step 4: 5-Chloro-2-(4- -hydroxy-] -methyl-ethyl)-1 11--I0-oxa-lI-azadibenzo[ a,d]cyclohepten-5-yli dene]-propyl -piperazin- I -yl)-benzoi c acid rnethyl ester To a solution of 5-chloro-2-piperazin-1-yI-benzoic acid methyl ester (0.23g, 0. 9I6mmol) in isopropanol (8.0 mL) was added 2,6-lutidine 16 mL, 1.33 inmol) and catalytic potassium iodide. This mixture was heated to 80 'C and treated with 2-[5-(3-bromo-propylidene)-5,l1 1-dihydro-1I0-oxa- I-aza-dibenzo[a,d]cyclohepten-7yl3-propan-2-ol 0.26 g, 0.67 inmol) in portions over 2h. The solution was then stirred at 80 'C for an additional 18 h. The reaction mixture was concentrated in -3 00vacuo, then purified by flash chromatography on silica gel (gradient elution from ethyl acetate/5 %methanol to 90% ethyl acetate/i 0% Methanol) to yield the title compound. 'H-NMR (DMSO) 8: 1.40 (6H, 2.15-2.55 (8H, in), 2.75-2.95 (4H, mn), 3.75 (3H, 5.20 (2H, br 6. 10 (1H, 6.65 (1lH, dd), 7.00-7.60 (6H, in), 7.70 (1H, dd), 8.50 (1Hi, dd). ESI-MS rn/z :548 (M UV retention time: 1.56 min.

Example 542 2-(4-Chloro-phenyl)-N-(1- 1-hydroxy- 1-methyl-ethyl)- 1 IH- 10-oxa- 1 -aza dibenzo[a,d] cyclohepten-5-ylidenel-propyl)}-pipenidin-4-yl)-acetaniide Step 1: 4-[2-(4-Chloro-phenyl)-acetylamino] -piperi dine- I -carboxylic acid tert-butyl ester To a solution of 4-amino- piperidine 1-carboxylic acid tert-butyl ester (0.44 g, 2.2 mrnol) and 4-chlorophenyl acetic acid (0.34 g, 2 nmol) indi chloromnethane mL) were added EDCJ (0.5 5 g, 2.8 rnrol), HOBT (0.42 g, 2.8 mmnol) and Nmethylmorpholine (0.6 g, 6 minol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuc diluted with dichioromethane and extracted with saturated aqueous sodium bicarbonate solution. The aqueous layer was back extracted twice with dichloromethane. The combined organics were dried over sodium sulfate and concentrated in vacuo. Crude product was purified using a short plug of silica gel using ethyl acetate to give the desired product

'H-NM.R(CDCL

3 5: 1.15-1.25 (2H, in), 1.40 (9H, 1.80-1.90 (2H, in), 2.85 (2H4, dd), 3.5 (2H, 4.00 (1 H, br 5.20 (1H, 7.15-7.35 in). ESI-MS rni/z 353 (M LUV retention time: 2.47 min.

Step 2: 2-(4-Chloro-phenyl)-N-piperi din-4-yl-acetaide A solution of 4-[2-(4-chloro-phenyl)-acetylamino]-piperidine- I -car-boxylic acid tert-butyl ester (0.55 g, 1.54 mmol) in dichioromethane (8.0 inL) cooled at 0 0

C

was treated with trifluoroacetic acid and warmed to room temperature and -3 01stirred for 2 h. The reaction mixture was concentrated in i'acuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organic layers were dried over sodium sulfate and concentrated in vacuc. The crude product was purified on silica using gradient elution from ethyl acetate/methanol to ethyl acetate/methanol 'H-NMR (CDCL 3 8: 1.15-1.25 (21-,mi), 1. 80- 1.90 (2H, mn), 2.60-2.75 (2H, in), 2.90-3.10 (2H, in), 3.5 (2H1, 3.85 (1H, in), 5.20 (1IH, 7.15-7.35 (4H, mn). ESI-MS m/z 253 (M UV retention time: 0.S7 min.

Step 3: 2-(4-Chloro-phenyD)-N-(1- I-hydroxy- 1-methyl-ethyl)-I11H-I 0-oxa- 1aza-d ib enzo d)cycloheptel- 5 -yli denle]-proPYl I -piperidin-4-yl)-acetamide To a solution of 2-4clr-hnl--ipndn4y-ctmd (0.2 g, 0.8 inmol) in isopropanol (6.0 tnt) was added 2,6-lutidine (0.095 mL, 0.8 minolI) and catalytic potassium iodide. This mixture was heated to 80 *C and treated with (3-bromo-propylideiie)-5,1 1-dihydro-I 1 -oxa- I -aza-dibenzo~a,d]cyclohepten-7-yl]propan-2-o] 15 g, 0.4 ininol) in portions over 2h. The solution was then stirred at S0 'C for an additional 1S h. The reaction mixture was concentrated inl vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl %methanol to 90% ethyl acetate/20% methanol) to yield the title compound. 'H-NMR (CDCL 3 5: 1.15-1.50 (4H, in), 1.60 1.80-2.85 (8H, mn), 3.50 (2H, 3.70-3.90 (IH, in), 5.20 (2H1, br 6.05(1H, 6.80 (IR, 7.20- 7.40 (7H, in) 7.60 (1IH,dd), 8.50 (1IH,dd). ESI-MS m-iz: 546 (M UTV retention time: 1 .24 min.

Example 543 2- (5 {2 oro-phenyl)-ethyl -amino] -ethyl) -ethyl -amino)-propyli de ee] 5,1 1-dihydro- 10-oxa-l1-aza-dibenzo[a,d]cyclohepten-7-yl} -propan-2-ol Step 1: {3-f2(4-hloro-phenylamino)-ethylaino]-Propylidene} -5,11 -dihydro- I 0-oxa-1 -aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-oI -302- To a solution of N-(4-chloro-phenyl)-ethane-1,2-diamine (0.68 g, 3.96 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.31 mL, 2.64 mmol) and catalytic potassium iodide. This mixture was heated to 80 0 C and then treated with 2-[5-(3-bromo-propylidene)-5, 1-dihydro- 10-oxa-l1-aza-dibenzo[a,d]cyclohepten- 7 yll-propan-2-ol 0. 15 g, 0.4 mmol) in portions over 2h. The solution was then stirred at 80 'C for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound. 'H-NMIR (DMS0) 5: 1.40 (6H, 2.20-2.40 (2H, in), 2.70- 2.90(3H, mn), 3.10-3.30 5.20 (2H, br, 5.80 (IH, mn), 6.15 (lH, 6.60- 6.70 (IH, mn), 7.10-7.30 (4H, m) 7.50 (2H, mn), 7.80 (IH, dd), 8.50 (1H, dd). ESI-MS mlz: 464 (M UV retention time: 1.40 min.

Step 2: 2 (5 2 -[(4-Chloro-phenyl)-etliyl -amino] -ethyl) -ethyl -amino)propylidene]-5,11I -dihydro- I 0-oxa-]I -aza-dibenzo[a,d~cyclohepten-7-yl} -propan-2-ol To a solution of J3 2 -(4-chloro-phenylamino)-ethyl amino] propylidene} -5,11 -dihydro- 1 0-oxa- 1 aza-dibenzo[a,d)cyclohepten-7-yl)-propan- 2 -ol 13 g, 0.27 minol) in dichloroethane (5.0 mL) was added acetaldehyde (0.045 mL, 0.81 imol), sodium triacetoxyborohydride (0.17 0.81 rnxol) and cataly-tic acetic acid and stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/m ethanol 'H-NMR (CDCL 3 5: 0.90-1.20 (6H, 2 x 1.60 (6H,s), 2.20-2.40 (2H, in), 2.45-2.65 (6H, in), 3.20-3.40 (4H, 2 x 5.30 (2H, br, 6.10 (lH, 6.50 dd), 6.80 (1H, 7.10 (2H, dd) 7.20-7.35 (214, in), 7.45 (1H, dd),7.55 (1H, dd), 8.50 (1H, dd). ESI-MS mlz: 520 (M UV retention time: 1.51 min.

-303- Example 544 1 -(4-Chloro-phenyl)-4- 1-hydroxy- 1-methyl-ethyl)-I 11H-i 0-oxa-1 -azadibenzo~a,d]cyclo hepten-5-yli dene]-propyl) -piperazine-2-carboxylic acid ami de Step 1: 1 -(4-Chloro-phenyl)-4- 1-hydroxy- 1-methyl-ethyl)- 11H-I 0-oxa-lI-azadibenzo[a,d]cyclo hepten-5-ylidene]-propyl)}-pi~perazine-2-carbonitrile To a solution of f 3-[2-(4-chloro-phenylamino)-ethylamino]propyli dene) -5,11 -dihydro- 1 0-oxa- 1 -aza-dibenzo(a,d]cyclohepten-7-yl)-propan-2-ol (0.4 g, 0.86 mmol) in toluene (6 mL) was added triethylamine (0.48 m.L, 3.44 rnmol) and 2,3-dibromopropionitrile 19 mL, 1. 72 rnmol) and reaction mixture was heated to 110 'C (reflux) and stirred overnight for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1LON NaGH solution. The aqueous layer was back extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated.

The crude product was purified using a short plug of silica gel using ethyl acetate to give the title compound. 'H-NMR (CDCl 3 8: 1.05 (6H, 2.20-2.70 (8H, 2 x rn), 3.00 (IH, in), 3.10-3.40 (3H, 2 x in), 4.50 (IH, br, s) 5.30 (2H, br, 6.20 (lH, t), 6.70-6.90 2 x 7.10-7.35 (4H, mn), 7.50 (2H, 8.50 (1H, dd). ESI-MS m/z: 515 (M UTV retention time: 2.36 min.

Step 2: 1 -(4-Chloro-phenyl)-4- I-hydroxy- 1-methyl-ethyl)-I11H-I 0-oxa- 1aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl) -piperazine-2-carboxylic acid anmide To a solution of I -(4-chloro-phenyl)-4- -hydroxy- I1-methyl-ethyl)- I1I H-i I0-oxa- 1 -aza-dibenzo [a,d]cyclohepten-5-ylidene]-propyl -piperazine-2carbonitrile 12 g, 0.23 rnmol) in methanol (0.5 inL) and THF (0.5 mL) was added 1.0 N NaOH (0.5 mL, 0.5mmol) and the resulting mixture was heated to reflux at 80 'C for 18 h. Additional 2.0 N NaOH (0.5 mL, 0.5 minol) was added to the reaction mixture and refluxed further for 18 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCI and extracted with ethyl acetate(3x). The combined organics were dried over sodium sulfate and -304concentrated. The crude product was purified on a short plug of silica gel using gradient elution from ethyl acetate/methanol to give the title compound.

'H-NMR (CDC1 3 8: 1.05 (6H, 2.20-2.70 (8H, 2 x min), 3.00 (1H, mn), 3.10-3.40 (3H, 2 x 4.50 (1H, br, 5.30 (2H, br, 6.00(IH, br, 6.20 (1H, 6.40 (1H, br,s), 6.70-6.90 (3H, 2 x 7.10-7.35 (4H, 7.50 (2H, 8.50 (IH, dd).

ESI-MS nm/z :515 (M UV retention time: 1.32 min.

