BRPI0712301A2 - compound, pharmaceutical composition, method of antagonizing a dp-2 receptor, and use of a compound - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, ANTAGONIZATION METHOD OF A DP-2 RECEIVER, AND, USE OF A COMPOUND Compounds of substituted phenyl acetic acid of formula (I), pharmaceutical compositions, methods for their preparation and methods are provided, which are useful in treatment and prevention of disorders or conditions, which respond to DP2 receptor modulation, in particular, related inflammatory and immune disorders and conditions, such as asthma, allergic rhinitis and atopic dermatitis.

Description

"COMPOUND, PHARMACEUTICAL COMPOSITION, ANTAGONIZATION METHOD OF A DP-2 RECEIVER, AND USE OF A COMPOUND"

BACKGROUND OF THE INVENTION

Prostaglandin D2 (PGD2) is the main proinflammatory mediator abundantly secreted by stem cells activated by allergen exposure from a previously sensitized host. PGD2 is capable of producing a multitude of relevant pathobiological responses to inflammatory disorders, including airway constriction, leukocyte influx, increased vascular permeability, edema, and mucus secretion. The biological actions of PGD2 are mediated by at least 3 distinct G protein coupled receptors. The high affinity receptors DP-1 (formerly known as DP) and DP-2 (formerly known as the orphan receptor "G 44 protein receptor", GPR44 and the "TH2 cell-expressed chemoattractant receptor homolog", CRTH2 ( See Hiral, H., ET AL, J. Exp. Med. 2001, 193 (2): 255-61; Nagata, KJ Biol. Regul. Homeost. Agents 2002, 17 (4): 334-7) and the recipient. Thromboxane A2, TP, to which PGD2 binds with low affinity.

The DP-2 receptor is a major contributor to the pathophysiological actions of PGD2. Accordingly, pharmaceutical substances targeting this receptor are likely to be therapeutically beneficial for a disturbing host, specifically for inflammatory conditions having an allergic component, such as asthma (Vide Hang, JJ). Microbiol Immunol Infect 2005, 38 (3): 158-63). DP-2 is selectively expressed in Eosinophils, Basophils, and highly polarized TH2 cells in humans. These cell types are known contributors to inflammatory disorders and other conditions. Activation of DP-2, a chemoattractant receptor, stimulates chemotaxis of human, eosinophil, and basophilic TH2 cells, both in vitro and in vivo, and can mediate recruitment of cell types relevant to diseased sites and exacerbate organ damage. terminal.

DP-2 agonists are able to directly activate inflammatory cells and DP-2 mediated activation and mediator release from Eosinophils and Basophils has been reported (see Gervais, FG et al. J. Allergy Clin Immunol (2004), 108 (6: 982-8; Yoshimura-Uchiyama, C. et al., Clin Exp. Allergy 2004, 34 (8): 1283-90). TH2 effector T lymphocytes will construct the inflammatory cytokines IL-4, IL-5, and IL-13 in response to DP-2 stimulation (See Xue, L. et al., J. Immunol., 2005, 175 ( 10: 6531 - 6) These cytokines, in turn, act as important regulators of inflammatory responses and support TH2 cell differentiation, stem cell growth, IgE differentiation and synthesis, and differentiation, infiltration, and survival. of eosinophils.

This suggests that the PGD2 / DP-2 pathway acts as a positive feedback loop and increases biological responses in disorders associated with excessive or unregulated PGD2 production. Therefore, pharmaceutical agents that interfere with this pathway may prove useful in treating a wide range of allergic and inflammatory conditions and other disorders.

The usefulness of PGD2 antagonists in treating inflammatory disorders is supported by clinical studies with Ramatroban® (Baynas, BAY u3405). Clinical studies have shown a beneficial effect of Ramatroban® on rhinitis symptoms, as well as inflammatory markers in nasal washes, suggesting anti-inflammatory activity. Ramatroban® was initially described as a selective TP antagonist, and its clinical effects on rhinitis were thought to be mediated by TP. Recent findings, however, have revealed that Ramatroban® has dual specificity and antagonizes both TP and DP-2 receptors (See Sugimoto, H., et al., J. Pharmacol. Exp. Ther., 2003, 305 (1) : 347-52). In light of the presence of DP-2 on pivotal inflammatory cells involved in allergic rhinitis, and the stimulating effects of PGD2 and other DP-2 antagonists on these cells, it is reasonable to postulate that the clinical benefit of Ramatroban® in allergic rhinitis is due. , to a large extent, to its activity against the DP-2 receptor.

It can therefore be inferred that selective DP-2 antagonists may be useful in the treatment of allergic rhinitis, other inflammatory conditions, other conditions in which the PGD2 pathway is unregulated, as well as other disorders in which the usefulness of Ramatroban® has been established.

Minami et al. demonstrated the efficacy of Ramatroban® on edema in experimental allergic conjunctivitis (Vide Minami, K. et al. Immunopharmacol. 2004, 4 (12): 1531 - 5). DP-2 has been shown to play an essential role in allergic disorders, specifically in IgE-mediated skin responses that occur in chronic contact hypersensitivity (See Mitsumori, S. Curr. Pharm., Des., 2004, 10 ( 28): 3533 - 8); Moroi, R., et al., 30th Annu. Meet Jpn. Sound. Invest. Dermatol. (April 20 - April 22, Yokohama), 2005, Summary, 48).

Numerous compounds have been reported as PGD2 receptor modulators and / or useful for treating allergic and inflammatory disorders. WO 200602418 discloses a series of sulfamylbenzimidazol-1-yl acetic acid compounds with DP-2 or PGD2 antagonist activity. WO 200 6021759 discloses a series of biphenyloxyacetic acid derivatives with PGD2 modulating activity, said to be useful for the treatment of respiratory disorders. WO 2005019171, WO 2004106302 and WO 2005054232 set forth a series of acetic acid-indole, -indazole and -benzimidazole compounds, said to be useful for the treatment of respiratory disorders. WO 2005105717 discloses phenoxy acetic acid compounds with DP-2 antagonistic activity. EO 2005018529 discloses acetic acid compounds believed to be useful for the treatment of asthma and rhinitis. WO 2005040114 and WO 2005040112 describe a series of compounds with DP-2 or PGD2 antagonistic activity, said to be useful for the treatment of allergy, asthma and atopic dermatitis. WO 2004058164, U.S. Patent Publications discloses a number of compounds, believed to be useful for the treatment of allergy, asthma, cancer and inflammation. EO 2004096777 discloses a series of pyridine derivatives which are useful for the treatment of DP-2 mediated conditions including asthma, conjunctivitis, dermatitis, atopic rhinitis, allergic sinusitis. WO 22004078719 discloses a series of indole compounds, said compounds being useful for the treatment of asthma and allergic rhinitis. Patent Publication No. 2004132772 discloses a series of tetrahydroquinoline compounds as DP-2 antagonists, said to be useful for the treatment of allergic asthma and allergic rhinitis. Patent Publication No. 2004132772 discloses a series of tetrahydroquinoline compounds as DP-2 antagonists, said to be useful for the treatment of allergic asthma and allergic rhinitis. WO 2003066-46, WO 2003066047, WQO 2003 101961, WO 2003101981, WO 200400745 'set forth a series of indole acetic acids, which are useful for the treatment of asthma, chronic obstructive pulmonary disease (COPD), rhinitis and other conditions. allergic. WO 2003097598 discloses a series of compounds, believed to exhibit PGD2 receptor antagonism. US Patent No. 4,656. 192 discloses a series of Tropolone compounds, believed to be useful as antitumor agents. EP 1170594 discloses methods for the identification of compounds useful for treating prostaglandin D2 mediated conditions, a ligand for the orphan receptor DP-1. GB 1356834 discloses a number of compounds, believed to have anti-inflammatory, analgesic and antipyretic activity.

Even so, there is a relative shortage of drugs that selectively modulate non-aminergically linked G protein-coupled receptors on the market (see Beaumont K. et al., Bioorg. Med. Chem. Lett., 2005, 15 (16): 3658-64). SUMMARY OF THE INVENTION

It has now surprisingly been found that certain phenyl acetic acids are potent DP-2 receptor antagonists. In certain embodiments, phenyl acetic acids are selective DP-2 receptor antagonists over PGD2 receptors. The phenyl acetic acid compounds of the invention are expected to be useful for the treatment or prevention of medical conditions or disorders responsive to DP-2 antagonism or symptoms associated with such medical conditions or disorders such as those having an allergic or inflammatory component. Exemplary conditions or disorders, which may be treated or avoided with the compounds and compositions of the invention, are provided below.

Among the general aspects of the present invention, the invention provides compounds, pharmaceutical compositions, and methods useful for treating or preventing conditions and disorders associated with inflammation and / or allergic processes. In particular, the invention provides compounds, pharmaceutical compositions and methods useful for the treatment or prevention of asthma, allergic conditions, inflammatory conditions, cancer and viral infection.

The compounds of the invention have the general structure (I):

<formula> formula see original document page 6 </formula>

Within the above formula, L is selected from the group consisting of a CR6R7, CO, CNR6 and CS.

A is a 5-14 membered heterocyclic ring having 1-4 ring heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being monocyclic or polycyclic, optionally substituted by 1- 3 substituents R8.

Q 1 is selected from the group consisting of: a bond, C 1-4 alkylene, C 1-4 heteroalkylene, -CO-, -NH-, -O-, -SOq-, -C (O) O-, -OC (O) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -COH2HNSOq.

R1, R2, R3, R6 and R7 are each independently selected from the group consisting of H, C1-6 alkyl, C0-6 alkylaryl and C0-e 'alkyl heteroaryl, wherein the aryl or heteroaryl moieties are optionally substituted by C1-6 alkyl, CN, OR, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR.

Each R4 is independently selected from the group consisting of C1-6 alkyl, C0-4 alkyl-C3-10 cycloalkyl, C0-4 alkylaryl, C0-4 alkyletheroaryl, C2-4 alkenylaryl, C2-6 alkynylaryl 4, C0-4 alkyleterocyclyl, CN, amino, NHCOR1, hydroxy, C1-6 alkoxy, OC (O) R1, -OC0-4alkylaryl, OC0-4alkylcycloalkyl C3-10, OC0-4alkylheterocyclyl C 3-10, OC 0-4 alkyl NR, nitro, halo, and C 1-6 haloalkyl; or are combined together with R 6 to form an aryl or heteroacyclyl ring system having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the alkyl, aryl and heterocyclyl moieties are each optionally substituted by 1 to 3 substituents each independently selected from the group consisting of C1-6 alkyl, CN, CONHR1, CO2R1, amino, C1-6 alkoxy. 6, halo, C1-6 haloalkyl and SOqR1.

R5 is selected from the group consisting of C1-6 alkyl, C0-4 alkylaryl, C2-4 alkenylaryl and C0-4 alkyletheroaryl each of which is optionally substituted by 1-3 R9 substituents. Each R8 is independently selected from the group consisting of C1-6 alkyl, C0-6 alkylC3-6 cycloalkyl, C0-6 alkylaryl, Co-6 alkyletheroaryl, oxo, C1-6 alkyl, CN3 OR5 C1-6 haloalkyl, C1-6 heteroalkyl NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, C (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC ( O) R and NRC (O) OR.

Each R9 is independently selected from the group consisting of C1-6 alkyl, CN, OR, oxo, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR.

Each R is independently selected from the group consisting of H, C1-6 alkyl, C0-4 alkyl heteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl or when bonded to the same nitrogen atom may be combined. to form a 5-8 membered ring having 1-4 ring heteroatoms, each independently selected from the group consisting of nitrogen, oxygen and sulfur.

The subscript η is independently O, 1, 2, 3, or 4.

Each subscript q is independently O, 1 or 2.

The invention also provides pharmaceutically acceptable salts, hydrates, solvates and prodrugs of compounds of structure I. Examples of prodrugs are compounds wherein R1 is C1-6 alkyl, C0-6 alkylaryl or C0-6 alkyletheroaryl. the aryl or heteroaryl moieties are optionally substituted as described herein.

The invention also provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, excipient or diluent.

The invention also provides methods for antagonizing a DP-2 receptor comprising contacting a DP-2 receptor with a compound of structure I, as well as methods for selectively agonizing a DP-2 receptor with one or more PGD2 receptors. . The invention also provides methods for treating or preventing a disorder responsive to antagonizing a DP-2 receptor, as well as methods for treating or preventing a disorder or condition associated with elevated PGD2 levels, or a metabolite. comprising administering to a patient in need thereof a therapeutically effective amount of a compound of structure I.

The invention further provides methods for treating or preventing an inflammatory disorder or condition with an inflammation or allergic component as provided herein.

The invention also provides methods for treating or preventing a DP-2 mediated condition or disorder and / or one or more other PGD2 receptors, for example DP-1, which comprises administering to a patient in need thereof. a therapeutically effective amount of a compound of formula I.

The invention also provides methods for selectively modulating DP-2 in the presence of one or more other PGD2 receptors, e.g. DP-1 receptors, which comprise contacting a cell with a compound of structure I.

Other objects, features and advantages of the invention will become apparent to one skilled in the art from the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

The abbreviations used herein are conventional unless otherwise defined. The following abbreviations are used: EtOAc - ethyl acetate, DMF = N, N-Dimethyl formamide, NMP = N-methylpyrrolidine, THF = tetrahydrofuran, RT = room temperature, TFA = triflurooacetic acid, LDA = lithium diisopropylamine, n- BuLI = n-butyllithium, NA2CO3 = sodium carbonate, DME = dimethyl ether, K2PO4 = potassium phosphate, CH2Cl2 or DCM = dichloromethane, Et3N = triethylamine, DEEA = Hunig base or diisopropyl ethylamine, KOH = potassium hydroxide, NaOH = sodium hydroxide, TMS = tyrimethylsilyl, Tf = trifluoromethylsulphyl, Boc = t-butyl carbonyl, Bz - benzyl, IPA = isopropyl alcohol, NBS = N-bromosuccinamide, AIBN = azoisobutyronitrile (also azbisisobutylnitrile), Pin = pinacolato, Cs = carbonate cesium, IIV = human immunodeficiency virus, RLV = Raucher leukemia virus, IgE = immunoglobulin E.

It is noted herein that as used in this report and the claims only, the singular forms "a", "one" and "o" include plural references, unless the context clearly dictates otherwise.

The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, a cyclic hydrocarbon radical, or a combination thereof, which is fully saturated having the designated number of carbon atoms (i.e. C1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl (cyclohexyl) methyl, cyclopropylmethyl, homologues and isomers of, for example, n-pentyl, n hexyl, n-heptyl, n-octyl, and the like.

The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain, or a cyclic hydrocarbon radical, or a combination thereof, which may be mono- or polyunsaturated, having the number of atoms of designated carbon (that is, C 2-8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl) and other homologues and isomers thereof.

The term "alkynyl", by itself or part of another substituent, means a straight or branched chain hydrocarbon radical, or a combination thereof, which may be mono- or polyunsaturated, having the designated number of carbon atoms ( that is, C 2-8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethinyl, 1- and 3-propynyl, 3-butynyl and higher homologues and isomers thereof.

The term "alkylene" by itself or as part of another substituent means a divalent alkyl-derived radical as exemplified by -CH 2 CH 2 CH 2 CH 2 -. Typically, an alkyl (or alkylene) group should have from 1 to 24 carbon atoms, which groups having 10 or less carbon atoms are preferred in the present invention. A "lower alkyl" or "lower alkylene" group is a shorter chain alkyl or alkylene group generally having eight or fewer carbon atoms.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in the conventional sense, and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or an atom. sulfur, respectively. Similarly, the term dialkylamino refers to an amino group having two attached alkyl groups, which may be the same or different.

The term "heteroalkyl", in itself or in combination with another term, means, unless otherwise stated, a straight or branched chain, or a cyclic hydrocarbon radical, or combinations thereof, consisting of the number mentioned carbon atoms and one or more heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The O, N and S heteroatom (s) may be placed at any positions within the heteroalkyl group. The Si heteroatom may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include -CH 2 -CH 2 -O-CH 3, -CH 2 -CH 2 -NH-CH 3, -CH 2 -CH 2 -N (CH 3) -CH 3, -CH 2 -S-CH 2 -CH 3, -CH 2-CH 2, -S ( O) -CH 3, -CH 2 -CH 2 -S (O) 2-CH 3, -CH = CH-O-CH 3, -Si (CH 3) 3, -CH 2 -CH = N-OCH 3, and -CH = CH-N (CH3) -CH3. Up to two heteroatoms may be consecutive such that, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si (CH 3) 3. When a prefix, such that (C2 -Cs) is used to refer to a heteroalkyl group, the number of carbons (2-8) in this example) is intended to include heteroatoms as well. For example, a C 2 heteroalkyl group is intended to include, for example, -CH 2 OH (a carbon atom and a hetero atom substituting a carbon atom) and -CH 2 SH. The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heeroalkyl as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms may also occupy one or both of the chain termini (e.g. alkylenoxy, alkylenedioxy, alkylene amino, alkylenediamine, and the like). Furthermore, for alkylene and heteroalkylene linking groups, there is no orientation of the linking group involved.

The terms "cycloalkyl", "heterocyclyl" and "heterocyclic ring", by themselves or in combination with other terms, represent, unless otherwise noted, cyclic versions of "alkyl" or "heteroalkyl", respectively. Accordingly, the terms "cycloalkyl" and "heterocyclic ring" are intended to be included in the terms "alkyl" and "heteroalkyl", respectively. Additionally, for a heterocyclic ring, a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclopetyl, and the like. Examples of a heterocyclic ring include pyrrolidinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, piperazinyl, piperazin-1-oxide, morpholinyl, thiomorpholinyl, azepanyl, azepinyl, oxazepane, thiazepane, azocanyl, azolinhydroquinyl dihydrobinyl, dihydrolazin, and the like.

The terms "halo" or "halogen", by themselves or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include alkyl substituted by halogen atoms, which may be the same or different, in a number within a range of (2m '+ 1), where m' is the total carbon number in the alkyl group. For example, the term "C1-6 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monoaloalkyl (alkyl substituted with a halogen atom) and polyaloalkyl (alkyl substituted with halogen atoms in a number in the range of two to (2m '+ 1) halogen atoms). The term "peraloalkyl" means, unless otherwise noted, alkyl substituted by (2m '+ 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "C 1-6 peraloalkyl" is intended to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term "aryl" means, unless otherwise mentioned, a typically aromatic, polyunsaturated hydrocarbon substituent, which may be a single ring or multiple rings (up to three rings), which may be fused together or separately. covalently linked. The term "heteroaryl" refers to aryl groups (or rings) containing from one to four heteroatoms, selected from the group consisting of Ν, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized. , and the nitrogen atom (s) are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. Nonlimiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2 oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl , 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl , 5-indolyl, 1H-indazol, carbazole, α-carboline, β-carboline, γ-carboline, 1-isoquinolia, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4- quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl and 8-quinolyl.

In some embodiments, the term "aryl" refers to a phenyl or naphthyl group which is substituted or unsubstituted. In some embodiments, the term "heteroaryl" refers to a pyrrolyl, pyrazyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, iSOquinolyl, quinoxalinyl or quinoxalinyl group , which is substituted or unsubstituted.

For the sake of brevity, the term "aryl, when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term" arylalkyl "is intended include those radicals in which an aryl group is attached to an alkyl group (for example benzyl, phenethyl, pyridylmethyl and the like, including those alkyl groups in which a carbon atom (for example a methylene group) may be substituted for example an oxygen atom (e.g. phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like). Each of the above terms (e.g. "alkyl", "heteroalkyl", "Aryl" and "heteraryl" are intended to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated Preferred substituents for each radical type are provided below.

The substituents for alkyl and heteroalkyl radicals (as well as those preferred groups such as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocyclyl) may be a variety of groups, selected from: -OR ', = O, = NR ", = N-OR ', -NR'R", -SR ", halogen, -SiR'R" R "', -OC (O) R ', -C (O) R', -CO2 R ', -CONR'R ", -OC (O) NR'R", -NR "C (0) R", -NR "-C (0) NR" R "\ -NR '- SO2NR" R "', - NR "CO 2 R ', -NH-C (NH 2 = NH, -NR'C (NH 2) = NH, -NH-C (NH 2) = NH, -NH-C (NH 2) = NR', -S (O) R ', -SO2R', -SO2NR'R ", -NR" SO2R, -CN and -NO2, in a number η from zero to three, those groups having zero, one or two substituents being particularly preferred. , R "and R '" each independently refer to hydrogen, unsubstituted C1-6 alkyl and heteroalkyl, unsubstituted aryl, aryl substituted by one to three halogens, unsubstituted alkyl groups, alkoxy or thioalkoxy, or C1-6 arylalkyl groups. When R "and R" are attached to the same atom of nitrogen, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR "R" is intended to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group should have from zero to three substituents, those groups having two or less substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical may be monosubstituted or unsubstituted. Even more preferably an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups such as trialoalkyl (e.g., -CF3 and -CH2CF3).

In some embodiments, substituents for alkyl and heteroalkyl radicals are selected from: -OR ', = O, -NRR ", -SR', halogen, -Si R'R" R "', -OC (O) R ', -C (O) R', -CO2R ', -CONR'R ", - 0C (0) NR'R", -NR "C (0) R', -NR" CO2 R ', -NR' - S02NR "R" ', -S (O) R', -SO2R ', -SO2NRiR ", -NR" SO02R, -NC and -NO2, where R' and R "are as defined above. In some embodiments, substituents are selected from: -OR ', = O, -NR'R ", halogen, -OC (O) R', -CO2R ', -CONR'R", -OC (O) NR'R ", -NR" C (O) R ', -NR "CO2R', -NR'-SO2NR" R "', -SO2R', -SO2R ', -SO2NR'R", -NR "SO2R, - CN and -NO2.

Similarly, the substituents for two aryl and heteroaryl groups are varied and are selected from: -halogen, -OR ', -OC (O) R', -NR "R ', -SR', -CN, -NO2, -CO2R ', -CONR'R ", -C (O) R', -OC (O) NR'R", -NR "C (O) R ', -NR" C (O) 2R' -NR'-C (O) NR "R" ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR', -S (O ) R ', -S (O) 2R', -S (O) 2NRiR ", - N3, - CH (Ph) 2, C1-6 perfluoroalkoxy, and C1-6 perfluoroalkyl, in a number from zero to number total open valences in the aromatic ring system; and wherein R ', R "and R'" are independently selected from hydrogen, C1-6 alkyl and heteroalkyl, substituted (unsubstituted aryl) - C1-6 alkyl and (unsubstituted aryl) oxy - C1-6 alkyl.

Two of the substituents on the adjacent atoms of the eryl or heteroaryl ring may be optionally substituted by a substituent of the formula -T-C (O) - (CH2) q-U, where TeU are independently -ΝΉ-, -O-, -CH2 or a single bond, eq is 0, 1 or 2. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula -A- (CH 2) rB-, wherein AeB are independently -CH 2 -, -O-, -NH-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR '- or a single bond, er is 1, 2 or 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula - (CH2) - X- (CH2) t5 where s are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2-, or -S (O) 2NR '. The substituent R 'on -NR' w - S (O) 2NR'- is selected from hydrogen or unsubstituted C1-6 alkyl. On the other hand, R 'is as defined above.

As used herein, the term "heteroatom" is intended to include oxygen (O), nirogen (N), sulfur (s), and silicon (Si).

The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds, which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. Where the compounds of the present invention contain relatively acid functionalities, base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. Where the compounds of the present invention contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in an inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, carbonic monohydrogen, phosphoric, phosphoric monohydrogen, phosphoric dihydrogen, sulfuric, sulfuric monohydrogen, iodridic, or the like. as well as salts derived from non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, sulfonic benzene, p-tolyl sulfonic, citric, tartaric , sulfonic methane, and the like. Also included are amino acid salts, such as arginate and the like, and organic acid salts, such as glucuronic and galactonic acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-79 (1977) Certain specific compounds of the present invention may contain both basic and acid functionalities, which allow the compounds to be converted to either base addition salts or acid addition salts Other known pharmaceutically acceptable carriers those skilled in the art are suitable for the present invention.

Neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The source form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, on the other hand, the salts are equivalent to the source form of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds which are readily subjected to chemical changes under physiological conditions in order to provide the compounds of formula I, which are DP-2 receptor antagonists. In addition, prodrugs may be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs may be slowly converted to the compounds of the invention when placed in a reservoir of a transdermal patch with a suitable enzyme or chemical reagent. Prodrugs are often useful because in some situations they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, while the parent drug is not. The prodrug may also exhibit adequate solubility in pharmaceutical compositions relative to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those based on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (for example, where R1 is C1-6 alkyl, C0-6 alkylaryl or unsubstituted or substituted C0-6 alkyletheroaryl). substituted, the "prodrug"), but is then metabolically hydrolyzed to carboxylic acid (e.g., where R1 is H, the "active entity"). Additional examples include peptidyl derivatives of a compound of the invention.

Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms, and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple or amorphous crystalline forms. Generally, all physical forms are equivalent to the uses contemplated by the invention and are intended to be included within the scope of the invention.

Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be included within the scope of the invention. These isomers may be decomposed or synthesized in an asymmetric manner using conventional methods to make the isomers "optically pure", i.e. substantially free of their other isomers. If, for example, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the cleavage auxiliary group of to provide the pure desired enantiomers. Alternatively, when the molecule contains a basic functional group such as amino, or an acid functional group such as carboxy, the diastereomeric salts are formed with an optically pure acid or base, followed by resolution of the diastereomers thus formed via fractional crystallization or chromatographic media, well known in the art, and subsequent recovery of pure enantiomers.

The compounds of the invention may also contain unnatural proportions of atomic isotopes in one or more atoms, which constitute such compounds. For example, the compounds may be radiolabelled with radioactive isotopes, such as, for example, tritium (3H), iodine -125 (125l) or carbon -14 (14c). Radiolabelled compounds are useful as therapeutic or prophylactic agents, for example cancer therapeutic agents, screening agents, for example DP-2 assay reagents, and diagnostic agents, for example as an in vivo imaging agent. . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

An "antagonist" or "inhibitor" refers to an agent or molecule, which inhibits or binds to, partially or totally blocks stimulation or activity, decreases, terminates, prevents, delays activation. or the enzymatic activity, inactivates, desensitizes, or down-regulates the activity of a receptor of the invention. As used herein, "antagonist" also includes a reverse or inverse agonist.

