WO2008090357A2 - N, n; -substituted piperazines binding to melanocortin receptor - Google Patents

N, n; -substituted piperazines binding to melanocortin receptor Download PDF

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WO2008090357A2
WO2008090357A2 PCT/GB2008/000263 GB2008000263W WO2008090357A2 WO 2008090357 A2 WO2008090357 A2 WO 2008090357A2 GB 2008000263 W GB2008000263 W GB 2008000263W WO 2008090357 A2 WO2008090357 A2 WO 2008090357A2
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alkyl
compound
halo
group
optionally substituted
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PCT/GB2008/000263
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WO2008090357A3 (en
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Shubh D. Sharma
Yi-Qui Shi
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Palatin Technologies, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to tetra-substituted piperazine compounds that bind to one or more melanocortin receptors and are agonists, antagonists, mixed agonist- antagonists, inverse agonist or antagonists of inverse agonists with respect to one or more melanocortin receptors, and use thereof for the treatment of metabolic, immune, inflammation-related and other melanocortin receptor-mediated disorders, including treatment of obesity and related energy homeostasis disorders and diseases.
  • Background Art :
  • melanocortin-1 receptors MC1-R
  • me!anocortin-2 receptors M2-R
  • ACTH adrenocorticotropin
  • MC3-R and MC4-R melanocortin-3 and melanocortin-4 receptors
  • MC5-R melanocortin- 5 receptors
  • compounds specific for MC1-R are believed to be useful for treatment of melanoma.
  • Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of cachexia, as a weight gain aid, or alternatively for treatment of obesity, and generally for food intake and metabolism-related purposes.
  • Compounds specific for MC3-R and MC4-R can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction.
  • Such compounds may also have application in treatment of drug addiction, including alcohol abuse or addiction, as anxiolytic agents, and for treatment of depression.
  • melanocortin receptor-specific compounds such as MC1-R agonists, can be used as tanning agents to increase melanin production in the skin, acting as chemo-preventive agents against harmful effects of UV solar radiation.
  • Compounds specific for MC1-R, MC3-R or both may further be useful in regulation of inflammatory processes.
  • melanocortin receptors There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as for compounds that are either agonists or antagonists for specific melanocortin receptors.
  • High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists.
  • melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
  • piperazine and piperidine compounds known, such as those disclosed in WO 02/070511 (Bristol-Myers Squibb Company), WO 02/059095 (EIi Lilly and Company), and WO 00/74679 (Merck & Co., Inc.), asserted to be specific for melanocortin or related receptors.
  • such compounds have at most two functional substituted groups, have relatively poor affinity and specificity, and are not suitable for use as a drug compound.
  • High affinity compounds for such receptors can be used to exploit varied physiological responses associated with the receptors, either as agonists or antagonists. There is thus a need for compounds that are more selective, including higher affinity and specificity, and in particular for compounds that have at least three or four biologically active substituted groups. This invention addresses that need.
  • WO 02/085925 "Melanocortin Receptor Ligands", to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, piperazine structures with four or more substituted groups, methods to synthesize piperazine structures, methods to synthesize piperazine structures with four or more substituted groups, or methods to synthesize optically pure structures, and further does not disclose structures with a single substituent group that is a single D-Phe or D-NaI residue, or a derivative or homolog thereof, optionally with an amine capping group.
  • the invention provides melanocortin receptor-specific piperazine compounds, of the formulae:
  • J and Q are independently a cyclic radical or two cyclic radicals linked by a bond, -CH 2 -, or
  • J and Q are unsubstituted or optionally substituted with one or two R 8 groups, wherein Q may optionally be fused to V when L 3 is absent, wherein J may optionally be fused to V 1 when L 1 is absent;
  • R 3a and R 3b are both H or R 3a and R 3b come together to form an oxo group
  • R 4a and R 4b are both H or R 4a and R 4b come together to form an oxo group; one or two of R 1a , R 1b , R 2a , and R 2b are alkyl or alkylcycloalkyl and the remaining of R 1a , R 1b ,
  • R 2a , and R 2b are hydrogen, provided that at least one of R 1a and R 1b and at least one of R 2a and R 2b are hydrogen;
  • R 6 is H and R 7 is a group of the formula: ⁇ 2
  • R 8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
  • each occurrence of R 9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R 10 , CN, OH, oxo, halo,
  • each occurrence of R 10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
  • the invention further provides pharmaceutical compositions comprising a compound of structures I, II, III, IV or an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof.
  • Such pharmaceutical compositions may be - employed in a method for affecting melanocortin receptor function in a human or non-human mammal, the method comprising the step of administering the pharmaceutical composition.
  • Such pharmaceutical composition may further be employed in a method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition to the human or non-human mammal in a pharmaceutically effective amount.
  • the condition may be selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above-optimal body weight, obesity, below-optimal body weight and cachexia.
  • the present invention further provides compounds that are agonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R.
  • the compounds alternatively are antagonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R.
  • the compounds alternatively are inverse agonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R.
  • the compounds alternatively are antagonists of an inverse agonist of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R.
  • the invention further includes methods for altering a disorder or condition associated with the activity of a melanocortin receptor, comprising administering to a patient a pharmaceutically effective amount a compound of the invention.
  • the disorder or condition is an eating disorder such as cachexia.
  • the disorder or condition is obesity and associated impairment of energy homeostasis.
  • the disorder or condition is sexual dysfunction such as erectile dysfunction or female sexual dysfunction.
  • One object of the present invention is to provide conformationally constrained and optically pure isomers of tetra-substituted piperazines, wherein the pendant group substituents are amino acid moieties, amino acid side chain moieties or derivatives thereof, such that the resulting ring compound biologically mimics a relevant reverse turn peptide structure.
  • Another object of the present invention is to provide methods for the synthesis of optically pure compounds of the invention.
  • Another object of the present invention is to provide piperazine compounds with four pendant groups, such pendant groups consisting of any moiety other than H, O, S, or a halogen.
  • Another object of the present invention is to provide piperazine core compounds wherein pendant groups are provided, which pendant groups are or include amino acid side chain moieties.
  • Another object of the present invention is to provide a compound of the invention ) wherein such compound is specific for one or more melanocortin receptors.
  • Another object of the present invention is to provide a method for synthesis of compounds of the invention.
  • the invention provises melanocortin receptor-specific piperazine i compounds, of the formulae:
  • J and Q are independently a cyclic radical or two cyclic radicals linked by a bond, -CH 2 -, or
  • J and Q are unsubstituted or optionally substituted with one or two R 8 groups, wherein Q may optionally be fused to V when L 3 is absent, wherein J may optionally be fused to V 1 when L 1 is absent;
  • R 3a and R 3b are both H or R 3a and R 3b come together to form an oxo group
  • R 4a and R 4b are both H or R 4a and R 4b come together to form an oxo group; one or two of R 1a , R 1b , R 2a , and R 2b are alkyl or alkylcycloalkyl and the remaining of R 1a , R 1b ,
  • R 2a , and R 2b are hydrogen, provided that at least one of R 1a and R 1b and at least one of R 2a and R 2b are hydrogen;
  • R 6 is H and R 7 is a group of the formula: W , or R 6 and R 7 each form a bond to a group of the formula:
  • R 8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, 0 heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
  • each occurrence of R 9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, aikyl-NH- 5 alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R 10 , CN, OH, oxo, halo,
  • each occurrence of R 10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5. 5
  • the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric
  • O isomers O isomers
  • enantiomers or diastereomers.
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass the racemic form of compounds of the invention as well as all enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomehc mixtures.
  • a compound of the invention is considered optically active or enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 90% ee (enantiomeric excess) or greater, preferably, equal to or greater than 95% ee with respect to a particular chiral center.
  • a compound of the invention is considered to be in enantiomerically enriched form when the compound has an enantiomeric excess of greater than about 80% ee, preferably greater than about 90% ee.
  • a racemic mixture means about 50% of one enantiomer and about 50% of its corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically pure, enantiomerically enriched, and racemic mixtures of compounds of the invention.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the compounds of the invention When administered to a patient, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition.
  • isolated means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture.
  • the compounds of the invention are purified by conventional techniques.
  • purified means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a single compound of the invention (or an enantiomeric or diastereomeric mixture thereof) by weight of the isolate. 3.
  • treat contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder.
  • the term "pharmaceutically effective amount” means the amount of a compound of the invention that will elicit a biological or medical response in the mammal that is being treated by a medical doctor or other clinician.
  • prophylactically effective or “preventive” means the amount of a compound of the invention that will prevent or inhibit affliction or mitigate affliction of a mammal with a medical condition that a medical doctor or other clinician is trying to prevent, inhibit, or mitigate before a patient begins to suffer from the specified disease or disorder.
  • salt(s) includes but is not limited to salts of acidic or basic groups that may be present in the compounds of the invention.
  • Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to .
  • salts containing pharmacologically acceptable anions including but not limited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e.,
  • Compounds of the invention that include an amino moiety also can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds of the invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium lithium, zinc, potassium, and iron salts.
  • alkyl group means a saturated, monovalent, unbranched or branched hydrocarbon chain.
  • alkyl groups include, but are not limited to, (Ci-C 6 ) alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methy!-2-propyl, 2- methyl-1 -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-1 -propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopent
  • alkenyl group means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to (C 2 -C 6 ) alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2- butenyl, 4-(2-methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • alkynyl group means monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • the triple bond of an alkynyi group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, (C 2 -C 6 ) alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4- butyl-2-hexynyl.
  • An alkynyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • aryl group means a monocyclic or polycyclic-aromatic radical comprising carbon and hydrogen atoms.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, naphthyl, and biphenyl as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aryl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below.
  • An aryl group optionally may be fused to a cycloalkyl group, fused to another aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group.
  • an aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 ) aryl”.
  • heteroaryl group means a monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazyl, indolyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)-triazolyl, (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phienyl, isoxazolyl, oxazolyl, pyrazolyl, tetrazolyl, oxadiazole, thiadiazolyl, isoxazolyl, triazinyl, and pyrazinyl.
  • a heteroaryl can be unsubstituted or optionally substituted with one or two suitable substituents as defined below.
  • a heteroaryl group optionally may be fused to another heteroaryl group, fused to an aryl group, fused to a cycloalkyl group, or fused to a heterocycloalkyl group.
  • cycloalkyl group means a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds.
  • cycloalkyl groups include, but are not limited to, (C 3 -C 7 ) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below.
  • a cycloalkyl group optionally may be fused to another cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group.
  • heterocycloalkyl group means a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl group may be fused to an aryl or heteroaryl group.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyi, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below.
  • a heterocycloalkyl group optionally may be fused to a cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to another heterocycloalkyl group.
  • a heterocycloalkyl group can be fused to or substituted with an aryl group or heteroaryl group, for example, but not limited to, 1 ,2,3,4-tetrahydroisoquinolinyl and 1 ,2,3,4-tetrahydroquinolinyl, tetrahydronaphthyridinyl, phenylpiperidinyl, and piperidinyipyridinyl.
  • a heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as (C 3 -C 6 ) heterocycloalkyl.
  • a heterocycloalkyl group is fused to or substituted with an aryl group or a heteroaryl group.
  • heterocyclic radical or “heterocyclic ring”
  • heterocyclic radical or “heterocyclic ring” mean collectively a heterocycloalkyl group or a heteroaryl group.
  • cyclic radical means collectively an aryl group, a cycloalkyl group, a heterocycloalkyl group or a heteroaryl group.
  • alkoxy group means an -O-alkyl group, wherein alkyl is as defined above.
  • An alkoxy group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • the alkyl chain of an alkyloxy group is from. 1 to 6 carbon atoms in length, referred to herein as "(Ci-C 6 ) alkoxy”.
  • aryloxy group means an -O-aryl group, wherein aryl is as defined above.
  • An aryloxy group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 ) aryloxy.”
  • the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred to herein as a "lower alkoxycarbonyl” group.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • halo and “Hal” encompass fluoro, chloro, bromo, and iodo.
  • suitable substituent means a group that does not nullify the synthetic, therapeutic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
  • R' is a group of the formula "B"
  • the compounds of the invention can be obtained via standard, synthetic methodology. Some convenient methods are illustrated in Schemes 1-8 below. Starting materials useful for preparing the compounds of the invention and intermediates therefor, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • Protecting groups utilized herein denote groups which generally are not found in the final therapeutic compounds but which are intentionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed or converted to the desired group at a later stage of the synthesis and compounds bearing such protecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly, the precise structure of the protecting group is not critical.
  • One general strategy includes developing a linear intermediate using chiral building blocks such as amino acid derivatives.
  • the linear intermediate can be cyclized using a Mitsunobo reaction strategy or by spontaneous cyclization through reactive groups such as a reaction between an amine and an ester or between an amine and an aldehyde function.
  • the driving force for intramolecular reaction versus intermolecular reaction is the thermodynamically favored reaction forming a six-membered ring structure.
  • the methodology incorporates conditions that do not involve inversion or racemization of chiral centers.
  • the desired chiral product is easily purified by methods known in the art, such as flash chromatography on a silica gel column.
  • the group containing the Q ring is preferably made by use of an aldehyde derivative of a D-amino acid.
  • an aldehyde derivative of a D-amino acid By use of an ⁇ -amino aldehyde the resulting group has, in its most basic form, the general structure:
  • the compounds of the invention can be synthesized by adapting the synthetic methods described in the patent documents cited in the Cross Reference to Related Applications above, particularly U.S. Patent Application Serial No. 10/837,519, published as U.S. Patent Publication No. 2004/0224957 A1 , hereby incorporated herein by reference.
  • the compounds may be formulated by any means known in the art, including but not limited to tablets, capsules, caplets, suspensions, powders, lyophilized forms and aerosols and may be mixed and formulated with buffers, binders, stabilizers, anti-oxidants and other agents known in the art.
  • the compounds may be administered by any systemic or partially systemic means known in the art, including but not limited to intravenous injection, subcutaneous injection, administration through mucous membranes, oral administration, dermal administration, skin patches, aerosols and the like.
  • the invention further provides a pharmaceutical composition that includes a compound of this invention and a pharmaceutically acceptable carrier.
  • the compound of this invention may thus be formulated or compounded into pharmaceutical compositions that include at least one compound of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • pharmaceutically acceptable carriers including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • water containing at least one or more buffering constituents is suitable, and stabilizing agents, preservatives and solubilizing agents may also be employed.
  • stabilizing agents, preservatives and solubilizing agents may also be employed.
  • solid administration formulations any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, fatty acids and the like.
  • topical administration formulations anyof-a variety of creamsr ointments, gels, lotions and the like may be employed.
  • non-active ingredients will constitute the greater part, by weight or volume, of the preparation.
  • any of a variety of measured-release, slow-release or time-release formulations and additives may be employed, such that the dosage may be formulated so as to effect delivery of a compound of this invention over a period of time.
  • the compounds of this invention may be in the form of any pharmaceutically acceptable salt.
  • Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful.
  • suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
  • the compounds and pharmaceutical compositions of this invention may be administered by injection, which injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art.
  • injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art.
  • Administration means may include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration and the like.
  • the dosage for- treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect.
  • Nasal administration is a particularly preferred route of administration, and in one embodiment a relatively higher proportion of the compound is delivered to the brain by means of nasal administration than is delivered if the compound is systemically administered, such as by injection.
  • nasal administration by-passes, or partially by-passes, the blood-brain barrier, permitting more effective dosing to the central nervous system.
  • Nasal administration may be by means of a liquid spray, gel or powder.
  • nasal administration is meant any form of intranasal administration of any of the compounds and pharmaceutical compositions of this invention.
  • compounds and pharmaceutical compositions of this invention include an aqueous solution, such as a solution including saline, citrate or other common excipients or preservatives, formulated for intranasal administration.
  • compounds and pharmaceutical compositions of this " invention include a dry or powder formulation, formulated for intranasal administration.
  • a preparation for nasal administration can take a variety of forms, such as for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension.
  • dispensers and delivery vehicles are known in the art, including single-dose ampoules, metered dose devices, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like.
  • any of a number of devices including but not limited to the DirectHaler Nasal device made by Direct-Haler A/S, controlled particle dispersion devices made by Kurve Technology, and devices made by OptiNose AS.
  • the methods, teachings and devices disclosed in U.S. Patent Nos. 6,648,848, 6,715,485, and 6,811 ,543 are incorporated here by reference.
  • any of a variety of strategies and compounds to increase permeability of the nasal mucosa may be employed, including but not limited to small-molecule permeation enhancers and tight junction-modulator peptides.
  • the pharmaceutical composition can be in a solid, semi-solid, or liquid form.
  • the compound and other components may be mixed together by blending, tumble mixing, freeze-drying, solvent evaporation, co-grinding, spray-drying, and other techniques known in the art.
  • a semi-solid pharmaceutical composition suitable for intranasal administration can take the form of an aqueous or oil-based gel or ointment.
  • the compound and other components can be mixed with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide or other similar materials that form hydrophilic gels.
  • the microspheres can be internally loaded or coated with compound, and upon administration form a gel that adheres to the nasal mucosa.
  • the formulation is liquid, it being understood that this includes an aqueous solution, an aqueous suspension, an oil solution, an oil suspension, or an emulsion, depending on the physicochemical properties of the compound and other components.
  • excipients necessary or desirable for formulation, stability, and/or bioavailability are included in the pharmaceutical composition.
  • exemplary excipients include sugars (such as glucose, sorbitol, mannitol, or sucrose), uptake enhancers (such as chitosan), thickening agents and stability enhancers (such as celluloses, polyvinyl pyrrolidone, starch, and the like), buffers, preservatives, and/or acids and bases to adjust the pH.
  • an absorption promoting component is included in the pharmaceutical composition.
  • Exemplary absorption promoting components include surfactant acids, such as cholic acid, glycocholic acid, taurocholic acid, and other cholic acid derivatives, chitosan and cyclodextrins.
  • the pharmaceutical composition may further include optional components, such as humectants. preservatives and the like.
  • a humectant or moisturizing agent can be employed to decrease water loss from the pharmaceutical composition and optionally moisturize nasal mucosa.
  • Exemplary humectants include hygroscopic materials such as glycerine, propylene glycol, polyethylene glycol, polysaccharides and the like. Preservatives may be employed, to prevent or limit bacteria and other microbial growth.
  • benzalkonium chloride such as 0.05% benzalkonium chloride.
  • Other preservatives include benzyl alcohol, methylparaben, propylparaben, butylparaben, chlorobutanol, phenethyl alcohol, phenyl mercuric acetate and the like.
  • the pharmaceutical composition may also include rheology modifying agents, such as for varying the viscosity of the pharmaceutical composition.
  • rheology modify agents include polyers and similar materials, such as sodium carboxymethyl cellulose, algin, carageenans, carbomers, galactomannans, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycols, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum and combinations of the foregoing.
  • Such agents may also and further service as bioadhesives, to extend the residence time of a compound of the invention within the nasal mucosa.
  • compounds and pharmaceutical compositions of this invention are appropriately buffered by means of saline, acetate, phosphate, citrate, acetate or other buffering agents, which are at any physiologically acceptable pH, generally from-about pH 4 to about pH 8.
  • a combination of buffering agents may also be employed, such as phosphate buffered saline, a saline and acetate buffer, and the like.
  • a 0.9% saline solution may be employed.
  • a 50 mM solution may be employed.
  • compounds and pharmaceutical compositions of this invention are administered directly into the lung, lntrapulmonary administration may be performed by means of a metered dose inhaler, a device allowing self-administration of a metered bolus of a compound and pharmaceutical composition of this invention when actuated by a patient during inspiration.
  • a metered dose inhaler a device allowing self-administration of a metered bolus of a compound and pharmaceutical composition of this invention when actuated by a patient during inspiration.
  • Both dry powder inhalation and nebulized aerosols may be employed.
  • compounds and pharmaceutical compositions of this invention may be in a dried and particulate form.
  • the particles are between about 0.5 and 6.0 ⁇ m, such that the particles have sufficient mass to settle on the lung surface, and not be exhaled, but are smalLenough-that . .
  • any of a variety of different techniques may be used to make dry powder microparticies, including but not limited to micro-milling, spray drying and a quick freeze aerosol followed by lyophilization. With micro-particles, the constructs may be deposited to the deep lung, thereby providing quick and efficient absorption into the bloodstream. Further, with such approach penetration enhancers are not required, as is sometimes the case in transdermal, nasal or oral mucosal delivery routes. Any of a variety of inhalers can be employed, including propellant-based aerosols, nebulizers, single dose dry powder inhalers and multidose dry powder inhalers.
  • metered dose inhalers which are used to deliver medications for the treatment of asthma, chronic obstructive pulmonary disease and the like.
  • Preferred devices include dry powder inhalers, designed to form a cloud or aerosol of fine powder with a particle size that is always less than about 6.0 ⁇ m.
  • Microparticle size may be controlled by means of the method of making.
  • the size of the milling head, speed of the rotor, time of processing and the like control the microparticle size.
  • the nozzle size, flow rate, dryer heat and the like control the microparticle size.
  • the nozzle size, flow rate, concentration of aerosoled solution and the like control the microparticle size.
  • the compounds and pharmaceutical compositions of this invention may be formulated for and administered by means of an injection, typically a deep intramuscular injection, such as in the gluteal or deltoid muscle, of a time release injectable formulation.
  • a compound or pharmaceutical composition of this invention is formulated with a PEG, such as poly(ethylene glycol) 3350, and optionally one or more additional excipients and preservatives, including but not limited to excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH, and the like.
  • a compound or pharmaceutical composition of this invention is formulated with a poly(ortho ester), which may be an auto-catalyzed poly(ortho ester) with any of a variable percentage of lactic acid in the polymeric backbone, and optionally one or more additional excipients.
  • poly (D,L-lactide-co-glycolide) polymer PLGA polymer
  • PLGA polymer poly (D,L-lactide-co-glycolide) polymer
  • PLGA polymer polymer
  • a hydrophilic end group such as PLGA RG502H from Boehringer Ingelheim, Inc. (Ingelheim, Germany).
  • Such formulations may be made, for example, by combining a construct of this invention in a suitable solvent, such as methanol, with a solution of PLGA in methylene chloride, and adding thereto a continuous phase solution of polyvinyl alcohol under suitable mixing conditions in a reactor.
  • a suitable solvent such as methanol
  • PLGA polyvinyl alcohol
  • any of - a number of injectable and biodegradable polymers, which are preferably also adhesive polymers may be employed in a time release injectable formulation.
