MX2008015696A - Substituted phenyl acetic acids as dp-2 antagonists. - Google Patents

Substituted phenyl acetic acids as dp-2 antagonists.

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Publication number
MX2008015696A
MX2008015696A MX2008015696A MX2008015696A MX2008015696A MX 2008015696 A MX2008015696 A MX 2008015696A MX 2008015696 A MX2008015696 A MX 2008015696A MX 2008015696 A MX2008015696 A MX 2008015696A MX 2008015696 A MX2008015696 A MX 2008015696A
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MX
Mexico
Prior art keywords
phenyl
acid
piperazin
acetic
ylmethyl
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MX2008015696A
Other languages
Spanish (es)
Inventor
Kerry Fowler
Joshua Odingo
Amy Oliver
Thomas Dudler
Francine Farouz
Nataly Hawthorn
Danwen Huang
Musong Kim
Mark Reed
Fuqiang Ruan
Eugene Thorsett
Angela Judkins
Original Assignee
Icos Corp
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Application filed by Icos Corp filed Critical Icos Corp
Publication of MX2008015696A publication Critical patent/MX2008015696A/en

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Abstract

Substituted phenyl acetic acid compounds of formula (I), pharmaceutical compositions, methods for their preparation and methods are provided that are useful in the treatment and prevention of disorders or conditions responsive to DP 2 receptor modulation, in particular, inflammatory and immune related disorders and conditions, such as asthma, allergic rhinitis and atopic dermatitis.

Description

PHENYL ACETIC ACIDS SUBSTITUTED AS DP-2 ANTAGONISTS BACKGROUND OF THE INVENTION Prostaglandin D2 (PGD2) is the main pro-inflammatory mediator abundantly secreted by activated mast cells through the allergenic exposure of a previously sensitized host. PGD2 is able to produce a multitude of pathobiological responses relevant to inflammatory disorders including airway constriction, leukocyte influx, increased vascular permeability, edema and mucosal secretion. The biological actions of PGD2 are mediated by at least 3 different receptors coupled to the G protein: the high affinity receptors DP-1 (formerly known as DP) and DP-2 (formerly known as the orphan receptor "protein receptor"). G "GPR44 and" the homologous chemoattractant receptor expressed on Th2 cells ", CRTH2 (See Hirai, H. et al., 'J. Exp. Med., 2001, 193 (2): 255-61; Nagata, KJ Biol. Regul. Homeost, Agents 2003, 17 (4): 334-7) and the A2 receptor of thromboxane, TP, to which PGD2 binds with low affinity.The DP-2 receptor is a major contributor to the pathophysiological actions of PGD2 Therefore, it is likely that pharmacists who target this receptor are therapeutically beneficial to a host of disorders, specifically inflammatory conditions that they have an allergic component, such as asthma (See Huang, J., J. 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 well known contributors to inflammatory disorders and other conditions. Activation of DP-2, a chemoattractant receptor, stimulates the chemotaxis of human Th2 cells, eosinophils and basophils both in vitro and in vivo, and may mediate recruitment of relevant cell types in diseased sites and exacerbate ultimate organ damage . DP-2 agonists are capable of directly activating inflammatory cells and activation mediated by DP-2 and release of the eosinophil and basophil mediator 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). In addition, Th2 effector T lymphocytes will elaborate the inflammatory cytosines IL-4, IL-5 and IL-13 in response to the stimulation of DP-2 (See Xue, L., et al., J. Immunol., 2005, 175 (10): 6531-6). These cytosines, in turn, act as important regulators of inflammatory responses and support Th2 cell differentiation, mast cell growth, differentiation and synthesis of IgE, and differentiation, infiltration and survival of eosinophils. This suggests that the PGD2 / DP-2 pathway acts as a positive feeding circuit and increases pathological responses in disorders associated with excessive or unregulated production of PGD2. Consequently, pharmaceutical agents that interfere with this trajectory may have utility in the treatment of a wide range of allergic and inflammatory conditions and other disorders. The utility of PGD2 antagonists in the treatment of 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 on inflammatory markers in nasal washes, suggesting an anti-inflammatory activity. Ramatroban® was initially described as a selective TP antagonist, and it is believed that its clinical effects in rhinitis are mediated by TP. However, recent discoveries revealed that Ramatroban® possesses a double 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 in the pivotal inflammatory cells involved in allergic rhinitis and the stimulatory effects of PGD2 and other DP-2 agonists in these cells, it is reasonable to postulate that The clinical benefits of Ramatroban® in allergic rhinitis are long-term due to its activity against the DP-2 receptor. Accordingly, it can be inferred that selective DP-2 antagonists may be useful in the treatment of allergic rhinitis, other inflammatory conditions, other conditions where the PGD2 pathway is not regulated, as well as other disorders where it has been established the utility of Ramatroban®. Minami et al., Have demonstrated the effectiveness of Ramatroban® in edema in experimental allergic conjunctivitis (See Minami, K., et al., Int. Immunopharmacol., 2004, 4 (12): 1531-5). It has been shown that DP-2 exerts 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. Soc. Invest. Dermatol. (April 20 -April 22, Yokohama) 2005, Abst. 48). Numerous compounds have been reported as modulators of PGD2 receptors and / or useful for the treatment of allergic and inflammatory disorders. WO 2006021418 describes a series of sulfamyl-benzoimidazole-1-ylacetic acid compounds with antagonist activity for DP-2 or PGD2. WO2006021759 describes a series of biphenyloxyacetic acid derivatives having activity modulator of PGD2 and DP-2 that are said to be useful for the treatment of respiratory disorders. WO 2005019171, WO 2004106302 and WO 2005054232 describe a series of acetic acid-indole, -indazole and -benzimidazole compounds which are said to be useful for the treatment of respiratory disorders. WO 2005105727 describes phenoxy acetic acid compounds with DP-2 antagonist activity. WO2005018529 discloses phenoxy acetic acid compounds which are said 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 antagonist activity that are said to be useful for the treatment of allergy, asthma and atopic dermatitis. WO 2004058164, U.S. Patent Publication. No. 2005038070 and WO 2005007094 describe a series of compounds that are said to be useful for the treatment of allergy, asthma, cancer and inflammation. WO 2004096777 describes a series of pyrimidine derivatives useful for the treatment of conditions mediated by DP-2, including asthma, conjunctivitis, dermatitis, atopic rhinitis, allergic sinusitis. WO 2004078719 describes a series of indole compounds that are said to be useful for the treatment of asthma and allergic rhinitis. The patent publication of E.U. No 2004132772 describes a series of compounds of tetrahydroquinoline as DP-2 antagonists that are said to be useful for the treatment of allergic asthma and allergic rhinitis. O 2003066046, O 2003066047, WO 2003101961, WO 2003101981 and WO 2004007451 describe a series of indole acetic acids which are said to be useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), rhinitis and other conditions. WO2003097598 describes a series of compounds that are said to exhibit antagonism to the PGD2 receptor. The U.S. Patent No. 4,656,192, describes a series of tropolon compounds that are said to be useful as anti-tumor agents. EP 1170594 describes methods for the identification of compounds useful for the treatment of conditions mediated by prostaglandin D2, a ligand for the orphan receptor DP-2. GB 1356834 describes a series of compounds that are said to possess anti-inflammatory, analgesic and antipyretic activity. Even so, there is a relative shortage in the drug market that selectively modulates bound non-aminergic receptors coupled to the G protein (see Beaumont K., et al., Bioorg, Med. Chem. Lett., 2005, 15 (16 ): 3658-64). SUMMARY OF THE INVENTION It has surprisingly been discovered that certain phenyl acetic acids are potent DP-2 receptor antagonists. In certain modalities, phenyl acids acetic acid are selective antagonists of the DP-2 receptor on other PGD2 receptors. It is expected that the phenylacetic acid compounds of the invention are potentially useful for the treatment or prevention of medical conditions or disorders that respond to the antagonism of DP-2, or of the symptoms associated with such medical conditions or disorders, such as those that have an allergic or inflammatory component. Examples of conditions or disorders treatable or avoidable with the compounds and compositions of the invention are given below. Among the various aspects of the present invention, the invention provides compounds, pharmaceutical compositions and methods useful for treating or preventing conditions and disorders associated with inflammatory and / or allergic processes. In particular, the invention provides compounds, pharmaceutical compositions and methods useful for treating or preventing asthma, allergic conditions, inflammatory conditions, cancer and viral infection. The compounds of the invention have the general structure (I): Within the above formula, L is selected from the group consisting of a CR6R7, CO, CNR6 and CS, A is a heterocyclic ring of 5-14 members having heteroatoms of 1-4 rings each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being monocyclic or polycyclic, optionally substituted with 1-3 substituents R8. Q1 is selected from the group consisting of: a bond, Ci-C4 alkylene, Ci-C4 heteroalkylene, -CO-, -NH-, -O-, -SOq-, -C (0) 0-, -OC (O ) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -COCH2HNSOq. Each R1, R2, R3 R6 and R7 is independently selected from the group consisting of H, Ci_6 alkyl, C0.6 alkylaryl and C0-6 alkylheteroaryl; wherein the aryl or heteroaryl moieties are optionally substituted with Ci-6 alkyl, CN, OR, Ci-6 haloalkyl, Ci-6 heteroalkyl, NR2, NO2, halo, C (0) R, C02R, CONR2, SOqR, SOqNR2 , OC (0) OR, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) OR. Each R4 is independently selected from the group consisting of Ci-6 alkyl, C0-4 alkyl C3-cycloalkyl, C0-4 alkylaryl, C0-4 alkylheteroaryl, C2-4 alkenylaryl, C2_4 alkynylaryl, C0-4 alkylheterocyclyl, CN, amino , NHCOR1, hydroxy, Ci-6 alkoxy, OCÍOR1, -O-alkylaryl C0-, O- C0-4 alkylheteroaryl, -0-alkylCO-4-cycloalkyl C3-i0, 0-alkylC0-4heterocyclyl C3-i0, O-alkylC0-4NR8, nitro, halo and haloalkyl Ci-6; or combine with each other or with R6 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 with from 1 to 3 substituents each independently selected from the group consisting of Ci-6 alkyl, CN, CONHR1, CO2R1, amino, Ci-6 alkoxy, halo , haloalkyl Cl-6 and SOqR1. R5 is selected from the group consisting of Ci-6 alkyl, C0-4 alkylaryl, C2-4 alkenylaryl, C2-4 alkynylaryl, C0-4 alkylheteroaryl, each of which is optionally substituted with 1-3 substituents of R9. Each R8 is independently selected from the group consisting of Ci-6alkyl, C0-6cycloalkylC3-6alkyl, C0.6alkylaryl, C0.6alkylheteroarylcarboxy, Ci-e alkyl, CN, OR, C1-6 haloalkyl, Ci_6 heteroalkyl, NR2 , N02, halo, C (0) R, C02R, CONR2, SOqR, SOqNR2, 0C (0) 0R, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) OR. Each R9 is independently selected from the group consisting of Ci-S alkyl, CN, OR, oxo, Ci_6 haloalkyl, Ci-6 heteroalkyl, NR2, NO2, halo, C (0) R, C02R, C0NR2, SOqR, SOqNR2, OC (0) OR, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) OR. Each R is independently selected from the group consisting of H, Ci-6 alkyl, C0-4 alkylheteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl or, when attached to the same nitrogen atom, can be combined to form a 5-8 membered ring having heteroatoms of 1-4 rings each independently selected from the group consisting of nitrogen, oxygen and sulfur. The subscript n is independently 0, 1, 2, 3 or 4. Each subindex q is independently 0, 1 or 2. The invention also provides pharmaceutically acceptable salts, hydrates, solvates and prodrugs of the compounds of structure I. Examples of prodrugs are compounds wherein R 1 is C 1-6 alkyl, C 0-6 alkylaryl or C 0-6 alkylheteroaryl wherein the aryl or heteroaryl portions are optionally substituted as described herein. The invention also provides pharmaceutical compositions comprising a compound of the 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 aggregating a DP-2 receptor on one or more PGD2 receptors. The invention also provides methods for treating or preventing a disorder or condition that responds to the antagonism of a DP-2 receptor as well as methods for treating or preventing a disorder or condition associated with elevated levels of PGD2 or a metabolite thereof, comprising administering to a subject 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 condition or disorder mediated by DP-2 and / or one or more different PGD2 receptors, eg, DP-1, which comprises administering to a subject in need, 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 different PGD2 receptors, eg, DP-1, which comprises contacting a cell with a compound of structure I .
Other objects, features and advantages of the invention will become apparent to those 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 = ethylacetate, DMF =?,? - dimethyl formamide, NMP = N, methylpyrrolidine, THF = tetrahydrofuran, RT = room temperature, TFA = trifluoroacetic acid, LDA = lithium diisopropylamine, n-BuLi = n -butyl lithium, Na2C03 = sodium carbonate, DME = dimethyl ether, K2P04 = potassium phosphate, CH2C12 or DCM dichloromethane, Et3N = triethylamine, DIEA = Hunig's base or diisopropyl ethylamine, KOH = potassium hydroxide, NaOH = sodium hydroxide , TS = trimethylsilyl, Tf trifluoromethylsulfonyl, Boc = t-butylcarbonyl, Bz benzyl, IPA = isopropyl alcohol, NBS = N-bromosuccinamide, AIBN = azobisisobutyronitrile (also azobisbutylonitrile), Pin = pinacolato, Cs2C03 = cesium carbonate, HIV = human immunodeficiency, RLV = Raucher leukemia virus, IgE = immunoglobulin E. It is noted herein, as used in this specification and in the appended claims, the singular forms "a", "an" and "the "include the reference to the plural, unless the context clearly dictates otherwise. The term "alkyl" by itself or as part of another substituent means, unless otherwise defined, a straight or branched or cyclic hydrocarbon radical, or a combination thereof, which is fully saturated , which has the designated carbon atom number (ie, Ci-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, homologs 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 cyclic hydrocarbon radical, or a combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms. designated carbon (ie, C2-C8 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 higher homologs and isomers thereof. The term "alkynyl", by itself or as part of another substituent, means a hydrocarbon radical of straight or branched chain, or combinations thereof, which may be mono or polyunsaturated, which has the number of carbon atoms designated (i.e., C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1 and 3-propynyl, 3-butynyl and higher homologs and isomers thereof. The term "alkylene", by itself or as part of another substituent, means a bivalent radical derived from alkyl, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, those groups having 10 or fewer preferred carbon atoms in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, which generally has eight or fewer carbon atoms. The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the rest of the molecule by an oxygen atom, an amino group, or a sulfur atom, 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", by itself or in combination with another term, means, unless define from another matera, a straight or branched or cyclic chain hydrocarbon radical, or combinations thereof, consisting of a defined number of carbon atoms and from one to three heteroatoms selected from 0, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom optionally quaternized. The heteroatom (s) 0, N and S may be placed in any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-0-CH3f -CH2-CH2-H-CH3, -CH2-CH2-N (CH3) -CH3i -CH2-S-CH2-CH3 / -CH2-CH2 / -S (0) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-0-CH3, -Si (CH3) 3, -CH2-CH = N-OCH3 and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si (CH3) 3. When a prefix such as (C2-C8) is used to refer to a heteroalkyl group, the number of carbons (2-8 in this example) is also intended to include heteroatoms. For example, a C2 heteroalkyl group is intended to include, for example, -CH20H (a carbon atom and a heteroatom replacing a carbon atom) and -CH2SH. The term "heteroalkylene", by itself or as part of another substituent, means a bivalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2. For the heteroalkylene groups, the heteroatoms may also occupy either or both of the chain terminals (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino and the like). Still further, for the alkylene and heteroalkylene linking groups, no orientation of the linking group is implied. The terms "cycloalkyl", "heterocyclyl" and "heterocyclic ring", by themselves or in combination with other terms, represent, unless otherwise defined, cyclic versions of "alkyl" and "heteroalkyl", respectively. Therefore, the terms "cycloalkyl" and "heterocyclic ring" are intended to be included in the terms "alkyl" and "heteroalkyl", respectively. Additionally, for a heterocyclic ring, the heteroatom can occupy the position in which the heterocycle is bound to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclopentyl and the like. Examples of a heterocyclic ring include pyrrolidinyl, pyrrolyl, piperadynyl, tetrahydropyridinyl, piperazinyl, piperazin-1-oxide, morpholinyl, thiomorpholinyl, azepanyl, azepinyl, oxazepan, thiazepam, azocanyl, azocinyl, indolyl, azaindole, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydrobenzooxazepinyl, dihydrodibenzooxepin and the like. The terms "halo" or "halogen", by themselves or as part of another substituent, mean, unless otherwise defined, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl", are intended to include alkyl substituted with halogen atoms, which may be the same or different, in a number ranging from one to (2m '+ 1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "haloalkyl Cl-6" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with a halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m '+ 1) halogen atoms). The term "perhaloalkyl" means, unless otherwise defined, alkyl substituted with (2m '+ 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term perhaloalkyl C! -6", is intended to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl and the like.The term" aryl "means, unless defined by another way, a typically aromatic polyunsaturated hydrocarbon substituent which may be of a single ring or multiple rings (up to three rings) which is they merge with each other or they are linked covalently. The term "heteroaryl" refers to aryl groups (or rings) containing one to four heteroatoms selected from the group consisting of N, 0 and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the ) Nitrogen atom (s) is optionally quaternized (s). A heteroaryl group can be attached to the rest of the molecule by a heteroatom. Non-limiting examples of the 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, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, lH-indazole, carbazole, alpha-carboline, beta-carboline, gamma-carboline, 1-isoquinolyl, 5-isoquinolyl, 2 - . 2-quinhoxalinyl, 5-quinolalinyl, 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 that is not replaced or replaced. In some embodiments, the term "heteroaryl" refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group is unsubstituted or substituted. For 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 to include those radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (eg. , a methylene group) has been replaced, for example, by an oxygen atom (eg, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl and the like). Each of the foregoing terms (e.g., "alkyl", "heteroalkyl", "aryl" and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated. Preferred substituents for each type of radical are given below. The substituents for the alkyl and heteroalkyl (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocyclyl) can be a variety of groups selected from: -OR ', = 0, = NR', = N-OR ', -NR 'R', -SR ', halogen, -SiR'R "R'", -0C (0) R ', C (0) R ', -C02R', -CONR'R ", -0C (0) NR'R", - R "C (0) R ', -NR' -C (0) NR '' R ' '', -NR '-S02- R "R"', -NR "C02R ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR ', -S (0) R', -S02R ', -SONR'R'. -NR''S02R, -CN and -N02, in a number that fluctuates from zero to three, being those groups that have zero, one or two particularly preferred substituents R ', R "and R" "each independently refer to hydrogen, unsubstituted Ci-6alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl , alkoxy or trioalkoxy groups, or aryl-Ci_6alkyl groups When R 'and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5, 6 or 7 membered ring. , -NR'R "is intended to include 1-pyrrolidinyl and 4-morpholinyl Typically, an alkyl or heteroalkyl group will 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 will be unsubstituted or mono substituted. More preferably, an alkyl or heteroalkyl radical is you will find not replaced. From the above-discussed substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3). In some embodiments, the substituents for the alkyl and heteroalkyl radicals are selected from: -0R ', = 0, -NR'R ", -SR', halogen, -SiR'R" R "', -0C (0) R ', -C (0) R', -C02R ', -CONR'R', -0C (0) NR'R '', -NR''C (0) R ', -NR "C02R', - NR '-S02NR' 'R' '', -S (0) R ', -S02R', -S02NR'R '', -NR "S02, -CN and -N02, wherein R 'and R" are as defined above, in some embodiments, the substituents are selected from: -0R ', = 0, -NR'R ", halogen, -OC (0) R', -C02R ', -CONR'R", -0C (0) NR'R ", - R" C (0) R ', -NR''C02R', -NR '-S02NR' 'R' '', S02R ', -S02NR'R ", -NR '' S02R, -CN and -N02 Similarly, the substituents for the aryl and heteroaryl groups are varied and are selected from: halogen, -0R ', -OC (0) R', -NR'R '' , -SR ', -R', -CN, -N02, -C02R ', -CONR'R' ', -C (0) R', -0C (O) NR 'R' ', -NR''C (0) R ', NR''C (0) 2R', -NR '-C (O) NR' 'R' '', -NH-V (NH2) = NH, -NR 'C (NH2) = NH, -NH-C (NH2) = NR ', -S (0) R', -S (0) 2R ', -S (0) 2NR'R ", -N3, -CH (Ph) 2, perfluoroCi -6alcoxy, and perfluoroCi-6a Iquilo, in a number that fluctuates from zero to the total number of open valences in the aromatic ring system; and wherein R ', R "and R"' 'are independently selected from hydrogen, Ci_6 alkyl and unsubstituted heteroalkyl, aryl and heteroaryl, (aryl not substituted) -Ci-6alkyl and (unsubstituted aryl) oxy-CX-6alkyl · Two of the substituents on the adjacent atoms of the aryl or heteroaryl ring may be optionally replaced with a substituent of the formula -TC (O) - ( CH2) qU-, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is 0, 1 or 2. Alternatively, two of the substituents on the adjacent ring atoms aryl or heteroaryl may be optionally replaced with a substituent of the formula -A- (CH2) rB ~ where A and B are independently -CH2-, -O-, -NH-. -S-, -S (O) -, -S (0) 2-, -S (0) 2NR'- or a single bond, and r is 1, 2 or 3. One of the double bonds of the new ring thus formed it can be optionally replaced with a double link. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can be optionally replaced with a substituent of the formula - (CH2) gX- (CH2) t-, where syt are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (0) 2- or -S (0) 2NR'-. The substituent R 'in -NR' - and -SO (0) 2 NR'- is selected from hydrogen or unsubstituted Ci-6 alkyl. Otherwise, R 'is as defined above. As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), Sulfur (S) and silicone (Si). The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either close to 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. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either close to or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic or phosphorous acids, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and Similary. Also included are amino acid salts such as arginate and the like and salts of organic acids such as glucuronic or galacturonic acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities which allow the compounds to be converted into addition salts, either base or acid. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The form of origin of the compound differs from the various salt forms in certain physical properties, such as, the solubility in polar solvents, but, otherwise, the salts are equivalent to the form of origin of the compound for the purposes of the invention . In addition to the salt forms, the invention provides compounds that are in prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the formula I which are DP-2 receptor antagonists. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention, when placed in a transdermal patch reservoir with an enzyme or suitable chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the original drug. For example, they can be bioavailable by oral administration while the drug of origin does not. The prodrug may also have an improved solubility in the pharmaceutical compositions on the original 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 that is administered as an ester (eg, wherein R1 is substituted or unsubstituted Ci_6 alkyl, C0.6 alkylaryl or C0.e alkylheteroaryl, "prodrug") , but then, metabolically hydrolyzed to the 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 can exist in undissolved forms as well as in dissolved forms, including hydrated forms. In general, the dissolved forms are equivalent to the undissolved forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention. Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. These isomers can be dissolved or synthesized asymmetrically 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 can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the prepared diastereomeric mixture is separated and the auxiliary group is divided to provide the desired pure enantiomers. Alternatively, when the molecule contains a basic functional group, such as amino or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by crystallization media. fractional or chromatographic well known in the art and the subsequent recovery of the pure enantiomers. The compounds of the invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, e.g., cancer therapeutic agents, research reagents, e.g., reagents for DP-2 analysis and diagnostic agents, e.g., in vivo visualization agents. 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 that inhibits or binds to, blocks, partial or totally, stimulation or activity, decreases, closes, prevents, retards, activates or enzymatic activity, inactivates, desensitizes or sub-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 that binds to a receptor of the invention, stimulates, increases, opens, activates, facilitates, improves activation or enzymatic activity, sensitizes or over-regulates activity of a receiver of the invention. "Modulators" of the activity is used to refer to "ligands", "antagonists" and "agonists" identified using in vivo analysis for the activity and its homologs and mimetics. Modulators include ligands of natural and synthetic origin, antagonists, agonists, molecules and the like. Analyzes for identifying antagonists and agonists include, e.g., applying putative modulator compounds to the 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, treated with a potential activator, inhibitor or modulator, are compared with control samples without the inhibitor, activated or modulator for examine the degree of effect. A relative activity value of 100% is assigned to the control samples (not treated with modulators). Inhibition is achieved when the activity value of a receptor of the invention relative to the control is about 80%, optionally 50% or 25-1%. The activation is achieved when the activity value of a receiver of the invention in relation to the control is 110%, optionally 150%, optionally 200-500% or 1000-3000% higher. The terms "treated", "treated", "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 of a disr. or condition and / or alleviate, mitigate or prevent one or more causes of a disr or condition. The treatments, accng to the invention, can be applied preventively, prophylactically, palliatively or curatively. The terms "prevent", "prevent", "prevention" and grammatical variations thereof, as used herein, refer to a method for delaying or partially or completely preventing the onset or occurrence of a disr or condition and / or one or more of its symptoms or to prevent a subject from acquiring or re-acquiring a disr or condition or to reduce the risk in a subject of acquiring or re-acquiring a disr or condition or one or more of its symptom . The term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the subject compound that will emit the biological or medical response of a tissue, system, animal or human being sought by the researcher, veterinarian, medical doctor and other physician . The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some degree, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity, and the age, weight, etc., of the mammal being treated. The phrase "selectively" or "specifically" when referring to the link to a receptor, refers to a binding reaction determining the presence of the receptor, frequently in a homogeneous population of receptors and other biological ones. Thus, under the designated conditions, the compounds bind to a particular receptor at least twice the background and more typically at more than 10 to 100 times the background. The specific binding of a compound under such conditions requires a compound selected for its specificity for a particular receptor. For example, small organic molecules can be screened to obtain only those compounds which bind specifically or selectively to a selected receptor and not to other receptors or proteins. A variety of analysis formats can be used to select compounds that are selective for a particular receptor. For example, high throughput screening analyzes are routinely used to select compounds that are selective for a particular receptor. The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like . In preferred embodiments, the subject is a human. 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, ie, proteins having one or more deletions, insertions or amino acid substitutions of natural or unnatural origin (eg, 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 more preferably at least about 95% identical.