An "agonist" or "activator" refers to an agent or molecule, which binds to a receptor of the invention, stimulates, enhances, opens, activates, facilitates, increases enzymatic activation or activity, sensitizes or regulates up to activity of a receptor of the invention.

Activity "modulators" are used to refer to "ligands", antagonists "and" agonists "identified through the use of in vitro and in vivo assays for activity and their counterparts and mimetics. Modulators include ligands, antagonists, agonists. Naturally occurring and synthetic molecules and the like Assays for identifying antagonists and agonists include, for example, applying putative modular compounds to cells in the presence or absence of a receptor of the invention, and then determining the Functional effects on a receptor of the activity of the invention Samples or assays, comprising a receptor of the invention, which are treated with activator, inhibitor or potential modulator, are compared control samples without inhibitor, activator or modulator, in a manner such as examine the extent of the effect. Control samples (non-modular) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a receptor of the invention relative to control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a receiver of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000 - 3000%, or higher.

The terms "treating", "treating", "treatment" and grammatical variations thereof, as used herein, include retarding, alleviating, mitigating or partially or completely reducing the intensity of one or more of the symptoms relating to a given condition. disorder or condition and / or alleviate, mitigate or prevent one or more causes of a disorder or condition. The treatments according to the invention may be applied in a preventative, prophylactic, palliative or curative manner.

The terms "prevent", "preventing", "prevention" and grammatical variations thereof as used herein refer to a method of partially or completely delaying or deleting the onset or recurrence of a disorder or condition and / or one or more of its pertinent symptoms or to prevent a patient from acquiring or regaining a disorder or condition, or in order to reduce a patient's risk of acquiring or regaining a disorder or condition or one or more of their pertinent symptoms.

The term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the compound in question that will cause a biological or medical response of a tissue, system, animal or human being sought by the researcher, veterinarian , treating physician or other clinician. The term "therapeutically effective amount" includes the amount of a compound which, when administered, is sufficient to prevent the development of or to some extent alleviate one or more symptoms of the condition or disorder being treated. The therapeutically effective amount will depend on the compound, disorder or condition, and its severity and also on the age, weight, etc., of the mammal to be treated.

The phrase "selectively" or "specifically" when referring to binding to a receptor, refers to a binding reaction, which is determinative of receptor presence, often in a heterogeneous population of receptors and other biological agents. Thus, under the designated conditions, the compounds bind to a particular receptor at twice the reference, and typically more than 10 to 100 times the reference. Specific binding of a compound under such conditions requires a compound, which is selected because of its specificity for a particular receptor. For example, small organic molecules, which may be selected to obtain only those compounds that specifically or selectively bind to a selected receptor, and not to other receptors or proteins. A variety of assay formats can be used to select compounds which are selective for a particular receptor. For example, high flow sweep assays are routinely used to select compounds that are selective for a particular receptor.

The "patient" is defined herein to include animals, such as mammals, which include, but are not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the patient is a human being.

As used herein, the term "DP-2" refers to a DP-2 receptor protein (RefSeq Accession No. NP-007469) or a variant thereof, which is capable of mediating a cellular response to PGD2 in vitro. or in vivo. DP-2 variants include proteins substantially homologous to native DP-2, that is, proteins having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., DP-2 derivatives, homologs and fragments). The amino acid sequence of the DP-2 variant is preferably at least 80% identical to a native DP-2, more preferably at least about 90% identical, and even more preferably of at least 80%. at least about 95% identical.

As used herein, the terms "another PGD2 receptor" or "another PGD2 receptor" and the like refer to a prostanoid receptor protein other than DP-2, or variant thereof, which is capable of mediating a cellular response. PGD2 in vitro or in vivo. Another PGD2 receptor may be PGD2 selective, for example DP-1 (RefSeq Accession No. NP-000944), or may also interact with one or more other prostanoids (e.g., EP1, EP2, EP3, and EP4, FP, IP and TP). Other variants of PGD2 include proteins substantially homologous to a corresponding native prostanoid receptor, other than DP-2, ie proteins having one or more naturally occurring or unnatural amino acid deletions, insertions or substitutions (e.g., derivatives, homologs and fragments of another PGD2 receptor). The amino acid sequence of other variants of the PGD2 receptor is preferably at least 80% identical to other corresponding native PGD2 receptors, more preferably at least about 90% identical, and more preferably of at least 80%. at least about 95% identical. Preferably, another PGD2 receptor is DP-1.

As used herein, the term "DP-1" refers to a DP-1 receptor protein (RefSeq Accession No. NP-000944) or a variant thereof, which is capable of mediating a cellular response to PGD2 in vitro. or in vivo. DP-1 variants include proteins substantially homologous to native DP-1, that is, proteins having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., FP-1 derivatives, homologues and fragments). The amino acid sequence of the DP-1 variant is preferably at least about 80% identical to a native DP-1, more preferably at least about 90% identical, and even more preferably. at least about 95% identical.

As used herein, the term "TP" refers to a TP receptor protein (RefSeq Accession No. NP-963998) or a variant thereof, which is capable of mediating a cellular response to PGD2 in vitro or in vivo. TP variants include proteins substantially homologous to native TP, that is, proteins having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., TP derivatives, homologs and fragments). The amino acid sequence of the TP variant is preferably at least about 80% identical to a native TP, more preferably at least about 90% identical, and more preferably at least about 80% identical. 95% identical.

The terms "modular", "modulation" and the like refer to the ability of a compound to increase or decrease the function and / or expression of DP-2 and / or one or more other PGD2 receptors, for example DP -1, wherein such a function may include transcriptional regulatory activity and / or protein binding. Modulation may occur in vitro or in vivo. Modulation as described herein includes inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with DP-2 and / or one or more other PGD 2 receptors, either directly or indirectly, and / or the up-regulation or down-regulation of DP-2 expression and / or one or more other PGD2 receptors, either directly or indirectly. In a preferred embodiment, the modulation is straightforward. Inhibitors or antagonists are compounds that, for example, bind to or partially or partially block stimulation, decrease, prevent, inhibit, retard activation, inactivate, desensitize, or down-regulate signal transduction. . Activators or agonists are compounds that, for example, bind to, stimulate, increase, open, activate, facilitate, increase activation, activate, sensitize or up-regulate signal transduction. The activity of a compound to inhibit DP-2 function and / or one or more other PGD2 receptors can be demonstrated in a biochemical assay, for example, a binding assay, or a cell-based assay, for example, a transient transfection assay.

As used herein, the term "condition or disorder responsive to PGD2 or PGD2 receptor modulation" and related terms and phrases refer to a condition or disorder associated with improper activity, for example less than or greater than than normal, activity of a PGD2 receptor, which responds at least partially to, or affected by modulation of a PGD2 receptor (e.g., a PGD2 receptor antagonist or agonist results in some improvement in patient well-being). in at least some patients). Improper functional activity of a PGD2 receptor may originate as a result of PGD2 receptor expression in cells that do not normally express the receptor, greater than normal PGD2 production, or slower than normal metabolic PGD2 inactivation or elimination. or its active metabolites, increased expression of a PGD2 receptor or degree of intracellular activation (leading to, for example, immune and inflammatory system disorders and conditions) or decreased expression of a PGD2 receptor. A condition or disorder associated with a PGD2 receptor may include a "DP-2 mediated disorder or condition".

As used herein, the phrases "condition or disorder responsive to antagonism of a DP-2 receptor" and related phrases and terms refer to a condition or disorder characterized by improper activity, for example, greater than to normal DP-2. Improper DP-2 functional activity can be originated as a result of DP-2 expression in cells that normally do not express DP-2, or increased DP-2 expression or degree of intracellular activation (leading to, for example, disorders, and conditions related to the immune and inflammatory system). A condition or disorder that responds to DP-2 receptor antagonization can be completely or partially mediated by improper DP-2 functional activity. However, a condition or disorder that responds to antagonism of a DP-2 receptor is one in which DP-2 modulation results in some effect on the underlying condition or disorder (e.g., a DP-2 antagonist). results in some improvement in patient well-being in at least some patients).

Modes of the Invention

A class of DP-2 antagonizing compounds has been discovered. Depending on the biological environment (e.g., cell type, pathological condition of the host, etc.) these compounds may antagonize DP-2 and / or one or more other PGD2 receptors (e.g., ligand binding). By antagonizing DP-2 and / or one or more other PGD2 receptors, the compounds will find use as therapeutic agents capable of modulating disorders and conditions that respond to DP-2 and / or one or more other modulation. PGD2 and / or DP-2 mediated receptors and / or one or more other PGD2 receptors. Examples of such conditions and disorders are provided below.

While the compounds of the invention are believed to exert their effects through selective interaction with DP-2, the mechanism of action by which the compounds act constitutes a non-limiting embodiment of the invention. For example, the compounds of the invention may interact with PGD2 receptor subtypes other than DP-2. However, as noted herein, the present invention specifically contemplates the activity of the exposed compounds in order to electively antagonize the DP-2 receptor with respect to, for example, the DP-1 receptor. , and / or to other prostanoid receptors, for example, the TP receptor.

The compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.

Compostyos of the Invention

In one embodiment, the present invention provides the compounds of general structure (I):

<formula> formula see original document page 27 </formula>

Within the above formula, L is selected from the group consisting of CR6R7, CO, CNR6 and CS.

A is a 5-14 membered heterocyclic ring having 1 - 4 ring heteroatoms, each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being monocyclic or polycyclic, optionally substituted by 1-3 substituents R 8.

Q1 is selected from the group consisting of: a bond, C1-4 alkylene-C1-4 heteroalkylene, -CO-, -NH-, -O-, -SOq-, -C (O) O-, - OC ( O) -, - CONH -, - NHCO-, -NHCONH -, -NHSOq-, - SOq-NH- and - COCH2HNSOq.

R1, R2, R3, R6 and R7 are each independently selected from the group consisting of H, C1-6 alkyl, C0-6 alkylaryl and C0-6 alkyletheroaryl; wherein the aryl or heteroaryl moieties are optionally substituted by C1-6 alkyl, CN, OR, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR.

Each R4 is independently selected from the group consisting of C1-6 alkyl, C0-4 alkyl-C3-10 cycloalkyl, C0-4 alkylaryl, C0-4 alkyletheroyl, C2-4 alkenylaryl, C2-4 alkynylaryl, C0 -4, CN, amino, NHCOR1, hydroxy, C1-6 alkoxy, OC (O) R1, -OC0-4alkylaryl, OC0-4alkyl-C3-10 cycloalkyl, OC0-4alkyl-C3-10 heterocyclyl, OC0-4alkyl heterocyclyl C3-10, OC0-4alkyl NR8, nitro, halo and haloalkyl Q-6; or are combined together or with R 6 to form an aryl or heterocyclyl ring system having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the alkyl, aryl and heterocyclyl moieties are each optionally substituted by 1 to 3 substituents each independently selected from the group consisting of C1-6 alkyl, CN, CONHR1, CO2R1, amino, C1-6 alkoxy. 6, halo, C1-6 haloalkyl and SOqR1.

R5 is selected from the group consisting of C1-6 alkyl, C0-4 alkylaryl, C2-4 alkenylaryl, C2-4 alkynylaryl and C0-4 alkyletheroaryl, each of which is optionally substituted by 1-3 R9 substituents.

Each R8 is independently selected from the group consisting of C1-6 alkyl, C0-6 alkyl-C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkyletheroaryl, oxo, C1-6 alkyl, CN, OR, haloalkyl C1-6, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CO2R, CONR2, SOqR, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR.

Each R9 is independently selected from the group consisting of C1-6 alkyl, CN, OR, oxo, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR.

Each R is independently selected from the group consisting of H, C1-6 alkyl, C0-4 alkyl heteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl, or when bonded to the same nitrogen atom, be combined to form a 5-8 membered ring having 1-4 ring heteroatoms, each independently selected from the group consisting of nitrogen, oxygen and sulfur.

The subscript η is independently O, 1, 2, 3 or 4;

Each subscript q is independently O, 1 or 2.

In another embodiment, the present invention provides pharmaceutically acceptable derivatives thereof.

In another embodiment, L is CR6 R7. In another embodiment, L is CO. In another embodiment, L is CNR6. In another mode, L is CS.

In another embodiment, R1, R2, R, R and R are each independently selected from the group consisting of H, C1-6 alkyl and C0-6 alkylary. In one embodiment, R1, R2, R3 R 6 and R 7 are each independently selected from the group consisting of H, CH 3 and phenyl. In one embodiment, R1 is H. In another embodiment, R2 and R3 are H.

In another embodiment, A has the structure (II): <formula> formula see original document page 30 </formula>

on what,

Y is selected from the group consisting of a bond, CH2, Ν, O, N and SOq;

R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;

the subscript ρ is independently 0, 1 or 2;

each dashed ring bond independently indicates the presence of a single, double or standard bond;

the dotted line indicates the binding point to Q1 and the wavy line indicates the binding point to L.

In another embodiment, A is selected from the group consisting of pyrrolidinyl, pyrrolyl, piperadinyl, tetrahydropyridinyl, piperazinyl, piperazin-1-oxide, morpholinyl, thiomorpholinyl, azepanyl, azepinyl, oxazepane, thiazepane, azocanyl, azocanil, azocanil, azocanyl, azocanil azaindole, tetrahydroquinolinyl and decahydroquinolinyl.

In another embodiment, A has the formula selected from the group, which consists of: <formula> formula see original document page 31 </formula>

m is an integer from 0 to 3; and

the dotted line indicates the binding point to Q1 and the dotted line indicates the binding point to L.

In another embodiment, Q 1 is selected from a bond, C 1-4 alkylene, heteroalkylene C 1, -CO-, -NH-, -O-, -SOq-, -C (O) O-, -OC (O) - , -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -COCH2HNSOq. In another embodiment, Q1 is a bond. In another embodiment, Q1 is C1-6 alkylene. In another embodiment, Q1 is heteroalkylene C-. In another embodiment, Q1 is -CO-. In another embodiment, Q1 is -NH-. In another embodiment, Q1 is an -O-. In another embodiment, Q1 is -OC (O) -. In another embodiment, Q1 is -CONH-. In another embodiment, Q1 is -NHCO-. In another embodiment, Q1 is NHCONH-. In another embodiment, Q1 is -NHSOq. In another mode, Q1 is -SOqNH In another mode, Q1 is -COCH2HNSOq.

In another embodiment, the compound has a structure (III):

<formula> formula see original document page 32 </formula>

on what:

Y is selected from the group consisting of a bond, CH2, N, O, NO and SOq.

R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;

the subscript m is independently O, 1 2 or 3;

the subscript ρ is independently O, 1 or 2; and each dashed ring bond independently indicates the presence of a single, double or standard bond.

In another embodiment, L is CR6R7. In another embodiment, L is CO. In another mode, L is CS.

In another embodiment, the compound has the structure (IV): <formula> formula see original document page 33 </formula>

on what:

Y is selected from the group consisting of a bond, CH2, N ,NO and SOq;

R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;

the subscript m is independently O, 1, 2 or 3;

the subscript ρ is independently O, 1 or 2; and

each dashed ring bond indicates the presence of a single, double or standard bond.

In another embodiment, Y is CH2 and ρ is 0.

In another embodiment, L is CR6R7.

In another embodiment, Q1 is a bond.

In another embodiment, Y is SOq and ρ is 0.

In another embodiment, the compound is selected from the group consisting of:

[4- (4-Chloro-benzyloxy) -3-thiomorpholin-4-ylmethyl-phenyl] -acetic acid;

[4- (4-Chloro-benzyloxy) -3- (1,1-dioxo-1β-thiomorpholin-4-ylmethyl) -phenyl] -acetic acid;

and [4- (4-Fluoro-benzyloxy) -3- (1,1-dioxo-1β-thiomorpholin-4-ylmethyl) -phenyl] -acetic acid;

In another embodiment, Y is O and ρ is 0. In another embodiment, the compound is the

[4- (4-Chloro-benzyloxy) -3-morpholin-4-ylmethyl-phenyl] -acetic acid.

In another embodiment, Y is N and ρ is 0.

In another embodiment, the compound is selected from the group consisting of:

[4- (4-Chloro-benzyloxy) -3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [3-oxo-4- (4-trifluoromethyl-phenyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; and

[3- (4-Benzyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid.

In another embodiment, Q1 is -CO-.

In another embodiment, the compound is selected from the group consisting of:

(4- (4-Chloro-benzyloxy) -3- {4- [2- (4-methoxy-phenyl) -acetyl] -piperazin-1-ylmethyl} -phenyl) -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (2- p -tolyl-acetyl) -pyrazin-1-ylmethyl] -phenyl} -acetic acid;

(4- (4-Chloro-benzyloxy) -3- {4- [2- (4-chloro-phenyl) -acetyl] -piperazin-1-ylmethyl} -phenyl) -acetic acid;

[3- (4-Benzoyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

{4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazin-1-yl} -oxo-acetic acid methyl ester; and

{4- (4-Chloro-benzyloxy) -3- [4- (2-hydroxy-2-phenyl-acetyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid.

In another embodiment, Q'is -C (O) O-.

In another embodiment, the compound is selected from the group consisting of:

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid tert-butyl ester;

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid methyl ester;

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid isopropyl ester;

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid ethyl ester;

In another embodiment, Q1 is SOq-.

In another embodiment, the compound is selected from the group consisting of:

{4- (2,6-Difluoro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-2-fluoro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{3- (2-Fluoro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[3- (4-Benzenesulfonyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (4-fluoro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[3- [4- (4-Chloro-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

(4- [4- (3-Methoxy) -benzyloxy] -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3,5-bis- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4-Cyclopentyloxy-3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] phenyl} -acetic acid;

{2- [4- (Toluene-4-sulfonyl) -piperazin-1-ylmethyl] -biphenyl-4-biphenyl-4-yl} -acetic acid;

{4-Benzyloxy-3- [4- (toluene-4-sulfinyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4-Cyclopropylmethoxy-3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4-Phenylethynyl-3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (4-methoxy-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (3,4-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[3- [4- (2-Chloro-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

(4- (4-Chloro-benzyloxy) -3- [4- (toluene-3-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (quinoline-8-sulfonyl) -piperazin-1-ylmethyl] phenyl} -acetic acid;

{4-Phenethyl-3- [4- (toluene-4-sulfonyl) -pyprazin-1-ylmethyl] -phenyl} -acetic acid;

{4'-Chloro-2- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -biphenyl-4-yl} -acetic acid;

[3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] -4- (4-trifluoromethyl-benzyloxy) -phenyl] -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (2,4-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Cyano-benzyloyl) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4-Phenyloxy-3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[3- [4- (4-tert-Butyl-benzenesulfonyl) -piperazin-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (3,5-dimethyl-isoxazol-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

(4- (4-Chloro-benzyloxy) -3- [4- (naphthalene-2-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (pyridine-3-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (3,5-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (4-ethyl-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (naphthalene-1-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[3- [4- (4-Bromo-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid;

{4- (4-Methoxy-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Methyl-benzyloxy) -3- {4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Methyl-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4-Cyclohexylmethoxy-3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

[4- (4-Chloro-benzyloxy) -3- (4-phenylmethanesulfonyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

{4- (2,4-Dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

4- {4-Carboxymethyl-2- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenoxymethyl} -benzoic acid;

{4- (4-Fluoro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4-thiophene-3-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (3,4-Dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Nitro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (2-phenyl-etenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (4-chloro-3-trifluoromethyl-benzenesulfonyl) -piperazin-1-yl) -ethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (2-phenyl-ethanesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [4- (4-nitro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; and

{4- (4-Chloro-benzyloxy) -3- [2-oxo-4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid.

In another embodiment, the compound is selected from the group consisting of:

(4-Hydroxy-3- {phenyl- [4- (toluene-4-sulfonyl) -piperazin-1-yl] methyl} -phenyl) -acetic acid;

(3- {(2-Hydroxy-phenyl) - [4- (toluene-4-sulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid; (3- {Phenyl- [4- (toluene-4-sulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid;

(3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] -phenylmethyl} -phenyl) -acetic acid;

{3 - [(4-Benzenesulfonyl-piperazin-1-yl) -phenyl-methyl] -phenyl} -acetic acid;

{3 - {(4-Methanesulfonyl-piperazin-1-yl) -phenyl-methyl] -phenyl} -acetic acid;

{3 - [(4-Benzenesulfonyl-piperazin-1-yl) -phenyl-methyl] -5-chloro-phenyl} -acetic acid;

(3 - {(4-Chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) -piperazin-1-yl] -methyl} -4-hydroxy-phenyl) -acetic acid;

(3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] -p-tolyl-methyl} -4-hydroxy-phenyl) -acetic acid;

(3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] -p-tolyl-methyl} -phenyl) -acetic acid;

(3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] p-tolyl-methyl} -phenyl) -acetic acid; and

(3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] -phenyl-methyl} -phenyl) -acetic acid.

In another embodiment, R 4 and R 6 are combined together to form an aryl or heterocyclyl ring system.

In another embodiment, the compound has the structure IVa: <formula> formula see original document page 40 </formula>

where Y2 is selected from the group consisting of N,

O and S; each R12 is independently selected from the group consisting of C1-6 alkyl, CN, CONHR1, CO2R1, amino, C1-6 alkoxy, halo, C1-6 haloalkyl and SOqR1 are or are combined together of a way to form an aryl or heteroaryl ring; and the subscript u is independently 1, 2 or 3.

In another embodiment, the compound is selected from the group consisting of:

2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo oxepin-2-yl) acetic acid;

2- (11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrobenzofb, e] oxepin-2-yl) acetic acid;

2- (9-chloro-11- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid;

2- (9-chloro-1- 1- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid; and

2- (11- (2-Oxo-4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid.

In another embodiment, the compound is 1- (5-carboxymethyl) -2- (2,4-dichlorobenzyloxy) benzyl) -4-tosylpiperazine N-oxide.

In another embodiment, Q1 is -C (O) O-.

In another embodiment, the compound is selected from the group consisting of:

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid tert-butyl ester.

In another embodiment, Q1 is -CONH-.

In another embodiment, the compound is selected from the group consisting of:

[4- (4-Chloro-benzyloxy) -3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

[4- [4- (3-Methyl-butoxy) -benzyloxy] -3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

[4- (4-Chloro-benzyloxy) -3,5-bis (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

[4-Cyclopentyloxy-3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

[4-Cyclopropylmethoxy-3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid;

[3- (4-Benzylcarbamoyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid.

In another embodiment, Y is CH2 and ρ is 0.

In another embodiment, the compound is selected from the group consisting of:

[4- (4-Chloro-benzyloxy) -3-piperidin-1-ylmethyl-phenyl] acetic acid; and

[4- (4-Chloro-benzyloxy) -3- (4-hydroxy-piperidin-1-ylmethyl) -phenyl] -acetic acid.

In another embodiment, Q1 is -NHSOq-.

In another embodiment, the compound is selected from the group consisting of:

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -pyrrolidin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -piperidin-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) azepan-1-ylmethyl] -phenyl} -acetic acid;

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -3,4,7,8-tetrahydro-2H-azocin-1-ylmethyl] -phenyl} -acetic; and

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -azocan-1-ylmethyl] -phenyl} -acetic acid.

In another embodiment, L is CO.

In another embodiment, the compound is selected from the group consisting of:

{4- (4-Chloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazine-1-carbonyl] -phenyl} -acetic acid; and

{4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -azocan-1-ylmethyl] -phenyl} -acetic acid.

In another embodiment, L is CO.

In another embodiment, the compound is selected from the group consisting of:

{4- (4-Chloro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazine-1-carbonyl] -phenyl} -acetic acid; and

[4- (4-Chloro-benzyloxy) -3- (4-methanesulfonyl-piperazine-1-carbonyl) -phenyl] -acetic acid.

In another embodiment, the compound has the structure (V): <formula> formula see original document page 43 </formula>

on what:

Y is selected from the group consisting of a bond, CH2, N, O, NO, and SOq;

R10 and R11 are H or are combined together to form an aryl, heteroaryl, or cycloalkyl ring;

the subscript m is independently O, 1, 2 or 3;

the subscript ρ is independently O, 1 or 2; and

each dashed ring bond independently indicates the presence of a single, double or standard bond.

In another embodiment, L is CR6R7. In another embodiment, L is CO. In another mode, L is CS.

In another embodiment, Q1 is a bond. In another embodiment, Q1 is C1-4 alkylene.

In another embodiment, Q1 is C1-4 heteroalkylene. In another embodiment, Q1 is -CO-. In another embodiment, Q1 is -NH-. In another embodiment, Q1 is -O-. In another embodiment, Q1 is SOq. In another embodiment, Q1 is -C (O) O-. In another embodiment, Q1 is -OC (O) -. In another embodiment, Q1 is -CONH-. In another embodiment, Q1 is -NHCO-. In another embodiment, Q1 is -NHCONH-. In another embodiment, Q1 is -NHSOq-. In another embodiment, Q1 is -SOqNH -. In another embodiment, Q1 is -COCH2HNSOq. Other embodiments are set forth in US Patent Application, Dudler et al, and filed June 9, 2006 entitled "Substituted Phenyl Acetic Acids as DP-2 Antagonists", US Power of Attorney No. 01433 -003500 (which is incorporated herein). , by reference in its entirety).

The invention encompasses new compounds, new pharmaceutical compositions and / or new methods of use. Although some of the compounds disclosed herein are available from commercial sources, the pharmaceutical compositions, or methods using these compounds, are new. Unless otherwise indicated, it is to be understood that the invention includes those compounds which are novel, as well as pharmaceutical compositions, various methods (e.g., methods of treating or preventing certain conditions and disorders mediated by DP-2. and / or one or more other PGD2 receptors), and the like, which both include the novel compounds of the invention and compounds that are commercially available. Compound Preparation

Synthetic routes to the compounds provided herein are also described below in Schemes A-I and the Examples. One of skill in the art will understand that synthetic pathways may be modified to use different starting materials and / or alternative reagents so that the desired transformations are effected.