  • the teachings of U.S. Patents 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and methods of formulation disclosed therein, are incorporated here by reference.
  • the formulation may be such that an injection is required on a weekly, monthly or other periodic basis, depending on the concentration and amount of construct, the biodegradation rate of the polymer, and other factors known to those of skill in the art.
  • the actual quantity of compound of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired.
  • the dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired effect. This may readily be determined by one of ordinary skill in the art through means such as pharmacokinetic studies, plasma half-life studies, dose escalation studies, and the like.
  • a pharmaceutically effective amount includes an amount of a compound or pharmaceutical composition of this invention that is sufficient to induce the desired effect.
  • the compounds of this invention are highly active, with dose responses as low as 0.01 ⁇ g/kg, generally with optimal or peak dose responses between about 0.01 ⁇ g/kg and 25 ⁇ g/kg, depending on the specific compound and the route of administration.
  • the compound can be administered at 0.01 , 0.05, 0.1, 0.5, 1 , 5, 10, 50, 100, or 500 ⁇ g/kg body weight, depending on specific compound selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art.
  • Conventional dose response studies and other pharmacological means may be employed to determine the optimal dose for a desired effect with a given compound, given formulation and given route of administration.
  • the compound may be employed for decreasing food intake and/or body weight in combination with any other agent or drug heretofore employed as a diet aid, or for decreasing food intake and/or body weight.
  • the compound may be employed for increasing food intake and/or body weight in combination with any other agent or drug heretofore employed for ' increasing food intake and/or body weight.
  • Drugs that reduce energy intake include, in part, various pharmacological agents, referred to as anorectic drugs, which are used as adjuncts to behavioral therapy in weight reduction programs.
  • Classes of anorectic drugs include, but are not limited to, noradrenergic and serotonergic agents.
  • Noradrenergic medications may be described as those medications generally preserving the anorectic effects of amphetamines but with weaker stimulant activity.
  • the noradrenergic drugs, except phenylpropanolamine generally act through a centrally mediated pathway in the hypothalamus that causes anorexia. Phenylpropanolamine, a racemic mixture of norephedrine esters, causes a release of norepinephrine throughout the body and stimulates hypothalamic adrenoreceptors to reduce appetite.
  • Suitable noradrenergic agents include, but are not limited to, diethylpropion such as TENUATETM (1 -propanone, 2-(diethylamino)-1 -phenyl-, hydrochloride) commercially available from Merrell; mazindol (or 5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1- a]isoindol-5-ol) such as SANOREXTM commercially available from Novartis or MAZANORTM commercially available from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol, alpha-(i-aminoethyl)-, hydrochloride); phentermine (or Phenol, 3-[[4,5-duhydro-1 H-imidazol- 2-yl)ethyl](4-methy!phenyl)amino], monohydrochloride) such as ADIPE ⁇ X-PTM commercially available
  • Suitable non-limiting serotonergic agents include sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4- chlorophenyI)-N,N-dimethyl-(alpha)-(2-methylpropyl)-, hydrochloride,- monohydrate)- commercially available from Knoll, fenfluramine such as PondiminTM (Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)-, hydrochloride) commercially available from Robbins; dexfenfluramine such as ReduxTM (Benzeneethanamine, N-ethyl-alpha-methyl-3- (trifiuoromethyl)-, hydrochloride) commercially available from Interneuron.
  • sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers of cyclobut
  • Fenfluramine and dexfenfluramine stimulate release of serotonin and inhibit its reuptake.
  • Sibutramine inhibits the reuptake of serotonin, norepinephrine and dopamine, but does not stimulate secretion of serotonin.
  • serotonergic agents useful with the practice of the present invention include, but are not limited to, certain auoretic gene 5HT1a inhibitors (brain, serotonin) such as carbidopa and benserazide as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; and certain neurokinin 1 receptor antagonist and selective serotonin reuptake inhibitors including fluoxetine, fluvoxamine, paroxtine, sertraline and other useful compounds as disclosed by U.S. Pat. No. 6,162,805 which is incorporated herein by reference.
  • Other potential inhibitors that may be employed include 5HT2c inhibitors.
  • Other useful compounds for reducing energy intake include, but are not limited to, certain aryl-substituted cyclobutylalkylamines as disclosed by U.S. Pat. No. 6,127,424 which is incorporated herein by reference; certain trifluoromethylthiophenylethylamine derivatives as disclosed by U.S. Pat. No. 4,148,923 which is incorporated herein by reference; certain compounds as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; certain kainite or AMPA receptor antagonists as disclosed by U.S. Pat. No. 6,191 ,117 which is incorporated herein by reference; certain neuropeptide receptor subtype 5 as disclosed by U.S. Pat. No. 6,140,354 which is incorporated herein by reference; and certain alpha-blocking agents as disclosed by U.S. Pat. No. 4,239,763 which is incorporated herein by reference.
  • cholecystokinin and serotonin act to decrease appetite and food intake.
  • Leptin a hormone produced by fat cells, controls food intake and energy expenditure.
  • a decrease in weight is associated with a decrease in circulating levels of leptin, suggesting its role in weight homeostasis.
  • Obese patients with high leptin levels are thought to have peripheral leptin resistance secondary to the down- regulation of leptin receptors.
  • Non-limiting examples of useful compounds affecting feeding behavior include certain leptin-lipolysis stimulated receptors as disclosed by WO 01/21647 which is incorporated herein by reference; certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970 which is incorporated herein by reference; certain compounds • ⁇ having nucleotide sequences of the mahogany gene as disclosed by WO 00/05373 which is incorporated herein by reference; and certain sapogenin compounds as disclosed by U.S. Pat. No. 4,680,289 which is incorporated herein by reference.
  • PPAR peroxisome proliferator activated receptor
  • monoamine oxidase inhibitors that decrease energy intake or increase energy expenditure are useful with the practice of the present invention.
  • Suitable, but non- limiting examples of monoamine oxidase inhibitors include befioxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, avalyctatone, pirlindol, amiflamine, sercloremine, azabemide, milacemide, caroxazone and other certain compounds as disclosed by WO 01/12176 which is incorporated herein by reference.
  • Certain compounds that increase lipid metabolism are also useful with the practice of the present invention. Such compounds include, but are not limited to, useful evodiamine compounds as disclosed by U.S. Pat. No. 6,214,831 which is incorporated herein by reference.
  • Nutrient partitioning -agents -and digestive inhibitors are another strategy in the treatment of obesity by interfering with the breakdown, digestion or absorption of dietary fat in the gastrointestinal tract.
  • Gastric and pancreatic lipases aid in the digestion of dietary triglycerides by forming them into free fatty acids that are then absorbed in the small intestine. Inhibition of these enzymes leads to inhibition of the digestion of dietary triglycerides.
  • Non-limiting examples include a lipase inhibitor, orlistat, such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2- oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247 which is incorporated herein by reference.
  • orlistat such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2- oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247 which is incorporated herein by reference.
  • thermogenic medications Agents that increase energy expenditure are also referred to as thermogenic medications.
  • suitable thermogenic medications include xanthines, such as caffeine and theophylline, selective ⁇ -3-adrenergic agonists, for example certain compounds in U.S. Pat. No. 4,626,549 which is incorporated by reference herein, and ⁇ -2- . adrenergic and growth hormones compounds as described in U.S. Pat. Nos. 4,937,267 and 5,120,713 which are incorporated by reference herein.
  • a total dosage of the above-described obesity control agents or medications, when used in combination with a compound of this invention can range from 0.1 to 3,000 mg/day, preferably from about 1 to 1 ,000 mg/day and more preferably from about 1 to 200 mg/day in single or 2-4 divided doses.
  • the exact dose is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.
  • Agents or drugs employed for increasing food intake and/or body weight include appetite stimulants such as megastrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoterone.
  • appetite stimulants such as megastrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoterone.
  • Selected compounds are tested in assays to determine binding and functional status, and are tested in animal models of feeding behavior as discussed below.
  • the following assays and animal models are employed, with modifications, if any, as discussed in the examples.
  • a competitive inhibition binding assay is performed using membrane homogenates prepared from HEK-293 cells that express recombinant hMC4-R, hMC3-R, or hMC5-R, and from B-16 mouse melanoma cells (containing endogenous MC1-R). In some instances, HEK-293 cells that express recombinant hMC1-R are employed. In the examples that follow, all MC3-R, MC4-R and MC5-R values are for human recombinant receptors. MC1-R values are for B-16 mouse melanoma cells, unless the heading is "hMC1-R", in which case the value is for human recombinant MC1-R.
  • Assays are performed in 96 well GF/B Millipore multiscreen filtration plates (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (Fraction V). Membrane homogenates are incubated with 0.2nM (for hMC4-R) 0.4 nM (for MC3-R and MC5-R) or 0.1 nM (for mouse B16 MC1-R or hMC1-R) [l 125 ]-NDP- ⁇ -MSH (Perkin Elmer) and increasing concentrations of test compounds in buffer containing 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI 2 , 2 mM MgCI 2 , 0.3 mM 1 ,10-phenanthroline, and 0.2% bovine serum albumin. After incubation for 60 minutes at 37° C, the assay mixture is filtered and the membranes washed three times with ice-cold buffer. Filters are dried and counted in
  • Non-specific binding is measured by inhibition of binding of [l 125 ]-NDP- ⁇ -MSH in the presence of 1 ⁇ M NDP- ⁇ -MSH. Maximal specific binding (100%) is defined as the. difference in radioactivity (cpm) bound to cell membranes in the absence and presence of 1 ⁇ M NDP- ⁇ - MSH. Radioactivity (cpm) obtained in the presence of test compounds is normalized with respect to 100% specific binding to determine the percent inhibition of [l 125 ]-NDP- ⁇ -MSH binding. Each assay is conducted in triplicate and the actual mean values are described, with results less than 0% reported as 0%. Ki values for test compounds are determined using Graph-Pad Prism® curve-fitting software.
  • the assay mixture contained 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI 2 , 2 mM MgCI 2 , 0.3 mM 1 ,10-phenanthroline, 0.5% bovine serum albumin, membrane homogenates, radioligand [I 125 J-AgRP (83-132) (Perkin Elmer) and increasing concentrations of compounds in a total volume of 200 ⁇ l_. Binding is measured at radioligand concentrations of 0.2 nM. After incubating for 1 hour at 37° C, the reaction mixture is filtered and washed with assay buffer containing 500 mM NaCI. The dried discs are punched out from the plate and counted on a gamma counter. The total binding of the radioligand did not exceed 10% of the counts added to the reaction mixture. Ki values for test compounds are determined using Graph-Pad Prism ® curve-fitting software.
  • HEK-293 cells that express MC4-R Confluent HEK-293 cells that express recombinant hMC4-R are detached from culture plates by incubation in enzyme-free cell dissociation buffer. Dispersed cells are suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCI 2 , 1 mM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-1-methyl-xanthine (IBMX), a phosphodiesterase inhibitor.
  • IBMX 3-isobutyl-1-methyl-xanthine
  • the cells are plated in 96-well plates at a density of 0.5 x 10 5 cells per well and pre- incubated for 30. minutes. Cells are . exposed for 1 hour at 37° C to test compounds dissolved- ⁇ in DMSO (final DMSO concentration of 1 %) at a concentration range of 0.05 - 5000 nM in a total assay volume of 200 ⁇ l_. NDP- ⁇ -MSH is used as the reference agonist.
  • cells are disrupted by the addition of 50 ⁇ l_ of lysis buffer (cAMP EIA kit, Amersham) followed by vigorous pipetting. Levels of cAMP in the lysates are determined using a cAMP EIA kit (Amersham). Data analysis is performed by nonlinear regression analysis with Graph-Pad Prism ® software. The maximum efficacies of the test compounds are compared to that achieved by the reference melanocortin agonist NDP- ⁇ MSH.
  • mice Male C57BL/6 mice are obtained from Jackson labs (Bar Harbor, ME). Animals are individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/off light cycle. Water and pelleted (Harlan Teklad 2018 18% Protein Rodent Diet) food is provided ad libitum. The mice are dosed IP (by intraperitoneal injection) after a 24 hour fast or IN (by intranasal administration) with vehicle or selected compounds (0.1-3 mg/kg, and in some cases up to 10 mg/kg). All animals are dosed once a day (or up to four consecutive days) at the start of the "lights off' period. The changes in food intake weight for the 4 hour and 20 hour period after dosing relative to control animals administered vehicle are determined.
  • Mass values are determined using a Waters MicroMass ZQ device .utilizing a positive mode. Mass determinations are compared with calculated values and expressed in the form of mass weight plus one (M+1 or M+H).
  • Proton NMR data is obtained using a Bruker 300 MHz spectrometer. The spectra are obtained after dissolving compounds in a deuteriated solvent such as chloroform, DMSO 1 or methanol as appropriate.
  • a deuteriated solvent such as chloroform, DMSO 1 or methanol as appropriate.
  • Example 1 (R)-2-Amino-1-[(2S,5R)-2-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-3- naphthalen-2-yl-propionyl)-5-cyclohexylmethyl-piperazin-1-yl]-3-naphthalen-2- yl-propan-1-one
  • the compound of Example 1 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Cyclohexyl-Ala-OMe and Boc-D-2-Nal-OH were used.
  • Example 2 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-cyclohexylmethyi-pipera2in-1-yl ⁇ -3-(2,4- dichloro-phenyl)-propan-1 -one
  • the compound of Example 2 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Cyclohexyl-Ala-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
  • Example 3 The compound of Example 3 was made by the methods of Scheme 1 described above, in which (E)-3-(2,4-D ⁇ chloro-phenyl)-acrylic acid was used.
  • Example 4 was made by the methods of Scheme 1 described above, in which (1R,2S)-2-Phenyl-cyclopropanecarboxylic acid was used.
  • Example 5 The compound of Example 5 was made by the methods of Scheme 1 described above, in which (E)-3-m-tolyl-acrylic acid was used.
  • Example 6 (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid 2,4-dichloro-benzylamide
  • the compound of Example 6 was made by the methods of Scheme 1 described above, in which the urea bond was formed by the reactions of 1-10 with triphosgene and subsequently 2, 4-di-chlorobenzylamine.
  • Example 7 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
  • Example 8 (R)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propionyl]-5- [3-(2-amino-ethylamino)-propyl]-2-methyl-piperazin-1-yl ⁇ -3-(2,4-dimethyl- phenyl)-propan-1 -one
  • the compound of Example 8 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2,4-di-methyl-Phe-OH were used.
  • Example 9 (R)-2-Amino-1-[(2R,5S)-5-[3-(2-amino-ethylamino)-propyl]-4-((R)-2-amino-3- naphthalen-2-yl-propionyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan- 1-one
  • the compound of Example 9 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2-Nal-OH were used.
  • Example 10 (R)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-prop ⁇ onyl]-5- [S ⁇ -amino-ethylamino ⁇ propyll ⁇ -methyl-piperazin-i-ylJ-S ⁇ S.A-dichloro- phenyl)-propan-1 -one
  • the compound of Example 10 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and BocD-3,4-di-CI-Phe-OH were used.
  • Example 11 (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid [2-(2,4-dichlo ⁇ >phenyl)-ethyl]-amide
  • the compound of Example 11 was made by the methods of Scheme 1 described above, in which the urea bond was formed by the reactions of 1-10 with triphosgene and subsequently 2-(2,4-Dichloro-phenyl)-ethylamine.
  • Example 12 N- ⁇ 3-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5-methyl-4- ((IR ⁇ R ⁇ -phenyl-cyclopropanecarbonyO-piperazin- ⁇ -yO-propylJ-guanidine
  • the compound of Example 12 was made by the methods of Scheme 1 described above, in which (1 R,2R)-2-phenyl-cyclopropanecarboxylic acid was used.
  • Example 13 N- ⁇ 3-[(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1-(9-oxo-6,7,8,9- tetrahydrO- ⁇ H-benzocycloheptene- ⁇ -carbonyO-piperazin ⁇ -ylj-propyl ⁇ - guanidine
  • the compound of Example 13 was made by the methods of Scheme 1 described above, in which 9-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid was used.
  • Example 14 E)-1 - ⁇ (2R,5S)-4-[(R)-2-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5-[3-1 H- imidazol-2-ylamino)-propyl]-2-methyl-piperazin-1-yl ⁇ -3-quinolin-2-yl-propenone
  • Example 14 The compound of Example 14 was made by the methods of Scheme 1 described above, in which 1-7 was reacted with (E)-3-Quinolin-2-y!-acrylic acid to form 1-8. Method C in Scheme 8 was used in a reaction with aminoimdazole. Finally Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
  • Example 15 (E)-1- ⁇ (2R l 5S)-4-[(R)-2-Amino-3-(2 l 4 ⁇ lichloro-phenyl)-propionyl]-5-I3-(1 H- imidazol-2-ylamino)-propyl]-2-methyl-p ⁇ perazin-1-yl ⁇ -3-phenyl-propenone
  • the compound of Example 15 was made by the methods of Scheme 1 described above, in which 1-7 was reacted with (E)-3-Phenyl-acrylic acid to form 1-8. Method C in Scheme 8 was used in a reaction with aminoimdazole. Finally Boc-2,4-di-chloro-Phe-OH was used as QCOOH.
  • Example 16 3-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-N-(1 H-imidazol-2-yl)-propionamide
  • the compound of Example 16 was made by the methods of Scheme 1 described above, in which method A in Scheme 8 was used in a reaction with aminoimdazole and Boc- 2,4-di-chloro-Phe-OH was used as QCOOH.
  • Example 17 1- ⁇ (2R,5S)-4-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propyl]-5-[3-(3-amino- propylamino)-propyl]-2-isobutyl-piperazin-1-yl ⁇ -2-naphthalen-2-yl-ethanone
  • the compound of Example 17 was made by the methods of Scheme 2 described above, in which Boc-NH(CH 2 ) 3 NH 2 was used to synthesize analog of 2-7.
  • Example 18 1- ⁇ (2R,5S)-5-[3-(4-Amino-butylamino)-propyl]-4-[(R)-2-amino-3-(2,4-dichloro- phenyl)-propyl]-2-isobutyl-piperazin-1-yl ⁇ -2-naphthalen-2-yl-ethanone
  • the compound of Example 18 was made by the methods of Scheme 2 described above, in which Boc-NH(CH 2 ) 4 NH 2 was used to synthesize analog of 2-7.
  • Example 19 The compound of Example 19 was made by the methods of Scheme 2 described above, in which Boc-NH(CH 2 ) 5 NH 2 was used to synthesize analog of 2-7.
  • Example 20 1- ⁇ (2R,5S)-5- ⁇ 3-[(2-Amino-ethyl)-methyl-amino]-propyl ⁇ -4-[(R)-3-(2,4-ciichloro- phenyl)-2-d ⁇ methylamino-propyl]-2-isobutyl-piperazin-1-yl ⁇ -2-naphthalen-2-yl- ethanone
  • the compound of Example 20 was made by the methods of Scheme 2 described above, in which methylation of amine was conducted by the reaction with formaldehyde in the presence of HB(AcO) 3 .
  • Example 21 (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-1 H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-pipera2in-1-yl]-3-(2,4-dichloro-phenyl)-propan-1-one
  • the compound of Example 21 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used in a reaction with aminoimdazole sulfate. Finally Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
  • Example 22 (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid ((1S,2S)-2-phenyl-cyclopropyl)-amide
  • the compound of Example 22 was made by the methods of Scheme 1 described above, in which (1S,2S)-2-Pheny!-cyclopropyl)-carbamic acid was used as QCOOH.
  • Example 23 was made by the methods of Scheme 1 described above, in which 2-[tert-Butoxycarbonyl-(4-trifluoromethyl-phenyl)-amino]-benzoic acid was used as QCOOH.
  • Example 24 N- ⁇ 3-[(2S,5R)-5-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5- carbonyl]-4-(2-naphthalen-2-yl-acetyi)-piperazin-2-yl]-propyl ⁇ -guanidine
  • the compound of Example 24 was made by the methods of Scheme 1 described above, in which 4-Methyl-2-(4-trifiuoromethyl-phenyl)-thiazole-5-carboxylic acid was used as QCOOH.
  • Example 25 N-(3- ⁇ (2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1 -[(1 S,2S)-2-(4- trifluoromethyl-benzoyO-cyclohexanecarbonylJ-piperazin ⁇ -yiy-propyl)- guanidine
  • the compound of Example 25 was made by the methods of Scheme 1 described above, in which (1S,2S)-2-(4-Trifluoromethyl-benzoyl)-cyciohexanecarboxylic acid was used as QCOOH.
  • Example 26 N-(3- ⁇ (2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1 -[(1 R,2R)-2-(4- trifluoromethyl-benzoyO-cyclohexanecarbonylj-piperazin ⁇ -yll-propyl)- guanidine
  • the compound of Example 26 was made by the methods of Scheme 1 described above, in which (1R,2R)-2-(4-Trifluoromethyl-benzoyl)-cyclohexanecarboxylic acid was used as QCOOH.
  • Example 27 1 - ⁇ (2R,5S)-5-[3-(2-Amino-ethylamino)-propyl]-4-[(R)-3-(2,4-dichloro-phenyl)-2- dimethylamino-propyl]-2-isobutyl-piperazin-1-yl ⁇ -2-naphthalen-2-yl-ethanone
  • the compound of Example 27 was made by the methods of Scheme 2 described above, in which methylation of the amine was obtained by reaction with formaldehyde in the presence of HB(AcO) 3 .
  • Example 28 N- ⁇ 3-[(2S,5R)-1-[4-(4-Chloro-phenyl)-thiazole-2-carbonyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-pipera2in-2-yl]-propyl ⁇ -guanidine
  • Example 28 was made by the methods of Scheme 1 described above, in which 4-(4-Chloro-phe ⁇ yl)-thiazole-2-carboxylic acid was used as QCOOH.
  • Example 30 was made by the methods of Scheme 1 described above, in which 2-(4-Chloro-benzyloxy)-benzoic acid was used as QCOOH.
  • Example 31 was made by the methods of Scheme 1 described above, in which 5-(4-Chloro-phenyl)-thiophene-2-carboxylic acid was used as QCOOH.
  • Example 32 was made by the methods of Scheme 1 described above, in which 2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid was used as QCOOH.
  • Example 33 was made by the methods of Scheme 1 described above, in which 3-(4-Trifluoromethyl-phenoxy)-benzoic acid was used as QCOOH.
