WO2010096854A1 - Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors - Google Patents

Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors Download PDF

Info

Publication number
WO2010096854A1
WO2010096854A1 PCT/AU2009/000229 AU2009000229W WO2010096854A1 WO 2010096854 A1 WO2010096854 A1 WO 2010096854A1 AU 2009000229 W AU2009000229 W AU 2009000229W WO 2010096854 A1 WO2010096854 A1 WO 2010096854A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
diazepan
oxo
optionally substituted
group
Prior art date
Application number
PCT/AU2009/000229
Other languages
French (fr)
Inventor
Mark Arnold Thomas Blaskovich
Peter Joseph Cassidy
Original Assignee
Mimetica Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mimetica Pty Ltd filed Critical Mimetica Pty Ltd
Priority to PCT/AU2009/000229 priority Critical patent/WO2010096854A1/en
Publication of WO2010096854A1 publication Critical patent/WO2010096854A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to methods of modulating the activity of a receptor selected from the group consisting of the melanocortin-3 receptor and the melanocortin-4 receptor.
  • the present invention relates to the use of a family of 1 ,4-diazepan-2- ones and derivatives thereof to modulate the activity of the melanocortin-3 and / or melanocortin-4 receptors.
  • the invention also relates to methods and uses of the compounds in the treatment of conditions in which agonism or antagonism of the melanocortin-3 and / or melanocortin-4 receptors is beneficial.
  • the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are G- protein coupled receptors (GPCRs) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been isolated and cloned to date: MC1 R, MC2R, MC3R, MC4R and MC5R.
  • the melanocortin receptors participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down-regulation) of melanocortin receptor signalling activity.
  • the melanocortin receptor family members are regulated by natural peptide agonists such as adrenocorticotropic hormone (ACTH) and the melanocyte stimulating hormones ( ⁇ -, ⁇ -, ⁇ -
  • MSH derived from proopiomelanocortin (POMC), and by peptide antagonists such as Agouti signal protein (ASP) and Agouti-related peptide (AGRP).
  • POMC proopiomelanocortin
  • ASP Agouti signal protein
  • AGRP Agouti-related peptide
  • the MC1 R is widely expressed and is associated with pigmentation in melanocytes and with inflammation responses in many cells involved in the immune system.
  • the MC2R differs from the other melanocortin receptors in that it binds only ACTH but not MSH ligands. It is highly expressed in the adenal gland and controls corticosteroid synthesis.
  • the MC3R is found in the brain, but also elsewhere in the body, and appears to play a role in the regulation of energy homeostasis, and possibly sexual dysfunction.
  • the MC4R is found almost exclusively in the brain, with some reports of its presence elsewhere. It has been strongly associated with feeding control, and also implicated with sexual desire.
  • the MC5R is widely expressed in peripheral tissues, particularly in the exocrine glands, with some receptor also expressed in the brain.
  • MC3R (Gantz 1993a) and MC4R (Gantz 1993b) were first cloned and expressed from humans in 1993. Both MC3R and MC4R play a role in regulating energy balance and food intake (Adan 2006, Bertile 2006, Butler 2006, Emmerson 2007, Foster 2007, Lam 2007,
  • MC4R knockout mice are obese and suffer from hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar 1997). Genetic studies strongly associate MC4R sequence variants with obesity (Thorleifsson 2009, Wilier 2009). MC3R knockout mice have increased fat mass and reduced lean body mass (Chen
  • mice lacking both MC3R and MC4R become more obese than mice lacking only MC4R (Chen 2000).
  • MC3R and MC4R have also been associated with sexual dysfunction, particularly in the control of penile erection (Wessells 2005, King 2007, Shadiach 2007, Wikberg 2008).
  • PT-141 bremelanotide
  • ⁇ -MSH shows immunosuppressive effects in humans, suppressing a variety of inflammation responses, and both MC3R and MC4R have been implicated in these immunomodulating activities (Catania 2004, Lasaga 2008, Getting
  • MC4R has also been linked to depression and anxiety disorders (Chaki
  • peptides e.g. Holder 2002, Holder 2003
  • peptide derivatives e.g. Mutulis
  • Therapeutic regulation of biological signal transduction includes modulation of MC3R- and / or MC4R- mediated cellular events including, inter alia, inhibition or potentiation of interactions among MC3R- and / or MC4R- binding and activating or deactivating molecules, or of other agents that regulate MC3R and / or MC4R activities.
  • An increased ability to so regulate MC3R and / or MC4R may facilitate the development of methods for modulating receptor signalling or other biological processes, and for treating conditions associated with such pathways such as obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the present invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof comprising exposing the receptor or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):
  • Y is a group of formula -(CR 9 9 IR-)1 ⁇ 0 ⁇ N) n -;
  • R is an amino acid side chain group
  • R 1 is selected from the group consisting of H, optionally substituted C-rC 12 alkyl, optionally substituted CH 2 (C 6 -C 18 aryl) optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted CrC 12 heteroalkyl, optionally substituted C 3 - Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci ⁇ heteroaryl;
  • R 2 and R 3 are each independently selected from the group consisting of H, optionally substituted d-C ⁇ alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -
  • Ci 2 alkynyl optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted CrCisheteroaryl, or
  • R 5a , R 5b and R 6 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted CrCi 2 heteroalkyl, optionally substituted Ci-Ci 0 heteroalkenyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted
  • Ci ⁇ heteroaryl optionally substituted amino, optionally substituted carboxy, optionally substituted carboxamide, optionally substituted Ci-Ci 2 alkyloxy, and optionally substituted thio;
  • each R 9 and R 10 is independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci- Ci ⁇ heteroaryl;
  • each R 11 and R 12 is independently selected from the group consisting of H, and optionally substituted CrC 12 alkyl;
  • n is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • r is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
  • s is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
  • the receptor or fragment or analogue or functional equivalent thereof is in a cell and the method comprises exposing the cell to a compound of formula (I).
  • the invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal comprising administering a MC3R- and / or MC4R -modulating amount of a compound of the invention to the mammal.
  • the invention provides the use of a compound of the formula (I) in modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC3R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC4R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of both MC3R and MC4R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides a method of preventing or treating a condition associated with the activity of a receptor selected from the group consisting of
  • MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula
  • the compound may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the invention provides for the use of a compound of formula (I) in the preparation of a medicament for preventing or treating a condition associated with the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal.
  • a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal.
  • the medicament is adapted to be administered topically.
  • the medicament is adapted to be administered orally.
  • the compound is administered parenterally.
  • the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the term "optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups.