In addition, one of skill in the art will recognize that protecting groups may be necessary for the preparation of certain compounds and will be aware of those conditions compatible with a selected protecting group. Accordingly, the methods and reagents described herein are all expressed as non-limiting embodiments. Scheme A

<formula> formula see original document page 45 </formula>

In some embodiments, as shown in Scheme A, an alkyl phenyl acetate of formula A is mixed with a para formaldehyde solution and a substituted heterocycle such that a piperidine or a substituted piperidine in a solvent system such that the alcohol isopropyl for 1 to 12 hours at reflux to give B. If the phenyl ring of alkyl phenyl acetate A is replaced by a hydroxyl group (as shown), alkylation of the phenyl ring using an alkyl halide or appropriate aryl in the presence of a base such that K2CO3 or CsCO3 in a solvent such that DMF at temperatures ranging from 20 to 60 ° C or acetone at temperatures ranging from 20 to 80 ° C leads to additional substituted C compounds. Saponification with a base such as potassium hydroxide (KOH) or sodium hydroxide (NaOH) in a solvent system such as methanol: water over a period of 1-6 hours at temperatures between 35-65 ° C. Alternatively, treatment of B with triflic anhydride in DCM, followed by a palladium (0) mediated cross-coupling with aryl boronic acid in a solvent such that dioxane or DME at temperatures in the range from 20 to 90 ° C with a base such as sodium carbonate leads to compounds of the general formula Ε. Saponification with a base such as lithium hydroxide (LiOH), potassium hydroxide (KOH) or sodium hydroxide (NaOH) in a solvent system such that THF: water or methanol: water over a period of 1 -6 hours at temperatures of 35-65 ° C leads to a carboxylic acid of formula F.

Scheme Bl

<formula> formula see original document page 46 </formula> Scheme B2

<formula> formula see original document page 47 </formula>

In some embodiments, as shown in Scheme B1, treatment of benzaldehyde H with a suitably protected heterocycle and aryl boronic acid in a solvent, such as dioxane, at a temperature ranging from 20 to 100 ° C. for a period of 1 to 12 hours leads to I. Saponification of I using the reaction conditions described in Scheme A leads to J. Compound I can also be treated with triflic anhydride or N-phenyl triflimide in DCM , in temperature, which varies in a range from room temperature to 50 ° C. Treatment with a palladium (0) source in the presence of formic acid followed by saponification as shown in Scheme A leads to K. As shown in Scheme B2, Benzaldehyde GGG, which was obtained by treating a halotoluene with N-bromosuccinimide and AIBN in a solvent, such as carbon tetrachloride, followed by the addition of trimethyl amine N-oxide in a solvent, such that acetonitrile, at temperatures ranging from a room temperature to up to 80 ° C for 15 hours. Oxidation of F with a Jone reagent in a solvent such that acetone, followed by the Arndt-Eister reaction, leads to G. Aryl bromide G can be converted to the corresponding benzaldehyde via a palladium (0) mediated reaction, in a solvent such as toluene in the presence of carbon monoxide.

Scheme C

<formula> formula see original document page 48 </formula>

In some embodiments, as shown in scheme C, ketone I was treated with sodium borohydride in a solvent such as methanol at temperatures ranging from 10 to 35 ° C, followed by a thionyl chloride treatment in DCM. at room temperature over a period of 12 hours to provide J. Treatment of J with a suitably protected heterocycle in a solvent such that AcCN at temperatures ranging from 20 ° C to at 95 ° C for a period of 2 to 13 hours, followed by saponification as described in Scheme A, leads to K.

Scheme D

In some embodiments, as shown in scheme D, substituted L-benzaldehyde may be treated with a Grignard alkyl or aryl reagent in a solvent system such that TH at temperatures ranging within a range of from -20 ° C. C at 20 ° C over a period of a few hours to provide secondary alcohol M. An in situ chloride formation by treating M with thionyl chloride in a suitable solvent such as DCM for some hours at room temperature, followed by a modified Finkelstein reaction in the presence of a suitably protected heterocycle in a solvent system such that AcCN for a few hours at temperatures ranging from -10 ° C at 80 ° C, it leads to Ν. Aryl bromide N is then transformed into an O-boronate ester using optional palladium (0) coupling conditions. Additional palladium (0) coupling of O with ethyl-2-bromo acetate in the presence of a base such as K2CO3 in a solvent system such that dioxane or DME at temperatures which are in a range from 15 to 85 ° C leads to phenyl acetate Ρ. Saponification of P using the conditions described in Scheme A leads to K.

£ scheme

<formula> formula see original document page 49 </formula>

In some embodiments, as shown in Scheme Ε, phenyl acetate A is treated with paraformaldehyde in AcCN at temperatures ranging from 25 to 100 ° C, and leads to Q. potassium, for example in a solvent system such that acetone / water for a few hours under reflux conditions leads to benzoic acid R. This acid S may then be coupled to a substituted heterocycle such that a piperidine or piperazine, using, for example HATU and a base such as ET3N or DIEA in a solvent such as AcCN at room temperature over a period of 2 to 12 hours.

Scheme F

<formula> formula see original document page 50 </formula>

In some embodiments, as shown in Scheme F, alkylation of phenol A with a commercially available benzyl bromide using a base such as K 2 CO 3 or CS 2 CO 3 in a solvent such as acetone or DMF at temperatures which are situated in a range of 20 to 100 ° C, followed by saponification under the conventional conditions described in Scheme A, leads to phenyl acetic acid T. A Friedel Craft reaction, catalyzed by polyphosphoric acid in a solvent, such that acetic anhydride, at temperatures that are in the range of 30 to 90 ° C for a few hours, followed by an in situ esterification with hydrochloric acid in a solvent such as methanol leads to tricyclic U. Reduction of U under conventional conditions using sodium borohydride (NaBH4) in methanol for a few hours, followed by treatment with thionyl chloride in a solvent such that DCM as described in Scheme C or D leads to V. Compsot V is then evolved to W using the reaction conditions previously described for Scheme C or D. Scheme G

<formula> formula see original document page 51 </formula>

In some embodiments, as shown in Scheme G, benzaldehyde X is reacted with an amino acid such that Boc-Lysine or Boc-Ornithine using sodium cyanoboroidide in the presence of zinc chloride in a solvent such as methanol for up to 30 minutes to provide amino acid Ζ. Cyclization from Z to AA is carried out under conventional coupling conditions such as hydroxybenzotriazole (HOBT) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC1) in a solvent system such that DCM or DMF, at temperatures that are within a range of -30 to 50 ° C for up to 12 hours. Saponification as described in Scheme A leads to heterocycle BB.

Scheme H

<formula> formula see original document page 51 </formula> In some embodiments, as shown in Scheme Η, benzyl bromide CC may be reacted with a heterocycle such that DD in the presence of a base such as CS2CO3 or K2CO3 in a solvent system such as AcCN / DMF at temperatures that are in the range of 10 to 75 ° C for a few hours, followed by the removal of a protecting group and alkylation as described in Schemes G and A. Saponification of EE leads to compound FF using standard reaction conditions as described in Scheme A.

Scheme I

<formula> formula see original document page 52 </formula>

In some embodiments, as shown in Scheme H, the reductive amination of benzaldehyde GG with alken-1-amine under the conventional conditions described in Scheme G leads to HH. Coupling the amine HH to a protected amino acid such that 2- (tert-butoxycarbonylamino) pent-4-enoic acid in the presence of HATU and a base such as triethyl amine or DIEA in a solvent such that AcCN or DMF, for a few hours, leads to II. Grubb catalyzed ring closure by first generation catalysis of a solvent such that DCM for a few hours at temperatures which are in the range of 20 to 90 ° C leads to the seven membered lactam JJ. Removal of the protecting group, followed by sulfonylation and saponification using the reaction conditions described in Scheme A, leads to lactam MM. Hydrogenation of JJ under 1 atmosphere of hydrogen in a solvent such as benzene in the presence of a rhodium catalyst such that RhCl (PPh3) 3 for a few days leads to the unsaturated heterocycle KK. Again, removal of the protecting group under acidic conditions, followed by sulfonylation and saponification as described in Scheme A, leads to LL.

Compound Analysis

In yet another aspect, the invention includes methods for evaluating putative specific DP-2 agonists or antagonists and / or one or more other PGD2 receptors. Accordingly, the invention is directed to the use of these compounds in the preparation and performance of screening assays for compounds that modulate the function of DP-2 and / or one or more other PGD2 receptors. For example, the compounds of this invention are useful for DP-2 mutants and / or one or more other PGD2 receptor mutants, which are excellent scanning tools for potent compounds. In addition, the compounds of this invention are useful for establishing or determining the binding site of other compounds to DP-2 and / or one or more other PGD2 receptors, for example by competitive inhibition.

The compounds of the present invention are also useful for the evaluation of putative DP-1 specific moduli with respect to one or more other PGD2 receptors, for example by competitive inhibition. The compounds of the present invention are also useful for evaluating putative DP-12 specific moduli with respect to one or more other PGD2 receptors. One of skill in the art will appreciate that the full evaluation of PGD2 receptor specific antagonists has been hampered by the lack of availability of non-peptidyl (metabolically resistant) specific compounds with high affinity for these receptors. The compounds provided herein are particularly useful in this context.

The above and other assays described herein are designed so that they may be conducted in a high flow format in order to detect or quantify the presence, quantification or other properties of particular compounds, either individually or as a collection containing a large number of potential therapeutic compounds (potential modulating compounds). Any of the test stages may be automated and the compounds from any convenient source may be provided for the assay. Assays are typically performed in parallel (e.g. in microtiter formats or microtiter plates in robotic assays. Preferred assays detect DP-2, DP-2 and / or one or more other PGD2 receptor functions.

High flow sweeping systems are commercially available (see, for example, Zymark Corp., Hopkinton Mass: Air Technical Industries, Mentor Ohio; Beckman Instruments, Inc., Fullerton California; Precision Systems, Inc., Natick Mass; etc.). ). These systems typically automate entire procedures including the entire sample and reagent pipette procedure, liquid distribution, timed incubations, and final microplate readings in appropriate detector (s) for the assay. These configurable systems provide high flow and quick start, as well as a high degree of flexibility and fit. Manufacturers of such systems provide detailed protocols for high flow systems. Thus, for example, Zymark Corp. provides technical bulletins, which describe scanning systems for detecting gene transcription, ligand binding, and the like. Usage Methods

The present invention relates to the identification of phenyl acetic acid derivatives and their use as DP-2 receptor functional antagonists for the treatment of conditions or disorders measured by PGD2, and pharmaceutical compositions containing these derivatives and processes for their derivation. preparation.

In particular, the compounds and derivatives of formula I have activity as modulators of DP-2 receptor activity, and therefore may be used in the treatment of conditions or disorders, which are caused by excessive, unbalanced or unregulated expression of PGD2 and its derivatives. metabolites. Non-limiting examples of such conditions and disorders include:

1) Conditions or disorders of the respiratory system such as obstructive airway diseases such as: asthma, eg intermittent and persistent asthma, extrinsic (allergic) asthma, intrinsic (non-allergic) asthma, extrinsic - mixed intrinsic asthma, asthma Exercise-Induced, Night Asthma, Bronchial Asthma, Seasonal Asthma, Occupational Asthma, Cough-Variant Asthma, Severe Corticosteroid-Dependent Asthma, Steroid-Resistant Asthma, Allergic Bronchopulmonary Asperlogylosis, Asthma Triad (Including Nasal Polyps of Asthma, and Sensitivity aspirin), and allergic airway syndrome; bronchitis, for example acute and chronic bronchitis, allergic rhinobronchitis, eosinophilic bronchitis, and chronic obstructive pulmonary disease (COPD); rhinitis, including acute and chronic rhinitis, atropic rhinitis, seasonal allergic and non-allergic rhinitis (for example, rhinitis nervosa, hay fever, and vasomotor rhinitis), perennial and vasomotor rhinitis, nasal polyposis, nasal congestion, drug rhinitis; sarcoidosis; farmers' lung diseases and related diseases; fibroid lung; cystic fibrosis; idiopathic interstitial fibrosis; chronic cough associated with inflammation; and sinusitis, for example allergic, acute, subacute, and chronic sinusitis; 2) Skin and eye conditions or disorders such as dermatitis, for example allergic contact dermatitis, atopic dermatitis (eczema), contact (and irritant contact) dermatitis, dermatitis dermatitis, neurodermatitis, perioral dermatitis, seborrheic dermatitis, dermatitis stasis, diaper dermatitis, dyshidrotic dermatitis (pomfolix), nummular dermatitis, chronic lichen simplex, and urticaria; conjunctivitis, eg viral, allergic, bacterial, and chemical / toxic conjunctivitis; psoriasis; urticaria; erythemas; cutaneous eosinophilia, and chronic skin ulcers;

3) Conditions or disorders of the gastrointestinal system, such as food-induced allergies (for example, those that remotely affect the intestines, such as migraine, rhinitis and eczema); eosinophil gastroenteritis; mastocytosis; ulcerative colitis; Crohn's disease; irritable bowel syndrome; celiac disease;

4) Conditions or disorders of the central nervous system, such as inflammatory pain, neuropathic pain;

5) Conditions or disorders related to other systems: eg esosinophilic fasciitis; hyper IgE syndrome; systemic stem cell disorder; idiopathic thrombocytopenia purpura; atherosclerosis; lupus erythematosus; systemic lupus erythematosus; sepsis; reperfusion injury; glomerulonephritis; allergic nephritis; nephritic syndrome; eosinophil-related disorders such as Churg-Strauss syndrome; basophilic leukocytosis and basophilic leukemia and acquired immunodeficiency syndrome;

6) Conditions or disorders related to the skeletal and joint systems, for example arthritis and conditions associated with it, for example osteoarthritis (AO), osteonecrosis, psoriasis arthritis, Reiter's syndrome (reactive arthritis), tendonitis, bursitis, inflammation of joint lining, ankylosing spondylitis, Behcet's disease, childhood arthritis, idiopathic skeletal hyperostosis (DISH), Ehlers-Danlos syndrome, rheumatoid arthritis, Felty's syndrome, fibromyalgia, gout, pseudo-gout, infectious arthritis, lupus, tissue disease mixed connective tissue, osteoarthritis, Paget's disease, polymyalgia remática, polyarteritis nodosa, Wegener's granulomatosis, myositis (polymyositis dermatomyositis), psoriasis arthritis, Raynoud's phenomenon, and Still's disease;

7) Autoimmune conditions or disorders, eg systemic lupus erythematosis, antiphospholipid syndrome, rheumatoid arthritis, Sjogren's syndrome, scleroderma, systemic vasculitis, eg giant cell arteritis, Takayasus arteritis, polyarteritis nodosa, Kawasaki disease , Wegner's granulomatosis, Churg Strauss syndrome, Microscopic polyangitis, Henoch-Schonlein purpura, Essential cryoglobulinemic vasculitis, Cutaneous lecocytoclastic angitis, Autoimmune hemolytic anemia, Idiopathic thrombocytopenic purpura, Autoimmune neutropenia, Malzheimer's disease, Malzheimer's disease autoimmune polyglandular tumors, multiple sclerosis, myasthenia gravis, Behcet's syndrome, pernicious anemia, primary biliary sclerosis, autoimmune hepatitis, autoimmune myocarditis, Goodpasture's syndrome, glomerular nephritis, and tubulointerstitial nephritis; and

8) Other conditions or disorders associated with elevated PGD2 levels, or their metabolites.

In yet another aspect, the invention provides methods for treating or preventing a disorder or condition associated with DP-2 and / or one or more other PGD2 receptors upon administration to a patient having such a condition or disorder. of a therapeutically effective amount of a compound or composition of the invention. In a group of modalities, disorders and conditions, including chronic conditions and disorders of humans or other species, may be treated with DP-2 modulators, or antagonists, and / or one or more other PGD2 receptors. These disorders and conditions include (1) inflammatory or allergic diseases, such as systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect bite allergies, food allergies (including celiac disease and the like) and mastocytosis, (2) inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vasculitis, Behcet's syndrome, (4) psoriasis of inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact, urticaria, viral skin disorders such as those derived from human papillomavirus, or HIV or RLV infection, parasitic, fungal and other parasitic skin disorders, and lupus erythematosis, (5) asthma diseases and allergic respiratory diseases, such as allergic asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung disease, p (6) autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosis, type I diabetes, myasthenia gravis, multiple sclerosis, Grave's disease, gromerulonephritis, scleroderma, including, for example, systemic scleroderma, fasciitis, including, for example, eosinophilia fasciitis (Schulman's syndrome), Sjogren's syndrome, hyper IgE syndrome, soft tissue disease, and inflammatory myopathies and the like, (7) rejection of graft, solid organ transplant rejection, bone marrow transplant rejection, (8) fever, (9) cardiovascular diseases such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure , atherosclerosis, coronary artery disease, restenosis, thrombosis and vascular stenosis, (10) cerebrovascular disorders, such as traumatic brain injury, stroke, injury by ischemic reperfusion and aneurysm, (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (eg, esophagus, stomach, pancreas) brain, thyroid, blood and lymphatic systems, (12) flbrose, connective tissue disease and sarcoidosis, (13) genital and reproductive conditions, such as erectile dysfunction, (14) gastrointestinal disorders, such as gastritis, ulcers, nausea, pancreatitis and vomiting; (15) neurological disorders, such as Alzheimer's disease, (16) sleep disorders, such as insomnia, narcolepsy, sleep apnea and Pickick's syndrome, (17) pain, (18) kidney disorders, (19) eye disorders such as glaucoma, (20) infectious diseases, viral infections such as HIY, and bacterial infections such as sepsis, (21) inflammation, (22) runny noses, and (23) nasal congestion.

In yet another aspect, the invention provides methods for treating or preventing a condition or disorder mediated, regulated or influenced by Th 2 cells, eosinophils, basophils, platelets, Langerhans cells, dendritic cells, or stem cells, which comprise: administering to a patient who has such a condition or disorder a therapeutically effective amount of one or more compounds or compositions in question.

In yet another aspect, the invention provides methods for treating or preventing a PGD2-mediated, regulated or influenced condition or disorder thereof and 13,14-dihydro-15-Keto-PGD2 and 15-deoxy -Δ 1214PGJ2, which comprises administering to a patient having such a condition or disorder a therapeutically effective amount of one or more of the compounds or compositions in question.

In yet another aspect, the invention provides methods for treating or preventing a condition or disorder responsive to modulation of DP-2 and / or one or more other PGD2 receptors comprising administering to a patient having such a condition or disorder is a therapeutically effective amount of one or more of the compounds or compositions in question.

In yet another aspect, the invention provides methods for treating or preventing a DP-2 mediated condition or disorder and / or one or more other PGD2 receptors, which comprises administering to a patient having such a condition or disorder a therapeutically effective amount of one or more of the compounds or compositions in question.

In yet another aspect, the invention provides methods for modulating DP-2 and / or one or more other PGD2 receptors, which comprises contacting a cell with one or more of the compounds or compositions in question.

Depending on the disorder being treated and the condition of the patient, the compounds of the invention may be administered orally, parenterally (for example, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), via inhalation, or nasal, vaginal, rectal, sublingual or topical (e.g., transdermal, local) routes of administration, and may be formulated, alone or in combination, in appropriate dosage unit formulations containing non-pharmaceutically acceptable carriers. conventional toxicants, adjuvants and vehicles appropriate for each route of administration. The invention also contemplates administration of the compounds of the invention in a depot formulation in which the active ingredient is released over a defined period of time.

In the treatment or prevention of various conditions and disorders according to the invention associated with DP-2 and / or one or more other PGD2 receptors, an appropriate dosage level will generally be from about 0.001 to 100 mg per patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level should be from about 0.01 to about 25 mg / kg per day; more preferably from about 0.05 to about 10 mg / kg per day. A suitable dosage level may be about 0.01 to 25 mg / kg per day, about 0.05 to 10 mg / kg per day, or about 0.1 to 5 mg / kg per day. Within this range, the dosage may be from 0.005 to 0.05, from 0.05 to 0.5 or from 0.5 to 5.0 mg / kg per day. For oral administration, the compositions are preferably provided as tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 0, 15, O, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient for symptomatic dosage adjustment to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level and dosage frequency for each particular patient will vary and will depend on a variety of factors, including the activity of the specific compound employed, metabolic stability, and duration of action of that particular compound. compound, age, body weight, general health, sex, diet, mode and time period of administration, excretion rate, drug combination, the severity of the particular condition, and the therapy to which the host is submitted.

Compositions

In another aspect, the invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified quantities.

By "pharmaceutically acceptable" is meant that the carrier or excipient is compatible with the other ingredients of the formulation and is not deleterious to the recipient. The formulation may enhance one or more pharmacokinetic properties (e.g. oral bioavailability, membrane permeability) of a compound of the invention (referred to herein as the active ingredient).

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

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example in the form of tablets, lozenges, chewable tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or moles, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agent and preservatives in order to provide compositions that are pharmaceutically elegant and palatable. The tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of the tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in US Patent Nos. 4,256,108; Nos. 4,166,452 and 4,265,874, to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules. that the active ingredient is mixed with water or an oily medium, for example with peanut oil, liquid paraffin, or olive oil.

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

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added in order to provide a pleasant oral taste preparation. These compositions may be preserved by the addition of an antixoidant such as ascorbic acid.

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

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

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulsifier, a preservative and coloring and flavoring agents.

The pharmaceutical compositions may be in the form of an injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned hereinabove. The sterile injectable preparation may also be a sterile injectable solution or suspension in a similarly non-toxic acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the pharmaceutically acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose a bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable substances.

The pharmaceutical compositions may also be administered as suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at rectal temperature, and will therefore be fused to the rectum in order to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, petroleum jelly, solutions or suspensions, etc., containing the compounds of the invention may be employed.

As used herein, topical application is also intended to include buccal solutions and gargling solutions.

Pulmonary Administration

Inhalable powder

In some embodiments, the agents are administered directly to the lung by inhalation. Accordingly, agents for use according to the invention may be formulated as inhalable powders, in admixture with suitable physiologically acceptable excipients (see, US Patent Publication No. 20060034776, which is incorporated herein by reference with respect to methods). administration of suitable inhalation pharmaceutical agents).

For aerosol administration to humans or other primates and mammals, the aerosol is generated by a medical nebulizer system, which supplies the aerosol through a mouthpiece, face mask, etc., from which the mammalian host You can extract the aerosol into the lungs. Various nebulizers are known in the art and may be used in the method of the present invention. Selection of a nebulizer system depends on whether alveolar or airway distribution (ie trachea, primary, secondary or tertiary bronchi, etc.) is desired. The composition is formulated so that it is not irritating at the required dosage.

Nebulizers useful for airway delivery include those typically used in the treatment of asthma. Such nebulizers are also commercially available. A therapeutic amount of the agent is an amount sufficient to prevent, treat or palliate for asthma by administering the composition to the lung of the host mammal, in particular the bronchopulmonary and broncholopulmonary alveoli or smooth muscles and tracheal, bronchial epithelial cells. , bronchi, bronchioles and alveoli. Thus, an effective amount of the aerosol compound of the invention is a sufficient dose for treatment to be effected, i.e. to cause relief or reduction of symptoms, to inhibit worsening of symptoms, in a way to prevent the onset of symptoms, and the like. Dosages of pre-established compositions, which constitute an effective amount, can be determined in view of this exposure by that of ordinary skill in the art by performing routine trials with appropriate controls. Comparison of appropriate treatment groups with controls will indicate whether a particular dose is effective for preventing or reducing particular symptoms.

The total amount of compound supplied to a mammalian host will depend on many factors, including the total aerosolized amount, nebulizer type, particle size, mammalian host breathing patterns, the severity of lung disease, the composition concentration of the compound in aerosol solution and the duration of inhalation therapy.

Despite the interaction factors described above, one of ordinary skill in the art will be able to design effective protocols, particularly if the aerosol particle size is optimized. Based on estimates of nebulizer efficiency, an effective dose usually provided is in the range of about 1 mg / treatment to about 500 mg / treatment, although more or less can be found to be effective depending on the patient, agent. , dosage regimen and desired result. It is generally desirable to administer higher doses when treating more severe conditions. If treatment is repeated, the mammalian host may be monitored to ensure that there is no adverse response to treatment. The frequency of treatments depends on a number of factors, such as the amount of agent administered per dose, as well as the patient's health and history.

Propellant Gas Driven Inhalation Aerosols

Propellant gas-containing inhalation aerosols according to the invention may contain agents for use according to the invention dissolved in the propellant gas or in dispersed form. Propellant gases which will be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG1334, TG227, and mixtures thereof. Propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, preservatives and pH adjusting agents. All of these ingredients are known in the art. When in dispersed form, the agents may, for example, be formulated to have a particle size of up to 10 microns or preferably from 0.1 to 5 microns, or from 1 to 10 microns. 5 microns.

The above mentioned propellant propelled inhalation aerosols may be administered using inhalers known in the art, such as metered dose inhalers. Thus, in another aspect, the present invention relates to pharmaceutical propellant-containing aerosol pharmaceutical compositions as described hereinbefore combined with one or more inhalers suitable for the administration of such aerosols.

C. Inhalable Propellant-Free Inhalable Solutions or Suspensions

Propellant-free inhalable solutions and suspensions of the agents for use according to the invention are contemplated. The solvent used may be an aqueous or alcoholic solution, preferably an ethanolic solution. The solvent may be water itself or a mixture of water and ethanol. The relative proportion of ethanol compared to water is not limited, but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume, and more preferably up to 30 percent, in volume. The remainder of the volume consists of water.

Combination Therapy

The pharmaceutical compositions and methods of the invention may further comprise other therapeutically active compounds as cited herein useful in the treatment of asthma, allergic diseases, inflammatory conditions and cancer and conditions associated therewith (e.g., cardiovascular disease) or another adjuvant. . In many cases, compositions comprising a compound of the invention and an alternative agent have additive or synergistic effects when administered.

The compounds of the invention may be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the disorder or conditions for which the compounds of the invention are useful, including inflammatory conditions, immune disorders, asthma, rhinitis. allergic, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, viral infection, thrombosis, fibrosis, runny nose, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, inflammation, pain, conjunctivitis, nasal congestion, urticaria and those pathologies mentioned above. Such other agents, or drugs, may be administered via a route and in an amount usually employed for them, simultaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the invention also include those containing one or more other active ingredients or therapeutic agents in addition to a compound of the invention.