  • Example 34 was made by the methods of Scheme 1 described above, in which 2-(3-Fluoro-benzylsulfanyl)-benzoic acid was used as QCOOH.
  • Example 35 NEED N- ⁇ 3-[(2S,5R)-1 -[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propyl]-5-isobutyl-
  • Example 36 4-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dimethyl-phenyl)-propyl]-5-methyl-4-(2- ) naphthalen-2-yl-acetyl)-piperazin-2-ylmethyl]-benzamidine
  • the compound of Example 36 was made by the methods of Scheme 3 described above.
  • Example 37 The compound of Example 37 was made by the methods of Scheme 4 described ) above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
  • Example 38 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-methyl-piperazin-1-yl ⁇ -3-(3,4-dichloro- phenyl)-propan-1 -one
  • the compound of Example 38 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3,4-di-CI-Phe-OH were used.
  • Example 39 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-methyl-piperazin-1-yl ⁇ -3-(2,4-dimethyl- phenyl)-propan-1 -one
  • the compound of Example 39 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
  • Example 40 (R)-2-Amino-1- ⁇ (2S,5R)-2-[4-(2-amino-ethylamino>butyl]-4-[(R)-2-amino-3-(4- trifluoromethyl-phenyl)-propionyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(4- trifluoromethyl-phenyl)-propan-1-one
  • the compound of Example 40 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-trifluromethyl-Phe-OH were used.
  • Example 41 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(4-chloro-phenyl)-propionyl]-2-[4-(2- amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(4-chloro-phenyl)- propan-1-one
  • the compound of Example 41 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-CI-Phe-OH were used.
  • Example 42 (R)-2-Amino-1- ⁇ (2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-[(R)-2-amino-3-(3- trifluoromethyl-phenyl)-propionyl]-2-isobutyl-piperazin-1-yl ⁇ -3-(3- trifluoromethyl-phenyl)-propan-1-one
  • the compound of Example 42 was made by the methods of Scheme 4 described above, in which Fmoc-I_ys(Trt)-OH, D-Leu-OMe and Boc-D-3-trifluromethyl-Phe-OH were used.
  • Example 43 1- ⁇ (2R,5S)-5-[4-(2-Amino-ethylamino)-butyl]-4-[3-(3,4-dichloro-phenyl)- propionyl]-2-isobutyl-piperazin-1-yl ⁇ -3-(3,4-dichloro-phenyl)-propan-1-one
  • the compound of Example 43 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-CI-propionic acid were used.
  • Example 44 The compound of Example 44 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-CI-propionic acid were used. The 3,4-di-CI-propionic acid was converted to the corresponding aldehyde for a reductive alkylation reaction.
  • Example 45 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used for the reaction with (6-Amino-pyridin- 2-yl)-carbamic acid tert-butyl ester. Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
  • Example 46 was made by the methods of Scheme 1 described above, in which 2-(3,4-Dichloro-benzyloxy)-benzoic acid was used as QCOOH.
  • Example 47 was made by the methods of Scheme 1 described above, in which 2-(4-Chioro-phenoxy)-benzoic acid was used as QCOOH.
  • Example 48 The compound of Example 48 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(R)-3-Amino-4-(2,4-dichloro-phenyl) -butyric acid were used.
  • Example 49 (R)-3-Amino-1- ⁇ (2S,5R)-4-[(R)-3-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(2,4-dichloro- phenyl)-propan-1 -one
  • the compound of Example 49 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(S)-3-Amino-4-(2,4-dichloro-phenyl)
  • Example 50 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(4-chloro-2-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(4- chloro-2-methyl-phenyl)-propan-1-one
  • the compound of Example 50 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-OH were used.
  • Example 51 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(2-chloro-4-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(2- chloro-4-methyl-phenyl)-propan-1-one
  • the compound of Example 51 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methyl-2-chloro-Phe-OH were used.
  • Example 52 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(3,4-difluoro-phenyl)-propionyl]-2-[4- (2-amino-ethylamino)-butyI]-5-isobutyl-piperazin-1-yl ⁇ -3-(3,4-difluoro-phenyl)- propan-1-one
  • the compound of Example 52 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-F-Phe-OH were used.
  • Example 53 (R)-2-Amino-1-[(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-4- phenyl-butyryl)-2-isobutyl-piperazin-1-yl]-4-phenyl-butan-1-one
  • the compound of Example 53 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-homo-Phe-OH were used.
  • Example 54 (R)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(4-tert-butyl-phenyl)-propionyl]-5-[4- (2-amino-ethylamino)-butyl]-2-isobutyl-piperazin-1-yl ⁇ -3-(4-tert-butyl-phenyl)- propan-1-one
  • Example 54 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-tBu-Phe-OH were used.
  • Example 55 1- ⁇ (2R,5S)-5-[4-(2-Amino-ethylamino)-butyl]-4-[3-(3,4-dimethyl-phenyl)- propionyl]-2-isobutyl-piperazin-1-yI ⁇ -3-(3,4-dimethyl-phenyl)-propan-1-one
  • the compound of Example 55 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-methyl-propionic acid were used.
  • Example 56 (R)-2-Amino-1- ⁇ (2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl- ⁇ -tS-C ⁇ .S ⁇ jthiadiazol- ⁇ -ylamino ⁇ propylj-piperazin-i -ylJ-S-naphthalen- 2-yl-propan-1-one
  • Example 56 The compound of Example 56 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-1 ,3,4-thiadiazole.
  • Example 57 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(3,4-dimethyl-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(3,4-dimethyl- phenyl)-propan-1 -one
  • the compound of Example 57 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
  • Example 58 (R)-2-Amino-1- ⁇ (2S,5R)-4-[(R)-2-amino-3-(4-chloro-3-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl ⁇ -3-(4- chloro-3-methyl-phenyl)-propan-1-one
  • Example 58 The compound of Example 58 was made by the methods of Scheme 4 described above, in which Fmoc-l_ys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-OH were used.
  • Example 59 The compound of Example 59 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methoxy-Phe-OH were used.
  • Example 60 was made by the methods of Scheme 4 described bove, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-phenyI-Phe-OH were used.
  • Example 61 The compound of Example 61 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 1 ,2,4-triazole.
  • Example 62 N-fS-pS. ⁇ R ⁇ I-P-CS ⁇ -Dichloro-phenoxy ⁇ benzoy ⁇ - ⁇ -methyM ⁇ -naphthaien-
  • Example 62 The compound of Example 62 was made by the methods of Scheme 1 described above, in which 2-(3,4-di-Chloro-phenoxy)-benzoic acid was used as QCOOH.
  • Example 63 The compound of Example 63 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 4-amino-4H-1 ,2,4-triazole.
  • Example 64 (R)-2-Amino-1- ⁇ (2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(thiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-naphthalen-2-yl- propan-1 -one
  • Example 64 was made by the methods of the Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used.
  • the method C in Scheme 8 was used for incorporation of 2-aminothiazole.
  • Example 65 (R)-2-Amino-1- ⁇ (2R,5SH-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(5-methyl-thiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-naphthalen- 2-yl-propan-1-one
  • Example 65 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-5-methylthiazole.
  • Example 66 The compound of Example 66 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-4-methylthiazole.
  • Example 67 (R)-2-Amino-3-(2,4-dichloro-phe ⁇ yl)-1 -[(2S,5R)-2-(3-imidazol-1 -yl-propyl)-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-propan-1-one
  • the compound of Example 67 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method D in Scheme 8 was used for incorporation of imidazole.
  • Example 68 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-[(2S,5R)-5-methyl-2-[3-(2-methyl-2H- tetrazol-5-ylamino)-propyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-propan- 1-one
  • Example 68 The compound of Example 68 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method C in Scheme 8 _. was used for incorporation of 5-amino-2-methyltetrazole.
  • Example 69 (R)-2-Amino-3-(2,4-dichloro-phe ⁇ yl)-1 -[(2S,5R)-5-methyl-2-[3-(2-methyl- imidazol-1 -yl)-propyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-1 -yl]-propan-1 ⁇
  • the compound of Example 69 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method D in Scheme 8 was used for incorporation of 5-methylimidazole.
  • Example 70 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-[(2S,5R)-5-methyl-4-(2-naphthalen-2-yl- acetyl)-2-(3-[1 ,2,4]triazol-1 -yl-propyl)-piperazin-1 -yl]-propan-1 -one
  • the compound of Example 70 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method C in Scheme 8 was used for incorporation of 1,2,4-triazole.
  • Example 71 (R)-2-Amino-1- ⁇ (2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(5-methyl-[1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3- naphthalen-2-yl-propan-1 -one
  • the compound of Example 66 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-5-methyl-1 ,3,4- thiadiazole.
  • Example 72 N- ⁇ (R)-2-[(2S,5R)-4-((R)-2-Acetylamino-3-naphthalen-2-yl-propionyl)-5- isobutyl-2-(3-[1,2,4]triazol-1-y!-propyl)-piperazin-1-yl]-1-naphthalen-2-ylmethyl- 2-oxo-ethyl ⁇ -acetamide
  • Example 72 The compound of Example 72 was derived from Example 61 , in which the free amino groups were acetylated by the reaction of acetic anhydride with Example 61 in the presence of pyridine.
  • Example 73 The compound of Example 73 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 5-amino-3-methylisoxazole.
  • Example 74 The compound of Example 74 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 3-amino-5-methylisoxazole.
  • Example 75 1 -[(2R,5S)-5-[3-(2-Amino-1 H-imidazol-4-yl)-propyl]-4-((1 S,2S)-1 -amino-2- phenyl-cyclopropanecarbonyl ⁇ -methyl-piperazin-i-ylj ⁇ -naphthalen ⁇ -yl- ethanone
  • Example 75 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and (1S,2S)-1-Amino-2-phenyl-cyclopropanecarboxylic acid was used as QCOOH.
  • Example 76 1 -[(2R,5S)-5-[3-(2-Amino-1 H-imidazol-4-yl)-propyl]-4-((1 S,2R)-1 -amino-2- phenyl-cyclopropanecarbonyl ⁇ -methyl-piperazin-i-yl ⁇ -naphthalen ⁇ -yl- ethanone
  • Example 76 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and (1 S,2R)-1-Amino-2-phenyl-cyclopropanecarboxylic acid was used as QCOOH.
  • Example 77 The compound of Example 77 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2 -NaI-OH were used. Method C in Scheme 8 was used for incorporation of aminopyrazine.
  • Example 78 (R)-2-Amino-1-[(2S,5R)-2-[2-(2-amino-3H-imidazol-4-yl)-ethyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-phenyl-propan-1-one
  • the compound of Example 78 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and Boc-D-Phe-OH was used as QCOOH.
  • Example 79 (R)-2-Amino-1-[(2S,5R)-2-[3-(5-amino-tetrazol-2-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1 -one
  • the compound of Example 79 was made by the methods of Scheme 1 described above, in which method D in Scheme 8 was used in a reaction with 5-aminotetrazole and Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
  • Example 80 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-5-isobutyl-4-(2-naphthalen-2- yl-acetyl ⁇ - ⁇ II .S ⁇ Jthiadiazol ⁇ -ylaminoJ-propyll-piperazin-i-ylJ-propan-i- one
  • the compound of Example 80 was made by the methods of Scheme 1 described above, in which method C in Scheme 8 was used in a reaction with 2-amino-1 ,3,4-thiadiazole and Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
  • Example 81 (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yi-propionyl)-5-(3- hydroxy-propyl)-2-isobutyl-piperazin-1-yl]-3-naphthalen-2-y!-propan-1-one
  • the compound of Example 81 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Naf-OH were 5 used.
  • Example 82 (R)-2-Amino-1- ⁇ (2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- ) isobutyl-5-[3-(isoxazol-3-ylamino)-propyl]-piperazin-1-yl ⁇ -3-naphthalen-2-yl- propan-1-one
  • Example 82 The compound of Example 82 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 3-aminoisoxazole.
  • Example 83 The compound of Example 83 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-aminopyrimidine.
  • Example 84 (R)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-phenyl- propan-1-one
  • the compound of Example 84 was made by the methods of Scheme 7 described above, in which Boc-D-Phe-OH was used as QCOOH.
  • Example 85 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyi]-piperazin-1-yl ⁇ -3-phenyl- propan-1-one
  • the compound of Example 85 was made by the methods of Scheme 7 described above, in which Boc-L-Phe-OH was used as QCOOH.
  • Example 86 ([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-(2,4-dichloro-phenyl)- propan-1-one
  • the compound of Example 86 was made by the methods of Scheme 7 described above, in which Boc-D-Phenylglycine-OH was used as QCOOH.
  • Example 87 The compound of Example 87 was made by the methods of Scheme 7 described above, in which Boc-L-phenylglycine-OH was used as QCOOH.
  • Example 88 2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1-one
  • the compound of Example 88 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and 2,4-di-CI-phenylpropionic acid was used as QCOOH.
  • Example 89 3-Amino-1-[(2S,5R)-2-[3-(2-amino-3H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(4-chloro-phenyl)-propan-1-one
  • the compound of Example 89 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and Boc-3-Amino-3-(4-chloro-phenyl)-propionic acidwas used as QCOOH.
  • Example 90 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-5-isobutyl-4-(3-phenyl- propionyl)-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl ⁇ -propan-1 ⁇ one
  • Example 90 The compound of Example 90 was made by the methods of Scheme 7 described above, in which phenylpropionic acid was used as QCOOH.
  • Example 93 ([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl ⁇ -propan-1 -one
  • the compound of Example 93 was made by the methods of Scheme 7 described above, in which phenylacetic acid was used as QCOOH.
  • Example 94 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1 - ⁇ (2S,5R)-5-isobutyl-4-(2-1 H-tetrazol-5- yl-acetyl)-2-[3-([1 ,3,4]thiad ⁇ azol-2-ylamino)-propyl]-p ⁇ pera2in-1 -yl ⁇ -propan-1 - one
  • Example 94 The compound of Example 94 was made by the methods of Scheme 7 described above, in which (1 H-Tetrazol-5-yl)-acetic acid was used as QCOOH.
  • Example 95 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-4-(3-furan-2-yl-propionyl)-5- isobutyl-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl ⁇ -propan-1 -one
  • the compound of Example 95 was made by the methods of Scheme 7 described above, in which 3-Furan-2-yl-propionic acid was used as QCOOH.
  • Example 96 3-Amino-1-[(2S,5R)-2-[3-(2-amino-5-ethyl-3H-imidazol-4-yl)-propyl]-5-methyl- 4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(4-chloro-phenyl)-propan-1-one
  • the compound of Example 96 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-amino-4-ethyl-imdazole and Boc-3-Amino-3-(4-chloro-phenyl)-propionic acid was used as QCOOH.
  • Example 97 1-[(2S,5R)-2-[3-(2-Amino-5-methyl-3H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen ⁇ -yl-acetyl ⁇ piperazin-i-yO-S ⁇ -dichloro-phenyO-propan-i-one
  • the compound of Example 97 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-amino-4-methyl- imdazole and 2,4-di-chloro-phenyl-propionic acid was used as QCOOH.
  • Example 98 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1 - ⁇ (2S,5R)-4-(1 H-im ⁇ dazole-4-carbonyl)- ⁇ -isobutyl ⁇ -p-Cfi .S ⁇ jthiadiazol ⁇ -ylaminoj-propylJ-piperazin-i-ylJ-propan-i- one
  • the compound of Example 98 was made by the methods of Scheme 7 described above, in which 1 H-lmidazole-4-carboxylic acid was used as QCOOH.
  • Example 99 (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-(3-methoxy-propyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1 -one
  • the compound of Example 99 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used.
  • the hydroxyl group was converted to OMe group by reaction with TMS-CHN 2 in the presence of HBF 4 .
  • Example 100 (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-propyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
  • the compound of Example 100 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used.
  • the hydroxyl group was converted to Me group by mesylation of the hydroxyl group and reaction with lithium triethylborohydride.
  • Example 101 (R)-2-Amino-1- ⁇ (2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-[2-(1 H- imidazol-2-yl)-ethyl]-2-isobutyl-piperazi ⁇ -1-yl ⁇ -3-naphthalen-2-yl-propan-1-one
  • the compound of Example 101 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nai-OH were used.
  • the imidazole group was formed by Dess-Martin oxidation of hydroxyl group to aldehyde and subsequent reaction with glyoxal trimer and ammonium acetate in acetic acid under microwave condition at 100° C for 5 minutes.
  • Example 102 (S ⁇ -Amino-i- ⁇ R. ⁇ SH- ⁇ R ⁇ -amino-S-C ⁇ -dichloro-phenyO-propionylJ-Z- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-naphthalen- 2-yl-propan-1-one
  • the compound of Example 102 was made by the methods of Scheme 7 described above, in which Boc-L-2-Nal-OH was used as QCOOH.
  • Example 103 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl ⁇ -3-naphthalen- 2-yl-propan-1-one
  • the compound of Example 103 was made by the methods of Scheme 7 described above, in which Boc-D-2-Nal-OH was used as QCOOH.
  • Example 104 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-5-isobutyl-4-(2-methyl-3- phenyl-propionyl)-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ - propan-1-one
  • the compound of Example 104 was made by the methods of Scheme 7 described above, in which 2-Methyl-3-phenyl-propionic acid was used as QCOOH..
  • Example 105 ([1 ,3,4]thiadiazol-2-ylamino)-propyl]-4-[3-(4-trifluoromethyl-phenyl)-propionyl]- piperazin-1 -yl ⁇ -propan-1 -one
  • the compound of Example 105 was made by the methods of Scheme 7 described above, in which 3-(4-Trifluoromethyl-phenyl)-propionic acid was used as QCOOH.
  • Example 106 ([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-(2,4-dichloro-phenyl)- propan-1-one
  • the compound of Example 106 was made by the methods of Scheme 7 described above, in which Cyclohexyl-acetic acid was used as QCOOH.
  • Example 107 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-5-isobutyl-4-(1 H-pyrazole-4- carbonyO ⁇ -fS ⁇ fi .S. ⁇ thiadiazol ⁇ -ylaminoJ-propylj-piperazin-i-y ⁇ -propan-i- one
  • Example 107 The compound of Example 107 was made by the methods of Scheme 7 described > above, in which 1 H-Pyrazole-4-carboxylic acid was used as QCOOH.
  • Example 108 (S)-2-Amino-1 - ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-(2,4- dichloro-phenyl)-propan-1 -one
  • Example 108 The compound of Example 108 was made by the methods of Scheme 7 described above, in which Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
  • Example 109 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-pheny!)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-(4-chloro- phenyl)-propan-1 -one
  • Example 109 The compound of Example 109 was made by the methods of Scheme 7 described above, in which Boc-D-4-CI-Phe-OH was used as QCOOH.
  • Example 110 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-S-p ⁇ fi .S. ⁇ thiadiazol ⁇ -ylamino ⁇ propylj-piperazin-i-ylJ-S ⁇ -chloro- phenyl)-propan-1 -one
  • the compound of Example 110 was made by the methods of Scheme 7 described above, in which Boc-D-2-Ci-Phe-OH was used as QCOOH.
  • Example 111 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl- ⁇ -P-di .S ⁇ Jthiadiazol ⁇ -ylaminoJ-propyO-piperazin-i-y ⁇ -S ⁇ S-chloro- phenyl)-propan-1 -one
  • the compound of Example 111 was made by the methods of Scheme 7 described above, in which Boc-D-3-CI-Phe-OH was used as QCOOH.
  • Example 112 (S)-2-Amino-1- ⁇ (2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl ⁇ -3-(3,4- dichloro-phenyl)-propan-1-one
  • Example 112 was made by the methods of Scheme 7 described above, in which Boc-D-3,4-di-CI-Phe-OH was used as QCOOH.
  • Example 113 4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl ⁇ -guanidine
  • the compound of Example 113 was made by the methods of Scheme 1 described above, in which (1S,2R)-2-(4-Chloro-benzoyl)-cyclohexanecarboxylic acid was used.
  • Example 114 4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl ⁇ -guanidine
  • the compound of Example 114 was made by the methods of Scheme 1 described above, in which (1 R,2S)-2-(4-Chloro-benzoyl)-cyclohexanecarboxylic acid was used.
  • Example 115 (R)-2-Am ⁇ no-1-[(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-3-p- tolyl-propionyl)-2-isobutyl-piperazin-1-yl]-3-p-tolyl-propan-1-one
  • the compound of Example 114 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methyl-Phe-OH were used.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 117 (S)-2-Amino-1-[(2R,5S)-4-[(R)-2-amino-3-(4-fluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Example 118 (R)-2-Amino-1 -[(2R,5S)-4-[(R)-2-amino-3-(4-fluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Example 119 (R)-2-Amino-1-[(2R,5S)-4-[(R)-2-amino-3-(2,4-difluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1 -yl]-3-naphthalen-2-yl-propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Example 120 1-[(2R,5S)-2-Benzyl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3-hydroxy-propyl)- piperazin-1-yl]-2-naphthalen-2-yl-ethanone
  • Example 121 1-[(2S,5R)-5-Benzyl-4-[3-(3,4-dichloro-phenyl)-propionyl]-2-(3-hydroxy- propyl)-piperazin-1 -yl]-3-(3,4-dichloro-phenyl)-propan-1 -one
  • Example 122 (R)-2-Amino-1-[(2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-5- benzyl ⁇ -CS-hydroxy-propyO-piperazin-i-yll-S- ⁇ -dichloro-phenyO-propan-i- one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 124 (R)-2-Amino-1 -[(2R,5S)-2-ben2yl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3- hydroxy-propyl)-piperazin-1-yl]-3-(3,4-dichloro-phenyl)-propan-1-one The following compound was synthesized.
  • Example 125 1 -[(2R,5S)-2-Benzyl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3-piperazin-1 -yl- propyl)-piperazin-1-yl]-2-naphthalen-2-yl-ethanone The following compound was synthesized.