  • R a , R b , R c and R d are each independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C 1 -C 1 0 heteroalkyl, C 3 -Ci 2 cycloalkyl, C 3 -Ci 2 cycloalkenyl, C r Ci 2 heterocycloalkyl, C r Ci 2 heterocycloalkenyl, C 6 -Ci 8 aryl, Ci-Ci ⁇ heteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
  • Examples of particularly suitable optional substituents include F, Cl, Br, I, CH 3 , CH 2 CH 3 , OH, OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , and CN.
  • amino acid side chain group represents a natural or unnatural side chain group present in a protein.
  • the term includes side chain moieties present in naturally occurring proteins including the naturally occurring amino acid side chain moieties identified in table 1 below.
  • the term also includes derivatives or analogs thereof.
  • derivative or analogue of an amino acid side chain group includes modifications and variations to naturally occurring side chain groups. With reference to the table above most of the naturally occurring amino acid side chain groups may be classified as alkyl, aryl, arylalkyl or heteroalkyl moieties. As such derivatives of amino acid side chain groups include straight or branched, cyclic or non-cyclic alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl or heteroalkyl moieties.
  • Amino acid side chain groups as discussed above also include optionally substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heteroalkyl moieties.
  • the optional substituents may be selected from the group defined above.
  • the optional substituents may be selected from but are not limited to OH, Cl, Br, F, COOH, C00R z , CONH 2 , NH 2 , NHR Z , NR Z R Z , SH, SR Z , SO 2 R 2 , SO 2 H and SOR Z wherein R z is an alkyl, aryl or arylalkyl moiety.
  • the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • a modifier indicating the number of carbon atoms present in the moiety.
  • the modifier “CrC 6 " in front of the term “alkyl” indicates that the alkyl moiety has from 1 to 6 carbon atoms.
  • the modifier “C 1 -C- I s" in front of the term “heteroaryl” indicates that the heteroaromatic ring may have from 1 to 18 carbon atoms as part of the total number of atoms in the ring system.
  • examples of acyl include acetyl and benzoyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2- 6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C 1 -C 6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 14 alkyl, more preferably a C 1 -C 10 alkyl, most preferably CrC 6 unless otherwise noted.
  • suitable straight and branched CrC 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • “Mono-alkylamino” means a Alkyl-NH- group, in which alkyl is as defined herein.
  • “Dialkylamino” means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a CrC 6 alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
  • the alkyloxy is a C-i-C ⁇ alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Alkyloxyary refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
  • Alkyloxyheteroary refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
  • Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the alkyl group is preferably a CrC 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C 6 -C 18 aryl group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
  • exemplary arylalkenyl groups include phenylallyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci -5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Aryloxy refers to an aryl-O- group in which the aryl is as defined herein.
  • the aryloxy is a C 6 -Ci 8 aryloxy, more preferably a C 6 -Ci 0 aryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond.
  • Cyclic group refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system.
  • Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • the group may be a terminal group or a bridging group.
  • Cycloalkyl refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
  • the cycloalkyloxy is a CrC ⁇ cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
  • the group may be a terminal group or a bridging group.
  • the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
  • the cycloalkenyloxy is a Ci-C ⁇ cycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Haloalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • a haloalkyl group typically has the formula C n H (2n+ i- m) X m wherein each X is independently selected from the group consisting of F, Cl, Br and I.
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • m is typically 1 to 6, more preferably 1 to 3.
  • Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • the group may be a terminal group or a bridging group.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, pheno
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein.
  • the heteroaryloxy is a Ci-Ci 2 heteroaryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
  • heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
  • Heterocycloalkenyl refers to a heterocycloalkyl as defined herein but containing at least one double bond.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkyl refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
  • the heterocycloalkyloxy is a Cr C 6 heterocycloalkyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
  • the heterocycloalkenyloxy is a C 1 -C 6 heterocycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
  • a hydroxyalkyl group typically has the formula C n H( 2n +i- x )(OH) x
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • x is typically 1 to 6, more preferably 1 to 3.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the group may be a terminal group or a bridging group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms have the same atomic number as, but an atomic mass or mass number different from, the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • Prodrug means a compound that undergoes conversion to a compound of formula
  • an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by FJ. Leinweber, Drug Metab. Res., 18:379, 1987.
  • an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule.
  • prodrugs for these and other functional groups, including amines are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R.Oliyai, H. Maag and J Tilley; Springer, 2007).
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the term "functional equivalent” is intended to include variants of the specific receptor described herein. It will be understood that receptors may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given receptor isoform is different to the prototypical receptor; the molecule maintains biological activity as a receptor. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription.
  • R 1 , R 2 , R 3 , R 5a , R 5b , R 6 , X, Y and r are as defined above,
  • Z is a group of formula -(CR 13 R 14 ) q -;
  • R 4b is selected from the group consisting of H, optionally substituted CrCi 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
  • R 4a and R 4b when taken together with any R 13 or R 14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety
  • R 13 and R 14 are each independently selected from the group consisting of H, halogen, OH, Ci-Ci 2 alkyl, C 6 -Ci 8 aryl, Ci-Ci 2 hydroxyalkyl, Ci-Ci 2 haloalkyl, Ci-Ci 2 alkyloxy and d- Ci 2 haloalkyloxy, or when taken together with the carbon to which they are attached R 13 and R 14 form an optionally substituted C 3 -Ci 2 cycloalkyl, or an optionally substituted Ci-Ci 2 heterocycloalkyl group, or
  • R 13 and R 14 when taken together with one of R 4a , and R 4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
  • R 13 and R 14 when taken together with one of R 15 , R 16 , R 17 , R 18 , R 19 or R 20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
  • each R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 is independently selected from the group consisting of H, optionally substituted d-Ci 2 alkyl, optionally substituted C 1 -
  • Ci 2 heteroalkyl optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl, or
  • R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
  • R 15 , R 16 , R 17 , R 18 , R 19 and R 20 when taken together with one of R 13 and R 14 and the atoms to w Vhi IiicOhI i t Uh iet/y y a ⁇ rieG a ⁇ tut ⁇ ac ⁇ ihed f iouri m i n a ⁇ in i s ouuubostuitiuutiuedu c oyycoliiico
  • q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
  • a particularly useful subset of compounds of formula (I) are compounds where Y is a group of the formula -(CR 9 R 10 X 1 -.
  • n is 1 and Y is -CR 9 R 10 -.
  • n is 2 and Y is -CR 9 R 10 CR 9 R 10 -.
  • each R 9 and R 10 is independently selected from H and CH 3 .
  • R 9 and R 10 are both H.