Example 545 1-(4-Chloro-phenyl)-4- -hydroxy-1-methyl-ethyl)-l 1 H-1 0-oxa- 1 -azadibenzo[a,d]cyclo hepten-5-ylidene]-propyl} -piperazine-2-carbonitrile To a solution of (3-[2-(4-chloro-phenylamino)-ethylamino]propylidene} -5,1 -dihydro- 10-oxa- -aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol (0.4 g, 0.87 mmol) in toluene (6 mL) was added triethylamine (0.48 mL, 3.44 mmol) and 2,3-dibromopropionitrile (0.19 mL, 1.72 mmol) and reaction mixture was heated to 110 'C (reflux) and stirred overnight for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1.ON NaOH solution. The aqueous layer was back extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated.

The crude product was purified using a short plug of silica gel using ethyl acetate to give the desired product. 1 H-NMR (CDCI 3 8: 1.05 (6H, 2.20-2.70 (8H, 2 x min), 3.00 (1H, 3.10-3.40 (3H, 2 x 4.50 (1H, br, 5.30 (2H, br, 6.20 (1H, t), 6.70-6.90 (3H, 2 x 7.10-7.35 (4H, min), 7.50 (2H, 8.50 (1H, dd). ESI-MS m/z: 515 (M UV retention time: 2.36 min.

Example 546 1-(4-Chloro-phenyl)-4- -hydroxy-1-methyl-ethyl)- 11H-10-oxa-1-azadibenzo[a,d] cyclohepten-5-ylidene]-propyl) -piperazine-2-carboxylic acid methyl ester -305- Step 1: Piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9ylmethyl) ester 2-methyl ester To a solution of piperazine-1,2,4-tricarboxylic acid 1 -tert-butyl ester 4-(9Hfluoren-9-ylmethyl) ester (2.21 mmol) in toluene: methanol was added equimolar trimethylsilyldiazomethane (2.0 M in hexanes) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate 5 to hexane/ethyl acetate ESI-MS m/z 467 (M UV retention time: 3.04 min.

Step 2 Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9Hfluoren-9-ylmethyl) ester 2-methyl ester (2.03 mmol) in DMF (4.0 mL) was added diethylamine and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified using ethyl acetate/ methanol ESI-MS m/z 245(M UV retention time: 0.78 min.

Step 3: 4-(4-Chloro-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3methyl ester 4-Chloro phenyl boronic acid (2.0 equiv, 3.68 mmol) and piperazine-1,2dicarboxylic acid I -tert-butyl ester 2-methyl ester (1.0 equiv, 1.84 mmol) were dissolved in dichloromethane followed by the addition of copper acetate (1 .0 equiv), 4A molecular sieves and pyridine (2.0 equiv). The reaction mixture was stirred at room temperature for 72h. The reaction mixture was concentrated in i'acuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate ESI-MS m/z :354 (M UV retention time: 2.88 mm.

Reference: Tetrahedron Letters, 2001, 42, 3415-3418 -306- Step 4: 1 -(4-Chloro-phenyl)-piperazine-2-Carboxylic acid methyl ester A solution of 4-(4-chloro-phenyl)-piperazifle- 1,3-dicarboxylic acid I -tertbuty] ester 3-methyl ester (0.4 g, 1. 13 mmol) in dichloromethane (5.0 niL) cooled at 0 'C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification. ESI-MS m/z :254 (M UTV retention time: 1.01 min.

Step 5 1 -(4-Chloro-phenyl)-4- -hydroxy- I -methyl-ethyl)- 11 H- I 0-Oxa- 1 aza-dibenzo~a,d) cyclohepten-5-ylidene]-propyl} -piperazine-2-carboxylic acid methyl ester To a solution of 1-(4-chloro-phenyl)-piperazifle-2-carboxylic acid mnethyl ester 14 g, 0.53 mmol) in acetonitrilIe: water 1) was added potassium carbonate (0.083 0.6 nimol) and -(3-bromo-propylidene)-5,l11-dihydro- 10-oxa- 1aza-dibenzo[a,d~cyclohepten-7-yl1-propafl- 2 -ol (150 mng, 0.4 mmol) and the resulting mixture was stirred at 50 'C for 5 hours. The reaction mixture was concentrated in i'acuo, diluted with ethyl acetate, and dried over sodium sulfate.

The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol

'H-NMTR

(CDCI3) 5: 1.05 2.20-2.70 (SH, 2 x in), 3.00 (1K, mn), 3.10-3.40 (311, 2 x in), 3.55 4.50 (1 H, br,s), 5.30 (2H, br,s), 6.20 (111, 6.70-6.90 (3H, 2 x 7.1 0-7.35 (4H, in), 7.50 (2H, 8.50 (1H, dd). ESI-MS nm/ z 548 (M U'V retention time: 1.62 min.

Example 547 Isopropyl-carbamic acid 5- {3 -[4-(4-chioro-phenyl)-4-hydroxy-3 ,3 -diniethyl piperidin- 1-yl)-propylidene} -5,1 1-dihydro- 10-oxa-l1-a'za-dibenzo[a,d]cyclohepten-7yl ester -307- {3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l-yl]propylidene)-5,11 -dihydro-I 0-oxa-1 -aza-dibenzo[a,d]cyclohepten-7-ol (0.27 mmol, equiv) was dissolved in tetrahydrofuran and treated with triethylamine (1.50 equiv) and isopropyl isocyanate (0.4 rmmol, 1.50 equiv). The resulting mixture was heated to 50 °C for 18 h. The reaction mixture was concentrated and crude product was purified on silica using gradient elution from ethyl acetate (100%) and ethyl acetate/methanol 'H-NMR (CDCI 3 8: 0.70 (3H, 0.90 (3H, 1.1 (3H, 1.25 (3H, 1.4 (1H, 1.6 (1H, 2.30-2.50 (8H, 2.70 (2H, 3.80- 4.00 (3H, 3.55 (3H, 4.85 (1H, 5.30 (2H, br, 6.20 (1H, 6.80-7.00 (2H, dd), 7.20-7.45 (6H, 7.60 (1H, dd), 8.50 (1H, dd). ESI-MS m/ z 576 (M UV retention time: 1.58 min.

Example 548 3-(4-Chloro-phenyl)-1 -ethyl-1-(1 1 -hydroxy- 1-methyl-ethyl)- 11 H-1 0-oxa-1 aza-dibenzo [a,d]cyclohepten-5-ylidene]-propyl}-pyrrolidin-3-yl)-urea Step 1: 3-Ethylamino-pyrrolidine- I-carboxylic acid tert-butyl ester To a solution of 3-amino-l-N-Boc pyrrolidine (1 eq, 5.37 mmol) in methanol (20 mL) was added acetaldehyde (0.95 eq) and the resulting mixture was heated to 80 OC and stirred for 2 then stirred at room temperature overnight.

Sodium borohydride (0.95 eq, 5.1 mmol) was added and reaction mixture was stirred for an additional 2h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate to hexane /ethyl acetate 'H-NMR (CDCL 3 1.05 (3H, 1.45 (9H, 1.60-1.75 (1H, 2.00-2.10 (1H, 2.68 (4H, 2.90-3.15 (1H, 3.25-3.65 (4H, m).

ESI-MS m/z 215 (M UV retention time: 0.75 min.

-308- Step 2: 3-[3-(4-Chloro-phenyl)- -ethyl-ureido]-pyrrolidine- -carboxylic acid tertbutyl ester To a solution of 3-ethylamino-pyrrolidine-l-carboxylic acid tert-butyl ester (0.33 g, 1.5 mmol) in DMF (5.0 mL) was added drop wise a solution of 4chlorophenyl isocyanate (0.23 g, 1.51 mmol) in DMF (2.5 mL) at room temperature and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified on silica using hexane/ethyl acetate followed by ethyl acetate (100%) to give the desired product as white foamy solid.

ESI-MS m/z 368 (M UV retention time: 2.61 min.

Step 3: 3-(4-Chloro-phenyl)-1-ethyl- -pyrrolidin-3-yl-urea A solution of 3-[3-(4-chloro-phenyl)- -ethylureido]-pyrrolidine-I -carboxylic acid tert-butyl ester (0.4 g, 1.08 mmol) in dichloromethane (5.0 ml) cooled at 0 °C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z 268 (M UV retention time: 1.02 min.

Step 4 3-(4-Chloro-phenyl)-1 -ethyl-l {3-[7-(1-hydroxy-1 -methyl-ethyl)- 11H- 10-oxa-l-aza-dibenzo [a,d]cyclohepten-5-ylidene]-propyl} -pyrrolidin-3-yl)-urea To a solution of 3-(4-chloro-phenyl)- 1-ethyl-i -pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in acetonitrile:water was added potassium carbonate (0.16 g, 0.8 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-l-azadibenzo[a,d]cyclohepten-7-yl]-propan- 2 -ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50 °C for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate/methanol to ethyl acetate/methanol to give the desired product -309as yellow solid. 'H-NMR (CDC 3 5: 1.05 (3H, 1.40 (6H, 1.80 (1H, 2.20- 2.40 (3H, 2.50-3.00 (8H, 3.40 (4H, q and 4.20 (1H, 5.20 (2H, br, s), 6.20 (1H, 6.65(1H, 7.00 (2H, dd), 7.20-7.40 (5H, 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br ESI-MS m/z 561 (M UV retention time: 1.45 min.

Example 549 {3-[3-(4-Chloro-benzyloxy)-pyrrolidin- I-yl]-propylidene}-5,11-dihydro-10oxa- -aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol Step 1: -3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of (R)-3-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (1.14 mmol, 1.0 eq) in THF (2.5 mL) was added to a suspension of sodium hydride (1.15 eq) in THF (2.5 mL) cooled at 0 OC and the resulting mixture was stirred for min. A solution of 4-chlorobenzyl bromide (1.31 mmol, 1.15 eq) in THF mL) was then added drop wise and reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (1.0 ml) and diluted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate 'H-NMR (CDCL 3 1.45 (9H, 1.80-2.05 (2H, 3.30-3.55 (4H, 4.05 (1H, 4.45 (2H, s), 7.15-7.30 (4H, ESI-MS m/z :311 (M UV retention time: 2.94 min.

Step 2: (R)-3-(4-Chloro-benzyloxy)-pyrrolidine A solution of (R)-3-(4-chlorobenzyloxy)-pyrrolidine-l-carboxylic acid tertbutyl ester (0.88 mmol) in dichloromethane cooled at 0 C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI- MS m/z 211(M UV retention time: 0.97 min.

-3 Step 3: {3-[3-(4-Chloro-benzyloxy)-pyITolidifl-1I-yl]-propylidene} -5,11dihydro- 10-ox a-I -aza-dibenzo[a,d]cycloheptefl-7-yl)-propanf- 2 -ol To a solution of (R)-3-(4-chloro-benzyloxy)-pyrrolidifle (0.88 mmol, 2.0 eq) in acetonitrile:water 1) was added potassium carbonate (0.88 mmol, 2.0 eqv) and (E)-2-[5-(3-bromo-propylidene)-S ,1 1 -dihydro- I 0-oxa- I -azadibenzo[a,d]cycloheptel-7-yl]-propal- 2 -oI and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuc, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by Reverse Phase HPLC. 'H-NMR (CDCl 3 5: 1.40 (6H, 1.15-1.35 (1 H, in), 1.85-2.05 (1H, mn), 2.20-2.40 (IH, mn), 2.35-2.65 (8H, mn), 3.90-4. 10 (1H, in), 4.30- 4.50 (2H, 5.10-5.30 (2H, br, 6.05 (1H, 6.50 (lH, dd), 7.10-7.50 (4H,mi), 7.70 (IH, dd), 8.50 (IH, dd). ESI-MS m/z: 505 (M UV retention time: 1.52 min.