  • Example 126 (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-5-ethyl-3H-imiciazol-4-yl)-propyl]-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)- propan-1-one
  • Example 127 (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-5-methyl-3H-imidazol-4-yl)-propyl]-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)- propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 128 (R)-2-Amino-3-(2,4-dichloro-pehnyl)-1-[(2S,5R)-2-(3-hydroxy-propyl)-5- isobutyl-4-(2-naphthalen-2-yl-acetyI)-piperazin-1-yl]-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 129 (R)-2-Amino-3-(2,4-dichloro-phenyl)-1- ⁇ (2S,5R)-5-isobutyl-2-[3-(isoxazol-3- ylamino)-propyl]-4-[3(4-trifluoromethyl-phenyl)propionyl]-piperazin-1-yl ⁇ - propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 131 (R)-2-Amino-1- ⁇ (R)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-piperazin-1 -yl ⁇ -3-(2,4-dichloro-phenyl)-propan-1 -one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 132 Acetic acid 4-[(2S,5R)-1 ,4-bis((R)-2-amino-3-naphthalen-2-yl-propionyl)-5- methyl-piperazin-2-yl]-butyI ester
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 135 Acetic acid 4- ⁇ (2S,5R)-1 ,4-bis-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-
  • Example 136 (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-(4- hydroxy-butyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 137 (R)-2-Amino-1-[(2R,5S)-5-[3,2-amino-ethylamino]-propyl]-4-((R)-2-amino-4- phenyl-butyryl)-2-isobuty!-piperazin-1-yl]-4-phenyl-butan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nlW) (NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 138 (R)-2-Am ⁇ no-H(2S,5R)-2-butyl-4-[2-(3,4-dichloro-phenyl)-ethyl]-5-methyl- piperazin-1 -yl ⁇ -3-naphthalen-2-yl-propan-1 -one
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 139 (R)-2-Amino-1-[(2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-5- methyl-2-(4-mo ⁇ holin-4-yl-butyl)-piperazin-1-yl]-3-(3,4-dichloro-phenyl)- propan-1-one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nWI) (NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 140 (SS ⁇ RH ⁇ -Amino-S-quinolin-S-yl-propionyO-S-butyl-i-P ⁇ S ⁇ -dichloro- phenyl)-ethyl]-6-methyl-piperazin-2-one The following compound was synthesized.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 145 2-Amino-1-[(2R,5S)-4-(2-amino-3-quinoxalin-2-yl-propionyl)-5-(3-hydroxy- propyl)-2-methyl-piperazin-1-yl]-3-quinoxalin-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 146 2-Amino-1-[(2R,5S)-4-(2-amino-3-quinoxalin-6-yl-propionyl)-5-(3-hydroxy- propyl)-2-methyl-piperazin-1-yl]-3-quinoxalin-6-yl-propan-1-one
  • Ki (nM) NDP- ⁇ -MSH) MC1-R MC3-R MC4-R MC5-R
  • Example 147 2-Amino-1-[(2S,5R)-4-(2-amino-3-quino!in-3-yl-propionyl)-2-(3-hydroxy- propyl)-5-methyl-piperazin-1 -yl]-3-quinolin-3-yl-propan-1 -one
  • the following compound was synthesized. Following purification, the compound was tested as described above with the results shown. _
  • Ki (nM) (NDP-G-MSH) MC1-R MC3-R MC4-R MC5-R

Abstract

Melanocortin receptor-specific piperazine compounds, of the formula (I) wherein the variables are as defined in the specification, and pharmaceutically acceptable salts thereof. Compounds disclosed herein bind to one or more melanocortin receptors and may be an agonist, a partial agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist as to one or more melanocortin receptors, and may be employed for treatment of one or more melanocortin receptor-associated conditions or disorders, including specifically treatment of obesity and related conditions.

Description

Melanocortin Receptor-Specific Piperazine Compounds
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is related to U.S. Patent Application Serial No. 11/464,069, entitled "Melanocortin Receptor-Specific Piperazine and Keto-Piperazine Compounds", filed on August 11, 2006, which claimed priority to U.S. Provisional Patent Application Serial No. 60/707,488, entitled "Substituted Melanocortin Receptor-Specific Piperazine Compounds", filed on August 11, 2005; and to U.S. Patent Application Serial No. 11/464,053, entitled "Melanocortin Receptor-Specific Compounds with Diamine Groups", filed on August 11 , 2006, which claimed priority to U.S. Provisional Patent Application Serial No. 60/707,488, entitled "Substituted Melanocortin Receptor-Specific Piperazine Compounds", filed on August 11 , 2005; and to U.S. Patent Application Serial No. 11/464,051 , entitled "Substituted Melanocortin Receptor-Specific Single Acyl Piperazine Compounds", filed on August 11 , 2006, which claimed priority to U.S. Provisional Patent Application Serial No. 60/707,488, entitled "Substituted Melanocortin Receptor-Specific Piperazine Compounds", filed on August 11 , 2005; and to U.S. Patent Application Serial No. 10/837,519, entitled "Melanocortin Receptor-Specific Compounds", filed on April 30, 2004, which claimed priority to U.S. Provisional Patent Application Serial No. 60/546,393, entitled "Melanocortin Receptor-Specific Tetra-Substituted Piperazine Compounds", filed on February 19, 2004, and U.S. Provisional Patent Application Serial No. 60/467,442, entitled "Tetra-, Penta- and Hexa-Substituted Piperazine Compounds and Derivatives", filed on May 1 , 2003. The specification of each of the foregoing patent applications is incorporated herein by reference.
BACKGROUND OF THE INVENTION
Field of the Invention (Technical Field):
The present invention relates to tetra-substituted piperazine compounds that bind to one or more melanocortin receptors and are agonists, antagonists, mixed agonist- antagonists, inverse agonist or antagonists of inverse agonists with respect to one or more melanocortin receptors, and use thereof for the treatment of metabolic, immune, inflammation-related and other melanocortin receptor-mediated disorders, including treatment of obesity and related energy homeostasis disorders and diseases. Background Art:
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, me!anocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R), expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin- 5 receptors (MC5-R), expressed in a wide distribution of tissues.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma. Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of cachexia, as a weight gain aid, or alternatively for treatment of obesity, and generally for food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction. Such compounds may also have application in treatment of drug addiction, including alcohol abuse or addiction, as anxiolytic agents, and for treatment of depression. Other melanocortin receptor-specific compounds, such as MC1-R agonists, can be used as tanning agents to increase melanin production in the skin, acting as chemo-preventive agents against harmful effects of UV solar radiation. Compounds specific for MC1-R, MC3-R or both may further be useful in regulation of inflammatory processes.
There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as for compounds that are either agonists or antagonists for specific melanocortin receptors. High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
There are piperazine and piperidine compounds known, such as those disclosed in WO 02/070511 (Bristol-Myers Squibb Company), WO 02/059095 (EIi Lilly and Company), and WO 00/74679 (Merck & Co., Inc.), asserted to be specific for melanocortin or related receptors. However, in general such compounds have at most two functional substituted groups, have relatively poor affinity and specificity, and are not suitable for use as a drug compound. There is a significant need for compounds with high specificity for discrete receptors, such as melanocortin and other receptors, as well as compounds that are agonists- or antagonists for such receptors. High affinity compounds for such receptors can be used to exploit varied physiological responses associated with the receptors, either as agonists or antagonists. There is thus a need for compounds that are more selective, including higher affinity and specificity, and in particular for compounds that have at least three or four biologically active substituted groups. This invention addresses that need.
WO 02/085925, "Melanocortin Receptor Ligands", to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, piperazine structures with four or more substituted groups, methods to synthesize piperazine structures, methods to synthesize piperazine structures with four or more substituted groups, or methods to synthesize optically pure structures, and further does not disclose structures with a single substituent group that is a single D-Phe or D-NaI residue, or a derivative or homolog thereof, optionally with an amine capping group.
Commonly owned U.S. Patent Application Serial No. 10/837,519, published as Publication No. US 2004/0224957 A1 , discloses piperazine compounds specific for one or more melanocortin receptors, but does not disclose piperazine or keto-piperazine compounds with four substituted groups where one substituted group includes a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, and the remaining three substituted groups each include a ring structure.
There remains a significant need for compounds specific for MC4-R for treatment of conditions relating to regulation of energy homeostasis, including use- as agents for attenuating food intake and body weight gain, for treatment of obesity, and treatment of other food intake and metabolism-related purposes.
SUMMARY OF THE INVENTION
In one embodiment, the invention provides melanocortin receptor-specific piperazine compounds, of the formulae:
Figure imgf000005_0001
Figure imgf000005_0002
or enantiomers, stereoisomers or diastereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:
V and V1 are independently a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, -(CH2Jy-. -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2Jy. or
-HC=CH-;
J and Q are independently a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or
-O-, wherein J and Q are unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V when L3 is absent, wherein J may optionally be fused to V1 when L1 is absent;
L1 and L3 are independently a bond, -(CH2Jy. -HC=CH-, or -CH(NH2)CH2-, or
-CH(NCH3C(=O))CH2-, -(CH2JyNHKCH2Jy. -(CH2)y-C(=O)-(CH2)y-, -(CH2)y-O-(CH2)y-, or
-(CH2JyS-(CH2Jy-, wherein -(CH2)y- is unsubstituted or optionally substituted with an alkyl group;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R4a and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen;
R6 is H and R7 is a group of the formula: \2
W , or R6 and R7 each form a bond to a group of the formula:
Figure imgf000006_0001
R10 .
L2 is a bond, -(CH2)2-, -aryl-, -(CH2)Z-NH-, -(CH2)Z-N(alkyl)-, -(CH2)Z-C(=O)-NH-, or
-(CH2)z-C(=O)-N(alkyl)-;
W is aryl, cycloalkyl, alkyl, heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is OH, HN-C(NH2)=NH, -HN-C(N(OH)H)=NH,
-C(NH2)=NH, or -(CH2)y-N(R10)2; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
O-R9, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo),
N3, NO2, N(R9)2, C(=O)N(R9)2, OC(=O)N(R9)2, NR9OH, C(=0)R9, C(=O)OR9, OC(=O)R9,
S-R9, or S(=O)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo,
C(=O)OH, C(=O)haio, OC(=O)halo, C(halo)3, CH(halo)2> CH2(halo), N3, NO2, N(R10)2,
C(=O)N(R10)2, OC(=O)N(R10)2, NR10OH, C(=O)H, C(=O)R10, C(=O)OR10, OC(=O)R10, or
S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
The compounds falling within the defeninitions of structures I, II, III, and IV are referred to herein as compounds of the invention.
In another embodiment, the invention further provides pharmaceutical compositions comprising a compound of structures I, II, III, IV or an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof. Such pharmaceutical compositions -may be - employed in a method for affecting melanocortin receptor function in a human or non-human mammal, the method comprising the step of administering the pharmaceutical composition. Such pharmaceutical composition may further be employed in a method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition to the human or non-human mammal in a pharmaceutically effective amount. In such method, the condition may be selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above-optimal body weight, obesity, below-optimal body weight and cachexia.
The present invention further provides compounds that are agonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R. The compounds alternatively are antagonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R. The compounds alternatively are inverse agonists of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R. The compounds alternatively are antagonists of an inverse agonist of a melanocortin receptor, including one or more of MC1-R, MC3-R, MC4-R, or MC5-R.
The invention further includes methods for altering a disorder or condition associated with the activity of a melanocortin receptor, comprising administering to a patient a pharmaceutically effective amount a compound of the invention. In one embodiment the disorder or condition is an eating disorder such as cachexia. In another embodiment the disorder or condition is obesity and associated impairment of energy homeostasis. In yet another embodiment the disorder or condition is sexual dysfunction such as erectile dysfunction or female sexual dysfunction.
One object of the present invention is to provide conformationally constrained and optically pure isomers of tetra-substituted piperazines, wherein the pendant group substituents are amino acid moieties, amino acid side chain moieties or derivatives thereof, such that the resulting ring compound biologically mimics a relevant reverse turn peptide structure.
Another object of the present invention is to provide methods for the synthesis of optically pure compounds of the invention. Another object of the present invention is to provide piperazine compounds with four pendant groups, such pendant groups consisting of any moiety other than H, O, S, or a halogen.
j Another object of the present invention is to provide piperazine core compounds wherein pendant groups are provided, which pendant groups are or include amino acid side chain moieties.
Another object of the present invention is to provide a compound of the invention ) wherein such compound is specific for one or more melanocortin receptors.
Another object of the present invention is to provide a method for synthesis of compounds of the invention.
i Other objects, advantages and novel features, and the further scope of applicability of the present invention will be set forth in part in the detailed description to follow, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
I DETAILED DESCRIPTION
1. COMPOUNDS OF THE INVENTION
In one embodiment, the invention provises melanocortin receptor-specific piperazine i compounds, of the formulae:
Figure imgf000009_0001
Il
Figure imgf000009_0002
or enantiomers, stereoisomers or diastereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein: V and V1 are independently a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, -(CH2V. -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2V, or
-HC=CH-;
J and Q are independently a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or
-O-, wherein J and Q are unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V when L3 is absent, wherein J may optionally be fused to V1 when L1 is absent;
L1 and L3 are independently a bond, -(CH2V. -HC=CH-, or -CH(NH2)CH2-, or
-CH(NCH3C(=O))CH2-, -(CH2VNH-(CH2V, -(CH2)y-C(=O)-(CH2V, -(CH2VO-(CH2V, or
-(CH2)y-S-(CH2)y-, wherein -(CH2V 's unsubstituted or optionally substituted with an alkyl group;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R4a and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen;
R6 is H and R7 is a group of the formula: W , or R6 and R7 each form a bond to a group of the formula:
Figure imgf000010_0001
L2 is a bond, -(CH2)2-, -aryl-, -(CH2)Z-NH-, -(CH2)2-N(alkyl)-, -(CH2)Z-C(=O)-NH-, or 5 -(CH2)z-C(=O)-N(alkyl)-;
W is aryl, cycloalkyl, alkyl, heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is OH, HN-C(NH2)=NH, -HN-C(N(OH)H)=NH,
-C(NH2)=NH, or -(CH2)y-N(R10)2; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, 0 heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
O-R9, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=0)halo, C(halo)3, CH(halo)2, CH2(halo),
N3, NO2, N(R9)2, C(=O)N(R9)2, OC(=O)N(R9)2, NR9OH, C(=O)R9, C(=O)OR9, 0C(=0)R9,
S-R9, or S(=O)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, aikyl-NH- 5 alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo,
C(=0)0H, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R1O)2,
C(=O)N(R10)2, OC(=O)N(R10)2, NR10OH, C(=O)H, C(=O)R10, C(=O)OR10, OC(=O)R10, or O S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5. 5
2. ISOMERIC PURITY AND ISOLATION
The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric
O isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass the racemic form of compounds of the invention as well as all enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomehc mixtures.
A compound of the invention is considered optically active or enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 90% ee (enantiomeric excess) or greater, preferably, equal to or greater than 95% ee with respect to a particular chiral center. A compound of the invention is considered to be in enantiomerically enriched form when the compound has an enantiomeric excess of greater than about 80% ee, preferably greater than about 90% ee. As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of its corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically pure, enantiomerically enriched, and racemic mixtures of compounds of the invention.
Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
When administered to a patient, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, "isolated" means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds of the invention are purified by conventional techniques. As used herein, "purified" means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a single compound of the invention (or an enantiomeric or diastereomeric mixture thereof) by weight of the isolate. 3. DEFINITIONS
"treat" "treating" and "treatment"
The terms "treat," "treating" and "treatment," as used herein, contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder.
"pharmaceutically effective amount"
As used herein, the term "pharmaceutically effective amount" means the amount of a compound of the invention that will elicit a biological or medical response in the mammal that is being treated by a medical doctor or other clinician.
"prophylacticallv effective", "preventing" or "preventive"
As used herein, the term "prophylactically effective" or "preventive" means the amount of a compound of the invention that will prevent or inhibit affliction or mitigate affliction of a mammal with a medical condition that a medical doctor or other clinician is trying to prevent, inhibit, or mitigate before a patient begins to suffer from the specified disease or disorder.
"pharmaceutically acceptable saltfs)"
The term "pharmaceutically acceptable salt(s)", as used herein includes but is not limited to salts of acidic or basic groups that may be present in the compounds of the invention. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to . prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds of the invention that include an amino moiety also can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds of the invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium lithium, zinc, potassium, and iron salts. "alkyl group"
As used herein, the term "alkyl group" means a saturated, monovalent, unbranched or branched hydrocarbon chain. Examples of alkyl groups include, but are not limited to, (Ci-C6) alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methy!-2-propyl, 2- methyl-1 -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-1 -propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
"alkenyl group"
As used herein, the term "alkenyl group" means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to (C2-C6) alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2- butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
"alkvnyl group"
As used herein, the term "alkynyl group" means monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein. The triple bond of an alkynyi group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C2-C6) alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4- butyl-2-hexynyl. An alkynyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
"aryl group"
As used herein, the term "aryl group" means a monocyclic or polycyclic-aromatic radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, naphthyl, and biphenyl as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below. An aryl group optionally may be fused to a cycloalkyl group, fused to another aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group. Preferably, an aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6) aryl".
"heteroaryl group"
As used herein, the term "heteroaryl group" means a monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazyl, indolyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)-triazolyl, (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phienyl, isoxazolyl, oxazolyl, pyrazolyl, tetrazolyl, oxadiazole, thiadiazolyl, isoxazolyl, triazinyl, and pyrazinyl. A heteroaryl can be unsubstituted or optionally substituted with one or two suitable substituents as defined below. A heteroaryl group optionally may be fused to another heteroaryl group, fused to an aryl group, fused to a cycloalkyl group, or fused to a heterocycloalkyl group.
"cvcloalkyl group"
As used herein, the term "cycloalkyl group" means a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below. A cycloalkyl group optionally may be fused to another cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group.
"heterocvcloalkyl group"
As used herein, the term "heterocycloalkyl group" means a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may be fused to an aryl or heteroaryl group. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyi, thiomorpholino, and pyranyl. A heterocycloalkyl group can be unsubstituted or optionally substituted with one or two suitable substituents as defined below. A heterocycloalkyl group optionally may be fused to a cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to another heterocycloalkyl group. For example, a heterocycloalkyl group can be fused to or substituted with an aryl group or heteroaryl group, for example, but not limited to, 1 ,2,3,4-tetrahydroisoquinolinyl and 1 ,2,3,4-tetrahydroquinolinyl, tetrahydronaphthyridinyl, phenylpiperidinyl, and piperidinyipyridinyl.
In a preferred embodiment, a heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as (C3-C6) heterocycloalkyl. In another preferred embodiment, a heterocycloalkyl group is fused to or substituted with an aryl group or a heteroaryl group.
"heterocyclic radical" or "heterocyclic ring"
As used herein, the terms "heterocyclic radical" or "heterocyclic ring" mean collectively a heterocycloalkyl group or a heteroaryl group.
"cyclic radical"
As used herein, the term "cyclic radical" means collectively an aryl group, a cycloalkyl group, a heterocycloalkyl group or a heteroaryl group.
"alkoxy group"
As used herein, the term "alkoxy group" means an -O-alkyl group, wherein alkyl is as defined above. An alkoxy group can be unsubstituted or optionally substituted with one or two suitable substituents. Preferably, the alkyl chain of an alkyloxy group is from. 1 to 6 carbon atoms in length, referred to herein as "(Ci-C6) alkoxy".
"aryloxy group"
As used herein, the term "aryloxy group" means an -O-aryl group, wherein aryl is as defined above. An aryloxy group can be unsubstituted or optionally substituted with one or two suitable substituents. Preferably, the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6) aryloxy."
"carbonyl"
As used herein, a "carbonyl" group is a divalent group of the formula C(=O).
"oxo"
As used herein, an "oxo" group is a group of the formula (=0). "alkoxycarbonyl"
As used herein, the term "alkoxycarbonyl" group means a monovalent group of the formula -C(=O)-alkoxy. Preferably, the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred to herein as a "lower alkoxycarbonyl" group. >
"carbamoyl"
As used herein, the term "carbamoyl" group means the radical -C(=O) N(R')2, wherein R' is chosen from the group consisting of hydrogen, alkyl, and aryl.
) "halogen"
As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine. Correspondingly, the meaning of the terms "halo" and "Hal" encompass fluoro, chloro, bromo, and iodo.
> "suitable substituent"
As used herein, the term "suitable substituent" means a group that does not nullify the synthetic, therapeutic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: alkyl; alkenyl; alkynyl; aryl; heteroaryl; heterocycloalkyl; cycloalkyl; O-alkyl; O- i alkenyl; O-alkynyl; O-aryl; CN; OH; oxo; halo; C(=O)OH; C(=0)halo; OC(=O)halo; CF3; N3;
NO2; NH2; NH(alkyl); N(alkyl)2; NH(aryl); N(aryl)2; C(=0)NH2; C(=O)NH(alkyl); C(=O)N(alkyl)2;
C(=O)NH(aryl); C(=O)N(aryl)2; OC(=O)NH2; C(=O)NH(heteroaryl); C(=O)N(heteroaryl)2;
NHOH; NOH(alkyl); NOH(aryl); OC(=O)NH(alkyl); OC(=O)N(alkyl)2; OC(=O)NH(aryl);
OC(=O)N(aryl)2; CHO; C(=O)(alkyl); C(=O)(aryl); C(=O) O(alkyl); C(=O)O(aryl); OC(=O)(alkyl); OC(=O)(aryl); OC(=O)O(alkyl); OC(=O)O(aryl); S-alkyl; S-alkenyl; S-alkynyl;
S-aryl, S(=O)2H, S(=O)2alkyl, S(=O)2aryl, S(=O)2alkenyl, and S(=O)2alkynyl, . One of skill in art can readily choose a suitable substituent based on the synthesis, stability and pharmacological activity of the compound of the invention.
As used herein in the chemical structure drawings, the above "wavy line" indicates a bond at the point that a chemical group is attached to another chemical group. Thus, according to this definition, the chemical formula "A" below:
Figure imgf000016_0001
wherein R' is a group of the formula "B",
Figure imgf000017_0001
represents the compound below
Figure imgf000017_0002
4. SYNTHESIS OF COMPOUNDS OF THE INVENTION
The compounds of the invention can be obtained via standard, synthetic methodology. Some convenient methods are illustrated in Schemes 1-8 below. Starting materials useful for preparing the compounds of the invention and intermediates therefor, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
Protecting groups utilized herein denote groups which generally are not found in the final therapeutic compounds but which are intentionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed or converted to the desired group at a later stage of the synthesis and compounds bearing such protecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly, the precise structure of the protecting group is not critical.
Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, "Protective Groups in Organic Chemistry", Plenum Press, London and New York, 1973; Greene, Th. W. "Protective Groups in Organic Synthesis", Wiley, New York, 1981; "The Peptides", Vol. I, Schroder and Lubke, Academic Press, London and New York, 1965; "Methoden der organischen Chemie", Houben-Weyl, 4th Edition, Vol.15/I1 Georg Thieme Verlag, Stuttgart 1974, the disclosures of which are incorporated herein by reference.