As used herein, the terms "other PGD2 receptor", "other PGD2 receptor" and the like, refer to a prostanoid receptor protein other than DP-2, or a variant thereof, which is capable of mediate a cellular response to PGD2 in vitro or in vivo. Another PGD2 receptor can be selective for PGD2, eg, DP-1 (RefSeq Accession No. NP-000944) or it can also interact with one or more different prostanoids (eg, EP1, EP2, EP3 and EP4, FP, IP and TP). Other variants of the PGD2 receptor include proteins substantially homologous to a corresponding native prostanoid receptor other than DP-2, ie, proteins having one or more deletions, insertions or substitutions of natural or non-natural origin (eg, derivatives, homologs and fragments). from another PGD2 receiver). The amino acid sequence of other PGD2 receptor variants is preferably at least about 80% identical to the other corresponding native PGD2 receptors, more preferably at least about 90% identical and more preferably 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, i.e., proteins having one or more deletions, insertions or substitutions of natural or unnatural origin (e.g., derivatives of DP-1, homologs 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 more preferably at least about 95% identical. As used herein, the term "TP" refers to a TP 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, i.e., proteins having one or more deletions, insertions or substitutions of natural or non-native origin (e.g., TP derivatives, homologs and fragments). The amino acid sequence of the TP variant is at least about 80% identical to the native TP, more preferably at least about 90% identical and more preferably at least about 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 different PGD2 receptors, eg, DP -1, where such Function may include the transcriptional regulatory activity and / or the protein binding. Modulation can occur in vitro or in vivo. Modulation, as described herein, includes the inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with DP-2 and / or one or more different PGD2 receptors, either direct or indirectly, and / or the over-regulation or sub-regulation of the expression of DP-2 and / or one or more different PGD2 receptors, either directly or indirectly. In a preferred embodiment, the modulation is direct. Inhibitors or antagonists are compounds that, e.g., bind to, totally or partially block stimulation, decrease, prevent, inhibit, retard activation, inactivate, desensitize, or sub-regulate signal transduction. The ability of a compound to inhibit the function of DP-2 and / or one or more different PGD2 receptors can be demonstrated in a biochemical analysis, eg, a binding analysis or a cell-based analysis, eg, an analysis of transient transfection. As used herein, the term "condition or disorder that responds to the modulation of PGD2 or a PGD2 receptor" and related terms and phrases, refers to a condition or disorder associated with inappropriate activity, eg, less than or greater than normal, of a PGD2 receptor and that it responds at least partially to, or is affected by the modulation of a PGD2 receptor (e.g., an antagonist or PGD2 receptor agonist results in some improvement in patient well-being in at least some patients). Inappropriate functional activity of a PGD2 receptor may arise as a result of the expression of a PGD2 receptor in cells that do not normally express the receptor, a higher than normal production of PGD2, or a slower or slower inactivation or metabolic clearance than normal of PGD2 or its active metabolites, an increased expression of a PGD2 receptor or the degree of intracellular activation (leading, eg, to disorders and inflammatory conditions and related to immunity) or a decreased expression of a PGD2 receptor. A condition or disorder associated with a PGD2 receptor may include a "condition or disorder mediated by DP-2." As used herein, the phrases "condition or disorder that responds to the antagonism of a DP-2 receptor" and related phrases and terms, refers to a condition or disorder characterized by an inappropriate activity, eg, greater than the normal, of DP-2. Inappropriate functional activity of DP-2 may arise as a result of the expression of DP-2 in cells that do not normally express DP-2 or an increased expression of DP-2 or an intracellular activation degree (leading to, e.g., disorders and inflammatory conditions and related to immunity). A condition or disorder that responds to the antagonism of a DP-2 receptor may be completely or partially mediated by an inappropriate DP-2 functional activity. However, a condition or disorder that responds to the antagonism of a DP-2 receptor is one in which modulation of DP-2 results in some effect on the underlying condition or disorder (eg, a DP-2 antagonist). results in some improvement in the patient's well-being at least in some patients). Modalities of the Invention A class of compounds that antagonize DP-2 has been discovered. Depending on the biological environment (e.g., cell type, host pathological condition, etc.), these compounds can antagonize DP-2 and / or one or more different PGD2 receptors (e.g., ligand binding). By antagonizing DP-2 and / or one or more different PGD2 receptors, the compounds will find their use as therapeutic agents capable of modulating disorders and conditions that respond to the modulation of DP-2 and / or one or more different PGD2 receptors. and / or mediated by DP-2 and / or one or more different PGD2 receptors. Examples of such conditions and disorders are provided below. Although it is believed that the compounds of the invention exert their effects by selectively interacting with DP-2, the The mechanism of action by which the compounds act is not a limiting mode 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 described compounds to selectively antagonize the DP-2 receptor on, eg, a DP-1 receptor, and / or other prostanoid receptors, eg, the receptor TP. The compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein. Compounds of the Invention In one embodiment, the present invention provides compounds of the general structure (I): (i) 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 heteroatoms of 1-4 rings selected each independently of the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being monocyclic or polycyclic, optionally substituted with 1-3 substituents R8. Q1 is selected from the group consisting of: a bond, Ci-C4 alkylene, Ci-C4 heteroalkylene, -C0-, -NH-, -0-, -S0q-, -C (0) 0-, -0C (0 ) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -C0CH2HNS0q. Each R 1, R 2, R 3 R 6 and R 7 is independently selected from the group consisting of H, C 1-6 alkyl, C 0 6 alkylaryl and C 0 -C G alkylheteroaryl; wherein the aryl or heteroaryl moieties are optionally substituted with Ci-6alkyl, CN, OR, haloalkyl Ci-6, heteroalkyl Ci-6, NR2, N02, halo, C (0) R, C02R, C0NR2, SOqR, SOqNR2 , 0C (0) 0R, 0C (0) R, 0C (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) 0R. Each R4 is independently selected from the group consisting of Ci-6 alkyl, C0-4 alkyl C3-cycloalkyl, C0-4 alkylaryl, C0-4 alkylheteroaryl, C2-4 alkenylaryl, C2.4 alkynylaryl, C4-4 alkylheterocyclyl, CN , amino, NHCOR1, hydroxy, Ci-6 alkoxy, OCYOJR1, -OC-4-alkylaryl, O-alkylheteroaryl CO-4, -0-alkylCO-4-cycloalkyl C3-10, 0-alkylC0-4heterocycloalkyl C3-i0, O- alkylC0-4NR8, nitro, halo and haloalkyl Ci-6 or combine with each other or with R6 to form an aryl or heterocyclyl ring 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 with from 1 to 3 substituents each independently selected from the group consisting of Ci-6 alkyl, CN, CONHR1, CO2R1, amino, Ci-6 alkoxy, halo , haloalkyl Cl-6 and SOqR1. R5 is selected from the group consisting of alkyl Ci-6, C0-4 alkylaryl, C2-4 alkenylaryl, C2-4 alkynylaryl, C0-4 alkylheteroaryl, each of which is optionally substituted with 1-3 substituents of R9. Each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkylcycloalkyl, C 1-6 alkylaryl / C 0-6 alkylheteroaryl oxo, C 1-6 alkyl, CN, OR, Ci-6 haloalkyl, Ci-6 heteroalkyl, NR 2 , N02, halo, C (0) R, C02R, CONR2, SOqR, SOqNR2, OC (0) OR, OC (0) R, OC (0) NR2í NRC (0) NR2, NRC (0) R and NRC (0) 0R. Each R9 is independently selected from the group consisting of Ci-e alkyl, CN, OR, oxo, Ci-6 haloalkyl, Ci-6i heteroaryl NR2, NO2, halo, C (0) R, C02R, C0NR2, SOqR, SOqNR2, OC (0) OR, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) 0R. Each R is independently selected from the group consisting of H, C1-6 alkyl, C0-4 alkylheteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl or, when they bind to the same nitrogen atom, they can be combined to form a 5-8 membered ring having heteroatoms of 1-4 rings each independently selected from the group consisting of nitrogen, oxygen and sulfur. The subscript n is independently 0, 1, 2, 3 or 4. Each subscript q is independently 0, 1 or 2. In another embodiment, the present invention provides pharmaceutically acceptable derivatives thereof. In another embodiment, L is CR6R7. In another modality, L is CO. In another modality, L is CNR6. In another modality, L is CS. In another embodiment, R1, R2, R3, R6 and R7 are each independently selected from the group consisting of H, Ci_e alkyl and C0-6 alkylaryl. In one embodiment, R1, R2, R3, R6 and R7 are each independently selected from the group. group consisting of H, CH3 and phenyl. In one embodiment, R1 is H. In another embodiment, R2 and R3 are H. In another embodiment, A has the structure (II): where And it is selected from the group consisting of a bond, CH2, N, O, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript p is independently 0, 1 or 2; each ring link in dashes independently indicates the presence of a single, double or normalized link; the dotted line indicates the point of attachment to Q1 and the wavy line indicates the point of attachment 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, oxazepan, tiazepan, azocanyl, azocinyl, indolyl, azaindole, tetrahydroquinolinyl and decahydroquinolinyl. In another modality, A has a formula selected from the group consisting of: where m is an integer from 0 to 3; and the dashed line indicates the point of attachment to Q1 and the wavy line indicates the point of attachment to L. In another embodiment, Q1 is selected from a bond, Ci-C4 alkylene, Ci-C4 heteroalkylene, -C0-, - NH-, -O-, -S0q-, -C (0) 0-, -0C (0) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOqNH- and -COCH2HNSOq. In another mode, Q1 is a link. In other embodiment, Q1 is Ci-C4 alkylene. In another embodiment, Q1 is C1-C4 heteroalkylene. In another modality, Q1 is -C0-. In another modality, Q1 is a -NH-. In another mode, Q1 is a -0-. In another embodiment, Q1 is -S0q-. In another embodiment, Q1 is -C (0) 0-. In another mode, Q1 is -0C (0) -. In another embodiment, Q1 is -C0NH-. In another modality, Q1 is -NHC0-. In another embodiment, Q1 is -NHC0NH-. In another embodiment, Q1 is -NHSOg-. In another embodiment, Q1 is -S0qNH-. In another embodiment, Q1 is -C0CH2HNS0q. In another modality, the compound has the structure (III): (III) wherein Y is selected from the group consisting of a bond, CH2, N, O, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 2, 3 or 3; the subscript p is independently 0, 1 or 2; and each ring link in dashes indicates independently the presence of a single, double or normalized link; In another embodiment, L is CR6R7. In another modality, L is CO. In another modality, L is CS. In another modality, the compound has the structure (IV): (IV) wherein Y is selected from the group consisting of a bond, CH2, N, 0, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1, 2 or 3; the subscript p is independently 0, 1 or 2; and each ring link in dashes independently indicates the presence of a single, double or normalized link. In another modality, Y is CH2 and p is 0. In another modality, L is CR6R7. In another mode Q1 is a link.
In another embodiment, Y is Soq and p 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-l-lambda6-thiomorpholin-4-ylmetyl) phenyl] acetic acid and [4- (4-fluoro-benzyloxy) -3- (1, 1-dioxo-l lambda6-thiomorpholin-4-ylmethyl) phenyl] acetic In another embodiment, Y is O and p is 0. In another embodiment, the compound is [4- (4-chloro-benzyloxy) -3-morpholine -4-ylmethyl-phenyl] acetic In another embodiment, Y is N and P 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) -perazin} -l-ylmethyl] phenyl} acetic acid and [3- (4-benzyl-piperazin-l-ylmethyl) -4- (4-chloro-benzyloxy) phenyl] acetic acid, In another embodiment, Q1 is -CO- In another modality, the compound e selects from the group consisting of: Acid (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) piperazin-1-ylmethyl] phenyl} acetic; Acid (4- (4-chloro-benzyloxy) -3-. {4- [2-chloro-phenyl] -acetyl] piperazin-1-ylmethyl} phenyl) acetic; [3- (4-Benzoyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) phenyl] acetic acid; Methyl ester of acid. { 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) benzyl] piperazin-1-yl} oxo-acetic; and Acid. { 4- (4-chloro-benzyloxy) -3- [4- (2-hydroxy-2-phenyl-acetyl) piperazin-1-ylmethyl] phenyl} acetic 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) iperazine-1-carboxylic acid tert-butyl ester; [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid isopropyl ester; and 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) benzyl] piperazine-1-carboxylic acid ethyl ester In another embodiment, Q1 is -S0 - In another embodiment, the compound is selected from the group consisting of it consists of: Acid { 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) iperazin-1-ylmethyl] phenyl} -acetic acid;; [3- [4- (4-Chloro-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) phenyl} -acetic acid: Acid { 4- [4- (3-methoxy ) benzyloxy] -3- [4- (toluene-4-sulfonyl) iperazin-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-yl} acetic acid; {.4-benzyloxy-3- [4- (toluene-4 -sulfonyl) piperazin-l-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; [3- [4- (2-Chloro-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (toluene-3-sulfonyl) -perazin-1-ylmethyl] -phenyl} acetic, · Acid. { 4- (4-chloro-benzyloxy) -3- [4- (quinoline-8-sulfonyl) piperazin-1-ylmethyl] -phenyl} acetic; (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- (Toluene-4-sulfonyl) piperazin-1-ylmethyl] -4- (4-trifluoromethyl-benzyloxy) phenyl] acetic acid; {4- (4-chloro-benzyloxy) -3- acid} [4- (2,4-Dichloro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl] -acetic acid: {4- (4-cyano-benzyloxy) -3- [4- (toluene-4 sulfonyl) iperazin-1-ylmethyl] phenyl Jacético; Acid { 4-phenethyloxy-3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic [3- [4- (4-tert-Butyl-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) phenyl] acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (3, 5-dimethyl-isoxazole-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (naphthalene-2-sulfonyl) iperazin-1-ylmethyl] phenyl-Jacético; Acid { 4- (4-chloro-benzyloxy) -3- [4- (pyridine-3-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (3, 5-dichloro-benzenesulfonyl) piperazin-1-ylmethyl] phenyl-Jacético; Acid { 4- (4-chloro-benzyloxy) -3- [4- (4-ethyl-benzenesulfonyl) piperazin-1-ylmethyl] phenyl] acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (naphthalene-1-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; [3- [4- (4-Bromo-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) phenyl] acetic acid; Acid { 4- (4-methoxy-benzyloxy) -3- [4-toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-methyl-benzyloxy) -3- [4-toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; 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-1-acetic acid; Acid { 4- (2,4-dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; 4- Acid. { 4-carboxymethyl-2- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenoxymethyl J-benzoyl; 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-1-acetic acid; [4- (3,4-Dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-nitro-benzyloxy) -3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-phenyl-ethenesulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (4-chloro-3-trifluoromethyl-benzenesulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-phenyl-ethanesulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; [4- (4-Chloro-benzyloxy) -3- [4- (4-nitro-benzenesulfonyl) piperazin-1-ylmethyl] phenyl-1-acetic acid; and Acid. { 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: Acid (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; Acid (3- [phenyl- [4- (toluene-4-sulfonyl) piperazin-1-yl] methyl] phenyl) acetic acid; (3- {[[4- (4-Fluoro-benzenesulfonyl) piperazin-1-yl] phenyl-methyl} phenyl) acetic acid; 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; (3- {(-chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) piperazin-1-yl], ethyl} 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; Acid (3- { [4-chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) iperazin-1-yl] methyl} phenyl) acetic; and Acid (3 { [4- (4-fluoro-benzenesulfonyl) iperazin-1- il] phenyl-methyl} phenyl) acetic. In another embodiment, R4 and R6 combine with each other to form an aryl or heterocyclyl ring system. In another embodiment, the compound has the structure (IVa): IVa wherein Y2 is selected from the group consisting of N, 0 and S; each R12 is independently selected from the group consisting of Ci-6alkyl, CN, CONHR1, CC ^ R1, amino, Ci-6alkoxy, halo, haloalkyl Cl-6, and SOqR1 or combine with each other to form an aryl ring or heteroaryl; 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 [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-11- (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- acid 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. In another embodiment, the compound is 1- (5- (carboxymethyl) -2- (2,4-dichlorobenzyloxy) benzyl) -4-tosylpiperazine N-oxide. In another embodiment, Q1 is -C (0) 0-. 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 modality, Q1 is -CO H-. 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 acid] -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 CH 2 and p is 0. In another embodiment, the compound is selected from group consisting of: [4- (4-chloro-benzyloxy) -3-piperidin-1-ylmethyl-phenyl] acetic acid and [4- (4-chloro-benzyloxy) -3- (4-hydroxy-piperidin-) acid] l-ylmethyl) phenyl] acetic acid. In another embodiment, Q1 is -NHSOq-. In another embodiment, the compound is selected from the group consisting of: Acid. { 4- (4-chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) pyrrolidin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) piperidin-1-ylmethyl] phenyl-1-acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) azepan-l-ylmethyl] phenyl-Jacético; Acid { 4- (4-chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) -3,4,7,8-tetrahydro-2H-azocin-1-ylmethyl] phenyl-1-acetic acid; and Acid. { 4- (4-chloro-benzyloxy) -3- [2-oxo-3- (toluene-4-sulfonylamino) azocan-1-ylmethyl] phenyl-1-acetic acid. In another modality, L is CO. In another embodiment, the compound is selected from the group consisting of: 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. In another modality, the compound has the structure (V): .. wherein (V) Y is selected from the group consisting of a bond, CH2, N, O, NO, and SOq; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1, 2 or 3; the subscript p is independently 0, 1 or 2; and each ring link in dashes independently indicates the presence of a single, double or normalized link. In another embodiment, L is CR6R7. In another modality, L is CO. In another modality, L is CS. In another mode, Q1 is a link. In another embodiment, Q1 is Cx-C4 alkylene. In another embodiment, Q1 is heteroalkylene 0? -04. In another modality, Q1 is -CO-. In another modality, Q1 is a -NH-. In another mode, Q1 is a -0-. In another embodiment, Q1 is -S0q-. In another embodiment, Q1 is -C (0) 0-. In another mode, Q1 is -0C (0) -. In other modality, Q1 is -CONH-. In another embodiment, Q1 is -NHCO-. In another modality, Q1 is -NHCONH-. In another embodiment, Q1 is -NHSOq-. In another modality, Q1 is -SOqNH-. In another embodiment, Q1 is -COCH2H SOq. Other modalities are described in the Request for U.S. Patent, Dudler et al., Filed June 9, 2006, entitled "Substituted phenyl acetic acids as DP-2 antagonists" (substituted phenyl acetic acids as DP-2 antagonists) lawyer's note No. 014233-003500US ( 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 compounds described herein are available from commercial sources, the pharmaceutical compositions or methods for using these compounds are new. Unless otherwise indicated, it will be understood that the invention includes those compounds that are new, as well as pharmaceutical compositions, various methods (eg, methods for treating or preventing certain conditions and disorders mediated by DP-2 and / or a or more different PGD2 receptors), and the like, which include both the novel compounds of the invention and the compounds that are commercially available. Preparation of the Compounds The synthetic routes for the compounds provided herein are also described in Schemes A-I and in the Examples. The person skilled in the art will understand that the synthetic routes can be modified to use different starting materials and / or alternate reagents to achieve the desired transformations. Additionally, the person skilled in the art will recognize that protection groups may be necessary for the preparation of certain compounds and will recognize those conditions compatible with a selected protection group. Accordingly, the methods and reagents described herein are all expressed as non-limiting modalities. Scheme A In some embodiments, as shown in Scheme A, an alkyl phenyl acetate of the formula A is mixed in a solution of formaldehyde and a heterocyclic substituted, such as a piperidine or a substituted piperazine, in a solvent system such as isopropyl alcohol for 1 to 12 hours at reflux to provide B. If the phenyl ring of the alkyl phenyl acetate A is replaced with a hydroxyl group (as shown), the alkylation of the phenol, using an alkyl or aryl halide in the presence of a base such as K2C03 or CsC03 in a solvent such as DMF at temperatures ranging from 20 to 60 ° C, or in 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, for a period of 1-6 hours at temperatures between 35-65 ° C, leads to a carboxylic acid of the formula D. Alternatively, the treatment of B with triflic anhydride in DCM, followed by palladium (0) mediated cross coupling with a boronic acid in a solvent such as dioxane or DME, at temperatures ranging from about at 90 ° C, with a base such as sodium carbonate, leads to the compounds with the general formula E. Saponification with a base such as lithium hydroxide (LiOH), potassium hydroxide (KOH) or sodium hydroxide (NaOH) in a solvent system such as THF: water methanol: water, for a period of 1-6 hours at a temperature of between 35-65 ° C, leads to a carboxylic acid of 1 formula F. Scheme Bl Scheme B2 MBOJC CO. to'uefte "Br f¾¡ÜA < ¾, pph4 R4 GGG In some embodiments, as shown in Scheme Bl, the treatment of benzaldehyde H with a suitably protected heterocycle and an 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. the saponification of 1 using the reaction conditions described in Scheme A, leads to J. Compound I can also be treated with a triflic anhydride or N-phenyl triflimide in DCM at temperatures ranging from room temperature to 50 ° C. Treatment with a source of palladium (0) in the presence of formic acid, followed by the saponification mentioned in Scheme A, leads to K. As shown in Scheme B2, benzaldehyde GGG was obtained by the treatment of a halotoluene with N -bromosuccinimide and AIBN in a solvent such as carbon tetrachloride, followed by the addition of trimethylamine N-oxide in a solvent such as acetonitrile, at temperatures ranging from room temperature to 80 ° C for 15 hours. Oxidation of F with Jone reagent in a solvent such as acetone, followed by the Arndt-Eistert reaction, leads to G. Aryl bromide G can be converted to the corresponding benzaldehyde by a palladium (0) -mediated reaction in a solvent such as toluene in the presence of carbon monoxide.