Examples of other therapeutic agents, which may be obtained with a compound of the invention, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA antagonists; (b) corticosteroids, such as beclomethasone, methyl prednisolone, betamethasone, prednisone, prenisolone, tramcinolone, dexamethasone, fluticasone, flunisolide, and hydrocortisone, and corticosteroid analogues such as budesonide; (immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (Sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, for example mofetil (d) antihistamines (H1-histamine antagonists), such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenyl pyraline, tripelenaoamine, hydroxyzine, metdilazine, trimethazine, promethazine, promethazine, , antazoline, phenyramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, decarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as β-2 agonists (eg terbutaline, metaproterenol, phenoterol, phenoterol, phenoterol). , salmeterol, bitolterol and pyrbuterol) and combinations of β-2 - corticosteroid agonists (eg salmeterol fluticasone (Advair®), formoterol budesonide (Symbicort®), theophylline a, chromoline, sodium cromoline, nedocromil, aropine, ipratropium, ipratropium bromide, leukotriene antagonists (eg zafirlucast, montelucast, sodium montelucast (Singulair®), pranalucast, iralucast, pobilucast and SKB - 106. 203), inhibitors leukotriene biosynthesis (zileutone, BAY -1005); (f) non-steroidal antiinflammatory agents (NSAIDs), such as propionic acid derivatives (for example, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, microprofen, microprofen, , pyrprofen, pranoprofen, suprofen, thiaprofenic acid and thioxaprofen), acetic acid derivatives (eg indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenic acid, fentiazac, furofenac, ibufenaco, tipobacaine, isobacaine, isofacetan tolmetin, zidomethacin and zomepirac), fenamic acid derivatives (eg flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (eg diflunisal and flufenisal), oxycases (eg isoxicam , piroxicam, sudoxicam and tenoxicam), salicylates (e.g. acetyl salicylic acid and sulfasalazine) and pyrazolones (e.g., apazone, bezpiperilone, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone): (g) cyclooxygenase-2 (COX -2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) type IV phosphdiesterase inhibitors (PDE-IV); (i) other PGD2 receptor antagonists, especially DP-1 antagonists; (j) opioid analgesics, such as codeine, fentanyl, hydromorphone, levorfanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbupine and pentazocine; (k) cholesterol lowering agents such as HMG - CoA reductase inhibitors (eg, lovastatin, simbvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (eg cholestyrylamine and colestipol), vitamin B3 (also known as nicotinic acid, or niacin), vitamin B6 (pyridoxine, vitamin B12 (cyanocolabamine), fibric acid derivatives (eg gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and cholesterol absorption inhibitors (e.g. beta-sitosterol and acylCOA-cholesterol acyl transferase (ACAT) inhibitors such as melinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthase inhibitors; (a) antithrombotic angetnes, such as thrombolytic agents (e.g. streptokinase, alteplase, amistrepalase and reteplase), heparin, hirudin and varvarin derivatives, O-blockers (eg atenolol), agon O-adrenergic istas (e.g. isoproterenol), ACE inhibitors and vasodilators (e.g. sodium nitroprusside, nicardipine hydrochloride, nitroglycerine and enalopriolate); (m) antidiabetic agents, such as insulin and insulin simulators, sulfonyl urea (eg glyburide, meglinatide), biguanides, eg metoformin (Glucophage®), α-glucosidase (acarbose) inhibitors, thiazolidinone compounds, e.g. rosiglitazone (Avandia®), troglitazone (Rezulino), ciglitazone, pioglitazone (Actos®) and englitazone; (n) interferon beta preparations (interferon β - 1 α, interferon β -1β); (O) gold compounds such as auranofin and aurothioglucose, (p) TNF inhibitors, for example etanercept (Enbrel®), antibody therapies such as rotoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) , infliximab (Remicade ®) and TNF D2E6 antibody, (q) lubricants or emollients such as petrolatum and lanolin, keratolytic agents, vitamin D3 derivatives (eg calcipotriene and calcipotriol (Dovonex®)), PUVA, anthraline (Drithrocreme ®), etretinate (Tegison®) and isotretinoin; therapeutic agents for multiple sclerosis such as interferon β - 1 β (Betaseron®), interferon β-Ia (Avonex ®), azathioprine (Imurek®, Imuran®). Glatiramer acetate (Capoxone®), a glucocorticoid (eg prednisolone) and cyclophosphamide; (s) other compounds, such as 5-amino salicylic acid and prodrugs thereof; (t) DNA alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg azathiprine, 6-mercapatopurine, methotrexate, a folate and 5-fluorouracil antagonist, a pyrimidine antagonist), microtubule disrupting agents (e.g. vincristine, vinblastine, paclitaxel, colchicine, nocodazole and vinorelbine), DNA intercalating agents (eg doxorubicin, daunomycin and cisplatin), DNA synthesis inhibitors such as hydroxyurea, DNA crosslinking agents, for example. mitomycin C, hormone therapy (eg tamoxifen, and flutamide), cytostatic agents, eg imatinib (ST 1571, Gleevec®) and rituximab (Rituxan®), FLAP inhibitors, and PLA2 inhibitors. The weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally speaking, an effective dose of each will be used. Thus, for example, when a compound of the invention is combined with an NSAID, the weight ratio of the compound of the invention to the NSAID will generally be in the range of from about 1000: 1. at about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of a compound of the invention and other active ingredients will generally be within the range mentioned, but in In each case, an effective dose of each active ingredient should be used.

Asthma Diagnosis

Methods of diagnosing asthma and other inflammatory and obstructive disorders and conditions are well known to those of ordinary skill in the art. For example, spirometry can be used to assess lung function. The diagnosis of asthma, in particular, may be made in part based on family history or personal history of a severe and sudden episode or recurrent episodes of sneezing, coughing or shortness of breath, which may be associated with exposure. to an allergen or exacerbated or precipitated by moderate exercise. Typically, an examination is involved in order to detect the disorder or condition.

Using a nasal speculum, the nose can be examined for signs of disturbance or allergic condition, such as increased nasal secretions, swelling or polyps, which may be causing asthma.

A stethoscope can be used to hear the sounds of the lungs produced during breathing. Wheezing sounds are one of the main indicators of obstructed nasal passages associated with asthma. In addition, allergic conditions, such as eczema or hives, can often be associated with asthma.

Pulmonary function tests are particularly useful in confirming the diagnosis of respiratory disorders or conditions. These tests include spirometry, in order to determine vital capacity, the maximum amount of air a person can inhale or exhale; peak expiratory flow rate, also known as peak flow rate, which is the maximum flow rate a person can generate during forced exhalation; and forced expiratory volume, which is the maximum amount of air a person can exhale in one second.

If the measurements are below normal for a person of that age, a bronchodilator drug used for asthma treatment may be administered to open blocked air passages and the spirometry is repeated. If measurements have been significantly improved, asthma is likely.

Additionally, asthma can be diagnosed by triggering the individual with exercise, or by inhaling a constricting airway chemical or by taking several breaths of cold air. Following challenge with a substance or activity that produces symptoms, the spirometry test is again administered. If spirometry measurements fall significantly, asthma is indicated.

The following examples are offered by way of illustration only and are not intended to limit the scope of the invention. Those of skill in the art will readily recognize a variety of noncritical parameters that could be modified to provide essentially similar results.

EXAMPLE

General Methods:

The invention will now be illustrated by the following non-limiting examples. The title and subtitle compounds of the examples and methods were named using ChemDraw Ultra (version 7.0) from CambridgeSoft Inc. Scintillation column chromatography refers to normal phase silica chromatography. The reagents and solvents used may be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis. USA). The solvents were dried with MgSO4 or NA2SO4. Evaporations were performed by rotary evaporation in vacuo and elaboration procedures were performed after removal of residual solids as drying agents by filtration. Unless otherwise noted, operations were performed at room temperature, ie in the range of 18-25 ° C and under an atmosphere of an inert gas such as argon or nitrogen. Yields are provided for illustration only and are not necessarily the maximum that can be achieved. The structures of the end products of structure (1) were confirmed by nuclear magnetic resonance (generally proton (PMR) and mass spectral techniques). NMR 1 spectra were recorded on a Varian ™ 400 MHz NMR spectrometer.

Proton magnetic resonance chemical shift values were measured in delta scale, δ, in parts per million (ppm). Significant peaks are tabulated in that order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), Hertz coupling constant (Hz) and a number of protons. Intermediates were generally not fully characterized and purity was determined by thin layer chromatography (TILC), high performance liquid chromatography (BPLC), mass spectrometry (ms); NMR or infrared (IR) analysis. Mass spectra were recorded by one of three methods of Liquid Chromatography / Mass Spectrometry (LC / MS):

Method A:

Processed on an Agilent 1100 HPLC on a 3 micron Fenomenex Luna C 18 column, 30 χ 2.0 mm internal diameter, at a flow rate of 0.300 ml / min. The column at 35 ° C was eluted with a gradient comprising an increase in AcCN (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the table below. Analytes were monitored at 214 nm and 254 nm. The analytes were sprayed on an 80 V charged Agilent electrospray source and detected after passage into a single quadripole.

Gradient:

<table> table see original document page 76 </column> </row> <table>

Method B:

Processed on an Agilent 1100 HPLC on a 3 micron Fenomenex Luna C18 column with an internal diameter of 30 χ 2.0 mm at a flow rate of 0.300 ml / min. The column at 35 ° C was eluted with a gradient comprising an increase in AcCN (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the table below. The analytes were monitored at 214 nm and 254 nm. The analytes were sprayed on an Agilent multimode source in an 80 V charged electrospray mode and detected after passing through a single quadripole.

Gradient

<table> table see original document page 77 </column> </row> <table>

Method C:

Processed on an Agilent 1100 HPLC on a 3 micron Fenomenex Luna Cl8 column with an internal diameter of 30 χ 2.0 mm at a flow rate of 0.300 ml / min. The column at 35 ° C was eluted with a gradient comprising an increase in methanol (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the table below. . The analytes were monitored at 215 nm and 254 nm. The analytes were sprayed on an Agilent multimode source in an 80 V charged atmospheric chemical ionization mode and detected after passage through a single quadripole.

Gradient

<table> table see original document page 77 </column> </row> <table>

Examples 1-53 <formula> formula see original document page 78 </formula>

Method 1 A:

<formula> formula see original document page 78 </formula>

To tert-Butyl 4- (2-hydroxy-5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (0.412 mmol, 0.150 g) in DMF (1 mL) was added K 2 CO 3 (0 , 82 mmol, 0.113g), alkyl halide, R4X (0.58 mmol) and catalytic KI. The reaction was stirred at 100 ° C until the absence of starting material was observed. Once complete, the reaction mixture was made by quenching with water, and then extracted several times into EtOAc. The combined organic substances were washed with brine and dried with NA2SO4. The material was filtered, dried and used for further purification. <table> table see original document page 79 </column> </row> <table> <table> table see original document page 80 </column> </row> <table>

Method 8

<formula> formula see original document page 80 </formula>

To piperazine (0.12 mmol) in 2 ml of methylene chloride was added DIEA (0.15 mmol) and acid chloride (0.12 mmol). The reaction was stirred at room temperature until judged complete by LC / MS. The product was purified by reverse phase HPLC (Rainin) using a 1: 3 gradient and CH 3 CN / H 2 O / 0.1% formic acid to a 9: 1 gradient of CH 3 CN / H 2 O / 0.1% acid. formic over a period of 23 minutes. <table> table see original document page 81 </column> </row> <table> <table> table see original document page 82 </column> </row> <table>

Example 54

4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-tert-butyl ester

<formula> formula see original document page 82 </formula>

To tert-Butyl 4- (2-hydroxy-5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (0.41 mmol, 0.150 g) in DMF (1 mL) was added K 2 CO 3 (0.82 mmol, 0.113 g), alkyl halide, R4aX (0.58 mmol) and catalytic KI. The reaction was stirred at 100 ° C until the absence of starting material was observed. Once complete, the reaction mixture was processed by sudden cooling and then extracted several times into EtOAc. The combined organic substances were washed with brine and dried with NA2SO4. The material was filtered, dried and used without further purification.

Example 55

Methyl 2- (4- (4-chlorobenzyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-methyl) phenyl) acetat

(Compound 55A) and

2- (4- (4-chlorobezyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-ylmethyl) phenyl) acetic acid

(Compound 55B)

Methyl 2- (4- (4-chlorobenzyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-ylmethyl) phenyl) acetate

(Compound 55A)

<formula> formula see original document page 83 </formula>

To methyl 2- (4- (4-chlorobenzyloxy) -3- (piperazine-1-ylmethyl) phenyl) acetate (0.13 mmol) in AcCN with TEA (0.31 mmol, 0.043 mL) was added 2 chloropyrimidine (0.13 mmol, 0.015 g). The mixture was heated at 80 ° C for 72 hours, and then dried with MgSO4. The desired matrix was used without further purification. LC / MS (Method A); Temp. Amb. = 2.66 minutes, MS m / z (δ + H) 467.2.

2- (4- (4-chlorobenzyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-ylmethyl) phenyl) acetic acid

(Compound 55B) <formula> formula see original document page 84 </formula>

The title material was prepared from methyl 2- (4- (4-chlorobenzyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-ylmethyl) phenyl) acetate using method 2. MS m / z 453.2 (Μ + Η). LC / MS (Method A), Temp. Amb. = 2.55 minutes.

Example 56

Methyl 2- (4- (4-3,4-dichlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate

(Compound 56A) and

2- (4- (3,4-dichlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

<formula> formula see original document page 84 </formula>

The title compounds were prepared according to General Methods 1A to 2 using 1,2-dichloro-4- (chloromethyl) benzene and 4-methylphenyl sulfonyl chloride.

Compound 56B LC / MS: (Method A), Temp. Amb. - 2,975 minutes. MS (M / z 563 (+ +)).

Example 57

2- (4- (4-Fluorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 57A) and 2- (4- (4-fluorobenzyloxy) -3- (( 4-tosylpiperazin-1-yl) methyl) phenyl acetic

(Compound 57B)

<formula> formula see original document page 85 </formula>

The title compounds were prepared according to General Methods 1a to 2 using 1- (chloromethyl) -4-fluorobenzene and 4-methylphenyl sulfonyl chloride; however, after hydrolysis, the final product was isolated as an HCl salt by acidifying the reaction mixture with 1.0 N aqueous HCl without further purification. Compound 57 B LC / MS: (Method A), Rt = 2,763 minutes. MS (m / z) 513 (δ + H).

Example 58

Methyl 2- (4- (4-nitrobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 58A) and

2- (4- (4-nitrobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 58 B) <formula> formula see original document page 86 </formula>

Compounds were prepared according to Methods 1A to 2 using 1- (chloromethyl) -4-nitrobenzene and 4-methylphenyl sulfonyl chloride. 58 B

MS (m / z) 540 (δ + H). 1H-NMR (300Mhz5 CDCl3) δ 8.29 (2H, d), 7.6 (5H, m), 7.35 (3H <m), 6.95 (1H, d), 5.22 (2H , s), 4.28 (2H, s), 3.61 (2H (d)), 3.45 (4H, br. s), 3.18 (4H, br. s), 2.43 (3H, s).

Example 59

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (3,5-dichlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 59A)

2- (4- (4-chlorobenzyloxy) -3 - ((4- (3,5-dichlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 59 B)

<formula> formula see original document page 86 </formula>

The title compounds were prepared according to General Methods 1a to 2 using 3,5-dichlorobenzene-1-sulfonyl chloride and 1- (chloromethyl) -4-chlorobenzene. The crude mixture was purified by HPLC affording the title compound as a TFA salt. 59B. 1H-NMR (300 MHz5 DMSO-C16) δ: 8.24 (1 Η, s), 8.02 (1 Η, t), 7.76 (1 Η, s), 7.44 (4 Η, dt), 7.32 - 6.98 (3 Η, m), 5.23 (2Η, t), 4.48 - 3.95 (4 Η, ν. Br. S), 3.6 (2Η, s), 3.47 - 2.73 (4 Η, ν. Br. S).

Example 60

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-ethylphenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 60 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-ethylphenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 60B)

<formula> formula see original document page 87 </formula>

The title compounds were prepared according to conventional Methods IA to 2 using 4-ethylbenzene-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compound 60B- same MS (m / z) 544 (δ + H). 1H-NMR (300 MHz, DMSO-d6) δ 8.21 (1H, s), 7.61 (2H, d), 7.42 (4H, dd), 7.23 (2H, s), 7, 14 - 6.92 (2H, m), 5.09 (2H, s), 4.2 (2H, br. S), 3.81 - 3.51 (8H, v. Br), 3, Δ (2H, s), 2,772H, dq), 1,19 (3H, t).

Example 61

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-naphthalene-1-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 61 A)

2- (4- (4-chlorobenzyloxy) -3 - ((4-naphthalen-1-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 61 B) <formula> formula see original document page 88 < / formula>

The title compounds were prepared according to General Methods IA to 2 using naphthalene-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compound 61 B MS (m / z) 566 (δ + H). 1H-NMR (300 MHz5 DMSOd6) δ: 8.62 (1HH d), 8.3 (1H, d), 8.14 (2H, m), 7.69 (3H, m), 7.43 (4H (dd), 7.23 (2H, s), 7.04 (1H, d), 5.09 (2H, s), 4.24 (2H, br. s), 3.96-3, 53 (4H, br. M), 3.41 (2H, s), 3.1 (2H, br. S), 2.8 (2H, br. S).

Example 62

(E) -2- (4- (4-chlorobenzyloxy) -3 - ((4-styrylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate,

(Compound 62A)

(E) -2- (4- (4-chlorobenzyloxy) -3 - ((4- (styrylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 62B)

<formula> formula see original document page 88 </formula>

The title compounds were prepared according to General Methods 1A to 2 using (E) -2-phenylethenesulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compound 62 B, LC / MS: (Method A), Temp. Amb. = 2.838 minutes. MS (z / z) 542 (+ +).

Example 63

Methyl 2- (3 - ((4- (4-chloro-3- (trifluoromethyl) phenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate, (Compound 63 A) and

2- (3 - ((4- (4-chloro-3- (trifluoromethyl) phenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 63 B)

<formula> formula see original document page 89 </formula>

The title compounds were prepared according to General Methods IA to 2 using 4-chloro-3- (trifluoromethyl) benzen-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compsot 63B LC / MS: (Method A); Temp. Amb. = 3.229 minutes. MS (MI z) 628 (δ + H).

Example 64

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-phenethylsulfnyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 64A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4-phenethylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 64B) <formula> formula see original document page 90 </formula>

The title compound (s) were prepared according to General Methods IA to 2 using 2-phenylethanesulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Upon acidification of the reaction mixture with 1.0 N HCl, a white solid was formed. The solid was collected by filtration, washed with water, and dried under high vacuum to provide pure compound 64 B.

LC / MS: (Method A), Temp. Amb. = 2.854 minutes. MS (m / z) 544 (δ + H).

Examples 65 - 68

Scheme 1

<formula> formula see original document page 90 </formula>

General Method Stage A: 65:

Intermediate Al (100 mg, 0.32 mmol) was dissolved in 5 mL of DMF. To the solution was added alkyl bromide (0.35 mmol, 1.1 equivalents) and K 2 CO 3 (0.48 mmol, 1.5 equivalents). The reaction was heated to 85 ° C and stirred for 20-24 hours. The reaction was then allowed to cool to room temperature, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, concentrated. The crude residue was purified by reverse phase HPLC (Column: Phenomenex, 150 χ 10 mm, 10 micro, Luna 10 μ: Gradient: 90%: 10%; 0.05% H2O / CH3CN / TTA (or formic acid) to 10% / 90% / 0.05% H2O / CH3CN / TFA (or formic acid) for 20 minutes.

Stage B:

Fractions containing intermediate B1 from HPLC purification at stage A were placed in wells and 5-8 ml of 1.0 N aqueous KOH was added. The resulting mixture was stirred until the reaction was complete as confirmed by LC / MS analysis. The reaction was then acidified to pH 2-4 with 1.0 N HCl and extracted with EtOAc / propyl alcohol. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to provide the desired product.

Example 65

2- (4-Isopropoxy-3- (S, S-dioxothiomorpholine methyl) phenyl) methyl acetate (Compound 65 A) and 2- (4-Isopropoxy-3- (S, S-dioxothiomorpholine methyl) acid phenyl) acetic (Compound 65 B)

<formula> formula see original document page 91 </formula>

The title compound (s) were prepared by acronym with General Method Stages A-B 65 using 2-bromo propane. LC / MS: Method C, Temp. Amb. = 5.59 minutes. MS (m / z) 342 (δ + H).

Example 66

2- (4-Isopentyloxy-3- (S, S-dioxothiomorpholine methyl) phenyl) acetic acid (Compound 66 A)

and

2- (4-Isopentyloxy-3- (S, S-dioxothiomorpholine methyl) phenyl) acetic acid (Compound 66 B) <formula> formula see original document page 92 </formula>

The title compound (s) was (were) prepared according to General Method Stages A-B 65 using 1-bromo-3-methyl butane. LC / MS Method C, Temp. Amb. = 6,370 minutes. MS (m / z) 370 (δ + H).

Example 67

(S) -2- (4- (2-methylbutoxy) -3- (S, S-dioxothiomorpholine methyl) phenyl) acetate

(Compound 67 A)

(S -2- (4- (2-Methylbutoxy) -3- (S, S-dioxothiomorpholine methyl) phenyl) acetic acid

(Compound 67 B)

<formula> formula see original document page 92 </formula>

The title compound (s) was (were) prepared according to General Method Stages A-B 65 using (S) -1-bromo-2-methyl butane. LC / MS: Method C, Temp. Amb. = 6.290 minutes. MS (m / z) 370 (δ + H).

Example 68

2- (4-Isobutoxy-3- (thiomorpholine Ι, Ι'-dioxide methyl) phenyl) acetic acid (Compound 68 A)

and

2- (4-Isobutoxy-3- (thiomorpholine 1,1'-dioxide methyl) phenyl) acetic acid (Compound 68 Β).

<formula> formula see original document page 93 </formula>

The title compound (s) were prepared according to General Method 65 AB stages using 1-bromo-2-methyl propane, however the product recovered from Stage B was insufficiently pure and was subjected to HPLC purification. Compound 68 B LC / MS: (Method A), Temp. Amb. = 2,744 minutes. MS (m / z) 356 (δ + H).

Example 69

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 69 D)

<formula> formula see original document page 93 </formula>

Stage A:

T-Butyl 4- (2- (isopentyloxy) -5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (Compound 69 A)

K 2 CO 3 (379 mg, 2.74 mmol) and 1-chloro-3-methyl butane (107 mg, 1.51 mmol) were added to a stirred solution of 4- (2-hydroxy-5- (2-methoxy-2 t-butyl oxoethyl) benzyl) piperazine -1-carboxylate (500 mg, 1.37 mmol) or DMF (5 ml) at 80 ° C. The resulting suspension was cooled after 16 hours, then diluted with ethyl acetate (20 ml). The organic layer was washed with H 2 O (30 mL), dried with Na 2 SO 4 and then concentrated to afford crude ether (492 mg) as a brown oil. The compound was taken to the next stage without purification.

<formula> formula see original document page 94 </formula>

Stage B: Methyl 2- (4- (isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (Compound 69 B).

TFA (0.211 ml) was added to a stirred solution of the above t-butyl 4- (2- (isopentyloxy) -5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (492 mg) in CH 2 Cl 2 (5 mL) at room temperature. The reaction mixture was stirred overnight and then resinated with saturated NaHCO 3 (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried with NA2 SO4 and concentrated to dryness to afford piperazine (300 mg) as a brown oil. . The compound was taken to the next stage without purification.

Stage C: methyl 2- (4-isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl acetate

(Compound 69 C)

DIEA (0.156 mL, 0.897 mmol) and TsCl (94 mg, 0.493 mmol) were added to a stirred solution of methyl piperazine 2- (4-isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (150 mL). mg, 0.448 mmol) in CH 2 Cl 2 (5 mL) at room temperature. The resulting suspension was suddenly cooled with saturated NaHCO 3 (20 mL) after 16 hours and the aqueous layer was extracted with CH 2 Cl 2 (3 x 15 mL). The combined organic layers were dried with NA 2 SO 4 and then concentrated to afford sulfonamide. The compound was taken to the next stage without purification.

<formula> formula see original document page 95 </formula>

Stage D: 2- (4- (Isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 69 D)

Solid LiOH (64 mg, 1.53 mmol) was added to a stirred solution of 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) methyl (187 mg, 0.383 mmol ) in THF / MeOH / H 2 O (5 mL, 3: 1: 1) at room temperature. After stirring overnight, the resulting mixture was suddenly cooled with 1 N HCl (<pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried with NA 2 SO 4, and concentrated to afford crude acid (226 mg) as a brown oil. HPLC purification provided pure compound: ES / MS, m / z 476 (Μ + Η).

Example 70

2- (4- (isopentyloxy) -3 - ((4-phenylcarbamoyl) piperazin-1-yl) methyl) phenyl acetic acid

(Compound 70 B) <formula> formula see original document page 96 </formula>

Stage Α:

Methyl 2- (4- (isopentyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 70 A)

DIEA (0.156 mL, 0.897 mmol) and PhNCO (0.054 mL, 0.493 mmol) were added to a stirred solution of methyl piperazine 2- (4- (isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (150 mL). mg, 0.448 mmol) in CH 2 Cl 2 (5 mL) at room temperature. The resulting solution was suddenly cooled with saturated NaHCOs (20 mL) after stirring overnight. The aqueous layer was extracted with CH 2 Cl 2 (3 x 20 mL), dried with NA 2 SO 4 and concentrated to afford urea as a brown oil (183 mg). The compound was taken to the next stage without purification.

<formula> formula see original document page 96 </formula>

Stage B: 2- (4- (Isopentyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl acetic acid

(Compound 70 B).

