MXPA00007140A - Chemokine receptor antagonists and methods of use therefor - Google Patents

Abstract

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by structural formula (I) and physiologically acceptable salts thereof.

Description

ANTAGONISTS OF RECEPTORS OF CHEMOQUINES AND METHODS OF USE RELATED APPLICATIONS This application is a continuation of part of the United States patent application with Serial No. 09 / 148,823, filed on September 4, 1998, which is a continuation of part of the United States patent application. United with the Serial No. 09 / 010,320, filed on January 21, 1998, now abandoned, whose complete teachings are incorporated here as a reference.

BACKGROUND OF THE INVENTION Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that promote the recruitment and activation of multiple leukocyte and lymphocyte lineages. They can be released by many kinds of tissue cells after activation. The continuous release of chemokines to inflammation sites mediates the ongoing migration of effector cells into chronic inflammation. The chemokines characterized to date are related in the primary structure. They share four conserved cysteines, which form disulfide bonds. Based on this matter of conserved cysteines, the family is divided into two main branches, called CXC chemokines (chemokines a), and CC chemokines (chemokines ß), in which the first two conserved cysteins are separated by an intermediate residue, or adjacent respectively (Baggiolini, M. and Dahinden, CA, Immunology Today, 15: 127-133 (1994)). The C-X-C chemokines include several potent chemoattractants and neutrophil activators, such as interleukin 8 (IL-8), PF4 and neutrophil activating peptide 2 (NAP-2). CC chemokines include RANTES of the English "Regulated on Activation, Normal T Expressed and Secreted" (T Normal Expressed and Secreted, Regulated during Activation), the inflammatory proteins of macrophages la and lß (MlP-la and MlP-lß) , eotaxin and the 1-3 chemotactic proteins of human monocytes (MCP-1, MCP-2 and 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 MlP-la, have been implicated in a wide range of acute and chronic human inflammatory diseases including respiratory diseases, such as asthma and allergic disorders. Chemokine receptors are members of a superfamily of coupled G-protein receptors (GPCRs) that share structural features that reflect a common mechanism of signal transduction action (Gerard, C. and Gerard, N.P., Annu Rev. Immunol. , 12: 775-808 (1994); Gerard, C. and Gerard, N.P., Curr. Opin. Immunol. , 6: 140-145 (1994)). Among the conserved features are seven hydrophobic domains that extend over the plasma membrane, which are connected by extracellular and intracellular hydrophilic loops. The majority of the homology of the primary sequence occurs in the hydrophobic transmembrane regions, the hydrophilic regions being more diverse. The first receptor for the C-C chemokines that was cloned and expressed binds the MlP-la and RANTES chemokines. Accordingly, this MIP-la / RANTES receptor was termed CC chemokine receptor 1 (also referred to as CCR-1; Neote, K., et al., Cell, 72: 415-425 (1993); Horuk, R et al, WO 94/11504, May 26, 1994; Gao, J.-I. et al., J. Exp. Med., 177: 1421-1427 (1993)). Three receptors that bind and / or signal in response to RANTES have been characterized: CCR3 mediates the binding and signaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath et. al., J. Exp. Med., 183: 2437 (1996)), CCR4 binds chemokines including RANTES, MlP-la, and MCP-1 (Power, et al., J. Biol. Chem., 270: 19495 (1995)), and CCR5 binds to chemokines including MlP-la, RANTES, and MlP-lβ (Samson, et al., Biochem 35: 3362-3367 (1996)). RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of T cells. The responses of these different cells may not all be mediated by the same receptor, and it is possible that the CCR1, CCR4, and CCR5 receptors show some selectivity in the distribution of the receptor and the function among leukocyte types, as has already been shown for CCR3 (Ponath et al.). In particular, the ability of RANTES to induce targeted migration of monocytes and a recall population of circulating T cells (Schall, T. et al., Na ture, 347: 669-11 (1990) suggests that this chemokine and its receptor or receptors may play a critical role in chronic inflammatory diseases or, since these diseases are characterized by destructive infiltrates of T cells and monocytes, many of the existing drugs have been developed as antagonists of biogenic amine receptors, for example, As antagonists of the dopamine and histamine receptors, no receptor antagonists have yet been developed for the larger proteins such as chemokines and C5a Small molecule antagonists of the interaction between the chemokine CC receptors and their liga, including RANTES and MlP-la, could provide useful compouto inhibit harmful inflammatory processes "of Sennated "by the interaction of the ligand with the receptor, as well as valuable tools for the investigation of receptor-ligand interactions.

SUMMARY OF THE INVENTION It has now been found that a class of small organic molecules are antagonists of the function of the chemokine receptors and can inhibit the activation and / or the recruitment of leukocytes. An antagonist of chemokine receptor function is a molecule that can inhibit the binding and / or activation of one or more chemokines, including CC chemokines such as RANTES, MlP-la, MCP-2, MCP-3 and MCP- 4 to one or more chemokine receptors on leukocytes, other cell types, or both. As a consequence, the processes and cellular responses mediated by chemokine receptors can be inhibited by these small organic molecules. Based on this discovery, a method for treating a disease associated with the recruitment and / or aberrant activation of leukocytes as well as a method for treating a disease mediated by chemokine receptor function is described. The method comprises administering to a subject in need thereof an effective amount of a compound or small organic molecule that is an antagonist of the function of chemokine receptors. Compounds or small organic molecules that have been identified as antagonists of chemokine receptor function are discussed in detail here below, and can be used for the manufacture of a medicament to treat or prevent a disease associated with recruitment and / or the aberrant activation of leukocytes. The invention also relates to the compounds and small organic molecules described for use in the treatment and prevention of a disease associated with the recruitment and / or aberrant activation of leukocytes. Also included in the invention are pharmaceutical compositions comprising one or more of the compounds or small organic molecules that have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier. The invention further relates to novel compounds that can be used to treat an individual with a disease associated with the recruitment and / or aberrant activation of leukocytes and methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing the preparation of the compounds represented by the Structural Formula (I). Figure 2 is a diagram showing the preparation of the compounds represented by Compound (Vl-b). Figure 3 is a diagram showing the preparation of the compounds represented by Structural Formula (I).

Figure 4 is a diagram showing the preparation of the compounds represented by Structural Formula (I), where Z is represented by Structural Formula (III) and where Ring A and / or Ring B of Z is substituted with R40. Figure 5 is a schematic showing the preparation of the compounds represented by Structural Formula (I), where Z is represented by Structural Formula (III) and where Ring A and / or Ring B of Z is substituted with - (0) u- (CH2) t-COOR20, XO) uXCH2) t-OC (0) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t -NHC (0) 0-R20. Figures 6A-6Z show the structures of the exemplary compounds of the present invention. Figure 7 shows the preparation of the compounds represented by Structural Formula (I), where Z is represented by Structural Formulas (III) and where Ring A or Ring B of Z is substituted with R40.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to small molecule compounds that are modulators of the function of chemokine receptors. In a preferred embodiment, the small molecule compounds are antagonists of chemokine receptor function. Accordingly, cellular processes or responses mediated by the binding of a chemokine to a receptor can be inhibited (reduced or prevented), in whole or in part), including migration of leukocytes, activation of mtegpna, transient increases in calcium concentration [Ca + 7? tracelular free, and / or the release of granules of proinflammatory mediators. The invention further relates to a method of treatment, including prophylactic and therapeutic treatments, of a disease associated with the recruitment and / or aberrant activation of leukocytes or mediated by chemokines or by the function of chemokine receptors, including alterations. chronic inflammatories characterized by the presence of T cells, monocytes and / or eosophils sensitive to RANTES, MlP-la, MCP-2, MCP-3 and / or MCP-4, including but not limited to diseases such as arthritis ( eg, rheumatoid arthritis), atherosclerosis, arteriosclerosis, ischemia / reperfusion injury, diabetes mellitus (eg, diabetes mellitus type 1), psoriasis, multiple sclerosis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, the rejection of transplanted organs and tissues (that is, acute rejection by allograft, chronic rejection by allograft), the syndrome of jerte frent ° to the host, as well as allergies and asthma. Other diseases associated with the aberrant recruitment and / or activation of leukocytes that can be tridated (including prophylactic treatments) with the methods described herein are the inflammatory diseases associated with the Human Immunodeficiency Virus (HIV), eg, encephalitis. associated with AIDS, cutaneous maculopapular rash related to AIDS, AIDS-related interstitial pneumonia, AIDS-related enteropathy, periportal hepatic inflammation related to AIDS and AIDS-related glomerulonephritis. The method comprises administering to a subject in need of treatment an effective amount of a compound (ie, one or more compounds) that inhibits the function of chemokine receptors, inhibits the binding of a chemokine to leukocytes, to other cell types , or both, and / or that inhibits the migration of leukocytes to, and / or activation in, sites of inflammation. The invention further relates to methods for producing an antagonistic effect on the chemokine receptor, such as CCR1, in a mammal comprising administering to the mammal a compound as described herein. According to the method, chemotaxis and / or chemokine-mediated activation of pro-inflammatory cells carrying receptors for chemokines can be inhibited. As used herein, "pro-inflammatory cells" include but are not limited to leukocytes, since chemokine receptors can be expressed in other cell types, such as neurons and epithelial cells. While not wishing to be bound by any concerted theory or mechanism, it is believed that the compounds of the invention are antagonists of the chemokine receptor CCR1, and that the therapeutic benefits derived from the method of the invention are the result of the antagonistic effect on function. of CCRl. Thus, the method and compounds of the invention can be used to treat a medical condition involving cells that express CCR1 on their surface and that respond to signals transduced through CCR1, as well as the specific conditions listed above. In one embodiment, the antagonist of chemokine receptor function is represented by structural formula (I): (I) and the physiologically acceptable salts thereof. Z is a non-aromatic heterocyclic cycloalkyl or ring group fused to one, two or more aromatic rings, wherein each Z ring is independently substituted or unsubstituted. 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 (L) spacer groups for (CH2) n may be employed. M is > NR2 or > CRXR2. M is preferably > C (OH) R2. R1 is -H, -OH, -N3, a halogen atom, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S - (substituted aliphatic group), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- ( substituted aliphatic group), -COOH, -CN, -CO-NR3R4, -NR3R4; or R1 may be a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M. R1 is preferably -H or -OH. R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group. R2 is preferably an aromatic group or a substituted aromatic group. R3, R4, R5 and R6 are independently -H, 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 group non-aromatic heterocyclic or substituted non-aromatic heterocyclic group. R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, can alternatively form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring. In embodiments where M is > CR1R2 and R1 is a covalent bond between the carbon atom of M and an adjacent carbon atom of the ring containing M, the antagonist of chemokine function may be represented by the Structural Formula (la). (the) Z, n and R are described as in the Structural Formula In a preferred embodiment, Z is a tricyclic ring system comprising two carbocyclic aromatic groups fused to a six, seven or eight member cycloalkyl group or a non-aromatic heterocyclic ring. In one example, Z is represented by Structural Formula (II): (II) The phenyl rings of Structural Formula (II), labeled "A" and "B", are referred to herein as "Ring A" and "Ring B", respectively. The central ring, labeled "C", is referred to as "Ring C" and may be, for example, a non-aromatic carbocyclic ring of six, seven or eight members (eg, a cycloheptane or cyclooctane ring) or a ring non-aromatic heterocyclic. When Ring C is a non-aromatic heterocyclic ring, it may contain one or two heteroatoms such as nitrogen, sulfur or oxygen.

When Z is represented by Structural Formula (II), the tricyclic ring system can be connected to the rest of the molecule by a covalent double bond between a carbon atom of Ring C and the carbon atom which, as described in FIG. Structural Formula (I), is attached to Z. Ring A, Ring B, or both of the Formula Structural (II) may not be substituted.

Alternatively, Ring A, Ring t, or both may have one or more substituents. Suitable substituents are described here below. In an example, Ring A or Ring B is substituted with - (0) n- (CH2) tC (0) OR2 °, - (0) u- (CH2) t-OC (0) R °, - (0) u- (CH2) tC ( 0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R2 °. u is zero or one. t is an integer, such as an integer from zero to about three, and the methylene group - (CH 2) t_ may be substituted or unsubstituted. R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R21 and R22, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. Ring C optionally contains one or more substituents, as described herein below. Examples of suitable tricyclic ring systems, Z, are provided by the Structural Formula (III): ^ (III) Ring A and Ring B of Structural Formula (III) are described as for Structural Formula (II). Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -0-CH2-, -CH2-O-, -NRC-CH2-, -CH2-NRC -, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH-.H-, -NRc-CO- or -CO-NRc -. Preferably, Xx is -CH2-0-, -CH2-CH2-, -CH2-S-, -NRc-CO- or -C0-NRc-. Rc 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, Rc is - (CH2) s-COOR 3 ° 0; CH2) SC (0) -NR31R32 or (CH2) s-NHC (0) -0-R 3 ~ 0 where is an integer, such as a whole from one to about three; R 30 R 31 and R 32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R3L and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring. Other examples of tricyclic ring systems for Z include the benzodiazepines, benzoxazepines, benzoxazines, phenothiazines and the groups represented by the following structural formulas: In another preferred embodiment, Z is a tricyclic ring system comprising two aromatic groups fused to a cycloalkyl group of seven or eight members 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 the Structural Formula (IV): (IV) Ring A of the 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, e.g., a heteroaryl group or a carbocyclic aryl group. Suitable substituents are described here below. In an example, Ring A and / or Ring B is substituted with - (O (CH2 tC (0) OR 20, (0) u- - (0) u- (CH2) t ~ C (O) -NR21R22 or - (0) u- (CH2) t -NHC (0) 0-R2 ° as described above, u, t, R20, R21, and R22 are described as above.

Xi and Rc can be described as before for the Formula Structural (III). In another embodiment of the present invention Z is represented by Structural Formula (IV), where Ring A is a pyridyl group and Ring B is an aromatic or heteroaromatic group. In this embodiment Ring A and Ring B are independently substituted or unsubstituted, and the Ring B is preferably a phenyl group. Xi and Rc are described as before for Structural Formula (III). In another embodiment of the present invention Z is represented by the Structural Formula (V): (V) Ring A and Ring B can be independently substituted or unsubstituted as described above in Structural Formula (II), and Xi can be described as above for Structural Formula (III). In a preferred embodiment, Ring B of Structural Formula (V) is substituted in para position in relation to the carbon atom of Ring B which is attached to Xi of Ring C, and Z is represented by the Structural Formula XX ^ (SAW) Xi can be described as before for the Structural Formula (II). Preferably Xx is -CH2-0-, -CH2-CH2- or -CH2-S-. R40 is a substituent as described herein below. Preferably R40 is an aliphatic group, a substituted aliphatic group, -O- (aliphatic group) or -0- (substituted aliphatic group). More preferably R40 is -O-alkyl, such as -0-CH3, -0-C2H5, -0-C3H7 or -O-C4H9. In another embodiment, the antagonist of chemokine activity may be represented by Structural Formula (VII): (VII) and the physiologically acceptable salts thereof. n and M are described as in the Structural Formula (I). Z is as described herein, preferably as described in Structural Formula (V) or (VI). q is an integer, such as an integer from zero to about three, and the ring containing M can be substituted or unsubstituted. Thus, the antagonist of the chemokine function can be represented, for example, by the Structural Formulas (Vlla) - (Vlld): (Vlla) (Vllb) (VIIc) (Vlld) and the physiologically acceptable salts thereof, wherein Z, n and M are described as in Structural Formula (VII), and the ring containing M is substituted or unsubstituted. In another embodiment of the present invention, the novel compound used in these methods is included. The compounds described herein can be obtained in the form of the configurational isomers E and Z. It is expressly pointed out that in the invention the compounds of the E configuration and the Z configuration are included around the double bond that connects the C ring of Z to the rest of the molecule, and a method for treating a subject with compounds of the E configuration, the Z-configuration, and mixtures thereof. Therefore, in the structural formulas presented here, the symbol: it is used to represent both the E configuration and the Z configuration. Preferably Ring A and the alkylene chain attached to Ring C are in cis configuration. For example, the compounds can have the configuration: It is understood that one configuration may have more activity than another. The desired configuration can be determined by tracking the activity, using the methods described herein. Additionally, certain compounds of the invention can be obtained in the form of different stereoisomers (e.g., diastereomers and enantiomers). It is noted that all isomeric and racemic mixtures of the described compounds are included in the invention and a method of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures. Again, it is understood that one of the stereoisomers may be more active than the other. The desired isomer can be determined by screening. Also included in the present invention are the physiologically acceptable salts of the compounds represented by the Structural Formulas (I) to (Vlld). The salts of the compounds containing an amine or other alkaline group can be obtained, for example, by reaction 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 counter anion such as chloride, bromide, iodide, acetate, perchlorate and the like. The salts of the compounds containing a carboxylic acid or other acid functional group can be prepared by reaction with a suitable base, for example, a hydroxide. The salts of the acid functional groups contain a countercation such as sodium, potassium, ammonium, calcium and the like. As used herein, aliphatic groups include straight chain, branched or cyclic C1-C20 hydrocarbons that are completely saturated or that contain one or more units of unsaturation. For example, suitable aliphatic groups include linear, branched or cyclic substituted or unsubstituted C 1 -C 2 alkyl, alkenyl or alkynyl groups. Aromatic groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic or heteroaryl aromatic groups such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl , 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. When these rings are fused, for example, to Ring C, the established anchor point can be either of the two fused links. Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more of the other rings. Examples include tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-quinolinyl, 3 -quinolinyl, 1-isoquinolinyl, 2-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, and the like. Also included within the scope of the term "aromatic group", as used herein, is a group in which one or more carbocyclic aromatic rings and / or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, eg, benzocyclopentane, benzo-cyclohexane. The non-aromatic heterocyclic rings are non-aromatic carbocyclic rings that include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring may be five, six, seven or eight members and / or be fused to another ring, such as cycloalkyl on an aromatic ring. Examples include 3-lH-benzimidazol-2-one, 3-l-alkyl-benzimidazol-2-one, 3-l-methyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydro -thiophenyl, 3-tetrahydrothiophenyl, 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, diazolonyl substituted in N, 1-phthalimidyl, 1-3-alkylphthalimidyl, benzoxane, benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolane, benzothiano.

Suitable substituents of an aliphatic group, aromatic group (carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, a halogen, azido, -CN, -COOH, -OH, -CONR24R25, -NR24R25, -OS (O) 2NR24R25, S (0) 2NR R25, -S03H, -S (0) 2NH2, guanidino, - (O) u- (CH2) tC (O) OR20, - (O ) u- (CH2) t-OC (O) R20, - (0) u- (CH2) tC (0) -NR21R22, - (0) u- (CH2) t-NHC (0) 0-R2 °, -QH, -Q- (aliphatic group), -Q- (substituted aliphatic group), -Q- (aryl), -Q- (aromatic group), -Q- (substituted aromatic group '-Q- (CH2) p - (unsubstituted substituted aromatic group) (p is an integer of 1-5), -Q- (non-aromatic heterocyclic group) or -Q- (CH2) p- (non-aromatic heterocyclic group).

R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -NHC (O) -O- (aliphatic group), -NHC ( O) -O- (aromatic group), -NHC (O) -O- (non-aromatic heterocyclic group) and where R21 and R22, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. t is an integer from zero to about three, and the methylene group - (CH2) t-, may be substituted or unsubstituted. u is zero or one. Q is -0-, -S-, -S (0) -, -S (0) 2-, -0S (0) 2-, -C (0) -, -0C (0) -, -C ( 0) 0-, -C (0) C (0) -0-, -0-C (0) C (0) -, -C (0) NH-, -NHC (O) -, -0C (0 ) NH-, -NHC (0) 0-, -NH-C (0) -NH-, -S (0) 2NH-, -NHS (O) 2-, -N (R23) -, -C (NR23 NHNH-, -NHNHC (NR23) -, -NR24C (0) - or -NR24S (0) 2-- R23 is -H, an aliphatic group, a benzyl group, an aryl group or a non-aromatic heterocyclic group. R 24 and R 25 are independently -H, -OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group or a non-aromatic heterocyclic group. The substituted non-aromatic heterocyclic ring, the benzyl group or the aromatic group may also have a substituted aliphatic or aliphatic group, as a substituent. The substituted aliphatic group can also have an oxo group, an epoxy group, a non-aromatic heterocyclic ring, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group as a substituent. The substituted non-aromatic heterocyclic ring can also have = 0, = S, = NH or = (aliphatic, aromatic or substituted aromatic group) as a substituent. The substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or the substituted benzyl group may have more than one substituent. The acyl groups include aliphatic, aromatic carbonyl, aliphatic sulfonyl and substituted and unsubstituted aromatic sulfonyl carbonyl groups. Suitable electron-withdrawing groups include, for example, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -CH = NH, -CN, -N02 and halogens. In the structural formulas represented here, the single or double bond by which a group or chemical radical is connected to the rest of the molecule or compound is indicated by the following symbol: For example, the corresponding symbol in the Structural Formulas (II), (III) and (IV) indicates the double bond by means of which the central ring of the tricyclic ring system is connected to the rest of the molecule represented by the Structural Formula (I) . The "subject" is preferably a bird or a mammal, such as a human, but may also be an animal in need of veterinary treatment, eg, domestic animals (eg, dogs, cats, and the like), farm animals (eg, cows). , sheep, poultry, pigs, horses, and the like) and laboratory animals (eg, rats, mice, guinea pigs, and the like). The "effective amount" of a compound is the amount that results from 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 the recruitment and / or aberrant activation of leukocytes. Examples of such processes include leukocyte migration, the integrin activation, the transient increase of the intracellular free [Ca2 +] i calcium concentration and the release of proinflammatory mediator granules. Alternatively, the "effective amount" of a compound is an amount sufficient to achieve a desired therapeutic and / or prophylactic effect, such as the amount that occurs in the prevention of or decrease in symptoms associated with a disease associated with recruitment. and / or the aberrant activation of leukocytes.