In some embodiments, as shown in Scheme C, the ketone I was treated with sodium borohydride in a solvent such as methanol at temperatures ranging from -10 to 35 ° C, followed by treatment with thionyl chloride in DCM at room temperature over a period of 12 hours, to provide J. The treatment of J with a suitably protected heterocycle in a solvent such as AcCN at temperatures ranging from 20 to 95 ° C for a period of 2 to 13 hours, followed by a saponification as described in Scheme A, leads to K. Scheme D In some modalities, as shown in Scheme D, the substituted benzaldehyde L can be treated with an alkyl or aryl Gringard reagent in a solvent system such as THF at temperatures ranging from -20 to 20 ° C over a period of a few hours to provide the secondary alcohol. A chloride formation in situ, to the treatment of M with thionyl chloride in a solvent such as DCM, for a few hours at room temperature, followed by a modified Finkelstein reaction in the presence of a suitably protected heterocycle in a solvent system such as AcCN for a few hours at temperatures ranging from -10 to 80 ° C, leads to N. Aryl bromide N is then transformed to an ester boronate O using standard coupling conditions with palladium (0). Coupling with additional palladium (0) of O with ethyl-2-bromo acetate in the presence of a base such as K2C03 in a solvent system such as dioxane or DME, at temperatures ranging from 15 to 85 ° C, leads to phenyl acetate P. Saponification of P using the conditions described in Scheme A, leads to K. Scheme E In some embodiments, as shown in Scheme E, phenyl acetate A is treated with paraformaldehyde in AcCN at temperatures ranging from 25 to 100 ° C, and leads to Q. Oxidation of Q with potassium permanganate, for example, in a solvent system such as acetone / water for a few hours under reflux conditions, leads to benzoic acid R. This acid S can then be coupled to a substituted heterocycle, such as 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 for a period of 2 to 12 hours. Scheme F In some embodiments, as shown in Scheme F, the alkylation of a phenol A with a benzyl bromide commercially available, using a base such as K2C03 or Cs2C03 in a solvent such as acetone or DMF at temperatures ranging from 20 to 100 ° C, followed by a saponification using the standard conditions described in Scheme A, leads to the phenyl acetic acid T A Friedel Craft reaction catalyzed by polyphosphoric acid in a solvent such as acetic anhydride at temperatures ranging from 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 the tricyclic U. Reduction of U under standard reaction conditions using sodium borohydride (NaBH4) in methanol for a few hours, followed by treatment with thionyl chloride in a solvent such as DC, as described in Scheme C or D, leads to V. Compound V then evolves to W using the reaction conditions previously described in Scheme C or D. Scheme G In some embodiments, as shown in scheme G, benzaldehyde X is reacted with an amino acid such as Boc-lysine or Boc-ornithine, using sodium cyanoborohydride in the presence of zinc chloride in a solvent such as methanol for up to 30 minutes. minutes, provides the amino acid Z. Cyclization from Z to AA takes place under standard coupling conditions such as hydroxybenzotriazole (HOBT) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCl) in a solvent such as DC or DF, at temperatures ranging from -30 to 50 ° C, for up to 12 hours. The saponification, as described in Scheme A, leads to the heterocycle BB. Scheme H In some embodiments, as shown in Scheme H, the benzyl bromide CC can be reacted with a heterocycle such as DD in the presence of a base such as Cs2C03 or K2C03 in a solvent system such as AcCN / DMF a temperatures ranging from 10 to 75 ° C for a few hours, followed by removal of the protection p and alkylation as described in Schemes G and A. Saponification of EE leads to the FF compound using standard reaction conditions as described in Scheme A. Scheme I i. LÍOH LL r (3Ctrtn MH In some embodiments, as shown in Scheme H, the reductive amination of benzaldehyde GG with an alken-1 -amine under the standard conditions described in Scheme G, leads to HH. The coupling of the amine HH to a protected amino acid such as 2- (tert-butoxycarbonylamino) pent-enoic acid in the presence of HATU and a base such as triethylamine or DIEA in a solvent such as AcCN or DMF for a few hours, leads to H. The first generation Grubb catalytic ring catalyzed closure in a solvent such as DCM for a few hours at temperatures ranging from 20 to 90 ° C, leads to seven-membered lactam JJ. Removal of the protection p 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 as RhCl (PPh 3) 3, for a few days, leads to the unsaturated heterocycle KK. Again, removal of the protection p under acidic conditions followed by sulfonylation and saponification, as described in Scheme A, leads to LL. Analysis of the Compounds In yet another aspect, the invention includes methods for evaluating putative agonists or antagonists specific to DP-2 and / or one or more different PGD2 receptors. Accordingly, the invention is directed to the use of these compounds in the preparation and execution of analysis of detection for compounds that modulate the function of DP-2 and / or one or more different PGD2 receptors. For example, the compounds of this invention are useful for mutants of DP-2 and / or one or more mutants of the different PGD2 receptors, which are excellent detection 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 different PGD2 receptors, e.g., by competitive inhibition. The compounds of the present invention are also useful for the evaluation of putative modulators specific for DP-2 and / or on one or more different PGD2 receptors. The person skilled in the art will appreciate that the complete evaluation of specific antagonists of PGD2 receptors has been obstructed by the lack of availability of specific non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. The compounds provided herein are particularly useful in this context. The above and other analyzes described herein are designed to be compliant to a high performance format for detecting or quantifying the presence, absence, quantification, or other properties of particular compounds, individually or as a library containing a large number of compounds Potential Therapeutics (potential modulator compounds). Any of the steps of the analysis can be automated and compounds can be provided to the analysis from any convenient source. Analyzes are typically operated in parallel (e.g., in microtiter plate formats in robotic analyzes). Preferred assays detect the enhancement or inhibition of DP-2, the function of DP-2 and / or one or more different PGD2 receptors. High performance detection systems are commercially available (see e.g., Zymark Corp. Hopkinton Mass.; Air Technical Industries, Mentor Ohio; Beckman Instruments, Inc., Fullerton Calif .; Precision Systems Inc., Natick Mass .; etc.). These systems typically automate complete procedures, including pipetting of all sample and reagent, fluid supply, timed incubations and final microplate readings in the appropriate detector (s) for analysis. These configurable systems provide high performance and fast start-up as well as a high degree of flexibility and suitability. The manufacturers of such systems provide detailed protocols for several high performance systems. Therefore, for example, Zymark Corp. provides technical bulletins describing detection systems to detect the modulation of gene transcription, ligand binding, and the like. Methods of Use The present invention relates to the identification of phenylacetic acid derivatives and their use as functional antagonists of the DP-2 receptor for the treatment of conditions or disorders mediated by PGD2, to pharmaceutical compositions containing these derivatives and to processes for their preparation. In particular, the compounds and derivatives of the general formula I have activity as modulators of DP-2 receptor activity and, consequently, can be used in the treatment of conditions or disorders caused by excessive, unbalanced or unregulated expression of PGD2 and its metabolites. The non-limiting example of such conditions and disorders includes: 1) Conditions or disorders of the respiratory system such as obstructive respiratory diseases such as: asthma, eg, intermittent and persistent asthma, extrinsic asthma (allergic), intrinsic asthma (non-allergic) , extrinsic-intrinsic mixed asthma, exercise-induced asthma, nocturnal asthma, bronchial asthma, seasonal asthma, occupational asthma, variant cough asthma, severe chronic asthma dependent corticosteroid asthma, asthma resistant to steroids, bronchopulmonary aspergillosis allergic, triad of asthma (including nasal polyps of asthma and sensitivity to aspirin) and allergic respiratory syndrome; bronchitis, e.g., acute and chronic bronchitis, allergic rhinobronchitis, eosinophilic bronchitis, and chronic obstructive pulmonary disease (COPD)); rhinitis, including acute and chronic rhinitis, atrophic rhinitis, allergic and nonallergic rhinitis, seasonal (e.g., rhinitis nervosa, pollen rhinitis, and vasomotor rhinitis), perennial and vasomotor rhinitis, nasal polyposis, nasal congestion, rhinitis medicamentosa; sarcoidosis; farm and related lung diseases; fibroid lungs; cystic fibrosis; idiopathic interstitial fibrosis; chronic cough associated with inflammation; and sinusitis, e.g., allergic, acute, sub-acute and chronic sinusitis; 2) Conditions or disorders of the skin and eyes such as dermatitis, eg, allergic contact dermatitis, atopic dermatitis (eczema), contact dermatitis (and irritant contact), dermatitis excematosa, neurodermatitis, perioral dermatitis, seborrheic dermatitis, ischemic dermatitis , diaper dermatitis, dyshidrotic dermatitis (pomfolix), nummular dermatitis, autosensitization dermatitis, chronic lichen simplex and urticaria; conjunctivitis, e.g., viral, allergic, bacterial and chemical / toxic conjunctivitis; psoriasis; urticaria; erythema; cutaneous eosinophilia; and chronic skin ulcers; 3) Conditions or disorders of the gastrointestinal system such as food-induced allergies (e.g., those that have remote effects from the intestine, such as migraine, rhinitis and ezcema); eosinophilic 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: e.g., eosinophilic fasciitis; hyper IgE syndrome; systemic mast cell disorder; idiopathic thrombocytopenic purpura; atherosclerosis; lupus erythematosus; systemic lupus erythematosus; sepsis; reperfusion injury; glomerulonephritis; allergic nephritis; Nephritic syndrome; disorders related to eosinophils 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, eg, arthritis and conditions associated with it, eg, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive arthritis), tendonitis, bursitis, inflammation of the joint overlay, ankylosing spondylitis, Behcet's disease, infantile arthritis, hyperostosis idiopathic diffuse skeletal disease (DISH), Ehlers-Danlos syndrome, rheumatoid arthritis, Felty syndrome, fibromyalgia, gout, pseudo-gout, infectious arthritis, lupus, mixed connective tissue disease, osteoarthritis, Paget's disease, polymyalgia rheumatica, polyarteritis nodosa, granulomatosis of egener, myositis (polymyositis dermatomyositis), psoriatic arthritis, Raynoud's phenomenon, and Still's disease; 7) Autoimmune conditions or disorders, eg, systemic lupus erythematosus, anti-phospholipid syndrome, rheumatoid arthritis, Sjogren's syndrome, scleroderma, systemic vasculitis, giant cell arteritis (temporal), Takayasu's arteritis, polyarteritis nodosa, Kawasaki's disease, granulomatosis Wegener, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schonlein purpura, essential cryoglobulinemic vasculitis, cutaneous leukocytoclastic angiitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, autoimmune neutropenia, diabetes mellitus, Hashimoto's disease, Grave's disease, autoimmune polyglandular syndromes, sclerosis multiple, 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 levels of PGD2 or its 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 different PGD2 receptors, by administering to a subject, having such a condition or disorder, a therapeutically effective amount of a compound or composition of the invention. In a group of embodiments, disorders and conditions, including chronic conditions and disorders of humans or other species, can be treated with modulators or antagonists of DP-2 and / or one or more different PGD2 receptors. These disorders and conditions include (1) inflammatory or allergic diseases such as systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, allergies to insect pickets, 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 and inflammatory dermatosis such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria , viral cutaneous pathologies such as those derived from human papillomavirus, HIV infection or VLR, cutaneous bacterial, fungal and other parasitic pathologies, and cutaneous lupus erythematosus, (5) asthma and respiratory allergic diseases such as asthma allergic, allergic rhinitis, otitis media, allergic conjunctivitis, pulmonary hypersensitivity diseases, chronic obstructive pulmonary disease and the like, (6) autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis , multiple sclerosis, Grave's disease, glomerulonephritis, scleroderma, including eg, systemic scleroderma, fasciitis, including, eg, eosinophilic fasciitis (Schulman's syndrome), Sjogren's syndrome, hyper IgE syndrome, soft tissue disease, and inflammatory myopathies and similar, (7) rejection of the graft (including, eg, rejection of the xenograft, and graft-versus-host disease), eg, rejection of the skin graft, rejection of organ transplantation, rejection of bone marrow transplantation, (8) fever , (9) cardiovascular disorders such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, car diomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, thrombosis and vascular stenosis, (10) cerebrovascular disorders such as traumatic brain injury, stroke, ischemic reperfusion and aneurysm, (11) cancers of the breast, skin, prostate, cervix , uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (eg, esophagus, stomach, pancreas), brain, thyroid, blood and lymphatic system, (12) fibrosis, 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 syndrome and Pickwick syndrome, (17) pain, (18) kidney disorders, (19) eye disorders such as glaucoma, (20) infectious diseases, viral infections such as HIV, and bacterial infections such as sepsis, (21) inflammation, (22) run-off 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 Th2 cells, eosinophils, basophils, platelets, Langerhans cells, dendritic cells or mast cells, comprising administering, to a subject having such a condition or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions. In yet another aspect, the invention provides methods for treating or preventing a condition or disorder mediated, regulated or influenced by PGD2 and its metabolites, such as 13, 14-dihydro-15-keto-PGD2 and 15-deoxy-delta12, 14PGJ2, that comprise administering, to a subject that has such a condition or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions. In yet another aspect, the invention provides methods for treating or preventing a condition or disorder responsive to the modulation of DP-2 and / or one or more different PGD2 receptors, comprising administering, to a subject having such a condition or disorder. , a therapeutically effective amount of one or more of the subject compounds or compositions. In yet another aspect, the invention provides methods for treating or preventing a condition or disorder mediated by DP-2 and / or one or more different PGD2 receptors, comprising administering, to a subject having such a condition or disorder, a therapeutically effective of one or more of the subject compounds or compositions. In yet another aspect, the invention provides methods for modulating DP-2 and / or one or more different PGD2 receptors, comprising contacting a cell with one or more of the subject compounds or compositions. Depending on the disorder being treated and the subject's condition, the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, injection or implant routes of administration). subcutaneous), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal, local), and may be formulated alone or together, in appropriate dosage unit formulations containing appropriate conventional pharmaceutically acceptable non-toxic carriers, adjuvants, and carriers. for each route of administration. The invention also contemplates the administration of the compounds of the invention in a depot formulation, in which the active ingredient is released for 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 different PGD2 receptors, an appropriate dose level will generally be from about 0.001 to 100 mg per kg of weight daily body, which can be administered in single or multiple doses. Preferably, the dose level would 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 dose level may be from about 0.01 to 25 mg / kg per day, from about 0.05 to 10 mg / kg per day or from about 0.1 to 5 mg / kg per day. Within this range the dose can 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 provided preferably in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 150.0, 300.0, 400.0, 500.0, 600.0, 750.0 , 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dose for the patient to be treated. The compounds can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day. However, it will be understood that the specific dose level and frequency of the dose for any particular patient may vary and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, severity of the particular condition, and the host experiencing the therapy . 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 ingredients specified (and in the specified quantity, if indicated), as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified quantities. By "pharmaceutically acceptable" is meant that the vehicle or excipient is compatible with the other ingredients of the formulation and is not harmful to the recipient thereof. The formulation can improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (referred to herein as an 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 step of placing the active ingredient in association with the vehicle that constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active target compound is included in an amount sufficient to produce the effect desired about the process, condition or disorder. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions intended for oral use can 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 agents and preservatives, in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with other pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients, for example, can be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and, consequently, provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They can also be coated by the techniques described in the U.S. Patents. Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release. Formulations for oral use can 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, wherein the Active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and acacia gum; the dispersing or wetting agents may be a phosphatide of natural origin, for example, lecithin, or condensation products of an alkylene oxide with acids fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant 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 can be a vegetable oil, for example olive oil or arachis oil or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example gum acacia or gum tragacanth, phosphatides of natural origin for example, soybean seed, lecithin and partial esters or esters derived from fatty acids and hexitol anhydrides, for example, monooleate sorbitan, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene monooleate sorbitan. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that can be used, are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any fixed soft oil including synthetic mono or diglycerides can be employed. In addition, fatty acids such as oleic acid find their use in the preparation of injectables. The pharmaceutical compositions can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which It is solid at ordinary temperatures but is liquid at the rectal temperature and, consequently, will melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. are used, which contain the compounds of the invention. As used herein, the topical application is also intended to include the use of mouth rinses and gargles. Pulmonary Administration Inhalable Powders In some modalities, agents are administered directly to the lung by inhalation. Accordingly, the agents for use according to the invention can be formulated as inhalable powders in admixture with suitable physiologically acceptable excipients (see U.S. Patent Publication No. 20060034776 which is incorporated herein by reference with respect to the appropriate methods to administer pharmaceutical agents by inhalation). For aerosol delivery in humans or other primates and mammals, the aerosol is generated by a medical nebulizer system that delivers the aerosol through a buccal piece, face mask, etc., from which the mammalian host can introduce the aerosol to the lungs Various sprayers are known in the art and can be used in the method of the present invention. The selection of a nebulizer system depends on whether an alveolar or respiratory supply is desired (i.e., trachea, primary, secondary or tertiary bronchi, etc.). The composition is formulated so as not to be too irritating in the required dose. 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 alleviate asthma after administration of the composition to the lung of the mammalian host, particularly the alveoli or bronchopulmonary way and the soft muscle in a bronchiolopulmonary fashion and to the epithelial cells of the trachea, bronchi, bronchioles, and alveoli. Therefore, an effective amount of the aerosol compound of the invention is a sufficient dose to effect the treatment, that is, to cause the relief or reduction of the symptoms, to inhibit the worsening of the symptoms, to prevent the onset of the symptoms and the like. The doses of the present compositions that constitute an effective amount, can be determined in view of this description by the one of ordinary experience in the technique, carrying out routine tests with appropriate controls. Comparison of appropriate treatment groups with controls will indicate whether a particular dose is effective in preventing or reducing particular symptoms. The total amount of a compound delivered to a mammalian host will depend on many factors, including the total amount aerosolized, the type of nebulizer, the particle size, the respiration patterns of the mammalian host, the severity of the lung disease, the concentration of the composition of the compound in the aerosolized solution and the extension of the inhalation therapy. In spite of the interacting factors described above, one of ordinary skill in the art will be able to easily design effective protocols, particularly if the aerosol particle size is optimized. Based on estimates of the efficiency of the nebulizer, an effective dose delivered commonly falls in the range of about 1 mg / treatment to about 500 mg / treatment, although it may be more or less effective depending on the subject, the agent, the dose regimen , and the desired result. Generally, it is desirable to administer higher doses when treating more severe conditions. If the treatment is repeated, the mammalian host can be monitored to ensure that no There is an adverse response to treatment. The frequency of treatments depends on a number of factors, such as the amount of the agent administered per dose as well as the health and history of the subject. Inhaled aerosols for inhalation with propellant gas Inhalation aerosols containing a propellant gas according to the invention may contain the agents for use according to the invention, dissolved in a propellant gas or in dispersed form. The propellant gases that can be used to prepare the aerosols for inhalation 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 halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane. The propellant gases mentioned above can be used by themselves or in mixtures thereof, the particularly preferred propellant gases are halogenated alkane derivatives selected from TG134a, TG227, and mixtures thereof. The aerosols for inhalation activated with propellant, according to the invention, may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, preservatives and pH adjusters. All these ingredients are known in the art.