Solid LiOH (67 mg, 1.61 mmol) was added to a stirred solution of methyl 2- (4- (isopentyloxy) -3 - ((4- (phenylcarbamoyl) piprazin-1-yl) methyl) phenyl) acetate ( 183 mg, 0.403 mmol) in THF / MeOH / H 2 O (5 mL, 3: 1: 1) at room temperature. After stirring overnight, the resulting mixture was suddenly cooled with 1 N HCl (<pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried with NA 2 SO 4, and concentrated to afford a crude acid (226 mg) as a brown oil. HPLC purification provided pure compound: ES / MS m / z 440.2 ((+ H); LC / MS (Method C); Temp. Amb. = 2.58 minutes.

Example 71

Methyl 2- (4- (cyclopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 71A)

and 2- (4-cyclopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 71 B):

The title compound (s) were obtained using bromo cyclopentane and 4-methylphenyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl acid ) methyl) phenyl) acetic: Compound 71B,

ES / MS, m / z 473.3 (M + H); LC / MS (Method C), Temp. Amb. - 2.65 minutes.

Example 72

Methyl 2- (4- (cyclopentyloxy) -3 - ((4-phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 72A), and

2- (4- (cyclopentyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 72 B); <formula> formula see original document page 98 </formula>

The title compound (s) were obtained using bromine cyclopentane and phenyl isocyanate using the method described for

2- (4- (Isopentyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid.

Compound 72B ES / MS, m / z 438.3 (δ + H); LC / MS (Method C), Temp. Amb. = 2.50 minutes.

Example 73

Methyl [3- (4-chloro-benzyloxy) -3,5-bis- (4-phenylcarbamyl-piperazin-1-ylmethyl) -phenyl] -acetate,

(Compound 73 A) and

[4- (4-Chloro-benzyloxy) -3,5-bis (4-phenicarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid

(Compound 73B):

<formula> formula see original document page 98 </formula>

The title compound (s) were obtained using (1-eloromethyl) -4-elorobenzene and phenyl isocyanate using the method described for 2- (4- (4-chlorobenzyloxy) - 3 - ((4- (phenylcarbamoyl) piperazin-1-yl) phenyl) acetic ES / MS, m / z 712 (α + H);

Methyl 2- (4- (cyclopropylmethoxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate,

(Compound 74A) and

2- (4- (cyclopropylmethoxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 74B):

<formula> formula see original document page 99 </formula>

The title compound (s) was obtained using bromo methyl cyclopropane and 4-methyl phenyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin -1-yl) methyl) phenyl) acetic.

Compound 74 B:

ES / MS, m / z 459.3 (M + H); LC / MS (Method C), Temp.

Amb. = 2.62 minutes.

Example 75

Methyl 2- (4- (cyclopropylmethoxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate,

(Compound 75A), and

2- (4- (Cyclopropylmethoxy) -3- ((4-phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid, (Compound 75B): <formula> formula see original document page 100 </formula>

The title compound (s) were obtained using bromo methyl cyclopropane and phenyl isocyanate using the method described for

2- (4- (Isopentyloxy) -3 - ((4-phenylearbamyl) piperazin-1-yl) methyl) phenyl) acetic acid.

Compound 75 B: ES / MSm / z 424.3 (M + H); LC / MS (Method C), Temp. Amb. = 2.46 minutes.

Example 76

Methyl 2- (4-methoxy-3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate,

(Compound 76A), and

2- (4-Methoxy-3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 76 B):

<formula> formula see original document page 100 </formula>

The title compound (s) were obtained using iodomethane and 4-methyl phenyl sulfonyl chloride using the Method described for

2- (4- (Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 76 B: ES / MSm / z 419.2 (M + H); LC / MS (Method C), Temp. Amb. = 2.50 minutes. Example 77

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-methoxyphenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid, (Compound 77A) and

2- (4- (4-Chlorobenzyloxy) -3 - ((4- (4-methoxyphenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid, (Compound 77B):

<formula> formula see original document page 101 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 4-methoxy phenyl sulfonyl chloride using the

Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 77 B:

ES / MS, m / z 545.1 (M + H); LC / MS: (Method A), Temp. Amb. - 2.79 minutes.

Example 78

Methyl 1- (4- (4-chlorobenzyloxy) -3 - ((4- (3,4-dichlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate, (Compound 78A), and

2- (4- (4-Chlorobenzyloxy) -3 - ((4- (3,4-dichlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid, (Compound 78 B): <formula> formula see original document page 102 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 3,4-dichloro phenyl sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 78 B:

ES / MS, m / z 585.2 (M + H); LC / MS: (Method C), Temp. Amb. = 3.12 minutes.

Example 79

Methyl 1- (4- (4-chlorobenzyloxy) -3 - ((4- (2-chlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate,

(Compound 79A), and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (2-chlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 79 B):

<formula> formula see original document page 102 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 2-chloro phenyl sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 79 B:

ES / MS, m / z 549.2 (M + H); LC / MS: (Method C), Temp. Amb. = 2.85 minutes.

Example 80

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (m-tolylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate,

(Compound 80A), and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (m-tolylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 80 B):

<formula> formula see original document page 103 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 3-methylphenyl sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 80 B:

ES / MS, m / z 529.3 (M + H); LC / MS: (Method C), Temp.

Amb. - 2.85 minutes.

Example 81

2- (4- (4-chlorobenzyloxy) -3 - ((4- (quinolin-8-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 81A), and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (quinolin-8-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 81 B):

<formula> formula see original document page 104 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and quinoline-8-sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 81 B:

ES / MS, m / z 529.3 (M + H); LC / MS: (Method C), Temp. Amb. = 2.65 minutes.

Example 82

Methyl 2- (3- (4-tosylpiperazin-1-yl) methyl) -4- (4- (trifluoromethyl) benzyloxy) phenyl) acetate,

(Compound 82A), and

2- (3- (4-tosylpiperazin-1-yl) methyl) -4- (4- (trifluoromethyl) benzyloxy) phenyl) acetic acid,

(Compound 82 B): <formula> formula see original document page 105 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-trifluoromethyl benzene and 4-methyl sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 82 B:

ES / MS, m / z 563.3 (M + H); LC / MS: (Method C), Temp. Amb. - 3.04 minutes.

Example 83

4 - ((4-carboxymethyl) -2 - ((4-tosylpiperazin-1-yl) methyl) phenoxy) methyl) benzoic acid,

The title compound (s) were obtained using 1-chloromethyl 4-trifluoromethyl benzene and 4-methylsulfonyl chloride using the Method described for 2- (4-isopentyloxy) -3-Acid - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic followed by hydrolysis using the method described in Biorg. Med. Chem. Letters, 2005, 15: 5247-5252.

ES / MS, m / z 563.3 (M + H); LC / MS: (Method C), Temp. Amb. = 2.46 minutes.

Example 84

Methyl {4- (2,4-dichloro-benzyloxy) -3- [1-oxy-4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetate,

(Compound 84A) and {4- (2,4-Dichloro-benzyloxy) -3- [1-oxy-4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid (Compound 84B )

<formula> formula see original document page 106 </formula>

The title compound obtained using 1-chloromethyl 4-trifluoromethyl benzene and 4-methyl sulfonyl chloride using the Method described for

2- (4-Isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, followed by treatment with mCPBA in CH 2 Cl 2. Compound 84B: ES / MS m / z 580.1 (δ + H).

Examples 85-88

Scheme 2 <formula> formula see original document page 107 </formula>

Example 85

2- (2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-3-yl) acetic acid (Compound 85 C)

<formula> formula see original document page 107 </formula>

Stage A:

Tert-Butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (trifluoromethylsulfonyloxy) benzyl) piperazine-1-carboxylate

(Compound 85A)

<formula> formula see original document page 107 </formula>

Trifluoromethane sulfonic anhydride (0.691 mL, 4.12 mmol), DIEA (0.718 mL, 4.12 mmol), and DMAP (33 mg, 0.274 mmol) were added to a stirred solution of 4- (2-hydroxy T-Butyl 5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (1 g, 2.74 mml) in CH 2 Cl (20 ml) at 0 ° C. The resulting suspension was warmed to room temperature and stirred overnight, followed by the addition of saturated NaHCO 3 (30 mL). The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers were dried with NA 2 SO 4, and then concentrated to afford the crude product (1,945 g) as a yellow oil. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided pure material (0.85 g, 62%).

<formula> formula see original document page 108 </formula>

Stage B:

Tert-Butyl 4 - ((4- (2-methoxy-2-oxoethyl) biphenyl-2-yl) methyl) piperazine-1-carboxylate,

(Compound 85B)

Palladium tetrakis (22 mg, 0.0191 mmol) and phenyl boronic acid (51 mg, 0.421 mmol) were added to a stirred solution of 4- (5- (2-methoxy-2-oxoethyl) -2- (trifluoromethylsulfonyloxy) tert-Butyl) benzyl) piperazine-1-carboxylate (190 mg, 0.383 mmol) in 2 M dimethoxy methane / NA2 CO3 (2: 1, 9 mL). After refluxing for 3 days, the resulting suspension was cooled, and then the organic layer was concentrated. Water (10 ml) was added to a mixture and the aqueous layer was extracted with ether (3 x 10 ml). The combined organic layers were dried with NA2 SO4 and then concentrated to afford crude material (342 mg). The compound was taken to the next stage without purification.

Stage C: 2- (2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid (Compound 85C) <formula> formula see original document page 109 </formula>

The compound was prepared using the Method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, Stages A-D: ES / MS m / z 465 0.1 (M + H); LC / MS (Method C), Temp. Amb. = 3.12 minutes.

Example 86

2- (4'-methyl-2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid,

(Compound 86A), and

Methyl 2- (4'-methyl-2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetate,

(Compound 86B)

<formula> formula see original document page 109 </formula>

The compound was prepared using the method described for 2- (2- ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid using 4-methyl boronic acid.

Compound 86 B: ES / MS m / z 479.3 (δ + H); LC / MS (Method C), Temp. Amb. = 3.04 minutes.

Example 87

Methyl 2- (4'-chloro-2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetate,

(Compound 87A) and

2- (4'-chloro-2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic

(Compound 87 B):

<formula> formula see original document page 110 </formula>

The compound was prepared using the method described for 2- (2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid using 4-chloro boronic acid.

Compound 87 B: ES / MS m / z 499.3 (M + H); LC / MS (Method C), Temp. Amb. = 3.27 minutes.

Example 88

Methyl 2- (4'-chloro-2- (thiomorpholinoxymethyl) biphenyl-4-yl) acetate,

(Compound 88A) and

2- (4'-chloro-2- (thiomorpholinindioxymethyl) biphenyl-4-yl) acetic acid,

(Compound 88B)

<formula> formula see original document page 110 </formula> The compound was prepared using a Method similar to that described for:

2- (4'-chloro-2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid from

Methyl 2- (4-hydroxy-3- (S, S-dioxothiomorpholine-methyl) phenyl) acetate.

Compound 88 B: ES / MS m / z 394.1 (M + H); LC / MS (Method A), Temp. Amb. = 3.31 minutes.

Example 89

2- (4- (phenylethynyl) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic (Compound 89 B)

<formula> formula see original document page 111 </formula>

Stage A:

Tert-Butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (phenylethynyl) benzyl) piperazine-1-carboxylate (Compound 89 A).

Palladium tetrakis (5 mg, 0.43 μπιοί), CuI (0.2 mg, 0.86 μπιοί), Et3N (0.12 mL, 0.86 mmol), and phenyl acetylene (0.06 mL, 0.52 mml), were added to a solution of tert-butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (trifluoromethylsulfonyloxy) benzyl) piperazine-1-carboxylate (215 mg, 0.43 mmol) in DMF (1 m 1) in a sealed tube. Argon was bubbled through the solution for 2 minutes, and the reaction vessel was sealed. The tube was heated at 110 ° C overnight, followed by the addition of NA2HCO3 (5 ml) after cooling. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with H 2 O (10 mL), dried with NA 2 SO 4, and concentrated to afford crude product (34 mg) as a brown oil. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided pure title material (65 mg, 33%) as a pale yellow oil.

<formula> formula see original document page 112 </formula>

Stage B: 2- (4-Phenylethynyl) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl acetic acid,

(Compound 89 B).

The compound was prepared using a similar Method as described for 2- (2 - ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid: ES / MS, m / z 489.3 (+ H);

LC / MS (Method C), Temp. Amb. - 3.19 minutes.

Example 90

2- (4-Phenethyl-3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 90)

<formula> formula see original document page 112 </formula>

Palladium on carbon (5% w / w, 0.1 mg, 0.11 μmol) was added to a solution of 2- (4- (phenylethynyl) -3- ((4-tosylpiperazin-1-yl) methyl) acid phenyl) acetic acid (5.4 mg, 1.1 μmol) in acetic acid (1 ml). The reaction vessel was attached to a flask (H2) and stirred for 2 hours. The resulting suspension was filtered through CELITE and the filter cake was washed with MTBE (20 mL). The combined organic layers were concentrated to provide crude product. HPLC purification provides pure product: ES / MS, m / z 493.3 ((+ H); LC / MS (Method C), Temp. Amb. - 3.35 minutes.

Examples 91-92

Scheme 3

<formula> formula see original document page 113 </formula>

Example 91

2- (4- (4-chlorobenzyloxy) -3 - ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 91 D)

<formula> formula see original document page 113 </formula>

Stage A: methyl 2- (4-hydroxy-3 - ((3-oxopiperazin-1-yl) methyl) phenyl) acetate,

(Compound 91 A)

Paraformaldehyde (89 mg, 2.95 mmol) and piperazin-2-one (500 mg, 2.68 mmol) were added to a stirred solution of 4-hydroxy methyl phenyl acetate (408 mg, 2.68 mmol) in i-PrOH (10 ml). The resulting mixture was refluxed overnight, cooled, and then concentrated. The residue was redissolved in EtOAc (20 mL) and the organic layer was washed with H 2 O (20 mL), dried with NA 2 SO 4 and concentrated to afford the crude product. The compound was taken to the next stage without purification.

<formula> formula see original document page 114 </formula>

Stage B: methyl 2- (4- (4-chlorobenzyloxy) -3- (3-oxopiperazin-1-yl) methyl) phenyl) acetate,

(Compound 91 B).

K 2 CO 3 (567 mg, 4.1 mmol) and 4-chlorobenzyl bromide (463 mg, 2.26 mmol) were added to a stirred solution of 2- (4-hydroxy-3 - ((3-oxopiperazin-1-yl methyl) phenyl) methyl acetate (570 mg, 2.05 mmol) in DMF (10 mL) at room temperature. The mixture was stirred overnight and then diluted with EtOAc (20 mL). The organic layer was washed with H 2 O (20 mL), dried with NA 2 SO 4, and concentrated to afford the desired crude material (601 mg) as a yellow oil. The compound was taken to the next stage without purification. Stage C:

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 91 C)

Solid K 2 CO 3 (192 mg, 1.39 mmol), CuI (13 mg, 0.07 mmol), ethyl diamine (0.005 mL, 0.07 mmol) and 4-trifluoromethyl iodobenzene (0.122 mL, 0.834 mmol) were added. to a stirred solution of methyl 2- (4- (4-chlorobenzyloxy) -3 - ((3-oxopiperazin-1-yl) methyl) phenyl) acetate (280 mg, 0.695 mmol) in dioxane (2 mL) . The mixture was degassed (argon gas) and the reaction vessel was sealed, and then heated to 110 ° overnight. After cooling, the suspension was filtered through a silica gel plug and the filter cake was washed with EtOAc (40 mL). The combined organic layers were concentrated to provide crude product, which can be taken to the stage without further purification.

<formula> formula see original document page 115 </formula>

Stage D:

2- (4- (4-chlorobenzyloxy) -3 - ((3-oxo-4- (4- (trifluoromethyl) phenyl) pyrazin-1-yl) methyl) phenyl) acetic acid,

(Compound 91D)

The compound was prepared by using the Method similar to Stage D of the method to produce 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid. ES / MS, m / z 533.3 (δ + H); LC / MS (Method C), Temp. Amb. = 3.35 minutes.

Example 92

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (phenylsulfonyl) piperidin-1-yl) methyl) (phenyl) acetate

(Compound 92 A), and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (phenylsulfonyl) piperidin-1-yl) methyl) phenyl) acetic acid,

(Compound 92B) and

<formula> formula see original document page 116 </formula>

The compound was prepared using the similar method described for 2- (4- (4-chlorobenzyloxy) -3 - ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl acid ) acetic except for the use of 4- (phenylsulfonyl) piperidine. Compound 92 B: ES / MS, m / z 514.1 (δ + H); LC / MS (Method C), Temp. Amb. = 2.58 minutes.

Example 93

2- (3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 93)

Scheme 4

<formula> formula see original document page 116 </formula>

DIEA (0.611 mL, 3.51 mmol) and 1-tosylpiperazine (420 mg, 1.75 mmol) were added to a stirred solution of methyl 2- (3- (bromo methyl) phenyl) acetate (300 mg, 1.17 mmol) in CH 3 CN (10 mL) at 50 ° C. The mixture was stirred overnight, cooled, and then suddenly resinated with H 2 O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried with NA 2 SO 4, and concentrated to afford the crude ester (695 mg) as a yellow oil. Flash silica gel flash chromatography (3: 1, hexane / EtOAc) provided pure ester (178 mg, 37%), which was hydrolyzed using NaOH in MeOH: water to provide crude acid. HPLC purification provided pure product; ES / MS, m / z 389.1 (δ + H); LC / MS (Method A), Temp. Amb. = 2.317 minutes.

Examples 94-96

Scheme 5

<formula> formula see original document page 117 </formula>

Example 94

2- (4-Hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 94B) <formula> formula see original document page 118 </formula>

Phenyl boronic acid (188 mg, 1.54 mmol) and 1-tosylpiperazine (371 mg, 1.54 mmol) were added to a stirred solution of methyl 2- (3-formyl-4-hydroxyphenyl) acetate (300 mg, 1.54 mmol) in dioxane (10 mL) at 90 ° C. After stirring for 16 hours, the reaction mixture was cooled, then suddenly cooled with H2O (10 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layer was dried with Na2 SO4, and then concentrated to afford the crude ester (1.3 g) as a yellow solid. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided the desired material (567 mg, 74%) as a white solid.

<formula> formula see original document page 118 </formula>

Stage B: 2- (4-Hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 94 B)

Solid LiOH (161 mg, 3.84 mmol) was added to a stirred solution of methyl 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetate (190 mg, 0 , 384 mmol) in THF / MeOH / H 2 O (5 mL, 3: 1: 1) at room temperature. After stirring overnight, the resulting mixture was suddenly cooled with 1 N HCl (<pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried with NA 2 SO 4, and concentrated to afford a crude acid (85 mg) as a brown oil. Purification by HPLC provided pure Compound 94B: ES / MS m / z 481.1 (Μ + H); LC / MS: (Method A), Temp. Amb. = 3.43 minutes.

Example 95

Methyl 2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl) -4-hydroxyphenyl) acetate

(Compound 95A), and

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl-4-hydroxyphenyl) acetic acid,

(Compound 95 B).

<formula> formula see original document page 119 </formula>

The compound was prepared using the Method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid from 4-methyl phenyl boronic acid. 95B: ES / MSm / z 499.2 (M + H); LC / MS (Method B) Temp. Amb. = 3.535 minutes.

Example 96

Methyl 2- (3 - ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) -4-hydroxyphenyl) acetate (Compound 96 A) and

2- (3 - ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) -4-hydroxyphenyl) acetic acid (Compound 96B): <formula> formula see original document page 120 </ formula>

The compound was prepared using the Method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid from 4-chloro phenyl boronic acid. Compound 96 B: ES / MS m / z 519.1 (M + H); LC / MS (Method B), Temp. Amb. = 3,767 minutes.

Example 97

2- (3 - ((2-hydroxyphenyl) (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, (Compound 97B)

<formula> formula see original document page 120 </formula>

Stage A: 2 - ((3- (hydroxymethyl) phenyl) (4-tosylpiperazin-1-yl) methyl) phenol

3- (hydroxymethyl) benzaldehyde (0.35 mL, 3.29 mmol) and 1- tosylpiperazine (790 mg, 3.29 mmol) were added to a stirred solution of 2-phenol boronic acid in dioxane (30 mL) at 90 ° C. After stirring for 16 hours, the reaction mixture was cooled and was then suddenly cooled with H2O (40 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried with NA2SO4 and concentrated to provide crude material (1.53 g), which was used in the subsequent stage without further purification. <formula> formula see original document page 121 </formula>

Stage Β: 2- (3- (2-Hydroxyphenyl) (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

2 - ((3- (hydroxymethyl) phenyl) (4-tosylpiperazin-1-yl) methyl) phenol was converted to benzyl chloride by the use of SOCl2, followed by KCN treatment. A hydrolysis of benzyl nitrile provided the desired material using the Biorg Method. Med. Chem Letters, 2005, 15, 5247-5252, which was then purified with HPLC: ES / MS m / z 481.2 (δ + H); LC / MS (Method B), Temp. Amb. = 3.33 minutes.

Example 97

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl) phenyl acetic acid,

(Compound 97).

<formula> formula see original document page 121 </formula>

DIEA (0.331 ml, 1.99 mmol), Tf 2 O (0.335 ml, 1.99 mmol), and DMAP (16 mg, 0.132) were added to a stirred solution of 2- (3 - ((4- (4 - fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl-4-hydroxyphenyl) methyl acetate (700 mg, 1.32 mml) in CH 2 Cl 2 (10 ml) at room temperature.

After stirring for 1.5 hours, the resulting mixture was suddenly cooled with saturated NaHCOs (10 mL), and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were dried with NA 2 SO 4 and concentrated to afford crude triflate (1.07 g) as a brown oil. Silica gel chromatography (3: 1, hexanes / EtOAc) provided the triflate (760 mg, 86%) as a white solid. Triflate (100 mg, 0.155 mmol) was dissolved in DMF (2 mL). To this solution were added formic acid (15 µl, 0.434 mmol), Et3N (91 µl, 0.65 mmol), PdCl2 (PPh3) 2, and dppp (10 mg, 0.023 mmol). The resulting suspension was degassed under sealed Ar and heated at 90 ° C for 17 hours. After cooling to room temperature, the reaction mixture was poured into H 2 O (10 mL) and the aqueous layer was extracted with Et 2 O (3 x 10 mL). The combined organic layers were washed with 1 N HCl (15 mL), brine (15 mL), dried with Na 2 SO 4, and concentrated to afford crude deoxygenated product (262 mg). Saponification of the methyl ester as described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid led to the desired material.

ES / MS, m / z 483.2 (M + H); LC / MS (Method B), Temp. Amb. = 3.33 minutes.

Example 98

Methyl 2- (3 - ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate,

(Compound 98 A) and

2- (3 - ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 98 B). <formula> formula see original document page 123 </formula>

The compound was prepared using the Method described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl) phenyl) acetic acid from

Methyl 2- (3 - ((4-chloro phenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) -4-hydroxyphenyl) acetate.

Compound 98 B; ES / MS, mJ ζ 503.1 (Μ + H); LC / MS (Method B), Temp. Amb. = 3.33 minutes.

Example 99

R-2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid and

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid

(Compound 99 B and C)

Scheme 6

<formula> formula see original document page 123 </formula>

Stage A: Methyl 2- (3- (chloro (phenyl) methyl) phenyl) acetate, (Compound 99 A) <formula> formula see original document page 124 </formula>

Solid NaBH4 (505 mg, 13.3 mmol) was added to a solution of 2- (3-benzylphenyl) acetic acid (850 mg, 3.34 mmol) in MeOH (30 mL) at 0 ° C. The resulting solution was suddenly cooled with NaHCO 3 (30 mL) after 5 minutes and the aqueous layer was extracted with EtOAc (and χ 20 mL). The combined organic layers were washed with brine (30 mL), dried with Na 2 SO 4, and concentrated. The residue was redissolved in CH 2 Cl 2 (20 mL) and SoCl 2 (1.2 mL, 16.7 mmol) was added. The resulting mixture was concentrated after stirring overnight to afford crude chloride. Flash chromatography (3: 1, hexanes / EtOAc) provided pure material.

Stage B: R-2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) (methyl) phenyl) acetic acid and

S-2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid,

Compound 99 B and C).

<formula> formula see original document page 124 </formula>

1- (4-fluorophenylsulfonyl) piperazine (320 mg, 1.31 mmol), DIEA (0.57 mL, 3.28 mmol), and NaI (16 mg, 0.109 mmol) were added to a stirred solution of 2- ( Methyl 3- (chloro (phenyl) methyl) phenyl) acetate in CH 3 CN (15 ml). The resulting suspension was heated to 80 ° C and stirred overnight. After cooling, the reaction mixture was suddenly cooled with saturated NaHCO3 (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried with Na 2 SO 4 and concentrated. The resulting ester was hydrolyzed using a similar Method as a preparation of 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid. Purification by HPLC provided pure material. Both enantiomers were also separated by chiral HPLC (Chiralpak AD-H, 4,6 χ 250 mm, 80% heptanes: 20% IPA: 0.1% TFA, 40 ° C, 1.90 ml / min) . 98 B, Room Temperature = 14.479 minutes, 98 C, Room Temperature = 22, 119 minutes. ES / MS, m / z 469.2 (M + H); LC / MS (Method B), Room Temperature = 3.653 minutes.

Example 100

Methyl 2- (3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 100 A) and

2- (3- (Phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 100 B).

methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid from 1- (4-methylphenylsulfonyl) piperazine. Compound 100 B: 1H NMR (400 MHz, DMSO-d6) δ 12.31 (1H, brs), 7.61 (2 H, dd, J = 0.9, 8.1 Hz), 7.48 (2H , dd, J = 0.7, 7.7 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.26 = 7.14 (6H, m), 7.05 (1H, dd, J = 1.1, 7.3 Hz), 4.28 (1H,

<formula> formula see original document page 125 </formula>

The title compound (s) were prepared using (s), 3.49 (2 Η, s), 2.88 (4 Η, brm), 2.44 (3 Η, s) 2.35 (4, brm); ES / MS5 m / ζ 465.2 (δ + H); LC / MS (Method B);

Temp. Amb. - 3.750 minutes.