Example 550 [4Cloo- ezl- ouy -aio -yr l' i-I-yl} -propylide-ne)-5,1 I1di'hydro- 10-ox a-I -aza-dibenzo[ad~cyclohePtefl-7-yi]-propafl 2 -ol Step 1: 3 -(4-Chloro-benzylainino)-pyrrolidine- I -carboxylic acid tert-butyl ester 3-ainino-1-N-Boc pyrrolidine (1.0 eq, 2.68 rnmol), 4-chlorobenzy] bromide (1.0 eq, 2.68 inmol), and potassium carbonate 1.75 eq) were mixed in ethanol (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuc, taken up in ethyl acetate, filtered and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate. ESI-MS m/z 311 (M UJV retention time: 1. 18 min.

Step 2: 3- [(4-Chloro-benzyl)-isobutyl-anifino] -pyrrolidine-lI-carboxylic aci d tertbury] ester -311- To a solution of 3-(4-chloro-benzylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.4 g, 1.28 mmol) and isobutyraldehyde (0.14 g, 1.92 mmol) in dichloroethane was added sodium triacetoxy borohydride (0.81 g, 3.85 mmol) and catalytic acetic acid. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate 'H-NMR (CDCI 3 8: 0.80 (6H, 2 x 1.45 (9H, s), 1.60-1.90 (2H, 2.20 (2H, 3.00-3.70 (7H, 7.20 ESI-MS /z 367 (M UV retention time: 1.89 min.

Step 3: (4-Chloro-benzyl)-isobutyl-pyrrolidin-3-yl-amine To a solution of 3-[(4-chloro-benzyl)-isobutyl-amino]-pyrrolidine- 1 carboxylic acid tert-butyl ester in dichloromethane cooled at 0 OC was added trifluoroacetic acid and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification.

ESI-MS m/z 267(M UV retention time: 0.93 min.

Step 4: {3-[(4-Chloro-benzyl)-isobutyl-amino]-pyrrolidin-1 -yl propylidene)-5,11 -dihydro- 10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol To a solution of (4-chloro-benzyl)-isobutyl-pyrrolidin-3-yl-amine (0.16 g, 0.6 mmol) in acetonitrile:water was added potassium carbonate (0.8 rnmol) and (E)-2-[5-(3-bromo-propylidene)-5, 11-dihydro- 10-oxa- -azadibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50 °C for 24 h. The reaction was concentrated, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by -3 12flash chromatography using ethyl acetate/methanol 'H-NMR (CDC1 3 6: 0.80 (6H, 1.55(6H, 1.60-1.90 (4H, in), 2.15 (1K, 2.20-2.60 (6H, in), 3.25-3.60 (2H, in), 5.30 (2H, br, 6.10 (1H, 6.80 (lH, dd), 7.15-7.30 (6H, in), 7.40 (1H, 7.5 5 (1lH, dd), 8.45 (1lH, dd). ESI-MS mlz :560 (M UV retention time: 1.66 min.

Example 551 3 -(4-Chloro-benzyl)-isopropyl-amilo]-pyrroli din- 1 -yI}I -propylid ene)-5, 11dihydro-1I0-oxa-l1 aza-dibenzo[a,dcycloheptef-7yl]-propan- 2 -ol Step 1: 3 -Isopropylarnino-pyrrolidine- I -carboxylic acid tert-butyl ester To a solution of (R)-3-ainino- 1 -N-Boc pyrrolidine (1.0 eq, 2.68 mrnol) in methanol (15 mL) was added acetone (1.07 eq), sodium cyano borohydride (2.0 eq) and few drops of acetic acid and the resulting mixture was stirred at room temp erature overnight. The reaction mixture was concentrated dissolved inl dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate 'K-NMR (CDCI 3 8: 1.05 (6H, 1.45 (9H, 1.60 (1K, in), 2.80-3.00 (2H, in), 3.20-3.70 (4H, mn). ESI-MS inlz: 229 (M 1), UV retention time: 0.77 min.

Step 2: 3-[(4-Chloro-benzyl)-isopropyl-amTiflo] -pyrrol idine- I -carboxyli c acid tertbutyl ester To a solution of isopropyl-pyrrolidin-3-yl-ainine (0.3 g, 1.31 inmol) in dichloroethane (5.0 ml) was added 4-chlorobenzaldehyde (0.22 g,1.57 mrnol), sodium triacetoxy borohydride (0.83 g, 3.93 mmol) and catalytic acetic acid and the resulting reaction mixture was stirred at room temperature overni ght The reaction mixture was concentrated, dissolved in dichloromethane and washed with aqueous sodium bicarbonate. The combined organics were washed with brine and -313dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate (50%).'H-NMvIR (CDCI 3 6: 1.05 (6H, 1.45 (9H, 1 (1H, in), 2.80-3.00 (2H, in), 3.20-3.70 (4H, in), 7.20 (4H, mn). ESI-MS in/z :.353(M UJV retention time: 1.49 min.

Step 3: (4-Chloro-benzyl)-isopropyl-py-rolidin-3 -y]-amine A solution of 3-[(4-chloro-benzyl)-isopropyl-amino]-pyrroli dine- Icarboxylic acid tert-butyl ester in dichioromethane cooled at 0 'C was treated with trifluoroacetic acid and warmed to room temperature and stirred for 2 hours.

The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI- MS ml/z: 253 (M 1, LUV retention time: 0.59 min.

Step 4: {3-[(4-ChlOro-benzyl)-isopropyl-amino] -pyrrolidin- 1-y] propylidene)-5,1 1 -dihydro- I 0-oxa- 1 -aza-dibenzo[ad]cyclohepten-7-yl]-propan-2-oI To a solution of (4-chloro-benzyl)-isopropyl-pyrroldin-3-yl-amine (0.68 minol, 1.7 eq) in acetonitri le:water 1) was added potassium carbonate 8 rnimol, 2 eq) and (E)-2-[5-(3-bromo-propylidene)-5,1 1-dihydro-1I0-oxa-l1-azadibenzo~a,d~cyclohepten-7-yl]-propan-2-oI (0.4 mmol, 1.0 eq) and the resulting mixture was stirred at 50 'C for 24 h. The reaction mixture was concentrated in 1'acuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatogaphy using ethyl acetate/methanol ']H-NNIR

(CDCI

3 6: 0.85 (6H, 1.50-1.90 (1 OH, in), 2.10-2.60 (8H, rn), 3.50 (3H, in), 5.30 (2H, br, 6.10 (lH, 6.80 (IH, dd), 7.10-7.40 (8H,mi), 7.50 (1H, 8.50 (1H, dd). ESI-MS irlz 546 (M UV retention time: 1.40 min.

Example 552 2-[(4-Chloro-benzyl)-( -hydroxy-1-methyl-ethy])-I 11H-I 0-oxa-1 -aza dibenzo[a,d)cyclo hepten-5-yildene] -propyl)}-pyrrolidin-3 -yl)-amino]-acetarnide -314- Step 1: 3-(Carbamoylmethyl-amino)-pyrrolidine- -carboxylic acid tert-butyl ester To a solution of (R)-3-amino-l-N-Boc pyrrolidine (0.5 g, 2.68 mmol) and 2bromo acetamide (0.44 g, 3.21 mmol) in DMF (6.0 mL) was added potassium carbonate (1.11 g, 8.04 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and re-dissolved in dichloromethane. Potassium carbonate was filtered off and filtrate was concentrated and purified using ethyl acetate/methanol 'H-NMR (CDCI 3 8: 1.50 (9H, s), 1.60-1.80 (2H, 2.10 (1H, 3.10-3.60 (6H, 5.65 (1H, br, 6.90 (1H, br, ESI-MS m/z 367(M UV retention time: 0.61 min.

Step 2: 3-[Carbamoylmethyl-(4-chloro-benzyl)-amino]-pyrrolidine-l-carboxylic acid tert-butyl ester To a solution of 3-(carbamoylmethyl-amino)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4chlorobenzaldehyde 0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 'H-NMR (CDC1 3 5: 1.50 (9H, 1.60-1.80 (2H, 2.10 (1H, 3.10-3.60 (SH, 5.65 (1H, br, 6.90 (1H, br, s) 7.20-7.40 (4H, ESI-MS m/z 367(M UV retention time: 1.94 min.

Step 3: 2-[(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetamide A solution of 3-[carbamoylmethyl-(4-chloro-benzyl)-amino]-pyrrolidine- carboxylic acid tert-butyl ester (0.49 g, 1.32 mmol) in dichloromethane cooled at 0 °C was treated with trifluoroacetic acid The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium -3 bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification* ESI-MS mlz: 267 (M UV retention time: 0.82 min.

Step 4: 2-[(4-Chloro-benzyl)-( -hydroxy- 1-methyl-ethyl)-II1H-i 0-oxa-1 aza dibenzo cyclohepten- 5-ylid en e) -propy] -pyrroli din- 3 -yl)-amino] -acetan i de To a solution of 2- [(4-chl oro -benzyl)-pyrroli din-3 -yl -amino] aetar-iide (0.21 g, 0.8 mmol) in acetonitrile:water was added potassium carbonate (0.6 rnol) and (E)-2-[5-(3-bromo-propyli dene)-S,1 1-dihydro-I 1 -oxa-] -azadibenzo[a,d]cyclohepten-7-y]]-propan-2-ol 15 g, 0.4 ninol) and the resulting mixture was stirred at 50 TC for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by HPLG. 'H--NMTR (CDCI 3 5: 1.35 (6H, 1.55-1.75 (1H, in), 1.80-2.00 (1IH, in), 2.20-2.85 (8H, mn), 2.90-3.10 (2H, 3.30-3.50 (lH, 3.60 (IH, 4.80-5.30 (2H, br, 6.10 6.70 (lH, dd), 7.00-7.45 (7H 7.70 (IH, dd), 8.50 (IH, dd). ESI-MS m/z :562 (M UV retention time: 1.31 min.

Example 553 2-[(4-Chloro-benzyl)-(1- {3 I-hydroxy- 1-methyl-ethyl)-I 1H-I 0-oxa- I-azadibenzo[a,d] cycl ohepten- 5 yli den e] -propyl -pyrroli1din-3 amino] -N-ethyl acetamnide Step 1: 3-(Methoxycarbonylmethyl-amino)-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (R)-3-amino-1 -N-Boc pyrrolidine (0.5 g, 2.68 mrnol) and methyl bromo acetate (0.49 g, 2.95 mol) in DMF (6.0 mL) was added potassium carbonate (1.11 g, 8.04 inmol) and the reaction mixture was stirred at room temperature overnilght. The reaction mixture was concentrated and re-dissolved in dichloromethane. Potassium carbonate was filtered off and filtrate was con centrated -3 16and purified using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate H-NMR (CDC1 3 5: 1.40 (9H, 1.70 (2H, in), 2.00 (1H, in), 3.20-3.60 (5H, in), 3.79 (3H, br ESI-MS m/z :258(M UV retention time: 0.74 min.