  • Y is -CH 2 -.
  • Y is - CH 2 CH 2 -.
  • Y is -C(CHs) 2 -.
  • R 2 is H or C-i-C ⁇ alkyl. In a specific embodiment R 2 is H.
  • R 3 is H or CrC 6 alkyl. In a specific embodiment R 3 is H.
  • This provides compounds of formula (Ib).
  • R 1 , R 4 , R 5a , R 5b , R 6 , Z and r are as defined above.
  • R 4 is selected from the group consisting of H, Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, C 3 -
  • Ci 2 cycloalkyl optionally substituted C 6 -Ci 8 aryl, optionally substituted C-linked d-
  • R 4 is optionally substituted Ci-Ci ⁇ heteroaryl. In another embodiment R 4 is optionally substituted C 3 -Ci 2 cycloalkyl. In another embodiment R 4 is Cr Ci 2 alkyl
  • R 15 and R 16 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, azepan-1-yl, morpholin-4-yl, and piperazin-1-yl.
  • R 16 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • R 17 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • r is selected from the group consisting of 0, 1 , 2, 3, and 4. In one specific embodiment r is 0. In another specific embodiment r is 1. In yet a further specific embodiment r is 2. In yet a further specific embodiment r is 3. In an even further specific embodiment r is 4.
  • Z is a group of formula -(CR 13 R 14 ) q -.
  • R 13 and R 14 are independently selected from H and C 1 -C 6 alkyl.
  • R 13 and R 14 are each independently selected from H and CH 3 .
  • R 13 and R 14 are both H.
  • at least one of R 13 and R 14 when taken together with at least one of R 4a and R 4b and the atoms to which they are attached form an optionally substituted heterocycloalkyl group.
  • Z is -(CH 2 ) q -
  • q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5. In one specific embodiment q is 1. In another specific embodiment q is 2, in yet an even further specific embodiment q is 3, and in yet an even further specific embodiment q is 4.
  • R 4b is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group, an optionally substituted C 2 -Ci 2 heterocycloalkenyl group or an optionally substituted Ci-Ci 8 heteroaryl group.
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azepan-1-yl, azetidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
  • the compound of formula (I) is one in which one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group.
  • one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, and piperazinyl.
  • the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5R), as in formula (Id):
  • R 1 , R 4a , R 4b , R 5a , R 5b , R 6 , and Z are as defined for formula (Ic).
  • the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5S), as in formula (Ie):
  • R 1 , R 4a , R 4b , R 5a , R 5b , R 6 , A and Z are as defined for formula (Ic).
  • R 1 is selected from the group consisting of an optionally substituted amino acid, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl, optionally substituted CH 2 (C 6 - Ci 8 aryl), and optionally substituted Ci-Ci 8 heteroaryl.
  • R 1 - X is an optionally substituted amino acid.
  • R 1 is optionally substituted C 6 -C 18 aryl.
  • the C 6 -C 18 aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C 6 -C 18 aryl is a monocyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a bicyclic moiety.
  • R 1 is optionally substituted CH 2 (C 6 -Ci 8 aryl).
  • the C 6 -Ci 8 aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C6-Ci 8 aryl is a monocyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a bicyclic moiety.
  • R 1 is an optionally substituted C 6 -Ci 8 aryl selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl.
  • R 1 is an optionally substituted CH 2 (C 6 -Ci 8 aryl) with the aryl group selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl.
  • the moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above.
  • Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl.
  • substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
  • suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
  • R 1 is optionally substituted biphenyl
  • the point of attachment of R 1 to the remainder of the molecule may be at the 2-, 3- or 4- position relative to the point of attachment of the second phenyl ring.
  • the biphenyl may be an optionally substituted biphen-2-yl, or an optionally substituted biphen-3-yl, or an optionally substituted biphen-4-yl.
  • the optionally substituted biphenyl is an optionally substituted biphen-4-yl.
  • the optionally substituted biphenyl may be substituted in any suitable position.
  • R 1 is optionally substituted naphthyl
  • the point of attachment of R 1 to the remainder of the molecule may be at the 1 or 2 position.
  • the naphthyl may be an optionally substituted naphth-1-yl, or an optionally substituted naphth-2-yl.
  • the optionally substituted naphthyl is an optionally substituted naphth-2-yl.
  • the optionally substituted naphthyl may be substituted in any suitable position.
  • Suitable optionally substituted naphth-2-yls include, but are not limited to, 6-fluoro-naphth-2-yl, 6- bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 6- methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and 6-amino-naphth-2-yl.
  • R 1 is optionally substituted Ci-Ci 8 heteroaryl.
  • the Ci-Ci 8 heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the Ci-Ci 8 heteroaryl is a monocyclic moiety. In certain embodiments the Ci-C-isheteroaryl is a bicyclic moiety.
  • heteroaryl moieties include, but are not limited to, indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3- yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophen-2-yl. These may also be optionally substituted as discussed above.
  • R 1 is an optionally substituted C 2 -C 12 alkenyl.
  • the optionally substituted alkenyl may contain one or more double bonds with each of the double bonds being independently in the E or Z configuration.
  • the alkenyl contains a single double bond which is in the E configuration.
  • R 1 is an optionally substituted C 2 -Ci 2 alkenyl of the formula:
  • R is selected from the group consisting of H, halogen and optionally substituted d- Ci 2 alkyl;
  • R 1b and R 1c are each independently selected from the group consisting of H, halogen, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl.
  • R 1a is H. In one form of this embodiment R 1b is H. This provides compounds where R 1 is of the formula:
  • R 1c is optionally substituted Ce- Ci 8 aryl.
  • the C 6 -Ci 8 aryl may be monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C 6 -C 18 aryl is a monocyclic moiety. In certain embodiments the C 6 -C 18 aryl is a bicyclic moiety.
  • R 1c is an optionally substituted C 6 -C 18 aryl selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl.
  • the moieties may be unsubstituted or may be substituted with one or more optional substituents.
  • a wide variety of optional substituents may be used as defined above.
  • Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol- 1-yl, and 3,5-dimethyl-pyrazol-1-yl.
  • substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
  • suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
  • R 5a and R 5b are independently selected from H and CrC 6 alkyl. In one embodiment R 5a and R 5b are each independently selected from H and CH 3 . In one specific embodiment R 5a and R 5b are both H. In one embodiment of the compounds suitable for use in the invention R 6 is an optiona allllyy ssuubbssttiittuutteedd aallkkyyll group. In one embodiment invention R 6 is an optionally substituted alkyl group of the formula:
  • R is H.