Example 101

2- (3-phenyl (4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) methyl acetate (Compound 101 A) and 2- (3- (phenyl (4- (phenylsulfonyl) piperazin-1-yl) acid ) methyl) phenyl) acetic,

(Compound 101 B):

<formula> formula see original document page 126 </formula>

The title compound (s) were (were) prepared using the methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) pyrazin-1-yl) (phenyl) methyl) phenyl acid ) acetic from (phenylsulfonyl) piperazine. Compound 101 B: ES / MS, m / z 451.2 (δ + H): LC / MS (method B), Temp. Amb. = 3,954 minutes.

Example 102

Methyl 2- (3 - ((4-methylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetate (Compound 102 A) and

2- (3 - ((4-methylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic (Compound 102 B)

<formula> formula see original document page 126 </formula>

[265] The title compound (s) were prepared using the methodology described for

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid from (methylsulfonyl) piperazine. Compound 102 B; ES / MS, m / z 389.1 (M + H); LC / MS (Method B), Room Temperature = 2,686 minutes.

Example 103

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) propanoic acid,

(Compound 103 A) and

<formula> formula see original document page 127 </formula>

2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) propanoic acid,

(Compound 103 B)

The compound was prepared by a similar method as the preparation of 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic from ketoprofen: Compound B: ES / MS, mJ δ 483.2 (δ + H); LC / MS (Method B), Room Temperature = 3.9 minutes

Example 104

2- (3-chloro-5- (phenyl (4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid,

(Compound 104 E) Scheme 7

<formula> formula see original document page 128 </formula>

Stage A: (3-Bromo-5-chlorophenyl) (phenyl) methanol (Compound 104 A)

1.0 M (in THF) of PhMgBr (4.1 mL, 4.1 mmol) was slowly added to a stirred solution of 3-bromo-5-chloro benzaldehyde (600 mg, 2.73 mmol) in THF (20 mL). ml) at 0 ° C. The resulting mixture was stirred for 1.5 hours and then suddenly cooled with saturated NH 4 Cl (20 mL) and the aqueous phase extracted with EtOAc. The combined organic layers were washed with brine, dried with Na 2 SO 4, and then concentrated to afford 1.02 g crude alcohol. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided pure material (512 mg, 63%).

Stage Β: t-Butyl 4- (4-bromo-5-chlorophenyl) (phenyl) methyl) piperazine-1-carboxylate

(Compound 104B)

<formula> formula see original document page 129 </formula>

SOCl 2 (0.611 mL, 8.4 mmol) was added to a stirred solution of (3-bromo-5-chlorophenyl) (phenyl) methanol (500 mg, 1.68 mmol) in CH 2 Cl 2 (10 mL) at room temperature. After stirring for 4 hours, the solution was concentrated. The residue was redissolved in CH3 CN (15 mL) and DIEA (0.878 mL, 5.04 mmol), NaI (25 mg, 0.168 mmol) and t-butyl piperazine-1-carboxylate (470 mg, 2.52 mmol) have been added. The resulting mixture was heated to 80 ° C and stirred overnight. After cooling to room temperature, saturated NA 2 CO 4 (20 mL) was added and the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried with NA 2 SO 4, and concentrated. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided pure material.

Stage C

Tert-Butyl 4- (3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) (phenyl) methyl) piperazine-1-carboxylate (Compound 104C)

<formula> formula see original document page 129 </formula> AcOK (160 mg, 1.62 mmol) and pinacolborane (165 mg, 0.65 mmol) were added to a solution of 4 - ((3-bromo-5- t-butyl chlorophenyl (phenyl) methyl) piperazine-1-carboxylate (250 mg, 0.54 mmol) in dioxane (5 mL). The resulting solution was degassed using argon, followed by the addition of PDCl2 (dppf) (20 mg, 0.027 mmol) and dppf (15 mg, 0.027 mmol). The reaction mixture was heated at 80 ° C for 4 hours, cooled, and then concentrated. The residue was dissolved in hexane and activated carbon was added, and then filtered through CELITE. The combined organic layers were concentrated to provide crude material. Silica gel column chromatography (9: 1, hexanes / EtOAc) provided pure material (189 mg, 69%).

Stage D:

T-Butyl 4 - ((3-chloro-5- (2-ethoxy-2-oxethyl) phenyl) (phenyl) methyl) piperazine-1-carboxylate

(Compound 104 D)

<formula> formula see original document page 130 </formula>

K 2 CO 3 (160 mg, 1.16 mmol) and 1-bromoethyl ester (0.039 mL, 0.351 mmol) were added to a solution of 4 - ((3-chloro-5- (4,4,5,5- tert-Butyl tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl (phenyl) methyl) piperazine-1-carboxylate (180 mg, 0.351 mmol) in toluene (5 ml) The resulting solution was degassed using argon, followed by the addition of PD (PPh3) 4 (13 mg, 0.011 mmol) and Cu 2 O (1.5 mg, 0.011 mmol) .The reaction mixture was heated at 80 ° C for 16 hours, cooled, and then concentrated to afford a crude ester (80 mg) .Silica gel column chromatography (3: 1, hexanes / EtAc) provided pure material (36 mg, 22%).

Stage E: 2- (3-Chloro-5- (phenyl (4-phenylsulfonyl) pyrazin-1-yl) methyl) phenyl) acetic acid

(Compound 104E)

The compound was prepared by a similar method as described for the preparation of 2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid:

ES / MS, m / z 485.2 (M + H); LC / MS (Method B), Temp. Amb. = 3.9 minutes.

Example 105

Methyl 2- (3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (pyridin-3-yl) methyl-4-hydroxyphenyl) acetate ((Compound 105A) and

2- (3 - ((4- (4-fluorophenyl sulfonyl) piperazin-1-yl) (pyridin-3-yl) methyl) -4-hydroxyphenyl) acetic acid (Compound 105 B)

<formula> formula see original document page 131 </formula>

The compound was prepared using the Method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid from 3-pyridyl boronic acid and 4-fluorophenyl sulfonyl.

Compound 105 Β: LC / MS, Room Temperature = 2.61 minutes (Method A); MS (λz 486.1 (M + + Η)).

Example 106

2- (4- (4-Chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) acetic acid (Compound 106 B)

<formula> formula see original document page 132 </formula>

Scheme 8

<formula> formula see original document page 132 </formula>

Stage A: 2- (4-Chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzoic acid (Compound 106 A)

<formula> formula see original document page 132 </formula>

To a suspension of methyl-4-hydroxyphenyl acetate (11.6 g, 70 mml, 1.0 equivalent), magnesium chloride (10 g, 105 mml, 1.5 equivalents) and triethyl amine (36.6 mL, 265 mL). 0.5 mmol) in AcCN (200 mL) was added pulverized paraformaldehyde (15.3 g, 472.5 mmol, 7 equivalents). The resulting white suspension was then transferred to an oil bath, a reflux condenser was attached thereto, and was then refluxed at 82 ° C for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 1.0 M hydrochloric acid (at pH 4) and then extracted with EtOAc (400 mL). The extract was dried with NaSCO 4 and concentrated to afford methyl aldehyde intermediate 2- (3-formyl-4-hydroxyphenyl) acetate (6.2 g). LC / MS: (Method A) MS / m / z 195, (M + H), (Amb. Temp = 3.7 minutes).

The crude aldehyde (3 g, 9.43 mmol) was placed in a 500 mL reaction flask and dissolved in acetone (40 mL) and then transferred to an oil bath at 40 ° C. A hot solution of potassium permanganate (2.61 g, 16.5 mmol) in acetone-H2 O (60 mL, 5: 1) was then added and stirred at 40 ° C overnight. Acid base work-up provided 3.96 g of crude product 2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxothyl) benzoic acid. LC / MS: Method A, MSm / z 333.0 (δ + H), Temp. Amb. = 3.58 minutes.

Stage B: 2- (4- (4-Chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) acetic acid

(Compound 106 B).

<formula> formula see original document page 133 </formula>

2- (4-Chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzoic acid 100 mg, 0.299 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N 'hexafluorophosphate , N'-hexamethyluronium (HATU, 113.5 mg, 0.299 mmol) and N, N-diisopropylethylamine (0.067 mL, 0.389 mmol) were dissolved in ACCN (2 mL) in a reaction flask, and stirred for 10 minutes. . 1- (tosyl) piperazine (71.8 mg, 0.299 mmol) was then added and the resulting solution was then stirred for 10 hours. The product was precipitated from solution and was then filtered and washed to afford 110 mg of pure 2- (4- (4-chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) ester) methyl acetate. LC / MS (Method A), MSm / z 557.1 (δ + H), Tmp. Amb. = 4.02 minutes).

The ester (100 mg, 0.18 mmol) and lithium hydroxide (100 mg, excess) were then suspended in a mixture of MeOH 2 (2: 1) and stirred for 8 hours. The mixture was then diluted with EtOAc (60 mL), washed with 1.0 M HCl (50 mL) and then brine. The solution was then dried and concentrated to afford the product (109.7 mg). LC / MS: (Method A), MS m / z 543.1 (Μ + H), (Amb. Temp = 3.71 minutes).

Example 107

Methyl 2- (4- (4-chlorobenzyloxy) -3- (4-methylsulfonyl) piperazine-1-carbonyl) phenyl) acetate,

(Compound 107A) and

2- (4- (4-chlorobenzyloxy) -3- (4-methylsulfonyl) piperazine-1-carbonyl) phenyl) acetic acid,

(Compound 107 B).

<formula> formula see original document page 134 </formula>

The title material (s) were prepared from methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate and 1- (methylsulfonyl) piperazine according to the Method described for

2- (4- (4-chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) acetic acid,

Compound 107 B: LC / MS: (Method A), MS m / z 467.1 (M + H), (Ambient Temp. = 3.19 minutes).

Example 108

Methyl 2- (4- (4-chlorobenzyloxy) -3- (S, S-dioxothiomorpholine-4-carbonyl phenyl) acetate,

(Compound 108 A) and 2- (4- (4-chlorobenzyloxy) -3- (S, S-dioxothiomorpholine-4-carbonyl) phenyl) acetic acid (Compound 108 B):

<formula> formula see original document page 135 </formula>

The compound (s) was (were) prepared from methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate and thiomorpholine dioxide according to the method described for

2- (4- (4-chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) acetic acid. LC / MS:

(Method A), MSm / z 438.1 (Μ + H), (Amb. Temp = 3.11 minutes).

Examples 109-101

Scheme 9 <formula> formula see original document page 136 </formula>

Example 109

(S, Z) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2 H) - yl) methyl) phenyl) acetic (Compound 109 D)

Stage A

Methyl 2- (3- (but-3-enylamino) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate,

(Compound 109 A) <formula> formula see original document page 137 </formula>

To a vigorously stirred suspension in 3-en-1-amine hydrochloride (202 mg, 1.89 mmol) in brine (3 mL) and CH 2 Cl 2 (2 mL) was added 2 M NaOH at pH = 14. The organic layer was separated, dried (NA 2 SO 4) and added directly to a flask under an inert atmosphere containing methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate (200 mg, 0.63 mmol). In a separate vial, sodium cyanoborohydride (40 mg, 0.63 mmol) was carefully added in a single portion to a solution of zinc chloride (325 μl, 1 Μ) in 1 ml MeOH5 at room temperature. as the mixture boiled. The mixture was allowed to stir for 10 minutes, and then the total was added by cannula to the flask containing the stirred solution of but-3 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate -en-1-amine. The mixture was stirred for 10 minutes and then suddenly cooled with NaHCOs (10 mL), then extracted with CH 2 Cl 2 (2 x 10 mL), dried (NA 2 SO 4) and concentrated in vacuo to afford 2- (3 - ((but - 3-enylamino) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (300 mg) as a colorless oil. LC / MS (Amb. Temp = 2.35 minutes, (Method A), m / z 374 M + H).

Stage B:

(S) methyl 2- (3 - ((N- (but-3-enyl) -2- (tert-butoxycarbonylamino) pent-4-enamido) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate, ( Compound 109 B): <formula> formula see original document page 138 </formula>

To a solution of (S) -2- (tert-Butoxycarbonylamino) pent-4-enoic acid (409 mg, 2.67 mmol), 2- (3- ((bt-3-enylamino) methyl) -4- ( Methyl 4-chlorobenzyloxy) phenyl) acetate (1 g, 2.67 mmol) and Hunigs base (0.98 mL, 5.34 mmol) in DMF (10 mL) was added HATU (1 g, 2.67 mmol) ). The reaction was stirred for 1 hour and then poured into 200 mL of water and extracted with EtOAc (3 x 20 mL), dried (NA2SO4) and concentrated in vacuo. Column chromatography (silica gel, 20-40% EtOAc / hexane) provided 2- (3 - ((N- (but-3-enyl) -2- (tert-butoxycarbonylamino) pent-4-enamido) methyl (S) -methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (0.8 g, 1.4 mmol, 52%); LC / MS (Temp. Amb. = 4.35 minutes, (Method A), 571 M + H).

Stage C:

2- (3- ((3- (tert-Butoxycarbonylamino) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (S, Z) methyl, (Compound 109 C)

<formula> formula see original document page 138 </formula>

A solution of (S) -methyl 2- (3 - ((N-3-enyl) -2- (tert-butoxycarbonylamino) pent-4-enamido) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate 100 mg, 0.175 mmol) and a first generation Grubb catalyst (34 mg, 0.032 mmol) in CH 2 Cl 2 (35 mL) was heated at 50 ° C for 8 hours. The mixture was concentrated and subjected to column chromatography (silica gel, 20-40% EtOAc / hexane) to afford 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxo-3, (S, Z-Methyl) 4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (70 mg, 1.4 mmol, 74 %);

1H-NMR (300 MHz, CDCl3): 7.4 - 7.3 (m, 4 H), 7.15 - 7.1 (M, 2 H), 6.85 (d, 1 H), 5.9 (d, 1 H), 5.7 (m, 1 H), 5.4 (δ, 1H), 5, 1 (s, 2 H), 4.9 (d, 1 H), 4, 8 ( Δ, 1 H), 4.3 (d, 1 H), 3.8 (m, 1 H), 3.7 (s, 3 H), 3.5 (s, 2 H), 3.2 ( m, 1 H), 2.8 (m, 1 H), 2.4 (m, 3 H), 1.45 (s, 9 H).

Stage D:

(S, Z) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2H) -yl acid ) methyl) phenyl acetic (Compound 109 D):

<formula> formula see original document page 139 </formula>

To a solution of:

(S) -methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxoazocan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (100 mg, 0.183 mmol) in CH 2 Cl 2 (2 mL) was added TFA (1 mL). The solution was then stirred for 1 hour and then neutralized (saturated NaHCO 3), extracted with CH 2 Cl 2 (2 x 10 mL), dried (NA 2 SO 4) and concentrated in vacuo. 63 μΐ, 0.44 mmol) and p-toluene sulfonyl chloride (52 mg, 0.27 mmol) The solution was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H 2 O ( 2 ml), to which was added LiOH (75 mg, 1.76 mmol) The solution was stirred vigorously for 1 hour, then acidified with HCl (2 M), extracted with EtOAc (3 x 10 ml) , dried (NA 2 SO 4) and concentrated in vacuo The crude residue was subjected to preparative HPLC purification, followed by lyophilization of the fractions to provide (S, Z) -2- (4- (4-chlorobenzyloxy) acid -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) phenyl) acetic as a colorless solid, (75 mg, 0, 13 mmol, 70%); 1H NMR (300 MHz, CDCl 3) 12.2 (br s, 1 H), 7.9 (d, 1 H), 7.7 (d, 2 H), 7.45 (s, 4 H), 7.3 (d, 2 H), 7.1 (dd, 1 H), 6.95 (d, 1 H), 6.85 (d, 1 H), 5.5 (m, 1 H), 5.35 (m, 1 H), 5.1 (s, 2 H), 4.5 - 4.4 (m, 1 H), 4.35 (d, 1 H), 4.1 (d, 1 H) 3.55 (m, 2 H), 3.4 (s, 2 H), 3.2 -3.1 (m, 1 H), 2.3 (m, 6 H).

Example 110

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110 A) and

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110 B).

<formula> formula see original document page 140 </formula>

Stage A:

(S) Methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxoazocan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate, (Compound 110 AA). A solution of:

2- (3- ((3- (tert-Butoxycarbonylamino) -2-oxo -3,4,7,8-tetrahydroazocin-1 (2H) -yl) methyl-4- (4-chlorobenzyloxy) phenyl) acetate S, Z-methyl) (50 mg, 0.092 mmol) and RhCl (PPh3) 3 (6.6 mg, 0.018 mmol) in benzene (2 mL) under a hydrogen atmosphere were stirred for 48 hours. then concentrated and subjected to column chromatography (silica gel, 20-50% EtOAc, hexane) to afford 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxoazocan-1-yl) (S) -methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (45 mg, 0.082 mmol, 89%); 1H NMR (300 MHz, d6-DMSO): 7.4-7 , 3 (m, 4 H), 7.15 - 7.10 (m, 2 H), 6.85 (d, 1 H), 5.7 (d, 1 H), 5.1 (d, 1 H), 5.0 (s, 2 H), 4.7 (m, 1 H), 4.2 (d, 1 H), 3.7 (m, 1 H), 3.65 (s, 3 H), 3.55 (s, 2 H), 3.2 (m, 1 H), 1.7-1.5 (m, 6H), 1.4 (m, 10 H).

Stage B:

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110 AB):

<formula> formula see original document page 141 </formula>

A solution of

(S) -methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxoazocan-1-yl) methyl-4- (4-chlorobenzyloxy) phenyl) acetate (100 mg, 0.18 mmol) TFA (1 mL) was added in CH 2 Cl 2 (2 mL) The solution was stirred for 1 hour then neutralized (saturated NaHCO 3), extracted with CH 2 Cl 2 (2 mL), dried (NA 2 SO 4) and concentrated in vacuo. dissolved in CH 2 Cl 2 (2 mL), to which was added triethylamine (63 µl, 0.44 mmol) and p-toluene sulfonyl chloride (52 mg, 0.27 mmol) The solution was stirred for 2 hours and concentrated in The residue was dissolved in THF (3 mL) and H 2 O (2 mL), to which LiOH (75 mg, 1.76 mmol) was added, the solution was vigorously stirred for 1 hour, and then acidified with HCl (2M). ), extracted with EtOAc (3x10 mL), dried (NA2SO4) and concentrated in vacuo The crude residue was subjected to preparative HPLC purification, followed by lyophilization of the fractions to afford (S) -2- ( 4- (4-chlorobenzyloxy) -3- (( 3- (4-methylphenyl sulfonylamino) -2-oxoazocan-1-yl) methyl) phenyl) acetic as a colorless solid, (40 mg, 0.068 mmol, 40%); 1H-NMR (300 MHz, d6-DMSO) 12.3 (br s, 1H), 7.85 (d, 1H), 7.7 (d, 2 H), 7.45 (s, 4 H), 7 1.3 (d, 2 H), 7.0 (m, 2 H), 5.1 (s, 2 H), 4.5 (d, 1 H), 4.4 (m, 1 H), 4 , 2 (d, 1H), 3.55 (m, 2 H), 3.1 - 3.0 (m, 1 H), 2.3 (s, 3 Η), 1.5 - 1.0 ( m, 8H).

Example 111

(R, Z) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) phenyl) methyl acetate (Compound 111) and

(R, Z) —2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo -3,4,7,8-tetrahydroazocin-1 (2H) -yl acid) ) methyl) phenyl) acetic (Compound 111).

The title materials were obtained using the method described for (R, Z) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7) , 8-Tetrahydroazocin-1 (2H) -yl) methyl) phenyl) acetic) from (R) -2- (tert-butoxycarbonylamino) pent-4-enoic acid.

Compound 111B: 1H NMR (300 MHz, CDCl3): 12.2 (br s, 1H), 7.9 (d, 1 H), 7.7 (d, 2 H), 7.45 (s, 4H) , 7.3 (d, 2 H), 7.1 (dd, 1H), 6.95 (d, 1 H), 6.85 (d, 1 H), 5.5 (m, 1 H), 5.1 (s, 2 H), 4.5 - 4.4 (m, 1 H), 4.35 (d, 1 H), 4.1 (d, 1 H), 3.55 (m, 2 H), 3.4 (s, 2 H), 3.2 - 3.1 (m, 1 H), 2.3 (m, 6H).

Example 112: methyl (R) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetate (Compound 112A), and

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 112 B).

The title material was obtained using the Method described for (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxazocan-1-yl) methyl) phenyl acid ) acetic from (R) -2- (tert-butoxycarbonylamino) pent-4-enoic acid.

Compound 112 B: 1H NMR (300 MHz5 d6-DMSO) 12.3 (br s, 1 H), 7.85 (d, 1 H), 7.7 (d, 2H), 7.45 (s, 4 H), 7.3 (d, 2 H), 7.0 (m, 2 H), 5.1 (s, 2 H), 4.5 (d, 1 H), 4.4 (m, 1 H), 4.2 (d, 1 H), 3.55 (m, 2 H), 3.1 - 3.0 (m, 1 H), 2.3 (s, 3 H), 1.5 - 1.0 (m, 8H).

Example 113

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl acetic acid (Compound 113A) and (S) - 2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic (Compound 113B).

<formula> formula see original document page 144 </formula>

(S) -2- (tert-Butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5- (2-methoxy) -2-oxoethyl) benzylamino) hexanoic acid (Compound 113A)

<formula> formula see original document page 144 </formula>

To a solution of methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate (250 mg, 0.78 mmol) in methanol (3 mL) was added Boc-Lysine (386 g, 1.57 mmol). ). The mixture was stirred for 20 minutes. In a separate vial, zinc chloride (400 μL, 1 Μ) was added to 3 ml of methanol, followed by sodium cyanoborohydride (50.2 mg, 0.78 mmol) carefully added in a single portion as that the mixture went into effervescence. The mixture was allowed to stir for 10 minutes, and then the total was added by cannula to the flask containing the stirred solution of methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate and Boc-L -Lysine. The reaction was stirred for 10 minutes, then suddenly cooled with brine (5 mL), extracted with EtOAc (3x15 mL), dried (NA 2 SO 4), and concentrated in vacuo. The crude residue was passed through a silica buffer (CH 2 Cl 2 / MeOH, 10% -20%) to provide (S -2- (tert-butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) acid ) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic as a colorless oil (250 mg, 0.45 mmol, 58%) LC / MS (Ambient Temp = 2.5105 min, (Method A ), m / ζ 549, M + Η).

Stage Β:

(S) -methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxoazepan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 113B)

<formula> formula see original document page 145 </formula>

To a solution of (S) -2- (tert-Butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic acid (250 mg, 0.45 mmol ) and triethylamine (0.2 ml, 1.3 mmol) in DM (25 ml) were added HOBT (73.7 mg, 0.55 mml) and 1- [3- (dimethylamino) propoyl] -3- ethylcarbodiimide (104 mg, 0.546 mmol). The solution was then stirred for 18 hours, and then concentrated in vacuo. The residue was passed through a silica buffer (EtOAc) to afford 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxozepan-1-yl) methyl) -4- (4- (S) -methyl chlorobenzyloxy) phenyl) acetate as a colorless oil (150 mg, 0.28 mmol, 62%). LC / MS Temp. Amb. = 4.23 minutes, (Method A), MSm / z 531 Μ + Η).

Stage C:

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid (Compound 113 C)

<formula> formula see original document page 146 </formula>

To a solution of (S) -methyl 2- (3 - ((3-tert-butoxycarbonylamino) -2-oxoazepan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (150 mg, 0 28 mmol) in CH 2 Cl 2 (2 mL) was added TFA (1 mL). The solution was then stirred for 1 hour, then neutralized (saturated NaHCO 3), extracted with CH 2 Cl 2 (2 x 10 mL), dried (Na 2 SO 4) and concentrated in vacuo.The residue was dissolved in pyridine (1.5 mL) to which was dissolved. p-toluene sulfonyl chloride (50 mg, 0.27 mmol) was added. The solution was stirred for 18 hours and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H 2 O (2 mL) to which was added. LiOH (55 mg, 1.36 mmol) The solution was vigorously stirred for 24 hours, then acidified with HCl (2 M), extracted with EtOAc (3 x 10 mL), dried (NA2SO4) and concentrated in vacuo. The crude protein was subjected to preparative hPLC purification, followed by lyophilization of the fractions to provide (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2) acid. - oxoazepan-1-yl) methyl) phenyl) acetic as a colorless solid, (20 mg, 0.035 mmol, 12.5%) 1 H NMR (300 MHz, (16-DMSO): 7.7 (d, 2 H ), 7.55 (d, 1H), 7.35 (d, 2 H), 7.2 ( t, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 6.85 (d, 1H), 4.6 (d, 1H), 4.25 (d, 1 H), 4.1 (m, 1 H), 3.5 (s, 2 H), 3.4 - 3.3 (m, 1 H), 3.2 - 3, 1 (m, 1 H ), 2.4 (s, 3 Η), 1.7-1.4 (m, 5 Η), 1, 3 - 1.0 (m, 1 Η).

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid

(Compound 113 B).

The title material was obtained by using Boc-R-lysine following the Method described for (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-acid) - oxoazepan-1-yl) methyl) phenyl) acetic.

1H-NMR (300 MHz, d6-DMSO) 7.7 (d, 2 H), 7.55 (d, 1 H), 7.35 (d, 2 H), 7.2 (t, 1H), 7 , 15 (d, 1H), 7.05 (s, 1 H), 6.85 (d, 1 H), 4.6 (d, 1 H), 4.25 (d, 1 H), 4, 1 (m, 1 H), 3.5 (s, 2 H), 3.4 - 3.3 (m, 1 H), 3.2 - 3, 1 (m, 1 H), 2.4 ( s, 3 H), 1.7-1.4 (m, 5H), 1.3-1.0 (m, 1 H).

Example 114

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid (Compound 114A) and

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid (Compound 114B)

<formula> formula see original document page 148 </formula>

Stage A

(S) -methyl 2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopinOlidin-1-yl) methyl) phenyl) acetate (Compound 114 A)

<formula> formula see original document page 148 </formula>

A mixture of (S) -tert-2- (3- (bromomethyl) -4- (4-chlorobenzyloxy) phenyl) methyl acetate (0.7 g, 1.82 mmol), 2-oxopyrrolidin-3-ylcarbamate butyl (439 mg, 2.19 mmol) and CS 2 CO 3 (1.92 g, 5.97 mmol) in CH 3 CN (3 mL) and DMF (1 mL) was heated at 55 ° C for 12 hours.