The amount of compound administered to the individual will depend on the type and severity of the disease and the characteristics of the individual, such as general health, age, sex, body weight and tolerance to the drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine the appropriate dosages depending on these and other factors. Typically, the 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. The antagonist of chemokine receptor function can also be administered in combination with one or more additional therapeutic agents, e.g. theophylline, β-adrenergic bronchodilators, corticosteroids, antihistamines, anti-allergic agents, immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone, methylprednisolone) 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. In parenteral administration, for example, systemic administration may be included, such as by intramuscular, intravenous, subcutaneous or intraperitoneal injection. The compound can also be administered orally (e.g., by diet), transdermally, topically, by inhalation (e.g., intrabronchial, intranasal, oral inhalation or intranasal qotas), or rectally, depending on the disease or condition to be treated. Oral or parenteral administration are the preferred modes of administration. The compound can be administered to the individual together with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for the treatment of HIV infection, the inflammatory disease, or the other diseases discussed above. The formulation of the compound to be administered will vary according to the selected route of administration (e.g., solution, emulsion, capsule). Suitable carriers may contain inert ingredients that do not interact with the compound. Standard pharmaceutical formulation techniques can be employed, such as those described in Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Suitable carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing approximately 0.9% mg / ml of benzyl alcohol), phosphate buffered saline, Hanks solution, Ringer's solution with lactate and the like. Methods for encapsulating the compositions (such as in a hard gelatin or cyclodextran coating) are known in the art (Baker, et al., "Controlled Relase of Biological Active Agents," John Wiley and Sons, 1986). The activity of the compounds of the present invention can be evaluated using suitable assays, such as receptor binding assays and chemotaxis assays. For example, as described in the Embodification Section, small molecule antagonists of RANTES and MlP-la binding have been identified using THP-1 cells that bind to RANTES and undergo chemotaxis in response to RANTES and MlP-la as model for leukocyte chemotaxis. Specifically, a high-throughput receptor binding assay that controls the binding of RANTES-I125 and MIP-la-I125 to THP-1 cell membranes was used to identify small molecule antagonists that block the binding of RANTES and MlP-la . The compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by the binding of a chemokine to its receptor, such as chemotaxis, integrin activation and the release of a mediator in granules. . They can also be identified by virtue of their ability to block the chemotactic response of HL-60, T cells, peripheral blood mononuclear cells, and eosinophils mediated by RANTES and MlP-la. The compounds described herein can be prepared according to the schemes shown in Figures 1-5 and 7. The schemes are described in greater detail below. Figure 1 shows the preparation of the compounds represented by Structural Formula (I). L1 is PPh3Cl, PPh3Br, PPh3I, or (EtO) 2P (0), L2 is a suitable leaving group such as halogen, p-toluenesulfonate, mesylate, alkoxy, phenoxy; Gp is a suitable protecting group such as tetrahydropyranyl; and the other symbols are defined as before. In Step 1 of Figure 1, a Wittig reaction is carried out in a solvent such as ether, or tetrahydrofuran (THF) in the presence of a base such as sodium hydride, n-butyl lithium or lithium diisopropylamide (LDA). ) at 0 ° C to the reflux temperature of the solvent used for 5 minutes to 72 hours. The compounds represented by Formula II in Figure 1 can be prepared by the methods described in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, the entire teachings of which they are incorporated here as a reference. In Step 2 of Figure 1, deprotection is carried out with an acid in a solvent such as methanol at room temperature to the reflux temperature of the solvent used for 5 minutes to 72 hours. Alternatively, a compound represented by Formula V in Figure 1 can be prepared directly from step 1 without isolating an intermediate. The reaction mixture obtained after the usual treatment of the reaction described in step 1 can be dissolved in the solvent and reacted with the acid. In Step 3 of Fiqura 1, the hydroxy group can be converted to a removable group by known methods. The compounds represented by Formula VI in Figure 1 can be prepared by the methods described 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 of the room temperature at the reflux temperature of the solvent used for 5 minutes to 72 hours . Figure 2 shows the preparation of the compounds represented by Compound (Vl-b). In Step 1 of Figure 2, a Grignard reaction in a solvent such as ether, tetrahydrofuran (THF) of 0 ° C can be carried out at the reflux temperature of the solvent used for 5 minutes to 72 hours. Compound VII is commercially available. In Step 2 of Figure 2, bromination can be carried out with brominating agents such as hydrobromic acid, bromotrimethylsilane or boron tribromide-methyl sulfide complex in a solvent such as acetic acid, dichloromethane or dichloroethane. the ambient temperature at the reflux temperature of the solvent used for 5 minutes to 72 hours. Figure 3 shows the preparation of the compounds represented by Structural Formula (I). In Figure 3, a reductive amination can be carried out with reducing reagents such as sodium cyanoborohydride, sodium acetoxyborohydride or sodium borohydride in a solvent such as methanol, ethanol, tetrahydrofuran (THF), dichloromethane or dichloroethane from room temperature to the reflux temperature of the solvent used for 5 minutes to 72 hours. Figure 4 shows the preparation of the compounds represented by Structural Formula (I), where Z is represented by Structural Formulas (III) and where Ring A and / or Ring B in Z is substituted with R40. 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 hydride of sodium and a catalyst such as an alkali metal iodide from room temperature to the reflux temperature of the solvent used for 5 minutes to 72 hours. Figure 5 is a diagram showing the preparation of the compounds represented by Structural Formula (I), where Z is represented by the Structural Formulas (III) and where Ring A and / or Ring B in Z is substituted with - (O) u- (CH2) t-COOR20, - (0) u- (CH2) t-OC (0) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u - (CH2) t-NHC (0) 0-R2 °. In Figure 5, the hydrolysis reaction can be carried in a mixture of an aqueous solution of alkali metal hydroxide and a solvent such as methanol, ethanol, tetrahydrofuran (THF) or dioxane from room temperature to reflux temperature. of the solvent used for 5 minutes to 72 hours. The acylation reaction can be carried out using dicyclohexylcarbodiimide (DCC) or (l-ethyl-3- (3-dimethylaminopropyl) 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 a temperature of 0 to 100 ° C for 5 minutes to 72 hours Figure 7 shows the preparation of the compounds represented by Structural Formula (I), where Z is represented by the Structural Formulas (III) and where Ring A and / or Ring B in Z is substituted with R40.L4 is a suitable leaving group such as halogen or trifluoromethylsulphonate In Figure 7, an coupling reaction with palladium such as Stille coupling, Suzuki coupling, Heck reaction, or carboxylation using carbon monoxide using a palladium catalyst such as tetrakis- (triphenylphosphine) pal adio, bis (triphenylphosphine) -palladium chloride and palladium acetate in a solvent such as tetrahydrofuran (THF), 1,4-dioxane, toluene, dimethylformamide (DMF), or dimethyl sulfoxide (DMSO) in the presence of an additive (where appropriate) necessary) such as triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride, or lithium chloride from room temperature to the reflux temperature of the solvent used for 5 minutes to 72 hours. The compounds represented by the Structural Formula (I), where Z is represented by the Structural Formulas (III) or (IV), X is -CO-NRc- and Rc is - (CH2) s-COOR30, - (CH2) S-C (0) -NR31R32 or - (CH2) s-NHC (0) - O-R30, can be prepared by the appropriate modification of the scheme shown in Figures 1-5 and 7. In a modification the starting substance shown in Figure 1 is used, where X is -CO-NH-. The amide is then alkylated with L3- (CH2) s-COOR30, where L3 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. While Figures 1-5 and 7 show the preparation of compounds in which Rings A and B are phenyl rings, analogous compounds can be prepared. with heteroaryl groups for Rings A and B using starting materials with heteroaryl groups in the corresponding positions. These starting substances can be prepared according to the methods described 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.

EXAMPLIFICATION Example 1-4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) propyl] piperidin-4-ol To a solution of 5 - (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene (described in JP 48-030064) (200 mg) in DMF (10 ml) were added 4- (4-chlorophenyl) - 4-hydroxypiperidine (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 ° C for 24 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. purified by chromatography on silica gel eluting with ethyl acetate-hexane (1: 1) to give the title compound (250 mg) .H NMR (CDC13) 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), EM m / z: 444 (M + l).

Example 2-4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz- [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by 11- (3-bromopropylidene) -6,11-dihydrodibenz- [b, e] ] oxepin. H1 NMR (CDC13) d: 1.61-2.16 (5H, m), 2.37-2.80 (8H, m), 5.22 (2H, broad s), 5.70 (0.6xlH, t), 6.03 (0.4xlH, t), 6.73-6.90 (2H, m), 7.09-7.45 (10H, 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 # TIB202). The cells were harvested by centrifugation, washed twice with PBS (phosphate buffered saline), and the cell pellets were frozen at -70 to -85 ° C. The frozen pellet was thawed in ice-cooled lysis buffer consisting of 5 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), aprotinin, leupeptin, and chymostatin (protease inhibitors) 5 μg / ml each, and 100 μg / ml PMSF (phenylmethanesulfonyl fluoride - also a protease inhibitor), at a concentration of 1 to 5 x 107 cells / ml . This procedure produced cell lysis. The suspension was well mixed to resuspend all the frozen cell pellet. Nuclei and cell debris were separated by centrifugation at 400 x g for 10 minutes at 4 ° C. The supernatant was transferred to a new tube and the membrane fragments were collected by centrifugation at 25,000 x g for 30 minutes at 4 ° C. The supernatant was aspirated and the pellet was resuspended in freezing buffer consisting of 10 mM HEPES, pH 7.5, 300 mM sucrose, aprotinin, leupeptin, and 1 μg / ml chemostat of each, and 10 μg / ml of PMSF (approximately 0.1 ml per 108 cells). All groups were resolved using a mini-homogenizer, and the total protein concentration was determined using a kit for protein analysis (Bio-Rad, Hercules, CA, cat # 500-0002). The membrane solution was then aliquoted and frozen at -70 to -85 ° C until needed.

In the Bonding Assays, the membranes described above were used. Membrane protein (2 to 20 μg of total membrane protein) was incubated with RANTES or MlP-la labeled with 0.1 to 0.2 nM I 125 with or without unlabeled competitor (RANTES or MlP-la) or different concentrations of compounds. The binding reactions were performed in 60 to 100 μl of binding buffer consisting of 10 mM HEPES, pH 7.2, 1 mM CaCl 2, 5 mM MgCl, and 0.5% BSA (bovine serum albumin), for 60 minutes 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) that were previously soaked in 0.3% polyethyleneimine. The filters were rinsed with approximately 600 μl of binding buffer containing 0.5 M NaCl, dried, and the amount of bound radioactivity was determined by scintillation counting in a Topcount beta-plate counter. The activities of the test compounds in the Table are reported below in the form of the IC5o values or the inhibitor concentration required for a 50% inhibition of the specific binding in receptor binding assays using RANTES-I125 or MIP-la125 as a ligand and membranes of THP-1 cells. The specific binding is defined as the total binding minus the non-specific binding; the non-specific binding is the amount of cpm that is still detected in the presence of unlabeled Rantes or MIP-la125 in excess.

Table BIOLOGICAL DATA Example IC50 (μM) 1 < 1 2 < 1 8 < 1 12 < 1 17 < 10 18 < 1 1 199 < 1 21 < 1 22 < 1 23 < 1 24 < 10 2 255 < 1 26 < 1 27 < 1 28 < 1 29 < 1 3 300 < 1 31 < 1 32 < 1 33 < 1 34 < 1 3 355 < 1 36 < 1 38 < 1 39 < 10 40 < 1 4 411 < 1 42 < 1 43 < 10 44 < 1 45 < 1 46 < 1 BIOLOGICAL DATA (cont.) Example IC50 (μM) 47 < 1 48 < 1 49 < 1 52 < 1 53 < 1 54 < 1 5 555 < 1 56 < 1 57 < 10 59 < 1 60 < 1 6 611 < 10 62 < 10 63 < 10 64 < 1 65 < 1 6,666 < 1000 67 < 1 68 < 10 69 < 1 71 < 1 7 722 < 10 73 < 10 74 < 1000 75 < 10 76 < 10 7 777 < 1 78 < 1 79 < 1 83 < 1000 85 < 1 86 > 10 89 > 10 BIOLOGICAL DATA (cont.) E p IC50 (μM) 90 < 1 91 < 1 111 < 1 114 < 1 117 < 1 118 < 1 128 < 1 130 < 1 131 < 1 132 < 1 133 < 1 134 < 1 135 < 1 138 < 1 139 < 140 > 10 141 < 1 142 < 10 143 < 1 144 < 1 145 < 10 146 > 10 147 < 10 148 < 10 149 < 1000 150 < 10 151 < 1 152 < 1 153 < 1 154 < 1 155 < 1 158 < 1 159 < 1 BIOLOGICAL DATA (cont.) Example IC50 (μM) 160 < 1 161 < 10 162 < 1 163 < 1 166 < 10 167 > 1 168 1 173 < 1 174 < 1 175 < 1 176 '< 1 178 < 1 181 < 1 182 < 1 183 < 1 184 < 10 185 < 1000 186 < 1 187 < 1 188 > 10 190 > 10 191 > 10 192 > 10 193 < 1 194 < 1 195 < 10 197 < 1 199 < 1 248 < Example 8- 4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz- [b, e] thiepin-11-ylidene) propyl] piperidin-4-oi Stage 1 The 11- (3- Bromopropylidene) -6,11-dihydrodibenz [b, e] -thiepine was prepared following the procedure of example 45, step 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one by 6,11-dihydrodibenz [b, e] tiepin-11-one. NMR H1 (CDC13) d: 2.50-2.64 (2H, m), 3.36-3.47 (3H, m), 4.99 (1H, d), 5.94 (1H, t) 6.98-7.31 (8H, m).

Step 2 The title compound was prepared following the procedure of example 45, step 3 but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] -cycloheptene by the product of step 1 1 H NMR (CDCl 3) d: 1.65-1.80 (3H, m), 1.95-2.70 (10H, m), 3.35 (1H, d), 4.98 (1H, d ), 5.96 (1H, t), 7.09-7.43 (12H, m). MS m / z: 462 (M + l) Example 12-1- [3- (5-Benzyl) -6,1-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -4- (4-cyclo-phenyl) -piperidine -4-ol To a solution of 4- (4-chlorophenyl) -1- [3- (6-hydrochloride, 11-dihydro-6-oxo-5H-dibenz [b, e] azepin-ll-ylidene) propyl] -piperidin-4-ol (Example 39) (300 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 200 mg), benzyl bromide (0.15 ml) 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the title compound (180 mg). 1 H-NMR (CDCl 3) d: 1.62-1.67 (2H, m), 1.99-2.20 (3H, m), 2.33-2.65 (8H, m), 5.10 ( 1H, d), 5.75 (1H, d), 5.94 (1H, t), 7.11-7, 42 (16H, m), 7.91 (1H, dd). MS m / z: 549 (M + l) Example 17-1- [3- (5-Carboxymethyl) -6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -4- (4-chlorophenyl) -piperidine -4-ol 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-5-e-toxicarbonylmethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl was dissolved ] piperidin-4-ol (Example 18) (1.0 g) in 1 M 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 precipitate was filtered to give the title compound (250 mg). H1 NMR (DMSO-d6) d: 1.44-1.61 (2H, m), 2.07-2.17 (1H, m), 2.35-3.01 (9H,), 4.28 (1H, d), 4.59 (1H, d), 5.83 (1H, t), 7, 18-7, 71 (12H,). MS m / z: 517 (M + l) Example 18-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol The title compound was prepared following the procedure of example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] -cycloheptene by 11- (3-bromopropylidene) - 5-ethoxycarbonyl-methyl-6-oxo-5H-dibenz [b, e] azepine.

NMR H1 (CDCl3) d: 1.30 (3H, t), 1.64-1.69 (2H, m), 1.97-2.10 (3H,), 2.38-2.71 (8H, m), 4.27 (2H, c), 4.32 (1H, d), 4.84 (1H, d), 5.88 (1H , t), 7.16-7.45 (11H, m), 7.88 (1H, dd). MS m / z: 545 (M + l) Example 19-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-methyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -piperidine- 4-ol The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] -cycloheptene by 11- (3-bromopropylidene) -5-methyl-6-oxo-5H-dibenz [b, e] azepine. 1 H NMR (CDCl 3) d: 1.58-2.06 (5H, m), 2.39-2.75 (8H, m), 2.53 (3H, s), 5.84 (1H, t) , 7.10-7.44 (11H, m), 7.85-7.89 (1H, m).

MS m / z: 473 (M + 1).

Example 21-4- (4-Chlorophenyl) -1- [3- (5H-dibenzo [a, d] cyclohepten-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 1 , but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] -cycloheptene with 5- (3-bromopropylidene) -5H-dibenzo [a, d] -cycloheptene. H1 NMR (CDCl3) d: 1.58-1.63 (2H,), 2.00-2.05 (2H, m), 2.26-2.46 (6H, m), 2.62-2 , 66 (2H, m), 5.55 (1H, t), 6.85 (2H, s), 7, 24-7, 40 (12H, m). MS m / z: 442 (M + 1).

Example 22-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyldibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] -cycloheptene by 11- (3-bromopropylidene) -6,1-dihydro-2 - ethoxycarbonyldibenz [b, e] oxepin. NMR H1 (CDC13) d: 1.65-1.70 (2H, m), 2.01-2.13 (3H, m), 2.41-2.80 (7H, m), 3.85 ( 3H, s), 5.40 (2H, broad s), 5.73 (0.6xlH, t), 6.09 (0.4xlH, t), 6.76 (0.6xlH, d), 6, 82 (0.4xlH, d), 7.21-7.43 (8H, m), 7.73 (1H, dd), 7.87 (0.6xlH, d), 7.97 (0.4xlH, d). MS m / z: 504 (M + 1).

Example 23-1- [3- (2-Butoxycarbonyl-6,11-dihydrodibenz- [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] -cycloheptene with 11- (3-bromopropylidene) -2- butoxy-6, 11-dihydrodibenz [b, e] oxepin. NMR H1 (CDCl3) d: 0.96 (3H, t), 1.53 (2H, c), 1.70-1.77 (3H, m), 2.02-2.14 (3H, m) , 2.39-2.78 (5H, m), 4.27 (2H, t), 5.27 (2H, broad s), 5.75 (0.8xlH, t), 6.10 (0.2xlH, t), 6.78 (1H, d), 7.27-7.43 (8H, m) , 7.76 (1H, dd), 7.89 (0.8xlH, d), 7.98 (0.2xlH, d). MS m / z: 546 (M + 1).

Example 24-1- [3- (2-Carboxy-6,11-dihydrodibenz [b, e] -oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol To a solution of 4 - (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyldibenz [b, e] oxepin-11-ylidene) -propyl] piperidin-4-ol (Example 22) (100 mg) in Ethanol (3 ml) was added an aqueous solution of 15% sodium hydroxide (0, 6 ml) and the mixture was refluxed for 12 hours. The solvent was removed by distillation under reduced pressure. Water and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitate was filtered to give the title compound (80 mg). H1 NMR (CD3OD) d: 1.73-1.79 (2H, m), 2.14-2.19 (2H, m), 2.80-2.93 (3H, m), 3.02- 3.11 (3H, m), 3.24-3.29 (2H,), 5.25 (2H, broad s), 5.61 (0.7xlH, t), 6.05 (0.3xlH, t), 6.72 (1H, d), 7.22-7.40 (8H, m), 7.52-7.65 (1H, m), 7.75 (0.7xlH, d), 7 , 80 (0, 3xlH, d). MS m / z: 490 (M + 1).

Example 25-4- (4-Chlorophenyl) -1- [α- (6,11-dihydro-2-dimethylaminocarbonyldibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] -cycloheptene with 11- (3-bromopropylidene) -2-dimethylamino-carbonyl-6 , 11-dihydrodibenz [b, e] oxepin. 1 H NMR (CDCl 3) d: 1.62-1.67 (2H, m), 2.00-2.12 (2H, m), 2.37-2.47 (8H, m), 2.89 ( 6H, s), 5.25 (2H, broad s), 5.68 (0.7xlH, t), 6.03 (0.3xlH, t), 6.71 (0.3xlH, d), 6, 78 (0.7xlH, d), 7, 13-7, 0 (10H, m). MS m / z: 517 (M + 1).