  • R 6a and R 6c are each independently selected from the group consisting of H, optionally substituted CrC 12 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
  • R 6a and R 6c are each independently selected from the group consisting of optionally substituted CrC 12 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
  • R 6a is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C 1 -C 5 heteroaryl.
  • R 6a is optionally substituted phenyl or optionally substituted C 1 - C 18 heteroaryl.
  • R 6c is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C 1 -C 5 heteroaryl.
  • R 6c is methyl, ethyl, phenyl or optionally substituted C 1 -C 5 heteroaryl.
  • r is 1
  • R ,5a is H
  • R 5b is selected from the group consisting of optionally substituted carboxy and optionally substituted carboxamide.
  • R 6 is selected from the group consisting of H, optionally substituted d-C ⁇ alkyl, optionally C 6 -Ci 8 aryl, or optionally substituted d- Ci ⁇ heteroaryl.
  • the optionally substituted alky group is selected from the group consisting of an optionally substituted CH 2 (C 6 -C 18 aryl) group and an optionally substituted CH 2 (C 1 -C 18 heteroaryl) group.
  • the compounds of formula (I) are modulators of the MC3R and / or MC4R and therefore may be used to modulate the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof by exposing MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof to a compound of the invention.
  • This can occur in vitro in assays where the modulation of MC3R and / or MC4R activity is desirable, however it is typically more beneficial when utilised in modulation of MC3R and / or MC4R activity in a patient.
  • the amount of modulation provided by the compounds of the invention will vary from compound to compound and will also be affected by the amount of compound administered.
  • the modulation can consist of upregulation or downregulation. In one embodiment the amount of upregulation or downregulation is at least 10%. In another embodiment the amount of upregulation or downregulation is at least 20%. In an even further embodiment the amount of upregulation or downregulation is at least 50%
  • the methods of the present invention may be used in the treatment of any condition in which modulation of the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof would lead to a beneficial effect on that condition.
  • the compounds suitable for use in the present invention may be used in methods of preventing or treating a condition associated either directly or indirectly with the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof in a mammal wherein an MC3R and / or MC4R modulating amount of the compound of the invention is administered to the mammal.
  • One condition associated with MC3R and / or MC4R activity is metabolic syndromes and conditions related thereto.
  • the condition is selected from the group consisting of obesity, eating disorders, and diabetes.
  • the eating disorder is selected from the group consisting of cachexia, anorexia, weight gain and weight loss.
  • the condition is Type Il diabetes.
  • Another condition associated with MC3R and / or MC4R activity is sexual dysfunction.
  • the sexual dysfunction is selected from the group consisting of erectile dysfunction and female sexual dysfunction.
  • the condition is erectile dysfunction.
  • the modulation of MC3R and / or MC4R may involve upregulation or downregulation. For example, downregulation of MC4R leads to increased food intake and weight gain and can thus be used in the treatment of cachexia.
  • upregulation of MC4R leads to weight loss and can thus be used in the treatment of obesity.
  • upregulation of MC4R leads penile erection and can thus be used in the treatment of erectile dysfucntion.
  • the methods of the invention may also be useful in prevention or treatment of a number of conditions that relate to biological processes controlled by MC3R and / or MC4R, such as diseases related to inflammation, depression, anxiety and addiction.
  • the compounds of formula (I) may also find application in treatments where reduced weight is desirable such as in dieting.
  • the compounds may thus be used in methods of reducing the weight a mammal, the method comprising administering an effective amount of a compound of formula (I).
  • the compounds of formula (I) may be used in the treatment of conditions in any species in which MC3R and / or MC4R is present, most typically mammals.
  • Examples of species in which MC3R and / or MC4R are found and hence species in which the compounds may be used include humans, rats, mice, dogs, and rhesus monkey.
  • the mammal is a human.
  • Administration of compounds within Formula (I) to a patient such as humans can be by topical administration, by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the compounds of formula (I) can be administered in any form or mode which makes the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
  • the compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of formula (I) while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • compositions which are formulated depending on the desired mode of administration.
  • compositions are prepared in manners well known in the art.
  • a compound of formula (I) is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the invention, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition.
  • Representative dosage forms will generally contain between from about 1 mg to about 500 mg of a compound of the invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • Compounds of the present invention may also be formulated for topical delivery in formulations such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches.
  • these topical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of a compound of the invention.
  • the compounds of formula (I) may be used or administered in combination with one or more additional drug (s), either concurrently or sequentionally.
  • the compounds of the present invention may be used in combination with one or more other pharmaceutically-active compounds, such as other metabolism altering, sexual dysfunction, anti-inflammatory, antianxiety, or antiaddiction medications. These components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
  • compositions suitable for use in the invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and non aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • the active agent may be in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle.
  • a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • compositions used for topical administration typically contain a pharmaceutically acceptable carrier which may be any vehicle that is toxicologically and pharmaceutically acceptable.
  • Typical pharmaceutically acceptable carriers that can be used in compositions of the present invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propylene glycol, polyethlyene glycol, fragrances, gel-producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, "Tweens," sorbitol, methyl cellulose, petrolatum, a mineral oil (vaseline oil), which may be any petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil, pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peach kernel oil, poppy
  • compositions for topical administration may be formulated in numerous forms. However, the composition may often take the form of an aqueous or oily solution or dispersion or emulsion or a gel or a cream.
  • An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • the oil phase of water-in-oil or oil-in-water emulsions may comprise for example: a) hydrocarbon oils such as paraffin or mineral oils; b) waxes such as beeswax or paraffin wax; c) natural oils such as sunflower oil, apricot kernel oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esters such as isopropyl palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such as cetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearyl alcohol); g) polypropylene glycol or polyethylene glycol ethers, eg PPG-14 butyl ether; or h) mixtures thereof.
  • hydrocarbon oils such as paraffin or
  • Emulsifiers used may be any emulsifiers known in the art for use in water-in-oil or oil- in-water emulsions.
  • Known cosmetically acceptable emulsifiers include: a) sesquioleates such as sorbitan sesquioleate, available commercially for example under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of derivatives of natural oils such as the polyethoxylated ester of hydrogenated castor oil available commercially for example under the trade name Arlacel 989 (ICI); c) silicone emulsifiers such as silicone polyols available commercially for example under the trade name ABIL WS08 (Th.
  • emulsifiers such as fatty acid soaps e.g. potassium stearate and fatty acid sulphates e.g. sodium cetostearyl sulphate available commercially under the trade name Dehydag (Henkel); e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); f) sorbitan esters, for example the emulsifiers available commercially under the trade name Span (ICI); g) ethoxylated sorbitan esters, for example the emulsifiers available commercially under the trade name Tween (ICI); h) ethoxylated fatty acid esters such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); i) ethoxylated mono-, di-, and triglycerides, for example the
  • Gels for topical administration may be aqueous or non-aqueous. Aqueous gels are preferred.