The reaction was diluted with H 2 O (20 mL) and extracted with EtOAc (3 x 5 mL), dried (NA 2 SO 4) and concentrated in vacuo. A solution of the residue in CH 2 Cl 2 (4 mL) was treated with TFA (4 mL) and then stirred for 30 minutes, and then concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (4 mL), to which was added triethylamine (228 μΐ, 1.64 mmol) and p-toluene sulfonyl chloride (117 mg, 0.61 mmol). The reaction was stirred for 12 hours and diluted with H2 O (20 mL) and extracted with CH2Cl2 (2 x 10 mL). Column chromatography (silica gel, (1: 1) EtOAc / hexane) provided 2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl (S) -methyl) phenyl acetate as a colorless oil (191 mg, 0.34 mmol, 15%). 1H-NMR (300 MHz, CDCl3): 7.8 (d, 2 H), 7.4 - 7.4 (m, 6H), 7.15 (dd, 1 H), 7.05 (m, 1 H ), 6.85 (d, 1 H), 5.2 (s, 1H), 5.0 (s, 2 H), 4.5 (m, 2 H), 3.7 - 3.6 (m , 4 H), 3.3 - 3.1, (m, 2 H), 2.6-2 2.5, (m, 1H), 2.4 (s, 3 H), 2.0 (m, 1H) .

Stage B:

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid (114 B)

<formula> formula see original document page 149 </formula>

To a solution of (S) -methyl 2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetate (190 mg, 0.34 mmol) in THF (1 mL) was LiOH (1.0 mL, 1%). The reaction was stirred for 12 hours and the THF was removed under vacuum. To the remaining aqueous mixture, 5 mL of HCl (1 M) was added and the resulting precipitate was filtered off and washed with H 2 O (15 mL) to afford (S) -2- (4- (4- chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic as a colorless solid (130 mg, 0.24 mmol, 70%); 1H-NMR (300 MHz, d6-DMSO) 8.1, (d, 1H), 7.75 (d, 2 H), 7.5 - 7.4 (m, 4 H), 7.35 (d, 2 H), 7.1 (d, 1 H), 7.00 (m, 2 H), 5.1 (s, 2 H), 4.3 (δ, 2 Η), 4.0 (m, 1 Η), 3.4 (s, 2 Η), 3.0 (m, 2Η), 2.0 -1.9 (m, 1 Η), 1.5 -1.4 (m, 1Η).

(R) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid

(Compound 114A)

The title material was produced from (R) -tert-butyl 2-oxopyrrolidin-3-ylcarbamate by using the exposed method for (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic. 1 H NMR (300 MHz, d 6-DMSO) 8.1 (d, 1 H), 7.75 (d, 2H), 7.5 - 7.4 (m, 4 H), 7.35 (d, 2H ), 7.1 (d, 1 H), 7.00 (m, 2 H), 5.1 (s, 2 H), 4.3 (m, 2 H), 4.0 (m, 1 H ), 3.4 (s, 2 H), 3.0 (m, 2 H), 2.3 (s, 3 H), 2.0 - 1.9 (m, 1H), 1.5 - 1 .4 (m, 1H).

Example 115

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115A) and

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115 B)

Figure 12

<formula> formula see original document page 150 </formula> Stage A:

(S) -2- (tert-Butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) pentanoic acid (Compound 115AA).

<formula> formula see original document page 151 </formula>

Using a method similar to that described for the preparation of (S) -2- (tert-butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic acid with following reagents: 4- (4-chlorobenzyloxy) -3-formylphenyl) (422 mg, 1.32 mmol); Boc-L-Ornithine (461 mg, 1.98 mmol); zinc chloride (622 µl, 1 M); sodium cyanoborohydride (83.1 mg, 1.98 mmol); (S) -2- (tert-Butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) pentanoic acid as a colorless oil ( 680 mg, 1.27 mmol, 96%). LC / MS, Temp. Amb. = 2.613 minutes, (Method A), MS m / z 535 M + Η.

Stage B:

(S) -methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 115 AB)

<formula> formula see original document page 151 </formula>

Using a Method identical to that described for the preparation of (S) 2- (3- ((3- (tert-Butoxycarbonylamino) -2-oxoazepan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate methyl with the following reagents:

(S) -2- (tert-Butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) pentanoic acid 800 mg, 1.49 mmol); triethylamine (0.62 ml, 4.48 mmol); HOBT (242 mg, 1.79 mmL); 1- [3- (dimethylamino) propoyl] -3-ethyl carbodiimide hydrochloride (344 mg, 1.79 mmol); (S) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (380 mg, 0.74 mmol, 50%). LC / MS, Temp. Amb. = 4.081 minutes (Method A), MS m / z 517 M + H.

Stage C:

(S) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115 B)

<formula> formula see original document page 152 </formula>

Using a Method identical to that described for the preparation of (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acid acetic acid: (S) -methyl 2- (3 - ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (742 mg, 1, 43 mmol); TFA (5 ml); p-toluene sulfonyl chloride (330 mg, 1.57 mmol); LiOH (92 mg, 4 mmol). Column chromatography (silica gel, Ο- 100% EtOAc / hexane) was provided (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidine) 1-yl) methyl) phenyl acetic as a colorless solid (400 mg, 0.7 mmol, 49%); 1H NMR (300 MHz, d6-DMSO): 12.2 (Brs, 1 Η), 7.85 (d, 1 Η), 7.75 (d, 2 Η), 7.5-7.4 (m, 4 Η), 7.35 (d, 1 Η), 7.11 (dd, 1 Η) , 7.00 (d, 1 Η), 7.05 (d, 1 Η), 5, 1 (s, 2 Η), 4.55 (d, 1 Η), 4.35 (d, 1 Η) , 3, 8 (m, 3), 3, 1 (m, 1), 2.4 (s, 3), 1.9 - 1.7 (m, 3).

(R) -2- (4- (4-Chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115 B)

<formula> formula see original document page 153 </formula>

The title material was obtained using the chemistry exposed for (S) -2- (4- (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl acid ) acetic from Boc-D-ornithine. 1H-NMR (300 MHz, d6-DMSO); 12.2 (brs, 1 H), 7.85 (d, 1 H), 7.75 (d, 2 H), 7.5 - 7.4, (m, 4H), 7.35 (d, 1 H), 7.11 (dd, 1 H), 7.00 (d, 1 H), 7.05 (d, 1 H), 5.1 (s, 2 H), 4.55 (d, 1 H), 4.35 (d, 1H), 4.35 (d, 1H), 3.8 (m, 1H), 3.1 (m, 1H), 2.4 (s, 3H) ), 1.9-1.7 (m, 3 H).

Example 116

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 116 A) and 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic (Compound 116B) <formula> formula see original document page 154 </formula>

The title compound (s) were obtained using 1-chloromethyl-4-chlorobenzene and 4-methylphenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic. Compound 116 B: LC / MS, Temp. Amb. = 2.77 minutes (Method A); MS (m / z) 529.26 (M + + H).

Example 117

{4- (4-Chloro-benzyloxy) -3,5-bis- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetate (Compound 117A) and {4- (4- Chloro-benzyloxy) -3,5-bis- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic

(Compound 117 B).

The title compound (s) were obtained using 1-chloromethyl-4-chlorobenzene and 4-methylphenyl sulfonyl chloride using the Method described for 2- (4) acid. - (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

<formula> formula see original document page 154 </formula>

Compound 117 Β: M + H: 782. Example 118

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 118 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 118B)

<formula> formula see original document page 155 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3 acid - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 118 B: LC / MS, Temp. Amb. = 2.73 (Method A); MS (m / z) 515.21 (M + + H).

Example 119

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 119A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 119B) <formula> formula see original document page 156 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 4-fluoro phenyl sulfonyl chloride using the Method described for 2- (4- ( isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 119B: LC / MS, Temp. Amb. = 2.73 minutes.

(Method A); MS (m / z) 533.23 (M + + H).

Example 120

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-chlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 120 A), and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-chlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic

(Compound 120 B).

<formula> formula see original document page 156 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 4-chloro phenyl sulfonyl chloride using the Method described for 2- (4- ( isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 120 B: Temp. Amb. = 2.85 minutes (Method A); MA (m / z) 549.21 (M + H).

Example 121

Methyl 2- (3- ((4- (4-bromophenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 121 A) and

2- (3- ((4- (4-Bromophenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid

(Compound 121 B).

<formula> formula see original document page 157 </formula>

The title compound (s) were obtained using 1-chloromethyl-4-chlorobenzene and 4-bromo phenyl sulfonyl chloride using the method described for 2- (4- isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 120B: LC / MS, Temp. Amb. = 2.83 minutes (Method A); MS (m / z) 595 (δ + H).

Example 122

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-thiophen-2-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 122 A) and 2- (4- (4-chlorobenzyloxy) -3 - ((4- (thiophen-2-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 122B)

<formula> formula see original document page 158 </formula>

1-Chloromethyl 4-chlorobenzene and 2-thiophene sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

122 B: LC / MS, Temp. Amb. = 2.73 minutes

(Method A); MS (m / z) 521.16 (M + + H).

Example 123

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-thiophen-3-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 123 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (thiophen-3-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 123B)

<formula> formula see original document page 158 </formula>

The title compound (s) were obtained using <formula> formula see original document page 159 </formula>

The title compound (s) was (were) obtained using

1-chloromethyl 4-chlorobenzene and 3-thiophene sulfonyl chloride, using the Method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid.

Compound 123 B: LC / MS, Temp. Amb. = 2.73 minutes (Method A); MS (m / z) 521.15 (M + + H).

Example 124

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-nitrophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 124 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-nitrophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 124B)

<formula> formula see original document page 159 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and 4-nitrophenyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) acid -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 124 B: LC / MS, Temp. Amb. = 2.92 minutes (Method A); MS (m / z) 561.0 (M + + H).

Example 125

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-methylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 125 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4- (4-methylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 125B)

<formula> formula see original document page 160 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and methyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3 acid - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 125 B: LC / MS, Temp. Amb. = 2.50 minutes (Method A); MS (m / z) 453.21 (M + + H).

Example 126

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((isopropylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 126 A) and 2- (4- (4-chlorobenzyloxy) -3 - ((4- (isopropylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 126B)

<formula> formula see original document page 161 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and isopropyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3 acid - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 126 B: LC / MS, Temp. Amb. = 2.62 minutes

(Method A); MS (m / z) 481.24 (M + + H).

Example 127

Methyl 2- (3- (4-butylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 127 A) and

2- (3 - ((4-Butylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid

(Compound 127B) <formula> formula see original document page 162 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and butyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -acetamide. 3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 127 B: LC / MS, Temp. Amb. = 2.69 minutes (Method A); MS (m / z) 495.24 (M + + H).

Example 128

Methyl 2- (4- (4-methoxybenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate

(Compound 128 A) and

2- (4 - ((4-Methoxybenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 128B)

<formula> formula see original document page 162 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and butyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -acetamide. 3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 128 B: LC / MS, Temp. Amb. = 2.69 minutes (Method A); MS (m / z) 525.30 (M + + H).

Example 129

Methyl 2- (4- (4-methoxybenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate

(Compound 129 A) and

2- (4 - ((4-methoxybenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 129B)

<formula> formula see original document page 163 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorobenzene and butyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -acetamide. 3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 129 B: LC / MS, Temp. Amb. = 2.85 minutes (Method A); MS (m / z) 509.31 (M + + H).

Example 130

Methyl 2- (4- (4-benzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate

(Compound 130 A) and

2- (4 - ((4-benzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 130B)

<formula> formula see original document page 164 </formula>

The title compound (s) were obtained using benzyl bromide and butyl sulfonyl chloride using the Method described for 2- (4- (isopentyloxy) -3- ( (4-tosylpiperazin-1-yl) methyl) phenyl) acetic.

Compound 130 B: LC / MS, Temp. Amb. = 2.81 minutes (Method A); MS (m / z) 495.32 (M + + H).

Example 131

Methyl 2- (3 - ((4- (benzylcarbamoyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 131 A) and

2- (3 - ((4- (benzylcarbamoyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid

(Compound 131 B).

<formula> formula see original document page 164 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and benzyl isocyanate using the Method described for 2- (4- (isopentyloxy) -3 acid - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic.

Compound 131 B: LC / MS, Temp. Amb. = 2.67 minutes (Method A); MS (m / z) 508.2 (M + + H).

Example 132

Methyl 2- (3 - ((4- (benzylpiperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 132 A) and

2- (3 - ((4- (benzylpiperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid

(Compound 132 B).

<formula> formula see original document page 165 </formula>

The title compound (s) was (were) obtained by the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4- (tosylpiperazin-1-yl ) methyl) phenyl) acetic from N-benzyl piperazine.

Compound 132 B: LC / MS, Temp. Amb. = 2.70 minutes (Method A); MS (m / z) 465.2 (M + + H).

Example 133

Methyl 2- (3 - ((4- (benzoylpiperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 133 A) and

2- (3 - ((4- (Benzoylpiperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 133 B).

<formula> formula see original document page 166 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and benzoyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic.

Compound 133 B: Temp. Amb. = 2.54 minutes (Method A); MS (m / z) 479.28 (M + + H).

Example 134

Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate

(Compound 134 A) and

2- (4 - (- 4- (4-chlorobenzyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 134 B).

<formula> formula see original document page 166 </formula> The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and phenyl isocinate using the Method described for 2- (4- (isopentyloxy) -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid.

Compound 134 B: Temp. Amb. = 2.58 minutes (Method A);

MS (m / z) 494.17 (M + + H).

Example 135

Methyl 2- (3 - ((4- (benzyloxycarbonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate

(Compound 135 A) and

<formula> formula see original document page 167 </formula>

2- (3 - ((4- (benzyloxycarbonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid

(Compound 135 B).

<formula> formula see original document page 167 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and benzyloxy chloroformate using the Method described for 2- (4- (isopentyloxy) -3- ( (4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic.

135 B: Temp. Amb. = 2.81 minutes (Method A);

MS (m / z) 509.16 (M + + H).

Example 136

Methyl 2- (4- (4- (chlorobenzyloxy) -3 - ((4- (2-phenylacetyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 136 A)

2- (4- (4- (chlorobenzyloxy) -3 - ((4- (2-phenylacetyl) piperazin-1-yl) methyl) phenyl) acetic acid

(Compound 136 B).

<formula> formula see original document page 168 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and 2-phenyl acetyl chloride using the Method described for 2- (4- (isopentyloxy) acid -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic.

136 B: Temp. Amb. = 2.62 minutes (Method A); MS (m / z) 493.15 (M + + H).

Example 137

{4- (4-Chloro-benzyloxy) -3- [4- (2-hydroxy-2-phenyl-acetyl) -piperazin-1-ylmethyl] -phenyl} -acetate (Compound 137A) and {4- (4-Chloro-benzyloxy) -3- [4- (2-hydroxy-2-phenyl-acetyl) -piperazin-1-ylmethyl] -phenyl} -acetic (Compound 137B)

<formula> formula see original document page 168 </formula>

The title compound (s) were obtained using 1-chloromethyl 4-chlorophenyl and 2-phenyl acetyl chloride using the Method described for 2- (4- (isopentyloxy) acid -3 - ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic.

Compound 137 B: MS (m / z) 509 (M + H).

Example 138

2- (4- (4-chlorobenzyloxy) -3 - ((2-oxo-4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 138D)

Figure 13

<formula> formula see original document page 169 </formula>

Stage A: Methyl 2- (3-formyl-4-hydroxyphenyl) acetate

A solution of methyl 2- (4-hydroxyphenyl) acetate (10 g, 60.2 mml) in TFA (50 mL) was refluxed with hexamethylene tetramine (8.44 g, 60.2 mmol) overnight; The solution was concentrated to remove excess TFA. The residue was suspended in H 2 O (50 mL), after being made alkaline with NA 2 CO 3, the mixture was extracted with EtAc (3 x 100 mL). The extract was washed with 1 N HCl (3 x 20 ml). The combined organic layers were dried with NA 2 SO 4. The product was used without further purification.

Stage B: Methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate

To the above crude aldehyde (549 mg, 2.83 mmol) in CH 3 CN (15 mL) was added 1-chloro methyl-4- (chlorobenzene) (500 mg, 3.44 mmol) and K 2 CO 3 (781 mg, 5.66 mmol) ). The reaction was heated at 85 ° C overnight. The solid was filtered through CELITE. The product was used without further purification. LC / MS, Temp. Amb. = 4.01 minutes (Method A); MS (m / z) 341.1 (M + 23).

Stage C: 2- (3- (Bromomethyl) -4- (4-chlorobenzyloxy) phenyl) methyl acetate (Compound 138 C)

To methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate (901 mg, 2.83 mmol) in MeOH (10 mL) was added NaBH4 (537 mg, 14.16 mmol) at 0 ° C. . The reaction was performed at room temperature overnight. H 2 O was added in order to suddenly cool the reaction, which was extracted with EtOAc (3 x 20 ml). The product was obtained after flash chromatography on silica gel. LC / MS, Temp. Amb. = 3.70 minutes.

(Method A); MS (m / z) 343.1 (M + + 23).

To alcohol (241 mg, 0.75 mmol) in CH 3 CN (10 mL) was added MMSCI (0.288 mL, 1.88 mmol) and LiBR (131 mg, 1.50 mmol). The solution was heated at 85 ° C overnight. The product (173 mg, 60%) was obtained after flash silica gel chromatography. LC / MS, Temp. Amb. = 3.69 minutes. (Method A); MS QAJ z) 384.1 (M + H).

Stage D: 2- (4- (4-Chlorobenzyloxy) -3 - ((2-oxo-4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid

(Compound 138D)

<formula> formula see original document page 170 </formula> Methyl 2- (3- (bromomethyl) -4- (4-chlorobenzyloxy) phenyl) acetate (92.7 mg, 0.24 mmol) in CH3CN (5 ml) were added 4-tosylpiperazin-2-one (92.2 mg, 0.36 mmol) and Cs2O3 (118 mg, 0.36 mmol). The reaction was heated at 85 ° C overnight. The solid was filtered through CELITE. The product was collected by silica gel scintillation chromatography. MS (m / z) 557.1 (M + + 23).

To this product (16.2 mg, 0.03 mmol) in THF (1 mL) was added 1 N LiOH (1 mL). The reaction was monitored by TLC until the starting material was consumed. It was diluted with EtOAc (10 mL), washed with 1 N HCl (3 x 5 mL). The organic layer was dried with NA 2 SO 4, and concentrated to provide the desired product (10.4 mg, 64%). MS (m / z) 543.1 (M + + H).

Example 139

Methyl 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholinomethyl) phenyl) acetate (Compound 139A) and 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholinomethyl) phenyl) acetic acid (Compound 139B) .

<formula> formula see original document page 171 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from thiomorpholine. Compound 139B: LC / MS, Temp. Amb. = 2.52 minutes (Method A); MS (m / z) 392.1 (M + + H).

Example 140 Methyl 2- (4- (4-chlorobenzyloxy) -3 - ((4-hydroxypiperidin-1-yl) methyl) phenyl) acetate

(Compound 140 A) and

2- (4- (4-chlorobenzyloxy) -3 - ((4-hydroxypiperidin-1-yl) methyl) phenyl) acetic acid

(Compound 140B)

<formula> formula see original document page 172 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from 4-hydroxy piperidine. Compound 140 B: LC / MS, Temp. Amb. = 2.38 minutes (Method A); MS (m / z) 390.1 (M + + H).

Example 141

Methyl 2- (4- (4-chlorobenzyloxy) -3- (morpholinomethyl) phenyl) acetate (Compound 141A) and

2- (4- (4-chlorobenzyloxy) -3- (morpholinomethyl) phenyl) acetic acid (Compound 141B) <formula> formula see original document page 173 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from morpholine. Compound 141 B: LC / MS, Temp. Amb. = 2.42 minutes (Method A); MS (m / z) 376.1 (M + + H).

Example 142

Methyl 2- (4- (4-chlorobenzyloxy) -3- (piperidin-1-ylmethyl) phenyl) acetate (Compound 142A) and

2- (4- (4-chlorobenzyloxy) -3- (piperidin-1-ylmethyl) phenyl) acetic acid (Compound 142B)

<formula> formula see original document page 173 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from piperidine. Compound 142 B: LC / MS, Temp. Amb. = 2.53 minutes (Method A); MS (m / z) 374.1 (M + +).

Example 143

Methyl 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholine-1-oxidomethyl) phenyl) acetate (Compound 143A) and

2- (4- (4-Elorobenzyloxy) -3- (thiomorpholine-1-oxidomethyl) phenyl) acetylic acid (Compound 143B)

<formula> formula see original document page 174 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from S-oxothiomorpholine. Compound 143 B: LC / MS, Temp. Amb. = 2.39 minutes (Method A); MS (m / z) 408.09 (M + + H).

Example 144

Methyl 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholine-1,1'-dioxomethyl) phenyl) acetate (Compound 144A) and

2- (4- (4-chlorobenzyloxy) -3- (thiomorpholine-1,1'-dioxomethyl) phenyl) acetic acid (Compound 144B) <formula> formula see original document page 175 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from S, S-dioxothiomorpholine. Compound 144 B: LC / MS, Temp. Amb. = 3.05 minutes (Method A); MS (m / z) 424.31 (M + + H).

Example 148

Methyl 2- (4- (4-fluorobenzyloxy) -3- (thiomorpholine-1,1'-dioxidomethyl) phenyl) acetate (Compound 145A) and

2- (4- (4-Fluorobenzyloxy) -3- (thiomorpholine-1,1'-dioxymethyl) phenyl) acetic acid (Compound 145B)

<formula> formula see original document page 175 </formula>

The title compound (s) were obtained using the same experimental method as described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) acid methyl) phenyl) acetic from S, S-dioxothiomorpholine and 1-bromomethyl-4-fluorobenzene. Compound 145 B: LC / MS, Temp. Amb. = 2.90 minutes (Method A); MS (m / z) 408.1 (M + + H).

Example 146

(11R) (11S) -2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl] acetic acid

[Compound 146D and E)

Scheme 14

<formula> formula see original document page 176 </formula>

Stage A: 2 - ((4- (carboxymethyl) phenoxy) methyl) benzoic acid (Compound 146A)

<formula> formula see original document page 176 </formula>

K 2 CO 3 (14.3 g, 104 mmol), NaI (390 mg, 2.6 mmol) and ethyl 2- (bromomethyl) benzoate (6.3 g, 26 mmol) were added to a stirred solution of phenyl 4-hydroxy. methyl acetate (4.3 g, 26 mmol) in 2-propanone (100 mL). The resulting mixture was redissolved in EtOH / H 2 O (10: 1, 150 mL) and solid KOH (14 g, 260 mmol) was added, followed by refluxing overnight. After concentration, the residue was dissolved in H 2 O (100 mL) and the aqueous layer was washed with ether (100 mL) and acidified with concentrated HCl (1 <pH). Filtration provided a crude acid (9.8 g), which was used in a subsequent reaction without further purification.

Stage B: Methyl 2- (11-oxo-6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate (Compound 146B) -Error in labeling

<formula> formula see original document page 177 </formula>

Polyphosphoric acid (50 g) was added to a stirred solution of 2 - ((4-carboxymethyl) phenoxy) methyl) benzoic acid (9.8 g) in acetic acid (17 ml) at 90 ° C. After stirring for 5 hours, the resulting mixture was cooled, and H 2 O (150 mL) was added. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried with Na 2 SO 4 and concentrated. The residue was redissolved in MeOH (150 mL) and HCl (g) was bubbled through for 5 minutes. The resulting solution was stirred overnight, and concentrated to provide a crude ester. Flash silica gel flash chromatography (3: 1, hexanes / EtOAc) provided the desired material.

Stage C: methyl 2- (1,1-chloro-6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate

(Compound 146C) <formula> formula see original document page 178 </formula>

NaBH 4 (430 mg, 11.3 mmol) was added to a stirred solution of methyl 2- (11-oxo-6,11-dihydrobenzeo [b, e] oxepin-2-yl) acetate (800mg, 2.83 mmol ) in MeOH (20 ml). After stirring for 5 minutes, the reaction mixture was suddenly cooled with saturated NaHCOs and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried with NA 2 SO 4 and concentrated. The residue was redissolved in CH 2 Cl 2 (20 mL) and SOCl 2 (1.0 3 mL, 14, 15 mmol) was added. After stirring for 1 hour, the reaction mixture was concentrated to provide crude material which was used in the subsequent reaction without further purification.

Stage D:

(11R) (11S) -2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid

(Compound 146D / 146E)

<formula> formula see original document page 178 </formula>

DIEA (1.1 ml, 6.35 mmol) and 1-tosyl piperazine (607 mg, 2.5 mmol) were added to a stirred solution of 2- (11-chloro-6,11-dihydrobenz [b, e] oxepin-2-yl) methyl acetate (640 mg, 2.11 mmol) in CH 2 Cl 2 (20 mL). The reaction mixture was suddenly cooled with saturated NaHCO 3 (20 mL) after stirring overnight, and the aqueous layer was extracted with CH 2 Cl 2 (3 x 15 mL). The combined organic layers were dried with NA2SCO4 and concentrated. The residue was redissolved in THF / MeOHZH 2 O (3: 1: 1.15 mL) and LiOH (621 mg, 14.8 mmol) was added. The aqueous layer was extracted with EtOAc (3 x 20 mL), dried with NA2SÜ4 and concentrated to afford crude acid (411 mg) as a pale yellow oil. Purification by HPLC provided pure title material. Both enantiomers (146a / 146B) were also separated by chiral HPLC: ES / MS, m / z 493.2 (Μ + H); LC / MS (Method B) Temp. Amb. = 3.602 minutes. Chiral LC (Chiralpak OD - H, 4.6 x 250 mm, 80% Hexanes: 20% IPA, 40 ° C, 1.0 ml / min). 146 A, Temp. Amb. = 12, 148 minutes, 146 B, Temp. Amb. = 25.056 minutes.