Example 26-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxymethylbenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol To a solution of ( 4-chlorophenyl) -1- [3- (6,1, -dihydro-methoxycarbonyldibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol (110 mg) in THF (8 ml) was added hydride of lithium aluminum (1.0 M, 0.42 ml) dropwise at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Aqueous sodium hydroxide (1M) was added to the reaction mixture to stir for 30 minutes, then ethyl acetate and brine 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 removed by distillation under reduced pressure. The res was purified by silica gel chromatography eluting with dichloromethane-methanol (10: 1) to give the title compound (90 mg). H1 NMR (CDC13) d: 1.61-1.66 (2H, m), 1.98-2.03 (2H, m), 2.39-2.48 (3H, m), 2.57- 2.79 (6H, m), 4.52 (2H, s), 5.20 (2H, broad s), 5.66 (0.8xlH, t), 6.01 (0.2xlH, t), 6.67 (0.2xlH, d), 6.79 (0.8xlH, d), 7.06 (1H, dd), 7.15-7.37 (9H, m). MS m / z: 476 (M + 1).

Example 27-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2- (1-hydroxy-1-methyl) ethyldibenz [b, e] oxepin-11-ylidene) propyl] -piperidine -4-ol To a solution of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyl dibenz [b, e] oxepin-11-ylidene) -propyl] piperidin-4-ol (60 mg) in THF (6 ml) was added magnesium chloride (3.0 M, 0.16 ml) dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours, the mixture The reaction was quenched with saturated aqueous ammonia, then 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 removed by distillation under reduced pressure. The res was purified by silica gel chromatography eluting with ethyl acetate-methanol (95: 5) to give the title compound (20 mg). 1 H-NMR (CDCl 3) d: 1.54 (0.7x6H, s), 1.62 (0.3x6H, s), 1.63-1.70 (2H, m), 2.03-2.10 ( 3H, m), 2.38-2.49 (3H, m), 2.62-2.82 (4H, m), 5.17 (2H, broad s), 5.68 (0.7xlH, c ), 6.05 (0.3xlH, t), 6.75 (0.3xlH, d), 6.83 (0.7xlH, d), 7.18-7.43 (10H, m). MS m / z: 504 (M + 1).

Example 28-4- (4-Chlorophenyl) -1- [3- (2-cyano-6,11-dihydro-dibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol The compound of title was prepared following the procedure of example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] -cycloheptene by 11- (3-bromopropylidene) -2-cyano-6 , 11-dihydrodibenz [b, e] oxepin. H1 NMR (CDC13) d: 1.67-1.72 (2H, m), 2.02-2.13 (2H, m), 2.37-2.77 (8H, m), 5.35 (2H, s wide), 5.75 (0.7xlH, t), 6.07 (0.3xlH, t), 6.78 (0.3xlH, d), 6.82 (0.7xlH, d), 7, 25-7.51 (10H, m). MS m / z: 471 (M + 1).

Example 29-1- [3- (2-Aminomethyl-6,1, -d-hydro-dibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin--ol To one solution of 4- (4-Chlorophenyl) -1- [3- (2-cyano-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol (380 mg) in EtOH ( 20 ml) was added Raney nickel (50% suspension in water, 60 mg), and the mixture was hydrogenated at 1.02 atm. for 2 hours. The mixture was filtered through celite and distilled off under reduced pressure. The res was purified by silica gel chromatography eluting with dichloromethane-methanol-aqueous ammonia (95: 5: 1) to give the title compound (130 mg). H1 NMR (CDCl3) d: 1.76-1.94 (3H, m), 2X8-2.34 (2H, m), 2.85-3.10 (8H, m), 3.88 (2H, s), 5.30 (2H, broad s), 5.59 (1H, t), 6. 78 (1H, d), 7.13-7.40 (10H, m). MS m / z: 475 (M + 1).

Example 30-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-nitro-dibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] -cycloheptene with 11- (3-bromopropylidene) -6,1-dihydro 2-nitrodibenz [b, e] oxepin. H1 NMR (CDC13) d: 1.62-1.67 (2H, m), 1.80-2.12 (3H, m), 2.28-2.78 (8H, m), 5.05 ( 0.3x2H, broad s), 5.40 (0.7x2H, broad s), 5.90 (0.7xlH, t), 6.17 (0.3xlH, t), 6.82 (0.3xlH, d), 6.92 (0.7xlH), 7.28-7.41 (8H, m), 7.82 (1H, dd), 8.15 (0.7xlH, d), 8.22 ( , 3xlH, d). MS m / z: 491 (M + 1).

Example 31-1- [3- (2-Amino-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol To a solution of 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-nitrodibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol (120 mg) in EtOH (15 ml) tin (II) chloride (190 mg) was added, and the mixture was heated to reflux for 1 hour. The was removed by distillation under reduced pressure. To the residue was added ethyl acetate and scaciocuba for neutralization. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (95: 5) to give the title compound (70 mg). 1 H-NMR (CDCl 3) d: 1.54-1.60 (2H, m), 1.85-2.00 (2H, m), 2, SO2.80 (8H, m), 3.88 (2H, s), 5.07 (2H, broad s), 5.66 (1H, t), 6.41-6.46 (2H, m), 6.59 (1H, d), 7.24-7, 49 (8H, m). MS m / z: 461 (M + 1).

Example 32-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol Step 1 The 11- ( 3-bromopropylidene) -6, 11-dihydro-2-hydroxy-dibenz [b, e] oxepin was prepared following the procedure of example 45, step 1 and 2, but replacing 5, 11-dihydro-7-methoxypyrido [2, 3-c] [1] enzoxepin-5-one by 6,11-dihydro-2-hydroxy-dibenz [b, e] oxepin-11-one. H1 NMR (CDC13) d: 2.69 (2H, c), 3.39 (2H, t), 5.20 (2H, broad s), 5.92 (1H, t), 6.50-6, 81 (4H, m), 7.17-7.37 (4H, m).

Step 2 The title compound was prepared following the procedure of Example 45, Step 3, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by the product of Step 1 H1 NMR (CDCl3) d: 1.60-1.75 (3H, m), 1.95-2.10 (2H, m), 2.35-2.80 (8H, m), 5.10. (2H, broad s), 5.93 (1H, t), 6.56 (2H, broad s), 6.71 (1H, broad s), 7.11-7.35 (8H, m). MS m / z: 462 (M + l) Example 33-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin-ll-ylidene) propyl] piperidin-4-ol Step 1 The 11- ( 3-bromopropylidene) -6, 11-dihydro-2-methoxy-dibenz [b, e] oxepin was prepared following the procedure of example 45, step 1 and 2, but replacing 5, 11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one by 6,11-dihydro-2-methoxydibenz- [b, e] oxepin-11-one. 1 H-NMR (CDCl 3) d: 2.74 (2H, c), 3.43 (2H, t), 3.77 (3H, s), 5.10 (2H, broad s), 6.02 (1H, t), 6.70-6.83 (3H, m), 7.21-7, 38 (4H, m).

Step 2 The title compound was prepared following the procedure of example 45, step 3, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by the product of step 1 H1 NMR (CDC13) d: 1.59-1.65 (2H, m), 1.95-2.66 (11H, m), 3.75 (3H, s), 5.10 (2H, s) width), 6.03 (1H, t), 6.69 (2H, broad s), 6.82 (1H, broad s), 7.20-7.40 (8H, m). MS m / z: 476 (M + l) EXAMPLE 34-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-ethoxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol To a solution of 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxydibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol (Example 32) (200 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 25 mg), ethyl iodide (0.052 ml) 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (1: 1) to give the title compound (170 mg). NMR H1 (CDCl3) d: 1.37 (3H, t), 1.60-1.65 (2H, m), 1.95-2.08 (3H, m), 2.28-75 (8H, m), 3.96 (2H, c), 5.15 (2H, broad s), 6.02 (1H, t), 6.68 (2H, broad s), 6.82 (1H, broad s) , 7.19-7, 42 (8H, m). MS m / z: 490 (M + l) Example 35-1- [3- (3-Bromo-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol Step 1 The 3-bromine -ll- (3-bromopropylidene) -6,11-dihydro-dibenz [b, e] oxepin was prepared following the procedure of example 45, step 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one by 3-bromo-6,11-dihydrodibenz- [b, e] oxepin-11-one. NMR H1 (CDC13) d: 2.74 (2H, c), 3.43 (2H, t), 3.77 (3H, s), 5.10 (2H, broad s), 6.02 (1H, t), 6.70-6.83 (3H, m), 7.21-7, 38 (4H, m).

Step 2 The title compound was prepared following the procedure of Example 45, Step 3, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by the product of Step 1 X-NMR (CDCl 3) d: 1.63-1.70 (3H, m), 1.96-2.10 (2H, m), 2.32-2.69 (8H, m), 5.20 (2H, broad s), 6.00 (1H, t), 6.92-7.00 (2H, m), 7.11-7.14 (1H, m), 7.24-7.42 (8H, m). MS m / z: 524, 526 (M + l) Example 36-4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4-methoxypiperidine To a solution of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin-11-ylidene) propyl] -p? Peridin-4-ol (Example 2) (400 mg) in DMF (5 ml. ) sodium hydride (60% in oil, 50 mg), methyl iodide (0.07 ml) was added 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (1: 1) to give the title compound (100 mg). 1 H-NMR (CDCl 3) d: 1.90-2.04 (4H, m), 2.34-2.62 (8H, m), 2.93 (3H, s), 5.25 (2H, broad s) ), 6.04 (1H, t), 6.75-6.91 (3H, m), 7, 09-7, 37 (9H, m). MS m / z: 460 (M + l) Example 37 - 4-Acetoxy-4- (4-chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidine To a solution of 4- (4-chlorophenyl) ) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin-11-ylidene) propyl] -piperidin-4-ol (Example 2) (200 mg) in dichloromethane (5 ml) acetyl chloride (0.06 ml), triethylamine (0.19 ml) were added and the mixture was stirred at room temperature for 1 hour. 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (1: 4) to give the title compound (190 mg). 1 H-NMR (CDCl 3) d: 1.98-2.85 (12H, m), 2.02 (3H, s), 2.93 (3H, s), 5.23 (2H, broad s), 6, 01 (1H, t), 6.73-6.90 (3H, m), 7, 11-7, 40 (9H, m). MS m / z: 480 (M + l) Example 38-1- [3- (8-Bromo-4,10-dihydrothieno [3,2- c] [1] benzoxepin-10-ylidene) propyl] piperidin-4- (4-chlorophenyl) -4-ol Step 1 8-Bromo-10- (3-bromopropylidene) -4,10-dihydro-thieno [3,2-c] [1] benzoxepin was preradio-, following the procedure of Example 45, step 1 and 2 , but replacing , 11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one by 4,10-dihydrothieno [3,2-c] [1] -benzoxepin-10-one. 1 H-NMR (CDCl 3) d: 2.84 (2H, c), 3.45 (2H, t), 5.10 (2H, s), 6.11 (1H, t), 6.65 (1H, d) ), 7.03-7.08 (2H, m), 7.38-7.43 (2H, m).

Step 2 The title compound was prepared following the procedure of Example 45, Step 3, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by the product of Step 1 H1 NMR (CDCl3) d: 1.66-1.75 (3H, m), 2.03-2.16 (2H, m), 2.40-2.86 (8H, m), 5.09 (0.7x2H, s), 5.14 (0.3x2H, s), 5.90 (0.3xlH, t), 6.10 (0.7xlH, t), 6.64 (0.7xlH, d ), 6.75 (0.3xlH, d), 6.90 (0.3xlH, d), 7.03-7.09 (2H, m), 7.21-7.45 (6H, m). MS m / z: 532 (M + l) Example 39-4- (4-Chlorophenyl) -1- [3- (6, 11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol 11- (3-bromopropylidene) -6,1-dihydro-6-oxo-5H -dibenz [b, e] azepine was prepared following the procedure of example 45, step 1 and 2, but replacing 5, 11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one by 6. , ll-dihydro-6-5H-dibenz [b, e] -azepin-6, 11-dione. 1 H-NMR (CDCl 3) d: 2.70-2.92 (2H, m), 3.45 (2H, t), 5.92 (1H, t), 7.08-7.58 (7H, m) , 8.05 (1H, dd), 9.00 (1H, broad s).

Step 2 The title compound was prepared following the procedure of Example 45, Step 3, but replacing 5- (3-bromopropylidene) -10,1-dihydro-5H-dibenzo [a, d] cycloheptene by the product of Step 1 . 1 H NMR (CDCl 3) d: 1.61-1.66 (2H, m), 1.97-2.20 (3H, m), 2.35-2.68 (8H, m), 5.80 ( 1H, t), 7.03-7.53 (11H, m), 8.02 (1H, dd), 9, 27 (1H, broad s). MS m / z: 459 (M + l) Example 40-4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-ethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 The title compound was prepared following the procedure of Example 12, but replacing the benzyl bromide with ethyl iodide. NMR H1 (CDCl3) d: 1.19-2.28 (3H, m), 1.63-1.69 (2H, m), 1.99- 2.16 (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 (11H, m), 7.85 (1H, dd). MS m / z: 487 (M + l) Example 41-1- [3- (5-n-Butyl-6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-1-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol The title compound was prepared following the procedure of example 12, but replacing benzyl bromide with ethyl iodide. H1 NMR (CDC13) d: 0.90-0.98 (3H, m), 1.25-2.20 (9H, m), 2.40-2.87 (8H,), 3.62-3 , 72 (1H, m), 4.52-4.64 (1H, m), 5.85 (1H, t), 7.16-7.45 (11H, m), 7.88 (1H, dd ). MS m / z: 515 (M + l) Example 42-4- (Chlorophenyl) -1- [3- (6,11-dihydro-5- (3-hydroxypropyl) -6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4-ol To a solution of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-ll-ylidene) propyl hydrochloride ] piperidin-4-ol (Example 39) (500 mg) were added sodium hydride (60% in oil, 200 mg), 2- (3-bromopropoxy) tetrahydro-2H-pyran (0.5 ml) 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 magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 1M hydrogen chloride in diethyl ether and stirred at room temperature for 1 hour. 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, magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate (1: 4) to give the title compound (250 mg). H1 NMR (CDC13) d: 1.25-2.87 (15H, m), 3.51-3.56 (2H, m), 3.76-3.82 (1H, m), 4.81- 4.87 (1H, m), 5.86 (1H, t), 7.16-7.45 (11H,), 7.82 (1H, dd). MS m / z: 517 (M + l) Example 43-1- [3- (5-t-Butoxycarbonylmethyl-6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-1-ylidene) propyl] -4- (4-chlorophenyl) - piperidin-4-ol The title compound was prepared following the procedure of example 12, but replacing the benzyl bromide with t-butyl bromoacetate. 1 H-NMR (CDCl 3) d: 1.50 (9H, s), 1.65-1.70 (2H, m), 1.95-2.10 (3H, m), 2.42-2.75 (8H, m), 4.24 (1H, d), 4.75 (1H, d), 5.88 (1H, t), 7.16-7.46 (11H, m), 7.90 (1H, dd). MS m / z: 573 (M + 1) Example 44-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [l] benzoxepino [2,3-b] pyridine- 5-ylidene) propyl] -p? Peridin-4-ol Step 1 To a solution of the product of Example 45, step 1 (4.3 g) in dichloromethane (100 ml) was added boron tribromide-methyl sulfide complex (19.3 g) and the mixture was heated to reflux for 3 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with a diluted NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1: 2) to give 5- (3-bromopropylidene) -5,1-dihydro-7-hydroxy [1] -benzoxepin [2, 3 -b] pyridine (3.2 g). NMR H1 (CDC13) d: 2.72 (2H, c), 3.45 (2H, t), 5.28 (2H, broad s), 6.03 (1H, t), 6.66-6, 80 (3H, m), 7.26 (1H, dd), 7.58 (1H, dd), 8, 51 (1H, dd).

Step 2: The title compound was prepared following the procedure of Example 45, step 3, but replacing 5- (3-bromopropylidene) -5,1-dihydro-7-methoxy [1] benzoxepin [2, 3-b] pyridine by the product of step 1. 1 H-NMR (DMSO-d6) d: 1, 46-1, 51 (2H, m), 1.74-1.85 (2H, m), 2.29-2.51 (8H, m), 5.15 (2H, broad s), 6.07 (1H, t), 6.61-6.70 (3H, m), 7.33-7.48 (5H, m) , 7.73 (1H, dd), 8.47 (1H, dd), 9, 06 (1H, s). MS m / z 463 (M + 1) Example 45-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine- 5-ylidene) propyl] -piperidin-4-ol Step 1 To a solution of 5,11-dihydro-7-methoxy [1] -benzoxepino [2,3-b] pyridin-5-one (0.5 g) in THF (50 ml) a 1M solution of cyclopropylmagnesium bromide in THF (25 ml) was added at 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 aqueous sodium chloride, and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1: 2) to give 5-cyclopropyl-5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ol ( 5.0 g).

Step 2 To a solution of the product from step 1 (4.3 q) in acetic acid (30 ml) was added 48% aqueous HBr (25 ml) 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 a diluted NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1: 4) to give 5- (3-bromopropylidene) -5,11-dihydro-7-methoxy [1] benzoxepin [2, 3- b] pyridine (5.6 g). H1 NMR (CDC13) d: 2.74 (2H, c), 3.46 (2H, t), 3.78 (3H, s), 5.25 (2H, broad s), 6.07 (1H, t), 6.72-6.82 (3H,), 7.21-7.42 (5H, m), 7.56 (1H, dd), 8.45 (1H, dd). Step 3 To a solution of the product from step 2 (1.1 g) in DMF (15 ml) were added 4- (4-chlorophenyl) -4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53). g) 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 washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10: 1) to give the title compound as the major regioisomer (0.86 g) and the minor regioisomer (0.05 g). Majority isomer H1 NMR (CDC13) d: 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, broad s), 6.07 (1H, t), 6.72-6.82 (3H, m), 7.21-7.42 (5H, m), 8.45 (1H, dd). MS m / z: 477 (M + 1) Minor isomer H 1 NMR (CDCl 3) d: 1.65-1.79 (3H, m), 2.01-2.13 (2H, m), 2.35- 2.76 (8H, m), 3.76 (3H, s), 5.22 (2H, broad s), 5.95 (1H, t), 6.72-6.80 (2H, m), 7.06 (1H, d), 7.16 (1H, dd), 7.28 (2H, d), 7.42 (2H, d), 7.66 (1H, dd), 8.39 (1H, dd). MS m / z: 477 (M + l) Example 46-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethoxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) propyl] -piperidin-4- The title compound was prepared following the procedure of Example 34, but replacing 4- (4-chlorophenyl) -l- [3- (6,11-dihydro-2-hydroxydibenz [b, e] -oxepin-11-ylidene ) propyl] piperidin-4-ol by 4- (4-chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy- [1] benzoxepino- [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol (example 44).