  • the gel will contain a thickening agent or gelling agent in order to give sufficient viscosity to the gel.
  • a variety of thickening agents may be used according to the nature of the liquid carrier and the viscosity required and these are recited hereinafter.
  • a particularly suitable thickener is a copolymer of acryloyl dimethyl tauric acid (or a salt thereof), preferably a copolymer of that monomer with another vinylic monomer.
  • the thickening agent is a copolymer of a salt of acryloyl dimethyl tauric acid with another vinylic monomer.
  • the salt may be a salt of a Group I alkali metal, but is more preferably an ammonium salt.
  • suitable copolymer thickening agents are: i) Ammonium acryloyl dimethyl taurate I vinyl pyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyl taurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).
  • composition may additionally comprise other components which will be well known to those skilled in the art such as emollients, humectants, emulsion stabilising salts, preservatives, chelating agents or sequestering agents (sequestrants), abrasives, antioxidants, stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumes and colourings.
  • the topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the amount of compound administered will preferably treat and reduce or alleviate the condition.
  • a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • the resulting secondary amine is acylated under standard peptide coupling conditions with the protected amino acid, P 2 -NHCH(U)-CO 2 H, where U represents either the final R side chain, a protected final side chain R-P 3 , or a precursor that requires chemical modification to form the final R side chain.
  • the ring system is generated by deprotection of the P 4 and P 5 protecting groups, followed by amide bond formation using standard peptide coupling reagents.
  • the P 4 protecting group is removed and cyclization achieved by thermal or base-induced cyclization with the P 5 - protected ester.
  • the cyclization produces a mixture of two diastereomers, A and B, from which the preferred diastereomers A can be separated by chromatography.
  • R 5a R 5b W ⁇ J, ⁇ r R 6
  • HPLC analyses were carried out on an Agilent 1100 Series Purification System with a Phenomenex Synergi 4 ⁇ Max-RP 8OA, 50 x 2.00 mm analytical HPLC column, with peak detection by UV.
  • the standard analysis employed a 1 mL/min flow rate of 0.05% trifluoroacetic acid (TFA) in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water
  • the organic phase is then washed with 1 N HCI (3 x 100 ml_), H 2 O (3 x 100 ml_), saturated NaHCO 3 aqueous solution (3 x 100 ml.) and brine (1 x 10 ml_).
  • the organic phase is then dried (MgSO 4 ) and the EtOAc removed to give the Weinreb amide (2) as a white solid or an oil.
  • HCI 200 ml_
  • the aqueous mixture is extracted with DCM (3x 100 ml.) and the organic layers combined and washed with 1 M HCI (2x 200 ml.) and H 2 O (3x 100 ml_).
  • the organic phase is dried (MgSO 4 ) to provide a solution of the ⁇ , ⁇ -unsaturated ketone (3).
  • the ⁇ , ⁇ - unsaturated ketone (3) may be isolated by rotary evaporation or it may be used in solution without further purification. If the intention is to use the ⁇ , ⁇ -unsaturated ketone (3) in solution the volume is reduced to 100 ml. by rotary evaporation and stored for later use.
  • the DIC may be replaced with HATU (15 mmol) and DIPEA (15 mmol).
  • the reaction is stirred at room temperature overnight.
  • the DCM is removed by rotary evaporation and the residue is taken up in EtOAc (100 ml_).
  • the organic layer is washed with saturated sodium bicarbonate solution (2 x 100 ml_), saturated ammonium chloride solution (2 x 100 ml.) and brine (2 x 100 ml_).
  • the organic phase is dried and the solvent removed under reduced pressure.
  • the residue is subjected to column chromatography on silica gel using petroleum ethe ⁇ EtOAc to give 5.
  • Example 5 General Procedure - P 2 Deprotection and Cyclization
  • the procedure adopted for the removal of the P 2 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
  • P 2 Fmoc: To compound 5 (2 mmol) in DCM (3 ml.) is added diethylamine (20 mmol). The reaction is stirred at room temperature for 1 hr. The DCM and diethylamine is then removed by rotary evaporation. DCM (5 ml.) and sodium triacetoxyborohydride (3 mmol) are then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO 4 ) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.
  • the procedure adopted for the removal of the P1 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
  • the reaction mixture is stirred at room temperature for 1.5 hrs, after which DCM (20 ml.) is added, the organic layer washed with saturated sodium bicarbonate solution (20 ml.) and H 2 O (20 ml_), dried (MgSO 4 ) and evaporated.
  • the residue may be purified by preparative HPLC to give the piperidinyl product.
  • the purified product is isolated as the TFA salt, but is readily converted into the free base via neutralisation with aqueous NaHCOs and extraction into an organic solvent, or further converted into the HCI salt by acidification with 1 N HCI.
  • the amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 ml.) was cyclized by addition of NaBH(OAc)3 (40mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hrs, followed by addition of saturated NaHCO 3 aqueous solution (3 ml_). The aqueous layer was extracted with DCM (3 x 3 ml.) and the combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc then EtOAc/IPA (9:1 ) to give the desired product 13 as a white solid. It was used in the next step without further purification. MS (ESI) 807 (M+1 ); HPLC f R 7.75 min.
  • fe/t-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate 34 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 ml.) and TFA (3 ml.) were stirred at room temperature 1 hr. The solvent was removed under reduced pressure, followed by addition of
  • Example 36 Synthesis of Compound 104 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2- diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
  • Example 54 Synthesis of Compound 46 bis (Cbz) 1-(3-((2S,7RS)-7-((S)-1-amino-2- (naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1 ,4-diazepan-2-yl)propyl)guanidine
  • Examples 58-66 Synthesis via Scheme 2: Preparation of all Four Diastereomers of N- ((1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide 52
  • the Alloc/allyl protected derivative 56 (840 mg, 1.1 1 mmol) was dissolved in a minimum of DCM. 1 ,3-Dimethylbarbituric acid (346 mg, 2.22 mmol) and catalytic Pd(PPh 3 ) 4 were added, and the reaction degassed under vacuum, sealed and stirred overnight. The reaction was diluted to 50 ml. with DCM, DIPEA (430 mg, 3.33 mmol) and BOP (540 mg, 1.22 mmol) were added, and the reaction stirred for 30 min.