Step 2: 3-[(4-Chloro-benzy)-methoxycarbolylmethyl1 mino]-pyrrolidine- 1carboxylic acid tert-butyl ester To a solution of 3 -(nethoxycarboiy1nethyl -amfilo)-PYrroli dinle- I1carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 niL) was added 4-chlorobenzaldehyde (0.34 g, 2.44 nimol), sodium triacetoxy borohydride (0.86 g, 4.06 inmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichioromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 'H-NMR (CDC1 3 6: 1.40 (911, 1.80 (1 H, 2.10 (1H, in), 3.00-3.80 (7H, in), 4.70(IH, br,s), 7.20 (4H,m).

ESI-MS m/z: 383(M UV retention time: 2.91mmi.

Step 3: 3 -[Carboxyrn ethy1-(4-ch]Ioro-benzyl)-aino] -pyTo li dine- I -carbox ylic acid tert-butyl ester A solution of 3 [(4-chloro-benzyl)flethoxycarbonyI methyl- aminlo] pyrrolidine-l-carboxylic acid tert-butyl ester (0.5 g, 1.31 mmiol) in methanol (4.00 mL) and 1.0 N NaOH (aqueous) (4.00 mL) was heated to reflux at 80 'C for 2.5 h.

The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with dichloromethane(3X). The product was used for the next step without further purification. ESI-MS rnlz: 369(M UV retention time: 1.85 min.

Step 4: 3 -[(4-Chloro-benzyl)-ethylcarbanoylnethyl-amiflo] -pyrroli dine- I carboxylic acid tert-butyl ester -317- To a solution of 3-[carboxymethyl -(4-chloro-benzyl)-amino] -pyrrolidine- carboxylic acid tert-butyl ester (0.48 g, 1.30 mmol) in tetrahydrofuran (10 nL) was added EDCI (0.39 g, 1.95 mmol), HOBT (0.26 g, 1.95 mmol), and stirred for min., followed by the addition of N-methyl nmorpholine (0.43 mL, 3.90 mmol) and N-ethyl amine (0.1 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 18 h. Upon concentration, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate to ethyl acetate (100%).

ESI-MS m/z 396 (M UV retention time: 2.18 min.

Step 5: 2-[(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-N-ethyl-acetamide A solution of 3-[(4-chloro-benzyl)-ethylcarbamoylmethyl-amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.31 mmol) in dichloromrnethane cooled at 0 'C was treated with trifluoroacetic acid The resulting mixture was wamled to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI- MS m/z 296 (M UV retention time: 1.02 min.

Step 6: 2-[(4-Chloro-benzyl)-(1- {3-[7-(I-hydroxy- -methyl-ethyl)-11H- aza-dibenzo[a,d] cyclohepten-5-ylidene]-propyl }-pyrrolidin-3-y)-amino]-N-ethylacetamide To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-N-ethylacetamide (0.09 g, 0.31 nmol) in acetonitrile:water was added potassium carbonate (0.07 g, 0.51 mmol) and (E)-2-[5-(3-brorno-propylidene)-5,11-dihydro- 1 O-oxa- I -aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.095 g, 0.25 mm ol) and the resulting mixture was stirred at 50 'C for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate.

-318- The crude product was purified on silica using ethyl acetate. 'H-NMR (CDC13) 6: 0.90 (3H, 1.40(6H, 1.60 (1H, 1.85 (1H, 2.10-2.55 (8H, 2.90-3.10 (4H, m),3.25-3.40 (4H, 3.55 (2H, 4.95 (2H, 5.10 (2H, br, 6.10 (1H, t), 6.70 (1H, dd), 7.15-7.25 (1H, dd), 7.25-7.45 (4H, 7.55-7.75 (2H, 8.50 (1H, dd). ESI-MS m/z: 589 (M UV retention time: 1.42 min.

Example 554 {3-[(4-Chloro-benzyl)-(2-hydroxy-ethyl)-amino]-pyrrolidin-l-yl} propylidene)-5,11-dihydro-10-oxa-l-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol Step 1: 3-[(4-Chloro-benzyl)-(2-hydroxy-ethyl)-amino]-pyrrolidine- -carboxylic acid tert-butyl ester To a solution of 3-[(4-chloro-benzyl)-methoxycarbonylmethyl-amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.44 g, 1.15 mmol) in methanol cooled to 0 OC was added sodium borohydride (0.13 g, 3.45 mmol) and the resulting mixture was heated to 65 'C for 16h. Additional sodium borohydride (0.26 g, 6.90 mmol) was added to the reaction mixture and stirred further at 65 °C for 18h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate to ethyl acetate ESI-MS m/z :355 (M UV retention time: 1.27 min.

Step 2: 2-[(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-ethanol A solution of 3-[(4-chloro-benzyl)-(2-hydroxy-ethyl)-amino]-pyrrolidine-1 carboxylic acid tert-butyl ester (0.22 g, 0.6 mmol) in dichloromethane cooled at 0 °C was treated with trifluoroacetic acid The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product -3 19was used without any further purification. ESI-MS m/z :255 (M UV retention time: 0.34 min.

Step 3: 2 5-(3 f 3- [(4-Chl oro-benzyl)-(2-hydroxy- ethyl)- amino] -pyrroli din- 1l-yl) propyl iden 5, 11 -dihydro- I 0-oxa- 1 aza-dibenzof a,d cyclohepten-7-yl] -propan-2 -o 1 To a solution of 2-[(4-chloro-benzyl)-pyi-rol idin-3 -yl-amino] -ethanol 15 g, 0.6 rumol) in acetonitrile:water was added potassium carbonate (0.11 g, 0.8 mniol) and -bromo-propylidene)-5,11 -dihydro- 10-oxa-l1-azadibenzo[ a,d) cyclohepten -7-yJ ]-prop an-2-ol 15 g, 0.4 rumol) and the resulting mixture was stirred at 50 'C for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified on silica. 'H-NMR (CDCI 3 6:1.40 (6H, 1.60 (IH, in), 1.80 (114, in), 2.10-2.60 (8H, in), 3.20-3.40 (6H, in), 3.50 (2H, in), 5.20 (2H, br, 6.15 (1H, 6.70 (IH, 7.18-7.42 (7H, mn), 7.70 (1H, dd), 8.50 (IH, dd). ESI-MS nihz: 548 (M UV retention time: 1.26 rmin.

Example 555 3-[(4-Chloro-benzyl)-(1- 1-hydroxy- 1-methyl-ethyl)-] I H-I0-oxa- I -azadibenzo~a,d]cyclo hepten-5 -yli dene] -propyl) -pyrrol idin-3 -yl)-amino] -prop i oni c acid methyl ester Step 1: 3 -Methox ycarbony] -ethyl amIn o)-pyrrolidine- 1-carboxylic acid tert-butyl ester To a solution of 3-amino- I-N-Boc pyrrolidine (0.5 g, 2.68 inmol) and 3bromo propionate (0.49 g, 2.95 iniol) in DM (6.0 m.L) was added potassium carbonate (1.11 g, 8.04 inmol) and the resulting mixture was stirred at roonm temperature overnight. .The reaction mixture was concentrated and re-dissolved in di1chlorom ethane, Potassium carbonate was filtered off and filtrate was concentrated and crude product was used further in the next step. ESI-MS inlz 272 (M +s UV retention time: 1.28 muin.

-320- Step 2: 3-[(4-Chloro-benzyl)-(2-methoxycarbonyl-ethyl)-amino]-pyrrolidine-1carboxylic acid tert-butyl ester To a solution of 3-(2-methoxycarbonyl-ethylamino)-pyrrolidine-1carboxylic acid tert-butyl ester (0.73 g, 2.68 mmol) in dichloroethane (10.0 mL) was added 4-chlorobenzaldehyde (0.42 g, 2.95 mmol), sodium triacetoxy borohydride (1.71g, 8.04 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane /ethyl acetate to hexane/ethyl acetate (50%).'H-NMR (CDCI 3 8: 1.35 (9H, 1.80 (1H, 1.90 (1H, 2.40 (2H, 2.85 (2H, 3.00-3.80 (7H, 4.70(1H, d), 7.20 (4H, ESI-MS m/z: 397 (M UV retention time: 1.99 min.

Step 3: 3-[(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-propionic acid methyl ester A solution of 3-[(4-chloro-benzyl)-(2-methoxycarbonyl-ethyl)-armn no]pyrrolidine-l-carboxylic acid tert-butyl ester (0.08 g, 0.2 mmol) in dichloromethane cooled at 0 oC was treated with trifluoroacetic acid The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS mr/z 297 (M UV retention time: 1.05 min.

Step 4: 3-[(4-Chloro-benzyl)-(1-(3-[7-(1-hydroxy- l-methyl-ethyl)-1 aza-dibenzo[a,d] cyclohepten-5-ylidene]-propyl -pyrroli din-3-yl)-amino]-propionic acid methyl ester To a solution of 3-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-propionic acid methyl ester (0.06 g, 0.2 mmol) in acetonitrile:water was added potassium -32 1carbonate (0.056 g, 0.4 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,1 1 -dihydro- I 0-oxa- 1 -aza-dibenzo cyclohepten-7 -yl ]-prop an-2-oI (0.065 g, 0. 17 nirnol) and reaction stirred at 50 'C for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using ethyl acetate/m ethanol 'H- NMR (CDCl 3 5: 1.40 (6H, 1.60 (1H, in), 1.80 (1H, in), 2.10-2.60 (8H, in), 3.20- 3.40 (6H, in), 3.50 (2H, m; 2H, 5.20 (2H, br 6.15 (LH, 6.70 (IH, 7.18- 7.42 (7H, in), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS mlz: 590 (M UJV retention time: 1.5 1min.

Example 556 3-[4-(4-Chloro-phenyl)-3-(S)-methy]-piperazin- I -yl]-propylidene} I dihydro- I 0-oxa- I -aza-dibenzo[a,d~cyclohepten-7-yl)-propan-2-ol Step 1: 3 -(S)-Methyl-piperazine-l1-carboxylic acid tert-butyl ester Triethylamine (3g, 4.2 mL, 30 nimol) was added to a solution of methyl piperazine (2 a, 20 inmol) in dichlorom ethane (40 inL) followed by di-tertbutyl-di carbonate (4.8 g, 22 rnmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodiun sulfate.

The crude product was purified using a short plug of silica gel using hexane/ethy] acetate 'H-N4R (CDGI 3 8: 1.03 (3H, 1.45 (9H, 1.65 (IH, 2.35- 2.42 (1 H, in), 2.66-2.80 (3H, mn), 2.92-2.95 (1 H, in), 3.92 (2H, br ESI-M S mlz: 201(M+1).

Step 2: ChlIoro-phenyl) -3 ethyl -piperazine- 1 -carbox yli1c acid tert-butyl ester To a mixture of 4-chlorobroinoberizene (1.05 g, 5.5 mmol) and Methyl-piperazine-lI-carboxylic acid tert-butyl ester (I g, 5 mino]) in toluenie m.L) was added tris(dibenzylideneacetone) dipalladium(0) (0.057 g,0.063 rimncl), -322- BINAP 12 g,0. 19 mmol) and sodium-1-butoxide (2.02 g, 21 mmol). The resulting mixture was heated 1 10 'C for 20h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodiumn bicarbonate and brine and dried over magnesium sulfate. Column chromatography (10% ethyl acetate/hexane) provided 0. 79 g (5 1 of the title compound.