One general strategy includes developing a linear intermediate using chiral building blocks such as amino acid derivatives. The linear intermediate can be cyclized using a Mitsunobo reaction strategy or by spontaneous cyclization through reactive groups such as a reaction between an amine and an ester or between an amine and an aldehyde function. In these cyclizations, the driving force for intramolecular reaction versus intermolecular reaction is the thermodynamically favored reaction forming a six-membered ring structure. In many instances, the methodology incorporates conditions that do not involve inversion or racemization of chiral centers. In some instances where a small percentage of racemate is observed, such as in use of an α-amino aldehyde in certain positions, the desired chiral product is easily purified by methods known in the art, such as flash chromatography on a silica gel column.
The group containing the Q ring is preferably made by use of an aldehyde derivative of a D-amino acid. By use of an α-amino aldehyde the resulting group has, in its most basic form, the general structure:
Figure imgf000018_0001
By way of example, where an aldehyde derivative of D-Phe is employed in synthesis, in the resulting compound r is 1 , and Q is phenyl. However, it can readily be seen that any D-amino acid may be employed as an aldehyde derivative, and may further be seen that rather than -NH2 any amine capping group may be employed in lieu of one or both hydrogen atoms. In synthesis, preferably an N-protected D-amino acid aldehyde is employed, where the N-protecting group is conventionally Boc or Fmoc. Because of the inherent instability of α-amino aldehydes in solution, these compounds are preferably synthesized immediately prior to use. Two different methods may be used for synthesis.
i In the first method, to an N-protected amino acid (such as with a Boc- or Fmoc-group) in dichloromethane was added TBTU (1 eq.) (here and elsewhere "eq." is an abbreviation for equivalent or equivalents, as the context requires) and NMM (1 eq.). The mixture was stirred for half an hour and N,O-dimethylhydroxylamine hydrochloride (1 eq.) and NMM (1 eq.) were added. The reaction was carried out overnight. The solvent was removed and EtOAc was i added. The organic phase was washed by aqueous sodium bicarbonate, brine and dried - over sodium sulfate. After evaporation of solvent and drying under vacuum the residue was dissolved in THF under nitrogen at -78° C. To this solution was added LAH (1 M in THF, 1.5 eq.) slowly. The solution was stirred for an additional half hour. The reaction was diluted by ether and quenched by aqueous potassium hydrogen sulfate. The organic phase was washed with 1 N HCI, water, brine and dried over sodium sulfate. After removal of solvent the aldehyde was used immediately for the next step reaction without purification.
In the second method, to an N-protected amino acid (such as with a Boc- or Fmoc- group) in THF was added borane-THF (1 M, 1.2 eq.) slowly at 0° C. The temperature was raised to room temperature and the solution stirred for 2 hours. The reaction was quenched by 1 N HCI and the solvent was evaporated. The crude product was purified on a silica gel column to give a pure N-protected amino alcohol. This alcohol was dissolved in dry dichloromethane and Dess-Martin periodinane (1.1 eq.) was added. The solution was stirred for 1 hour and the reaction was diluted by ether. The organic phase was washed by saturated sodium bicarbonate with 10% sodium thiosulfate, then water, then brine and dried over sodium sulfate. After removal of solvent the crude product was used for the next step reaction immediately without further purification.
In the synthetic methods employed, either of the foregoing methods may be employed to utilize a D-amino acid aldehyde.
In general, the compounds of the invention can be synthesized by adapting the synthetic methods described in the patent documents cited in the Cross Reference to Related Applications above, particularly U.S. Patent Application Serial No. 10/837,519, published as U.S. Patent Publication No. 2004/0224957 A1 , hereby incorporated herein by reference.
Scheme 1
FmocNH
Figure imgf000020_0001
1-1 1-2 1-3
FmocNH
Figure imgf000020_0003
Figure imgf000020_0002
1-6 1-7
Figure imgf000020_0004
1-8 1-9
Figure imgf000020_0005
1-11
1-10 Scheme 2
Figure imgf000021_0001
Figure imgf000021_0002
2-5 2-6
Figure imgf000022_0001
Scheme 3
Figure imgf000023_0001
Scheme 4
Figure imgf000024_0001
Figure imgf000024_0002
4-2
4-1
Figure imgf000024_0003
4-6
4-5 Scheme 4 (Continued)
Figure imgf000025_0001
4-8
4-7
Figure imgf000025_0002
4-12 Scheme 5
Figure imgf000026_0001
5-7
5-6 Scheme 5 (Continued)
Figure imgf000027_0001
5-9
5-8
Figure imgf000027_0002
5-10 5-11
Scheme 6:
Figure imgf000028_0001
Figure imgf000028_0002
Scheme 7:
Figure imgf000029_0001
Scheme 8: (addition of heterocyclic radicals)
Mitsunob condition
Figure imgf000030_0001
'OMs R Het
R Het
5. FORMULATIONS AND ADMINISTRATION
The compounds may be formulated by any means known in the art, including but not limited to tablets, capsules, caplets, suspensions, powders, lyophilized forms and aerosols and may be mixed and formulated with buffers, binders, stabilizers, anti-oxidants and other agents known in the art. The compounds may be administered by any systemic or partially systemic means known in the art, including but not limited to intravenous injection, subcutaneous injection, administration through mucous membranes, oral administration, dermal administration, skin patches, aerosols and the like.
The invention further provides a pharmaceutical composition that includes a compound of this invention and a pharmaceutically acceptable carrier. The compound of this invention may thus be formulated or compounded into pharmaceutical compositions that include at least one compound of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired. Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. For injection or other liquid administration formulations, water containing at least one or more buffering constituents is suitable, and stabilizing agents, preservatives and solubilizing agents may also be employed. For solid administration formulations, any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, fatty acids and the like. For topical administration formulations, anyof-a variety of creamsr ointments, gels, lotions and the like may be employed. For most pharmaceutical formulations, non-active ingredients will constitute the greater part, by weight or volume, of the preparation. For pharmaceutical formulations, it is also contemplated that any of a variety of measured-release, slow-release or time-release formulations and additives may be employed, such that the dosage may be formulated so as to effect delivery of a compound of this invention over a period of time.
The compounds of this invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
The compounds and pharmaceutical compositions of this invention may be administered by injection, which injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art. In general, any route of administration by which the compounds of this invention are introduced across an epidermal layer of cells may be employed. Administration means may include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration and the like. The dosage for- treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect.
Nasal administration is a particularly preferred route of administration, and in one embodiment a relatively higher proportion of the compound is delivered to the brain by means of nasal administration than is delivered if the compound is systemically administered, such as by injection. In part, nasal administration by-passes, or partially by-passes, the blood-brain barrier, permitting more effective dosing to the central nervous system. Nasal administration may be by means of a liquid spray, gel or powder. By "nasal administration" is meant any form of intranasal administration of any of the compounds and pharmaceutical compositions of this invention. Thus in one embodiment, compounds and pharmaceutical compositions of this invention include an aqueous solution, such as a solution including saline, citrate or other common excipients or preservatives, formulated for intranasal administration. In another embodiment, compounds and pharmaceutical compositions of this " invention include a dry or powder formulation, formulated for intranasal administration. A preparation for nasal administration can take a variety of forms, such as for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension. A variety of dispensers and delivery vehicles are known in the art, including single-dose ampoules, metered dose devices, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like. For dry powder delivery of the compound, it is possible and contemplated to use any of a number of devices, including but not limited to the DirectHaler Nasal device made by Direct-Haler A/S, controlled particle dispersion devices made by Kurve Technology, and devices made by OptiNose AS. In general, the methods, teachings and devices disclosed in U.S. Patent Nos. 6,648,848, 6,715,485, and 6,811 ,543 are incorporated here by reference. In any of the foregoing methods of nasal administration, any of a variety of strategies and compounds to increase permeability of the nasal mucosa may be employed, including but not limited to small-molecule permeation enhancers and tight junction-modulator peptides.
The pharmaceutical composition can be in a solid, semi-solid, or liquid form. For a solid form, the compound and other components may be mixed together by blending, tumble mixing, freeze-drying, solvent evaporation, co-grinding, spray-drying, and other techniques known in the art. A semi-solid pharmaceutical composition suitable for intranasal administration can take the form of an aqueous or oil-based gel or ointment. For example, the compound and other components can be mixed with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide or other similar materials that form hydrophilic gels. In one embodiment the microspheres can be internally loaded or coated with compound, and upon administration form a gel that adheres to the nasal mucosa. In another embodiment, the formulation is liquid, it being understood that this includes an aqueous solution, an aqueous suspension, an oil solution, an oil suspension, or an emulsion, depending on the physicochemical properties of the compound and other components.
For liquid formulations, excipients necessary or desirable for formulation, stability, and/or bioavailability are included in the pharmaceutical composition. Exemplary excipients include sugars (such as glucose, sorbitol, mannitol, or sucrose), uptake enhancers (such as chitosan), thickening agents and stability enhancers (such as celluloses, polyvinyl pyrrolidone, starch, and the like), buffers, preservatives, and/or acids and bases to adjust the pH. In one embodiment, an absorption promoting component is included in the pharmaceutical composition. Exemplary absorption promoting components include surfactant acids, such as cholic acid, glycocholic acid, taurocholic acid, and other cholic acid derivatives, chitosan and cyclodextrins. The pharmaceutical composition may further include optional components, such as humectants. preservatives and the like. A humectant or moisturizing agent can be employed to decrease water loss from the pharmaceutical composition and optionally moisturize nasal mucosa. Exemplary humectants include hygroscopic materials such as glycerine, propylene glycol, polyethylene glycol, polysaccharides and the like. Preservatives may be employed, to prevent or limit bacteria and other microbial growth. One such preservative that may be employed is benzalkonium chloride, such as 0.05% benzalkonium chloride. Other preservatives include benzyl alcohol, methylparaben, propylparaben, butylparaben, chlorobutanol, phenethyl alcohol, phenyl mercuric acetate and the like.
The pharmaceutical composition may also include rheology modifying agents, such as for varying the viscosity of the pharmaceutical composition. Exemplary rheology modify agents include polyers and similar materials, such as sodium carboxymethyl cellulose, algin, carageenans, carbomers, galactomannans, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycols, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum and combinations of the foregoing. Such agents may also and further service as bioadhesives, to extend the residence time of a compound of the invention within the nasal mucosa.
Depending on the formulation and route of administration, if in an aqueous solution compounds and pharmaceutical compositions of this invention are appropriately buffered by means of saline, acetate, phosphate, citrate, acetate or other buffering agents, which are at any physiologically acceptable pH, generally from-about pH 4 to about pH 8. A combination of buffering agents may also be employed, such as phosphate buffered saline, a saline and acetate buffer, and the like. In the case of saline, a 0.9% saline solution may be employed. In the case of acetate, phosphate, citrate, acetate and the like, a 50 mM solution may be employed.
In another route of administration, compounds and pharmaceutical compositions of this invention are administered directly into the lung, lntrapulmonary administration may be performed by means of a metered dose inhaler, a device allowing self-administration of a metered bolus of a compound and pharmaceutical composition of this invention when actuated by a patient during inspiration. Both dry powder inhalation and nebulized aerosols may be employed. Thus it is possible and contemplated that compounds and pharmaceutical compositions of this invention may be in a dried and particulate form. In one embodiment, the particles are between about 0.5 and 6.0 μm, such that the particles have sufficient mass to settle on the lung surface, and not be exhaled, but are smalLenough-that . . they are not deposited on surfaces of the air passages prior to reaching the iung. Any of a variety of different techniques may be used to make dry powder microparticies, including but not limited to micro-milling, spray drying and a quick freeze aerosol followed by lyophilization. With micro-particles, the constructs may be deposited to the deep lung, thereby providing quick and efficient absorption into the bloodstream. Further, with such approach penetration enhancers are not required, as is sometimes the case in transdermal, nasal or oral mucosal delivery routes. Any of a variety of inhalers can be employed, including propellant-based aerosols, nebulizers, single dose dry powder inhalers and multidose dry powder inhalers. Common devices in current use include metered dose inhalers, which are used to deliver medications for the treatment of asthma, chronic obstructive pulmonary disease and the like. Preferred devices include dry powder inhalers, designed to form a cloud or aerosol of fine powder with a particle size that is always less than about 6.0 μm.
Microparticle size, including mean size distribution, may be controlled by means of the method of making. For micro-milling, the size of the milling head, speed of the rotor, time of processing and the like control the microparticle size. For spray drying, the nozzle size, flow rate, dryer heat and the like control the microparticle size. For making by means of quick freeze aerosol followed by lyophilization, the nozzle size, flow rate, concentration of aerosoled solution and the like control the microparticle size. These parameters and others may be employed to control the microparticle size.
The compounds and pharmaceutical compositions of this invention may be formulated for and administered by means of an injection, typically a deep intramuscular injection, such as in the gluteal or deltoid muscle, of a time release injectable formulation. In one embodiment, a compound or pharmaceutical composition of this invention is formulated with a PEG, such as poly(ethylene glycol) 3350, and optionally one or more additional excipients and preservatives, including but not limited to excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH, and the like. In another embodiment a compound or pharmaceutical composition of this invention is formulated with a poly(ortho ester), which may be an auto-catalyzed poly(ortho ester) with any of a variable percentage of lactic acid in the polymeric backbone, and optionally one or more additional excipients. In one embodiment poly (D,L-lactide-co-glycolide) polymer (PLGA polymer) is employed, preferably a PLGA polymer with a hydrophilic end group, such as PLGA RG502H from Boehringer Ingelheim, Inc. (Ingelheim, Germany). Such formulations may be made, for example, by combining a construct of this invention in a suitable solvent, such as methanol, with a solution of PLGA in methylene chloride, and adding thereto a continuous phase solution of polyvinyl alcohol under suitable mixing conditions in a reactor. In general, any of - a number of injectable and biodegradable polymers, which are preferably also adhesive polymers, may be employed in a time release injectable formulation. The teachings of U.S. Patents 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and methods of formulation disclosed therein, are incorporated here by reference. The formulation may be such that an injection is required on a weekly, monthly or other periodic basis, depending on the concentration and amount of construct, the biodegradation rate of the polymer, and other factors known to those of skill in the art.
5.1 Pharmaceutically Effective Amount
In general, the actual quantity of compound of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired. The dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired effect. This may readily be determined by one of ordinary skill in the art through means such as pharmacokinetic studies, plasma half-life studies, dose escalation studies, and the like. Thus a pharmaceutically effective amount includes an amount of a compound or pharmaceutical composition of this invention that is sufficient to induce the desired effect.
In general, the compounds of this invention are highly active, with dose responses as low as 0.01 μg/kg, generally with optimal or peak dose responses between about 0.01 μg/kg and 25 μg/kg, depending on the specific compound and the route of administration. For example, the compound can be administered at 0.01 , 0.05, 0.1, 0.5, 1 , 5, 10, 50, 100, or 500 μg/kg body weight, depending on specific compound selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. Conventional dose response studies and other pharmacological means may be employed to determine the optimal dose for a desired effect with a given compound, given formulation and given route of administration.
5.2 Combination Therapy and Weight Regulation
It is also possible and contemplated to use compounds of this invention in combination with other drugs or agents for treatment of various weight and feeding-related disorders. Where the compound is an agonist or partial agonist, the compound may be employed for decreasing food intake and/or body weight in combination with any other agent or drug heretofore employed as a diet aid, or for decreasing food intake and/or body weight. Where ■ the compound is an antagonist, the compound may be employed for increasing food intake and/or body weight in combination with any other agent or drug heretofore employed for ' increasing food intake and/or body weight.
Drugs that reduce energy intake include, in part, various pharmacological agents, referred to as anorectic drugs, which are used as adjuncts to behavioral therapy in weight reduction programs. Classes of anorectic drugs include, but are not limited to, noradrenergic and serotonergic agents. Noradrenergic medications may be described as those medications generally preserving the anorectic effects of amphetamines but with weaker stimulant activity. The noradrenergic drugs, except phenylpropanolamine, generally act through a centrally mediated pathway in the hypothalamus that causes anorexia. Phenylpropanolamine, a racemic mixture of norephedrine esters, causes a release of norepinephrine throughout the body and stimulates hypothalamic adrenoreceptors to reduce appetite.
Suitable noradrenergic agents include, but are not limited to, diethylpropion such as TENUATE™ (1 -propanone, 2-(diethylamino)-1 -phenyl-, hydrochloride) commercially available from Merrell; mazindol (or 5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1- a]isoindol-5-ol) such as SANOREX™ commercially available from Novartis or MAZANOR™ commercially available from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol, alpha-(i-aminoethyl)-, hydrochloride); phentermine (or Phenol, 3-[[4,5-duhydro-1 H-imidazol- 2-yl)ethyl](4-methy!phenyl)amino], monohydrochloride) such as ADIPEΞX-P™ commercially available from Lemmon, FASTIN™ commercially available from Smith-Kline Beecham and lonamin™ commercially available from Medeva; phendimetrazine (or (2S,3S)-3,4-Dimethyl- 2phenylmorpholine L-(+)-tartrate (1 :1 )) such as METRA™ commercially available from Forest, PLEGINE™ commercially available from Wyeth-Ayerst; PRELU-2™ commercially available from Boehringer Ingelheim, and STATOBEX™ commercially available from Lemmon; phendamine tartrate such as THEPHORIN™ (2,3,4,9-Tetrahydro-2-methyl-9- phenyl-1 H-indenol[2,1-c]pyridine L-(+)-tartrate (1 :1 )) commercially available from Hoffmann- LaRoche; methamphetamine such as DESOXYN™ Tablets ((S)-N, (alpha)- dimethylbenzeneethanamine hydrochloride) commercially available from Abbott; and phendimetrazine tartrate such as BONTRIL™ Slow-Release Capsules (-3,4-Dimethyl-2- phenylmorpholine Tartrate) commercially available from Amarin.
Suitable non-limiting serotonergic agents include sibutramine such as MERIDIA™ capsules (a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4- chlorophenyI)-N,N-dimethyl-(alpha)-(2-methylpropyl)-, hydrochloride,- monohydrate)- commercially available from Knoll, fenfluramine such as Pondimin™ (Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)-, hydrochloride) commercially available from Robbins; dexfenfluramine such as Redux™ (Benzeneethanamine, N-ethyl-alpha-methyl-3- (trifiuoromethyl)-, hydrochloride) commercially available from Interneuron. Fenfluramine and dexfenfluramine stimulate release of serotonin and inhibit its reuptake. Sibutramine inhibits the reuptake of serotonin, norepinephrine and dopamine, but does not stimulate secretion of serotonin.
Other serotonergic agents useful with the practice of the present invention include, but are not limited to, certain auoretic gene 5HT1a inhibitors (brain, serotonin) such as carbidopa and benserazide as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; and certain neurokinin 1 receptor antagonist and selective serotonin reuptake inhibitors including fluoxetine, fluvoxamine, paroxtine, sertraline and other useful compounds as disclosed by U.S. Pat. No. 6,162,805 which is incorporated herein by reference. Other potential inhibitors that may be employed include 5HT2c inhibitors.
Other useful compounds for reducing energy intake include, but are not limited to, certain aryl-substituted cyclobutylalkylamines as disclosed by U.S. Pat. No. 6,127,424 which is incorporated herein by reference; certain trifluoromethylthiophenylethylamine derivatives as disclosed by U.S. Pat. No. 4,148,923 which is incorporated herein by reference; certain compounds as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; certain kainite or AMPA receptor antagonists as disclosed by U.S. Pat. No. 6,191 ,117 which is incorporated herein by reference; certain neuropeptide receptor subtype 5 as disclosed by U.S. Pat. No. 6,140,354 which is incorporated herein by reference; and certain alpha-blocking agents as disclosed by U.S. Pat. No. 4,239,763 which is incorporated herein by reference.
Moreover, several peptides and hormones regulate feeding behavior. For example, cholecystokinin and serotonin act to decrease appetite and food intake. Leptin, a hormone produced by fat cells, controls food intake and energy expenditure. In obese persons who are losing weight without medications, a decrease in weight is associated with a decrease in circulating levels of leptin, suggesting its role in weight homeostasis. Obese patients with high leptin levels are thought to have peripheral leptin resistance secondary to the down- regulation of leptin receptors. Non-limiting examples of useful compounds affecting feeding behavior include certain leptin-lipolysis stimulated receptors as disclosed by WO 01/21647 which is incorporated herein by reference; certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970 which is incorporated herein by reference; certain compounds • ■ having nucleotide sequences of the mahogany gene as disclosed by WO 00/05373 which is incorporated herein by reference; and certain sapogenin compounds as disclosed by U.S. Pat. No. 4,680,289 which is incorporated herein by reference.
Other useful compounds include certain gamma peroxisome proliferator activated receptor (PPAR) agonists as disclosed by WO 01/30343 and U.S. Pat. No. 6,033,656 which are incorporated herein by reference and certain polypeptides such as fibroblast growth factor-10 polypeptides as disclosed by WO 01/18210 which is incorporated herein by reference.
Moreover, monoamine oxidase inhibitors that decrease energy intake or increase energy expenditure are useful with the practice of the present invention. Suitable, but non- limiting examples of monoamine oxidase inhibitors include befioxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide, caroxazone and other certain compounds as disclosed by WO 01/12176 which is incorporated herein by reference.
Certain compounds that increase lipid metabolism are also useful with the practice of the present invention. Such compounds include, but are not limited to, useful evodiamine compounds as disclosed by U.S. Pat. No. 6,214,831 which is incorporated herein by reference.
Nutrient partitioning -agents -and digestive inhibitors are another strategy in the treatment of obesity by interfering with the breakdown, digestion or absorption of dietary fat in the gastrointestinal tract. Gastric and pancreatic lipases aid in the digestion of dietary triglycerides by forming them into free fatty acids that are then absorbed in the small intestine. Inhibition of these enzymes leads to inhibition of the digestion of dietary triglycerides. Non-limiting examples include a lipase inhibitor, orlistat, such as XENICAL™ capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2- oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247 which is incorporated herein by reference.
Agents that increase energy expenditure are also referred to as thermogenic medications. Non-limiting examples of suitable thermogenic medications include xanthines, such as caffeine and theophylline, selective β-3-adrenergic agonists, for example certain compounds in U.S. Pat. No. 4,626,549 which is incorporated by reference herein, and α-2- . adrenergic and growth hormones compounds as described in U.S. Pat. Nos. 4,937,267 and 5,120,713 which are incorporated by reference herein.