When they are in dispersed form, the agents, for example, can be formulated to have an average particle size of up to 10 microns or preferably from 0.1 to 5 microns, or from 1 to 5 microns. The above-mentioned propellant-activated inhalation aerosols according to the invention can be administered using inhalers known in the art, such as metered dose inhalers. Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of aerosols containing propellant gas as described above, combined with one or more inhalers suitable for administering these aerosols. Solutions or Inhalable, Propellant-Free Suspensions. Inhalable, propellant-free solutions and suspensions of the agents for use in accordance with the invention are contemplated. The solvent used can be an aqueous or alcoholic, preferably ethanolic solution. The solvent can be water alone 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 by volume. The rest of the volume is made up of water. Combination Therapy The pharmaceutical compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of asthma, allergic diseases, inflammatory conditions and cancer and pathologies associated therewith (eg, cardiovascular disease) or another adjuvant In many examples, compositions that include 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 condition 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, runoff, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, inflammation, pain, conjunctivitis, nasal congestion, urticaria and those pathologies noted above. Such other agents or drugs can be administered by a route and in a quantity commonly used for the same, 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 include those that also contain one or more other active ingredients or therapeutic agents in addition to a compound of the invention. Examples of other therapeutic agents that can be combined with a compound of the invention, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinoclone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and corticosteroid analogs such as budesonide; (c) immunosuppressants such as cyclosporine (cyclosporin A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other immunosuppressants type FK-506, and mycophenolate, eg, mycophenolate mofetil (CellCept®); (d) antihistamines (histamine Hl antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenylhydramine, diphenylethylamin, tripelenamine, hydroxyzine, metdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, phenylamine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxylylotadine and the like; (e) non-steroidal anti-asthmatics such as beta 2 -antagonists (eg, terbutaline, metaproterenol, fenoterol, isoetarin, albuterol, salmeterol, bitolterol, and pirbuterol) and combinations of beta 2 -blocker steroids (eg, salmeterol-fluticasone (Advair®) , formoterol-budesonid (Symbicort®)), theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene antagonists (eg, zafirlukast, montelukast, montelukast sodium (Singulari®), pranlukast, iralukast, pobilikast and SKB-106, 203), inhibitors of leukotriene biosynthesis (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (eg, alminoprofen, benoxaprofen, bucilloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, thiaprofenic acid, and thioxaprofen), acetic acid derivatives (eg, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxipinac, sulindac, thiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (eg, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (eg, diflunisal and flufenisal), oxicams (eg, isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (eg, acetylsalicylic acid and sulfasalazine) and pyrazolones (eg, apazone, bezpiperilon, feprazone, mofebutazone, oxifenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) phosphodiesterase type IV inhibitors (PDE-IV); (i) other PGD2 receptor antagonists, especially DO-1 antagonists; (j) opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butofanol, dezocin, nalbuphine and pentazocine; (k) cholesterol lowering agents such as HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (eg, cholestyramine and colestipol), vitamin B3 (also known such as nicotinic acid, or niacin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), fibric acid derivatives (eg, gemfibrozil, clofibrate, fenofibrate, and benzafibrate), probucol, nitroglycerin, and inhibitors of absorption of cholesterol) e.g., beta-sitosterol and inhibitors of acylCoA-cholesterol acyltransferase (ACAT) such as melinamide), inhibitors of HMG-CoA synthase, squalene epoxidase inhibitors and squalene synthetase inhibitors; (1) antithrombotic agents, such as thrombolytic agents (eg, streptokinase, alteplase, anistreplase and reteplase), derivatives of heparin, hirudin and warfarin, O-blockers (eg, atenolol), O-adrenergic agonists (eg, isoproterenol), inhibitors of ACE and vasodilators (eg, sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enaloprilat); (m) anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (eg, glyburide, meglinatide), biguanides, eg, metformin (Glucophage®), alpha-glucosidase (acarbose) inhibitors, thiazolidinone compounds, eg, rosiglitazone (Avandia®), troglitazone (Rezulin), ciglitazone, pioglitazone (Actos®) and englitazone; (n) preparations of beta interferon (interferon beta-1 alpha, interferon beta-1 beta); (o) gold compounds such as auranofin and aurothioglucose, (p) TNF inhibitors, eg, etanercept (Enbrel®, antibody therapies such as orthoclone (0KT3), daclizumab (Zenapax®), basiliximab (Simulect®), infliximab ( Remicade®) and antibody D2E6 TNF, (q) lubricants or emollients such as petrolatum and lanolin, keratolytic agents, vitamin D3 derivatives (eg, calcipotriene and calcipotriol (Dovonex®), PUVA, anthralin (Dithrocreme®), Atretinate (Tegison®) and Isotretinoin; (r) therapeutic agents for multiple sclerosis such as interferon beta-1 beta (Betaseron®), interferon beta-1 alpha (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid ( eg, prednisolone) and cyclophosphamide; (s) other compounds such as 5-aminosalicylic acid and prodrugs thereof; (t) DNA alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, azathioprine, 6-mercaptopurine, methotrexate, a folate antagonist and 5-fluoroacyl, a pyrimidine antagonist), microtubule fracturing agents (eg, vincristine) , vinblastine, paclitaxel, colchicine, nocodazole and vinorelbine), DNA intercalators (eg, doxorubicin, daunomycin and cisplatin), DNA synthesis inhibitors such as hydroxyurea, DNA crosslinking agents, eg, mitomycin C, hormone therapy (eg, tamoxifen and flutamide), cytostatic agents, eg, imatinib (ST157I, Gleevec®) and rituximab (Rituxan®), inhibitors of 5-lipoxygenase activation protein (FLAP), and PLA2 inhibitors. The weight ratio of the compound of the invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is combined with an NSAID, the weight ratio of the compound of the invention to the NSAID will generally range from about 1000: 1 to about 1: 1000, preferably from about 200: 1 to about 1: 200. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. Asthma Diagnosis Methods for diagnosing asthma and other disorders or inflammatory and obstructive inflammatory conditions are well known to those of ordinary skill in the art. For example, spirometry may be used to evaluate lung function. The diagnosis of asthma, in particular, may be made, in part, on the basis of family history or personal history of a severe and sudden episode or recurrent episodes of wheezing, coughing or shortness of breath that may be associated with exposure to an allergen. or exacerbated or precipitated by moderate exercise. Typically a physical examination is involved to detect the disorder or condition. Using a nasal speculum, the nose can be examined for signs of disorder or allergic condition such as increased nasal secretions, swelling, or polyps that can trigger asthma. A stethoscope can be used to listen to the sounds produced by the lungs during breathing. Whistling sounds are one of the main indicators of obstructed airways associated with asthma. In addition allergic conditions such as eczema or hives, are frequently associated with asthma. Pulmonary function tests are particularly useful in confirming the diagnosis of disorders or respiratory conditions. These tests include spirometry to determine vital capacity, the maximum amount of air that can be inhaled and exhaled; the peak expiratory flow rate, also known as the peak flow rate, which is the maximum flow rate that can be generated during a forced exhalation; and forced expiratory volume, which is the maximum amount of air that can be exhaled in a second. If the measurements are below normal for a person of their age, a bronchodilator drug used in the treatment of asthma can be given to open the clogged air passages and repeat spirometry. If the measurements increase significantly, it is the probability of asthma. In addition, asthma can be diagnosed by testing the individual with exercise or by inhaling a chemical constrictor. the airways or taking several breaths of cold air. After testing with a substance or activity that produces the symptom, the spirometry test is re-administered. If spirometry measurements fall significantly, asthma is indicated. The following examples are offered by way of illustration and are not intended to limit the scope of the invention. Those skilled in the art will readily recognize a variety of non-critical parameters that could be modified to produce essentially similar results. EXAMPLES General Methods: The invention will now be illustrated by the following non-limiting examples. The title and sub-title compounds of the examples and methods were named using ChemDraw Ultra (version 7.0) from Cambridge Soft Inc. Flash column chromatography refers to normal phase silica chromatography. The reagents and solvents used can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). The solvents were dried with MgSO4 or Na2SO4. The evaporations were carried out by rotary evaporation in vacuo and the production processes were carried out after removal of the residual solids such as drying agents, by filtration. Unless defined otherwise, the operations were carried out at room temperature, that is, in the range of 18-25 ° C and under an atmosphere of an inert gas such as argon or nitrogen. The returns are provided for illustration only and are not necessarily the maximum obtainable. The structures of the final products of the structure (I) were confirmed by nuclear magnetic resonance (usually protons) (PMR) and mass spectral techniques. The 1H-NMR spectra were recorded on a Spectrometer Varian 400 MHz NR. The proton magnetic resonance chemical change values were measured on the delta scale, delta, in parts per million. (ppm). Significant peaks are tabulated in the order: multiplicity (s, single, - d, double; t, triple; q, quadruple; m, multiple; br s, broad only), coupling constant (s) in Hertz (Hz) and number of protons. Intermediates were not fully characterized in general and purity was assessed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), mass spectrometry (MS), infrared (IR) or NMR analysis. The mass spectra were recorded by one of the three methods of liquid chromatography / mass spectrometry (LC / S): Method A: Introduction in an Agilent 1100 HPLC on a Luna C18 phenomenex column 3 micron 30 x 2.0 mm id at a flow rate of 0.300 ml / min. The column, at 35 ° C, was eluted with a gradient comprised of increasing AcCN (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the following table. The analytes were monitored at 214 nm and 254 nm. The analytes were vaporized in an Agilent electro-sputtering source charged at 80V and detected after passing through a single quadrupole. Gradient Method B: Introduction in an Agilent 1100 HPLC on a phenomenex Luna C18 column of 3 microns 30 x 2.0 mm id at a flow rate of 0.300 ml / min. The column, at 35 ° C, was eluted with a gradient comprised of increasing AcCN (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the following table. The analytes were monitored at 214 nm and 254 nm. The analytes were vaporized in an Agilent multi-mode source in electroaspersion charged at 80V and were detected after passing through a single quadrupole.
Gradient Method C: Introduction in an Agilent 1100 HPLC on a phenomenex Luna C18 column of 3 microns 30 x 2.0 mm id at a flow rate of 0.300 ml / min. The column, at 35 ° C, was eluted with a gradient comprised of increasing methanol (modified with 0.05% formic acid) and water (modified with 0.05% formic acid) as described in the following table. The analytes were monitored at 214 nm and 254 nm. The analytes were vaporized in an Agilent multi-mode source in atmospheric chemical ionization mode charged to 80V and detected after passing through a single quadrupole. Gradient Examples 1-53 Method 1A: To tert -butyl 4- (2-hydroxy-5- (2-methoxy-2-oxoethyl) benzyl) iperazine-l-carboxylate (0.41 mol, 0.150 g) in DMF (1 mL) was added K2C03 (0.82 mol, 0.113). g), alkyl halide, R4aX (0.58 mol) and catalytic KI. The reaction was stirred at 100 ° C until the absence of the starting material was observed. Once complete, the reaction mixture was produced by quenching with water and then extracting several times in EtOAc. The combined organics were washed with brine and dried over Na2SO4. The material was filtered, dried and used without further purification.
R4a Example Method R5 MW m / z Method Rt of Sint. Prom. LC / MS (min.) 27 5 447 447.2, A 2.60 xr 449.2 Method 8 To piperazine (0.12 mol) in 2 ml of methylene chloride, DIEA (0.15 mol) and acid chloride (0.12 mol) were added. The reaction was stirred at room temperature until complete by LC / MS. The product was purified by reverse phase HPLC (Rainin) using a gradient of 1: 3 CH3CN / H20 / 0.1% formic acid to a gradient of 9: 1 CH3CN / H20 / 0.1% formic acid, over a period of 23 minutes Example 54 4- [5-Carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-l-carboxylic acid tert-butyl ester (Compuest 54) To tert -butyl 4- (2-hydroxy-5- (2-methoxy-2-oxoethyl) benzyl) iperazine-l-carboxylate (0.41 mol, 0.150 g) in DMF (1 mL) was added K2C03 (0.82 mol, 0.113 g), alkyl halide, R4aX (0.58 mol) and catalytic KI. The reaction was stirred at 100 ° C until the absence of the starting material was observed. Once complete, the reaction mixture was produced by quenching with water and then extracting several times in EtOAc. The combined organics were washed with brine and dried over 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-ylmethyl) phenyl) acetate (Compound 55A) and 2- (4- (4-chlorobenzyloxy)) -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) To methyl 2- (4- (4-chlorobenzyloxy) -3- (piperazine-1-ylmethyl) phenyl) acetate (0.13 mol) in AcCN with TEA (0.31 mol, 0.043 ml), 2-chloropyrimidine (0.13 mol, 0.015 g). The mixture was heated at 80 ° C for 72 hours, then dried over MgSO4. The desired material was used without further purification. LC / MS (Method A) Rt = 2.66 minutes, MS m / z (M + H) 467.2. 2- (4- (4-Chlorobenzyloxy) -3- (4- (pyrimidin-2-yl) piperazine-1-ylmethyl) phenyl) acetic acid (Compound 55B) 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 (M + H). LC / MS (Method A), Rt = 2.55 minutes. Example 56 Methyl 2- (4- (3,4-dichlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 56A) and 2- (4- (3,4-Dichlorobenzyloxy) -3-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 56B) The title compounds were prepared according to General Methods 1A to 2 using 1,2-dichloro-4- (chloromethyl) benzene and 4-methyl phenyl sulfonyl chloride. Compound 56B LC / MS: (Method A), Rt = 2975 minutes. MS (m / z) 563 (M + H). Example 57 2- (4- (4-Fluorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 57A) and 2- (4- (4-fluorobenzyloxy) -3- acid ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 57B) 57B The title compounds were prepared according to General Methods 1A to 2 using 1- (chloromethyl) -4-fluorobenzene and -methyl phenyl sulfonyl chloride; however, after hydrolysis, the final product was isolated as an HCl salt upon acidification of the reaction mixture with 1. ON aqueous HCl without further purification. Compound 57B LC / MS: (Method A), Rt = 2763 minutes. MS (m / z) 513 (M + H). Example 58 Methyl 2- (4- (4-nitrobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 58A) and 2- (4- (4-nitrobenzyloxy) -3- acid ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 58B) The title compounds were prepared according to Methods 1A to 2 using 1- (chloromethyl) -4-nitrobenzene and 4-methyl phenyl sulfonyl chloride. Compound 58B MS (m / z) 540 (M + H). XH NMR (300 MHz, CDCl 3) delta: 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) and 2- (4- ( 4-chlorobenzyloxy) -3 - ((4- (3,5-dichlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 59B) 59B 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 yielding the title compound as a TFA salt. Compound 59B. 1 H NMR (300 MHz, DMSO-de) delta: 8.24 (1H, s), 8.02 (1H, t), 7.76 (1H, s), 7.44 (4H, dt), 7.32-6.98 (3H, m), 5.23 (2H, t), 4.48-3.95 (4H, v, br s), 3.6 (2H, s), 3.5 (2H, s), 3.47-2.73 (4H, v, br s). Example 60 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (4-ethylphenylsulfonyl) iperazin-1-yl) methyl) phenyl) acetate (Compound 60A) and 2- (4- (4-chlorobenzyloxy)) -3- ((4- (4-ethylphenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 60B) The title compounds were prepared according to Standard Methods 1A to 2 using 4-ethylbenzene-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compound 60B-equal MS (m / z) 544 (M + H). ?? NMR (300 MHz, DMSO-dg) delta: 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 s), 3.5 (2H, s), 2.7 (2H, dq), 1.19 (3H, t). Example 61 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (naphthalen-1-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 61A) and 2- (4- ( 4-chlorobenzyloxy) -3- ((4- (naphthalen-1-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 61B) The title compounds were prepared according to General Methods 1A to 2 using naphthalene-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene.
Compound 61B MD (M + H) 566 (M + H). XH MR (300 MHz, DMSO-dg) delta: 8.62 (1H, 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 Methyl (E) -2- (4- (4-chlorobenzyloxy) -3- ((4- (styrylsulfonyl) piperazin-1-ylmethyl) phenyl) acetate (Compound 62A) and Acid (E) -2- (4 - (4-chlorobenzyloxy) -3- ((4- (styrylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 62B) The title compounds were prepared according to General Methods 1A to 2 using (E) -2-phenylethenesulfonyl chloride and l-chloromethyl-4-chlorobenzene. Compound 62B LC / MS: (Method A), Rt = 2838 minutes. MS (m / z) 542 (M + H). Example 63 Methyl 2- (3- ((4- (4-chloro-3- (trifluoromethyl) phenylsulfonyl) piperazin-1-ylmethyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 63A) and 2- ( 3- ((4- (4-chloro-3- (trifluoromethyl) phenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 63B) The title compounds were prepared according to General Methods 1A to 2 using 4-chloro-3- (trifluoromethyl) benzene-1-sulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Compound 63B LC / MS: (Method A) Rt = 3,229 minutes. MS (m / z) 618 (M + H). Example 64 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (phenethylsulfonyl) 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) The title compounds were prepared according to General Methods 1A to 2 using 2-phenylethanesulfonyl chloride and 1-chloromethyl-4-chlorobenzene. Upon acidification of the reaction mixture with 1.0 N of HC1, a white solid broke. The solid was collected by filtration, washed with water and dried under high vacuum to provide pure compound 64B. LC / MS: (Method A), Rt = 2.854 minutes. MS (m / z) 544 (M + H).
Ex emplos Scheme 1 81 C1 General Method 65 Stage A: The intermediate Al (100 mg, 0.32 mol) was dissolved in 5 ml of DMF. To the solution was added alkyl bromide (0.35 mol, 1.1 equivalents) and K2C03 (0.48 mol, 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 and concentrated. The crude residue was purified by reverse phase HPLC (Column: Phenomenex, 250 x 10 mm, 10 microns, Luna 10 u; Gradient: 90%: 10%: 0.05% H20 / CH3CN / TFA (O formic acid) a 10%: 90%: 0.05% H20 / CH3CN / TFA (or formic acid) for 20 minutes). Step B: The fractions containing intermediate Bl from the HPLC purification in step A were drained and 5-8 ml of 1.0 N aqueous KOH was added. The resulting mixture was stirred until the reaction was completed as confirm by LC / MS analysis. The reaction was then acidified to pH 2.4 with 1.0 N of HC1 and extracted with EtOAc / isopropyl alcohol. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to yield the desired product. Example 65 Methyl 2- (4-isopropoxy-3- (S, S-dioxo-thiomorpholine methyl) phenyl) acetate (Compound 65A) and 2- (4-isopropoxy-3- (S, S-dioxo-thiomorpholine methyl) acid) phenyl) acetic (Compound 65B) The title compounds were prepared according to General Method 65, Steps A-B using 2-bromo propane. LC / MS: Method C, Rt = 5.59 minutes. MS (m / z) 342 (M + H). Example 66 2- (4-Isopentyloxy-3- (S, S-dioxo-thiomorpholine methyl) phenyl) acetic acid (Compound 66A) and 2- (4-isopentyloxy-3- (S, S-dioxo-thiomorpholine methyl) acid) phenyl) acetic (Compound 66B) The title compounds were prepared according to General Method 65, Steps A-B using l-bromo-3-methylbutane. LC / MS Method C, Rt = 6,370 minutes. MS (m / z) 370 (M + H). Example 67 Methyl (S) -2- (4- (2-methylbutoxy) -3- (S, S-dioxo-thiomorpholine methyl) phenyl) acetate (Compound 67A) and Acid (S) -2- (4- (2- methylbutoxy) -3- (S, S-dioxo-thiomorpholine methyl) phenyl) acetic acid (Compound 67B) The title compounds were prepared according to General Method 65, Steps A-B using (S) -1-bromo-2-methylbutane. LC / MS: Method C, Rt = 6.290 minutes. MS (m / z) 370 (M + H). Example 68 2- (4-Isobutoxy-3- (thiomorpholino 1,1'-dioxydimethyl) phenyl) acetic acid (Compound 68A) and 2- (4-isobutoxy-3- (thiomorpholino 1,1'-dioxymethyl) phenyl) acetic acid ( Compound 68B) The title compounds were prepared according to General Method 65, Steps A-B using l-bromo-2-methylpropane, however, the product recovered from step B was insufficiently pure and subjected to HPLC purification. Compound 68B, LC / MS: (Method A), Rt = 2744 minutes. MS (m / z) 356 (M + H). Example 69 2- (4- (Isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 69D) Step A: t-Butyl 4- (2- (isopentyloxy) -5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (Compound 69A) K2C03 (379 mg, 2.74 mol) and l-chloro-3-methylbutane (107 mg, 1.51 mol) were added to a stirred solution of t-butyl 4- (2-hydroxy-5- (2-methoxy-2 - oxoethyl) benzyl) piperazine-1-carboxylate (500 mg, 1.37 mol) in 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 H20 (30 mL), dried over Na2SO4 and concentrated to give the crude ether (492 mg) as a brown oil. The compound was taken to the next step without purification.
Step B: Methyl 2- (4- (isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (Compound 69B) TFA (0.211 ml) was added to a stirring solution of t-butyl ether 4- (2 - (crude isopentyloxy) -5- (2-methoxy-2-oxoethyl) benzyl) piperazine-1-carboxylate (492 mg) in CH2C12 (5 ml) at room temperature. The reaction mixture was stirred overnight, then warmed with saturated NaHCC-3 (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (20 1), dried over Na 2 SO 4 and concentrated to provide crude piperazine (300 mg) as a brown oil. The compound was taken to the next step without purification.
Step C: Methyl 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 69C) DIEA (0.156 ml, 0.897 mol) and TsCl (94 mg, 0.493 mol) to a stirred solution of crude piperazine methyl 2- (4- (isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (150 mg, 0.448 mol) in CH2C12 (5 ml) at room temperature . The resulting suspension was warmed with saturated NaHCO3 (20 mL) after 16 hours and the aqueous layer was extracted with CH2C12 (3 x 15 mL). The combined organic layers were dried over Na 2 SO 4, then concentrated to provide crude sulfonamide. The compound was taken to the next step without purification.