'H-NMIR(CDCI

3 5: 0.97 (3H, 1.48 (9H, 3.00-3.24 (3H, in), 3.32-3.38 (IH, in), 3.72-3.79 (2H, mn), 3.88-4.05 (1H, in), 6.81 (2H, 7.21 (2H, EST-MS mlz :3 11 UV retention time: 3.2 min.

Step 3: 3 4 -(4-Chloro-phenyl)-3(S)-methylpiperazin-1I-yl]-propylidene} 5,1 1 -dihydro-1 0-oxa- I -aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2oI 4 4 -Chloro-phenyl) -3 ethyl -piperazine- 1 -carboxylic acid tert-butyl ester (0.79 g, 2.6 iniol) was treated with 4M HCllDioxane (20 mL) at roorn temperature for 3h. The solvent was evaporated and the residue was taken up in dichoromethane and washed several times with saturated sodium bicarbonate. The combined organic phases were dried over sodium sulfate. The residue was carried to the next step without further purification.

To a solution of 4 4 -chloro-phenyl)-3-(S)-methyl-piperazine (0.56 g, 2.6 minol) in isopropanol (20 mL) was added 2,6-lutidine (0.305 mL, 2.6 inmol) and catalytic potassium iodide. This mixture was heated to 80 and then treated with 2-15-(3-bromo-propylidene)-5,l 1-dihydro-1I0-oxa-l1-aza-dibenzo[a,d]cyclohepten-7yl]-propan-2-ol (0.64 g, I .Ymmol), added in portions over 2h. The solution was then stirred at 80 *C for an additional 20 h. The reaction was concentrated in~ vacuo and purified by flash chromatography (100% dichloromethane to 2% miethanolI/di chi orom ethane) to yield the title compound 151 g, '1--NMR (CDCI3) 8: 1.0 (3H, 1.57 (6H, 1.79 1H), 2.25-2.52 (7H, mn), 2.66-2.69 (I1H, in), 2.98-3.12 (2H, in), 3.68-3.73 (11-H, mn), 5.32 (211I, br 6.17 (1lH, 6.82 (3H, 7.18-7.31 (4H, mn), 7.44 (1H, 7.56-7.60 (1H, mn), 8.50 (1H, dd). ESI-MS m/z: 504 UV retention time: 1.49 min.

-323- Example 557 2 {3-[4-(4-Chloro-phenyl)-3-(R)-methyl-piperazin- 1-yl] -propylidenle}-5,11 dihydro- 10-oxa- I-aza-dibenzo[a,d~cyclohepten-7-y])-propan-2-ol

IND

Step 1: 3-(R)-Methyl-piperazine-1 -carboxylic acid tert-butyl ester Triethylamnine (3g, 4.2 mL, 30 rnmol) was added to a solution of methyl piperazine (2 g, 20 niol) in dichloromethane (40 mL) followed by di-tertbutyl-dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichioromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate.

The crude product was purified using a short plug of silica gel using hexane/ethyl acetate 'H-N:MR (CDCI 3 8: 1.05 (3H, 1.45 (9H, 2.11 (1IH, 2.37- 2.44 (1 H, in), 2.66-2.79 (3H, ni) 2.93-2.96 (11H, mn), 3.93 (2H, br ESI-MS m/z: 201l(M+1).

Step 2: 4-(4-Chl oro-phenyl)-3-(R)-m ethyl!-piperazine- I -carboxyl ic acid tert-butyl ester To a mixture of 4-chlorobromobenzene (0.53 g, 2.75 mmol) and Methyl-piperazine-l-carboxylic acid tert-buty] ester (0.5 g, 2.5 rmol) in toluene mL) was added tris(dibeiizylideneacetone) dipalladium(0) (0.029 g, 0.032 rnmol), BINAP (0.058 g, 0.093 mm-ol) and sodiurn-t-butoxide (1.01 g, 10.5 mmol). The resulting mixture was heated I10 'C for 20h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Column chromatography ethyl acetate/hexane) provided the title compound.

'H-NM]4. (CDCL.J) 8: 0.98 (3H, 1.48 3.04-3.21 (3H, mn), 3.34-3.38 (1H, mn), 3.72-3.76 (2H, mn), 3.80-4.05 (1KH, in), 6.81 (2H, 7.21 (2H, ESI-MS m/z :3 11 UV retention time: 3.21 min.

-324- Step 3: {3-[4-(4-Chloro-phenyl)-3 -(R)-methyl-piperazin- 1-yl] -propyli dene} 5,1 1-dihydro- 10-oxa-l1-aza-dibenzo [a,djcyclohepten-7-yl)-propan-2-ol 4- (4-Chloro-phenyl)-3 ethyl -piperazine- I -carboxylic acid tert-butyl ester (0.36 g, 2.6 minol) was treated with 4M HCllDioxane (10 mL) at roomn temperature for 3h. The solvent was evaporated and the residue was taken up in dichloromethane and washed several times with saturated sodium bicarbonate. The combined organic phases were dried over sodium sulfate. The residue was taken to the next step without further purification.

To a solution of 4-(4-chl oro-phenyl)-3 ethyl -piperazine (0.2 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 m.L, 0.94 rnmol) and catalytic potassium iodide. This mixture was heated to 80 'C and then treated with 2-[5-(3-bromo-propylidene)-5, 1-dihydro-I 1 -oxa- 1 -aza-dibenzo~a,d)cyclohepten-7yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2h. The solution was then stirred at 80 'C for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichiloromethane to 2% methanol/dichloromethane) to yield the title compound.

'H-NMR (CDCI 3 5: 1.0 (3H, 1.57 (6H, 1 .72 1H), 2.25-2.55 (7H, in), 2.61-2.73 (1lH, ni), 2.96-3.17 (2H, in), 3.66-3.77 (1IH, in), 5.3 (2H, br 6.16 (1 H, 6.77-6.87 (3H, in), 7.17-7.31 (4H, in), 7.45 (1H, 7.59 (IH, dd), 8.51 (1H, dd).

ESI-MS m/z :504 UV retention time: 1.50 min.

Example 558 (1 -(4-Chloro-phenyl)-4- {3-[7-(l1-hydroxy- I-methyl-ethyl)-I11H-i 0-oxa-l1-azadi ben zo cyclohepten-S5-ylidenej -propyl I -piperazin-2 -yl)-aceti c, acid methyl ester Step 1: 4-(4-Chloro-phenyl)-3 -methoxycarbonylmethyl-piperazine-l1-carboxylic acid tert-butyl ester 4-Chlorophenyl boronic acid (1.08 gy, 6.97 inmol) and 3methoxycarbonylinethyl-piperazine-l1-carboxylic acid tert-butyl ester (0.9 g. 3.48 rnmol) were dissolved in dichioromethane. To this mixture was added copper -325acetate (0.63 g, 3.48 mmol), 4 A molecular sieves and pyridine (0.56 mL, 6.97 mmol) and the reaction mixture was stirred at room temperature for 72h. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate to hexane/ethyl acetate ESI-MS m/z 369 (M UV retention time: 2.97 min.

Step 2: (1-(4-Chloro-phenyl)-4- {3-[7-(1-hydroxy-l-methyl-ethyl)- 11H- 0-oxa-1aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperazin-2-yl)-acetic acid methyl ester 4-(4-Chloro-phenyl)-3-methoxycarbonylmethyl-piperazine- -carboxylic acid tert-butyl ester (0.19 g, 0.5 mmol) was treated with 4M HCl/Dioxane (10 rnL) at room temperature for 3h. The solvent was evaporated and the residue was taken up in dichloromethane and washed several times with saturated sodium bicarbonate.

The combined organic phases were dried over sodium sulfate. The residue was taken to the next step without further purification.

To a solution of 4-(4-Chloro-phenyl)-3-methoxycarbonylmethyl-piperazine (0.13 g, 0.5 mmol) in acetonitrile/water (10 mL) was added KCO 3 (0.2 g, 0.42 mmol) and 2-[5-(3-bromo-propylidene)-5,11 -dihydro-10-oxa- -azadibenzo[a,d]cyclohepten-7-yl]-propan-2-ol 0.16 g, 0.42 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated, partitioned between EtOAc/HO, and extracted with EtOAc The organics were combined, dried over Mg 2

SO

4 filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/ 50% hexane to 75% ethyl acetate/ 25% hexane to 100% ethyl acetate) to yield the title compound.

'H-NMR (CDCIl) 8: 1.57 (6H, 2.16-2.49 (8H, 2.78-3.01 (4H, 3.22 (1H, 3.54 (3H, 4.21-4.24 (1H, 5.29 (2H, br 6.19 (1H, 6.77-6.82 (3H, m), 7.17-7.30 (4H, 7.48 (IH, 7.58 (IH, dd), 8.51 (1H, dd). ESI-MS m/z 562 UV retention time: 1.63 min.

-326- Example 559 4-(4-Chloro-phenyl)-3,3-dimethyl-l- {3-[7-(2-morpholin-4-yl-ethoxy)- 11H-10-oxa- 1 -aza-dibenzo[a,d]cyclohepten-5-ylid ene]-propyl}-piperidin-4-ol To a solution of 5- {3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethylpiperidin- -yl]-propylidene) -5,11-dihydro- 10-oxa- 1 -aza-dibenzo[a,d]cyclohepten-7ol (0.15 g, 0.28 mmol) in DMF (1.5 mL) was added NaH(0.034 g, 0.84 mmol) and stirred for 20 min. at room temperature. 4-(2-Chloro-ethyl)-morpholine HCI (0.063 g, 0.34 mmol) was added and the solution was heated to 50 'C for 6h. The reaction was quenched with water and extracted with ethyl acetate The organics were combineddried over MgSO 4 filtered and concentrated, then purified by Biotage flash chromatography (5-10% methanol/dichloromethane) to yield the title compound (0.050 'H-NMR (MeOD) 6: 0.73 (3H, 0.85 (3H, 2.39-2.90 (1IH, 3.29-3.31 (3H, 3.69-3.72 (4H, 4.1 (2H, 5.20 (2H, br 6.18 (1H, 6.74-6.79 (2H, 6.89 (1H, 7.27-7.30 (2H, 7.43-7.47 (3H, 7.79 (1H, dd), 8.46 (1H, dd). ESI-MS m/z 604 UV retention time: 1.20 min.

Examples 560 571 General Procedures: The N-BOC protected amine (0.0565 0.6911 mmol) was subjected to IN NaOH, extracted with dichloromethane, washed with brine, dried over magnesium sulfate and filtered. The solution was evaporated via steady N 2 airflow. To the residue was added the corresponding bromide (0.8 eq), potassium carbonate (1.0 eq), 11 mLs of acetonitrile and 2.75 mLs water. The resulting solution was agitated via and orbital shaker for 48 hours. The vials were transferred to a heating plate and stirred at 500C for 48 hours. The solutions were quenched with a 1:1 brine/water mixture, washed with IN NaOH, dried over magnesium sulfate, filtered and concentrated via steady N 2 airflow. The residue was dissolved in dichloromethane and subjected to column *327chromatography (Si0 2 Biot age 1 2M column, 95% dichloromethane/5 %methanol with 0. 1% tri ethyl amine) to afford the desired product.