NMR H1 (CÜC13) d: 1.38 (3H, t), 1.67-1.72 (3H, m), 2.05-2.16 (2H, m), 2.40-2.80 ( 8H, m), 3.99 (2H, c), 5.26 (2H, broad s), 6.05 (1H, t), 6.71-6.82 (3H, m), 7.23- 7.43 (5H, m), 7.57 (1H, dd), 8, 47 (1H, dd). MS m / z: 491 (M + l) Example 47-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-isopropoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4- The title compound was prepared by following the procedure of Example 46, but replacing the ethyl iodide with isopropyl bromide. NMR H1 (CDCI3) d: 1.30 (6H, d), 1.60-1.70 3H,), 1.99-2.09 (2H, m), 2.33-2.69 (8H,), 4.37-4.48 (1H, m), 5.26 (2H, broad s), 6.06 (1H, t), 6.73-6.82 (3H, m), 7.21-7.43 (5H, m), 7, 55 (1H, dd), 8.47 (1H, dd). MS m / z: 505 (M + l) Example 48-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethoxycarbonylmethyloxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl bromoacetate. NMR H1 (CDCI3) d: 1.28 (3H, t), 1.63-1.68 (2H, m), 1.97-2.02 (3H, m), 2.33-2.68 (8H, m), 4.24 (2H, c), 4.55 (2H, s), 5.26 (2H, broad s), 6.06 (1H, t), 6.73-6.88 (3H, m), 7.21-7.42 (5H, m), 7.55 (1H, dd), 8.44 (1H, dd). MS m / z: 549 (M + l) Example 49-4- (4-Chlorophenyl) -1- [3- (7-cyanomethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4- The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with bromoacetonitrile. NMR H1 (CDCI3) d: 1.62-1.67 (2H, m), 1.94-2.06 (2H, m), 2.21 (1H, broad s), 2.34-2.66 (8H, m), 4.70 (2H, s), 5.26 (2H, broad s), 6.10 (1H, t), 6.80 (2H, broad s), 6.92 (1H, s wide), 7.22-7.41 (5H, m), 7.56 (1H, dd), 8.44 (1H, dd). MS m / z: 502 (M + l) Example 50-1- [3- (7- (2-Acetoxyethyl) oxy-5,11-dihydro [1] -benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) ) piperidin-4-oi The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2-bromoethyl acetate. 1 H-NMR (CDCl 3) d: 1.65-1.72 (2H, m), 1.97-2.09 (5H, m), 2.37-2.70 (8H, m), 4.11- 4.14 (2H, m), 4.37-4.41 (2H, m), 5.25 (2H, broad s), 6.07 (1H, t), 6.75-6.84 (3H , m), 7.23-7.43 (5H, m), 7.56 (1H, dd), 8.47 (1H, dd). MS m / z: 549 (M + l) Example 51-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyethyl) oxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4-ol To a solution of 1- [3- (7- (2-acetoxyethyl) oxy-5,11-dihydro [1] -benzoxepino [2,3-pyridin-5-ylidene] propyl] 4- (4-chlorophenyl) piperidin-4-ol (Example 50) (140 mg) in ethanol (5 ml) was added a 15% aqueous solution of sodium hydroxide (2 ml) 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10: 1) to give the title compound (120 mg). NMR H1 (CDC13) d: 1.64-1.69 (2H, m), 1.98-2.10 (3H, m), 2.36-2.79 (8H, m), 3.89- 3.94 (2H, m), 3.99-4.04 (2H, m), 5.24 (2H, broad s), 6.04 (1H, t), 6.71-6.84 (3H , m), 7.23-7.41 (5H, m), 7, 54 (1H, dd), 8, 43 (1H, dd). MS m / z: 507 (M + l) Example 52-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-morpholinoethyl) oxy [l] benzoxepino [2,3-pyridin-5-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 4- (2-chloroethyl) morpholine hydrochloride. 1 H-NMR (CDCl 3) d: 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 (4H, m), 4.04 (2H, t), .23 (2H, broad s), 6.05 (1H, t), 6.73-6.82 (3H, m), 7.20-7.41 (5H, m), 7.53 (1H , dd), 8.42 (1H, dd). MS m / z: 576 (M + l) Example 53-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro- [1] -benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperidin-4-ol Step 1: 5- (3-Bromopropylidene) -5,11-dihydro [1] benzoxepino- [2, 3-b] pyridine was prepared following the procedure of example 45, step 1 and 2, but replacing 5,11-dihydro -7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-one by 5,11-dihydro [l] benzoxepino [2,3-b] pyridin-5-one. NMR H1 (CDCl3) d: 2.71 (2H, c). 3.46 (2H, t), 5.33 (2H, broad s), 6.04 (1H, t), 7.01-7.17 (3H, m), 7.29 (1H, dd), 7.56 (1H, dd), 8, 53 (1H, dd).

Step 2: The title compound was prepared following the procedure of Example 45, step 3, but replacing 5- (3-bromopropylidene) -5,11-dihydro-7-methoxy [1] -benzoxepino [2,3-b] pyridine by the product of step 1. 1 H NMR (CDC13) d: 1.66-1.71 (2H, m), 2.00-2.20 (3H, m), 2.36-2.69 (8H , m), 5.34 (2H, broad s), 6.10 (1H, t), 6.83-6.96 (3H, m), 7.17-7.44 (6H, m), 7 , 60 (1H, dd), 8.46 (1H, dd). MS m / z: 447 (M + l) Example 54-1- [3- (8-Bromo-5,11-dihydro- [1] -benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4 -ol Step 1 8-Bromo-5- (3-bromopropylidene) -5,11-dihydro [1] -benzoxepino- [2, 3-b] pyridine was prepared following the procedure of example 45, step 1 and 2, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] -pyridin-5-one by 8-bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridine -5-ona. 1 H-NMR (CDCl 3) d: 2.75 (2H, q), 3.50 (2H, t), 5.38 (2H, broad s), 6.08 (1H, t), 6.85-6, 98 (2H, m), 7.18-7.35 (3H, m), 7.59 (1H, dd), 8.54 (1H, dd).

Step 2: The title compound was prepared following the procedure of Example 45, step 3, but replacing 5- (3-bromopropylidene) -5,1-dihydro-7-methoxy [1] -benzoxepino [2,3-b] pyridine by the product of step 1. 1 H-NMR (CDCl 3) d: 1.64-1.69 (2H, m), 1.90-2.07 (3H, m), 2.30- 2.67 (8H , m), 5.30 (2H, broad s), 6.08 (1H, t), 7.00-7.07 (2H, m), 7.13 (1H, d), 7.25-7 , 42 (5H, m), 7.56 (1H, dd), 8.47 (1H, dd). MS m / z: 525, 527 (M + 1) Example 55-4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-10-oxo-5H-pyrido [2,3-c] [2] benzazepin-5-ylidene) propyl] -piperidin-4-o1 Step 1 5- (3-Bromopropylidene) -10,1-dihydro-10-oxo-5H-pyrido [2, 3-c] [2 ] benzazepine was prepared following the procedure of example 45, step 1 and 2, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 10,11-dihydro- 5H-pyrido [2, 3-c] [2] -benzazepin-5, 10-dione. NMR H1 (CDC13) d: 2.75-2.90 (2H, m), 3.45 (2H, t), 5.92 (1H, t), 7.04-7.70 (5H, m) , 8.10 (1H, dd), 8.48 (1H, dd), 10.00 (1H, broad s).

Step 2: The title compound was prepared following the procedure of example 45, step 3, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene by the product of the step 1. H1 NMR (CDCl3) d: 1.64-1.69 (3H, m), 2.00-2.12 (2H, m), 2.35-2.70 (8H, m), 5 , 82 (1H, t), 7.08 (1H, dd), 7.23-7.62 (8H, m), 8.04 (1H, dd), 8.32 (1H, dd), 8.76 (1H, broad s). MS m / z: 460 (M + l) Example 56 - 4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-11-methyl-10-oxo-5H-pyrido [2,3-c] [2] benzazepin-5-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of example 36, but replacing 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] ] -oxepin-11-ylidene) propyl] piperidin-4-ol by 5- (3-bromo-propylidene) -10,11-dihydro-10-oxo-5H-pyrido [2, 3-c] [2] - Benzazepine 1 H-NMR (CDCl 3) d: 1.64-1.70 (3H, m), 2.00-2.10 (2H, m), 2.41-2.69 (8H, m), 3.62 ( 3H, s), 5.82 (1H, t), 7.07 (1H, dd), 7.25-7.54 (8H, m), 7.91 (1H, dd), 8.34 (1H , dd).

MS m / z: 474 (M + l) Example 57-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) ethyl] -piperidin-4- Step 1 To a solution of methyltriphenylphosphonium bromide (2.2 g) in THF (20 ml) was added a 1.6M solution of n-butyl lithium in hexane (2.9 ml) at 0 ° C for 30 minutes. To the reaction mixture cooled to 0 ° C was added 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one (1.0 g) drop to qota in the form of a THF solution (5 ml) 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 removed by distillation under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1: 4) to give 5,11-dihydro-7-methoxy-5-methylene-pyrido- [2,3-c] [1] benzoxepine ( 0.14 g).

Step 2 To a solution of DMF (0.54 ml) was added phosphorus oxychloride (0.41 ml) at 0 ° C for 10 minutes. To the reaction mixture was added the product of step 1 (210 mg) in carbon tetrachloride (5 ml) and the mixture was heated to reflux for 5 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 removed by distillation under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate-hexane (1: 4) to give 3- (5,11-dihydro-7-methoxy [1] benzoxepin [2, 3, b] pyridine-5 -ylidene, acetaldehyde (130 mg). H1 NMR (CDC13) d: 3.77 (0.7x3H, s), 3.79 (0.3x3H, s), 5.31 (2H, s), 6.46 (0.7xlH, d), 6.52 (0.3xlH, d), 6.78-7.40 (4H, m), 7.68 (0.3xlH, dd ), 7.78 (0.7xlH, dd), 8.55 (0.7xlH, dd), 8.64 (0.3xlH, dd), 9.62 (0.3xlH, d), 9.79 ( 0.7xlH, d).

Step 3 The title compound was prepared following the procedure of example 58, step 2, but replacing 3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-pyridin-5-ylidene) propanaldehyde by the product of step 2. 1 H-NMR (CDCl 3) d: 1.64-1.82 (2H, m), 1.92-2.22 (3H, m), 2.43-2.58 (2H , m), 2.79-3.45 (6H, m), 3.68 (0.3x3H, s), 3.70 (0.7x3H, s), 5.24 (2H, broad s), 6 , 18 (0.7xlH, t), 6.21 (0.3xlH, t), 6.72-7.42 (SH, m), 7.78 (0.3xlH, dd), 7.85 ( , 7xlH, dd), 8.42 (0.7xlH, dd), 8.46 (0.3xlH, dd). MS m / z: 463 (M + 1).

Example 58-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) ethyl] -piperidin- 4- Step 1. 3- (5,1-dihydro-7-methoxy [1] benzoxepino [2,3-b] -pyridin-5-ylidene) propenaldehyde was prepared following the procedure of Example 57, step 2, but replacing , 11-dihydro-7-methoxy-5-methylene [1] -benzoxepino [2,3-b] pyridine by 5,11-dihydro-7-methoxy-5- (propyl-1-ene) [1] benzoxepin [ 2, 3-b] pyridine (byproduct of example 45, step 3). NMR H1 (CDCl3) d: 3.78 (0.3x3H, s), 3.80 (0.7x3H, s), 5.32 (2H, broad s), 6.34-6.39 (1H, m) ), 6.72-7.38 (6H, m), 7.58 (0.7xlH, dd), 7.77 (0.3xlH, dd), 8.49 (0.3xlH, dd), 8, 60 (0.7xlH, dd), 9.51 (0.7xlH, d), 9.54 (0.3xlH, d).

Step 2 To a solution of the product from step 1 (90 mg) in dichloromethane (61 ml) were added sodium triacetoxyborohydride (170 mg), 4- (4-chlorophenyl) -4-hydroxypiperidine (70 mg) and acetic acid ( 0.02 ml) and the mixture was stirred at room temperature for 24 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 removed by distillation under reduced pressure. The residue was purified by chromatography on silica gel eluting with dichloromethane-methanol (95: 5) to give 4- (4-chlorophenyl) -1- [4- (5,11-dihydro-7-methoxy [1] benzoxepin [ 2, 3-b] pyridin-5-ylidene) buten-2-yl] -piperidin-4-ol (110 mg). NMR H1 (CDC13) d: 1.68-1.73 (2H, m), 2.04-2.16 (2H, m), 2.43-2.72 (3H, m), 2.77- 2.81 (2H, m), 3.08-3.13 (2H, m), 3.73 (0.3x3H, s), 3.77 (0.7x3H, s), 5.20 (2H, s wide), 5.98-6.05 (1H, m), 6.23-7.43 (10H, m), 7.58 (0.7xlH, dd), 7.65 (0.3xlH, dd) ), 8.37 (0.3xlH, dd), 8.45 (0.7xlH, dd). MS m / z: 489 (M + 1).

Step 3 To a solution of the product of step 2, (8 mg) in ethanol (2 ml) and 10% Pd-C (2 mg) was added and stirred in hydrogen (in a balloon) at room temperature during 1 hour. The mixture was filtered through celite and distilled off under reduced pressure to give the title compound (6 mg). H1 NMR (CDC13) d: 1.68-3.00 (15H, m), 3.77 (3H, s), 5.18-5.35 (2H, m), 5.94 (0.4H, t, E isomer), 6.06 (0.6H, t, Z isomer), 6.65-6.88 (3H, m), 7.05-7.73 (6H, m), 8.30- 8.56 (1H, m). MS m / z: 491 (M + 1).

Example 59-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] piperidin-4-phenyl-4-ol The compound of The title was prepared following the procedure of Example 45, Step 3, but replacing 4- (-chlorophenyl) -4-hydroxypiperidine with 4-phenyl-4-hydroxypiperidine. 1 H-NMR (CDCl 3) d: 1.68-1.73 (2H, m), 2.02-2.15 (3H, m), 2.38-2.72 (8H, m), 3.77 ( 3H, s), 5.26 (2H, broad s), 6.08 (1H, t), 6.72-6.83 (3H, m), 7.21-7.36 (4H, m), 7.46-7.49 (2H, m), 7.58 (1H, dd), 8, 46 (1H, dd). MS m / z: 443 (M + 1).

Example 60-4- (4-Bromophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] [2] pyridin-5-ylidene) propyl] -piperidine -4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-bromo-phenyl) -4-hydroxypiperidine. 1 H-NMR (CDCl 3) d: 1.65-1.69 (2H, m), 2.00-2.10 (3H, m), 2.37-2.71 (8H, m), 3.76 ( 3H, s), 5.24 (2H, broad s), 6.05 (1H, t), 6.70-6.82 (3H, m), 7.24 (1H, dd), 7.38 ( 2H, d), 7.44 (2H, s), 7, 52 (1H, dd), 8, 44 (1H, dd). MS m / z: 521, 523 (M + 1).

Example 61-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 4-hydroxy-piperidine. NMR H1 (CDC13) d: 1.43-1.60 (2H, m), 1.80-1.98 (2H, m), 2.00-2.18 (3H, m), 2.34- 2.48 (4H, m), 2.63-2.76 (2H, m), 3.64-3.73 (1H, m), 3.70 (3H, s), 5.35 (2H, s wide), 6.06 (1H, t), 6.74-6.84 (3H, m), 7.25 (1H, dd), 7.60 (1H, dd), 8.50 (1H, dd). MS m / z: 367 (M + 1).

Example 62-4-Benzyl-1- [3- (5,11-dihydro-7-methoxy [1] benzoxepin [2, 3-b] [2] pyridin-5-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-benzyl-4-hydroxypiperidine. 1 H-NMR (CDCl 3) d: 1.42-1.57 (3H, m), 3.62-1.75 (2H, m), 2.22-2.70 (8H, m), 2.79 ( 2H, s), 3.80 (3H, s), 5.25 (2H, broad s), 6.08 (1H, t), 6.73-6.84 (3H, m), 7.18- 7.24 (6H,), 7.57 (1H, dd), 8, 50 (1H, dd). MS m / z: 457 (M + 1).

Example 63 - 4-Cyano-l- [3- (5,11-Dihydro-7-ethoxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4-phenylpiperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-cyano-4-phenylpiperidine. H1 NMR (CDC13) d: 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, broad s), 6.08 (1H, t), 6.72-6.84 (3H, m), 7.24-7.58 (7H, m), 8.49 (1H, dd). MS m / z: 452 (M + 1).

Example 64-1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino- [2,3-b] [2] pyridin-5-ylidene) propyl] -4-phenylpiperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-phenyl-piperidine. H1 NMR (CDCI3) d: 1.73-1.79 (4H, m), 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, broad s), 6.08 (1H, t), 6.72-6.83 (3H, m), 7.17-7.31 (6H,), 7. 56 (1H, dd), 8, 49 (1H, dd). MS m / z: 426 (M + 1).

Example 65-4- (Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) piperidine. NMR-H1 (CDCl3) d: 1.68-1.74 (4H, m), 1.96-2.03 (2H, m), 2.36-2.48 (5H, m), 2.89 -2.94 (2H, m), 3.77 (3H, s), 5.27 (2H, broad s), 6.07 (1H, t), 6.73-6.83 (3H, m) , 7.10-7.27 (5H, m), 7. 57 (1H, dd), 8.48 (1H, dd). MS m / z: 461 (M + 1).

Example 66-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4-piperidinopiperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-piperidino-piperidine. NMR-H1 (CDC13) d: 1.40-2.00 (12H,), 2.15-2.60 (9H, m), 2.80-2.92 (2H, m), 3.80 ( 3H, s), 5.28 (2H, broad s), 6.05 (1H, t), 6.75-6.86 (3H, m), 7.3 (1H, dd), 7.55 ( 1H, dd), 8.46 (1H, dd). MS m / z: 434 (M + 1).

Example 67-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (2-keto-1-benzimidazolinyl) piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (2-keto-l-benzimidazolinyl) piperidine. NMR-H1 (CDCl3) d: 1.75-1.79 (2H, m), 2.03-2.15 (2H, m), 2.38-2.52 (6H, m), 2.93 -2.98 (2H, m), 3.78 (3H, s), 4.30-4.38 (1H, m), 5.30 (2H, broad s), 6.10 (1H, t) 6.73-6.84 (3H, m), 7.01-7.03 (3H, m), 7.21-7.28 (2H, m), 7.59 (1H, dd), 8.48 (1H, dd). MS m / z: 483 (M + 1).

Example 68-1- [3- (5,11-Dihydro-7-methoxy [1] enzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (2-keto-3-methyl- 1-benzimidazolinyl) piperidine The title compound was prepared following the procedure of example 36, but replacing 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin- 11-ylidene) propyl] piperidin-4-ol by 1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- ( 2-keto-1-benzimidazolinyl) piperidine. NMR-H1 (CDCI3) d: 1.72-1.76 (2H, m), 2.09-2.14 (2H, m), 2.23-2.54 (6H, m), 2.91 -2.96 (2H, m), 3.38 (3H, s), 3.77 (3H, s), 4.30-4.37 (1H, m), 5.27 (2H, s wide) , 6.08 (1H, t), 6.71-6.83 (3H, m), 6.93-7.06 (3H, m), 7.23-7.60 (2H, m), 8 , 08 (1H, dd), 8, 48 (1H, dd). MS m / z: 497 (M + 1).

Example 69 -8- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -1-phenyl-1,3,8-triazaspiro [4, 5] decan-4-one The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 1-phenyl-1,3,8- trizaspiro [4, 5] decan-4-one. NMR-H1 (CDCl3) d: 1.65-1.70 (2H, m), 2.36-2.41 (2H, m), 2.53-2.79 (8H, m), 3.76 (3H, s), 4.70 (2H, s), 5.25 (2H, broad s), 6.10 (1H, t), 6.71-6.88 (6H,), 7.21- 7.27 (3H, m), 7.58-7.61 (2H, m), 8, 48 (1H, dd). MS m / z: 497 (M + 1).

Example 70-4-Anilino-4-carbamyl-l- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine The compound of The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-anilino-4-carbamylpiperidine. NMR-H1 (CDCl3) d: 1.85-1.90 (2H, m), 2.03-2.08 (2H, m), 2.19-2.46 (6H, m), 2.62 -2.67 (2H, m), 3.75 (3H, s), 3.97 (1H, broad s), 5.27 (2H, broad s), 5.53 (1H, broad s), 6 , 03 (1H, t), 6.60 (2H, d), 6.70-6.85 (4H, m), 7.12-7.25 (4H, m), 7.53 (1H, dd), 8.46 (1H, dd). MS m / z: 485 (M + 1).

Example 71-1- (4-Chlorophenyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperazine The compound of The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with l- (4-chlorophenyl) piperazine. NMR-H1 (CDC13) d: 2.36-2.53 (8H, m), 3.07-3.09 (4H, m), 3.76 (3H, s), 5.26 (2H, s) width), 6.08 (1H, t), 6.72-6.81I5H, m), 7.16-7.28 (3H, m), 7.56 (1H, dd), 8.49 ( 1H, dd). MS m / z: 462 (M + 1).

Example 72-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (2-pyrimidyl) -piperazine The compound The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-pyrimidyl) -piperazine. NMR-H1 (CDCl3) d: 2.37-2.53 (8H, m), 3.74-3.83 (7H, m), 5.27 (2H, broad s), 6.08 (1H, t), 6.45 (1H, t), 6.72-6.83 (3H, m), 7.25 (1H, dd), 7.56 (1H, dd), 8.27 (2h, d), 8.49 (1H, dd).

MS m / z: 430 (M + 1).

Example 73-l-Cyclohexyl-4- [3- (5,11-dihydro-7-methoxy [1] -benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] piperazine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1-cyclohexyl-piperazine. NMR-H1 (CDCI3) d: 1.12-1.27 (6H, m), 1.74-1.86 (6H, m), 2.18-2.52 (11H, m), 3.76 (3H, s), 5.26 (2H, broad s), 6.04 (1H, t), 6.74-6.81 (3H, m), 7.23 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd). MS m / z: 434 (M + 1).

Example 74-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (2-furoyl) piperazine The compound of The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-furoyl) -piperazine. NMR-H1 (CDC13) d: 2.34-2.48 (8H, m), 3.71-3.74 (7H, s), 5.24 (2H, broad s), 6.05 (1H, dd), 6.42 (1H, dd), 6.70-6.80 (3H, m), 6.93 (1H, d), 7.23 (1H, dd), 7.42 (1H, d) ), 7.53 (1H, dd), 8, 46 (1H, dd). MS m / z: 446 (M + 1).