Step D: 2- (4- (Isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 69D) Solid LiOH (64 mg, 1.53 mol) was added to a stirred solution of methyl 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) (187 mg, 0.383 mol) in THF / MeOH / H20 (5 mL, 3: 1: 1) at room temperature. After stirring overnight, the resulting mixture was warmed with 1 N HCl (< pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and concentrated to give the crude acid (226 mg) as a brown oil. Purification of HPLC yielded the pure compound: ES / MS, m / z 476 (M + H). EXAMPLE 70 2- (4- (Isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 70B) Step A: Methyl 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 70a) DIEA (0.156 ml, 0.897 mol) and PhNCO (0.054 ml, 0.493 mol) were added to a stirring solution of piperazine methyl 2- (4- (isopentyloxy) -3- (piperazin-1-ylmethyl) phenyl) acetate (150 mg, 0.448 mol) in CH2C12 (5 mL) at room temperature. The resulting solution was quenched with aqueous NaHCO3 (20 mL) after stirring overnight. The aqueous layer was extracted with CH2C12 (3 x 20 mL), dried over Na2SO4, and concentrated to provide urea as a brown oil (183 mg). The compound was taken to the next step without purification. 2- (4- (Isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 70B). Solid LiOH (67 mg, 1.61 mol) was added to a stirred solution of methyl 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetate (183 mg). , 0.403 mol) in THF / MeOH / H20 (5 mL, 3: 1: 1). After stirring overnight, the resulting mixture was quenched with 1N CH1 (< pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and concentrated to give a crude acid (226 mg) as a brown oil. The purification HPLC gave the pure compound: ES / MS m / z 440.2 (M + H) LC / MS (Method C) Rt = 2.58 minutes. EXAMPLE 71 Methyl 2- (4- (cyclopentyloxy) -3- ((4-tosylpiperazin-2-yl) methyl) phenyl) acetate. (Compound 71A) and 2- (4- (Cyclopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 71B): The title compounds were obtained using bromine cyclopentane and 4-methyl phenyl sulfonyl chloride, using the described method for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 71B ES / MS, m / z 473.3 (M + H); LC / MS (method C) Rt = 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 72B): The title compounds were obtained using bromo 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 (M + H); LC / MS (method C) Rt = 2.50 minutes. Example 73 Methyl [4- (4-chloro-benzyloxy) -3,5-bis- (4-phenylcarbamoyl-piperazin-1-ylmethyl) phenyl] acetate (Compound 73A) and [4- (4-chloro-benzyloxy)] 3, 5-bis- (4-phenylcarbamoyl-piperazin-1-ylmethyl) phenyl] acetic acid (Compound 73B): The title compounds were obtained using (1-chloromethyl) -4-chlorobenzene and phenyl isocyanate, using the method described for 2- (4- (4-chlorobenzyloxy) -3- ((4- (phenylcarbamoyl) piperazine-1) acid -yl) phenyl) acetic acid ES / MS, m / z 712 (M + H) Example 74 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): The title compounds were obtained using bromine methyl cyclopropane and 4-methyl phenyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 74B: ES / MS, m / z 459.3 (M + H); LC / MS (Method C) Rt = 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): The title compounds were obtained using bromine methyl cyclopropane and phenyl isocyanate, using the method described for 2- (4- (isopentyloxy) -3- ((4-phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid. Compound 75B: ES / MS, m / z 424.3 (M + H); LC / MS (Method C) Rt = 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-tosylpiperazine-1) il) methyl) phenyl) acetic (Compound 76B): The title compounds 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 76B ES / MS m / z 419.2 (M + H); LC / MS (Method C) Rt = 2.50 minutes. Example 77 Methyl 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) iperazin-1-yl) methyl) phenyl) acetic acid (Compound 77B): The title compounds 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.
Compound 77B: ES / MS, m / z 545.1 (M + H); LC / MS: (Method A) Rt = 2.79 minutes. Example 78 Methyl 2- (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 78B): The title compounds 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. Compound 78B: ES / MS m / z 585.2 (M + H); LC / MS (Method C) Rt = 3.12 minutes. Example 79 Methyl 2- (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 79B): The title compounds 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 79B: ES / MS, m / z 549.2 (M + H); LC / MS (Method C) Rt = 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 80B): The title compounds were obtained using 1-chloromethyl 4-chlorobenzene and 3-methyl phenyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 80B: ES / MS, m / z 529.3 (M + H); LC / MS (Method C) Rt = 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 81B): The title compounds 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. Compound 81B: ES / MS, m / z 529.3 (M + H); LC / MS (Method C) Rt = 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-tosylpiperazine -l-yl) methyl) -4- (4- (trifluoromethyl) benzyloxy) phenyl) acetic acid (Compound 82B): The title compounds 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) acid) methyl) phenyl) acetic. Compound 82B: ES / MS, m / z 563.3 (M + H); LC / MS (Method C) Rt = 3.04 minutes. Example 83 4- ((4- (Carboxymethyl) -2- ((4-tosylpiperazin-1-yl) methyl) phenoxy) methyl) benzoic acid (Compound 83): The title compounds were obtained using 1-bromomethyl 4-cyano and 4-methyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3- ((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 539.3 (M + H); LC / MS (Method C) Rt = 2.46 minutes. EXAMPLE 84 Methyl. { 4- (2,4-dichloro-benzyloxy) -3- [l-oxy-4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetate (Compound 84A) and Acid. { 4- (2,4-dichloro-benzyloxy) -3- [l-oxy-4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic (Compound 84B): The title compounds were obtained using 2,4-dichlorobenzyl chloride and 4-methyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid. ) methyl) phenyl) acetic, followed by treatment with mCPBA in CH2C12. Compound 84B: ES / S, m / z 580.1 (M + H). Examples 85-88 Scheme 2 Example 85 2- (2- ((4-tosylpiperazin-1-yl) methyl) biphenyl-4 acid il) acetic (Compound 85C).
Step A: Ter-Butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (trifluoromethylsulfonyloxy) benzyl) piperazine-1-carboxylate (Compound 85A) Trifluoromethanesulfonic anhydride (0.691 ml, 4.12 mol), DIEA (0.718 ml, 4.12 mol) and DMAP (33 mg, 0.274 mol) were added to a stirring solution of t-butyl 4- (2-hydroxy-5- (2 - methoxy-2-oxoethyl) benzyl) piperazine-l-carboxylate (1.74 mol) in CH2C12 (20 mL) at 0 ° C. The resulting suspension was warmed to room temperature and stirred overnight followed by the addition of saturated NaHCO3 (30 mL). The aqueous layer was extracted with CH2C12 and the combined organic layers were dried over Na2SO4, then concentrated to give the crude (1.945 g) as a yellow oil. A flash chromatography on silica gel (3: 1 hexanes / EtOAc) provided the pure material (0.85 g, 62%).
Step B: Ter-butyl 4- ((4- (2-methoxy-2-oxoethyl) biphenyl-2-yl) piperazine-1-carboxylate (Compound 85B) Palladium tetrakis (22 mg, 0.0191 mol) and phenyl acid was added boronic (51 mg, 0.421 mol) to a stirred solution of tert -butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (trifluoromethylsulfonyl) benzyl) piperazine-1-carboxylate (190 mg, 0.383 mol) in dimethoxy methane / 2 M Na 2 CO 3 (2: 1.9 mL) After refluxing for 3 days, the resulting suspension was cooled, then the organic layer was concentrated, Water (10 mL) was added to a mixture and the aqueous layer was added. it was extracted with ether (3 x 10 mL) The combined organic layers were dried over Na2SO and concentrated to give the crude material (342 mg) The compound was taken to the next step without purification Step C: 2- ( 2- ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid (Compound 85C).
The compound was prepared using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, Steps AD: ES / MS m / z 465.1 (M + H); LC / MS (Method C) Rt = 3.12 minutes. Example 86 Methyl 2- (4-methyl-2- ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid (Compound 86A) and 2- (4'-methyl-2- ((4- tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetate (Compound 86B).
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 86B: ES / MS m / z 479.3 (M + H); LC / MS (Method C) Rt = 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 acid (Compound 87B): 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 87B: ES / MS m / z 499.3 (M + H); LC / MS (Method C) Rt = 3.27 minutes. Example 88 Methyl 2- (4'-chloro-2- (thiomorpholindioxy-methyl) biphenyl-4-yl) acetate (Compound 88A) and 2- (4'-Chloro-2- (thiomorpholindioxy-methyl) biphenyl-4-acid il) acetic (Compound 88B).
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 starting with methyl 2- (4- hydroxy-3- (S, S-dioxo-thiomorpholine-methyl) phenyl) acetate. Compound 88B: ES / MS m / z 394.1 (M + H); LC / MS: (Method A) Rt = 3.31 minutes. EXAMPLE 89 2- (4-Phenylethynyl) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 89B) Step A: Ter-butyl 4- (5- (2-methoxy-2-oxoethyl) -2- (phenylethynyl) benzyl) iperazine-1-carboxylate (Compound 89A) Palladium tetrakis (5 mg, 0.43 mol) was added, (0.2 mg, 0.86 umol), Et3N (0.12 ml, 0.86 mol), and phenyl acetylene (0.06 ml, 0.52 mol) to a solution of tert-butyl 4- (5- (2-methoxy-2-oxoethyl) -2 - (trifluoromethylsulfonyloxy) benzyl) piperazine-1-carboxylate (215 mg, 0.43 mol) in DMF (1 ml) in a sealed tube. HE it bubbled argon through the solution for 2 minutes, then the reaction vessel was sealed. The tube was heated at 110 ° C overnight followed by the addition of saturated Na 2 HCO 3 (5 ml) after cooling. The aqueous was extracted with EtOAc (3 x 10 mL) and the combined organic layer was washed with H20 (10 mL), dried over Na2SO4 and concentrated to give the crude (324 mg) as a brown oil. Flash chromatography on silica gel (3: 1, hexanes / EtOAc) afforded the pure title material (65 mg, 33%) as a light yellow oil.
Step B: 2- (4- (Phenylethynyl) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 89B). The compound was prepared using a method similar to that described for 2- (2- ((4-tosylpiperazin-1-yl) methyl) biphenyl-4-yl) acetic acid: ES / MS, m / z 489.3 (M + H ); LC / MS (Method C) Rt = 3.19 minutes. EXAMPLE 90 2- (4-Phenethyl-3- ((4-tosylpiperazine-l-) acid il) methyl) phenyl) acetic (Compound 90).
Palladium on carbon (5% w / w, 0.1 mg, 0.11 umol) was added to a solution of 2- (4 - (phenylethynyl) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid ( 5.4 mg, 1.2 mmol) in acetic acid (1 ml). The reaction vessel was attached to a balloon (H2) and stirred for 2 hours. The resulting suspension was filtered through CELITE and the filter mass was washed with MTBE (20 ml). The combined organic layer was concentrated to provide the crude product. HPLC purification afforded the pure product: ES / MS m / z 493.3 (M + H); LC / MS (Method C) Rt = 3.35 minutes. Examples 91-92 Scheme 3 Example 91 2- (4- (4-Chlorobenzyloxy) -3- ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 91D): Step A: Methyl 2- (4-hydroxy-3- ((3-oxopiperazin-1-yl) methyl) phenyl) acetate (Compound 91A). Paraformaldehyde (89 mg, 2.95 mol) and piperazin-2 -one (500 mg, 2.68 mol) were added to a stirred solution of 4-hydroxy methyl phenyl acetate (408 mg, 2.68 mol) in i-PrOH (10 ml). . The resulting mixture was refluxed overnight, cooled, then concentrated. The residue was redissolved in EtOAc (20 mL) and the organic layer was washed with H20 (20 mL), dried over Na2SO4 and concentrated to give the crude product. The compound was taken to the next step without purification.
Step B: Methyl 2- (4- (4-chlorobenzyloxy) -3- ((3-oxopiperazin-1-yl) methyl) phenyl) acetate (Compound 91B). Solid K2CO3 (567 mg, 4.1 mol) and 4-chlorobenzyl bromide (463 mg, 2.26 mol) was added to a stirred solution of methyl 2- (4-hydroxy-3- ((3-oxopiperazin-1-yl) methyl) phenyl) acetate (570 mg, 2.05 mol) in DMF (10 ml) at room temperature. The mixture was stirred overnight, then diluted with EtOAc (20 mL). The organic layer was washed with H20 (20 mL), dried over Na2SO4 and concentrated to provide the desired crude material (601 mg) as a yellow oil. The compound was taken to the next step without purification.
Step C: Methyl 2 (4- (4-chlorobenzyloxy) -3- ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 91C) K2C03 was added solid (192 mg, 1.39 mol), Cul (13 mg, 0.07 mol), ethyl diamine (0.005 ml, 0.07 mol) and 4- trifluoromethyl iodobenzene (0.122 ml, 0.834 mol) to a stirred solution of methyl 2- (4- (4-chlorobenzyloxy) -3- ((3-oxopiperazin-1-yl) methyl) phenyl) acetate (280 mg, 0.695 mol ) in dioxane (2 ml). The mixture was degassed (argon gas) and the reaction vessel was sealed and then heated at 110 ° C overnight. After cooling, the suspension was filtered through a plug of silica gel and the mass of the filter was washed with EtOAc (40 ml). The combined organic layer was concentrated to provide the crude product which was carried to the next step without further purification.
Step D: 2- (4- (4-Chlorobenzyloxy) -3- ((3-oxo-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 91D) The compound was prepared using a method similar to that of Step D of the method to produce 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid. ES / MS, m / z 533.3 (M + H); LC / MS (Method C) Rt = 3.35 minutes. Example 92 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (phenylsulfonyl) piperidin-1-yl) methyl) phenyl) acetate (Compound 92A) and 2- (4- (4-chlorobenzyloxy) -3 acid) - ((4- (phenylsulfonyl) piperidin-1-yl) methyl) phenyl) acetic acid (Compound The compound was prepared using a method similar to that described for 2- (4- (4-chlorobenzyloxy) -3- ((3-OXO-4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) phenyl) acetic, except that 4- (phenylsulfonyl) piperidine was used. Compound 92B. ES / MS, m / z 514.1 (M + H), LC / MS (Method C) Rt = 2.58 minutes. EXAMPLE 93 2- (· - ((4-Tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 93) Scheme 4 DIEA (0.611 ml, 3.51 mol) and 1-tosylpiperazine (420 mg, 1.75 mol) were added to a solution in stirring methyl 2- (3- (bromo methyl) phenyl) acetate (300 mg, 1.17 mol) in CH2CN (10 mL) at 50 ° C. The mixture was stirred overnight, cooled and then quenched with H20 (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried over Na2SO4 and concentrated to give the crude ester (695 mg) as a yellow oil. Flash chromatography on silica gel (3: 1, hexanes / EtOAc) yielded the pure ester (178 mg, 37%) which was hydrolyzed using NaOH in MeOH: water to give the crude acid. HPLC purification afforded the pure product: ES / MS, m / z 389.1 (M + H); LC / MS: (Method A) Rt = 2.317 minutes. Examples 94-96 Example 94 2- (4-Hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 94B) Step A: Methyl 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 94A) Phenyl boronic acid (188 mg, 1.54 mol) was added and 1-tosylpiperazine (371 mg, 1.54 mol) was added to a stirred solution of methyl 2- (3-formyl-4-hydroxyphenyl) acetate (300 mg, 1.54 mol) in dioxane (10 ml) at 90 ° C. After stirring for 16 hours, the reaction mixture was cooled, then quenched with H2) (10 mL) and the aqueous layer was extracted with CH2C12 (3 x 10 mL). The combined organic layer was dried over Na 2 SO 4 and concentrated to give the crude ester (1.3 h) as a yellow solid. Flash chromatography on silica gel (3: 1, hexanes / EtOAc) afforded the desired material (567 mg, 74%) as a white solid.
Step B: 2- (4-Hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 94B) Solid LiOH (161 mg, 3.84 mol) was added to a stirred solution of methyl 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetate (190 mg, 0.384 mol) in THF / MeOH / H20 (5 ml, 3: 1: 1) a room temperature. After stirring overnight, the resulting mixture was warmed with 1 N HCl (< pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and concentrated to give the crude acid (85 mg) as a brown oil. Purification of HPLC yielded pure compound 94B: ES / MS, m / z 481.2 (M + H); LC / S: (Method A) Rt = 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) iperazin-1-yl) (p-tolyl) methyl) -4-hydroxyphenyl) acetic acid (Compound 95B) The compound was prepared using the method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with 4-methyl phenyl boronic acid. Compound 95B. ES / MS m / z 499.2 (M + H); LC / S (Method B) Rt = 3.535 minutes. Example 96 Methyl 2- (3- ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) -4-hydroxyphenyl) acetate (Compound 96A) and 2- (3- (4 chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) -4-hydroxyphenyl) acetic acid (Compound 96B): The compound was prepared using the method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with 4-chloro phenyl boronic acid. Compound 96B. ES / MS m / z 519.1 (M + H); LC / MS (Method B) Rt = 3.767 minutes. Example 97 2- (3- ((2-Hydroxyphenyl) (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 97B).
Step A: 2- ((3- (hydroxymethyl) phenyl) (4-tosylpiperazin-1-yl) methyl) phenol. 3- (Hydroxymethyl) benzaldehyde (0.35 ml, 3. 29 mol) and 1-tosylpiperazine (790 mg, 3.29 mol) were added to a stirring solution of 2-phenol boronic acid in dioxane (30 ml) at 90 ° C. After stirring for 16 hours, the reaction mixture was cooled, then warmed with H20 (40 mL) and the aqueous layer was extracted with CH2C12 (3 x 20 mL). The combined organic layer was dried over Na 2 SO and concentrated to give the crude material (1.53 g) which was used in the subsequent step without further purification.
Step B: 2- (3- ((2-hydroxyphenyl) (4-tosylpiperazine- il) methyl) phenyl) acetic acid 2- ((3- (hydroxymethyl) phenyl) (4-tosylpiperazin-1-yl) methyl) phenol was converted to benzyl chloride using S0C12 followed by treatment with KCN. A hydrolysis of benzyl nitrile produced 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 (M + H); LC / MS (Method B) Rt = 3.33 minutes. Example 97 2- (3- ((4- (4-Fluorophenylsulfonyl) piperazin-1-yl) (P-tolyl) methyl) phenyl) acetic acid (Compound 97).
DIEA (0.346 ml, 1.99 mol), Tf20 (0.335 ml, 1.99 mol) and DMAP (16 mg, 0.132 mol) were added to a stirring solution of methyl 2- (3- ((4- (4-fluorophenylsulfonyl) piperazine). -1-yl) (p-tolyl) methyl) -4-hydroxyphenyl) acetate (700 mg, 1.32 mol) in CH2C12 (10 mL) at room temperature. After stirring for 1.5 hours, the resulting mixture was warmed with saturated NaHCO3 (10 mL) and the aqueous layer was extracted with CH2C12 (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated to provide crude triflate (1.07 g) as a brown oil. Chromatography on silica gel (3: 1 hexanes / EtOAc) afforded triflate (760 mg, 86%) as a white solid. The triflate (100 mg, 0.155 mol) was dissolved in DMF (2 mL). To this solution was added formic acid (15 ul, 0.434 mol), Et3N (91 ul, 0.65 mol), PdCl2 (PPh3) 2 and dppp (10 mg, 0.023 mol). The resulting suspension was degassed under Ar, sealed and heated at 90 ° C for 17 hours. After cooling to room temperature the reaction mixture was emptied into H20 (10 mL) and the aqueous layer was extracted with Et20 (3 x 10 mL). The combined organic layers were washed with 1 N HC1 (15 mL), brine (15 mL), dried over Na2SO4 and concentrated to provide the 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 / S, m / z 483.2 (M + H); LC / MS (Method B) Rt = 3.33 minutes. EXAMPLE 98 Methyl 2- (3- ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 98A) and 2- (3- ((4-chlorophenyl)) (4- (4-fluorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 98B) The compound was prepared using the method described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (p-tolyl) methyl) phenyl) acetic acid, starting with methyl 2- (3- ((4-chlorophenyl) (4- (4-fluorophenylsulfonyl) iperazin-1-yl) methyl) -4-hydroxyphenyl) acetate. Compound 98B: ES / MS, m / z 503.1 (M + H); LC / MS (Method B) Rt = 3.33 minutes. Example 99: Acid 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 99B and C) Scheme 6 A6 86 Step a: Methyl 2- (3- (chloro (phenyl) methyl) phenyl) acetate (Compound 99A) Solid NaBH4 (505 mg, 13.3 mol) was added to a solution of 2- (3-benzoylphenyl) acetic acid (850 mg, 3.34 mol) in MeOH (30 ml) at 0 ° C. The resulting solution was quenched with NaHCO3 (30 mL) r 5 minutes and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was redissolved in CH2C12 (20 mL) and SOCL2 (1.2 mL, 16.7 mol) was added. The resulting mixture was concentrated r being stirred overnight to provide the crude chloride. Flash chromatography (3: 1, hexanes / EtOAc) produced the pure material. Step B: R-2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) phenyl) methyl) phenyl) acetic acid and S-2- (3- (4- (4-fluorophenylsulfonyl) acid ) piperazin-1-yl) phenyl) methyl) phenyl) acetic acid (Compound 99B and C) 1- (4-fluorophenylsulfonyl) piperazine (320 mg, 1.31 mol), DIEA (0.57 ml, 3.28 mol) and Nal (16 mg, 0.109 mol) were added to a stirring solution of methyl 2- (3- (chloro ( phenyl) methyl) phenyl) acetate in CH 3 CN (15 mL). The resulting solution was heated to 80 ° C and stirred overnight. r cooling, the reaction mixture was quenched 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 over Na 2 SO 4 and concentrated. The resulting ester was hydrolyzed using a preparation method similar to 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid. The HPLC purification produced the pure material. Both enantiomers were also separated by chiral HPLC (Chirapak 1 AD-H, 4.6 x 250 mm, 80% heptanes: 20% IPA: 0.1% TFA, 40 ° C, 1.0 ml / minute). 98B Rt = 14,479 minutes, 98C Rt = 22,119 minutes. ES / MS, m / z 469.2 (M + H); LC / MS (Method B) Rt = 3.673 minutes. Example 100 Methyl 2- (3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 100A) and 2- (3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid ( Compound 100B) The title compounds were prepared using the methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) iperazin-1-yl) phenyl) methyl) phenyl) acetic acid starting with 1- (4-methylphenylsulfonyl) piperazine . Compound 100B: H MR (400 MHz, DMSO-d6) delta 12.31 (1H, brs), 7.61 (2H, 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, s), 3.49 (2H, s), 2.88 ( 4H, br), 2.44 (3H, s), 2.35 (4H, brm); ES / MS, m / z 465.2 (M + H); LC / MS (method B) Rt = 3,750 minutes. Example 101 Methyl 2- (3- (phenyl (4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 101A) and 2- (3- (phenyl (4-phenylsulfonyl) piperazin-1-yl) ) methyl) phenyl) acetic (Compound 101B): The title compounds were prepared using the methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) phenyl) methyl) phenyl) acetic acid starting with (phenylsulfonyl) piperazine. Compound 101B: ES / MS, m / z 451.2 (M + H); LC / MS (Method B) Rt = 3.594 minutes. Example 102 Methyl 2- (3- ((4- (methylsulfonyl) piperazin-1-yl) phenyl) methyl) phenyl) acetate (Compound 102A) and 2- (3- ((4- (methylsulfonyl) piperazine-1- il) phenyl) methyl) phenyl) acetic acid (Compound 102B) The title compounds were prepared using the methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) phenyl) methyl) phenyl) acetic acid starting with (methylsulfonyl) piperazine. Compound 102B: ES / MS, m / z 389.1 (M + H); LC / MS (Method B) Rt = 2686 minutes Example 103 2- (3- ((4- (4-Fluorophenylsulfonyl) piperazin-yl) phenyl) methyl) phenyl) propanoic acid (Compound 103A) and 2- (3-) Acid ((4- (4-Fluorophenylsulfonyl) piperazin-yl) phenyl) methyl) phenyl) ropanoic (Compound 103B) The title compounds were prepared using the methodology described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) phenyl) methyl) phenyl) acetic acid starting with s-ketoprofen: Compound 103B: ES / MS, m / z 483.2 (M + H); LC / MS (Method B) Rt = 3.9 minutes. EXAMPLE 104 2- (3-Chloro-5- (phenyl) (4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 104E) Scheme 7 Step A: (3-bromo-5-chlorophenyl) (phenyl) methanol (Compound 1.0 M (in THF) of PhMgBr (4.1 mL, 4.1 mol) was added slowly to a stirred solution of 3-bromo-5-chloro benzaldehyde (600 mg, 2.73 mol) in THF (20 mL) at 0 ° C. The resulting mixture was stirred for 1.5 hours, then warmed with NH4C1 (20 mL) and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to provide the crude alcohol (1.02 g). A chromatography Flash on silica gel (3: 1 hexanes / EtOAc) yielded the pure material (512 mg, 63%). Step B: t-butyl 4- ((3-bromo-5-chlorophenyl) (phenyl) methyl) piperazine-1-carboxylate (Compound 104B) SOCl2 (0.611 mL, 8.4 mol) was added to a stirred solution of (3-bromo-5-chlorophenyl) phenyl) methanol (500 mg, 1.68 mol) in CH2C12 (10 mL) at room temperature. After stirring for 4 hours, the solution was concentrated. The residue was redissolved in CH3CN (15 ml) and DIEA (0.878 ml, 5.04 mol), Nal (25 mg, 0.168 mol) and t-butyl piperazine-1-carboxylate (470 mg, 2.52 mol) was 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 layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. Flash chromatography on silica gel (3: 1 hexanes / EtOAc) yielded the pure material. Stage C: 4- ((3-chloro-5- (4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) phenyl) phenyl) methyl) iperazine-1-carboxylate (Compound 104C) AcOK (160 mg, 1.62 mol) and pinacolborane (165 mg, 0.65 mol) were added to a solution of t-butyl 4 - ((3-bromo-5-chlorophenyl) (phenyl) methyl) piperazine-1-carbocylate (250 mg, 0. 54 mol) in dioxane (5 ml). The resulting solution was degassed using argon, followed by the addition of PdCl2 (dppf) (20 mg, 0.027 mol) and dppf (15 mg, 0.027 mol). The reaction mixture was heated at 80 ° C for 4 hours, cooled and then concentrated. The residue was dissolved in hexanes and activated carbon was added, then filtered through CELITE. The combined organic layer was concentrated to provide the crude material. Flash chromatography on silica gel (9: 1, hexanes / EtOAc) yielded the pure material (189 mg, 69%). Step D: t-butyl 4- ((3-chloro-5- (2-ethoxy-2-oxoethyl) phenyl) (phenyl) methyl) piperazine-1-carboxylate (Compound 104D) K2C03 (160 mg, 1.16 mol) and 1-bromoethyl ester (0.039 ml, 0.351 mol) were added to a solution of tert-butyl 4- ((3-chloro-5- (4,4,5, 5-tetramethyl- 1,3-diocaborolan-2-yl) phenyl) (phenyl) methyl) iperazine-1-carboxylate (180 mg, 0.351 mol) in toluene (5 ml). The resulting solution was degassed using argon, followed by the addition of Pd (PPh3) 4 (13 mg, 0.011 mol) and Cu20 (1.5 mg, 0.011 mol). The reaction mixture was heated at 80 ° C for 16 hours, cooled and then concentrated to give the crude ester (80 mg). Flash chromatography on silica gel (3: 1, hexanes / EtOAc) yielded the pure material (36 mg, 22%). Step E: 2- (3-Chloro-5- (phenyl (4- (phenylsulfonyl) piperazin-1-yl) methylphenyl) acetic acid (Compound 104E) The compound was prepared using a method similar to that described for 2- (3- ((4- (4-fluorophenylsulfonyl) piperazin-1-yl) (phenyl) methyl) phenyl) acetic acid: ES / MS, m / z 485.2 (M + H); LCMS (Method B) Rt = 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-fluorophenylsulfonyl) piperazin-1-yl) (pyridin-3-yl) methyl) -4-hydroxyphenyl) acetic acid (Compound 105B) The compound was prepared using the method described for 2- (4-hydroxy-3- (phenyl (4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with acid 3-pyridyl boronic acid and 4-fluorophenyl sulfonyl chloride.