Example 560 N-(4-Chloro-benzyl)-N-(1- -hydroxy-1 -methyl-ethyl)-I11 H-I0-oxa- I-azad ibenzo [a,d ]cycl ohepten- 5-ylid ene] -propyl -pyrrolidin-3 -yl)-2 -m ethyl -butyrami de To a heated (77 0 C) stirring solution of I -(4-chloro-phenyl)-2-imidazolidin- 1 -yl- 4-methy]-hexan-3-one (110mg, 0.374mmo1), 2,6-lutidiene (130 p1, 11.229nmmol) and mLisopropanol was added 2-[5-(3-bromo-propylidene)-5,1 1-dihydro-l 0-oxa-I-azadibenzo[a,d]cyclohepten-7-yl]-propan-2-o (70 mg, 0. 187 mmol) portion-wise over a 30 minute period. The resulting solution was monitored using thin layer chromatography and allowed to stir at 77 0 C for 16 hours. The solution was concentrated in vacuo at 35 0 C. The residue was dissolved in ethyl acetate and subjected to column chromatogaphy (S'0 2 Biotage 1 2M column, gradient clution 100% ethyl acetate 4~ 92% ethyl acetate/8% methanol with 1 triethyl amine) to afford 54 mg of 1 -(4-chloro-phenyl)-2-(3- -hydroxy- 1-methyl-ethyl)- I1I H- I 0-oxa- I -irnidazolidin- 1 -yl)-4-merhyl -hex an-3one as a tan foam. LC/MS: tU, 1.68 nin, 588 amu.

Example 561 N-(4-Chloro-benzyl)-N-(1 1-hydroxy-1 -methyl-ethyl)-I 11H-I 0-oxa-l1-azadibeazo[a,d]cyclohepten-5-ylidene]-propyl)}-pyrrolidin-3 -yl)-acetanmide.

LCIMS: tuv 1.66 min, m/z 546 amu. 'H NTMR ((CD 3 2 S0): 8 8.54 7.70 (1 7.44 7.28 7.13 6.76 6.12(1 5.2 1 (3H,m), 5.00 4.63 4.50 3.12 2.39 2.27 2.18 1.90 1.60 1.43 1.21 0.92 (1IH,m).

Example 562 -328- N- Chi oro-benzyl)-N-( 1- 3 7 -hydroxy- 1 -methyl -ethyl)- I1 H-i 0-oxa-lI-azadibenzo[a,d] cyclohepten-5-yli dene] -propyl) -pyrrolidin-3-yl)-isobutyramide.

LC/MS: t, 1.56 min, M/i 574 amu.. 'H NMR ((CD 3 2 S0): 6 8.51 7.66 7.42 7.25 7.12 7.04 (1IH,d), 6.74 (1IH,d), 6.11 5.18 4.98 4.91 4.48 3.04 2.40 2.14 1 .40 1.04 0.90 (3H,m).

Example 563 N-(4-Chloro-benzyl)-N-(1- 1-hydroxy-l1-methyl-ethyl)- I IH- -pyrrolidin-:3-yJ)-propionami de.

LCIMS: tuv 1.49 min, 560 amu. 'H NMR ((CD 3 2 S0): 5 8.48 (1IH,d), 7.64 (I 7.40 7.27 7.07 6.72 (1 6.10 (1 5.1 7 (3 H,rn), 4.96 4.52 2.3 5 2.12 1.52 (1IH,m), 1.34 1 .00 0.89 (IH,m).

Example 564 Cyclopentanecarboxylic acid (4-chloro-benzyl)-(1- {3-[7-(l1-hydroxy- I1-m ethyl -ethyl)- 1 H- 10-oxa-l1-aza-dibenzo[a,djcyclohepten-5-ylidene]-propyl -pyrroildin-3-yl)-arnilde.

LC/MS: zu, 1.73 min, NI/z 600 amu. 'H NMR ((CD 3 6 8.50 7.65 7.40 7.24 7.11 7.02 6.72 6.11 (1H,m), 5.14 4.96 (1IH,s), 4.82 (1IH,m), 4.64 (211,m), 4.46 (1 3.13 (1 H,ri), 2.34 2.19 2.06 1.71 1.57 1.39 (6H,s).

Example 565 Cyclohexanecarboxylic. acid (4-chloro-benzyl)-(. 1- -hydroxy- I1-methyl-ethyl)- 1 I H-i 0-oxa-l1-aza-dibenzo[ad]cyclohepten-5-ylidene] -propyl) -pyrrolidin-3 -yl)-amide.

LC/MS: tu, 1.79 min, m/z 614 amu. 'H NMR ((CD 3 2 S0): 8 8.48 (1Hi,d), 7.64 7.39 7.23 7.10 7.00 6.69 6.08 (1H,m), -329- 5.13 4.95 4.58 4.43 2.73 2.34 (3H1,m), 2.12 1.67 1.38 1.29 1.03 Example 566 2 -Ethyl -hex anoic acid (4-chloro-benzyl)-( 1- I-hydroxy-l1-methyl-ethyl>- Ii H- oxa-l1-aza-dibenzo[a,djcyclohepten-5.ylidene]-propyl) -pyrrolidii-3 -yl)-amide.

LC/MS: tuv. 1.92 min,

M

/z 630 amu. 'H NIMR ((CD 3 2 S0): 5 8.44 7.61 (1 7.35 7.20 7.11 (1 7.02(1 6.68 6.05 5.10 4.91 4.61 4.44 2.66 2.32 2.07 1.46 1.34 (611,s), 1.17 0.94 0.75 (4H,rn), 0.60 (1IH,m).

Example 567 I -(4-Chloro-benzyl)- 1-hydroxy- 1-methyl-ethyl)-I 11H-i O-oxa-l1-azadi benzo[a,d]cyclohiepten-5-ylidene]-propyl }-pyrrolidin-3-y])-3-i sopropyl-urea.

LC/MS: tu, 1.53 min, m/iz 589 amu. 'H NMR ((CD 3 )2SO): 6 8.50 (IH,rn), 7.69 (1 7.40 7.32 7.19 6.71 6.09 5.17 (21i,m), 4.95 4.41 4.12 3.69 (IH,rn), 3.05 2.78 (2H,rn), 2.58 2.26 1.91 1.61 1.38 1.16 (1H,rn), 0.92 (6H,m).

Example 568 1 -(4-Chiloro-benzyl)-3-cyclohexyl-l1-(1- 1-hydroxy-l1-methyl-ethyl)- 111-1 0-oxa- I -aza-dibenzo~a,d]cyclohepten-5-ylidene]-propyl) -pyrrolidin-3-yl)-urea.

LC/MS: tu 1.70 min, 629 amu. 'H NlvfR ((CD 3 2 S0): 5 8.50 7.69 (I 7.40 7.32 (4H,rn), 7.18 6.70 6.10 (IH1,m), 5.16 (211,m), 4.95 (1IH,s), 4.43 4.02 (1IH,m), 3.14 (1 2.71 2.22 (3H,in4 1.8 7 1.62 1.38 0.98 (8H,m).

Example 569 -330- 1 -(4-Chloro-benzyl)-3 -ethyl- I 3- 1-hydroxy-l1-methyl-ethyl)- I 1H- 10-oxa- I -azadibenzo [a,d~cyclohepten-5 -ylidene]-propyl -pyrrolidin-3 -yl)-urea.

LC/MS: tuv 1.46 min, m/z 5.75 axnu. 'H NMIR ((CD 3 2 S0): 8 8.52 (1IH,d), 7.70 (I1H,d), 7.43 (2H,ni), 7.3 3 7.23 (1 H,dd), 7.17 6.73 (1IH,d), 6.13 (1IH,t), 5.19 4.98 (1IH,s), 4.43 4.20 (1 2.96 2.71 2.26 1.95 (2H,rn), 1.61 1.41 1.19 1.01 0.85 (2H,m).

Example 570 1 -(4-Chloro-benzyl)- I-hydroxy- 1-methyl-ethyl)-I 11H-I 0-oxa- I-azadibenzora,d] cyclohepten-5-ylidene]-propyl} -pyr-rolidin-3-yl)-3-( 1,1 ,3,3-tetramethylbutyl)-urea. LC/MS: tuv 2.05 min, m/z 659 amu.

Example 571 N-(4-Chloro-benzyl)-N-(l -hydroxy-l1-methyl-ethyl)-l 11H-) O -oxa- I -azadibenzo [a,d )cyclohepten-5-ylideine]-propy -pyrrolidin-3-yl)-methanesulfonarnide.

LC/MS: tu 1.49 min,

T

/=582 amu.

Additional compounds of the invention can be prepared by the schemes set forth in Figures 1 5, 7, 8A-8C, 9A-9E, I OA- I Od and 12-19 and by the procedures described herein.

Those skilled in the art will be able to recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Documlet 1-23)0 1207 330A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (34)