  • Example 64 Synthesis of Compounds 96 and 97 (3S,5R)-5-(N-Boc aminomethyl)-3-(N- Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one and (3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
  • Example 65 Synthesis of Compounds 62-65 5-(N-Boc aminomethyl)-3-(N,N'-Cbz 2 3- guanidinopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
  • frozen hMC3R and hMC4R plasma membranes were prepared as described below from transfected mammalian cells (prepared as in Example 76, using plasmid DNA containing the human MC3R or MC4R gene in a plasmid vector with a mammalian origin of replication.
  • the cell suspension was centrifuged again as previously and the pellet resuspended in 5 ml. of 0.25 M sucrose containing protease inhibitors.
  • the cells were homogenised by a 10 second pulse with an lka disperser followed by 30 seconds on ice. The homogenisation and ice incubation was repeated three times. The mixture was then centrifuged at 1260 x g for 5 mins. The supernatant was decanted into another centrifuge tube, to which a buffer containing 50 mM Tris, pH 7.4, 12,5 mM MgCI 2 , 5 mM EGTA and protease inhibitors was added to make the volume up to 30 ml_.
  • NDP-MSH radiolabeled in house and purified by HPLC:
  • Na 125 I (0.5 mCi, 17.4 Ci/mg) was added to 50 ⁇ l_ sodium phosphate (50 mM, pH 7.4) in an eppendorf tube precoated with IODOGEN. After incubation for 10 mins the phosphate buffer containing the iodine was added to NDP-MSH (10 ul at 1 mg/ml_) in a separate eppendorf tube. This was incubated for a further 10 mins. The iodinated NDP-MSH was purified by HPLC on a Zorbax SB 300 column using solvent A: 0.05% TFA and solvent B: 90% acetonitrile 0.045% TFA with a linear gradient, 0-67% B over 60 mins.
  • the 125 I NDP-MSH eluted at 52 mins after the unlabeled starting material (48 min) and was counted and stored in the freezer. It was used within 48 hrs, as radioactive decay and ligand decomposition resulted in greatly reduced specific binding observed after 72 hrs.
  • Incubation buffer 25 mM HEPES-KOH (pH 7.0), 1.5 mM CaCI 2 , 1 mM MgSO 4 , 0.1 M NaCI, 1 mM 1 ,10-phenanthroline, and 1 CompleteTM protease inhibitor tablet/100 mL (Roche, catalog number 1873580)
  • Perkin Elmer frozen hMC3 or hMC4 membranes catalog number RBXMC3M400UA / RBHMC4M400UA, 0.4 mL/vial; 400 microassays/vial, 0.78 mg/mL protein concentration
  • Vials of frozen membranes were thawed rapidly immediately before use, diluted with binding buffer and vortexed. Resuspended membranes were kept on ice until they were added to the wells of the plate.
  • ice-cold wash buffer (the above incubation buffer without 1 ,10- phenanthroline and CompleteTM protease inhibitor tablet).
  • the filters were dried in a 37 0 C oven, placed in a sample bag and 5 ml. Betaplatescint (Wallac) was added. Prepared filters were counted in cassettes in a Microbeta Trilux (Wallac) for 1 min. Non-specific binding just under 5%.
  • Representative compounds of the present invention were tested for binding in the hMC3R and hMC4R assays as in Example 74, as listed in Table 4. The compounds were tested as their trifluoroacetate or hydrochloride salts, or as their free base.
  • Example 76 Inhibition or stimulation of cAMP signal in cells expressing human MC4R Transient transfection of mammalian cell lines:
  • the mammalian cell line human embryonic kidney cells (HEK 293), were maintained in Dulbeccos Modified Eagle's medium (DMEM) with 5% fetal bovine serum, L- glutamine, high glucose and antibiotics/antimycotics.
  • DMEM Dulbeccos Modified Eagle's medium
  • cells were passaged using trypsin/EDTA and seeded into 75 cm 2 flasks so that they would be approximately 90% confluent the next day.
  • the next day, the cell media was replaced with fresh antibiotic/antimycotic-containing DMEM.
  • Approximately 100 ⁇ l of the transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA), was diluted in 1.0 ml.
  • OptiMEM serum and antibiotic/antimycotic-free OptiMEM in a sterile 15 ml. tube and incubated for 5 mins at room temperature. Following incubation, approximately 10-20 ⁇ g of plasmid DNA expressing the gene of interest (for example: Homo sapiens melanocortin 4 receptor) was diluted into the transfection mix and incubated for a further 30 mins at room temperature. The DNA/lipid solution was then added drop-wise to the media covering the cells while rocking the flask gently. 24 hrs post-transfection, the cells were passaged and seeded directly into two, 75cm 2 flasks and left to recover. 48 hrs post transfection, cells were harvested for use in assays with cell dissociation solution.
  • the gene of interest for example: Homo sapiens melanocortin 4 receptor
  • Cyclic-Adenosine Monophosphate [cAMP] stimulation assay HEK 293 cells transiently expressing the melanocortin MC4 receptor were suspended in stimulation buffer (Hanks buffered saline solution (HBSS), 0.1 % bovine serum albumin, protease inhibitors and 0.5 mM 3-lsobutyl-1 -methylxanthine) at 4 x 10 6 cells/mL. 5 ⁇ l of cells, plus the compounds/peptides as described below, were added to wells of a 384-well plate as soon as possible after resuspension.
  • stimulation buffer Hors buffered saline solution (HBSS), 0.1 % bovine serum albumin, protease inhibitors and 0.5 mM 3-lsobutyl-1 -methylxanthine
  • test compounds at varying concentrations were diluted in stimulation buffer at four times concentrate and 2.5 ⁇ l was added to wells containing cells. 2.5 ⁇ l of a four times required concentration of NDP-MSH or alpha-MSH was added to all wells containing compounds. Negative control wells contained two times concentrated NDP-MSH or alpha-MSH alone without compound. The concentration of NDP-MSH or alpha-MSH employed was calculated to give a response equivalent to approximately 60% of the maximal stimulation.
  • test compounds at varying concentrations were diluted in stimulation buffer at two times concentrate and 5 ⁇ l was added to wells containing cells.
  • Positive control wells contained NDP-MSH or alpha-MSH alone (no compound) at two times concentrate.
  • Basal level (of cAMP) control wells contained stimulation buffer only (no agonist or compounds).
  • Known concentrations of cAMP (standards) in stimulation buffer were included on the plate, but no cells were added to these wells. The plate was then incubated for 30 mins at 37 0 C with gentle shaking.