Generally, a total dosage of the above-described obesity control agents or medications, when used in combination with a compound of this invention can range from 0.1 to 3,000 mg/day, preferably from about 1 to 1 ,000 mg/day and more preferably from about 1 to 200 mg/day in single or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.
Agents or drugs employed for increasing food intake and/or body weight include appetite stimulants such as megastrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoterone.
ASSAYS AND ANIMAL MODELS
Selected compounds are tested in assays to determine binding and functional status, and are tested in animal models of feeding behavior as discussed below. The following assays and animal models are employed, with modifications, if any, as discussed in the examples.
6.1 Competitive Inhibition Assay Using FI125I-NDP-Q-MSH
A competitive inhibition binding assay is performed using membrane homogenates prepared from HEK-293 cells that express recombinant hMC4-R, hMC3-R, or hMC5-R, and from B-16 mouse melanoma cells (containing endogenous MC1-R). In some instances, HEK-293 cells that express recombinant hMC1-R are employed. In the examples that follow, all MC3-R, MC4-R and MC5-R values are for human recombinant receptors. MC1-R values are for B-16 mouse melanoma cells, unless the heading is "hMC1-R", in which case the value is for human recombinant MC1-R. Assays are performed in 96 well GF/B Millipore multiscreen filtration plates (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (Fraction V). Membrane homogenates are incubated with 0.2nM (for hMC4-R) 0.4 nM (for MC3-R and MC5-R) or 0.1 nM (for mouse B16 MC1-R or hMC1-R) [l125]-NDP-α-MSH (Perkin Elmer) and increasing concentrations of test compounds in buffer containing 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI2, 2 mM MgCI2, 0.3 mM 1 ,10-phenanthroline, and 0.2% bovine serum albumin. After incubation for 60 minutes at 37° C, the assay mixture is filtered and the membranes washed three times with ice-cold buffer. Filters are dried and counted in a gamma counter for bound radioactivity.
Non-specific binding is measured by inhibition of binding of [l125]-NDP-α-MSH in the presence of 1 μM NDP-α-MSH. Maximal specific binding (100%) is defined as the. difference in radioactivity (cpm) bound to cell membranes in the absence and presence of 1 μM NDP-α- MSH. Radioactivity (cpm) obtained in the presence of test compounds is normalized with respect to 100% specific binding to determine the percent inhibition of [l125]-NDP-α-MSH binding. Each assay is conducted in triplicate and the actual mean values are described, with results less than 0% reported as 0%. Ki values for test compounds are determined using Graph-Pad Prism® curve-fitting software.
6.2 Competitive Binding Assay Using FI125I-AqRP (83-132)
Competitive binding studies using [l125]-AgRP (83-132) are carried out using membrane homogenates isolated from cells that express hMC4-R. The assays are performed in 96-well GF/B Millipore multiscreen filtration plates (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (Fraction V). The assay mixture contained 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI2, 2 mM MgCI2, 0.3 mM 1 ,10-phenanthroline, 0.5% bovine serum albumin, membrane homogenates, radioligand [I125J-AgRP (83-132) (Perkin Elmer) and increasing concentrations of compounds in a total volume of 200 μl_. Binding is measured at radioligand concentrations of 0.2 nM. After incubating for 1 hour at 37° C, the reaction mixture is filtered and washed with assay buffer containing 500 mM NaCI. The dried discs are punched out from the plate and counted on a gamma counter. The total binding of the radioligand did not exceed 10% of the counts added to the reaction mixture. Ki values for test compounds are determined using Graph-Pad Prism® curve-fitting software.
6.4 Assay For Agonist Activity
Accumulation of intracellular cAMP is examined as a measure of the ability of the test compounds to elicit a functional response in HEK-293 cells that express MC4-R . Confluent HEK-293 cells that express recombinant hMC4-R are detached from culture plates by incubation in enzyme-free cell dissociation buffer. Dispersed cells are suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCI2, 1 mM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-1-methyl-xanthine (IBMX), a phosphodiesterase inhibitor. The cells are plated in 96-well plates at a density of 0.5 x 105 cells per well and pre- incubated for 30. minutes. Cells are. exposed for 1 hour at 37° C to test compounds dissolved- ■ in DMSO (final DMSO concentration of 1 %) at a concentration range of 0.05 - 5000 nM in a total assay volume of 200 μl_. NDP-α-MSH is used as the reference agonist. At the end of the incubation period, cells are disrupted by the addition of 50 μl_ of lysis buffer (cAMP EIA kit, Amersham) followed by vigorous pipetting. Levels of cAMP in the lysates are determined using a cAMP EIA kit (Amersham). Data analysis is performed by nonlinear regression analysis with Graph-Pad Prism® software. The maximum efficacies of the test compounds are compared to that achieved by the reference melanocortin agonist NDP-αMSH.
6.5 Food Intake After IN and IP Dosing
Changes in food intake are evaluated for selected compounds. Male C57BL/6 mice are obtained from Jackson labs (Bar Harbor, ME). Animals are individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/off light cycle. Water and pelleted (Harlan Teklad 2018 18% Protein Rodent Diet) food is provided ad libitum. The mice are dosed IP (by intraperitoneal injection) after a 24 hour fast or IN (by intranasal administration) with vehicle or selected compounds (0.1-3 mg/kg, and in some cases up to 10 mg/kg). All animals are dosed once a day (or up to four consecutive days) at the start of the "lights off' period. The changes in food intake weight for the 4 hour and 20 hour period after dosing relative to control animals administered vehicle are determined.
6.6 Determination Of Mass and Nuclear Magnetic Resonance Analysis
- The mass values are determined using a Waters MicroMass ZQ device .utilizing a positive mode. Mass determinations are compared with calculated values and expressed in the form of mass weight plus one (M+1 or M+H).
Proton NMR data is obtained using a Bruker 300 MHz spectrometer. The spectra are obtained after dissolving compounds in a deuteriated solvent such as chloroform, DMSO1 or methanol as appropriate.
7. EXAMPLES
The following compounds were synthesized using one of the foregoing schemes, or alternatively using one or more variants on one of the foregoing schemes. In the following listings, the chemical naming protocol and structure diagrams employ and rely on the chemical naming features as utilized by the ChemDraw program (available from Carnbridgesoft Corp.) or ISIS Draw (MDL Information Systems, Inc.). In particular, the compound names were derived from the structures using the Autonom program as utilized by ChemDraw Ultra or ISIS Draw. In the structure diagrams, hydrogens are assumed and not disclosed, except as otherwise shown.
Example 1 : (R)-2-Amino-1-[(2S,5R)-2-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-3- naphthalen-2-yl-propionyl)-5-cyclohexylmethyl-piperazin-1-yl]-3-naphthalen-2- yl-propan-1-one The compound of Example 1 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Cyclohexyl-Ala-OMe and Boc-D-2-Nal-OH were used.
Figure imgf000042_0001
Example 2: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-cyclohexylmethyi-pipera2in-1-yl}-3-(2,4- dichloro-phenyl)-propan-1 -one The compound of Example 2 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Cyclohexyl-Ala-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
Figure imgf000042_0002
Example 3: N-{3-[(2S,5R)-1-[(E)-3-(2,4-Dichloro-pheny!)-acryloyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 3 was made by the methods of Scheme 1 described above, in which (E)-3-(2,4-Dιchloro-phenyl)-acrylic acid was used.
Figure imgf000043_0001
Example 4: N-{3-[(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acety!)-1 -((1 R,2S)-2-phenyl- cyclopropanecarbonyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 4 was made by the methods of Scheme 1 described above, in which (1R,2S)-2-Phenyl-cyclopropanecarboxylic acid was used.
Figure imgf000043_0002
Example 5: N-{3-[(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acety!)-1-((E)-3-m-tolyl-acryloyl)- piperazin-2-yl]-propyl}-guanidine
The compound of Example 5 was made by the methods of Scheme 1 described above, in which (E)-3-m-tolyl-acrylic acid was used.
Figure imgf000044_0001
Example 6: (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid 2,4-dichloro-benzylamide The compound of Example 6 was made by the methods of Scheme 1 described above, in which the urea bond was formed by the reactions of 1-10 with triphosgene and subsequently 2, 4-di-chlorobenzylamine.
Figure imgf000044_0002
Example 7: (R)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-5- [3-(2-amino-ethylamino)-propyl]-2-methyl-piperazin-1-yl}-3-(2,4-dichloro- phenyl)-propan-1 -one
The compound of Example 7 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
Figure imgf000044_0003
Example 8: (R)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propionyl]-5- [3-(2-amino-ethylamino)-propyl]-2-methyl-piperazin-1-yl}-3-(2,4-dimethyl- phenyl)-propan-1 -one The compound of Example 8 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2,4-di-methyl-Phe-OH were used.
Figure imgf000045_0001
Example 9: (R)-2-Amino-1-[(2R,5S)-5-[3-(2-amino-ethylamino)-propyl]-4-((R)-2-amino-3- naphthalen-2-yl-propionyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan- 1-one The compound of Example 9 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and Boc-D-2-Nal-OH were used.
Figure imgf000045_0002
Example 10: (R)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propιonyl]-5- [S^-amino-ethylamino^propyll^-methyl-piperazin-i-ylJ-S^S.A-dichloro- phenyl)-propan-1 -one The compound of Example 10 was made by the methods of Scheme 5 described above, in which CbZ-GIu(OtBu)-OH, D-AIa-OMe and BocD-3,4-di-CI-Phe-OH were used.
Figure imgf000046_0001
Example 11 : (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid [2-(2,4-dichloπ>phenyl)-ethyl]-amide The compound of Example 11 was made by the methods of Scheme 1 described above, in which the urea bond was formed by the reactions of 1-10 with triphosgene and subsequently 2-(2,4-Dichloro-phenyl)-ethylamine.
Figure imgf000046_0002
Example 12: N-{3-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5-methyl-4- ((IR^R^-phenyl-cyclopropanecarbonyO-piperazin-Σ-yO-propylJ-guanidine The compound of Example 12 was made by the methods of Scheme 1 described above, in which (1 R,2R)-2-phenyl-cyclopropanecarboxylic acid was used.
Figure imgf000047_0001
Example 13: N-{3-[(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1-(9-oxo-6,7,8,9- tetrahydrO-δH-benzocycloheptene-δ-carbonyO-piperazin^-ylj-propyl}- guanidine The compound of Example 13 was made by the methods of Scheme 1 described above, in which 9-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid was used.
Figure imgf000047_0002
Example 14: E)-1 -{(2R,5S)-4-[(R)-2-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5-[3-1 H- imidazol-2-ylamino)-propyl]-2-methyl-piperazin-1-yl}-3-quinolin-2-yl-propenone
The compound of Example 14 was made by the methods of Scheme 1 described above, in which 1-7 was reacted with (E)-3-Quinolin-2-y!-acrylic acid to form 1-8. Method C in Scheme 8 was used in a reaction with aminoimdazole. Finally Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
Figure imgf000047_0003
Example 15: (E)-1-{(2Rl5S)-4-[(R)-2-Amino-3-(2l4<lichloro-phenyl)-propionyl]-5-I3-(1 H- imidazol-2-ylamino)-propyl]-2-methyl-pιperazin-1-yl}-3-phenyl-propenone The compound of Example 15 was made by the methods of Scheme 1 described above, in which 1-7 was reacted with (E)-3-Phenyl-acrylic acid to form 1-8. Method C in Scheme 8 was used in a reaction with aminoimdazole. Finally Boc-2,4-di-chloro-Phe-OH was used as QCOOH.
Figure imgf000048_0001
Example 16: 3-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-N-(1 H-imidazol-2-yl)-propionamide The compound of Example 16 was made by the methods of Scheme 1 described above, in which method A in Scheme 8 was used in a reaction with aminoimdazole and Boc- 2,4-di-chloro-Phe-OH was used as QCOOH.
Figure imgf000048_0002
Example 17: 1-{(2R,5S)-4-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propyl]-5-[3-(3-amino- propylamino)-propyl]-2-isobutyl-piperazin-1-yl}-2-naphthalen-2-yl-ethanone The compound of Example 17 was made by the methods of Scheme 2 described above, in which Boc-NH(CH2)3NH2 was used to synthesize analog of 2-7.
Figure imgf000049_0001
Example 18: 1-{(2R,5S)-5-[3-(4-Amino-butylamino)-propyl]-4-[(R)-2-amino-3-(2,4-dichloro- phenyl)-propyl]-2-isobutyl-piperazin-1-yl}-2-naphthalen-2-yl-ethanone The compound of Example 18 was made by the methods of Scheme 2 described above, in which Boc-NH(CH2)4NH2 was used to synthesize analog of 2-7.
Figure imgf000049_0002
Example 19: 1-{(2R,5S)-4-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propyl]-5-[3-(5-amino- pentylamino)-propyl]-2-isobutyl-piperazin-1-yl}-2-naphthalen-2-yl-ethanone
The compound of Example 19 was made by the methods of Scheme 2 described above, in which Boc-NH(CH2)5NH2 was used to synthesize analog of 2-7.
Figure imgf000049_0003
Example 20: 1-{(2R,5S)-5-{3-[(2-Amino-ethyl)-methyl-amino]-propyl}-4-[(R)-3-(2,4-ciichloro- phenyl)-2-dιmethylamino-propyl]-2-isobutyl-piperazin-1-yl}-2-naphthalen-2-yl- ethanone The compound of Example 20 was made by the methods of Scheme 2 described above, in which methylation of amine was conducted by the reaction with formaldehyde in the presence of HB(AcO)3.
Figure imgf000050_0001
Example 21 : (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-1 H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-pipera2in-1-yl]-3-(2,4-dichloro-phenyl)-propan-1-one The compound of Example 21 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used in a reaction with aminoimdazole sulfate. Finally Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
Figure imgf000050_0002
Example 22: (2S,5R)-2-(3-Guanidino-propyl)-5-methyl-4-(2-naphthalen-2-yl-acetyl)- piperazine-1-carboxylic acid ((1S,2S)-2-phenyl-cyclopropyl)-amide The compound of Example 22 was made by the methods of Scheme 1 described above, in which (1S,2S)-2-Pheny!-cyclopropyl)-carbamic acid was used as QCOOH.
Figure imgf000051_0001
Example 23: N-(3-{(2S,5R)-5-Methyl-4-(2-naphthalen-2-y[-acetyl)-1-[2-(4-trifluoromethy!- phenylamino)-benzoyl]-piperazin-2-yl}-propyl)-guanidine
The compound of Example 23 was made by the methods of Scheme 1 described above, in which 2-[tert-Butoxycarbonyl-(4-trifluoromethyl-phenyl)-amino]-benzoic acid was used as QCOOH.
Figure imgf000051_0002
Example 24: N-{3-[(2S,5R)-5-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5- carbonyl]-4-(2-naphthalen-2-yl-acetyi)-piperazin-2-yl]-propyl}-guanidine The compound of Example 24 was made by the methods of Scheme 1 described above, in which 4-Methyl-2-(4-trifiuoromethyl-phenyl)-thiazole-5-carboxylic acid was used as QCOOH.
Figure imgf000051_0003
Example 25: N-(3-{(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1 -[(1 S,2S)-2-(4- trifluoromethyl-benzoyO-cyclohexanecarbonylJ-piperazin^-yiy-propyl)- guanidine The compound of Example 25 was made by the methods of Scheme 1 described above, in which (1S,2S)-2-(4-Trifluoromethyl-benzoyl)-cyciohexanecarboxylic acid was used as QCOOH.
Figure imgf000052_0001
Example 26: N-(3-{(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1 -[(1 R,2R)-2-(4- trifluoromethyl-benzoyO-cyclohexanecarbonylj-piperazin^-yll-propyl)- guanidine The compound of Example 26 was made by the methods of Scheme 1 described above, in which (1R,2R)-2-(4-Trifluoromethyl-benzoyl)-cyclohexanecarboxylic acid was used as QCOOH.
Figure imgf000052_0002
Example 27: 1 -{(2R,5S)-5-[3-(2-Amino-ethylamino)-propyl]-4-[(R)-3-(2,4-dichloro-phenyl)-2- dimethylamino-propyl]-2-isobutyl-piperazin-1-yl}-2-naphthalen-2-yl-ethanone The compound of Example 27 was made by the methods of Scheme 2 described above, in which methylation of the amine was obtained by reaction with formaldehyde in the presence of HB(AcO)3.
Figure imgf000053_0001
Example 28: N-{3-[(2S,5R)-1-[4-(4-Chloro-phenyl)-thiazole-2-carbonyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-pipera2in-2-yl]-propyl}-guanidine
The compound of Example 28 was made by the methods of Scheme 1 described above, in which 4-(4-Chloro-pheπyl)-thiazole-2-carboxylic acid was used as QCOOH.
Figure imgf000053_0002
) Example 29: N-{3-[(2S,5R)-1 -[2-(4-Chloro-phenyl)-4-methyl-thiazole-5-carbonyl]-5-methyl-
4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine The compound of Example 29 was made by the methods of Scheme 1 described above, in which 4-(4-Chloro-phenyl)-thiazole-4-methyl-5-carboxylic acid was used as QCOOH.
Figure imgf000053_0003
Example 30: N-{3-[(2S,5R)-1-[2-(4-Chloro-benzyloxy)-benzoyl]-5-methyl-4-(2-naphthalen-2- yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 30 was made by the methods of Scheme 1 described above, in which 2-(4-Chloro-benzyloxy)-benzoic acid was used as QCOOH.
Figure imgf000054_0001
Example 31 : N-{3-[(2S,5R)-1-[5-(4-Chloro-phenyl)-thiophene-2-carbonyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 31 was made by the methods of Scheme 1 described above, in which 5-(4-Chloro-phenyl)-thiophene-2-carboxylic acid was used as QCOOH.
Figure imgf000054_0002
Example 32: N-{3-[(2S,5R)-1-[2-(4-Chloro-phenyl)-thiazole-5-carbonyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 32 was made by the methods of Scheme 1 described above, in which 2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid was used as QCOOH.
Figure imgf000055_0001
Example 33: N-(3-{(2S,5R)-5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1-[3-(4-trifluoromethyl- phenoxy)-benzoyl]-piperazin-2-yl}-propyl)-guanidine
The compound of Example 33 was made by the methods of Scheme 1 described above, in which 3-(4-Trifluoromethyl-phenoxy)-benzoic acid was used as QCOOH.
Figure imgf000055_0002
Example 34: N-{3-[(2S,5R)-1-[2-(3-Fluoro-benzylsulfanyl)-benzoyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 34 was made by the methods of Scheme 1 described above, in which 2-(3-Fluoro-benzylsulfanyl)-benzoic acid was used as QCOOH.
Figure imgf000055_0003
Example 35: NEED N-{3-[(2S,5R)-1 -[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propyl]-5-isobutyl-
4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yI]-propyl}-hydroxyguanidine The compound of Example 35 was made by the methods of Scheme 2 described above, in which 2-6 was reacted with BocNH-C(=NHBoc)-NHOtBu by method D in Scheme 8.
Figure imgf000056_0001
Example 36: 4-[(2S,5R)-1-[(R)-2-Amino-3-(2,4-dimethyl-phenyl)-propyl]-5-methyl-4-(2- ) naphthalen-2-yl-acetyl)-piperazin-2-ylmethyl]-benzamidine
The compound of Example 36 was made by the methods of Scheme 3 described above.
Figure imgf000056_0002
Example 37: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-methy!-piperazin-1-yl}-3-(2,4-dichloro- phenyl)-propan-1 -one
The compound of Example 37 was made by the methods of Scheme 4 described ) above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-2,4-di-CI-Phe-OH were used.
Figure imgf000057_0001
Example 38: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-methyl-piperazin-1-yl}-3-(3,4-dichloro- phenyl)-propan-1 -one The compound of Example 38 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3,4-di-CI-Phe-OH were used.
Figure imgf000057_0002
Example 39: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-methyl-piperazin-1-yl}-3-(2,4-dimethyl- phenyl)-propan-1 -one The compound of Example 39 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
Figure imgf000058_0001
Example 40: (R)-2-Amino-1-{(2S,5R)-2-[4-(2-amino-ethylamino>butyl]-4-[(R)-2-amino-3-(4- trifluoromethyl-phenyl)-propionyl]-5-isobutyl-piperazin-1-yl}-3-(4- trifluoromethyl-phenyl)-propan-1-one The compound of Example 40 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-trifluromethyl-Phe-OH were used.
Figure imgf000058_0002
Example 41 : (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(4-chloro-phenyl)-propionyl]-2-[4-(2- amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(4-chloro-phenyl)- propan-1-one The compound of Example 41 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-CI-Phe-OH were used.
Figure imgf000059_0001
Example 42: (R)-2-Amino-1-{(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-[(R)-2-amino-3-(3- trifluoromethyl-phenyl)-propionyl]-2-isobutyl-piperazin-1-yl}-3-(3- trifluoromethyl-phenyl)-propan-1-one The compound of Example 42 was made by the methods of Scheme 4 described above, in which Fmoc-I_ys(Trt)-OH, D-Leu-OMe and Boc-D-3-trifluromethyl-Phe-OH were used.
Figure imgf000059_0002
Example 43: 1-{(2R,5S)-5-[4-(2-Amino-ethylamino)-butyl]-4-[3-(3,4-dichloro-phenyl)- propionyl]-2-isobutyl-piperazin-1-yl}-3-(3,4-dichloro-phenyl)-propan-1-one The compound of Example 43 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-CI-propionic acid were used.
Figure imgf000060_0001
Example 44: N*1 *-(4-{(2S,5R)-1 Λ-Bis-tS-β^-dichloro-phenyO-propyO-δ-isobutyl-piperazin-
2-yl}-butyl)-ethane-1 ,2-diamine
The compound of Example 44 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-CI-propionic acid were used. The 3,4-di-CI-propionic acid was converted to the corresponding aldehyde for a reductive alkylation reaction.
Figure imgf000060_0002
Example 45: (R)-2-Amino-1-[(2S,5R)-2-[3-(6-amino-pyridin-2-ylamino)-propyl]-5-methyl-4- (2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1- one
The compound of Example 45 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used for the reaction with (6-Amino-pyridin- 2-yl)-carbamic acid tert-butyl ester. Boc-2,4-di-methyl-Phe-OH was used as QCOOH.