1. 2-naphthyl, 1 -antbracyl, 2 -anthracyl, N-imidazolyl, 2 -ixnidazolyl,
2. 4-imidazolyl,
3. 5-imidazolyl, 2-thienyt, 3-thienyl, 2-furanyl, 3-uranyl, 2 -pyrrolyi, 3-pyrrolyl, 2-pyridyl, 3-pyriclyl. 4-pyridyl, 2 -pyrimidyl, 4-pyriniidyl, 5 -pyrimidyl, 3 -pyridazinyl, 4-pyridazinyl, 3 -pyrazolyl, 4-pyrazolyl, 5-pyrazolyi, 2 -pyrazmnyl, 2-thiazolyl, 4-thiazolyl, 2-oxazolyi, 4-oxazolyl, 5-oxazolyl, temahycironiaphthyl, 2 -benzothienyl, 3-benzothitunyl, 2 -benzofuranyl, 3 -beazolijranyl. 2-indolyl, 3-indolyl, 2 -quinolinyl, 3-quinolinyl, 2-benzorihiazoly], 2 -berizooxazolyl, 2-benzirnidazolyl, I -isoquinolinyl, 3 -quinolinyl, 1 -isoindolyl, 3 -isoincioly], 8cridinyl, 3 -benzisoxazolyl, benzocyclopenryl, benzocyclohexy- said non-arornatic heterocyclic group is a five to eight-mnemrbered non- aromatic ring which contains one or more heteroaTorns independeutly seleced from the group consisting of nitrogen, oxygen or sulfur; said sub stituted ahphatic group is substituted with one or more sabstituents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromnatic group electron withdrawinig group, halo, azido, -CN, -CONR 2 4R.23 -NRAR2', -S(O) 2 NR 4 R 25 -SQ3H guanidino, OXalo, -C(=NRw)NR 2 'R7- -NR'O, _(Oy,(CH)C(O)_NR*2R2 -33;- -(OJ.-t(CHZ),.NHC(0)O-R2u, -Q-1U, -Q-(a~ipharic group),-Q-(substitu 1 ed aliphatiC group), -Q-(aryl), -Q-(arornatic group), -Q-(SubStlIUtad aromatic group), -Q(CH,),-(subsrituted or uflsubStituied aromatic group), -Q_(non-arornatjc lihcierocyclc goup) or -Q(C1 2 ),-(aon-aromatic heterocyclic group); sa~id substituted non-armatic heterocyclic ring Is substituted with one or more substituents Selected from the group consisting, of electron withdrawingo. group, halo, azido, -CN, _CONR*-,Rz5, -NR ,Rz, _OS(0)2-Np. 2 4R225 -S (O)2NR 2 4R2' -S0 3 1i, guanidmno, oxalo, -C(=NRIo)NR2'Rz2, =NqRw, -(OX -(CH,),-NHiC(Q)O.R2a Q-H, -Q-(aliphatic group), -Q-(subsrirured aliphatic -group). -Q-(aryl), -Q-(iiromatic group), -Q-(substituted aromaj gr' -Q-(CHz)P-(substituted or Uflsubsuruted aromatic group), -Q-(non-aromazc heterocyclic group) or -(non-ai-omaric heterocyclic group), sdid substituted aromatic group, substituted benzyl group, Rincv A when substituted arnd Ring B when substituted, are! substituted with one or more substituents ScIced from the -oup consisp.icg of electron withdrawing group, aliphatic group, substiruTed aliphatic group, aromatic group. substitUted&Mrn-iatic group, halu, £lzido, -CN, -C0NR 24 R 25 NR'Rzs OS(O) 2 N-R 2 4R -S(O),NR 2 "R23 -SO3H-, guanidino, oxalo, =N6, -1).OC(O)Ro 2 2 ),NC(O)O.Ru -Q-(aliphzttic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic g roup), -Q-(substitred aromrati c gro up), ('IijP-(:iubsriute or uis ubstitrued4 aromatic group), -Q -(non-aromatic hieterocyclic group) or -Q-(CH,)P-(non..a.omatic heterocycic group); Q is -0S(OX2.- -NHS(0y,-, -C(NR 2) NHNm... -NHNHCNR 2 -NR7 4 C(0J.. or R 2 0, R 2 1 and R2' are independently -1-L an aliphatic goup, an arorr atic group, a non-aromaic heterocyclic group, iNC(O)-O-(aizphatiC LToup), -335- -NHC(O)-O-(aromatic group) or .NHC(O)-O-(non-aomaic heterocyclic group) or R7-' and R 2, taken toogether with the nitrogen atom to which they are bonded, can form a substituted or uflsubstruted non-aromatic heterocyclic ring; R23 is an aliphatic group, a beazyl group, an aryl group or nonl- aromatic heterocyclic group; R' 4 and RWs are independently an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R 2 1 and R 5 taken together with the nitrogen atom to which they are bonded can form a substitu.ted or unsubstituted non-aromatic heterocyclic ring. R'O is a -OH, an aromatic group or a substituted aromatic group. T is zero to three; ui is zero or one; p is ont: to five. 2. The compound of Claim 1 wherein Ring A is unsubstituted and B is substituted para to the carbon atom of ring B that is bonded to X, in ring C, and Z is represented by the structural formula. -335- wherein WO 0 is -011i, -COOKI -NOr, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR 2 4 R 25 -CONR 4 R 2 -NR 3 'C(O)-(aliphatIc group), -NR 24 C(O)-(subsrjrated aliphatic group), -NR 24 S(o) 2 -(aliphalic group), -NTR*S(o)2_(SUbStiTutcd aliphatic group), -C(O)O-(aIphaic group), -C(O)O-(substjtuted aliphAtic group), -C(O)-(aliphatic group), -C(O)-(sUbStjrUyed aliphatic group), -O-(aliphatic group), -O-(substituted aliphatic group), -0-(arorzatic group), -O-(subsrituted aromatic group), an electron withdrawing group. -(O).-(CHA-C(O)ORo, 20 or {(O)u4(CH 2 Rzo, R7-1 or R2are independently an aliphatic group, a substitutedt aliphatic group, an aromatic -group, a substituted aromnatic group Or a non- aromatic hcrerocyclic group: or WI? and RI, taken together with the nitrogen atom to whtich they are bornded, form a non-aromatic heterocyclic rng,; R 24 and R 2 5 are independently an aliphatic group or a substitu.ted aliphatic group; u is zero or one; and t is an integer from zero to 3. 3. The compound of Claimn 2 wherein M is CR'R2; R' is -11 or -OH; and R 2 is a substituted aromatic group, wherein said substituted aromatic group is 4-halophenyl. 4. The compound of Claim 3 wherein said 4-halophenyl is selected from The group consisnng of 4-chiorophenyl, 4-bromnophenyl and 4.fluorophenyl. The compound of Claim 4 wherein said 4-halophenyl is 4-chlorophenyl.
4. 6. The compound of Claim 3 wherein X, is -CH 2 -337-
5. 7. The compound of Claim 2 wherein at least one of Rm, R 71 R 7 and R' is an aliphatic group or a substititued aliphatic group; wherein said aliphatic group is a CX- 6 alkYl and said substituted aliphatic group is aC 1 -Cc, alkyl substituted with a subslitutenT selected from the group Consisriuig of 1 ,C(O)ORz, and -O-(aliphatic group); t is zero To three; U is Zero Or One; and R 20 is C 1 -C 6 alkyl.
6. 8. The compound of Claim 7 wherein R U and R" 2 are both -H; R 72 and R 7 3 are independently selected from the group c61-isisting of C, -C 6 alkyl and subsrirued C 1 alkyl.
7. 9. The compound of Claim 8 wherein R72is -CH.. A method for treating a disease associated with aberrant leukcocyte recruitment, aberrant leuk-ocyte aciivation or aberrant leukcocyte recruitment and acTivation, comprising administering to a subject in need t~hereof an effective amount of a compound according to Claimr 1.
8. 11. A Pharmaceutical composition comprising a compound according to Claim I and a physiologicaily acceptable carrier. -338-
9. 12. A comnpound having the formula: R70R7 S=S(CH N M ,7 or physiologically 2icceptable sa~t thereof, wherein; n is one to four; M is >RR1 R, is-O1i; R is 4-halophenyl; R7 0 and R 7 1 are -K and R,7 and R73 are -CH 3 or R 7 and R' are -CH 3 and R 7 2 and R7' are H-; Zi CN X, is and W' 0 is selected from the group consisting of. -339- R On an
10. 13. The compound of Claim 12 wherein Rdw is
11. 14. The compound of Claim 12 wherein said 4-halophenyl is selected from the group consisting of 4-chiorophenyl, 4-bromophenyl and 4-fluorophenyl. The compound of Claim 14 wherein said 4-halophenyl is 4 -chlorophenyl.
12. 16. The compound of Claim15 wherein R" and R" are RI and R' are -CH, n is two, and the compound has the structure: -340-
13. 17. The compouLnd of Claim 16 wherein R40 is n
14. 19. A method for treating a disease associated with aben-ant leukocyre recuitmneni activation Or reecruitmnent and activatjoa. Comprising administrinng to a subject in need thereof an effective amount of a compound of Claim 12. 19. A mcchod for treating a disease associaled with abezm~ni leukOcYre recruirmenT activation or recruiunent and activaion, Comprising administering to a subject in need thereof an effective amount of a cotnpoundof Cai 17.
15. 20. A pharmaceutical composition comprising a compound of Claim 12 and a physiologically acceptable carrier.
16. 21. A compoundj having the structre: R HO~IhI' N 0 or a physiologically acceptable salt thereof, wherein is 4-halophenyl; and R" 0 is selected from the group consisting of- -341- -,J N on hand
17. 22. The compound oFClaijn 21 wherein R 40 i
18. 23. The compound of Claim 21 whereini R 2 is selected from the group consisting of 4 -chlorophenyi, 4-broinophenyl and 4 -fh.uorophenyi.
19. 24. The compound of Claim 23 wherein RVis 4 -chlorophenyl. The compound of Claim 22 wherein W 2 is 4 -chlorophenyl.
20. 26. A pharmaceutical composition comprising the compound of Claim 21 and a physiologically acceptable carrier.
21. 27. A method for treating a disease associated with aberrant leu]kocyme recruitment, aberrant leukocyte activation or aberrant leukocyre rcruiitmnt and acrivationL, comprising administering to a subj ect in need thereof an effective amnount of a coxnpo und of Clain 2 1.
22. 28. A method for treating a disease associated with aberrant leukocyte recmitentm aberrant leukocyte activation or aberrant leukocyte recruitment and acrivatioo, -342- COMPrising udnlinisteng to a subject in need thereof an effective amuount of a comrpound of Claim 29 The method of Claim 27 or Claim 28 wherein said disease is selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfison injury, diabetes mellirus, psoriasis, multiple sclerosis, inflamnmatry bowel diseases, rejection of a transplanted organ or rissue, graft versus host disease, allergy and asthmai. The method of Claun 29 wherein said disease is multiple sclerosis.
23. 31- The method of Claim 29 wherein said disease is arthrtis, and said arthuris is rheumatoid arthritis.