Example 75-4- (3-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4- The title compound was prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (3-chlorophenyl) -4-hydroxypiperidine. NMR-H1 (CDCl3) d: 1.61-1.75 (2H, m), 1.98 (1H, broad s), 1.99 (2H, td), 2.25 (3H, s), 2 , 30-2.76 (8H, m), 3.73 (3H, s), 5.22 (2H, broad s), 5.95 (0.1H, t, E-isomer), 6.04 ( , 9H, t, Z isomer), 6.71-6.89 (3H, m), 6.95 (1H, dd), 7.15-7.20 (0.3H, m, E isomer), 7 , 21-7.35 (2.7H, m, Z-isomer), 7.53 (0.9H, dd, Z-isomer), 7.65 (0.1H, dd, E-isomer), 8.35 (0H) , 1H, dd, E isomer), 8.45 (0.9H, dd, Z isomer). MS m / z: 477 (M + 1).

Example 76-4- (2-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine-4- The title compound was prepared following the procedure of Example 45, Step 3, but replacing 4- (4-chlorophenyl) -4-hydrox? p? pepdma by 4- (2-chlorophenyl) -4-hydroxy. ? p? per? dma. NMR-H1 (CDCl3) d: 1.98-2.08 (2H, m), 2.24 (2H, td), 2.38-2.78 (9H, m), 3.77 (3H, s) ), 5.27 (2H, broad s), 6.08 (1H, t), 6.82-6.75 (3H, m), 7.28-7.19 (3H, m), 7.33 (1H, dd), 7.49 (1H, dd), 7.58 (1H, dd), 8.40 (0.1H, dd, Z-isomer), 8.47 (0.9H, dd, E-isomer) ). MS m / z: 477 (M + 1).

Example 77-1- [3- (5,11-D? -hydro-7-methoxy? [1] benzoxepmo- [2, 3-b] p? Pdm-5? L? Deno) propyl] -4 - (4-fluorophen? L) p? Per? Dm-4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydrox? P ? per? dma by 4- (4-fluorophenyl) -4-h? drox? p? pepdma. NMR-H1 (CDCl3) d: 1.58-1.72 (2H, m), 2.04 (2H, td), 2.22-2.78 (9H, m), 3.75 (3H, s) ), 5.26 (2H, broad s), 6.09 (1H, t), 6.70-6.88 (3H, m), 7.00 (2H, dd), 7.23 (1H, dd) ), 7.42 (2H, dd), 7.56 (1H, dd), 8.41 (1H, dd). MS m / z: 461 (M + 1).

Example 78-1- [3- (5,11-D? -hydro-7-methoxy? [1] benzoxepmo- [2, 3-b] p? Pdm-5? L? Deno) propyl] -4 - (p-tolyl) p? per? d? n-4-ol The title compound was prepared following the procedure of example 45, step _ > , but replacing 4- (4-chlorophenyl) -4-h? drox? p? pepd? na by 4- (p-tolyl) -4-hydroxypiperidine. NMR-H1 (CDCl3) d: 1.65-1, l or (2H, m), 2.02 (2H, td), 2.31 (3H, s), 2.24-2.75 (9H, m), 3.75 (3H, s), 5.25 (2H, broad s), 6.07 (1H, t), 6.72-6.84 (3H, m), 7.13 (2H, d), 7.23 (1H, dd), 7.34 (1H, d), 7.56 (1H, dd), 8.43 (1H, dd). MS m / z: 457 (M + 1).

Example 79-4- (3,4-D? Chlorophenyl) -1- [3- (5,11-d? H? Dro-7-methoxy [1] benzoxepin- [2,3-b] pyridine-5- ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,4-dichlorophenyl) - 4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.58-1.72 (2H, m), 1.84 (1H, broad s), 2.02 (2H, dt), 2.32-2.72 (8H, m), 3.76 (3H, s), 5.27 (2H, broad s), 5.95 (0.1H, t, E isomer), 6.07 (0.9H, t, Z isomer), 6.72-6.85 (3H, M), 7.12-7.20 (0.2H, m, E-isomer), 7.21-7.32 (0.1H, m, Z-isomer), , 32-7.45 (1H, m), 7.52-7.56 (2H, m), 8.37 (0.9H, dd, E-isomer), 8.45 (0.1H, dd, isomer Z) MS m / z: 512 (M + l) Example 83-4- (5-Chloropyridin-2-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -piperidin-4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 4- (5-chloropyridin-2-yl) -4- hydroxypiperidine. NMR-H1 (CDCl3) d: 1.77-1.82 (2H,), 2.36-2.94 (11H, m), 3.77 (3H, broad s), 5.26 (2H, s) width), 6.07 (1H, t), 6.76-6.84 (3H, m), 7.26 (1H, dd), 8.49-7.48 (1H, d), 8.42 -8.53 (3H, m). MS m / z: 478 (M + l) Example 85-4- (5-Chloro-2-keto-1-benzimidazolinyl) -1- [3- (5,1, -dihydro-7-methoxy [1] benzoxepin- [2, 3-b] pyridine-Silidene) propyl] piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (-chlorophenyl) -4-hydroxypiperidine with 4- (5-chloro-2-keto-l-benzimidazolinyl) piperidine. NMR-H1 (CDCl3) d: 1.68-1.72 (2H, m), 2.03-2.60 (8H,), 2.90- 3.02 (2H, m), 3.78 ( 3H, s), 4.32-4.21 (1H,), 5.29 (2H, broad s), 5.95 (0.1H, t, E-isomer), 6.08 (0.9H, t , Z-isomer), 6.70-6.92 (3H, m), 7.02 (1H, dd), 7.08-7.20 (1H, m), 7.26 (1H, dd), 7.58 (0.9H, dd, Z-isomer), 7.70 (0.1H, dd, E-isomer), 8.42 (0.1H, dd, E-isomer), 8, 48 (0.9H, dd, Z-isomer), 10.5 (1H, s). (No NH is observed in the spectrum). MS m / z: 517 (M + l) Example 86-4- (p-Chloroanilino) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperidine The compound of title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 4- (p-chloroanilino) -piperidine. NMR-H1 (CDC13) d: 1.20-1.54 (2H, m), 1.85-2.20 (4H, m), 2.24-2.60 (4H, m), 2.73 (2H, m), 3.18 (1H, m), 3.77 (3H, s), 5.27 (2H, broad s), 6.06 (1H, t), 6.47 (2H, m ), 6.68-6.90 (3H, m), 7.07 (2H, m), 7.24 (1H, dd), 7.57 (1H, dd), 8.48 (1H, dd) . No NH signal was observed. MS m / z: 476 (M + l) Example 89-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (p-tosyl) piperazine The compound of The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1- (p-tosyl) -piperazine. NMR-H1 (CDCl3) d: 2.20-2.54 (11H, m), 2.85-3.10 (4H, m), 3.73 (3H, s), 5.16 (2H, s) width), 6.00 (1H, t), 6.66-6.85 (3H, m), 7.21 (1H, dd), 7.31 (2H, m), 7.51 (1H, dd), 7.61 (2H, m), 8, 45 (1H, dd). MS m / z: 506 (M + 1) Example 90-1 '- [3- (5,11-Dihydro-7-methoxy [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] spiro [isobenzofuran-1 (3H), 4'-piperidine] The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by spiro- [isobenzofuran-1] (3H), 4'-piperidine]. H-NMR (CDC13) d: 1.62-1.82 (2H, m), 1.92 (2H, td), 2.25-2.85 (8H, m), 3.76 (3H, s), 5.03 (2H, s), 5.30 (2H, broad s), 6.11 (1H, t), 6.68-6.90 (3H, m), 7.02-7, 34 (5H, m), 7.58 (1H, dd), 8, 48 (1H, dd). MS m / z: 455 (M + l) Example 91 - 5-Chloro-l '- [3- (5,11-dihydro-7-methoxy [1] -benzoxepin- [2,3-b] pyridin-5-ylidene) propyl] -spiro- [isobenzofuran- 1 (3H), '-piperidine] The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 5-chlorospiro- [isobenzofuran-1 (3H) , 4 '-piperidine]. NMR-H1 (CDCl3) d: 1.69-1.74 (2H, m), 1.81-1.93 (2H, m), 2.30-2.44 (4H,), 2.52- 2.63 (2H, m), 2.71-2.75 (2H, m), 3.79 (3H, s), 5.00 (2H, s), 5.28 (2H, broad s), 6.09 (1H, t), 6.73-6.84 (3H, m), 7.03 (1H, d), 7.17-7.28 (3H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS m / z: 489 (M + l) Example 111-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzothiepino- [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4 -ol The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5,11-dihydro [] ] benzothiepino [2,3-b] pyridin-5-one.