Compound 105B: LC / MS Rt = 2.61 minutes. (Method A); MS (m / z) 486.1 (M + + H). Example 106 2- (4- (4-Chlorobenzyloxy) -3- (4-cytosylpiperazine-1-carbonyl) phenyl) acetic acid (Compound 106B) Scheme 8 Step A: 2- (4-Chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzoic acid (Compound 106A) To a suspension of methyl-4-hydroxyphenyl acetate (11.6 g, 70 mol, 1.0 equivalent), magnesium chloride (10 g, 105 mol, 1.5 equivalents) and triethyl amine (36.6 ml, 265.5 mol) in AcCN (200 ml) was added powdered paraformaldehyde (15.3 g, 472.5 mol, 7 equivalents). The resulting white suspension was then transferred to an oil bath, a bound reflux condenser, and refluxed at 82 ° C for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 1.0 M hydrochloric acid (to pH 4) and then extracted with EtOAc (400 mL). The extract was dried with NaSO4 and concentrated to provide an intermediate of methyl 2- (3-formyl-4-hydroxyphenyl) acetate (6.2 g). LC / MS: (Method A) MS m / z 195.10 (M + H), (Rt = 3.47 minutes). The crude aldehyde (3 g, 9.43 mol) was placed in a 500 ml reaction flask and dissolved in acetone (40 ml) then transferred to an oil bath at 40 ° C. A hot solution of potassium permanganate (2.61 g, 16.5 mol) in acetone H20 (60 ml, 5: 1) was then added and stirred at 40 ° C overnight. An acid-based procedure provided 3.06 g of the crude product, 2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzoic acid. LC / MS Method A, MS m / z 333.0 (M + H), Rt = 3.58 minutes. Step B: 2- (4- (4-Chlorobenzyloxy) -3- (4-cytosylpiperazine-1-carbonyl) phenyl) acetic acid (Compound 106B) 2- (4-Chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzoic acid (100 mg, 0.299 mol), O- (7-azabenzotriazol-1-yl) -?,?,? ,? ' -tetramethyluronium hexafluorophosphate (HATU, 113.5 mg, 0.299 mol) and N, -diisopropylethylamine (0.067 ml, 0.389 mol) in ACCN (2 ml) in a reaction vial and stirred for 10 minutes. Then 1. (tosyl) piperazine (71.8 mg, 0.299 mol) was added and the resulting solution was stirred for 10 hours. The product was precipitated out of the solution and filtered and washed to provide 110 mg of pure ester, methyl 2- (4- (4-chlorobenzyloxy) -3- (4-tosylpiperazine-1-carbonyl) phenyl) acetate. LC / MS: (Method A), MS m / z 557.1 (M + H), (Rt = 4.02 minutes). The ester (100 mg, 0.18 mol) and lithium hydroxide (100 mg, in excess) were suspended in a mixture of MeOH-H20 (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 with brine. The solution was then dried and concentrated to provide the product (109.7 mg). LC / MS: (Method A), MS m / z 543.1 (M + H), (Rt = 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- acid) (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) acetic acid (Compound 107B).
The title materials 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 107B: LC / MS: (Method A), MS m / z 467.1 (M + H), (Rt = 3.19 minutes). Example 108 Methyl 2- (4- (4-chlorobenzyloxy) -3- (S, S-dioxo-thiomorpholine-4-carbonyl) phenyl) acetate (Compound 108A) and 2- (4- (4-chlorobenzyloxy) -3- acid) (S, S-dioxo-thiomorpholine-4-carbonyl) phenyl) acetic acid (Compound 108B) The title materials 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), MS m / z 438.1 (M + H), (Rt = 3.11 minutes). Example 109-110 Example 109 Acid (S, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3, 4,7, 8-tetrahydroazocin-1 (2H) -yl) methyl) phenyl) acetic (Compound 109D) Step A: Methyl 2- (3- ((but-3-enylamino) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 109A) To a vigorously stirred suspension of but-3-en-l-amine hydrochloride (202 mg, 1.89 mol) in brine (3 mL) and CH2C12 (3 mL), 2 M NaOH was added at pH = 14. Organic layer was separated, dried (Na2SO4) and added directly to a flask, under an inert atmosphere, containing methyl 2- (4- (4-chlorobenzyloxy) -3-phenylphenyl) acetate (200 mg, 0.63 mol). In a separate flask, sodium cyanoborohydride (40 mg, 0.63 mol) in one portion was carefully added to a solution of zinc chloride (315 ul, 1M) in 1 ml of MeOH as the mixture resulted in effervescence. The mixture was allowed to stir for 10 minutes, then the total was added via a cannula to the flask containing the stirring solution of 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate and but-3-en-l- amine. The mixture was stirred for 10 minutes, then warmed with NaHCO3 (10 mL), then extracted with CH2C12 (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo to provide methyl 2- (3- (( but-3-enylamino) methyl) -4- (4- chlorobenzyloxy) phenyl) acetate (300 mg) as a colorless oil. LC / MS (Rt = 2.35 minutes, (Method A), m / z 374 (M + H) Step B: (S) -methyl 2- (3- ((N- (but-3-enyl) -2 - (tert-butoxycarbonylamino) pent-4-enamido) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 109B) to a solution of (S) -2- (tert-butoxycarbonylamino) pent-4-eneic acid (409 mg, 2.67 mol), methyl 2- (3- ((but-3-enylamino) methyl) -4- (4 -chlorobenzyloxy) phenyl) acetate (1 g, 2.67 mol) and Hunig's base (0.98 ml, 5.34 mol) in DMF (10 ml), HATU (1 g, 2.67 mol) was added. The reaction was stirred for 1 hour, then was emptied into 200 ml of water and extracted with EtOAc (3 x 20 ml), dried (Na 2 SO 4) and concentrated in vacuo. Column chromatography (silica gel, 20.40% EtOAc / hexane), yielded (S) -methyl 2- (3- ((N- (but-3-enyl) -2- (tert-butoxycarbonylamino) pent-4- enamido) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (0.8 g, 1.4 mol, 52%); LC / MS (Rt = 4.35 minutes, (Method A), 571 (M + H).
Step C: (S, Z) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxo-3,4,7,8-tetrahydroazocin-l (2H) -yl) methyl) -4 - (4- chlorobenzyloxy) phenyl) acetate (Compound 109C) A solution of (S) -methyl 2- (3- ((N- (but-3-enyl) -2- (tert-butoxycarbonylamino) pent-4-enamido) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (100 mg, 0.175 mol) and first generation Grubb catalyst (34 mg, 0.032 mol) in CH2C12 (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 yield (S, Z) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2- oxo-3, 4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (70 mg, 1.4 mol, 74%); ?? NMR (300 MHz, CDC13) 7.4-7.3 (m, 4H), 7.15-7.1 (m, 2H), 6.85 (d, 1H), 5.9 (d, 1H), 5.7 (m, 1H), 5.4 (m, 1H), 5.1 (s, 2H), 4.9 (d, 1H), 4.8 (m, 1H), 4.3 (d, 1H), 3.8 (m, 1H), 3.7 (s, 3H), 3.5 (s, 2H) ), 3.2 (m, 1H), 2.8 (m, 1H), 2.4 (m, 3H), 1.45 (s, 9H).
Step D: Acid (S, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3, 4,7,8-tetrahydroazocin-1 (2H ) -yl) methyl) phenyl) acetic (Compound 109D) To a solution of (S) -methyl 2 - (3 - ((3 - (tert-butoxycarbonylamino) -2-oxoazocan-l-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (100 mg, 0.183 mol) in CH2C12 (2 mL) was added TFA (1 mL). The solution was stirred for 1 hour, then neutralized (saturated NaHCO3), extracted with CH2C12 (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2C12 (2 mL) to which was added triethylamine (63 ul, 0.44 mol) and p-toluene sulfonyl chloride (52 mg, 0.27 mol). The solution was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H20 (2 mL) to which LiOH (75 mg, 1.76 mol) was added. The solution was stirred vigorously for 1 hour, then acidified with HCl (2 M), extracted with EtOAc (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was subjected to preparative HPLC purification followed by lyophilization of the fractions to provide acid (S, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3, 4,7, 8-tetrahydroazocin-l (2H) -il ) methyl) phenyl) acetic acid as a colorless solid, (75 mg, 0.13 mol, 70%); XH NMR (300 MHz, CDC13) 12.2 (br s, 1H), 7.9 (d, 1H), 7.7 (d, 2H), 7.45 (s, 4H), 7.3 (d, 2H), 7.1 (dd, 1H) , 6.95 (d, 1H), 6.85 (d, 1H), 5.5 (m, 1H), 5.35 (m, 1H), 5.1 (s, 2H), 4.5-4.4 (m, 1H), 4.35 (d, 1H) ), 4.1 (d, 1H), 3.55 (m, 2H), 3.4 (s, 2H), 3.2-3.1 (m, 1H), 2.3 (m, 6H). EXAMPLE 110 Acid (R) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110A) and Acid ( S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110B) Step A: (S) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxoazocan-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 110AA) A solution of (S, Z) -methyl 2- (3- ((3- (ter- butoxycarbonylamino) -2-oxo-3, 4,7, 8-tetrahydroazocin-l (2H) -yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (50 mg, 0.092 mol) and RhCl (PPh3) 3 (16.6 mg, 0.018 mol) in benzene (2 ml) under an atmosphere of hydrogen was stirred for 48 hours. The mixture was concentrated and subjected to column chromatography (silica gel, 20-50% EtOAc / hexane) to provide (S) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2 -oxoazocan- 1-yl = methyl) -4- (4-chlorobenzyloxy) phenyl) acetate as a colorless oil (45 mg, 0.082 mol, 89%);? NMR (300 MHz, d6-DMSO) 7.4-7.3 (m, 4H) , 7.15-7.10 (m, 2H), 6.85 (d, 1H), 5.7 (d, 1H), 5.1 (d, 1H), 5.0 (s, 2H), 4.7 (m, 1H), 4.2 (d, lh ), 3.7 (m, 1H), 3.65 (s, 3H), 3.55 (s, 2H), 3.2 (m, 1H), 1.7-1.5 (m, 6H), 1.4 (m, 10H) Stage B: Acid (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 110AB) To a solution of (S) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2 -oxoazocan-1-yl) methyl) -4- (4- chlorobenzyloxy) phenyl) acetate (100 tng, 0.18 mol) in CH2C12 (2 mL) was added TFA (1 mL). The solution was stirred for 1 hour, then neutralized (saturated NaHCO3), extracted with CH2C12 (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2C12 (2 mL) to which was added triethylamine (63 ul, 0.44 mol) and p-toluene sulfonyl chloride (52 mg, 0.27 mol). The solution was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H20 (2 mL) to which LiOH (75 mg, 1.76 mol) was added. The solution was stirred vigorously for 1 hour, then acidified with HC1 (2M), extracted with EtOAc (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was subjected to preparative HPLC purification followed by lyophilization of the fractions to provide (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan) acid. -l-yl) methyl) phenyl) acetic acid as a colorless solid, (40 mg, 0.068 mol, 40%); 1H NR (300 MHz, dg-DMSO) 12.3 (br s, 1H), 7.85 (d, 1H), 7.7 (d, 2H), 7.45 (s, 4H), 7.3 (d, 2H), 7.0 (m, 2H), 5.1 (s, 2H), 4.5 (d, 1H), 4.4 (m, 1H), 4.2 (d, 1H), 3.55 (m, 2H), 3.1-3.0 (m, 1H), 2.3 (s) , 3H), 1.5-1.0 (m, 8H). Example 111 Methyl (R, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3, 4,7,8-tetrahydroazocin-1 (2H) methyl) phenyl) acetate (Compound 111) and Acid (R, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxo-3,4,7,8-tetrahydroazocin-l (2H) -il ) methyl) phenyl) acetic (Compound 111) The title materials were obtained using the method described for (S, Z) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido)) -2-oxo-3,4,7,8-tetrahydroazocin-1 (2H) -yl) methyl) phenyl) acetic acid, starting with (R) -2- (tert-butoxycarbonylamino) pent-4-ene acid.