Example 147

Methyl 2- (1- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate (Compound 147 A) and

2- (1- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic

(Compound 147B)

<formula> formula see original document page 179 </formula>

The title material was obtained by using the method written for 2- 911- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid using 4-fluoro phenyl sulfonyl piperazine: Compound 147 B: 1H NMR (400 MHz, DMSO-Cl6) δ 12.24 (1 H, brs), 7.75 (2 H, dd, J = 5.5, 7.87 Hz), 7.46 (2H, t, J = 8.8 Hz), 7.32 (4H, m), 7.06 (2 H, d, J = 8.0 Hz), 6.66 (1 H, d , J = 7.9 Hz), 6.37 (1H, d, J = 11.5 Hz), 4.65 (1H, d, J = 11.5 Hz), 4.03 (1H, s) 3.45 (2H, s) 2.83 (4H, brs), 2.36 (4H, m); ES / MS, m / z, 497.2 (Μ + Η): LC / MS (Method Β), Temp. Amb. = 3.560 minutes. Example 148

Methyl 2- (9-chloro-11- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate,

(Compound 148A), and

2- (9-chloro-11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid,

(Compound 148B)

<formula> formula see original document page 180 </formula>

The title material was obtained using the Method described for 2- (1- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid using 4 methyl phenyl sulfnyl piperazine and 5-chloro-2- (bromoethyl) benzoate. Compound 148B: ES / MS 527.1 (M + H); LC / MS (Method B), Temp. Amb. = 4.105 minutes.

Example 149

Methyl 2- (9-chloro-11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate (Compound 149 A) and

2- (9-chloro-11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid,

(Compound 149 B) <formula> formula see original document page 181 </formula>

The title material was obtained using the Method described for 2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid using 4- phenylsulfoyl piperazine and 5-chloro-2- (bromomethyl) benzoate. 149B: ES / MS 531.1 (M + H); LC / MS (Method B), Temp. Amb. = 4.105 minutes.

Example 150

Methyl 2- (11- (2-oxo-4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetate (Compound 150 A) and

2- (11- (2-oxo-4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid,

(Compound 150 B)

<formula> formula see original document page 181 </formula>

The title material was obtained using the Method described for 2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid using 4- tosyl piperazine-2-one and 2- (bromomethyl) benzoate. Compound 150B: ES / MS 507.2 (M + H); LC / MS (Method B), Temp. Amb. = 3.52 minutes.

Pharmacological Data

Receiver Interaction Test

Cell Culture Human Jurkat cells transfected with DP 2, DP 1 or TP receptors were cultured in a humidified atmosphere at 37 ° C (5% CO2) in RPMI 1640 medium (Gibco®, Invitrogen, USA) with 0% fetal bovine serum (Hyclone, Logan, UT, USA) plus penicillin streptomycin (Gibco®), L Glutamine (Gibco®), sodium pyruvate and 100 ml of G418. Cells were grown in T225 flasks (Corning®) and collected by centrifugation. Cell pellets were coelt from approximately 200 ml of cell suspension, pelleted by centrifugation, and stored at 20 ° C until processed as membanas.

Cell membrane preparation:

Frozen Jurkat cell pellets expressing either DP-2, DP-1 or TP were thawed on ice. Each pellet was suspended in a membrane buffer (25 mM Hepes®, pH 7.2, MgC12 pH 7.2, 1 mM EDTA), as well as Complete® protease inhibitor cocktail foods (Roche Mannheim Germany). The pellets were homogenized in a Dounce and centrifuged at 1900 for 10 minutes in a table top centrifuge (Beckamn Coulter Allegra ™ 6R). Supernatants were collected and the pellets resuspended in 20 ml membrane buffer, again placed in a Dounce, and centrifuge as above. The supernatants were placed in reservoirs and centrifuged in a Beckman J2-21 M centrifuge using a JA2O rotor at 10,000 RPM for 1.5 hours at 4 ° C. The supernatants were discarded and the pellets were resuspended in a membrane buffer and placed in reservoirs. Protein concentration was determined and the membranes adjusted to approximately 1.5 mg / ml.

DP-2 Binding Assay:

Interactions of the compound with DP-2 receptors were determined by competitive radioligand binding assays using membranes prepared from cells expressing DP-2 (prepared as above and 3 [HJPGD2 (166Ci / mmol) as a radioactive tracer). Assays were performed in a final volume of 150 μΐ assay buffer (10 mM Hepes®, 10 mM MNCl2, 1 mM EDTA, and 1% DMSO) .The serially diluted test article in a assay buffer was incubated with a tracer 1 nM and 10 μg radioactive reservoir of membranes prepared from cells expressing DP-2 in a 96-well polypropylene plate for one hour at room temperature The reaction mixture was then transferred to a fiber filter plate Milipore (Bedford, MA) MUltiScreen® FC MAFCNOB The plate was vacuum aspirated and washed twice with 200 μl vacuum aspiration binding buffer between each wash. r and 50 μl of Optiphase "Super Mix" scintillation cocktail (Wallac Oy Trku, Finland) was added to each reservoir. The plate was counted in a Wallac ™ micro beta liquid scintillation counter (Wallac Oy Turku, Finland) 1450.

DP-2 Chemotaxis Assay

The ability of the compounds of the invention to antagonize DP-2 receptor function was examined in chemotaxis assays using DP-2 transfected Jurkat cells. Compounds were serially diluted in complete media containing 1 nM PGD2 as a chemoattractant, and 600 μl of this mixture was transferred to the bottom reservoirs of a Costar Transwell® plate (pore size 8 μm). DP-2 transfected Jurkat cells were collected, resuspended in 7.5 χ 10 ^ 6 ml complete media, and 100 μl of this cell suspension was added to the inside of pore filter inserts. After equilibrating all components at 37 ° C in a cell incubator for 15 minutes, chemotaxis was initiated by transferring the filter inserts over the bottom reservoirs. Following 2 hours incubation in a reservoir at 37 ° C, the filter inserts were removed, the cell media were collected from the lower reservoirs and transferred to FACS tubes. The cells in each sample were then enumerated in a FACScan using CellQuest software.

Selectivity Assay

DP-I binding assay

DP-I binding assays were performed in substantially the same manner as DP-2 binding assay except that DP-1 transfected cell membranes were used.

Human TP Binding Assay

TP receptor interaction was determined in competition binding assays by using transfected TP receptor cell membranes (prepared as above and 3 [H] SQ29.5488 (48, 2 μCΐ / mmol) as a selective tracer for Assays were performed in a final volume of 150 μl binding buffer, 10 mM Hepes, 10 mM MnCl2, 1 mM EDTA and 1% DMSO Duplicate samples of the serial diluted test compound were incubated with 10 µl. μg / TP membrane reservoir in the presence of 3 nM 3 [H] SQ 29. 548. Following one hour incubation at room temperature, the reaction mixture was transferred to a Milipore® fiberglass filter plate (Bedford, MA) MultiScreen®, FC MAFCNOB The mixture was vacuum aspirated and washed 2 times with 200 μl binding buffer with vacuum aspiration between each wash.After drying 50 μl of the scintillation cocktail Optiphase Super Mix® (Wallac Oy Turku, Finland), the cocktail of Scintillation was added to each reservoir and radioactivity was quantified on a Wallac® 1450 micro beta liquid scintillation counter (Wallac Oy Turku, Finland).

All acidic compounds of the Examples, which were tested in the assay, exhibited IC50 values below 15 μ, for example the acidic compounds of Examples 1, 2, 3, 4, 5, 7, 6, 8, 9, 10, 11. , 13, 27, 40, 41, 42, 43, 44, 45, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 69, 70, 71, 72, 73, 74 , 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 106, 109, 109, 107, 110, 113, 114, 115, 116 117, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137 and 140. In some embodiments, the acidic compounds of the invention exhibited IC 50 values of less than 10 μΜ, for example the acidic compounds of examples 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 27, 40, 41, 42, 43, 44, 45, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 69, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 106, 109, 107, 110, 113, 114, 115, 116, 117, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 133, 134, 135, 136, 138 and 140. In some In both embodiments, the acid compounds of the invention exhibited IC 50 values below 1 μ. In some embodiments, the compounds of the invention exhibited IC values of less than 0.1 μΜ.

All acidic compounds of the Examples which were tested in the ligand binding assays described above exhibited an average IC 50 value which was 2-fold lower for DP-2 than DP-I and TP, for example compounds acids of examples 1, 25, 26, 27, 40, 43, 44, 45, 55, 58, 62, 63, 95, 96, 97, 98, 99, 100, 103, 106, 107, 109, 110, 113 , 114, 115, 118, 119, 120, 123, 131, 134, 137, 141, 143 and 144. In some embodiments, the acidic compounds of the invention exhibited an average IC50 value that was at least 10 times lower for DP -2 with respect to DP-I and TP, for example the acidic compounds of examples 1, 25, 26, 27, 40, 43, 44, 45, 55, 58, 62, 63, 95, 96, 97, 98, 99, 100, 103, 106, 107, 109, 110, 113, 114, 115, 118, 119, 120,123, 131, 134, 137, 143 and 144. In some embodiments, the acidic compounds of the invention exhibited an average IC50 value, which was at least 50 times lower, for DP-2 compared to DP-I and TP, for example acidic compounds of 1.27, 58, 62, 63, 95, 96, 97, 98, 99, 100, 103, 106, 107, 110, 113, 114, 115, 118, 119, 120, 123, 131, 134, 137 , 143 and 144.

All publications and patent applications cited in the report are incorporated herein by reference as if each individual publication or patent application was specifically and individually intended to be incorporated by reference. While the foregoing invention has been described in detail by way of illustration and exemplary for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art, in light of the teachings of this invention, that certain alterations and modifications may be introduced into them without departing from the spirit and scope of the appended claims.

Claims (17)

A compound, characterized in that it has the structure (I): wherein: A is a 5-14 membered heterocyclic ring having 1-4 ring heteroatoms, each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being monocyclic or polycyclic, optionally substituted by 1-3 substituents R 8; L is selected from the group consisting of CR6R7, CO, CNR6 and CS; Q1 is selected from the group consisting of: a bond, C1-4 alkylene, C1-4 heteroalkylene, -CO-, -NH-, -O-, -SOq-, -C (O) O-, - OC (O) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -COH2HNSOq. R1, R2, R3, R6 and R7 are each independently selected from the group consisting of H, C1-6 alkyl, C0-6 alkylaryl and C0-6 alkyletheroaryl; wherein the aryl or heteroaryl moieties are optionally substituted by C1-6 alkyl, CN, OR, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqNR2, OC ( O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR; each R4 is independently selected from the group consisting of C1-6 alkyl, C0-4 alkyl-C3-10 cycloalkyl, C0-4 alkylaryl, C0-4 alkyletheroaryl, C2-4 alkenylaryl, C2-6 alkynylaryl 4, C0-4 alkyl heterocyclyl, CN, amino, NHCOR1, hydroxy, C1-6 alkoxy, OC (O) R1, -OC0-4alkylaryl, OC0-4alkylcycloalkyl C3.10, OC0-4alkylheterocyclyl C 3-10, OC 0-4 alkyl NR, nitro, halo, and C 1-6 haloalkyl; or are combined together with R 6 to form an aryl or heterocyclyl ring system having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the alkyl, aryl and heterocyclyl moieties are each optionally substituted by 1 to 3 substituents each independently selected from the group consisting of C1-6 alkyl, CN, CONHR1, CO2R1, amino, C1-6 alkoxy. 6, halo, C1-6 haloalkyl and SOqR1; R5 is selected from the group consisting of C1-6 alkyl, C0-4 alkylaryl, C2-4 alkenylaryl and C0.4 alkyletheroaryl each of which is optionally substituted by 1-3 R9 substituents; each R8 is independently selected from the group consisting of C1-6 alkyl, C0-6 alkylC3-6 cycloalkyl, C0-6 alkylaryl, Co-6 alkyletheroaryl, oxo, C1-6 alkyl, CN, OR, C1-6 haloalkyl 6, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, C (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2 , NRC (O) R and NRC (O) OR; each R9 is independently selected from the group consisting of C1-6 alkyl, CN, OR, oxo, C1-6 haloalkyl, C1-6 heteroalkyl, NR2, NO2, halo, C (O) R, CO2R, CONR2, SOqR, SOqNR2, OC (O) OR, OC (O) R, OC (O) NR2, NRC (O) NR2, NRC (O) R and NRC (O) OR; each R is independently selected from the group consisting of H, C1-6 alkyl, C0-4 alkyl heteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl or when bonded to the same nitrogen atom may be combined to form a 5-8 membered ring having 1-4 ring heteroatoms, each independently selected from the group consisting of nitrogen, oxygen and sulfur; the subscript η is independently O, 1,2, 3, or 4; each subscript q is independently O, 1 or 2; and pharmaceutically acceptable derivatives thereof. A compound according to claim 1, wherein A has the structure (II): wherein: Y is selected from the group consisting of a bond, CH 2, N, NO and SOq; R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring; the subscript ρ is independently O, 1 or 2; each dashed ring bond independently indicates the presence of a single, double or standard bond. the dotted line indicates the binding point of Q1 and the wavy line indicates the binding point of L. A compound according to claim 1, characterized in that it has the structure (III): wherein: Y is selected from the group consisting of a bond, CH 2, N, NO and SOq; R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1, 2 or 3; the subscript ρ is independently 0, 1 or 2; and each dashed ring bond independently indicates the presence of a single, double or standard bond. A compound according to claim 1, characterized in that it has structure (IV); <formula> formula see original document page 190 </formula> where: Y is selected from the group consisting of a bond, CH2, N, O, NO and SOq; R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1 2 or 3; the subscript ρ is independently 0, 1 or 2; and each dashed ring bond independently indicates the presence of a single, double or standard bond. Compound according to Claim 1, characterized in that it is selected from the group consisting of: [4- (4-Chloro-benzyloxy) -3-thiomorpholin-4-ylmethyl-phenyl] -acetic acid ; [4- (4-Chloro-benzyloxy) -3- (1,1-dioxo-116-thiomorpholin-4-ylmethyl) -phenyl] -acetic acid; [4- (4-Fluoro-benzyloxy-3- (1,1-dioxo-116-thiomorpholin-4-ylmethyl) -phenyl] -acetic acid; [4- (4-chloro-benzyloxy) -3-morpholin-acid 4-ylmethylphenyl] acetic acid [4- (4-chloro-benzyloxy) -3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -phenyl] -acetic acid; -chloro-benzyloxy) -3- [3-oxo-4- (4-trifluoromethyl-phenyl) piperazin-1-ylmethyl] -phenyl} -acetic acid [3- (4-benzyl-piperazin-1-ylmethyl) -acetate 4- (4-chloro-benzyloxy) -phenyl] -acetic Acid (4- (4-chloro-benzyloxy) -3- {4- [2- (4-methoxy-phenyl) -aeetyl] -piperazin-1-one {4- (4-Eloro-benzyloxy) -3- [4- (2-p-tolyl-aeetyl) -piperazin-1-ylmethyl] -phenyl} -aethyl acid; - (4-chloro-benzyloxy) -3- {4- [2- (4-chloro-phenyl) -acetyl] -piperazin-1-ylmethyl} -phenyl) -acetic acid; [3- (4-benzoyl-piperazin) -1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid {4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazin-1-methyl ester {4- (4-Chloro-benzyloxy) -3- [4- ( 2-hydroxy-2-phenyl-acetyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid tert-butyl ester; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) benzyl] -piperazine-1-carboxylic acid tert-butyl ester; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic ester; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic ester; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic ester; {4- (2,6-Difluoro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-2-fluoro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (2-Fluoro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; [3- (4-Benzenesulfonyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (4-fluoro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; [3- [4- (4-Chloro-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; {4- (4-Methoxy-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl acetic acid; {4- (4-Chloro-benzyloxy) -3,5-bis [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4-Cyclopentyloxy-3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {2- [4- (Toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4-Benzyloxy-3- [4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; (4-Cyclopropylmethoxy-3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] -phenyl} -acetic acid; {4-phenylethynyl-3- [4- (toluene-4-sulfonyl) - piperazin-1-ylmethyl] -phenyl} acetic acid {4-phenylethynyl-3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- {4- (4-methoxy-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (3,4-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; [3- [4- (2-chlorobenzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (toluene-3-sulfonyl) -piperazin-2-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (quinoline-8-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4-Phenethyl-3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4'-Methyl-2- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -biphenyl-4-yl} -acetic acid; {4'-Chloro-2- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -biphenyl-4-yl} -acetic acid; [3- [4- (Toluenesulfonyl) piperazinylmethyl] -4- (4-trifluoromethyl-benzyloxy) -phenyl] -acetic acid; {4- (4-Chlorobenzyloxy) -3- [4- (2,4-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Cyano-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4-Phenyloxy-3- {4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; [3- [4- (4-tert-Butyl-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (3,5-dimethyl-isoxazol-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-chlorobenzyloxy) -3- [4- (naphthalen-2-sulfonyl) -piperazin-1-ylmethyl] -phenyl} acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (pyridin-3-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; Acid. {4- (4-Chloro-benzyloxy-3- [4- (3,5-dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; (4- (4-Chloro-benzyloxy) -3-acid - [4- (4-ethyl-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid {4- (4-chloro-benzyloxy) -3- [4- (naphthalen-1-sulfonyl) -piperazin -1-ylmethyl] -phenyl} acetic acid [3- [4- (4-bromo-benzenesulfonyl) -piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; - (4-Methoxy-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid {4- (4-methyl-benzyloxy) -3- [4] - (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic acid {4-cyclohexylmethoxy-3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] -phenyl} - [4- (4-Chloro-benzyloxy) -3- (4-phenylmethanesulfonyl-piperazin-1-ylmethyl) -phenyl] -acetic acid; {4- (2,4-dichloro-benzyloxy) -3- [Acid] 4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] -phenyl} -acetic acid 4- {4-carboxymethyl-2- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenoxymethyl} benzoic acid; {4- (4-fluoro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4-thiophene-3-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (3,4-Dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] phenyl} -acetic acid; {4- (4-nitro-benzyloxy) -3- [4-toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (2-phenyl-etenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (4-chloro-3-trifluoromethyl-benzenesulfonyl) -piperazin-1-yl) ethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (2-phenyl-ethanesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (4-nitro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; and {4- (4-Chloro-benzyloxy) -3- [2-oxo-4- (toluene-4-sulfonyl) -piperazin-1-ylmethyl] -phenyl} -acetic acid; and (4-Hydroxy-3- {phenyl- [4-toluene-4-sulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid; (3- {(2-Hydroxy-phenyl) - [4- (toluene-4-sulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid; (3- {Phenyl- [4- (toluen-4-sulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid; (3 - {[4- (4-Fluoro-benzenesulfonyl) -piperazin-1-yl] -phenyl-methyl} -phenyl) -acetic acid; {3 - [(4-Benzenesulfonyl-piperazin-1-yl) -phenylmethyl] -, phenyl} -acetic acid; {3 - [(4-Methanesulfonyl-piperazin-1-yl) -phenylmethyl] -phenyl} -acetic acid; (3 - [(4-Benzenesulfonyl-piperazin-1-yl) -phenyl-methyl-5-chloro-phenyl} -acetic acid (3 - {(4-chloro-phenyl) - [4- (4-fluoro) -benzenesulfonyl) piperazin-1-yl] methyl} -4-hydroxy-phenyl) -acetic acid (3 - {[4- (4-fluoro-benzenesulfonyl) -piperazin-1-yl] -p-tolyl methyl} -4-hydroxy-phenyl) -acetic acid (3- {[4- (4-fluoro-benzenesulfyl) -piperazin-1-yl] -p-tolyl-methyl} -phenyl) -acetic acid; 3 - {(4-chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) -piperazin-1-yl] -methyl} -phenyl) -acetic acid. A compound according to claim 1, characterized in that it has a structure IVa: wherein Y2 is selected from the group consisting of N, O and S; each R12 is independently selected from the group, which consited and C1-6 alkyl, CN, CONHR1, CO2R1, amino, C1-6 alkoxy, halo, C1-6 haloalkyl and SOqR1 are combined together to form a aryl or heteroaryl ring; and the subscript u is independently 1, 2 or 3. A compound according to claim 1, characterized in that it is selected from the group consisting of: 2- (1- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic; 2- (11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid; 2- (9-chloro-1- 1- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid; 2- (9-chloro-11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] -oxepin-2-yl) acetic acid; and 2- (11- (2-oxo-4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid; 1- (5- (carboxymethyl) -2- (2,4-dichlorobenzyloxy) benzyl) -4-tosylpiperazine N-oxide; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic tert-butyl ester; [4- (4-Chloro-benzyloxy) -3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid; [4- [4- (3-methyl-butoxy) -benzyloxy] -3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid; [4- (4-chloro-benzyloxy) -3,5-bis- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid; [4-Cyclopentyloxy-3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) -phenyl] -acetic acid; [4-Cyclopropylmethoxy-3- (4-phenylcarbamoyl-piperazin-1-ylmethyl) phenyl] -acetic acid; and [3- (4-benzylcarbamoyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; and [4- (4-chloro-benzyloxy) -3-piperidin-1-ylmethyl-phenyl] -acetic acid; {4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -pyrrolidin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -piperidin-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfomlamino) -azepan-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -3,4,7,8-tetrahydro-2H-azocin-1-ylmethyl] -phenic acid} -acetic; {4- (4-Chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -azocan-1-ylmethyl] -phenyl} -acetic acid; {4- (4-Chloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) -piperazine-1-carbonyl] -phenyl} -acetic acid; and [4- (4-chloro-benzyloxy) -3- (4-methanesulfonyl-piperazine-1-carbonyl) -phenyl] -acetic acid. A compound according to claim 1, characterized in that it has a structure (V): wherein Y is selected from the group consisting of a bond. CH 2, N, O, NO and SOq; R10 and R11 are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently O, 1, 2 or 3; the subscript ρ is independently O, 1 or 2; and each dashed ring bond independently indicates the presence of a single, double or standard bond. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 8 and a pharmaceutically acceptable carrier, excipient, diluent or delivery system. Method of antagonizing a DP-2 receptor, characterized in that it comprises contacting a DP-2 receptor with a compound as defined in any one of claims 1 to 8. Use of a compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable derivative thereof for preparing a medicament for the treatment or prevention of a disorder or condition that responds to the modulation of PGD2 or a PGD2 receiver. Use of a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable derivative thereof, for preparing a medicament for treating or preventing a disorder which responds to antagonizing a DP-2 receiver. Use of a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable derivative thereof, for preparing a medicament for treating or preventing a disorder or condition associated with elevated levels. PGD2, or a metabolite thereof. Use according to any one of claims 11-13, characterized in that the disorder or condition is selected from the group consisting of: obstructive airway diseases; bronchitis; chronic obstructive pulmonary disease; rhinitis; fibroid lung; cystic fibrosis; idiopathic interstitial fibrosis; chronic cough associated with inflammation; and sinusitis; conjunctivitis; dermatitis; psoriasis; urticaria; erythemas; cutaneous eosinophilia; chronic skin ulcers; food-induced allergies; eosinophilic gastroenteritis; mastocytosis; ulcerative colitis; Crohn's disease; irritable bowel syndrome; celiac disease; inflammatory pain; neuropathic pain; eosinophilic fasciitis; hyper IgE syndrome; systemic stem cell disorder; idiopathic thrombocytopenia purpura; atherosclerosis; lupus erythematosus; systemic lupus erythematosus; sepsis; reperfusion injury; glomerulonephritis; allergic nephritis; nephritic syndrome; eosinophil-related disorders, such as Chrug-Strauss syndrome; basophilic leukocytosis and basophilic leukemia; acquired immunodeficiency syndrome; basophilic leukocytosis and basophilic leukemia; acquired immunodeficiency syndrome; arthritis and conditions associated with this and other conditions or disorders associated with elevated levels of PGD2 or its metabolites. Use according to any one of claims 11 to 13, characterized in that said compound is used in combination with a second therapeutic agent. Use according to claim 15, characterized in that the second therapeutic agent is useful for preventing or treating a disorder or condition selected from the group consisting of asthma, rhinitis, allergic airway syndrome, allergic rhinobronchitis. , bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer's lung, fibroid lung, chronic cough, conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS complex - dementia, Huntington's disease, dementia frontotemporal, Lewy body dementia, vascular dementia, Guillain - Barré syndrome, chronic demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, CNS trauma, migraine, stroke, arthritis, rheumatoid arthritis , Behcet's disease, bursitis, carpal tunnel syndrome, inflammatory bowel disease Crohn's disease, ulcerative colitis, dermatomyositis, Ehlars-Danlos Syndrome (EDS), fibromyalgia, pain, osteoarthritis (AO), osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive arthritis), sarcoidosis, scleroderma, Sjogren's syndrome, soft tissue disease, Still's disease, tendonitis, polyarteritis Nodossa, Wegener's granulomatosis, myositis (polymyositis dermatomyisitis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus, type I diabetes, systemic diabetes, nephritic syndrome, glomerulonephritis, acute and chronic renal failure, eosinophilic fasciitis, Hypergege Syndrome, sepsis, septic shock, ischemic reperfusion injury, transplant rejection, graft host disease, eczema, psoriasis, fever, cancer, viral infection, thrombosis, fibrosis, runny nose , inflammation, nasal congestion, urticaria, contact hypersensitivity (including contact dermatitis), food allergies, eosinophilic gastroenteritis, amostocytosis, cne, ulcerative colitis, pruritis, angiedema, dermatitis dermatitis, erythema, cutaneous eisonophilia, chronic skin ulcers, celiac disease, systemic stem cell disorder; idiopathic thrombocytopenia purpura, Churg-Strauss syndrome, basophilic leukocytosis, basophilic leukemia, and acquired immunodeficiency syndrome (AIDS). Use according to claim 15, characterized in that said second therapeutic agent is selected from the group consisting of: a corticosteroid, a corticosteroid analogue, an antihistamine agne, a b2 agonist, a chromoline, a leukotriene antagonist, an anti-IgE antibody therapy, an anti-infectious agent, an antifungal agent, an immunosuppressive agent, a PGD2 or DP antagonist, a PDE4 inhibitor, a cytokine modulator, an agonist PPAR-γ, a 5-lipoxygenase inhibitor, a FLAP inhibitor, and a PLA2 inhibitor.