Figure imgf000061_0001
Example 46: N-{3-[(2S,5R)-1-[2-(3,4-Dichloro-benzyloxy)-benzoyl]-5-methyl-4-(2- naphthalen-2-y!-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 46 was made by the methods of Scheme 1 described above, in which 2-(3,4-Dichloro-benzyloxy)-benzoic acid was used as QCOOH.
Figure imgf000061_0002
Example 47: N-{3-[(2S,5R)-1-[2-(4-Chloro-phenoxy)-benzoyl]-5-methyl-4-(2-naphthalen-2- yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 47 was made by the methods of Scheme 1 described above, in which 2-(4-Chioro-phenoxy)-benzoic acid was used as QCOOH.
Figure imgf000061_0003
Example 48: (R)-3-Amino-1-{(2R,5S)-4-[(R)-3-amιno-4-(2,4-dichloro-phenyl)-butyryl]-5-[4- (2-amino-ethylamino)-butyl]-2-isobutyl-piperazin-1-yl}-4-(2,4-dichloro-phenyl)- butan-1-one
The compound of Example 48 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(R)-3-Amino-4-(2,4-dichloro-phenyl) -butyric acid were used.
Figure imgf000062_0001
Example 49: (R)-3-Amino-1-{(2S,5R)-4-[(R)-3-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(2,4-dichloro- phenyl)-propan-1 -one The compound of Example 49 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(S)-3-Amino-4-(2,4-dichloro-phenyl)
-butyric acid were used.
Figure imgf000062_0002
Example 50: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(4-chloro-2-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(4- chloro-2-methyl-phenyl)-propan-1-one The compound of Example 50 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-OH were used.
Figure imgf000063_0001
Example 51 : (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(2-chloro-4-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(2- chloro-4-methyl-phenyl)-propan-1-one The compound of Example 51 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methyl-2-chloro-Phe-OH were used.
Figure imgf000063_0002
Example 52: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(3,4-difluoro-phenyl)-propionyl]-2-[4- (2-amino-ethylamino)-butyI]-5-isobutyl-piperazin-1-yl}-3-(3,4-difluoro-phenyl)- propan-1-one The compound of Example 52 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-F-Phe-OH were used.
Figure imgf000064_0001
Example 53: (R)-2-Amino-1-[(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-4- phenyl-butyryl)-2-isobutyl-piperazin-1-yl]-4-phenyl-butan-1-one The compound of Example 53 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-homo-Phe-OH were used.
Figure imgf000064_0002
Example 54: (R)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(4-tert-butyl-phenyl)-propionyl]-5-[4- (2-amino-ethylamino)-butyl]-2-isobutyl-piperazin-1-yl}-3-(4-tert-butyl-phenyl)- propan-1-one
The compound of Example 54 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-tBu-Phe-OH were used.
Figure imgf000065_0001
Example 55: 1-{(2R,5S)-5-[4-(2-Amino-ethylamino)-butyl]-4-[3-(3,4-dimethyl-phenyl)- propionyl]-2-isobutyl-piperazin-1-yI}-3-(3,4-dimethyl-phenyl)-propan-1-one The compound of Example 55 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-methyl-propionic acid were used.
Figure imgf000065_0002
Example 56: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-δ-tS-Cπ .S^jthiadiazol-Σ-ylamino^propylj-piperazin-i -ylJ-S-naphthalen- 2-yl-propan-1-one
The compound of Example 56 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-1 ,3,4-thiadiazole.
Figure imgf000066_0001
Example 57: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(3,4-dimethyl-phenyl)-propionyl]-2- [4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(3,4-dimethyl- phenyl)-propan-1 -one The compound of Example 57 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
Figure imgf000066_0002
Example 58: (R)-2-Amino-1-{(2S,5R)-4-[(R)-2-amino-3-(4-chloro-3-methyl-phenyl)- propionyl]-2-[4-(2-amino-ethylamino)-butyl]-5-isobutyl-piperazin-1-yl}-3-(4- chloro-3-methyl-phenyl)-propan-1-one
The compound of Example 58 was made by the methods of Scheme 4 described above, in which Fmoc-l_ys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-OH were used.
Figure imgf000067_0001
Example 59: (R)-2-Amino-1-{(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-[(R)-2-amino-3-(4- methoxy-phenyl)-propionyl]-2-isobutyl-piperazin-1-yl}-3-(4-methoxy-phenyl)- propan-1-one
The compound of Example 59 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methoxy-Phe-OH were used.
Figure imgf000067_0002
Example 60: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-biphenyl-4-yl-propionyl)-5-[4-(2- amino-ethylamino)-butyl]-2-isobutyl-piperazin-1-yl}-3-biphenyl-4-yl-propan-1- one
The compound of Example 60 was made by the methods of Scheme 4 described bove, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-phenyI-Phe-OH were used.
Figure imgf000068_0001
Example 61 : (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-(3-[1 ,2,4]triazol-1 -yl-propyl)-piperazin-1 -yl]-3-naphthalen-2-yl- propan-1-one
The compound of Example 61 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 1 ,2,4-triazole.
Figure imgf000068_0002
Example 62: N-fS-pS.δR^I-P-CS^-Dichloro-phenoxy^benzoy^-δ-methyM^-naphthaien-
2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
The compound of Example 62 was made by the methods of Scheme 1 described above, in which 2-(3,4-di-Chloro-phenoxy)-benzoic acid was used as QCOOH.
Figure imgf000069_0001
Example 63: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-([1 ,2,4]tria2ol-4-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen-2- yl-propan-1-one
The compound of Example 63 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 4-amino-4H-1 ,2,4-triazole.
Figure imgf000069_0002
Example 64: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(thiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen-2-yl- propan-1 -one
The compound of Example 64 was made by the methods of the Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. The method C in Scheme 8 was used for incorporation of 2-aminothiazole.
Figure imgf000070_0001
Example 65: (R)-2-Amino-1-{(2R,5SH-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(5-methyl-thiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen- 2-yl-propan-1-one
The compound of Example 65 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-5-methylthiazole.
Figure imgf000070_0002
Example 66: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(4-methyl-thiazol-2-ylamino)-propy!]-piperazin-1-yl}-3-naphthalen- 2-yl-propan-1-one
The compound of Example 66 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-4-methylthiazole.
Figure imgf000071_0001
Example 67: (R)-2-Amino-3-(2,4-dichloro-pheπyl)-1 -[(2S,5R)-2-(3-imidazol-1 -yl-propyl)-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-propan-1-one The compound of Example 67 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method D in Scheme 8 was used for incorporation of imidazole.
Figure imgf000071_0002
Example 68: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-[(2S,5R)-5-methyl-2-[3-(2-methyl-2H- tetrazol-5-ylamino)-propyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-propan- 1-one
The compound of Example 68 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method C in Scheme 8 _. was used for incorporation of 5-amino-2-methyltetrazole.
Figure imgf000072_0001
Example 69: (R)-2-Amino-3-(2,4-dichloro-pheπyl)-1 -[(2S,5R)-5-methyl-2-[3-(2-methyl- imidazol-1 -yl)-propyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-1 -yl]-propan-1 ■ one The compound of Example 69 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method D in Scheme 8 was used for incorporation of 5-methylimidazole.
Figure imgf000072_0002
Example 70: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-[(2S,5R)-5-methyl-4-(2-naphthalen-2-yl- acetyl)-2-(3-[1 ,2,4]triazol-1 -yl-propyl)-piperazin-1 -yl]-propan-1 -one The compound of Example 70 was made by the methods of Scheme 1 described above, in which Boc-D-2,4-di-CI-Phe-OH were used as QCOOH. Method C in Scheme 8 was used for incorporation of 1,2,4-triazole.
Figure imgf000073_0001
Example 71 : (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(5-methyl-[1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3- naphthalen-2-yl-propan-1 -one The compound of Example 66 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-amino-5-methyl-1 ,3,4- thiadiazole.
Figure imgf000073_0002
Example 72: N-{(R)-2-[(2S,5R)-4-((R)-2-Acetylamino-3-naphthalen-2-yl-propionyl)-5- isobutyl-2-(3-[1,2,4]triazol-1-y!-propyl)-piperazin-1-yl]-1-naphthalen-2-ylmethyl- 2-oxo-ethyl}-acetamide
The compound of Example 72 was derived from Example 61 , in which the free amino groups were acetylated by the reaction of acetic anhydride with Example 61 in the presence of pyridine.
Figure imgf000074_0001
Example 73: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(3-methyl-isoxazol-5-ylamino)-propyl]-piperazin-1-yl}-3- naphthalen-2-yl-propan-1-one
The compound of Example 73 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 5-amino-3-methylisoxazole.
Figure imgf000074_0002
Example 74: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(5-methyl-isoxazol-3-ylamino)-propyl]-piperazin-1-yl}-3- naphthalen-2-yl-propan-1 -one
The compound of Example 74 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 3-amino-5-methylisoxazole.
Figure imgf000075_0001
Example 75: 1 -[(2R,5S)-5-[3-(2-Amino-1 H-imidazol-4-yl)-propyl]-4-((1 S,2S)-1 -amino-2- phenyl-cyclopropanecarbonyl^-methyl-piperazin-i-ylj^-naphthalen^-yl- ethanone
The compound of Example 75 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and (1S,2S)-1-Amino-2-phenyl-cyclopropanecarboxylic acid was used as QCOOH.
Figure imgf000075_0002
Example 76: 1 -[(2R,5S)-5-[3-(2-Amino-1 H-imidazol-4-yl)-propyl]-4-((1 S,2R)-1 -amino-2- phenyl-cyclopropanecarbonyl^-methyl-piperazin-i-yl^-naphthalen^-yl- ethanone
The compound of Example 76 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and (1 S,2R)-1-Amino-2-phenyl-cyclopropanecarboxylic acid was used as QCOOH.
Figure imgf000076_0001
Example 77: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-δ-CS^pyrimiclin^-ylaminoJ-propylJ-piperazin-i-yll-S-naphthalen^-yl- propan-1-one
The compound of Example 77 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2 -NaI-OH were used. Method C in Scheme 8 was used for incorporation of aminopyrazine.
Figure imgf000076_0002
Example 78: (R)-2-Amino-1-[(2S,5R)-2-[2-(2-amino-3H-imidazol-4-yl)-ethyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-phenyl-propan-1-one The compound of Example 78 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and Boc-D-Phe-OH was used as QCOOH.
Figure imgf000076_0003
Example 79: (R)-2-Amino-1-[(2S,5R)-2-[3-(5-amino-tetrazol-2-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1 -one The compound of Example 79 was made by the methods of Scheme 1 described above, in which method D in Scheme 8 was used in a reaction with 5-aminotetrazole and Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
Figure imgf000077_0001
Example 80: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-4-(2-naphthalen-2- yl-acetyl^-^II .SΛJthiadiazol^-ylaminoJ-propyll-piperazin-i-ylJ-propan-i- one The compound of Example 80 was made by the methods of Scheme 1 described above, in which method C in Scheme 8 was used in a reaction with 2-amino-1 ,3,4-thiadiazole and Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
Figure imgf000077_0002
Example 81 : (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yi-propionyl)-5-(3- hydroxy-propyl)-2-isobutyl-piperazin-1-yl]-3-naphthalen-2-y!-propan-1-one The compound of Example 81 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Naf-OH were 5 used.
Figure imgf000078_0001
Example 82: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- ) isobutyl-5-[3-(isoxazol-3-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen-2-yl- propan-1-one
The compound of Example 82 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 3-aminoisoxazole.
Figure imgf000078_0002
Example 83: (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-[3-(pyrimidin-2-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen-2-yl- propan-1-one
The compound of Example 83 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 8 was used for incorporation of 2-aminopyrimidine.
Figure imgf000079_0001
Example 84: (R)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-phenyl- propan-1-one The compound of Example 84 was made by the methods of Scheme 7 described above, in which Boc-D-Phe-OH was used as QCOOH.
Figure imgf000079_0002
Example 85: (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyi]-piperazin-1-yl}-3-phenyl- propan-1-one The compound of Example 85 was made by the methods of Scheme 7 described above, in which Boc-L-Phe-OH was used as QCOOH.
Figure imgf000079_0003
Example 86: (R)-2-Amino-1-{(2S,5R)-4-((R)-2-amino-2-phenyl-acetyl)-5-isobutyl-2-[3-
([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-(2,4-dichloro-phenyl)- propan-1-one The compound of Example 86 was made by the methods of Scheme 7 described above, in which Boc-D-Phenylglycine-OH was used as QCOOH.
Figure imgf000080_0001
Example 87: (R)-2-Amino-1-{(2S,5R)-4-((S)-2-amino-2-phenyl-acetyl)-5-isobutyl-2-[3-
([I .S^Jthiadiazol^-ylaminoVpropyO-piperazin-i-ylJ-S^Λ-clichloro-phenyl)- propan-1-one
The compound of Example 87 was made by the methods of Scheme 7 described above, in which Boc-L-phenylglycine-OH was used as QCOOH.
Figure imgf000080_0002
Example 88: 1-[(2S,5R)-2-[3-(2-Amino-3H-imidazo!-4-yl)-propyl]-5-methyl-4-(2-naphthalen-
2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1-one The compound of Example 88 was made by the methods of Scheme 1 described above, in which the method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and 2,4-di-CI-phenylpropionic acid was used as QCOOH.
Figure imgf000080_0003
Example 89: 3-Amino-1-[(2S,5R)-2-[3-(2-amino-3H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(4-chloro-phenyl)-propan-1-one The compound of Example 89 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-aminoimdazole sulfate and Boc-3-Amino-3-(4-chloro-phenyl)-propionic acidwas used as QCOOH.
Figure imgf000081_0001
Example 90: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-4-(3-phenyl- propionyl)-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl}-propan-1 ■ one
The compound of Example 90 was made by the methods of Scheme 7 described above, in which phenylpropionic acid was used as QCOOH.
Figure imgf000081_0002
Example 91 : (R)-1-{(2R,5S)-4-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-2-isobutyl-5-
[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-phenyl-butan-1-one The compound of Example 91 was made by the methods of Scheme 7 described above, in which (R)-3-Phenyl-butyric acid was used as QCOOH.
Figure imgf000082_0001
Example 92: (S)-1-{(2R,5S)-4-[(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionyl]-2-isobutyl-5-
[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl}-3-phenyl-butan-1 -one The compound of Example 92 was made by the methods of Scheme 7 described above, in which (S)-3-Phenyl-butyric acid was used as QCOOH.
Figure imgf000082_0002
Example 93: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-4-phenylacetyl-2-[3-
([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl}-propan-1 -one The compound of Example 93 was made by the methods of Scheme 7 described above, in which phenylacetic acid was used as QCOOH.
Figure imgf000082_0003
Example 94: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1 -{(2S,5R)-5-isobutyl-4-(2-1 H-tetrazol-5- yl-acetyl)-2-[3-([1 ,3,4]thiadιazol-2-ylamino)-propyl]-pιpera2in-1 -yl}-propan-1 - one
The compound of Example 94 was made by the methods of Scheme 7 described above, in which (1 H-Tetrazol-5-yl)-acetic acid was used as QCOOH.
Figure imgf000083_0001
Example 95: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-4-(3-furan-2-yl-propionyl)-5- isobutyl-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl}-propan-1 -one The compound of Example 95 was made by the methods of Scheme 7 described above, in which 3-Furan-2-yl-propionic acid was used as QCOOH.
Figure imgf000083_0002
Example 96: 3-Amino-1-[(2S,5R)-2-[3-(2-amino-5-ethyl-3H-imidazol-4-yl)-propyl]-5-methyl- 4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(4-chloro-phenyl)-propan-1-one The compound of Example 96 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-amino-4-ethyl-imdazole and Boc-3-Amino-3-(4-chloro-phenyl)-propionic acid was used as QCOOH.
Figure imgf000084_0001
Example 97: 1-[(2S,5R)-2-[3-(2-Amino-5-methyl-3H-imidazol-4-yl)-propyl]-5-methyl-4-(2- naphthalen^-yl-acetyl^piperazin-i-yO-S^^-dichloro-phenyO-propan-i-one The compound of Example 97 was made by the methods of Scheme 1 described above, in which method B in Scheme 8 was used in a reaction with 2-amino-4-methyl- imdazole and 2,4-di-chloro-phenyl-propionic acid was used as QCOOH.
Figure imgf000084_0002
Example 98: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1 -{(2S,5R)-4-(1 H-imιdazole-4-carbonyl)- δ-isobutyl^-p-Cfi .S^jthiadiazol^-ylaminoj-propylJ-piperazin-i-ylJ-propan-i- one The compound of Example 98 was made by the methods of Scheme 7 described above, in which 1 H-lmidazole-4-carboxylic acid was used as QCOOH.
Figure imgf000084_0003
Example 99: (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-(3-methoxy-propyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1 -one The compound of Example 99 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. The hydroxyl group was converted to OMe group by reaction with TMS-CHN2 in the presence of HBF4.
Figure imgf000085_0001
Example 100: (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2- isobutyl-5-propyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one The compound of Example 100 was made by the methods of Schemes 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. The hydroxyl group was converted to Me group by mesylation of the hydroxyl group and reaction with lithium triethylborohydride.
Figure imgf000085_0002
Example 101 : (R)-2-Amino-1-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-[2-(1 H- imidazol-2-yl)-ethyl]-2-isobutyl-piperaziπ-1-yl}-3-naphthalen-2-yl-propan-1-one The compound of Example 101 was made by the methods of Scheme 5 and 6 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nai-OH were used. The imidazole group was formed by Dess-Martin oxidation of hydroxyl group to aldehyde and subsequent reaction with glyoxal trimer and ammonium acetate in acetic acid under microwave condition at 100° C for 5 minutes.
Figure imgf000086_0001
Example 102: (S^-Amino-i-^R.δSH-^R^-amino-S-C∑Λ-dichloro-phenyO-propionylJ-Z- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-naphthalen- 2-yl-propan-1-one The compound of Example 102 was made by the methods of Scheme 7 described above, in which Boc-L-2-Nal-OH was used as QCOOH.
Figure imgf000086_0002
Example 103: (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1 -yl}-3-naphthalen- 2-yl-propan-1-one The compound of Example 103 was made by the methods of Scheme 7 described above, in which Boc-D-2-Nal-OH was used as QCOOH.
Figure imgf000086_0003
Example 104: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-4-(2-methyl-3- phenyl-propionyl)-2-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}- propan-1-one The compound of Example 104 was made by the methods of Scheme 7 described above, in which 2-Methyl-3-phenyl-propionic acid was used as QCOOH..
Figure imgf000087_0001
Example 105: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-2-[3-
([1 ,3,4]thiadiazol-2-ylamino)-propyl]-4-[3-(4-trifluoromethyl-phenyl)-propionyl]- piperazin-1 -yl}-propan-1 -one The compound of Example 105 was made by the methods of Scheme 7 described above, in which 3-(4-Trifluoromethyl-phenyl)-propionic acid was used as QCOOH.
Figure imgf000087_0002
Example 106: (R)-2-Amino-1-{(2S,5R)-4-(2-cyclohexyl-acetyl)-5-isobutyl-2-[3-
([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-(2,4-dichloro-phenyl)- propan-1-one The compound of Example 106 was made by the methods of Scheme 7 described above, in which Cyclohexyl-acetic acid was used as QCOOH.
Figure imgf000087_0003
Example 107: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-4-(1 H-pyrazole-4- carbonyO^-fS^fi .S.^thiadiazol^-ylaminoJ-propylj-piperazin-i-y^-propan-i- one
The compound of Example 107 was made by the methods of Scheme 7 described > above, in which 1 H-Pyrazole-4-carboxylic acid was used as QCOOH.
Figure imgf000088_0001
Example 108: (S)-2-Amino-1 -{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-(2,4- dichloro-phenyl)-propan-1 -one
The compound of Example 108 was made by the methods of Scheme 7 described above, in which Boc-D-2,4-di-CI-Phe-OH was used as QCOOH.
Figure imgf000088_0002
Example 109: (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-pheny!)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-(4-chloro- phenyl)-propan-1 -one
The compound of Example 109 was made by the methods of Scheme 7 described above, in which Boc-D-4-CI-Phe-OH was used as QCOOH.
Figure imgf000089_0001
Example 110: (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-S-p^fi .S.^thiadiazol^-ylamino^propylj-piperazin-i-ylJ-S^-chloro- phenyl)-propan-1 -one The compound of Example 110 was made by the methods of Scheme 7 described above, in which Boc-D-2-Ci-Phe-OH was used as QCOOH.
Figure imgf000089_0002
Example 111 : (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-δ-P-di .SΛJthiadiazol^-ylaminoJ-propyO-piperazin-i-y^-S^S-chloro- phenyl)-propan-1 -one The compound of Example 111 was made by the methods of Scheme 7 described above, in which Boc-D-3-CI-Phe-OH was used as QCOOH.
Figure imgf000089_0003
Example 112: (S)-2-Amino-1-{(2R,5S)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-5-[3-([1 ,3,4]thiadiazol-2-ylamino)-propyl]-piperazin-1-yl}-3-(3,4- dichloro-phenyl)-propan-1-one
The compound of Example 112 was made by the methods of Scheme 7 described above, in which Boc-D-3,4-di-CI-Phe-OH was used as QCOOH.
Figure imgf000090_0001
Example 113: N-{3-[(2S,5R)-1-[(1S,2R)-2-(4-Chloro-benzoyl)cyclohexanecarbonyl]-5-methyl-
4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine The compound of Example 113 was made by the methods of Scheme 1 described above, in which (1S,2R)-2-(4-Chloro-benzoyl)-cyclohexanecarboxylic acid was used.
Figure imgf000090_0002
Example 114: N-{3-[(2S,5R)-1-[(1R,2S)-2-(4-Chloro-benzoyl)cyclohexanecarbonyl]-5-methyl-
4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine The compound of Example 114 was made by the methods of Scheme 1 described above, in which (1 R,2S)-2-(4-Chloro-benzoyl)-cyclohexanecarboxylic acid was used.
Figure imgf000090_0003
Example 115: (R)-2-Amιno-1-[(2R,5S)-5-[4-(2-amino-ethylamino)-butyl]-4-((R)-2-amino-3-p- tolyl-propionyl)-2-isobutyl-piperazin-1-yl]-3-p-tolyl-propan-1-one The compound of Example 114 was made by the methods of Scheme 4 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methyl-Phe-OH were used.