Compound 111B: 1 H NMR (300 MHz, CDC13) 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) , 1H), 6.95 (d, 1H), 6.85 (d, 1H), 5.5 (m, 1H), 5.35 (m, 1H), 5.1 (s, 2H), 4.5-4.4 (m, 1H), 4.35 (d, 1H), 4.1 (d, 1H) ), 3.55 (m, 2H), 3.4 (s, 2H), 3.2-3.1 (m, 1H), 2.3 (m, 6H). Example 112 Methyl ® -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetate (Compound 112A) and Acid (R) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid (Compound 112B) The title material was obtained using the Method described for (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazocan-1-yl) methyl) phenyl) acetic acid, starting with acid. 2- (tert-butoxycarbonylamino) pent-4-ene. Compound 112B: ""? NMR (300 MHz, d6-DMSO) 12.3 (br s, 1H), 7.85 (d, 1H), 7.7 (d, 2H), 7.45 (s, 4H), 7.3 (d, 2H), 7.0 (m, 2H) , 5.1 (s, 2H), 4.5 (d, 1H), 4.4 (m, 1H), 4.2 (d, 1H), 3.55 (m, 2H), 3.1-3.0 (m, 1H), 2.3 (s, 3H) ), 1.5-1.0 (m, 8H). Example 113: Acid (R) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid (Compound 113A) and Acid ( S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid (Compound 113B) Step A: (S) -2- (tert-Butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5-methoxy-2-oxoethyl) benzylamino) hexanoic acid (Compound 113A) To a solution of methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate (250 mg, 0.78 mol) in methanol (3 mL) was added Boc-L-lysine (386 mg, 1.57 mol). The mixture was stirred for 20 minutes. In a separate flask, zinc chloride (400 ul, 1M) was added to 3 ml of methanol, followed by sodium cyanoborohydride (50.2 mg, 0.78 mol) carefully added in one portion as the mixture resulted in effervescence. The mixture was allowed to stir for 10 minutes, then the total was added via a cannula to the flask containing the stirring solution of methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate and Boc-L-lysine. The reaction was stirred for 10 minutes, then warmed with brine (5 mL), extracted with EtOAc (3 x 15 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was passed through a plug of silica (CH2Cl2 / 10% -20% MeOH) to give (S) -2- (3- (tert-butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy)) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic acid as a colorless oil (250 mg, 0.45 mol, 58%) LC / MS (Rt = 2.510 minutes, (Method A), m / z 549 (+ H). Step B: 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxoazepan-l-yl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 113B) To a solution of (S) -2- (tert-butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic acid (250 mg, 0.45 mol) and triethylamine (0.2 ml, 1.3 mol) in DMF (25 ml) was added HOBT (73.7 mg, 0.55 mol) and 1- [3-dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mol). The solution was stirred for 18 hours, then concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was passed through a plug of silica (EtOAc) to provide (S) -methyl 2- (3- ((3- (tert-butoxycarbonylamino) -2-oxoazepan-1-yl) methyl) -4- ( 4-chlorobenzyloxy) phenyl) acetate as a colorless oil (150 mg, 0.28 mol, 62%). LC / MS Rt = 4.23 minutes, (Method A), MS m / z 531 (M + H). Step C: Acid (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4- methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid (Compound 113C) 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 mol) in CH2C12 (2 mL) was added TFA (1 mL). The solution was stirred for 1 hour, then neutralized (saturated NaHCO3), extracted with CH2C12 (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in pyridine (1.5 ml) to which p-toluene sulfonyl chloride (50 mg, 0.27 mol) was added. The solution was stirred for 18 hours and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H20 (2 mL) to which LiOH (55 mg, 1.36 mol) was added. The solution was stirred vigorously for 24 hours, then acidified with HC1 (2M), extracted with EtOAc (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was subjected to preparative HPLC purification followed by lyophilization of the fractions to provide (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2 -oxoazepan) acid -1-yl) methyl) phenyl) acetic acid as a colorless oil (20 mg, 0. 035 mol, 12.5%); ¾ NMR (300 MHz, d6-DMSO) 7.7 (d, 2H), 7.55 (d, 1H), 7.35 (d, 2H), 7.2 (t, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 6.85 (d, 1H), 4.6 (d, 1H), 4.25 (d, 1H), 4.1 (m, 1H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 3.2-3.1 (m, 1H), 2.4"(s, 3H), 1.7-1.4 (m, 5H), 1.3-1.0 (ra, 1H). Acid-2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl ) phenyl) acetic (Compound 113B) The title material was obtained using Boc-R-lysine, following the method described for (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- ( 4-methylphenylsulfonamido) -2-oxoazepan-1-yl) methyl) phenyl) acetic acid XH NMR (300 MHz, d6-DMSO) 7.7 (d, 2H), 7.55 (d, 1H), 7.35 (d, 2H), 7.2 (t, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 6.85 (d, 1H), 4.6 (d, 1H), 4.25 (d, 1H), 4.1 (ra, 1H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 3.2-3.1 (m, 1H), 2.4 (s, 3H), 1.7-1.4 (m, 5H), 1.3-1.0 (m, 1H). 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) Scheme 11 Step A: (S) -methyl 2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2 -oxopyrrolidin-1-yl) methyl) phenyl) acetate (Compound 114A) A mixture of methyl 2- (3- (bromoethyl) -4- (4- chlorobenzyloxy) phenyl) acetate (0.7 g, 1.82 mol), (S) tert -butyl-2-oxopyrrolidin-3-ylcarbamate (439 mg, 2.19 mol) and Cs2CO3 (1.92 g, 5.97 mol) in CH3CN (3 ml) and DMF (1 mL) was heated at 55 ° C for 1 hour. The reaction was diluted with H20 (20 mL) and extracted with EtOAc (3 x 5 mL), dried (Na2SO4) and concentrated in vacuo. A solution of the residue in CH2C12 (4 mL) was treated with TFA (4 mL) and stirred for 30 minutes, then concentrated in vacuo. The residue was dissolved in CH2C12 (4 mL) to which was added triethylamine (228 ul, 1.64 mol) and p-toluene sulfonyl chloride (117 mg, 0.61 mol). The reaction was stirred for 12 hours, diluted with H20 (20 mL) and extracted with CH2C12 (2 x 10 mL). Column chromatography (silica gel, (1: 1) EtOAc / hexane), provided (S) -methyl 2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2- oxopyrrolidin-1-yl) methyl) phenyl) acetate as a colorless oil (191 mg, 0.34 mol, 15%); XH NMR (300 MHz, CDC13) 7.8 (d, 2H), 7.4-7.4 (m, 6H), 7.15 (dd, 1H), 7.05 (m, 1H), 6.85 (d, 1H), 5.2 (s, 1H) ), 5.0 (s, 2H), 4.5 (m, 2H), 3.7-3.6 (m, 4H), 3.3-3.1 (m, 2H), 2.6-2.5 (m, 1H), 2.4 (s, 3H), 2.0 (m, 1H). Step B: (S) -2- (4- (4-Chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid (114B) To a solution of (S) -methyl 2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methyl) phenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetate (190 mg , 0.34 mol) in THF (1 ml) was added LiOH (1.0 ml, 1). The reaction was stirred for 12 hours and the THF was removed under vacuum. To the remaining aqueous mixture was added 5 ml of HCl (1 M) and the resulting precipitate was filtered and washed with H20 (15 ml) to give (S) -2- (4- (4-chlorobenzyloxy) -3- acid. ((3- (4-Methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid as a colorless solid (130 mg, 0.24 mol, 70%); ¾ MR (300 MHz, d6-DMSO) 8.1 (d, 1H), 7.75 (d, 2H), 7.5-7.4 (m, 4H), 7.35 (d, 2H), 7.1 (d, 1H), 7.00 (m , 2H), 5.1 (s, 2H), 4.3 (m, 2H), 4.0 (m, 1H), 3.4 (s, 2H), 3.0 (m, 2H), 2.3 (s, 3H), 2.0-1.9 ( m, 1H), 1.5-1.4 (m, 1H). (R) -2- (4- (4-Chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopyrrolidin-1-yl) methyl) phenyl) acetic acid (Compound 114A) The title material was elaborated starting with (R) -tert-butyl 2-oxopyrrolidin-3-ylcarbamate, using the method described for (S) -2 - (4 - (4-chlorobenzyloxy) -3 - ((3- (4-methylphenylsulfonamido) -2) -oxopyrrolidin-1-yl) methyl) phenyl) acetic acid. ?? NMR (300 MHz), de-DMSO) 8.1 (d, 1H), 7.75 (d, 2H), 7.5-7.4 (m, 4H), 7.35 (d, 2H), 7.1 (d, 1H), 7.00 (m , 2H), 5.1 (s, 2H), 4.3 (m, 2H), 4.0 (m, 1H), 3.4 (s, 2H), 3.9 (m, 2H), 2.3 (s, 3H), 2.0-1.9 (m, 1H), 1.5-1.4 (m, 1H). Example 115 Acid (R) -2- ($ - (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115A) and Acid ( S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115B) Scheme 12 Step A: (S) -2- (tert-Butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) entanoic acid (Compound 115AA) Using a Method identical to that described for the preparation of (S) -2 (tert-butoxycarbonylamino) -6- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) hexanoic acid with the following Reagents: 4- (4-chlorobenzyloxy) -3-formylphenyl) (422 mg, 1.32 mol); Boc-L-ornithine (461 mg, 1.98 mol); zinc chloride (622 ul, 1M); sodium cyanoborohydride (83.1 mg, 1.32 mol); the (S) -2- (tert-butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) pentanoic acid was obtained as a colorless oil (680 mg, 1.27 mol, 96%). LC / MS Rt = 2.613 minutes. (Method A), MS m / z 535 M + H. Step B: (S) -methyl-2- (3- ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 115AB) Using a Method identical to that described for the preparation of (S) -methyl-2- (3- ((3- (tert-butoxycarbonylamino) -2-oxoazepan-l-yl) methyl) -4- (4-chlorobenzyloxy) phenyl ) acetate with the following reagents: (S) -2- (tert-butoxycarbonylamino) -5- (2- (4-chlorobenzyloxy) -5- (2-methoxy-2-oxoethyl) benzylamino) pentanoic acid (800 mg, 1.49 mol); triethylamine (0.62 ml, 4.48 mol); HOBT (242 mg, 1.79 mol); 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mol); (S) -methyl-2- (3- ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate was obtained as a colorless oil (380 mg, 0.74 mol, 50%). LC / MS Rt = 4081 minutes, (Method A), MS m / z 517 M + H. Step C: (S) -2- (4- (4-Chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115B) Using a Method identical to that described for the preparation of the acid (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxoazepan-l-yl) methyl) phenyl) acetic; (S) -methyl-2- (3- ((3- (tert-butoxycarbonylamino) -2-oxopiperidin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (742 mg, 1.43 mol); TFA (5 ml); p-toluene sulfonyl chloride (300 mg, 1.57 mol); LiOH (92 mg, 4 mol). Column chromatography (silica gel, 0-100% EtOAc / hexane) was obtained (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidine- 1-yl) methyl) phenyl) acetic acid as a colorless solid (400 mg, 0.7 mol, 49%); XH NMR (300 MHz, d6-DMSO); 12.2 (brs, 1H), 7.85 (d, 1H), 7.75 (d, 2H), 7.5-7.4 (m, 4H), 7.35 (d, 1H), 7.11 (dd, 1H), 7.00 (d, 1H) , 7.05 (d, 1H), 5.1 (s, 2H), 4.55 (d, 1H), 4.35 (d, 1H), 3.8 (m, 1H), 3.1 (m, 1H), 2.4 (s, 3H), 1.9-1.7 (m, 3H). (R) -2- (4- (4-Chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic acid (Compound 115B) The title material was obtained using the indicated chemistry for the acid (S) -2- (4- (4-chlorobenzyloxy) -3- ((3- (4-methylphenylsulfonamido) -2-oxopiperidin-1-yl) methyl) phenyl) acetic, starting with Boc-D-ornithine. 1 H NMR (300 MHz, d 6 -DMSO); 12.2 (brs, 1H), 7.85 (d, 1H), 7.75 (d, 2H), 7.5-7.4 (m, 4H), 7.35 (d, 1H), 7.11 (dd, 1H), 7.00 (d, 1H) , 7.05 (d, 1H), 5.1 (s, 2H), 4.55 (d, 1H), 4.35 (d, 1H), 3.8 (ra, 1H), 3.1 (ra, 1H), 2.4 (s, 3H), 1.9-1.7 (m, 3H). Example 116 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 116AA) and 2- (4- (4-chlorobenzyloxy) -3- acid) ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 116B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-methyl phenyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) acid. ) methyl) phenyl) acetic. Compound 116B: LC / MS Rt = 2.77 minutes. (Method A); MS (m / z) 529.26 (M + + H). Example 117 Methyl. { 4- (4-chloro-benzyloxy) -3,5-bis- [4- (toluene-4-sulfonyl) iperazin-1-ylmethyl] phenyl} acetate (Compound 117A) and Acid { 4- (4-chloro-benzyloxy) -3,5-bis- [4- (toluene-4-sulfonyl) iperazin-1-ylmethyl] phenyl} acetic (Compound 117B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-methyl phenyl sulfonyl chloride, using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid. ) methyl) phenyl) acetic. Compound 117B: M + H 782. Example 118 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 118A) and 2- (4- (4-chlorobenzyloxy) -3 acid) - ((4- (phenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 118B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 118B: LC / MS Rt = 2.73 minutes (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) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-fluoro-phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 119B: LC / MS Rt = 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 120A) and 2- (4- (4- chlorobenzyloxy) -3- ((4- (4-chlorophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 120B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-chloro-phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 120B: Rt = 2.85 minutes (Method A); MS (m / z) 549.21 (M + + H). Example 121 Methyl 2- (3- ((4- (4-bromophenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 121A) and 2- (3- (4 - (4-bromophenylsulfonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 121B) The title compounds were obtained using 1 - . 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 acid. Compound 120B: LC / MS Rt = 2.83 minutes (Method A); MS (m / z) 595 (M + + H).
Example 122 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (thiophen-2-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 122A) and 2- (4- (4 -chlorobenzyloxy) -3- ((4- (thiophen-2-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 122B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-thiophene sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) acid ) phenyl) acetic. Compound 122B: LC / MS Rt = 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 123A) and 2- (4- (4-chlorobenzyloxy) -3- ((4- (thiophen-3-ylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 123B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-thiophene sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) acid ) phenyl) acetic. Compound 123B: LC / MS Rt = 2.73 minutes (Method A); MS (m / z) 521.15 (M + + H). Example 124 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (4-nitrophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (compound 124A) and 2- (4- (4- chlorobenzyloxy) -3- ((4- (4-nitrophenylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 124B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 4-nitro phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3 - ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 124B: LC / MS Rt = 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 125A) and 2- (4- (4-chlorobenzyloxy)) -3- ((4- (Methylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 125B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and methyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 125B: LC / MS Rt = 2.50 minutes (Method A); MS (m / z) 453.21 (M + + H). Example 126 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4- (isopropylsulfonyl) piperazin-1-yl) methyl) phenyl) acetate (Compound 126A) and 2- (4- (4-chlorobenzyloxy)) -3- ((4- (isopropylsulfonyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 126B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and isopropyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 126B: LC / MS Rt = 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 127A) and 2- (3- ((4-butylsulfonyl)) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 127B) The title compounds were obtained using l-chloromethyl-4-chlorobenzene and butyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl acid ) acetic Compound 127B: LC / MS Rt = 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 128A) and 2- (4- (4-methoxybenzyloxy) -3- acid ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 128B) The title compounds were obtained using l-chloromethyl-4-methoxybenzene and 4-methyl phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 128B: LC / MS Rt = 2.69 minutes (Method A); MS (m / z) 525.30 (M + + H). EXAMPLE 129 Methyl 2- (4- (4-methylbenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 129A) and 2- (4- (4-methylbenzyloxy) -3- acid) ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 129B) The title compounds were obtained using l-chloromethyl-4-methylbenzene and 4-methyl phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) acid) methyl) phenyl) acetic. Compound 129B: LC / MS Rt = 2.85 minutes (Method A); MS (m / z) 509.31 (M + + H). EXAMPLE 130 Methyl 2- (4- (benzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetate (Compound 130A) and 2- (4- (benzyloxy) -3- (4- tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 130B) The title compounds were obtained using benzyl bromide and 4-methyl phenyl sulfonyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid .
Compound 130B: LC / MS Rt = 2.81 minutes (Method A); MS (m / z) 495. 32 (M ++ H). Example 131 Methyl 2- (3- ((4-benzylcarbamoyl) iperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 131A) and 2- (3- ((4-benzylcarbamoyl) piperazine-) 1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 131B) The title compounds were obtained using 1-chloromethyl-4-chlorophenyl and benzyl isocyanate using the method described for 2- (4- (isopentyloxy) -3- ((4-phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic. Compound 131B: LC / MS Rt = 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 132A) and 2- (3- ((4-benzylpiperazine-1) il) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic acid (Compound 132B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3 - ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid starting with N-benzyl piperazine. Compound 132B: LC / MS Rt = 2.70 minutes (Method A); MS (m / z) 465.2 (M + + H). EXAMPLE 133 Methyl 2- (3- ((4-benzoyl-piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 133A) and 2- (3- ((4-benzoyl-piperazine-1- il) methyl) -4- (4-chlorobenzyloxy) phenyl) acetic (Compound 133B) The title compounds were obtained using l-chloromethyl-4-chlorophenyl and benzoyl chloride using The method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid. Compound 133B: Rt = 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 134A) and 2- (4- (4-chlorobenzyloxy)) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 134B) The title compounds were obtained using l-chloromethyl-4-chlorophenyl and phenyl isocyanate using the method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl) acetic. Compound 134B: Rt = 2.58 minutes. (Method A); MS (m / z) 494.17 (M + + H). EXAMPLE 135 Methyl 2- (3- ((4- (benzyloxycarbonyl) piperazine-1- il) methyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 135A) and 2- (3- ((4- (benzyloxycarbonyl) piperazin-1-yl) methyl) -4- (4-chlorobenzyloxy) phenyl ) acetic (Compound 135B) The title compounds were obtained using l-chloromethyl-4-chlorophenyl and benzyloxy chloroformate using the method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) acid ) phenyl) acetic. Compound 135B: Rt = 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 136A) and 2- (4- (4- chlorobenzyloxy) -3- ((4- (2-phenylacetyl) piperazin-1-yl) methyl) phenyl) acetic acid (Compound 136B) The compue obtained using l-chloromethyl-4-chlorophenyl and 2-phenyl acetyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1-yl) methyl) phenyl acid ) acetic Compound 136B: Rt = 2.62 minutes. (Method A); MS (m / z) 493.15 (M + + H). Example 137 Methyl. { 4- (4-chloro-benzyloxy) -4- [4- (2-hydroxy-2-phenyl-acetyl) piperazin-1-ylmethyl] phenyl} acetate (Compound 137A) and Acid. { 4- (4-chloro-benzyloxy) -4- [4- (2-hydroxy-2-phenyl-acetyl) piperazin-1-ylmethyl] phenyl} acetic (Compound The title compounds were obtained using l-chloromethyl-4-chlorobenzene and 2-phenyl acetyl chloride using the method described for 2- (4- (isopentyloxy) -3- ((4- (phenylcarbamoyl) piperazin-1) acid il) methyl) phenyl) acetic. Compound 137B: 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) Scheme 13 A14 A15 A16 Step A: Methyl 2- (3-formyl-4-hydroxyphenyl) acetate A solution of methyl 2- (4-hydroxyphenyl) acetate (10 g, 60.2 mol) in TFA (50 ml) was refluxed with hexamethylenetetramine (8.44 g, 60.2 g). mol) overnight; the solution was concentrated to remove excess TFA. The residue was suspended in H20 (50 ml), after being made alkaline with Na 2 CO 3, the mixture was extracted with EtOAc (3 x 100 mL). The extract was washed with 1 N HCl (3 x 20 mL). The combined organic layers were dried over Na2SO4. The product was used without further purification. Step B: Methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate To the crude aldehyde (549 mg, 2.83 mol) above in CH3CN (15 mL) was added 1-chloro methyl-4- (chlorobenzene) ( 500 mg, 3.11 mol) and K2C03 (781 mg, 5.66 mol). The reaction was heated to 85 ° C overnight. The solid was filtered through CELITE. The product was used without further purification. LC / MS Rt = 4.01 minutes (Method A); MS (m / z) 341.1 (M ++ 23). Step C: Methyl 2- (3- (bromomethyl) -4- (4-chlorobenzyloxy) phenyl) acetate (Compound 138C) To methyl 2- (4- (4-chlorobenzyloxy) -3-formylphenyl) acetate (901 mg, 2.83 mol) in MeOH (10 mL) was added NaBH4 (537 mg, 14.16 mol) at 0 ° C. The reaction was carried out at room temperature overnight. H20 was added to quench the reaction, extracted with EtOAc (3 x 20 mL). The product was obtained after flash chromatography on silica gel. LC / MS Rt = 3.70 minutes. (Method A); MS (m / z) 343.1 (M ++ 23). To alcohol (241 mg, 0.75 mol) in CH3CN (10 ml) was added RMSCI (0.238 ml, 1.88 mol) and LiBr (131 mg, 1.50 mol). The solution was heated at 85 ° C overnight. The product (173 mg, 60%) was obtained after flash chromatography on silica gel. LC / MS Rt = 3.69 minutes. (Method A); MS (m / z) 384.1 (M + + H). Step D: 2- (4- (4-Chlorobenzyloxy) -3- ((2-oxo-4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid (Compound 138D) To methyl 2- (3- (bromomethyl) -4- (4-chlorobenzyloxy) phenyl) acetate (92.7 mg, 0.24 mol) in CH 3 CN (5 mL) was added 4-tosylpiperazin-2 -one (92.2 mg, 0.36 mol) and Cs2C03 (118 mg, 0.36 mol). The reaction was heated to 85 ° C overnight. The solid was filtered through CELITE. The product was collected after flash chromatography on silica gel. MS (m / z) 557.1 (M ++ 23). To this product (16.2 mg, 0.03 mol) in THF (1 mL) was added 1 N LiOH (1 mL). The reaction was monitored by TLC until the starting material was consumed. HE dilute with EtOAc (10 mL), washed with 1 N HCl (3 x 5 mL). The organic layer was dried over Na 2 SO 4 and concentrated to obtain 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 ) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with thiomorpholino. Compound 139B: LC / S Rt = 2.52 minutes. (Method A); MS (m / z) 392.1 (M + + H). Example 140 Methyl 2- (4- (4-chlorobenzyloxy) -3- ((4-hydropiperidin-1-yl) methyl) phenyl) acetate (Compound 140A) and 2- (4- (4-chlorobenzyloxy) -3- acid) ((4 -hydropiperidin- 1-yl) methyl) phenyl) acetic acid (Compound 140B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with 4-hydroxy piperidine . Compound 1 0B: LC / MS Rt = 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 ) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with morpholine. Compound 141B: LC / MS Rt = 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) acid ilmethyl) phenyl) acetic (Compound 1452B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with piperidine. Compound 142B: LC / MS Rt = 2.53 minutes. (Method A); MS (m / z) 374.1 (M + + H). Example 143 Methyl 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholine-1-oxydimethyl) phenyl) acetate (Compound 143A) and 2- (4- (4-Chlorobenzyloxy) -3- (thiomorpholine-1-oxydimethyl) phenyl) acetic acid (Compound 143B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with S-oxo thiomorpholine. . Compound 143B: LC / MS Rt = 2.39 minutes. (Method A); MS (m / z) 408.09 (M + + H). Example 144 Methyl 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholin-1,1'-dioxydimethyl) phenyl) acetate (Compound 144A) and 2- (4- (4-chlorobenzyloxy) -3- (thiomorpholine) -1,1 '-dioxydimethyl) phenyl) acetic acid (Compound 144B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with S, S- dioxo thiomorpholine. Compound 144B: LC / MS Rt = 3.05 minutes. (Method A); MS (m / z) 424.31 (M + + H). EXAMPLE 148 Methyl 2- (4- (4-fluorobenzyloxy) -3- (thiomorpholine-1,1'-dioxydimethyl) phenyl) acetate (Compound 145A) and 2- (4- (4-fluorobenzyloxy) -3- (thiomorpholine) -1,1 '-dioxydimethyl) phenyl) acetic acid (Compound 145B) The title compounds were obtained using the same experimental method described for 2- (4- (4-chlorobenzyloxy) -3- ((4-tosylpiperazin-1-yl) methyl) phenyl) acetic acid, starting with S, S- dioxo thiomorpholine and l-bromomethyl-4-fluorobenzene. Compound 145B: LC / MS Rt = 2.90 minutes. (Method A); MS (m / z) 408.1 (M + + H).
Example 146 Acid (11R) / (US) -2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 146D and E) E14 Stage A: 2- ((4- (carboxymethyl) phenoxy) methyl) benzoic acid (Compound 146A) Solid K2CO3 (14.3 g, 104 mol), Nal (390 mg, 2.6 mol) and ethyl -2 - (bromomethyl) benzoate (6.3 g, 26 mol) was added to a stirred solution of methyl 4-hydroxy phenylacetate (4.3 g). , 26 mol) in 2-propanone (100 ml). The resulting mixture was refluxed overnight, cooled, filtered through filter paper, and concentrated. The residue was redissolved in EtOH / H20 (10: 1, 150 ml) and solid KOH (14 g, 260 mol) was added followed by reflux overnight. After concentration the residue was dissolved in H20 (100 mL) and the aqueous was washed with ether (100 mL) and acidified with concentrated HCl (1 <pH). Filtration provided the crude acid (9.8 g) which was used in the subsequent reaction without further purification. Step B: Methyl 2- (11-oxo-6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 146B) error in marking Polyphosphoric acid (50 g) was added to a stirring solution of 2- ((4- (carboxymethyl) phenoxy) methyl) benzoic acid (9.8 g) in acetic acid (17 ml) a 90 ° C. After stirring for 5 hours, the resulting mixture was cooled and H20 (159 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 over Na2SO4 and concentrated. The residue was redissolved in MeOH (150 ml) and HCl (g) was bubbled through it for 5 minutes. The resulting solution was stirred overnight and concentrated to provide the crude ester. Flash chromatography on silica gel (3: 1, hexanes / EtOAc) yielded the desired material. Step C: Methyl 2- (ll-chloro-6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 146C) NaBH4 (430 mg, 11.3 mol) was added to a stirred solution of methyl 1- (11-oxo-6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (800 mg, 2.83 mol) in MeOH (20 mi). After stirring for 5 minutes, the reaction mixture was quenched with saturated NaHCO 3 (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was redissolved in CH2C12 (20 ml) and S0C12 (1.03 ml, 14.15 mol) was added. After stirring for 1 hour, the reaction mixture was concentrated to give the crude material which was used in the subsequent reaction without further purification. Step D: (11R) (US) -2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 146D / 146E) DIEA (1.1 ml, 6.35 mol) and 1-tosylpiperazine (607 mg, 2.5 mol) were added to a stirring solution of methyl 2- (ll-chloro-6,11-dihydrodibenzo [b, e] oxepin-2-yl). ) acetate (640 mg, 2.11 mol) in CH2C12 (20 ml). The reaction mixture was quenched with saturated NaHCO3 (20 mL) after stirring overnight and the aqueous layer was extracted with CH2C12 (3 x 15 mL). The organic layers were dried over Na2SO4 and concentrated. The residue was redissolved in THF / MeOH / H20 (3: 1: 1, 15 mL) and LiOH (621 mg, 14.8 mol) was added. After stirring overnight, the resulting mixture was quenched with 1N HCl (< pH 1). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and concentrated to give the crude acid (411 mg) as a yellow oil.