NMR-H1 (CDCl3) d: 1.66-1.78 (3H, m), 2.04-2.65 (10H, m), 3.66 (1H, broad d), 5.05 (1H, d wide), 6.03 (1H, t), 7.04-7.46 (10H, m), 8, 44 (1H, dd). MS m / z: 463 (M + l) Example 114-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4 -o1 The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-one by 5,11-dihydro-8 -methoxy [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDCl3) d: 1.66-1.70 (3H, m), 1.92-2.09 (2H, m), 2.34-2.70 (8H, m), 3.75 (3H, s), 5.32 (2H, broad s), 6.02 (1H, t), 6.39 (1H, d), 6.51 (1H, dd), 7.19-7.44 (6H, m), 7.57 (1H, dd), 8, 49 (1H, dd). MS m / z: 477 (M + l) Example 115-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4- The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5,11-dihydro-7- methyl [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDCl3) d: 1.50 (1H, broad s), 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 (2H, m), 5.30 (2H, broad s) ), 6.08 (1H, t), 6.76 (1H, d), 6.97 (1H, dd), 7.09 (1H, d), 7.24-7.44 (5H, m) , 7.57 (1H, dd), 8, 49 (1H, dd). MS m / z: 461 (M + l) Example 117-1- [3- (7-Chloro-5,11-dihydro [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl J -4- (4-chlorophenyl) -piperidin-4 -ol The title compound was prepared following the procedure of example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 7-chloro-5, -dihydro [l] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDC13) d: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.44 (4H, m), 2.52 -2.57 (2H, m), 2.66-2.70 (2H, m), 5.32 (2H, broad s), 6.13 (1H, t), 6.78 (1H, d) , 7.11 (1H, dd), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.51 (1H, dd). MS m / z: 481 (M + l) Example 118-1- [3- (7-Carboxy-5,11-dihydro [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) -piperidin-4 -ol A mixture of the product of Example 169 (500 mg), potassium acetate (330 mg), palladium (II) diacetate (10 mg), 1,1 '-bis (diphenylphosphino) ferrocene (93 mg), in dimethylsulfoxide (10 ml) was purged with carbon monoxide for 5 minutes and stirred in a carbon monoxide balloon at 60 ° C for 3 hours. Water was added to the reaction mixture, the precipitate was filtered. The solid was dissolved with ethyl acetate and a dilute sodium hydroxide solution. The aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitate was filtered to give the title compound (250 mg). NMR-H1 (DMSO-d6) d: 1.45-1.55 (2H, m), 1.75-1.85 (2H, m), 2.36-2.62 (8H, m), 5 , 42 (2H, broad s), 6.21 (1H, t), 6.90 (1H, d), 7.40-7.52 (5H, m), 7.75 (1H, dd), 7 , 83 (1H, dd), 7, 95 (1H, d), 8.56 (1H, dd). MS m / z: 491 (M + 1) Example 128-4- (4-Chlorophenyl) -1 - [3- (, 11-d? H? Dro-7-propoxy [1] benzoxepmo [2, 3-b The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with propyl iodide. NMR-H1 (CDC13) d: 1.03 (3H, t), 1.65-1.70 (2H, m), 1.78 (2H, c), 1.98-2.09 (3H, m ), 2.37-2.45 (4H, m), 5.51-2.56 (2H, m), 2.66-2.70 (2H, m), 3.88 (2H, t), 5.26 (2H, broad s), 6.08 (1H, t), 6.72-6.84 (3H, m), 7.23-7.43 (5H, m), 7.58 (1H , dd), 8, 43 (1H, dd). MS m / z: 505 (M + l) Example 130-4- (4-Chlorophenyl) -1- [3- (7-c? Cloprop? L-met? Lox? -5, ll-d? H? Dro [l] benzoxepino [2, 3-b] p? r? dm-5-ididene) propyl] p? pepd? n-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with cyclopropylmethyl iodide. NMR-H1 (CDCl3) d: 0.31-0.37 (2H, m), 0.60-0.67 (2H,), 1.21-1.28 (1H, m), 1.66- 1.72 (3H, m), 2.01-2.11 (2H, m), 2.37-2.71 (8H, m), 3.77 (2H, d), 5.27 (2H, broad s), 6.08 (1H, t), 6.73-6.86 (3H, m), 7.23-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS m / z: 517 (M + l) Example 131-4- (4-Chlorophenyl) -1- [3- (5,11-d? -hydro-7- (-dimethylaminoethyl) 0x1) [1] benzoxepin [2, 3-b] p? R? d? n-5? l? deno) prop? l] p? per? dm-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2- (2-chloride hydrochloride dimethylamine) -ethyl. NMR-H1 (CDCI3) d: 1.71-1.76 (2H, m), 2.12-2.21 (2H, m), 2.38 (6H, s), 2.40-2.79 (11H, m), 4.07 (2H, t), 5.28 (2H, broad s), 6.07 (1H, t), 6.74-6.86 (3H, m), 7.27 -7.46 (5H, m), 7, 59 (1H, dd), 8, 49 (1H, dd). MS m / z: 534 (M + l) Example 132-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (tetrazol-5-yl) methyloxy) [1] benzoxepin [2, 3-b] pyridine-Silidene) propyl ] piperidin-4-ol Step 1: 4- (4-chlorophenyl) -l- [3- (5,11-dihydro-7- (2-trifeni-methyl-tetra-1-yl-5-yl) methyloxy) [1] benzoxepino [2,3-b] pyridine-5 -ylidene) propyl] piperidin-4-ol was prepared following the procedure of Example 46, but replacing ethyl iodide with (2-triphenyl-methyltetrazol-5-yl) methyl chloride. NMR-H1 (CDC13) d: 1.64-1.70 (3H, m), 2.02-2.15 (2H, m), 2.35-2.71 (8H, m), 5.29 (2H, broad s), 5.33 (2H, s), 6.03 (1H, t), 6.77 (1H, d), 6.83 (1H, 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 from step 1 (530 mg) in acetone (2.5 ml), acetic acid (2.5 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 title compound (280 mg). NMR-H1 (DMSO-d6) d: 1.69-1.74 (2H, m), 1.99-2.09 (2H, m), 2.95-3.14 (8H,), 5, 18 (2H, broad s), 5.20 (2H, s), 6.14 (1H, t), 6.76 (1H, d), 6.93 (1H, dd), 7.04 (1H, d), 7.39-7.48 (5H, m), 7.78 (1H, dd), 8.52 (1H, dd). MS m / z: 545 (M + 1) Example 133-1- [3- (7-Carboxymethyloxy-5,11-dihydro [1] -benzoxepino [2,3-pyridin-5-ylidene] propyl] - 4- (4-chlorophenyl) piperidin-4-ol To a solution of the product of Example 48 (3.0 g) in methanol (50 ml) was added a solution of IN sodium hydroxide (8 ml) and the mixture was stirred to ambient temperature for 1 hour. The reaction mixture was distilled off under reduced pressure. The residue was dissolved with water and neutralized with IN hydrochloric acid. The precipitate was filtered and washed with water to give the title compound (2.6 g). NMR-H1 (DMSO-d6) d: 1.48-1.53 (2H, m), 1.76-1.88 (2H, m), 2.32-2.60 (8H,), 4, 60 (2H, s), 5.18 (2H, broad s), 6.16 (1H, t), 6.72-6.84 (3H, m), 7.34-7.48 (5H, m ), 7.73 (1H, dd), 8, 50 (1H, dd). MS m / z: 521 (M + l) Example 134-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-dimethylaminocarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4 -ol To a solution of the product of example 133 (420 mg) in dimethylformamide (17 ml) were added 1-hydroxybenzotriazole hydrate (250 mg), l- (3-di-ethylaminopropyl) -3-ethylcarbodiimide hydrochloride (310 mg). , dimethylamine hydrochloride (270 mg) and triethylamine (0.45 ml), and the mixture was 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 sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (380 mg). NMR-H1 (CDC13) d: 1.67-1.71 (2H, m), 1.95-2.11 (3H, m), 2.37-2.71 (8H, m), 2.97 (3H, s), 3.08 (3H, s), 4.64 (2H, s), 5.27 (2H, broad s), 6.09 (1H, t), 6.74-6.82 (2H, m), 6.93 (1H, d), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS m / z: 548 (M + l) Example 135-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-morpholinocarbonylmethyloxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with morpholine. NMR-H1 (CDC13) d: 1.67-1.71 (2H, m), 1.87 (1H, broad s), 2.00-2.11 (2H, m), 2.38-2, 71 (8H, m), 3.61-3.68 (8H, m), 4.65 (2H, s), 5.27 (2H, broad s), 6.09 (1H, t), 6, 74-6.83 (2H, m), 6.90 (1H, d), 7.25-7.44 (5H, m), 7.58 (1H, dd), 8.48 (1H, dd) . MS m / z: 590 (M + l) Example 138-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-ethoxycarbonyl-1-methylethyl) oxy] [1] benzoxepino [2,3-b] -pyridin-5 -ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromoisobutylate. NMR-H1 (CDCl3) d: 1.27 (3H, t), 1.56 (6H, s), 1.63-1.71 (3H, m), 2.01-2.10 (2H, m) ), 2.35-2.70 (8H.m), 4.24 (2H, c), 5.28. (2H, broad s), 6.05 (1H, t), 6.67-6.75 (2H, m), 6.87 (1H, d), 7.24-7.44 (5H, m) , 7.56 (1H, dd), 8.49 (1H, dd). MS m / z: 577 (M + l) Example 139-1- [3- (7- (1-Carboxy-1-methylethyl) oxy-5,11-dihydro [l] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperidin-4 -ol The title compound was prepared following the procedure of example 133, but replacing the product of example 48 with the product of example 138. RMN-H1 (DMSO-d6) d: 1.45-1.52 (8H, m ), 1.79-1.85 (2H, m), 2.28-2.53 (8H, m), 5.19 (2H, broad s), 6.07 (1H, t), 6.96 - 6.73 (2H, m), 6.85 (1H, d), 7.33-7.47 (5H, m), 7.71 (1H, dd), 8, 48 (1H, dd). MS m / z: 549 (M + l) Example 140-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-methoxyphenyl) -piperidin-4 -ol The title compound was prepared following the procedure of Example 45, Step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-methoxyphenyl) -4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.62-1.75 (2H, m), 2.08 (2H, td), 2.41-2.76 (9H, m), 3.77 (3H, s) ), 3.78 (3H, s), 5.26 (2H, broad s), 6.06 (1H, t), 6.75-6.871 (5H, m), 7.23 (1H, dd), 7.38 (2H, d), 7.57 (1H, dd), 8.45 (1H, dd). MS m / z: 473 (M + l) Example 141-4- (4-Cyanophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine-4- The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-cyanophenyl) -4-hydroxypiperidine. NMR-H1 (CDCI3) d: 1.58-1.70 (2H, m), 2.03 (2H, t), 2.31-2.64 (7H, m), 2.65-2.78 (2H, m), 3.75 (3H, s), 5.26 (2H, broad s), 5.95 (0.1H, t, E isomer), 6.05 (0.9H, t, isomer) Z), 6.70-6.80 (3H, m), 7.22 (1H, dd), 7.54-7.68 (5H, m), 8.31 (0.1H, dd, E-isomer) ), 8.39 (0.9H, dd, Z-isomer). MS m / z: 468 (M + l) Example 142-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-hydroxyphenyl) -piperidin-4 -o1 The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (-chlorophenyl) -4-hydroxypiperidine with 4- (4-hydroxyphenyl) -4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.76-1.88 (2H, m), 2.08-2.22 (2H, m), 2.45-2.95 (9H,), 3.76 ( 3H, s), 5.28 (2H, broad s), 5.95 (0.3H, t, E isomer), 6.04 (0.7H, t, Z isomer), 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-isomer), 8.46 (0.7H, dd, Z-isomer), 8.47 (0.3H, dd, E-isomer). No OH signal was observed. MS m / z: 473 (M + l) Example 143-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-fluoro-3-methyl- phenyl) piperidin-4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-fluoro-3-methylphenyl) -4 -hydroxypiperidine. NMR-H1 (CDCI3) d: 1.62-1.75 (2H, m), 2.05 (1H, broad s), 2.09 (2H, td), 2.25 (3H, s), 2.30-2.76 (8H, m), 3.76 (3H, s), .26 (2H, broad s), 5.96 (0.1H, t, E-isomer), 6.07 (0.9H, t, Z-isomer), 6.75-6.89 (3H, m) , 6.93 (1H, t), 7.11-7.20 (0.3H, m, 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 (0.1H, dd, E-isomer), 8.45 (0.9H, dd, Z-isomer) ). MS m / z: 475 (M + l) Example 144-4- (3,4-Difluorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine- 4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,4-difluorophenyl) -4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.58-1.72 (2H, m), 1.96 (2H, td), 2.33-2.71 (8H, m), 3.73 (3H, s), 5.23 (2H, broad s), 5.94 (0.1H, t, E isomer), 6.04 (0.9H, t, isomer) Z), 8.38-8.36 (0.9H, m, Z-isomer), 6.68-7.38 (4H, m), 7.50-7.62 (0.9H, m, Z-isomer) ), 7.63-7.68 (0.1H, m, E-isomer), 8.29-8.32 (0.1H, m, E-isomer), 8.32-8.44 (0.9H, m, Z isomer). No OH signal was observed. MS m / z: 479 (M + l) Example 145-4- (4-Chloro-3-trifluoromethylphenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine -4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chloro-3-trifluoromethylphenyl) -4-hydroxyoiperidine. . NMR-H1 (CDCl3) d: 1.62-1.74 (2H, m), 2.10 (2H, td), 2.35-2.80 (8H, m), 2.42 (1H, s) width), 3.76 (3H, s), 5.26 (2H, broad s), 6.07 (0.9H, t, Z-isomer), 6.03 (0.1H, t, E-isomer), 6.82-6.71 (3H, m), 7.24 (1H, dd), 7.43 (1H, d), 7.56 (1.8H, dd, Z-isomer), 7.65 ( , 2H, dd, E isomer), 7.83 (1H, d), 8.36 (0.1H, dd, E isomer), 8.44 (0.9H, dd, Z isomer). MS m / z: 545 (M + l) Example 146-4- (3,5-Dichlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine- 4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,5-dichlorophenyl) -4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.58-2.22 (5H, m), 2.38-2.77 (8H, m), 3.76 (3H, s), 5.26 (2H, s) width), 5.92 (0.1H, 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 (0.1H, dd, E-isomer), , 45 (0.9H, dd, Z-isomer). MS m / z: 512 (M + l) Example 147-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (2-pyridyl) piperidin-4- The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (2-pyridyl) -4-hydroxypiperidine. NMR-H1 (CDCl3) d: 1.54-1.65 (2H, m), 2.06 (2H, td), 2.07 (1H, broad s), 2.35-2.62 (7H, m), 2.73-2.87 (2H, m), 3.78 (3H, s), 5.28 (2H, broad s), 6.08, (1H, t), 6.72-6 , 85 (3H, m), 7.14-7.29 (2H, m), 7.57 (1H, d), 7.70 (1H, dd), 8.48 (2H, dd). MS m / z: 444 (M + l) Example 148-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (3-pyridyl) piperidin--ol The title compound was prepared following the procedure of Example 45, Step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (3-pyridyl) -4-hydroxypiperidine. NMR-H1 (CDCl3) d: 1.65-1.78 (2H, m), 2.08 (2H, td), 2.37-2.88 (7H, m), 2.63-2.79 (2H, m), 3.78 (3H, s), 5.28 (2H, broad s), 6.02 (0.1H, t, E isomer), 6.07 (0.9H, t, isomer) Z), 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 + l) Example 149-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (4-pyridyl) piperidin-4- ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (-chlorophenyl) -4-hydroxypiperidine with 4- (4-pyridyl) -4-hydroxypiperidine. NMR-H1 (CDC13) d: 1.58-1.72 (2H, m), 2.03 (2H, td), 2.34-2.89 (8H, m), 2.96 (1H, s) width), 3.76 (3H, s), 5.25 (2H, broad s), 6.06 (1H, t), 6.72-6.83 (3H, m), 7.24 (1H, dd), 7.37 (2H, dd), 7.56 (1H, dd), 8.45 (1H, dd), 8.48 (1H, dd). MS m / z: 444 (M + l) Example 150-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2, 3-b] iridin-5-ylidene) propyl] -4- (4-trifluoromethyl-phenyl) piperidine- 4-ol The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-trifluoromethylphenyl) -4-hydroxypiperidine. NMR-H1 (CDCl3) d: 1.64-1.75 (2H, m), 2.01 (1H, broad s), 2.16 (2H, td), 2.38-2.86 (8H, m), 3.76 (3H, s), 5.26 (2H, broad s), 6.04 (1H, t), 6.72-6.84 (3H, m), 7.23 (1H, dd), 7.56 (5H, m), 8, 42 (1H, dd). MS m / z: 511 (M + l) Example 151-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperidine The compound of The title was prepared following the procedure of example 44, step 2, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) piperidine. NMR-H1 (CDC13) d: 1.62-1.92 (4H, m), 1.94-2.18 (2H, m), 2.28-2.64 (5H, m), 2.99 (2H, m), 5.25 (2H, broad s), 6.00 (1H, t), 6.60-6.82 (3H, m), 7.02-7.36 (5H,), 7.50 (1H, dd), 8.47 (1H, dd). No OH signal was observed. MS m / z: 447 (M + l) Example 152-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethoxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -piperidine The compound of The title was prepared following the procedure of Example 46, but replacing the product of Example 44 with the product of Example 151. RMN-H1 (CDCl3) d: 1.40 (3H, t), 1.52-2.14 (6H , m), 2.30-2.57 (5H, m), 2.94 (2H, m), 4.00 (2H, c), 5.28 (2H, broad s), 6.07 (1H , t), 6.68-6.86 (3H, m), 7.05-7.36 (5H, m), 7.58 (1H, m), 8, 49 (1H, m). MS m / z: 475 (M + l) Example 153-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethoxycarbonylmethioxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine The title compound was prepared following the procedure of Example 48, but replacing the product of Example 44 with the product of Example 151. RMN-H1 (CDCl3) d: 1.29 (3H, t), 1.56-1.85 (4H, m), 1.99 (2H, td), 2.28-2.55 (5H, m), 2.91 (2H, m), 4.27 (2H, c), 4.58 (2H, s) ), 5.28 (2H, broad s), 6.09 (1H, t), 6.68-6.95 (3H, m), 7.07-7.32 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS m / z: 533 (M + l) Example 154-1- [3- (7- (Carboxymethyloxy-5,11-dihydro- [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine The compound of the title was prepared following the procedure of example 133, but replacing the product of example 48 with the product of example 153. X-NMR (CD3OD) d: 1.82-2.17 (4H, m), 2.69 ( 2H, m), 2.86 (1H, m), 3.07 (2H, m), 3.30 (2H, m), 3.57 (2H, m), 4.57 (2H, s), 5.21 (2H, broad s), 6.10 (1H, t), 6.70-7.04 (3H, m), 7.16-7.38 (4H, m), 7.44 (1H , m), 7.77 (1H, m), 8.47 (1H, m) No COOH signal was observed MS m / z: 505 (M + l) EXAMPLE 155-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-dimethylaminocarbonylmethyloxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] piperidine The title compound was prepared following the procedure of Example 134, but replacing the product of Example 133 with the product of Example 154. RMN-H1 (CDCl3) d: 1.58-1.92 (4H,), 2.04 (2H, m ), 2.30-2.68 (5H, m), 2.93 (2H, m), 2.98 (3H, s), 3.08 (3H, s), 4.65 (2H, s) , 5.28 (2H, broad s), 6.07 (1H, t), 6.70-6.98 (3H, m), 7.08-7.36 (5H, m), 7.60 ( 1H, m), 8.50 (1H, m). MS m / z: 532 (M + l) Example 156-1- [3- (7- (2-Acetoxyethyl) oxy-5,11-dihydro- [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] piperidine The title compound was prepared following the procedure of example 50, but replacing the product of example 44 with the product of example 151. RMN-H1 (CDCI3) d: 1.55-1.88 (4H, m), 1.90-2.32 ( 2h, M), 2.10 (3H, s), 2.28-2.60 (5H, m), 2.82-3.02 (2H, m), 4.14 (2H, dd), 4 , 41 (2H, dd), 5.29 (2H, broad s), 6.08 (1H, t), 6.72-6.90 (3H, m), 7.18-7.34 (5H, m), 7.57 (1H, m), 8.50 (1H, m). MS m / z: 533 (M + l) Example 157-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyethyl) oxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) -propyl ] piperidine The title compound was prepared following the procedure of Example 51, but replacing the product of Example 50 with the product of Example 156. RMN-H1 (CD3OD) d: 1.66-1.98 (4H, m), 2.04-2.73 (5H, m), 2.82-2.94 (2H, m), 3.22 (2H, m), 3.84 (2H, dd), 4.01 (2H, dd), 5.23 (2H, broad s), 6.13 (1H, t), 6.64-6.98 (3H, m), 7.13-7.34 (4H, m), 7, 45 (1H,), 7.77 (1H, m), 8.47 (1H, m). No OH signal was observed. MS m / z: 491 (M + l) Example 158-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-ethoxycarbonyl-1-methylethyl) oxy] [1] benzoxepin [2, 3-b] pyridin-5 -ylidene) propyl] piperidine The title compound was prepared following the procedure of example 138, but replacing the product of example 44 with the product of example 151. RMN-H1 (CDCl3) d: 1.28 (3H, t), 1.56 (6H, s), 1.56-1.85 (4H, m), 1.97 (2H, td), 2.28-2.55 (5H, m), 2.93 (2H, m), 4.24 (2H, c), 5.28 (2H, broad s), 6.04 (1H, t), 6.62-6.95 (3H, m), 7.07-7, 32 (5H, m), 7.57 (1H, dd), 8.50 (1H, dd). MS m / z: 561 (M + l) Example 159-1- [3- (7- (1-Carboxy-1-methylethyl) oxy-5,11-dihydro [l] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- ( 4-chlorophenyl) piperidine The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 158. RMN-H1 (CD3OD) d: 1.82-2.18 (4H, m), 2.70 (2H, m), 2.87 (1H, m), 3.12 (2H, m), 3.30 (2H, m), 3.60 (2H, m), 5, 25 (2H, broad s), 6.07 (1H, t), 6.67-7.04 (3H, m), 7.16-7.38 (4H, m), 7.58 (1H, m ), 7.96 (1H, m), 8.52 (1H, m). No COOH signal was observed. MS m / z: 533 (M + l) Example 160-1- [3- (8-Bromo-5,11-dihydro [1] benzoxepino- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) -piperidine The title compound was prepared following the procedure of Example 65, but replacing the product of Example 45, Step 2, by the product of Example 54, Step 1. RMN-H1 (CDCl3) d: 1.50-1.86 ( 4H,), 1.98 (2H, m), 2.26-2.60 (5H, m), 2.88 (2H, m), 5.30 (2H, broad s), 6.09 (1H , t), 6.96-7.36 (8H, m), 7.57 (1H, dd), 8.51 (1H, dd). MS m / z: 509 (M + l) Example 161-1- [3- (8-Carboxy-5,11-dihydro [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) -piperidine A solution of 1- L3- (8-romo-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine (Example 161) ( 130 mg) in THF (1.0 ml) was added a solution of n-butyl lithium in hexane 1.6 M (0.17 ml) at -78 ° C. After stirring 10 minutes at the same temperature, C02 (dry ice) was added to the mixture. After heating to room temperature, the mixture was added for 30 minutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluting with dichloromethane-methanol (5: 1) to give the title compound. NMR-H1 (CD3OD) d: 1.55-1.95 (4H, m), 2.17 (2H, td), 2.32-2.78 (5H, m), 3.00 (2H, m) ), 5.30 (2H, broad s), 6.19 (1H, t), 7.08-7.54 (8H, m), 7.76 (1H, dd), 8.45 (1H, dd) ). No COOH signal (50 mg) was observed. MS m / z: 475 (M + l) Example 162-1- [3- (7-Bromo-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (4-cyclo-phenyl) -piperidin-4 -ol The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-one by 8-bromo-5, -dihydro [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDC13) d: 1.60-1.71 (3H, m), 1.98-2.09 (2H, m), 2.34-2.69 (8H, m), 5.32 (2H, broad s), 6.13 (1H, t), 6.73 (1H, d), 7.22-7.44 (7H, m), 7.57 (1H, dd), 8.52 (1H, dd). MS m / z: "525, 527 (M + l) Example 163-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethyl [1] be z? Xepino [2, 3-b] pyridin-5-ylidene) ropil] -piperidin -4-ol The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5,11-dihydro -7-ethyl [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDCl3) d: 1.23 (3H, t), 1.52 (1H, broad s), 1.66-1.71 (2H, m), 1.98-2.06 (2H, m), 2.35-2.70 (11H, m), 5.31 (2H, broad s), 6.09 (1H, t), 6.79 (1H, d), 7.01 (1H, dd), 7.11 (1H, d), 7.25-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS m / z: 475 (M + l) Example 164-4- (4-Chlorophenyl) -i- [3- (5,11-dj hydro-8-vinyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4 -ol The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin -one by 5,11-dihydro-8- vinyl [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDC13) d: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.70 (8H, m), 5.22 (2H, d), 5.34 (2H, broad s), 5.70 (1H, d), 6.11 (1H, t), 6.61 (1H, dd), 6.89 (1H, d) ), 6.99 (1H, dd), 7.24-7.44 (6H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS m / z: 473 (M + l) Example 165-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-ethyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidin-4- A mixture of the product of example 164 (100 mg) and Pd-C (20 mg) in ethanol (2 ml) was stirred in a hydrogen balloon at room temperature for 1 hour. The mixture was filtered through celite and separated by distillation under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with chloroform-methanol (15: 1) to give the title compound (50 mg). NMR-H1 (CDCI3) d: 1.22 (3H, t), 1.55-1.77 (3H, m), 2.00-2.13 (2H, m), 2.33-2.74 (10H, m), 5.32 (2H, broad s), 6.07 (1H, t), 6.70 (1H, d), 6.78 (1H, dd), 7.19-7.44 (6H, m), 7.57 (1H, dd), 8, 49 (1H, dd). MS m / z: 475 (M + l) Example 166-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-9-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -piperidine-4- The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5,11-dihydro-7- methoxy [1] benzoxepino [2, 3-b] pyridin-5-one. NMR-H1 (CDCl3) d: 1.65-1.70 (2H, m), 1.95-2.06 (2H, m), 2.15 (1H, broad s), 2.37-2, 67 (8H, m), 3.83 (3H, s), 5.43 (2H, broad s), 6.09 (1H, t), 6.79-6.91 (3H, m), 7, 22-7.43 (5H, m), 7, 57 (1H, dd), 8.44 (1H, dd). MS m / z: 477 (M + l) Example 167-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-ethyl [1] benzoxepino [4, 3-c] pyridin-5-ylidene) propyl] -piperidin- 4- The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5, 11-dihydro- 7- methoxy [1] benzoxepino [4,3-c] pyridin-5-one. NMR-H1 (CDC13) d: 1.67-1.71 (2H, m), 1.97-2.08 (2H, m), 2.16 (1H, s), 2.40-2.69 (8H, m), 5.16 (2H, broad s), 6.14 (1H, t), 6.80 (1H, dd), 6.91 -6.97 (1H,), 7.13-7.19 (1H, m), 7.26-7.44 (6H, m), 7.50-8.54 (2H, m). MS m / z: 447 (M + l) Example 168-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro- [1] benzoxepino- [4, 3-d] pyrimidin-5-ylidene) propyl] -piperidin-4-ol The The title compound was prepared following the procedure of Example 45, but replacing 5, 11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one by 5,11-dihydro [l] benzoxepin [ 4, 3-d] pyrimidin-5-one. NMR-H1 (CDCl3) d: 1.68-1.72 (2H, m), 1.90 (1H, broad s), 2.06-2.19 (2H, m), 2.41-2, 78 (8H, m), 5.20 (2H, s), 6.12 (1H, t), 7.14-7.45 (8H, m), 8.72 (1H, s), 8.97 (1H, s). MS m / z: 448 (M + l) Example 169-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-trifluoromethanesulfonyloxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- To a solution of the product of example 44 (1.0 g) in pyridine (10 ml) was added trifluoromethanesulfonic acid anhydride (0.55 ml) at 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 chromatography eluting with ethyl acetate-methanol (10: 1) to give the title compound (1.1 g). NMR-H1 (CDC13) d: 1.56 (1H, broad s), 1.66-1.71 (2H, m), 1.97-2.09 (2H, m), 2.35-2, 69 (8H,), 5.35 (2H, broad s), 6.15 (1H, t), 6.88 (1H, d), 7.05 (1H, dd), 7.21-7.44 (6H, m), 7.60 (1H, dd), 8, 54 (1H, dd). MS m / z: 595 (M + l) Example 170-1- [3- (7-A1H-5,11-dihydro [1] benzoxepin- [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) -piperidin-4 -ol To a mixture of the product of example 169 (240 mg), allyltributyltin (0.19 ml), dichlorobis (triphenylphosphine) -palladium (II) (30 mg), lithium chloride (76 mg), in dimethylformamide (3 ml) ) in argon at 120 ° C for 2 hours. To the reaction mixture was added an aqueous solution of ammonium fluoride and ethyl acetate, 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 title compound (180 mg). NMR-H1 (CDCl3) d: 1.62-1.72 (3H, m), 2.03-2.11 (2H, m), 2.39-2.73 (8H, m), 3.31 (2H, d), 5.04-5.11 (2H, m), 5.29 (2H, broad s), 5.87-6.02 (1H, m,, 6.06 (1H, t) , 6.77 (1H, d), 6.99 (1H, dd), 7.10 (1H, d), 7.23-7.43 (5H, m), 7.57 (1H, dd), 8, 40 (1H, dd) Example 171-1- [3- (7- (2-t-Butoxycarboxy) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] -4- (4-chlorophenyl) piperidin-4-oi A mixture of the product of example 169 (1.7 g), t-butyl acrylate (, 85 ml), triethylamine (2.5 ml), 1,1'-bis (diphenylphosphino) ferrocene (250 mg) and palladium (II) diacetate (33 mg) in dimethylformamide (3 ml) in argon at 90 ° C. for 24 hours. Aqua 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 ethyl acetate-methanol (30: 1) to give the title compound (780 mg). NMR-H1 (CDC13) d: 1.45 (9H, s), 1.63-1.71 (3H, m), 1.98-2.10 (2H, m), 2.35-2.72 (8H, m), 5.35 (2H, broad s), 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 172-1- [3- (7- (2-Carboxy) ethenyl-5,11-dihydro- [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) ) piperidin-4-ol The product of example 171 (330 mg) was dissolved with a solution of 4N-1,4-dioxane hydrochloric acid (4 ml), 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 a solution of sodium hydroxide. The precipitate was filtered to give the title compound (190 mg). NMR-H1 (DMSO-d6) d: 1.45-1.52 (2H, m), 1.72-1.84 (2H, m), 2.25-2.58 (8H, m), 5 , 25 (2H, broad s), 6.28 (1H, t), 6.43 (1H, d), 6.82 (1H, d), 7.34-7.60 (8H, m), 7 , 75 (1H, dd), 8, 52 (1H, dd).

Example 173-4- (4-Chlorophenyl) -1- [3- (5,11-d? -hydro-7-propargyloxy [1] benzoxepin [2, 3-b] p? Pd? N-5? L-deno) -propyl] p? pepd? n-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with propargyl chloride. NMR-H1 (CDC13) d: 1.66-1.71 (2H, m), 1.79 (1H, broad s), 1.99-2.10 (2H, m), 2.35-2, 71 (9H, m), 4.66 (2H, d), 5.28 (2H, broad s), 6.10 (1H, t), 6.80-6.93 (3H, m), 7, 24-7.46 (5H, m), 7.59 (1H, dd), 8.48 (1H, dd). MS m / z: 501 (M + l) Example 174-4- (4-Chlorophenyl) -1- [3- (7-c? Clopentox? -5,11-dihydro [1] benzoxepino [2, 3-b] p? Pd? N-5-? deno) propyl] -p? per? d? n-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with cyclopentyl bromide. NMR-H1 (CDCl3) d: 1.54-2.18 (13H,), 2.41-2.72 (8H, m), 4.66-4.73 (1H, m), 5.27 ( 2H, s year), 6.08 (1H, t), 6.70-6.87 (3H, m), "", 23-7.44 (5H, m), 7.58 (1H, dd) , 8.49 (1H, dd). MS m / z: 531 (M + l) Example 175-4- (4-Chlorophenyl) -1- [3- (5,11-d? H? Dro-7- (2-methox? Et? L) ox?) [1] benzoxepmo [2, 3- b] p? pd? n-5? l? deno) -prop? l] p? per? d? n-4-ol The title compound was prepared following the procedure of example 46, but replacing ethyl iodide with 2-methoxyl chloride. NMR-H1 (CDCI3) d: 1.66-1.75 (3H, m), 2.00-2.11 (2H, m), 2.36-2.71 (8H, m), 3.45. (3H, s), 3.71-3.75 (2H, m), 4.07-4.11 (2H, m), 5.27 (2H, broad s), 6.09 (1H, t) , 6.75-6.91 (3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd). MS m / z: 521 (M + l) Example 176-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-dimethylaminocarbonyl-1-methylethyl) oxy) [1] benzoxepin [2, 3-b] pyridine-5 -ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of example 134, but replacing the product of example 133 with the product of example 139. RMN-H1 (CDC13) d: 1.59 (6H , s), 1.67-1.72 (2H, m), 1.99-2.09 (2H, m), 2.36-2.70 (9H, m), 2.96 (3H, s) ), 3.21 (3H, s), 5.25 (2H, broad s), 6.02 (1H, t), 6.60-6.77 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.44 (1H, dd). MS m / z: 576 (M + l) Example 177-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-ethoxycarbonylethyl) oxy) [1] benzoxepin [2, 3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromopropionate. NMR-H1 (CDCl3) d: 1.25 (3H, t), 1.59 (3H, d), 1.65-1.70 (2H, m), 1.98-2.08 (2H, m) ), 2.35-2.68 (8H, m), 2.80 (1H, broad s), 4.21 (2H, c), 4.68 (1H, c), 5.24 (2H, s) width), 6.07 (1H, t), 6.68-6.79 (2H, m), 6.88 (1H, d), 7.22-7.44 (5H, m), 7.56 (1H, dd), 8, 40 (1H, dd).