  • lysis buffer (10 % Tween 20, 1 M HEPES, 0.1 % BSA, protease inhibitors, ddH 2 O) was added to all wells to be measured. Detection of cAMP was then achieved using the Alphascreen cAMP kit (Perkin Elmer, USA), briefly described as follows. A dilution of 10 ⁇ l acceptor beads/mL of lysis buffer was prepared in low light conditions. 5 ⁇ l of diluted acceptor beads were added to each well to be measured, then the plate was incubated for 30 mins at room temperature, in the dark, with gentle shaking.
  • donor beads were diluted at 10 ⁇ l/mL of lysis buffer, to which 0.75 ⁇ l biotinylated cAMP/ml_ of lysis buffer was added. This mixture was allowed to incubate for 30 mins at room temperature (in the dark) before proceeding with the assay. Following incubation, 5 ⁇ l/mL of biotinylated cAMP/Donor bead mix were added per well in low light conditions and the plate was incubated in the dark, at room temperature, for a further hr. Plates were read on an Envision plate reader (Perkin Elmer) after 1 hr and ⁇ 16hrs incubation. cAMP concentration in the cells was determined by the use of a 'standard curve' generated from the output of known cAMP concentrations as described below.
  • Each assay plate contained a "standard curve" of known concentrations of cAMP, in
  • Antagonists for the Treatment of Depression and Anxiety Disorders Chen, A.S.; Marsh, DJ.; Trumbauer, M. E.; Frazier, E.G.; Guan, X.-M.; Yu, H.; Rosenblum, C. I.; Vongs, A.; Feng, Y.; Cao, L.; Metzger, J. M.; Strack, A.M.; Camacho, R. E.; MeIMn, T.N.; Nunes, C. N.; Min, W.; Fisher, J.; Gopal-Truter, S.; Maclntyre, D. E.; Chen, H.Y.; Van der Ploeg, L. HT.
  • M4R Receptor

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides compounds of Formula (I) that are useful for modulating the biological activity of the melanocortin-3 receptor (MC3R) and / or the melanocortin-4 receptor (MC4R). Compounds of this invention can be used to treat diseases and/or conditions in which modulation of MC3R and / or MC4R is beneficial. Such diseases and/or conditions include, but are not limited to, obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.

Description

METHODS OF MODULATING THE ACTIVITY OF THE MC3 AND/OR MC4 RECEPTORS AND TREATMENT OF CONDITIONS RELATED TO THESE RECEPTORS
FIELD OF THE INVENTION
The present invention relates to methods of modulating the activity of a receptor selected from the group consisting of the melanocortin-3 receptor and the melanocortin-4 receptor. In particular the present invention relates to the use of a family of 1 ,4-diazepan-2- ones and derivatives thereof to modulate the activity of the melanocortin-3 and / or melanocortin-4 receptors. The invention also relates to methods and uses of the compounds in the treatment of conditions in which agonism or antagonism of the melanocortin-3 and / or melanocortin-4 receptors is beneficial.
BACKGROUND OF THE INVENTION The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are G- protein coupled receptors (GPCRs) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been isolated and cloned to date: MC1 R, MC2R, MC3R, MC4R and MC5R. The melanocortin receptors participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down-regulation) of melanocortin receptor signalling activity.
Reviews of the melanocortin receptors and their potential as therapeutic targets have been published (Wikberg 2000, Wikberg 2001 , Voisey 2003, Bohm 2006). The melanocortin receptor family members are regulated by natural peptide agonists such as adrenocorticotropic hormone (ACTH) and the melanocyte stimulating hormones (α-, β-, γ-
MSH) derived from proopiomelanocortin (POMC), and by peptide antagonists such as Agouti signal protein (ASP) and Agouti-related peptide (AGRP). The MC1 R is widely expressed and is associated with pigmentation in melanocytes and with inflammation responses in many cells involved in the immune system. The MC2R differs from the other melanocortin receptors in that it binds only ACTH but not MSH ligands. It is highly expressed in the adenal gland and controls corticosteroid synthesis. The MC3R is found in the brain, but also elsewhere in the body, and appears to play a role in the regulation of energy homeostasis, and possibly sexual dysfunction. The MC4R is found almost exclusively in the brain, with some reports of its presence elsewhere. It has been strongly associated with feeding control, and also implicated with sexual desire. The MC5R is widely expressed in peripheral tissues, particularly in the exocrine glands, with some receptor also expressed in the brain.
MC3R (Gantz 1993a) and MC4R (Gantz 1993b) were first cloned and expressed from humans in 1993. Both MC3R and MC4R play a role in regulating energy balance and food intake (Adan 2006, Bertile 2006, Butler 2006, Emmerson 2007, Foster 2007, Lam 2007,
Marks 2006, Nargund 2006, Schuler 2006, Wikberg 2008). MC4R knockout mice are obese and suffer from hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar 1997). Genetic studies strongly associate MC4R sequence variants with obesity (Thorleifsson 2009, Wilier 2009). MC3R knockout mice have increased fat mass and reduced lean body mass (Chen
2000, Butler 2000), while mice lacking both MC3R and MC4R become more obese than mice lacking only MC4R (Chen 2000).
MC3R and MC4R have also been associated with sexual dysfunction, particularly in the control of penile erection (Wessells 2005, King 2007, Shadiach 2007, Wikberg 2008). A more potent and stable cyclic analog of α-MSH, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-OH,
(PT-141 , bremelanotide) induces an erectile response in human patients with erectile dysfunction (Diamond 2004, Shadiack 2006). α-MSH shows immunosuppressive effects in humans, suppressing a variety of inflammation responses, and both MC3R and MC4R have been implicated in these immunomodulating activities (Catania 2004, Lasaga 2008, Getting
2003, Giuliani 2007). MC4R has also been linked to depression and anxiety disorders (Chaki
2005, Chaki 2007), hypertension (Hall 2000), and addiction, with MC4R agonists potentially useful for reducing or inhibiting alcohol consumption (Ploj 2002).
A variety of peptides (e.g. Holder 2002, Holder 2003), peptide derivatives (e.g. Mutulis
2005), peptidomimetics (e.g. Mazur 2003, Tian 2008) and small molecules (e.g. Hruby 2007, Todorovic 2005, Uijainwalla 2007) that bind to and activate or inhibit MC3R and / or MC4R have been reported. However, there is still a need for compounds that act as agonists, antagonists, inverse agonists, alllosteric modulators, or otherwise bind to and modulate the activity of one or both of these receptors, and which also possess desirable characteristics for therapeutic use.