HPLC purification afforded the pure title material. Both enantiomers (146A / 146B) were also separated by chiral HPLC: ES / MS, m / z 493.2 (M + H); LC / MS (Method B) Rt = 3,602 minutes. Chiral LC (Chiralpak OD-H, 4.6 x 250 mm, 80% hexanes: 20% IPA, 40 ° C, 1.0 ml / min). 146A Rt = 12,148 minutes, 146B Rt = 25,056 minutes. EXAMPLE 147 Methyl 2- (11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 147A) and 2- (11-) Acid - (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 147B) The title material was obtained using the method described for 2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid using 4-fluoro phenyl sulfonyl piperazine: Compound 147B: 1 H NMR (400 MHz, DMSO-d 6) delta 12.24 (1H, brs), 7.75 (2H, dd, J = 5.5, 7.87 Hz), 7.46 (2H, t, J = 8.8 Hz), 7.32 (4H, m), 7.06 (2H, d, J = 8.0 Hz), 6.66 (1H, 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 (M + H); LC / MS (Method B) Rt = 3,560 minutes. Example 148 Methyl 2- (9-chloro-ll (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 148A) and 2- (9-chloro) acid -ll (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 148B) The title material was obtained using the method described for 2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid using 4-fluoro phenyl sulfonyl piperazine and 5-chloro-2- (bromomethyl) benzoate. Compound 148B: ES / MS, m / z 527.1 (M + H); LC / MS (Method B) Rt = 4.105 minutes. Example 149 Methyl 2- (9-chloro-ll- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 149A) and Acid 2- (9-Chloro-11- (4- (4-fluorophenylsulfonyl) piperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 149B) The title material was obtained using the method described for 2- (11- (4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid using 4-fluoro phenyl sulfonyl piperazine and 5-chloro-2- (bromomethyl) benzoate. Compound 149B: ES / MS, m / z 531.1 (M + H); LC / MS (Method B) Rt = 3,996 minutes. Example 150 Methyl 2- (11- (2-oxo-4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetate (Compound 150A) and 2- (11-) Acid (2-Oxo-4-tosylpiperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid (Compound 150B) The title material was obtained using the method described for 2- (11- (4-tosylpiperazin-1-yl) 6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid using tosyl piperazin-2-one and 2 - (bromomethyl) benzoate. Compound 150B: ES / MS, m / z 507.2 (M + H); LC / MS (Method B) Rt = 3.52 minutes. Pharmacological Data: Receptor Interaction Analysis Cell culture: Jurkat human cells transfected with DP-2, DP-1 or TP receptors were kept in culture in a humidified atmosphere at 37 ° C (5% C02) in RPMI 1640 medium (Gibco ®, Invitrogen, USA) with 10% fetal bovine serum (Hyclone, Logan, UT, USA) plus penicillin - streptomycin (Gibco ®, L - glutamine (Gibco ®, sodium pyruvate and 100 ug / ml G418. They were grown in T225 flasks (Corning®) and harvested by centrifugation Cell pellets were harvested from a cell suspension of approximately 200 ml, granulated by centrifugation and stored at 20 ° C until processed on membranes. : Granules of frozen Jurkat cells that expressed either DP-2, DP-1 or TP, were thawed on ice Each granule was suspended in membrane buffer (25 mM Hepes®, pH 7.2, 6 mM MgCl2, 1 EDTA mM) more tablet Complete® Protease Inhibitor Cocktail (Roche Mannheim, Germany). The granules were homogenized and centrifuged at 1900 rpm for 10 minutes in a tabletop centrifuge superior (Beckman Coulter Allegra® 6R). The supernatants were collected and the granules were resuspended in 10 ml of membrane buffer, homogenized again and centrifuged as above. The supernatants were drained and centrifuged in a Beckman J2-21M centrifuge using a JA20 rotor at 20,000 rpm for 1.5 hours at 4 ° C. The supernatants were discarded and the membrane granules were suspended in membrane buffer and emptied. The protein concentration was determined and the membranes adjusted to approximately 1.5 mg / ml. DP-2 binding analysis: The interactions of the compound with the DP-2 receptors were determined by means of competitive radioligand binding assays using the membranes prepared from cells expressing DP-2 (prepared as above) and 3 [H] PGD2 (166 Ci / mol) as a radioactive tracer. The analyzes were carried out in a final volume of 150 ul of analysis buffer (10 mM Hepes®, 10 mM MnCl2, 1 mM EDTA and 1% DMSO). The serially diluted test article in assay buffer was incubated with 1 nM of radioactive tracer and 10 ug / well of the membranes prepared from cells expressing DP-2 in a 96-well plate for one hour at room temperature. The reaction mixture was then transferred to a Millipore glass fiber filter plate (Bedford, MA) MultiScreen®, FC MAFCNOB. The plate was aspirated under vacuum and washed twice with 200 ul of binding buffer by suctioning vacuum between each wash. The plate was allowed to dry and a 50 ul scintillation cocktail of Optiphase "Super Mix" (Wallac OY Turku, Finland) was added to each well. The plate was counted in a Wallac ™ micro beta liquid scintillation counter (Wallac Oy Turku, Finland). Chemotaxis Analysis of DP-2 The ability of the compounds of the invention to antagonize DP-2 receptor function was examined in chemotaxis analyzes using Jurkat cells transfected with DP-2. The compounds were serially diluted in complete medium containing 1 nM of PGD2 as a chemoattractant, and 600 ul of this mixture was transferred into the bottom wells of a Costar Transwell® plate (pore size 8 um). Jurkat cells transfected with DP-2 were harvested, resuspended at 7.5 x 10 6 / ml complete medium, and 100 ul of this cell suspension was added into the pore filter inserts. After equilibrating all the components at 37 ° C in a cell incubator for 15 minutes, the chemotaxis was initiated by transferring the filter inserts onto the lower wells. After 2 hours of incubation in an incubator at 37 ° C, the filter inserts were removed, the medium with the cells was collected from the lower wells and transferred to FACS tubes. The Cells in each sample were then enumerated in a FACScan using CellQuest software. Selectivity Analysis DP-1 Linkage Analysis The DP-1 linkage analyzes were carried out substantially identically to the DP-2 linkage analysis, except that cell membranes transfected with DP-1 were used. Human TP binding analysis The TP receptor interaction was evaluated in competition binding analysis using membranes from cells transfected with TP receptor (prepared as above) and 3 [H] SQ29,548 (48.2 uCi / mol) as a selective TP tracker. The analyzes were carried out in a final volume of 150 ul of binding buffer (10 mM Hepes, 10 mM MnCl2, 1 mM EDTA and 1% DMSO.) Duplicate samples of the serially diluted test compound were incubated with 10 μM. ug / well of TP membranes in the presence of 3 nM of 3 [H] SQ29, 548. After an incubation of one hour at room temperature, the reaction mixture was transferred to a Millipore® glass fiber filter plate (Bedford , MA) MultiScreen®, FC MAFCNOB The mixture was aspirated in vacuo, and washed twice with 200 ul of binding buffer by aspirating the vacuum between each wash.After drying in air, 50 ul of the Optiphase scintillation cocktail was added.
Super Mix (Wallac Oy Turku, Finland) to each well and the radioactivity was quantified in a Wallac ™ micro beta 1450 liquid scintillation counter (Wallac Oy Turku, Finland). All the acid compounds of the Examples that were tested in the analysis exhibited IC50 values of less than 25 uM, for example, the acid compounds of the examples, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 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, 90, 91, 106, 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 compounds of acid of the invention exhibited IC50 values of less than 10 uM, for example, the acid compounds of examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 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, 77 , 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 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 embodiments, the acid compounds of the invention exhibited IC50 values less than 0.1 uM. In some embodiments, the compounds of the invention exhibited IC50 values less than 0.1 uM. All the acid compounds of the Examples which were tested in the ligand binding analysis described above exhibited an average IC50 value that was at least 2 times lower for DP-2 on DP-1 and TP, for example, the acid 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, 141, 143 and 144. In some embodiments, the acid compounds of the invention exhibited an average IC50 value that was at least 10-fold lower for DP-2 on DP-1 and TP, for example, the acid compounds of the 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 acid compounds of the invention exhibited an average IC50 value that was 50 times lower for DP-2 on DP-1 and TP, for example, the acid compounds of examples 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 this specification are incorporated herein by reference as if each publication or individual patent application is specifically and individually indicated by the reference. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity and Understanding, it will be readily apparent to those of ordinary skill in the art, in light of the teachings of this invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (11)

    CLAIMS A compound that has the structure
  1. (I> A is a 5-14 membered heterocyclic ring having heteroatoms of 1-4 rings each independently selected from the group consisting of nitrogen, oxygen and sulfur, the ring being heterocyclic, monocyclic or polycyclic, optionally substituted with 1-3 substituents R8; L is selected from the group consisting of CR6R7, CO, CNRS and CS; Q1 is selected from the group consisting of: a bond, Ci-C4 alkylene, C-C4 heteroalkylene, -CO-, - NH-, -O-, -SOq-, -C (0) 0-, -OC (O) -, -CONH-, -NHCO-, -NHCONH-, -NHSOq-, -SOgNH- and -COCH2HNSOq; R1, R2, R3 R6 and R7 is independently selected from the group consisting of H, Ci-6 alkyl, C0.6 alkylaryl and C0-e alkylheteroaryl, wherein the aryl or heteroaryl moieties are optionally substituted with Ci-6 alkyl, CN, OR, haloalkyl Ci-6, heteroalkyl Ci_6 / NR2, N02, halo, C (0) R, C02R, CONR2, SOqR,
  2. SOqNR2 OC (0) OR, OC (0) R, OC (0) NR2 / NRC (0) NR2, NRC (0) R and NRC (CC ^ - each R4 is independently selected from the group consisting of C1-6 alkyl , C0-4 alkyl C3-cycloalkyl, C0-4 alkylaryl, C0-4 alkylheteroaryl, C2-4 alkenylaryl, C2-4 alkynylaryl, C0-4 alkylheterocyclyl, CN, amino, HCOR1, hydroxy, Ci_6 alkoxy, OC (0) R1, -O-alkylaryl C0-4, 0-alkylheteroaryl C0-4 / -0-alkylC0-4Cycloalkyl C3-10, 0-alkylC0-4heterocycloalkyl C3-i0, O-alkylC0-4NR8, nitro, halo and haloalkyl Ci-6 or combine with each other or with R6 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 groups are each optionally substituted with from 1 to 3 substituents each independently selected from the group consisting of C1-6 alkyl, CN, CONHR1, C02R1, amino, Ci_6 alkoxy, halo, Ci_6 haloalkyl and SOgR1; the group consisting of Ci-6 alkyl, C0-4 alkylaryl, C2-4 alkenylaryl, C2-4 alkynylaryl, C0-4 alkylheteroaryl, each of which is optionally substituted with 1-3 substituents of R9; each R8 is independently selected from the group consisting of Ci-6 alkyl, C3-6 alkylcycloalkyl, C0-al alkylaryl, C0-6 alkyheteroaryl oxo, Ci_6 alkyl, CN,
  3. OR, haloalkyl Ci-6i heteroalkyl Ci-6, NR2, N02, halo, C (0) R, C02R, CONR2, SOqR, SOqNR2, OC (0) OR, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) OR; each R9 is independently selected from the group consisting of alkyl CN, OR, oxo, haloalkyl Ci-6, heteroalkyl Ci-6, NR2, N02, halo, C (0) R, C02R, CONR2, SOqR, SOqNR2, OC (0 ) OR, OC (0) R, OC (0) NR2, NRC (0) NR2, NRC (0) R and NRC (0) OR; each R is independently selected from the group consisting of H, Ci-6 alkyl, C0-4 alkylheteroaryl, C0-4 heterocyclyl, C3-8 cycloalkyl and C0-4 alkylaryl or, when attached to the same nitrogen atom, may be combined to forming a ring of 5-8 members having heteroatoms of 1-4 rings each selected independently of the group consisting of nitrogen, oxygen and sulfur; the subscript n is independently 0, 1, 2, 3 or
  4. 4. each subscript q is independently 0, 1 or 2; and pharmaceutically acceptable derivatives thereof. 2. The compound of claim 1, wherein A has the structure (II): wherein Y is selected from the group consisting of a bond, CH2, N, 0, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript p is independently 0, 1 or 2; each ring link in dashes independently indicates the presence of a single, double or normalized link; the dotted line indicates the point of attachment to Q1 and the wavy line indicates the point of attachment to L. 3. A compound of claim 1, having the structure (III): (III) wherein Y is selected from the group consisting of a bond, CH2, N, 0, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 1, 2, or 3; the subscript p is independently O, 1 or 2; and each ring link in dashes independently indicates the presence of a single, double or normalized link. . A compound of claim 1, having structure (IV): wherein Y is selected from the group consisting of a bond, CH2, N, O, NO, and SOq; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1, 2 or 3; the subscript p is independently 0, 1 or 2; and each ring link in dashes independently indicates the presence of a single, double or normalized link.
  5. 5. A compound of claim 1, selected from the group consisting of: [4- (4-Chloro-benzyloxy-3-thiomorpholine-4- ilmethyl-phenyl] acetic; [4- (4-Chloro-benzyloxy) -3- (1,1-dioxo-l-lambda6-thiomorpholin-4-ylmethyl) phenyl] -acetic acid; [4- (4-Fluoro-benzyloxy) -3- (1,1-dioxo-l-lambda6-thiomorpholin-4-ylmethyl) phenyl] acetic acid; [4- (4-Chloro-benzyloxy) -3-morpholin-4-ylmethyl-phenyl] acetic acid; [4- (4-Chloro-benzyloxy) -3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -phenyl] -acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [3-OXO-4- (4-trifluoromethyl-phenyl) piperazin-1-ylmethyl] phenyl} acetic; [3- (4-benzyl-piperazin-1-ylmethyl) -4- (4-chloro-benzyloxy) phenyl] acetic acid; (4- (4-Chloro-benzyloxy) -3-. {4- [2- (4-methoxy-phenyl) -acetyl] -piperazin-1-ylmethyl} -phenyl) -acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-p-tolyl-acetyl) piperazin-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; Methyl ester of acid. { 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) benzyl] piperazin-1-yl} oxo-acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-hydroxy-2-phenyl-acetyl) piperazin-1-ylmethyl] phenyl} acetic; Ter-butil 4- [5-carboxymethyl-2- (4-chloro-benzyloxy-benzyl] piperazine-l-carboxylic acid ester, 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) - tert-butyl ester benzyl] piperazine-l-carboxylic acid methyl ester 3- [5-carboxymethyl-2- (4-chloro-benzyloxy) benzyl] piperazine-l-carboxylic acid isopropyl ester 4- [5-carboxymethyl-2- ( 4-chloro-benzyloxy) benzyl] piperazine-l-carboxylic acid 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid ethyl ester; , 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-l-ilmet] acid il) -4- (4-chloro-benzyloxy) phenyl] acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (4-fluoro-benzenesulfonyl) piperazin-1-ylmethyl] phenyl} acetic; [3- [4- (4-Chloro-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) phenyl] -acetic acid; Acid { 4- (4-methoxy-benzyloxy) -3- [4- (toluene-4- sulfonyl) iperazin-l-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-yl} acetic; Acid { 4-benzyloxy-3- [4- (toluene-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) -perazin-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; [3- [4- (2-Chloro-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) -phenyl] -acetic acid; 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) 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) iperazin-1-ylmethyl] biphenyl-4-yl} acetic; [3- [4- (Toluene-4-sulfonyl) iperazin-1-ylmethyl] -4- (4-trifluoromethyl-benzyloxy) phenyl] acetic acid; Acid { 4- (4-chloro-benzyloxy) -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-phenethyloxy-3 - [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic; [3- [4- (4-tert-Butyl-benzenesulfonyl) piperazin-1-ylmethyl] -4- (4-chloro-benzyloxy) phenyl] acetic acid; Acid { 4- (4-chloro-benzyloxy) -3- [4- (3, 5-dimethyl-isoxazole-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (naphthalene-2-sulfonyl) iperazin-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-] ilmethyl] -4- (4-chloro-benzyloxy) phenyl] acetic; Acid { 4- (4-methoxy-benzyloxy) -3- [4-toluene-4-sulfonyl) iperazin-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; [4- (4-Chloro-benzyloxy) -3- (4-phenylmethanesulfonyl-piperazin-1-ylmethyl) phenyl] acetic acid; Acid { 4- (2,4-dichloro-benzyloxy) -3- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] phenyl} acetic; 4- Acid. { 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) iperazin-1-ylmethyl] phenyl} acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-phenyl-ethenesulfonyl) piperazin-1-ylmethyl] phenyl} acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (4-chloro-3-trifluoromethyl-benzenesulfonyl) piperazin-1- ilmethyl] phenyl} acetic; Acid { 4- (4-chloro-benzyloxy) -3- [4- (2-phenyl-ethanesulfonyl) -perazin-1-ylmethyl] -phenyl} acetic; [4- (4-Chloro-benzyloxy) -3- [4- (4-nitro-benzenesulfonyl) -piperazin-1-ylmethyl] -phenyl acid} acetic; and Acid. { 4- (4-chloro-benzyloxy) -3- [2-oxo-4- (toluene-4-sulfonyl) piperazin-1-ylmethyl] -phenyl} acetic; and Acid (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] -phenyl-methyl} phenyl) -acetic acid; 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) phenylmethyl] -5-chloro-phenyl} acetic; (3- ({(4-Chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) iperazin-1-yl], methyl} 4-hydroxy-phenyl) -acetic acid; Acid (3- { [4- (4-fluoro-benzenesulfonyl) piperazine-1) il] -p-tolyl-methyl} -4-hydroxy-phenyl) acetic; (3- {[4- (4-Fluoro-benzenesulfonyl) piperazin-1-yl] -p-tolyl-methyl} phenyl) -acetic acid; and (3- { [4-Chloro-phenyl) - [4- (4-fluoro-benzenesulfonyl) piperazin-1-yl] methyl} phenyl) acetic.
  6. 6. A compound of claim 1, having the structure IVa: IVa where Y2 is selected from the group consisting of N, 0 and S; each R12 is independently selected from the group consisting of Ci_6 alkyl, CN, CONHR1, CO2R1, amino, Ci-g alkoxy, halo, Ci-6 haloalkyl, and SOqR1 or combine with each other to form an aryl or heteroaryl ring; and the subscript u is independently 1, 2 or 3.
  7. 7. A compound of claim 1, selected from the group consisting of: 2- (11- (4-tosylpiperazin-1-yl) -6, 11-dihydrodibenzo acid [ b, e] oxepin-2-yl) acetic; 2- (11- (4- (4- fluorophenylsulfonyl) iperazin-1-yl) -6,11-dihydrodibenzo [b, e] oxepin-2-yl) acetic acid; 2- (9-Chloro-11- (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; N-oxide of 1- (5- (carboxymethyl) -2- (2,4-dichlorobenzyloxy) benzyl) -4-tosylpiperazine; 4- [5-carboxymethyl-2- (4-chloro-benzyloxy) -benzyl] -piperazine-1-carboxylic acid 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- (4-hydroxy-piperidin-1-ylmethyl) phenyl] acetic acid; 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) iperidin-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; Acid { 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; and [4- (4-Chloro-benzyloxy) -3- (4-methanesulfonyl-piperazine-1-carbonyl) phenyl] acetic acid.
  8. 8. A compound of claim 1 having structure (V): (V) where Y is selected from the group consisting of a bond, CH2, N, 0, NO and S0q; R10 and R11 are H or combine with each other to form an aryl, heteroaryl or cycloalkyl ring; the subscript m is independently 0, 1, 2 or 3; the subscript p is independently 0, 1 or 2; and each ring link in dashes independently indicates the presence of a single, double or normalized link.
  9. 9. A pharmaceutical composition comprising a compound of any of claims 1 to 8 and a pharmaceutically acceptable carrier, excipient, diluent or delivery system.
  10. 10. A method for antagonizing a DP-2 receptor comprising contacting a DP-2 receptor with a compound of any of claims 1 to 8.
  11. 11. The use of a compound of any one of claims 1 to 8 or a A pharmaceutically acceptable derivative thereof for preparing a medicament for treating or preventing a disorder or condition responsive to the modulation of PGD2 or a PGD2 receptor. The use of a compound of any one of claims 1 to 8 or a pharmaceutically acceptable derivative thereof to prepare a medicament for treating or preventing a disorder or condition responsive to antagonism of a PGD2 receptor. 17. The use of a compound of any one of claims 1 to 8 or a pharmaceutically derivative acceptable thereof to prepare a medicament for treating or preventing a disorder or condition associated with elevated levels of PGD2 or a metabolite thereof. The use of any of claims 11 to 13, wherein the disorder or condition is selected from the group consisting of: obstructive airways 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; erythema; 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 mast cell disorder; idiopathic thrombocytopenic purpura; atherosclerosis; lupus erythematosus; systemic lupus erythematosus; sepsis; reperfusion injury; glomerulonephritis; allergic nephritis; Nephritic syndrome; disorders related to eosinophils such as Churg-Strauss syndrome; basophilic leukocytosis and basophilic leukemia; acquired immunodeficiency syndrome; arthritis and conditions associated with them and other conditions or disorders associated with elevated levels of PGD2 or its metabolites. 15. The use of any of claims 11 to 13 wherein said compound is used in combination with a second therapeutic agent. The use of claim 15 wherein said second therapeutic agent is useful for preventing or treating a disorder or condition selected from the group consisting of: asthma, rhinitis, allergic respiratory 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, frontotemporal dementia, dementia of Lewy bodies, vascular dementia, Guillain-Barre syndrome, chronic demyelinating polyradiculoneuropathy, muítifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration, CNS trauma, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Behcet's disease, bursitis, carpal tunnel, intestinal disease inflammatory, Crohn's disease, ulcerative colitis, dermatomyositis, Ehlers-Danlos syndrome (EDS), fibromyalgia, pain, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter syndrome (reactive arthritis), sarcoidosis, scleroderma, Sjogren's syndrome, soft tissue disease, Still's disease, tendonitis, polyarteritis nodosa, granulomatosis of egener, myositis (polymyositis dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus (SLE), type 1 diabetes, systemic diabetes, nephritic syndrome, glomerulonephritis, acute and chronic renal failure, eosinophilic fasciitis, hyper IgE syndrome, sepsis, septic apocalypse, ischemic reperfusion injury, transplant rejection, graft-versus-host disease, eczema, psoriasis, fever, cancer, infection viral, thrombosis, fibrosis, run-off, inflammation, nasal congestion, urticaria, contact hypersensitivity (including contact dermatitis), food allergies, eosinophilic gastroenteritis, mastocytosis, acne, ulcerative colitis, pruritis, angioderma, dermatides, erythema, eosinophilia, cutaneous , chronic skin ulcers, celiac disease, disorder more systemic tocitos; idiopathic thrombocytopenic purpura, Churg-Strauss syndrome, basophilic leukocytosis, basophilic leukemia and acquired immunodeficiency syndrome (AIDS). The use of claim 15, wherein said second therapeutic agent is selected from the group consisting of: a corticosteroid, a corticosteroid analogue, an antihistamine, a beta 2 agonist, a cromolyn, a leukotriene antagonist, a therapy of anti-IgE antibodies, an anti-infective, an anti-fungal, an immunosuppressant, a PGD2 or DP antagonist, a PDE4 inhibitor, a cytosine modulator, a PPAR-gamma agonist, a 5-lipoxygenase inhibitor, a FLAP inhibitor, and a PLA2 inhibitor.
MX2008015696A 2006-06-09 2007-06-08 Substituted phenyl acetic acids as dp-2 antagonists. MX2008015696A (en)

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WO2007143745A2 (en) 2007-12-13
BRPI0712301A2 (en) 2012-01-17
EA200802415A1 (en) 2009-06-30
WO2007143745A3 (en) 2008-04-17
NO20090138L (en) 2009-03-05
CN101490024A (en) 2009-07-22

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