Example 178-1- [3- (7-Carboxyethyl) oxy-5,11-dihydro- [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine- 4-ol The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 177. RMN-H1 (DMSO-de) d: 1.46 (3H, d), 1 , 58-1.63 (2H, m), 1.98-2.06 (2H, m), 2.41-2.45 (2H, m), 2.72-2.86 (6P, m) , 4.74 (1H, c), 5.18 (2H, broad s), 6.11 (1H, t), 6.73 (2H, s), 6.84 XH, s), 7.36- 7.47 (5H, m), 7.73 (1H, dd), 8.50 (1H, dd). MS m / z: 535 (M + l) Example 179-4- (4-Chlorophenyl) -1- [3- (5,11-d? H? Dro-7- (1-ethoxycarbonylethyl) cyclobutoxy) [1] benzoxepmo [2, 3-b] -p? pdm-5? l? deno) prop? l] p? pepd? n-4-ol The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromo-cethobutanecarboxylate . NMR-H1 (CDC13) d: 1.19 (3H, t), 1.67-1.71 (2H, m), 1.92-2.11 (5H, m), 2.33-2.77 (12H, m), 4.21 (2H, c), 5.25 (2H, broad s), 6, C5 (1H, t), 6.47 (1H, dd), 6.70 XH, d) , 6.73 (1H, d), 7.23-7.44 (5H, m), 7.55 (1H, dd), 8.44 (1H, dd).

Example 180-1- [3- (7-Carbox?) C? Clobutox? -5, 11-d? H? Dro- [1] benzoxepmo [2, 3-b] p? Pdm-5? L? Deno ) propyl] -4- (4-chlorophenyl) p? per? dm-4-ol The title compound was prepared following the procedure of example 133, but replacing the product of example 48 with the product of example 179. RMN-H1 (DMSO-d6) d: 1.60-1.65 (2H, m), 1.86-2.08 (4H,), 2.24-2.90 (12H, m), 5.17 (2H , broad s), 6.05 (1H, t), 6.50 (1H, dd), 6.66 (1H, d), 6.73 (1H, d), 7.37-7.48 (5H , m), 7.74 (1H, dd), 8.51 (1H, dd). MS m / z: 561 (M + l) Example 181-1- [3- (7-Carbamo? Lmet? Lox? -5, 11-d? H? Dro- [1] benzoxepmo [2, 3-b] p? Pdm-5? L? Deno) propyl] -4- (4-chlorophenyl) p? per? d? n-4-ol The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with ammonium hydroxide. NMR-H1 (CDC13) d: 1.66-1.71 (2H, m), 1.98-2.09 (2H, m), 2.21 (1H, broad s), 2.38-2, 70 (8H, m), 4.45 (2H, s), 5.28 (2H, broad s), 6.09 (1H, t), 6.11 (1H, broad s), 6.58 (1H , broad s), 6.74-6.85 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS m / z: 520 (M + l) Example 182-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethylaminocarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with dimethylamine. NMR-H1 (CDC13) d: 1.67-1.72 (2H, m), 1.99-2.10 (2H, m), 2.36- 2.70 (9H, m), 2.89 (3H, d), 4.45 (2H, s), 5.28 (2H, broad s), 6.08 (1H, t), 6.66 (1H, broad s), 6.73-6, 84 (3H, m), 7.25-7.45 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS m / z: 534 (M + l) Example 183-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] -4-3-c] [1] benzoxypiepin- 5-ylidene) propyl] -4- (4-hydroxyphenyl) piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 4- (4- hydroxy-phenyl) piperidine. NMR-H1 (CDCl3) d: 1.52-1.88 (4H, m), 2.02 (2H, td), 2.28-2.60 (5H, m), 2.93 (2H, m ), 3.79 (3H, s), 5.28 (2H, broad s), 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 m / z: 461 (M + 1).

Example 184-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] -4-3-c] [1] benzoxypiepin- 5-ylidene) propyl] -4- (2-hydroxyphenyl) piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine by 4- (2- hydroxy-phenol) p? pepd? na. NMR-H1 (CDC13) d: 1.78-1.92 (4H, m), 2.12-2.25 (2H, m), 2.32-2.70 (4H, m), 2.80 -2.97 (1H, m), 3.01-3.15 XH, m), 3.77 (3H, s), 3.78 (1H, broad s), 5.28 (2H, broad s) , 6.03 (1H, t), 6.74-6.86 (4H, m), 7.05 (1H, dd), 7.11 (1H, dd), 7.56 (1H, dd), 8.48 (1H, dd). No OH signal was observed. MS m / z: 443 (M + 1).

Example 185-4- (7-Chloro-l, 2-benz? Soxazol-3-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepin [2, 3-b] pyridine -5-ididene) propyl] piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (7-chloro-1,2-benz ? soxazol-3-yl) piperidine. This piperidine was prepared by the same method described in J. Med. Chem. 28: 761-769 (1985). 1 H-NMR (CDCl 3) d: 1.94-2.20 (6H, m), 2.30-2.60 (4H, m), 2.86-3.14 (3H, m), 3.79 (3H, s), 5.29 (2H, broad s), 6.10 (1H, t), 6.70-6.88 (3H, m), 7.22 (1H, t), 7.27 (1H, dd), 7.50 (1H, dd), 7.57-7.68 (2H, m), 8.49 (1H, dd).

Example 186-4- (7-Chloroindol-3-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) propyl] - piperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (7-chloroindol-3-yl) pipepdma. This piperidine was prepared by the same method described in J. Med. Chem. 36: 4006-4014 (1993) and following the hydrogenation described in Example 58, step 3. RMN-H1 (CDC13) d: 1.66-1.88 (2H, m), 1.92-2.22 ( 4H, m), 2.32-2.63 (4H, m), 2.78 (1Hm), 2.97 (2H, m), 3.79 (3H, s), 5.29 (2H, broad s), 6.09 (1H, t), 6.70-6.87 (3H, m), 6.97-7.07 (2H, m), 7.12-7.30 ( 2H, m), 7.52 (1H, m), 7.59 (1H, dd), 8.45 (1H, broad s), 8.50 (1H, dd).

Example 187-4-Azido-4- (4-chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2, 3-b] pyridin-5-ylidene) -propyl] iperidine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-azido-4-4-chlorophenyl) piperidine. NMR-H1 (CDC13) d: 1.88 (2H, m), 2.55-2.85 (4H, m), 3.00-3.30 (6H, m), 3.75 (3H, s) ), 5.19 (2H, broad s), 5.97 (1H, t), 6.68-6.65 (3H,), 7.20- ^, 46 (5H, m), 7.63 ( 1H, dd), 8.35 (1H, dd). MS m / z: 477 (M + 1-N 2 + H 2).

Example 188-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepin- [2,3-b] pyridin-5-ylidene) -propyl] -4-phenylpiperidine-4-carboxylic acid methyl ester The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with methyl 4-phenylpiperidine-4-carboxylate. NMR-H1 (CDCl3) d: 1.82-2.15 (4H, m), 2.28-2.60 (6H, m), 2.78-2.82 (2H,), 3.62 ( 3H, s), 3.68 (3H, s), 5.26 (2H, broad s), 5.95 (0.1H, t, E-isomer), 6.05 (0.9H, t, Z-isomer) ), 6.82-6.70 (3H, m), 7.33-7.22 (6H, m), 7.65 (0.1H, dd, Z-isomer), 7.55 (0.9H, dd, E-isomer), 8.39 (0.1H, E-isomer), 8.48 (0.9H, dd, Z-isomer). MS m / z: 485 (M + 1).

Example 189 - 1- [3- (5,11-Dihydro-7-methox [1] -benzoxep [no] 2, 3-b] pyridin-5-ylidene) propyl] -4-phenyl-piperidin acid -4-carboxylic acid The title compound was prepared following the procedure of example 133, but replacing the product of example 48 with the product of example 188. RMN-H1 (CD3OD) d: 2.16-2.23 (2H, m ), 2.69-2.91 (4H, m), 3.00-3.16 (2H, m), 3.37-3.25 (2H, m), 3.68-3.73 (2H) , m), 3.76 (3H, s), 5.34 (2H, broad s), 6.24 (1H, t), 6.70-7.04 (3H, m), 7.26-7 , 55 (5H, m), 7.79-7.89 (1H, n), 8.21-8.34 (1H, m), 8.56-8.62 (0.1H, m), 8 , 63-8.77 (0.9H, m). MS m / z: 471 (M + 1).

Example 190-1- (2-Chlorophenylsulfonyl) -4- [3- (5,1, -d -hydro-7-methoxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) -propyl] piperazine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-chlorophenyl-sulfonyl) piperazine. NMR-H1 (CDCl3) d: 2.20-2.58 (8H, m), 3.12-3.38 (4H, m), 3.76 (3H, s), 5.22 (2H, s) width), 6.03 (1H.t), 6.64-6.90 (3H, m), 7.23 (1H, dd), 7.32-7.60 (4H, m), 8.01 (1H, dd), 8.48 (1H, dd). MS m / z: 526 (M + 1).

Example 191-1- (3-Chlorophenylsulfonyl) -4- [3- (5,1, -d -hydro-7-methoxy [1] benzoxepin [2, 3-b] pyridin-5-ylidene) -propyl] piperazine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophe- thol) -4-hydroxypiperidine with 1- (3-chlorophenylsulfomyl) piperazine. NMR-H1 (CDCl3) d: 2.20-2.60 (8H, m), 2.82-3.12 (4H, m), 3.76 (3H, s), 5.18 (2H, s) width), 6.00 (1H, t), 6.64-6.90 (3H, m), 7.23 (1H, dd), 7.42-7.78 (5H, m), 8.48 (1H, dd). MS m / z: 526 (M + 1).

Example 192-1- (4-Chlorophenylsulphyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) -propyl] piperazine The compound The title was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 1- (4-chlorophenylsulfonyl) piperazine. NMR-H1 (CDC13) d: 2.20-2.56 (8H, m), 2.82-3.10 (4H, m), 3.76 (3H, s), 5.18 (2H, s) width), 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 m / z: 526 (M + 1).

Example 193-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] b- ^ nzoxepino [2, 3-b] pyridin-5-ludene) propyl] -1 , 2,3,6-tetrahydropyridine The title compound was prepared following the procedure of example 44, step 2, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -1,2, 3,6-tetrahydropyridine. NMR-H1 (CDCl3) d: 2.37-2.72 (8H, m), 3.07 (2H, m), 5.25 (2H, broad s), 6.00 (1H, m), 6 , 07 (1H, t), 6.60-6.78 (3H, m), 7.18-7.47 (5H, m), 7.56 (1H, dd), 8.50 (1H, dd ). No OH signal was observed. MS m / z: 445 (M + 1).

Example 194-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-lead) propyl] -! 2 , 3, 6-tetrahydropyridine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophen? L) -4-h? Drox? P? Pepd? Na by 4- (4 -chlorophenyl) -1, 2, 3, 6-tetrah? drop? r? d? na. NMR-H1 (CDC13) d: 2.37-2.72 (8H, m), 3.06 (2H, m), 3.78 (3H, s), 5.27 (2H, broad s), 5 , 99 (1H, m), 6.10 (1H, t), 6.72-6.90 (3H, m), 7.20-7.44 XH, m), 7.60 (1H, dd) , 8.50 (1H, dd). MS m / z: 459 (M + 1).

Example 195-4- (7-Chloromodol-3-? L) -1- [3- (5,11-d? -hydro-7-methoxy [1] benzoxepin [2, 3-b] p? Pdm- 5-? L? Deno) propyl] -1,2,3,6-tetrahydropipdm The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-h? Drox ? p? per? d? na by 4- (7-chloromodol-3-? l) -1, 2, 3, 6-tetrah? drop? »- da. This pipepdma was prepared by the same method described in J. Med. Chem. 36: 4006-4014 (1993) 1-NMR (CDCl 3) d: 2.37-2.76 (8H, m), 3.14 (2H, m), 3.78 (3H, s), 5.29 (2H, broad s), 6.02-6.23 (2H, m), 6.67-6.90 (3H, m), 7.05 (1H, dd), 7.12-7.33 ( 3H, m), 7.60 (1H, dd), 7.77 (1H, m), 8.50 (1H, dd), 9.06 (1H, broad s).

Example 196-5-Chloro-l '- [3- (5,11-d? H? Dro-7-h? Drox? [1] -benzoxepmo [2, 3-b] p? R? D? N- 5-? L? Deno) propyl] spiro- [? Sobenzofuran-1 (3H), 4 '-piperidine] The title compound was prepared following the procedure of example 44, step 2, but replacing 4- (4-chlorofil ) -4-h? Drox? P? Perma by 5-chlorosp? Ro- [? Sobenzofuran-1 (3H), 4 '-pipepdine]. NMR-H1 (CDCl3) d: 1.66-1.71 (2H, m), 1.79-1.91 (2H, m), 2.26-2.73 (8H, m), 4.99 XH, s), 5.22 (2H, broad s), 6.07 (1H, t), 6.63-6.70 (2H, m), 6.76 (1H, d), 7.06 (1H, d), 7.19-7.32 (3H,), 7.60 (1H, dd) ), 8.47 (1H, dd), 8.63 (1H, s). MS m / z: 475 (M + 1).

Example 197 -5-Chloro-l '- [3- (5,11-dihydro-7- (2-methoxyethyl) oxy] [1] benzoxepino [2,3-b] pyridin-5-ylidene) -propyl] spiro [ isobenzofuran-1 (3H), 4'-piperidine] The title compound was prepared following the procedure of example 175, but replacing the product of example 44 with the product of example 196. RMN-H1 (CDC13) d: 1.69 -1.74 (2H, m), 1.83-1.94 (2H, m), 2.31-2.76 (8H, m), 3.45 (3H, s), 3.72-3 , 75 (2H, m), 4.08-4.11 (2H, m), 5.00 (2H, s), 5.28 (2H, broad s), 6.09 (1H, t), 6 , 74-6.82 (2H, m), 6.89 (1H, d), 7.04 (1H, d), 7.17-7.28 (3H, m), 7.57 (1H, dd ), 8.49 (1H, dd). MS m / z: (M + 1).

Example 198-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-dimethylaminocarbonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol The title compound was prepared following the procedure of Example 134, but replacing the product of Example 133 with the product of Example 118. RMN-H1 (CDC13) d: 1.65-1.70 (2H, m), 1, 99-2.09 (3H, m), 2.32-2.69 (8H, m), 2.17 (3H, s), 5.35 (2H, broad s), 6.15 (1H, t), 6.82 (1H, d), 7.19 (1H, dd), 7.28-7.46 (6H, m), 7.58 (1H, dd), 8, 49 (1H, dd).

Example 199-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1,1-di eti1-2-hydroxyethyl) oxy [1] benzoxepino [2,3-b] pyridine -5-ylidene) propyl] piperidin-4-ol To a product solution of example 138 (500 mg) in methanol (5 ml) was added sodium borohydride (330 mg), and the mixture was refluxed for 1 hour . The mixture was distilled off under reduced pressure. To the residue were added water and ethyl acetate, 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 elg with chloroform-methanol (10: 1) to give the title compound (440 mg). NMR-H1 (CDC13) d: 1.26 (6H, s), 1.66-1.70 (2H, m), 1.79 (1H, broad s), 2.00-2.08 (2H, m), 2.37-2.70 (9H, m), 3.58 (2H, s), 5.30 (2H, broad s), 6.05 (1H, t), 6.75-6, 84 (2H, m), 6.91 (1H, d), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS m / z: 535 (M + 1).

Example 200-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,2-dimethyl-2-hydroxyethyl) oxy] [1] benzoxepin [2,3-b] pyridin -5-ylidene) propyl] piperidin-4-ol To a solution of the product from example 48 (500 mg) in tetrahydrofuran (5 ml) was added a 0.95 M solution of methylmagnesium bromide-tetrahydrofuran (3.8 ml) at 0 ° C, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added an aqueous solution of ammonium chloride and ethyl acetate, the organic layer was separated and washed with saturated 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 title compound (360 mg). NMR-H1 (CDCl3) d: 1.34 (6H, s), 1.58 (1H, broad s), 1.66-1.71 (2H, m), 1.99-2.10 (2H, m), 2.25 (1H, broad s), 2.36-2.71 (8H, m), 3.77 (2H, s), 5.28 (2H, broad s), 6.09 (1H , t), 6.74-6.86 (3H, m), 7.24-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS m / z: 535 (M + 1), Example 234-1- [3- (5,11-Dihydro-7-me? Oxy [1] benzoxepino- [2, 3-blpyridin-5-ylidene) propyl] -4- (indol-3-yl) piperidine The The title compound was prepared following the procedure of Example 45, Step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (indol-3-yl) -piperidine. This piperidine was prepared by the same method described in J. Med. Chem. 36: 4006-4014 (1993) and following the hydrogenation described in Example 58, step 3. RMN-H1 (CDC13) d: 1.65-1.93 (2H, m), 1.94-2.28 ( 4H, m), 2.34-2.70 (4H, m), 2.81 (1H, m), 2.96 (2H,), 3.78 (3H, s), 5.28 (2H, s wide), 6.09 (1H, t), 6.70-7.42 (8H, m), 7.53-7.72 (2H, m), 8.28 (1H, broad s), 8 , 49 (1H, m).

Example 235-1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (indol-3-yl) -1 , 2,3,6-tetrahydropyridine The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (indol-3-yl) -1, 2, 3, 6-tetrahydropyridine. This piperidine was prepared by the same method described in J. Med. Chem. 36: 4006-4014 (1993). NMR-H1 (CDCI3) d: 2.35-2.77 (8H, m), 3.06-3.26 (2H, m), 3.78 (3H, s), 5.29 (2H, s wide), 6.05-6.22 (2H,), 6.70-6.88 (3H, m), 7.07-7.38 (5H, m), 7.60 (1H, dd), 7.87 (1H, m), 8.42 (1H, broad s), 8.50 (1H, m) 7 Example 236-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3- (ethoxycarbonyl) propyloxy [1] benzoxepin [2, 3-b] pyridine-Silidene) propyl] piperidine The title compound was prepared following the procedure of Example 153, but replacing ethyl bromoacetate with ethyl 4-bromobutyrate, 1 H-NMR (CDCl 3) d: 1.26 (3H, t), 1.56-1, 85 (4H, m), 2.01 (2H, td), 2.09 (2H, quint), 2.30-2.60 (7H, m), 2.93 (2H, m), 3.98 (2H, t), 4.15 (2H, c), 5.28 (2H, broad s), 6.07 (1H, t), 6.68-6.86 (3H, m), 7.07 -7.33 (5H, m), 7.58 (1H, dd), 8.50 (1H, dd), MS m / z: 561 (M + 1).

Example 237-1- [3- (7- (3-Carboxypropyl) oxy-5,11-dihydro- [1] benzoxepino [2, 3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) ) piperidine The title compound was prepared following the procedure of example 133, but replacing the product of example 48 with the product of example 236. RMN-H1 (CD3OD) d: 1.92-2.20 (6H, m), 2.48 (2H, t), 2.70 -3.02 (3H, m), 3.06-3.45 (4H, m), 3.66 (2H, m), 4.01 (2H, t), 5.48 (2H, broad s), 6.36 (1H, t), 6.85 (2H, s), 7.00 (1H, s), 7.20-7.40 (4H, m), 8.11 (1H, dd), 8.64 (1H, d), 8.81 (1H, d). No COOH signal was observed. MS m / z: 533 (M + 1).

Example 248-1 '- [3- (5,11-Dihydro-7-methoxy [1] benzoxepin- [2, 3-b] pyridin-5-ylidene) propyl] -6-methylspiro [H-3, 1- benzoxazin-4, 4 '-] piperidin-2 (1H) -one The title compound was prepared following the procedure of example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine per 6-methylspyro- [4 H -3,1-benzoxazin-4,4 '-piperidin] -2 (1 H) -one. NMR-H1 (CDC13) d: 1.99-2.06 (2H, m), 2.29 (3H, s), 2.32-2.69 (10H, m), 3.77 (3H, s) ), 5.27 (2H, broad s), 6.08 (1H, t), 6.69-6.83 (4H, m), 6.94 (1H, s), 7.02 (1H, d) ), 7.25 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd), 8.56 (1H, s). MS m / z: 498 (M + 1).