Figure imgf000091_0001
Example 116: N-{3-[(2S,5R)-1-(4'-Chioro-biphenyl-3-carbonyl)-5-methyl-4-(2-naphthalen-2- yl-acetyl)-piperazin-2-yl]-propyl}-guanidine
) The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000091_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10% -1 % 84% 18%
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
138
Example 117: (S)-2-Amino-1-[(2R,5S)-4-[(R)-2-amino-3-(4-fluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000092_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
5% -7% 14% %
Example 118: (R)-2-Amino-1 -[(2R,5S)-4-[(R)-2-amino-3-(4-fluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000092_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
2% -9% 31% %
Example 119: (R)-2-Amino-1-[(2R,5S)-4-[(R)-2-amino-3-(2,4-difluoro-phenyl)-propionyl]-5-(3- hydroxy-propyl)-2-methyl-piperazin-1 -yl]-3-naphthalen-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000092_0003
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
% % 37% %
Example 120: 1-[(2R,5S)-2-Benzyl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3-hydroxy-propyl)- piperazin-1-yl]-2-naphthalen-2-yl-ethanone
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000093_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
12% % 13% %
Example 121 : 1-[(2S,5R)-5-Benzyl-4-[3-(3,4-dichloro-phenyl)-propionyl]-2-(3-hydroxy- propyl)-piperazin-1 -yl]-3-(3,4-dichloro-phenyl)-propan-1 -one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000093_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
17% % 4% % Ki (nM) (NDP-O-MSH) MC1-R MC3-R MC4-R MC5-R
Ki (nM) (AgRP) MC3-R MC4-R
Example 122: (R)-2-Amino-1-[(2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-5- benzyl^-CS-hydroxy-propyO-piperazin-i-yll-S-^^-dichloro-phenyO-propan-i- one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000094_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
0% % 81 % %
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
180
Example 123: (R)-2-Amino-1-[(2S,5R)-5-benzyl-2-(3-hydroxy-propyl)-4-(2-naphthalen-2-yl- acetyl)-piperazin-1-yl]-3-(3,4-dichloro-pheny!)-propan-1-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000095_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
1 % % 30% %
Example 124: (R)-2-Amino-1 -[(2R,5S)-2-ben2yl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3- hydroxy-propyl)-piperazin-1-yl]-3-(3,4-dichloro-phenyl)-propan-1-one The following compound was synthesized.
Figure imgf000095_0002
Example 125: 1 -[(2R,5S)-2-Benzyl-4-(4'-chloro-biphenyl-2-carbonyl)-5-(3-piperazin-1 -yl- propyl)-piperazin-1-yl]-2-naphthalen-2-yl-ethanone The following compound was synthesized.
Figure imgf000095_0003
Example 126: (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-5-ethyl-3H-imiciazol-4-yl)-propyl]-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)- propan-1-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000096_0001
Ki (nM) (NDP -α-MSH)
MC1-R MC3-R MC4-R MC5-R
5380 2922 76 599
Ki (nM) (AgRP)
MC3-R MC4-R
4/128
Example 127: (R)-2-Amino-1-[(2S,5R)-2-[3-(2-amino-5-methyl-3H-imidazol-4-yl)-propyl]-5- methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)- propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000096_0002
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
4420 3373 46 611
Ki (nM) (AgRP) MC3-R MC4-R
7/61
Example 128: (R)-2-Amino-3-(2,4-dichloro-pehnyl)-1-[(2S,5R)-2-(3-hydroxy-propyl)-5- isobutyl-4-(2-naphthalen-2-yl-acetyI)-piperazin-1-yl]-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000097_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000 10000 855 4197
Example 129: (R)-2-Amino-3-(2,4-dichloro-phenyl)-1-{(2S,5R)-5-isobutyl-2-[3-(isoxazol-3- ylamino)-propyl]-4-[3(4-trifluoromethyl-phenyl)propionyl]-piperazin-1-yl}- propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000097_0002
Ki (nM) (NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
3808 3652 235 532
Example 130: (R)-2-Amino-1-[(2S,5R)-2-[2-(5-amino-2H-[1,2,4]triazol-3-yl)ethyl]-5-methyl-4- (2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-3-(2,4-dichloro-phenyl)-propan-1- one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000098_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000 4332 2499 3432
Example 131: (R)-2-Amino-1-{(R)-4-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propionyl]-2- isobutyl-piperazin-1 -yl}-3-(2,4-dichloro-phenyl)-propan-1 -one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000098_0002
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000 3090 555 2339
Example 132: Acetic acid 4-[(2S,5R)-1 ,4-bis((R)-2-amino-3-naphthalen-2-yl-propionyl)-5- methyl-piperazin-2-yl]-butyI ester
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000099_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
405
Example 133: (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-butyl-2- methyl-piperazin-1 -yl]-3-naphthalen-2-yl-propal-1 -one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000099_0002
Ki (nM) (NDP-α-MSH)
MC1-R MC3-R MC4-R MC5-R
188 Example 134: (R^-Amino-i-KZR.δSH-KR^-amino-S^S^-dichloro-phenylJ-propionyq-S- (4-hydedroxy-butyl)-2-methyl-piperazin-1-yl]-3-(3,4-dichloro-phenyl)-propan-1- " one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000100_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
79
Example 135: Acetic acid 4-{(2S,5R)-1 ,4-bis-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-
5-methyl-piperazin-2-yl}-butyl ester
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000100_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
7% % 72% % Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
368
Example 136: (R)-2-Amino-1-[(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-(4- hydroxy-butyl)-2-methyl-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000101_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
0% % 83% %
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
171
Example 137: (R)-2-Amino-1-[(2R,5S)-5-[3,2-amino-ethylamino]-propyl]-4-((R)-2-amino-4- phenyl-butyryl)-2-isobuty!-piperazin-1-yl]-4-phenyl-butan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000101_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
80% 86% 75% 87%
Ki (nlW) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
56
Example 138: (R)-2-Amιno-H(2S,5R)-2-butyl-4-[2-(3,4-dichloro-phenyl)-ethyl]-5-methyl- piperazin-1 -yl}-3-naphthalen-2-yl-propan-1 -one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000102_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000
Example 139: (R)-2-Amino-1-[(2S,5R)-4-[(R)-2-amino-3-(3,4-dichloro-phenyl)-propionyl]-5- methyl-2-(4-moφholin-4-yl-butyl)-piperazin-1-yl]-3-(3,4-dichloro-phenyl)- propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000103_0001
Ki (nWI) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
46
Example 140: (SS^RH^-Amino-S-quinolin-S-yl-propionyO-S-butyl-i-P^S^-dichloro- phenyl)-ethyl]-6-methyl-piperazin-2-one The following compound was synthesized.
Figure imgf000103_0002
Example 141 : (R)-2-Amino-1-{(2S,5R)-2-butyl-4-[2-(3,4-dichloro-phenyl)-ethyl]-5-methyl- piperazin-1-yl}-3-(3,4-dichloro-phenyl)-propan-1-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000103_0003
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
% % 77% %
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
2292
Example 142: (2S,5R)-2-Butyl-1,4-bis-[2-(3,4-dichloro-phenyl)-ethy[]-5-methyl-pipera2ine
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000104_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
% % 0% %
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
4994
Example 143: (3S,6R)-4-[(R)-2-Amino-3-(3,4-dichloro-phenyl)-propionyl]-3-butyl-1-[2-(3,4- dichloro-phenyl)-ethyl]-6-methyl-piperazin-2-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000105_0001
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
% % 60% %
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
1848
Example 144: (SS^RH^-Amino-S-quinolin-S-yl-propionyl^S-butyl-i-^-CS^-dichloro- phenyl)-ethyl]-6-methyl-piperazin-2-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000105_0002
Inhibition at 1 μM (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
% % 0% %
Example 145: 2-Amino-1-[(2R,5S)-4-(2-amino-3-quinoxalin-2-yl-propionyl)-5-(3-hydroxy- propyl)-2-methyl-piperazin-1-yl]-3-quinoxalin-2-yl-propan-1-one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000106_0001
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000
Example 146: 2-Amino-1-[(2R,5S)-4-(2-amino-3-quinoxalin-6-yl-propionyl)-5-(3-hydroxy- propyl)-2-methyl-piperazin-1-yl]-3-quinoxalin-6-yl-propan-1-one
The following compound was synthesized. Following purification, the compound was tested as described above with the results shown.
Figure imgf000106_0002
Ki (nM) (NDP-α-MSH) MC1-R MC3-R MC4-R MC5-R
10000
Example 147: 2-Amino-1-[(2S,5R)-4-(2-amino-3-quino!in-3-yl-propionyl)-2-(3-hydroxy- propyl)-5-methyl-piperazin-1 -yl]-3-quinolin-3-yl-propan-1 -one The following compound was synthesized. Following purification, the compound was tested as described above with the results shown. _
Figure imgf000106_0003
Ki (nM) (NDP-G-MSH) MC1-R MC3-R MC4-R MC5-R
1O0O0
Although the invention has been described in detail with particular reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above, and of the corresponding application(s), are hereby incorporated by reference .

Claims

What is claimed is:
1. A compound having the formula of structure
Figure imgf000108_0001
I or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
V and V1 are independently a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, or
-HC=CH-;
J and Q are independently a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or
-O-, wherein J and Q are unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V when L3 is absent, wherein J may optionally be fused to V when L1 is absent;
L1 and L3 are independently a bond, -(CH2)y-, -HC=CH-, or -CH(NH2)CH2-, or
-CH(NCH3C(=O))CH2-, -(CH2VNH-(CH2)y-, -(CH2)y-C(=O)-(CH2)y-, -(CH2)y-O-(CH2)y-, or
-(CH2)y-S-(CH2)y-, wherein -(CH2)y- is unsubstituted or optionally substituted with an alkyl group;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R43 and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen;
R6 is H and R7 is a group of the formula:
W , or R6 and R7 each form a bond to a group of the formula:
Figure imgf000109_0001
L2 is a bond, -(CH2),-, -aryl-, -(CH2)2-NH-, -(CH2)z-N(alkyl)-, -(CH2)Z-C(=O)-NH-, or
-(CH2)z-C(=O)-N(alkyl)-;
W is aryl, cycloalkyl, alkyl, heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is OH, HN-C(NH2)=NH, -HN-C(N(OH)H)=NH,
-C(NH2)=NH, or -(CH2)y-N(R10)2; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
O-R9, CN, OH, oxo, halo, C(=O)OH, C(=0)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo),
N3, NO2, N(R9)2, C(=O)N(R9)2l OC(=O)N(R9)2, NR9OH, C(=O)R9, C(=0)0R9, 0C(=0)R9,
S-R9, or S(=0)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo,
C(=O)OH, C(=O)halo, OC(=0)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R10)2,
C(=O)N(R10)2, OC(=O)N(R10)2, NR10OH, C(=O)H, C(=O)R10, C(=0)0R10, OC(=O)R10, or
S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A method for affecting melanocortin receptor function in a human or non- human mammal, comprising the step of administering the pharmaceutical composition of claim 2.
I
4. A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition of claim 2.
5. The method of claim 4, wherein the condition is selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight and cachexia.
6. A compound having the formula of structure II:
Figure imgf000110_0001
Il or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
W is aryl, cycloalkyl, alkyl, heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is OH, HN-C(NH2)=NH, -HN-C(N(OH)H)=NH,
-C(NH2)=NH, or -(CH2)y-N(R10)2;
V is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, or V is -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, Or -HC=CH-;
J is a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or -O-, wherein J is unsubstituted or optionally substituted with one or two R8 groups;
Q is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V when L3 is absent;
L1 is a bond, -(CH2Jy-. -HC=CH-, or -CH(NH2)CH2-, or -CH(NCH3C(=O))CH2-, wherein
-(CH2)y- is unsubstituted or optionally substituted with an alkyl group;
L2 is a bond, -(CH2)2-, -aryl-, -(CH2)Z-NH-, -(CH2)Z-N(alkyl)-, -(CH2)Z-C(=O)-NH-, or
-(CH2)z-C(=O)-N(alkyl)-;
L3 is absent, a bond, -(CH2)y-, -(CH2)y-NH-(CH2)y-, -(CH2)y-C(=OHCH2)y-, -(CH2)y-O-(CH2)y-, or -(CH2)y-S-(CH2)y-;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R4a and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R9, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=0)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R9)2, C(=O)N(R9)2, OC(=O)N(R9)2, NR9OH, C(=0)R9, C(=0)0R9, OC(=O)R9, S-R9, or S(=O)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R10)2, C(=O)N(R10)2, OC(=0)N(R10)2, NR10OH, C(=0)H, C(=O)R10, C(=0)0R10, OC(=O)R10, or S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
7. The compound of claim 6, wherein one or two of R1a, R1b, R2a, and R2b are alkyl and the remaining of R1a, R1b, R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen.
8. The compound of claim 6, wherein R2a is alkyl and R1a, R1b, and R2b are hydrogen.
9. The compound of claim 6, wherein R1a is alkyl and R1b, R2a, and R2b are hydrogen.
10. The compound of claim 6, wherein R3a and R3b come together to form an oxo group.
11. The compound of claim 6, wherein R4a and R4b come together to form an oxo group.
12. The compound of claim 6, wherein L2 is a bond, -(CH2)Z-, -phenyl-, -(CH2)ZNH-, -(CH2)zN(alkyl)-, -(CH2)2C(=O)NH-, or -(CH2)zC(=O)N(alkyl)-.
13. The compound of claim 6, wherein W is heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is HN-C(NH2)=NH, HN-C(N(OH)H)=NH, C(NH2)=NH, or (CH2)y-N(R10)2.
14. The compound of claim 13, wherein the heteroaryl group or the heterocycloalkyl group comprises at least one nitrogen atom.
15. The compound of claim 6, wherein W is -HN-C(NH2)=NH, -(CH2)y-N(R10)2, or a cyclic radical of the formula:
Figure imgf000112_0001
which cyclic radical is unsubstituted or optionally substituted with one or two R8 groups.
16. The compound of claim 6 wherein, W is alkyl and L2 is a bond.
17. The compound of claim 6, wherein V is -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, or -HC=CH- or a cyclic radical of the formula:
Figure imgf000112_0002
which cyclic radical is unsubstituted or optionally substituted with one or two R8 groups.
18. The compound of claim 6, wherein Q and J are independent aryl groups, or Q is two independent aryl groups linked by a bond, -CH2-, or -O-, or J is two independent aryl groups linked by a bond, -CH2-, or -O-, wherein Q and J are independently unsubstituted or optionally substituted with one or two R8 groups.
19. The compound of claim 6, wherein Q and J are independently a group of the formula:
Figure imgf000113_0001
Figure imgf000114_0001
which group is unsubstituted or optionally substituted with one or two R8 groups.
20. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.
21. A method for affecting melanocortin receptor function in a human or non- human mammal, comprising the step of administering the pharmaceutical composition of claim 20.
22. A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition of claim 20.
23. The method of claim 22, wherein the condition is selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight and cachexia.
24. A compound having the formula of structure III:
Figure imgf000114_0002
III or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W is aryl, cycloalkyl, alky!, heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is OH, HN-C(NH2)=NH, -HN-C(N(OH)H)=NH,
-C(NH2)=NH, or -(CH2)y-N(R10)2;
V is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, or V1 is -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, or -HC=CH-;
J is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V1 when L1 is absent;
Q is a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or -O-, wherein J is unsubstituted or optionally substituted with one or two R8 groups;
L1 is absent, a bond, -(CH2)y-, -(CH2)y-NH-(CH2)y-, -(CH2)y-C(=O)-(CH2)y-, -(CH2)y-O-(CH2)y-, or -(CH2)y-S-(CH2)y-;
L2 is a bond, -(CH2)Z-, -aryl-, -(CH2)Z-NH-, -(CH2)Z-N(alkyl)-, -(CH2)Z-C(=O)-NH-, or
-(CH2)2-C(=O)-N(alkyl)-;
L3 is a bond, -(CH2)y-, -HC=CH-, or -CH(NH2)CH2-, or -CH(NCH3C(=O))CH2-, wherein
-(CH2)y- is unsubstituted or optionally substituted with an alkyl group;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R4a and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
O-R9, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo),
N3, NO2, N(R9)2, C(=O)N(R9)2, OC(=O)N(R9)2, NR9OH, C(=0)R9, C(=0)0R9, OC(=O)R9,
S-R9, or S(=O)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo,
C(=O)OH, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R10)2,
C(=O)N(R10)2, OC(=O)N(R10)2, NR10OH, C(=O)H, C(=O)R10, C(=O)OR10, OC(=O)R10, or
S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
25. The compound of claim 24, wherein one or two of R1a, R1b, R2a, and R2b are alkyl and the remaining of R1a, R1b, R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen.
26. The compound of claim 24, wherein R2a is alkyl and R1a, R1b, and R2b are hydrogen.
27. The compound of claim 24, wherein R1a is alkyl and R1b, R2a, and R2b are hydrogen.
28. The compound of claim 24, wherein R3a and R3b come together to form an oxo group.
29. The compound of claim 24, wherein R4a and R4b come together to form an oxo group.
30. The compound of claim 24, wherein L2 is a bond, -(CH2)Z-, -phenyl-, -(CH2)ZNH-, -(CH2)2N(alkyl)-, -(CH2)ZC(=O)NH- , or -(CH2)zC(=O)N(alkyl)-.
31. The compound of claim 24, wherein W is heteroaryl or heterocycloalkyl, unsubstituted or optionally substituted with one or two R8 groups, or W is HN-C(NH2)=NH, HN-C(N(OH)H)=NH, C(NH2)=NH, or (CH2)y-N(R10)2.
32. The compound of claim 31 , wherein the heteroaryl group or the heterocycloalkyl group comprises at least one nitrogen atom.
33. The compound of claim 24, wherein W is -HN-C(NH2)=NH, - (CH2)y-N(R10)2, or a cyclic radical of the formula:
Figure imgf000116_0001
which cyclic radical is unsubstituted or optionally substituted with one or two R8 groups.
34. The compound of claim 24 wherein, W is alkyl and L2 is a bond.
35. The compound of claim 24, wherein V is -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, or-HC=CH- or a cyclic radical of the formula:
Figure imgf000117_0001
which cyclic radical is unsubstituted or optionally substituted with one or two R8 groups.
36. The compound of claim 24, wherein Q and J are independent aryl groups, or Q is two independent aryl groups linked by a bond, -CH2-, or -O-, or J is two independent aryl groups linked by a bond, -CH2-, or -O-, wherein Q and J are independently unsubstituted or optionally substituted with one or two R8 groups.
37. The compound of claim 24, wherein Q and J are independently a group of the formula:
Figure imgf000117_0002
Figure imgf000118_0001
which group is unsubstituted or optionally substituted with one or two R8 groups.
38. A pharmaceutical composition comprising a compound of claim 24 and a pharmaceutically acceptable carrier.
39. A method for affecting melanocortin receptor function in a human or non- human mammal, comprising the step of administering the pharmaceutical composition of claim 38.
40. A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition of claim 38.
41. The method of claim 40, wherein the condition is selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight and cachexia.
42. A compound having the formula of structure IV:
Figure imgf000119_0001
IV or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
V is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, or V is -(CH2V. -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2V. or -HC=CH-;
J is a cyclic radical or two cyclic radicals linked by a bond, -CH2-, or -O-, wherein J is unsubstituted or optionally substituted with one or two R8 groups;
Q is a cyclic radical, which is unsubstituted or optionally substituted with one or two R8 groups, wherein Q may optionally be fused to V when L3 is absent;
L1 is a bond, -(CH2V, -HC=CH-, or -CH(NH2)CH2-, or -CH(NCH3C(=O))CH2-, wherein -
(CH2V 's unsubstituted or optionally substituted with an alkyl group;
R3a and R3b are both H or R3a and R3b come together to form an oxo group;
R4a and R4b are both H or R4a and R4b come together to form an oxo group; one or two of R1a, R1b, R2a, and R2b are alkyl or alkylcycloalkyl and the remaining of R1a, R1b,
R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen; each occurrence of R8 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl,
O-R9, CN, OH, oxo, halo, C(=O)OH, C(=O)halo, OC(=O)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R9)2, C(=O)N(R9)2, OC(=O)N(R9)2, NR9OH, C(=O)R9, C(=O)OR9, OC(=O)R9,
S-R9, or S(=O)2R10; each occurrence of R9 is independently H, alkyl, alkenyl, alkynyl, aryl, alkyl-O-alkyl, alkyl-NH- alkyl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylcycloalkyl, O-R10, CN, OH, oxo, halo,
C(=O)OH, C(=O)halo, OC(=0)halo, C(halo)3, CH(halo)2, CH2(halo), N3, NO2, N(R10)2,
C(=O)N(R10)2, OC(=O)N(R10)2, NR10OH, C(=0)H, C(=O)R10, C(=O)OR10, OC(=O)R10, or
S-R10; each occurrence of R10 is independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl; each occurrence of z is an independent integer from 1 to 6; and each occurrence of y is an independent integer from O to 5.
43. The compound of claim 41, wherein one or two of R1a, R1b, R2a, and R2b are alkyl and the remaining of R1a, R1b, R2a, and R2b are hydrogen, provided that at least one of R1a and R1b and at least one of R2a and R2b are hydrogen.
44. The compound of claim 41, wherein R2a is alkyl and R1a, R1b, and R2b are hydrogen.
45. The compound of claim 41, wherein R1a is alkyl and R1b, R2a, and R2b are hydrogen.
46. The compound of claim 41 , wherein R3a and R3b come together to form an oxo group.
47. The compound of claim 41 , wherein R4a and R4b come together to form an oxo group.
48. the compound of claim 41 , wherein V is -(CH2)y-, -CH(NH2)CH2-, -CH(NCH3C(=O))CH2-, -NH(CH2)y-, or -HC=CH-.
49. The compound of claim 41, wherein Q and J are independent aryl groups, or Q is two independent aryl groups linked by a bond, -CH2-, or -0-, or J is two independent aryl groups linked by a bond, -CH2-, or -0-, wherein Q and J are independently unsubstituted or optionally substituted with one or two R8 groups.
50. The compound of claim 41 , wherein Q and J are independently a group of the formula:
Figure imgf000121_0001
Figure imgf000122_0001
which group is un substituted or optionally substituted with one or two R8 groups.
51. A pharmaceutical composition comprising a compound of claim 41 , and a pharmaceutically acceptable carrier.
52. A method for affecting melanocortin receptor function in a human or non- human mammal, comprising the step of administering the pharmaceutical composition of claim 51.
53. A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering the pharmaceutical composition of claim 51.
54. The method of claim 53, wherein the condition is selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight and cachexia.
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