24. 32. A compound having the formula: -rS k 4 XqT- or physiologically acceptable salt thereof; wherein: n is an integer from one to four, M is >NR 2 -O-CR'R 2 or -H-RR-- q' is an integer from zero to three; q' iszero or one; RIis -OH, -N 3 a halogen, an aliphatic group, a substituted aliphatic group, an axninoalkyl group, -O-(aliphatc group), -O-(substired aliphatic group), -SH, -S-(aIiphatic group), -S-(substited aliphatic group), -OC(O)-(aliphaTic grou.p), O0-C(O)-(substitu~ed aliphatic group), -C(O)O-(aliphaTic grouip), -C(O)O-(substituted aliphatic group), -COOHi, -CN, -343- -CO-NR 3 R, -NRiR 4 or R' is a covalent bond between the -ring atom at M and anl adjacent carbon atom in the rig which contains M; R7 is -OH, a halogen, an acyl group, a substituted acyl group. -N'RsRe- an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a nion-ar-omatic heterocyclic group, a substituted non-aromatic heterocyclic group, -O-(subszitured or unsubstituted aromatic group) or -O-(substiruted or unsuibstiruted aliphatic group); R' and Rb are independently -HL an acyl group, a substituted acyl group, an aliphatic group a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzy] group, a substituted beuzyl group, a non- aromatic heterocyclic group or a substituted non-aromatic hetrocyclic group. or R' anda R 2 R 3 and R4, or R' and R* taken together with the atom to which they are bonded, formn a substituted or unsubstjruted non-aromaTic carbocyclic or heterocyclic ring; Z is: X, is -CHr 2 -S-CM 2 O0CHi 2 -CH 2 _C11 2 -S0-CHZ-. -CH 2 -S(0)2-CH2-, -CHz-S(O) 2 -CH=CH-, a bond, or CNT,- is an aliphatic group, a substituted aliphatic group, an aromatic group, a substirured aromatic group, a benzyl group or a substituted berizyl group; said acyl group is an aliphiatic carbionyl, aromatic carbonyl, aliphatic sulfontyl or aromatic sudfonyl said aliphatic group is a CCC6 alkyl, alkenyl. or alkynyl; -344- said atomatic group is selected from the group consisting of phenyl, 1 -naphthyl, 2-naphthyl, I -3anthracyl, 2-anthracyl, N-irnidazolyl, 2 -imidazolyl, 4 -irnidazolyl, S-inidazolyl, 2-thienyl, 3-cbhienyl. 2 -flirayl, 3-furmyi, 2-pyrrolyl, 3 -pyrrolyL, 2 -pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrirnidyl, 4-pyrimidyl, 5-pyridyl, 3 -pyridaziy!, 4-pyridazinyl, 3 -pyrazolyl, 4 -pyrazolyl. -pyrazolyl, 2 -pymuzinyl, 2-tliiazolyl, 4-thiazolyl, S-thiazolyl, 2 -oxazolyL 4 -oxazolyl, 5-oxazoly1, retrahydronaphyhyl, 2 -benzothenyl, 3 -benizothienyl, 2 -benzofuranyl, 3-benzofuranyi, 2-indolyl, 3-inckly), 2 -quinoliny), 3-quinolinyl, 2-benzorthizzoly], 2-benzooxazolyl, 2 -benzimidazolyl, I-isoq uioli i, 3 -quinolinyj, I-isoiadolyl, 3 -isoirgdolyl, acridinyl, 3 -benzisoxazolyl, benzocyclopentyl, ben~zacyclohexyJ; said non-=rmaiic heterocyclic group is a five To eight-membred non- aromatic ring which contains one or more hereroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; said substituted aliphatic group is substituted with one or mnore substituents selected from the group consisting of oxo group, epoxy group, flop- aromatic heterocyclic rin, benzyl group, substituted benzyl group, aroraic group or substituted aromatic group electron withdr-awing group, halo, azido, _CN, -c0NR 24 R 25 _NR2 4 R7-' OS(O) 2 NR 2 R" -S(O)2NR 2 j 4 R5 _So guanidino. oxalo, -C(=N-RI')NR 2 R 22 =NRZu -(OX,-(CHO,-C(O)OR group), -Q-(aryl), -Q-(aroinatjc group), -Q-(substituted aromatic group), -Q-(CHz)-(substituted or unsubsitured aromatic group). -Q-(non-arurmatic heterocyclic group) or -Q(CHz)p-(non..azmaric heterocyclic group); said substituted nonl-aromatic heterocyclic ring is subsriture4 with one or more substiruents selected from the group consisting of electron withdrawing group, halo, azido, -CN, -CONR NR 5 -NR 2 _OS(O)ZNR 4 R 2 2 1NRR5, -SO 3 5H, guanidino, oxalo, -C(-=NR")NR 2 LRZ2 -=pR 6 0 -(OX._(CH 2 1 C(o)oRP2o, _()u(CH 2 )'_NHC(o)o..R2U' -Q,-(aliphaic gru)--sbbue dliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(subsjnutecj aromatic group), -345- -Q-(C~zJp-(substituted or unsubstilated aromatic group), -Q-(non-aromatic heTCrocycliC group) or -Q-(CH,)F,-(non-aromatic hieterocyclic group); said substituted aromatic group and substituted benzyl groupar substituted with one or more Substuents selected from the group Consisting of electron withdrawing group, halo, azido, -CN, _CONWR 2 4 R, NrW 4 -OS(O)2NRI7'. -S(O) 2 NR 2 ;R 25 -SO 3 H, guanidino, oxalo, -C(=NR6)NWzKRzz, group),-Q-(substiluted aliphatic group), -Q-(aryl), -Q-(aromnatc group), -Q-(substiruied aromnatic group), Q-(CHz)-(subsrituted or unsubstiluted. aromatic groap), -Q-(non-aromatic heterocyc-lic group) or -Q-(CH2)p-(non- aromatic heterocyclic group); Q is--_S- 1 -OS(O) 2 -OC(O)NH-, -NH-C(O)-N~H, -S(O)2NHi-, -C(NR2 R)NHNH-., -NHNHC(NR 3 or R 2 1 and R 2 2 are independently an aliphatic group, an aromatic group. a non-aromatic heterocyclic group. -NhC(O)-O-(aliphatic group), -NHC(O)-O-(aironiaric grou p) or -NHC(O)-O-(nonaomaric heterocyclic group) or R 2 and R2-, iaken ogether with the nitrogen atom to which they are bonded, can form a substituted or unsubShitttted nion-aromatic heterocyclic ring; R' is an aliphautc group, abeazyl group, an aryl group or non- aromatic heterocyclic group; R 2 4 and R7- are independently -OH, an aliphatic group, a substituted aliphatic group, a beuzyl group, an aryl group, non-aromatic heterocyclic group or R 2 and R' taken together with The nitrogen atom To which they are bonded can form a substituted or unsubstirured non-aromatic heterocyclic ring; R~ 60 is a -OH, an aromatic group or a substituxed aromatic broup; r is zero to three; u is zero or one: p is one to five; and -346- R'O is selected~ from the group consisting of NOO cooH CICccli COOH COOH COOH zL gZ OH -C H 33 The compound of Claim 3)2 wherein: q' is one; q is onc; M is >~CR&R 2 RLis or -OH; and RI is a subSTituted aromatic group.
25. 34. The compound of Claim 33 wherein R 2 is phenyl substituTed with a halogen- The compound of Claim 34 wherein V 2 is 4-chiorophenyl.
26. 36. The compound of Claim 35 wherein n X, is -CH 2 and R 1 is -01- -347-
27. 37. A method for treating a disease associated with aberrant leukocyte recruuflent, activation or recruitment and activation, comprising adinisering To a subject in need thereof an effective amount of a compound of Claim 32.
28. 38. A pharmaceutical composition comprising a compound~ of Claim 32 and a physiologically acceptable carrier.
29. 39. A compound having the formula: (CH~- R 2 or physiologically acceptable szlt thereof, wherein: IC0 n is one to four; R' is -OH, a halog-en, an acyl group, a substituted acyl group, -NR 5 R 6 an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a beazyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, -O-(substituted or unsubstitured aroin~iric group) or -O-(substituted or Unsubsrtuted aliphatic group); R' and R' are independently an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or and R" taken together with the atomn to which they are bonded, form a substituted or unlsubstinsred non-aromatic carbocyclic or heterocyclic ring; Z is- -348- -NRa,-C a bond, or -C0-NR,,- R, is -K-I an aliphatic group, a substituted aliphatic group. an aromatic group,-a substituted aromatic group, a benzyl group or a substituted bvnzy1 group; Ringc.s A and B are independently unsubstited or substituted; Said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfony]; said aliphatic group is a alkyl, alkenyl or alkynyl; said aromatic group is selected from the group consisting of phenyL, I -naphrhyl, 2-naphthyl, I -anthracyl, 2 -anthracyl, N-imidazolyl, 2 -iuzidazolyl, 4-imidazolyl, 5-irnidazolyl, 2-rhienyl, 3 -thienyl, 2-ftranyl, 3-furanyl, 2 -pyrrolyl, 3 -pyz-rolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrir-Ldyl, 4 -pyrinuidyl, 5-pyrirnidyl, 3 -pyridazinyl, 4 -pyridazinyl, 3 -pyrazoiyl, 4-pyrazolyL, 2 -pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazoly!, 2 -oxazolyi, 4-oxazolyl, 5-oxazolyl, Terrahydronaphthyl, 2-benzothienyl, 3 -beazothjenyl, 2-benzofurauyi, 3 -benzofuranyl, 2-incdolyl, 3-indolyl, 22-quinolinyL, 3 -quinolinyl, 2 -benzothiazolyl, 2-benzoaxazolyl. 2 -benzimidazolyl, I -isoquinolin, 3 -quinolinyl, 1 -isoindolyl, 3 -isoindolyl, acridinyl, 3 -benizisoxazolyl, berlzocyclopentyl, benzocyclohexyl; said nlon-aromatic heterocyclic group is a five to eight-mnemnbered non- aromatic ring which contains one or maore heieroa=5 independently selected from the group consisting of nitrogen, oxygen or sulfur, -349- Said substituted aliphatic group is Substituted with one or more substituens selected from the group constrmg of ox, group, epoxy group, non- aromatic heterocyclic ring, benzy] group, substituted benlzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, -CN, .CONR 4 Rz,, -NR 2 "R 2 5, -Q(O 2 NSR 2 5, PS(O 2 4 pZ S~igai oxalo, -C(=NR-)N2LR2, group), -Q-(aryl), -Q-(aromatic group), -Q-(substiyuted armatic group), -Q-(CHi;)p-(substita.Ied or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CIH 2 ),-(non-arornatic heterocyclic group); said substituted non-aromaric heterocyclic ring is substituted with one or more subsuLients selected fromn the group consisting of electron Withdrdwing group, halo, aziclo, -CN, -CONR 24 R, _NW 2 4 R1 5 -S(O),.NR4RZS, -SO 3 Ii, guanidino, oxalo, -C(=NR)NRZR7-2, -NR6O -Q-(ahphd-ic gru)--susiue aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substitutvd aromatic group), -Q-(CIHz)p-(substituted or unsubstittured aromatic group), -Q-(non-aromatic heterocycbc group) or -Q-(CHz),(nionaomatic heterocyclic group); said substituted aromatic group, substituted benzyl group, Ring A when substured and Ring B when substituted, are substituted with one or more substiruents selected fromn the group consisting of electron withdrawing group, halo, azido, -CN, OS(0) 2 NMW5, -S(O)zNR 2 4" 2 5 -SQIH, guaaidino, axala, C(-NR)NR 2 jR~z, -NcO, -Q-(aliphatic group), -Q-(substirUred aliphatic group), -Q-(axyl), -Q-(aromaric group), -Q-(substituted aromatic group), -Q(CH,,-(su.bstiruted or unsubstiruted aromatic group). -Q-(flon-aromatic heterocyclic group) or -Q-(CH,)p-(non-aromatic heterocyclic group); -350- Q is C(O) -NHIC(O)-, -OC(O)Nli-, -NI-S(0), 2 _C(NI-. 23 )NHNH-_, -NjiNHC(NR? 3 -NRC(O)- or -NR 24 S(OX R20, R 2 I and R 22 are independently -HK an aliphatic group, an axro~natjc gro up, a non-aromatic heterocyclic grouip, -NHjC(O)-O-(aliphaic group). -NHC(O)-O-(aromaijc group) or -NIJC(O)-O-(noriaromajic heterocyclic group) or and R71, taken Together with the nitrogen atom 1o which te r odd can form a substituted or unsubstiluted non-aroma tic heterocyclic ring; R 2 is an alipharic group, a benzyl group, an aryl group or non- aromatic heterocyclic group; R2' and R 25 are independently -OH, an aliphatic group, a substituted aliphAtic group, a benz:yl group, an aryl group, non-aromatic heterocyclic group or R-4 and Rz' taken together with the nitrogen atom to which they are bonded can fozmn a subsTituted or unsubsrtred non-aromatic heterocyclic ring; R' is a -OH, -Nlf,, a~n aromatic group or a substituted arormatic group; T is zero to three,- U is zero or one; p is oue TO five. The cotnp ou.nd according to Claim 3 9 wherein R' is -NR'.
30. 41. The compound of Claim 40 wherein: R'is aliphatic group or substituted aliphatic group; and R' is ben.Lyl or substituted benzyl; or R 5 and R' taken together with the atom to which they are bonded. form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
31. 42. The compound of Claim 41 wherein R' is ethyl, and RW is substituted benzy], wherein said substituted benz-yl is substituted with a halogen. -351-
32. 43. A method for treating a disease associated with aberrant leukocyte recrujrrnenl actiatio or ecrutmen and atiton, compris*n administering to a subject in need thereof an effective amount of a compound according to Claim 39.
33. 44. A pharmaceutical composition comprising a compound according to Claim 39 and a physiologically acceptable carrier. A prodrng of the compo d of~J 1?imI.
34. 46. The compound of Claim .39 wherein said compound has a formula selected fromn the group coasisting of: -352- 6z ~cI -353- NI1 IND4 Nj- c) 4 o~