Examples 4-7, 9-11, 13-16, 20, 80-82, 84, 87-88, 92-110, 112-113, 116, 119-127, 129, 136-137, 189, 193- 195, 210-233, 236, 238-247 shown in Figure 1 can be prepared by the schemes set forth in Figures 1-5 and by the procedures described above. Those skilled in the art will be able to recognize, or will be able to ascertain, using nothing more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is intended that such equivalents be encompassed by the appended claims.

Claims (111)

1. A method for treating a disease associated with the aberrant recruitment and / or activation of leukocytes comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula: and physiologically acceptable salts thereof, wherein: Z is a non-aromatic heterocyclic cycloalkyl or ring group fused to one or more aromatic rings, wherein each Z ring is independently substituted or unsubstituted. n is an integer from one to about four; M is > NR2 or > CR1R2; R1 is -H, -OH, -N3, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group ), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group). -C (O) O- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a group substituted aliphatic, 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; wherein: R3, R4, R5 and R6 are independently -H, 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 R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, alternatively form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring.

2. The method of Claim 1 wherein Z is represented by the following structural formula: wherein: Ring C is a substituted or unsubstituted C6, C or Cs non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; and Ring A and Ring B are independently substituted or unsubstituted.

3. The method of Claim 2, wherein Z is represented by the structural formula: • x ^ where: Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -O-CH2-, -CH2-O-, -NRC-CH2-, -CH2 -NRC-, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO- NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

4. The method of Claim 3, wherein: Ring A or Ring B is substituted with -OH, halogen, -O- (aliphatic group), -O- (substituted aliphatic group), -O- (aromatic group), - O- (substituted aromatic group), an electron-withdrawing group, - (0) u- (CH2) tC (0) OR2 °, - (0) u- (CH2) t-OC (0) R20, - (0 ) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R2 °; R, 2"X0 R, 2z1 'and R, 2" 2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from 0 to about 3.

5 . The method of Claim 3 wherein: R c e s - (CH 2) s-COOR 30, - (CH 2) S-C (0) -NR 31 R 32 or - (CH 2) S-NHC (0) -O-R 30; s is an integer from 1 to about 3; and R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.

6. The method of Claim 3, wherein R1 is -H or -OH.

7. The method of Claim 3, wherein: M is > C (0H) R2; and n is two.

8. The method of Claim 7, wherein R2 is a substituted aromatic or aromatic group.

9. The method of Claim 7, wherein R2 is an aromatic group substituted with halogen.

10. The method of Claim 9, wherein R2 is a 4-chlorophenyl group.

11. The method of Claim 1, wherein Z is represented by the following structural formula: where: Ring A is a substituted or unsubstituted heteroaryl group; Ring B is a substituted or unsubstituted carbocyclic aromatic or heteroaryl group; Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -O-CH2-, -CH2-O-, -NRC-CH2-, -CH2-NRC -, -SO-CH2-, -CH2-S0-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO-NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

12. The method of Claim 11, wherein: Ring A or Ring B is substituted with -OH, halogen, -O- (aliphatic group), -O- (substituted aliphatic group), -O- (aromatic group), - O- (substituted aromatic group), an electron-withdrawing group, 20 - (0) u- (CH2) tC (0) OR: o; (CH -0C (0) R 2"0 2) t (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R 20, where RR21"1 oo RR2" 2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, or R21 and R22, taken together with the nitrogen atom to which they are joined, form a non-aromatic heterocyclic ring, u is zero or one, and t is an integer from zero to about three.

11. The method of Claim 11, wherein: Xi is -NRC-CH2-, -CH2-NRC-, -NRc-CO- or -CO-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (0) -NR31R32 or - (CH2) s-NHC (0) -O-R30; s is an integer from 1 to about 3; R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.

14. The method of Claim 11, wherein Ring B is a substituted or unsubstituted heteroaryl group.

15. The method of Claim 11, wherein Ring A is a substituted or unsubstituted pyridyl group and Ring B is a substituted or unsubstituted aromatic carbocyclic group.

16. The method of Claim 11, wherein Ring A is a substituted or unsubstituted pyridyl group and Ring B is a substituted or unsubstituted heteroaryl group.

17. The method of Claim 11, wherein R1 is -H or -OH.

18. The method of Claim 11, wherein: M is > C (OH) R2; and n is two.

19. The method of Claim 18, wherein R2 is a substituted aromatic or aromatic group.

20. The method of Claim 18, wherein R2 is an aromatic group substituted with halogen.

21. The method of Claim 20, wherein R2 is a 4-chlorophenyl group.

22. The method of Claim 11, wherein Ring A is a substituted or unsubstituted heteroaryl group and the Ring B is a substituted or unsubstituted phenyl group.

23. The method of Claim 22, wherein M is > C (OH) R2; and n is two.

24. The method of Claim 23, wherein R2 is a substituted or unsubstituted aromatic group.

25. The method of Claim 23, wherein R2 is an aromatic group substituted with halogen.

26. The method of Claim 25, wherein R2 is a 4-chlorophenyl group.

27. The method of Claim 22, wherein: Ring A is a pyridyl group; n is two; M is > C (OH) R2; and R2 is a 4-chlorophenyl group.

28. The method of Claim 27, wherein Xx is -CH2-S- or -CH2-CH2-.

29. The method of Claim 27, wherein Xi is -CH2-O-.

30. The method of Claim 1, wherein Z is represented by the structural formula: where: Ring C is a substituted or unsubstituted C6, C or C8 non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; and Ring A and Ring B are independently substituted or unsubstituted.

31. The method of Claim 30, wherein Z is represented by the following structural formula: where: Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -0-CH2-, -CH2-0-, -NRC-CH2-, -CH2 -NRC-, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO- NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.

32. The method of Claim 31, wherein Ring B is substituted with -OH, halogen, -O- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0- (aromatic group) substituted), an electron-withdrawing group, (0) u- (CH2) tC (0) OR2 °, - (0) u- (CH2) t-OC (0) R2 °, - (0) u- (CH2 ) tC (0) -NR21R22 or: o:; CH2) t-NHC (O) OR 20, where R 20 R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a group substituted aromatic or a non-aromatic heterocyclic group; or R 21 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to about three.

33. The method of Claim 31, wherein: Xi is -NRC-CH2-, -CH2-NRC-, -NRc-CO- or -CO-NRc-; Rc is - (CH2) s-COOR, 330 (CH2; -C (O) -NR31R32 or - (CH2) s -NHC (O) -OR, 3-0 s is an integer from one to about three; R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.

34. The method of Claim 32, wherein Z is represented by the following structural formula: _X ^ where R40 is -OH, halogen, an aliphatic group, a substituted aliphatic group, -NR2R25, -Q- (aliphatic group), -Q- (substituted aliphatic group), -O- (aliphatic group), -O- (group aliphatic substituted), -O- (aromatic group), -O- (substituted aromatic group), an electron-withdrawing group, - (O) u- (CH2) tC (O) OR20, - (O) u- (CH2 ) t-OC (O) R20, XO) u- (CH2) tC (0) -NR21R22 or - (O) u- (CH2) t-NHC (O) O-R20; R, 2"0 or R, 2" 2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; Q is -NR24C (0) - or -NR24S (0) 2-; R 24 and R 25 are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

35. The method of Claim 34, wherein: Xi is -NRC-CH2-, -CH2-NRC-, -NRc-CO-, or -CO-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (0) -NR31R32 or - (CH2) s-NHC (0) -O-R30; R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

36. The method of Claim 34 wherein, R40 is -O-CH 3.

37. The method of Claim 36, wherein R1 is -OH.

38. The method of Claim 36, wherein M is > C (0H) R2 and n is two.

39. The method of Claim 38, wherein R2 is a substituted or unsubstituted aromatic group.

40. The method of Claim 38, wherein R2 is an aromatic group substituted with halogen.

41. The method of Claim 40, wherein R2 is a 4-chlorophenyl group.

42. The method of Claim 41, wherein Xi is -CH2-0-.

43. The method of Claim 41, wherein Xi is -CH2-S- or -CH2-CH2-.

44. The method of Claim 1, wherein Z is represented by the following structural formula: wherein: Ring B is a substituted or unsubstituted aromatic carbocyclic or heteroaryl group; and Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -O-CH2-, -CH2-O-, -NRC-CH2-, -CH2- NRC-, -SO-CH2-, -CH2-S0-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -C0-NRc -; where: Rc is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted behenyl group.

45. The method of Claim 44, wherein Ring B is substituted with -OH, halogen, -O- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0- (aromatic group) substituted), an electron-withdrawing group, (0) u- (CH2) tC (0) OR2 °, - (0) u- (CH2) t-OC (0) R2 °, - (0) u- (CH2 ) tC (0) -NR1R22 or - (0) "- (CH2) t-NHC (0) O-R20; wherein R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to about 3.

46. The method of Claim 44, wherein: X] is -NRC-CH2-, -CH2-NRC-, -NRc-C0-, or -C0-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (0) -NR31R32 or - (CH2) s-NHC (0) -O-R30; R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

47. The method of Claim 44, wherein R1 is -OH.

48. The method of Claim 44, wherein M is > C (OH) R2 and n is two.

49. The method of Claim 48, wherein R2 is a substituted or unsubstituted aromatic group.

50. The method of Claim 48, wherein R2 is an aromatic group substituted with halogen.

51. The method of Claim 50, wherein R2 is a 4-chlorophenyl group.

52. A method for treating a disease associated with the aberrant recruitment and / or activation of leukocytes comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula: and the physiologically acceptable salts thereof, wherein: n is an integer of one to about 4; M is > NR2 or > CR2; R1 is -H, -OH, -N3, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group ), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a group substituted aliphatic, 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; where: R3, R4, R5 and R6 are independently -H, 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 R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, alternatively form a substituted or unsubstituted carbocyclic or heterocyclic ring; q is from zero to three; the ring containing M is substituted or unsubstituted; Z is represented by the following structural formula: ^ where: Xi is "S-, -CH2-, -CH2-CH2- -CH2-S- -S-CH2-, -0-CH2-, -CH2-0-, -NRC-CH2-, -CH2-NRC -, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO-NRc- wherein: Rc is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group, and Ring A and Ring B are independently substituted or unsubstituted.

53. The method of Claim 52, wherein n is two; M is CRXR2; and R2 is a substituted aromatic group,

54. The method of Claim 53, wherein Z is represented by the following structural formula: where R 40 is -OH, halogen, an aliphatic group, a substituted aliphatic group, -NR24R25, -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, - (O) u- (CH2) tC (O) OR20, - (O) u- ( CH2) t-OC (O) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R20; or R, 2"2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached; united, they form a non-aromatic heterocyclic ring, Q is -NR24C (0) - or -NR24S (0) 2 ~; R24 and R25 are independently -H, -OH, an aliphatic group or a substituted aliphatic group; one, and t is an integer from zero to about 3.

55. The method of Claim 54, wherein R40 is -0-aliphatic group; and R1 is -OH

56. The method of Claim 55, wherein Xx is -CH2-0-.

57. A compound represented by the following structural formula: and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is > NR2 or > CR1R2; R1 is -H, -OH, -N3, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group ), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M; and R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a group non-aromatic heterocyclic or a substituted non-aromatic heterocyclic group; where RJ R "R- and R are independently -H, 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 a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group: or R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, alternatively form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by the following structural formula: where: Ring A is a substituted or unsubstituted heteroaryl group; Ring B is a substituted or unsubstituted aromatic carbocyclic or heteroaryl group; Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -0-CH2-, -CH2-O-, -NRC-CH2-, -CH2-NRC -, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO ~ NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

58. The compound of Claim 57 wherein: Ring A or Ring B is substituted with - (O) u- (CH 2) t C (O) OR 20, - (O) u- (CH 2) t-OC (O) R 20, - (0) u- (CH2) tC (0) -NR21R22 or - (O) u- (CH2) t-NHC (O) O-R20; R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to about 3.

59. The compound of Claim 57, wherein: Rc is - (CH 2) s-COOR 30, - (CH 2) S-C (0) -NR 31 R 32 or - (CH 2) s -NHC (0) -O-R 30; R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

60. The compound of Claim 57, wherein Ring B is a substituted or unsubstituted heteroaryl group.

61. The compound of Claim 57, wherein Ring A is a substituted or unsubstituted pyridyl group and the Ring B is a substituted or unsubstituted aromatic carbocyclic group.

62. The compound of Claim 57, wherein Ring A is a substituted or unsubstituted pyridyl group and the Ring B is a substituted or unsubstituted heteroaryl group.

63. The compound of Claim 57, wherein R1 is -H or -OH.

64. The compound of Claim 57, wherein M is > C (OH) R2 and n is two.

65. The compound of Claim 64, wherein R2 is a substituted aromatic or aromatic group.

66. The compound of Claim 64, wherein R2 is an aromatic group substituted with halogen.

67. The compound of Claim 66, wherein R2 is a 4-chlorophenyl group.

68. The compound of Claim 57, wherein Ring A is a substituted or unsubstituted heteroaryl group and Ring B is a substituted or unsubstituted phenyl group.

69. The compound of Claim 68, wherein M is > C (OH) R2; and n is two.

70. The compound of Claim 69, wherein R2 is a substituted or unsubstituted aromatic group.

71. The compound of Claim 69, wherein R2 is an aromatic group that is substituted with halogen.

72. The compound of Claim 71, wherein R. ' It is a 4-chlorophenyl group.

73. The compound of Claim 68, wherein: Ring A is a pyridyl group; n is two; M is > C (OH) R2; and R2 is a 4-chlorophenyl group.

74. The compound of Claim 73, wherein Xi is -CH2-S- or -CH2-CH2-.

75. The compound of Claim 73, wherein Xi is -CH2-0-.

76. A compound represented by the following structural formula: (CH ») r M and the physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is > NR2 or > CR1R2; R1 is -H, -OH, -N3, an aliphatic group, -0- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group) ), -OC (0) - (aliphatic group), -OC (0) - (substituted aliphatic group), -C (0) 0- (aliphatic group), -C (0) 0- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a group substituted aliphatic, 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; R3, R4, R5 and R6 are independently -H, 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 group non-aromatic heterocyclic or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, alternatively form a substituted or unsubstituted carbocyclic or heterocyclic ring; and Z is represented by the following structural formula: / ° where: Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -O-CHz-, -CH2-O-, -NRC-CH2-, -CH2 -NRC-, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO- NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.

77. The compound of Claim 76, wherein Ring B is substituted with -OH, halogen, -O- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -O- (aromatic group) substituted), an electron-withdrawing group, - (O) u- (CH2) tC (0) OR 20, XO) u- (CH2) t-OC (0) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R2 °; wherein R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to approximately three.

78. The compound of Claim 76, wherein: Xi is -NRC-CH2-, -CH2-NRC-, -NRc-C0- or -C0-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (O) -NR31R32 or - (CH2) s-NHC (0) -O-R30; R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group); or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

79. The compound of Claim 76, wherein Z is represented by the following structural formula: / ^ where R 40 is -OH, halogen, an aliphatic group, a substituted aliphatic group, -NR24R25, -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, - (O) u- (CH2) tC (O) OR20, - (O) - (CH2 ) t-OC (O) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (O) u- (CH2) t-NHC (O) O-R20; R, 2'1 'or R, 2"2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring, Q is -NR 2"4, C (0) -NR24S or; R, 2¿4, i and are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

80. The compound of Claim 79, wherein Xi is -NRC-CH2-, -CH2-NRC-, -NRc-CO-, or -CO-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (O) -NR31R32 or - (CH2) s-NHC (0) -O-R30; R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

81. The compound of Claim 80 wherein, R40 is -0-CH3.

82. The compound of Claim 81, wherein R1 is -OH.

3. The compound of Claim 81, wherein M is

84. The compound of Claim 83, wherein R2 is a substituted or unsubstituted aromatic group.

85. The compound of Claim 83, wherein R2 is an aromatic group substituted with halogen.

86. The compound of Claim 85, wherein R2 is a 4-chlorophenyl group.

87. The compound of Claim 86, wherein Xj. is - CH2-O-.

88. The compound of Claim 86, wherein Xi is -CH2-S- or -CH2-CH2-.

89. The compound of Claim 57, wherein Z is represented by the following structural formula: wherein: Ring B is a substituted or unsubstituted aromatic carbocyclic or heteroaryl group; and Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -0-CH2-, -CH2-0-, -NRC-CH2-, -CH2- NRC-, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO-NRc -; where: R c is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

90. The compound of Claim 89, wherein Ring B is substituted with -OH, halogen, -O- (aliphatic group), -O- (substituted aliphatic group), -0- (aromatic group), -O- (aromatic group) substituted), an electron-withdrawing group,: o); CH2) tC (0) OR 20 - (O) u- (CH2) t-0C (O) R20, - (O) u- (CH2) tC (0 ) -NR21R22 - (0) u- (CH2) t-NHC (O) O-R20; where R, 2"X0 R, 2" "1 or R, 2" 2 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to about three.

91. The compound of Claim 89, wherein: Xx is -NRC-CH2-, -CH2-NRC-, -NRc-CO-, or -CO-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (O) -NR31R32 or - (CH2) s-NHC (0) -O-R30; R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

92. The compound of Claim 89, wherein R1 is -OH.

93. The compound of Claim 89, wherein M is > C (OH) R2 and n is two.

94. The compound of Claim 93, wherein R2 is a substituted or unsubstituted aromatic group.

95. The compound of Claim 93, wherein R2 is an aromatic group substituted with halogen.

96. The compound of Claim 95, wherein R2 is a 4-chlorophenyl group.

97. A compound represented by the following structural formula: and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is > NR2 or > CR1R2; R1 is -H, -OH, -N3, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group ), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M; R2 is -H, -OH, 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; and Z is represented by the following structural formula: X ^ where: Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -O-CH2-, -CH2-0-, -NRC-CH2-, -CH2 -NRC-, -S0-CH2-, -CH2-S0-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-C0- or -CO- NRc-; Rc is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.

98. The compound of Claim 97, wherein Ring A or Ring B has at least two substituents.

99. The compound of Claim 97, wherein Ring A or Ring B is substituted with -OH, halogen, -0- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0 - (substituted aromatic group), an electron-withdrawing group, - (0) u- (CH2) t_C (0) 0R20, - (0) u- (CH2) t-OC (0) R2 °, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) O-R20; wherein R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the. nitrogen atom to which they are attached form a non-aromatic heterocyclic ring; u is zero or one; and t is an integer from zero to about three.

100. The compound of Claim 97, wherein: Xi is -NRC-CH2-, -CH2-NRC-, -NRc-CO-, or -CO-NRc-; Rc is - (CH2) s-COOR30, - (CH2) S-C (O) -NR31R32 or - (CH2) S-NHC (O) -O-R30; R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; and s is an integer from one to about three.

101. The compound of Claim 97, wherein: n is two; M is > C (OH) R2; and R2 is a substituted or unsubstituted aromatic group.

102. The compound of Claim 101, wherein R2 is an aromatic group substituted with halogen.

103. The compound of Claim 102, wherein R2 is a 4-chlorophenyl group.

104. The compound of Claim 103, wherein X is -CH2-S- or -CH2-CH2-.

105. The compound of Claim 103, wherein Xi is -CH2-0-.

106. A compound represented by the following structural formula: and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is > NR2 or > CR1R2; R1 is -H, -OH, -N3, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group) ), -OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; or R1 is a covalent bond between the ring atom of M and an adjacent carbon atom in the ring containing M; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group; wherein: R3, R4, R5 and R6 are independently -H, 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 R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are attached, alternatively form a substituted or unsubstituted carbocyclic or heterocyclic ring; q is from zero to three; the ring containing M is substituted or unsubstituted; Z is represented by the following structural formula: ^ where: Xi is -S-, -CH2-, -CH2-CH2-, -CH2-S-, -S-CH2-, -0-CH2-, -CH2-0-, -NRC-CH2-, -CH2 -NRC-, -SO-CH2-, -CH2-SO-, -S (0) 2-CH2, -CH2-S (0) 2-, -CH = CH-, -NRc-CO- or -CO- NRc-; where: R c is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.

107. The compound of Claim 106, wherein n is two; M is CRXR2; and R2 is a substituted aromatic group.

108. The compound of Claim 107, wherein Z is represented by the following structural formula: where: R40 is -OH, halogen, an aliphatic group, a substituted aliphatic group, -NR24R25, -Q- (aliphatic group), -Q- (substituted aliphatic group), -0- (aliphatic group), -0- ( substituted aliphatic group), -O- (aromatic group), -0- (substituted aromatic group), an electron-withdrawing group, - (0) u- (CH2) -C (0) OR 20X - (O) u- (CH2) t-OC (0) R, 20: or u- (CH2) tC (0) -NR21R22 or (0) u- (CH2) t-NHC (O) OR, 20, .- R, 2¿ 0X R, 2? 1 ± or R, 22? are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and? -2¿, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; Q is -NR24C (0) - or -NR24S (0) 2-; R 24 and R 25 are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

109. The compound of Claim 108, wherein R40 is -0-aliphatic group; and R1 is -OH.

110. The compound of Claim 109, wherein Xi is -CH2-0.

111. A method for producing an antagonistic effect on a chemokine receptor in a mammal in need thereof comprising administering a compound of Claim 52.