For the reasons described above it would be desirable to provide modulators of one or more receptors selected from the group consisting of MC3R and MC4R that could be useful in a number of therapeutic areas. Therapeutic regulation of biological signal transduction includes modulation of MC3R- and / or MC4R- mediated cellular events including, inter alia, inhibition or potentiation of interactions among MC3R- and / or MC4R- binding and activating or deactivating molecules, or of other agents that regulate MC3R and / or MC4R activities. An increased ability to so regulate MC3R and / or MC4R may facilitate the development of methods for modulating receptor signalling or other biological processes, and for treating conditions associated with such pathways such as obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
Accordingly there is still the need to develop improved methods of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R which would facilitate the treatment of MC3R- and / or MC4R- related conditions.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof comprising exposing the receptor or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):
Figure imgf000004_0001
Formula (I) wherein
Y is a group of formula -(CR 99IR-)1 ι0υN)n-;
X is selected from the group consisting -C(=O)-, -OC(=O)-, -NHC(=O)-,
-(CR11R12)s, and -S(=O)2-;
R is an amino acid side chain group;
R1 is selected from the group consisting of H, optionally substituted C-rC12alkyl, optionally substituted CH2(C6-C18aryl) optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted CrC12heteroalkyl, optionally substituted C3- Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ciβheteroaryl;
R2 and R3 are each independently selected from the group consisting of H, optionally substituted d-C^alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-
Ci2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted CrCisheteroaryl, or
R2 and R3 may be joined to form a linker between the two nitrogen atoms to which they are attached, wherein the linker is selected from the group consisting of -C(=O)-, -CH2-, -C(=O)CH2- and -CH2C(=O)- ;
R5a, R5b and R6 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted CrCi2 heteroalkyl, optionally substituted Ci-Ci0heteroalkenyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted
C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted Ci-
Ciβheteroaryl, optionally substituted amino, optionally substituted carboxy, optionally substituted carboxamide, optionally substituted Ci-Ci2alkyloxy, and optionally substituted thio;
each R9 and R10 is independently selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci- Ciβheteroaryl;
each R11 and R12 is independently selected from the group consisting of H, and optionally substituted CrC12alkyl;
n is an integer selected from the group consisting of 1 , 2, 3 and 4;
r is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
s is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment the receptor or fragment or analogue or functional equivalent thereof is in a cell and the method comprises exposing the cell to a compound of formula (I). In one embodiment the invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal comprising administering a MC3R- and / or MC4R -modulating amount of a compound of the invention to the mammal.
In yet a further aspect the invention provides the use of a compound of the formula (I) in modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof.
In yet a further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal.
In yet a further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC3R or fragment or analogue or functional equivalent thereof in a mammal.
In yet a further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC4R or fragment or analogue or functional equivalent thereof in a mammal.
In yet a further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of both MC3R and MC4R or fragment or analogue or functional equivalent thereof in a mammal.
In yet an even further aspect the invention provides a method of preventing or treating a condition associated with the activity of a receptor selected from the group consisting of
MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula
(I) to the mammal.
The compound may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
In one embodiment the invention provides for the use of a compound of formula (I) in the preparation of a medicament for preventing or treating a condition associated with the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal. In one aspect the medicament is adapted to be administered topically. In another aspect the medicament is adapted to be administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
DETAILED DESCRIPTION OF THE INVENTION
In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.
As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen.
The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, aryl heteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)Ra, -C(=O)ORa, C(=O)NRaRb, C(=NOH)Ra, C(=NRa)NRbRc, NRaRb, NRaC(=O)Rb, NRaC(=O)ORb, NRaC(=O)NRbRc, NRaC(=NRb)NRcRd, NRaSO2Rb,-SRa, SO2NRaRb, -0Ra OC(=O)NRaRb, OC(=O)Ra and acyl,
wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of H, C1-C12 alkyl, C1-C12 haloalkyl, C2-Ci2 alkenyl, C2-Ci2 alkynyl, C1-C10 heteroalkyl, C3-Ci2 cycloalkyl, C3-Ci2 cycloalkenyl, CrCi2 heterocycloalkyl, CrCi2 heterocycloalkenyl, C6-Ci8aryl, Ci-Ciβheteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
In one embodiment each optional substituent is independently selected from the group consisting of: halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH, and acyl.
Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN.
The term "amino acid side chain group" represents a natural or unnatural side chain group present in a protein. The term includes side chain moieties present in naturally occurring proteins including the naturally occurring amino acid side chain moieties identified in table 1 below.
Table 1. Amino Acid Side Chain Moieties
Figure imgf000008_0001
Figure imgf000009_0001
In addition to naturally occurring amino acid side chain groups as identified above the term also includes derivatives or analogs thereof. As used herein the term derivative or analogue of an amino acid side chain group includes modifications and variations to naturally occurring side chain groups. With reference to the table above most of the naturally occurring amino acid side chain groups may be classified as alkyl, aryl, arylalkyl or heteroalkyl moieties. As such derivatives of amino acid side chain groups include straight or branched, cyclic or non-cyclic alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl or heteroalkyl moieties.
Amino acid side chain groups as discussed above also include optionally substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heteroalkyl moieties. The optional substituents may be selected from the group defined above. For example, the optional substituents may be selected from but are not limited to OH, Cl, Br, F, COOH, C00Rz, CONH2, NH2, NHRZ, NRZRZ, SH, SRZ, SO2R2, SO2H and SORZ wherein Rz is an alkyl, aryl or arylalkyl moiety.
In the definitions of a number of substituents below it is stated that "the group may be a terminal group or a bridging group". This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.
Several terms are prefaced by a modifier indicating the number of carbon atoms present in the moiety. For example, the modifier "CrC6" in front of the term "alkyl" indicates that the alkyl moiety has from 1 to 6 carbon atoms. Further, the modifier "C1-C-Is" in front of the term "heteroaryl" indicates that the heteroaromatic ring may have from 1 to 18 carbon atoms as part of the total number of atoms in the ring system.
"Acyl" means an R-C(=O)- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Acylamino" means an R-C(=O)-NH- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2- 6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.
"Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C1-C14 alkyl, more preferably a C1-C10 alkyl, most preferably CrC6 unless otherwise noted. Examples of suitable straight and branched CrC6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group. "Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Mono-alkylamino" means a Alkyl-NH- group, in which alkyl is as defined herein. "Dialkylamino" means a (alkyl)2N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a CrC6 alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yNC(=O)- in which x is 1 or 2, and the sum of x+y =2. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkyloxy is a C-i-Cβalkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.
"Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Alkyloxyary" refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
"Alkyloxycarbonyl" refers to an alkyl-O-C(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group. "Alkyloxyheteroary" refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
"Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
"Alkylsulfinyl" means an alkyl-S-(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Alkylsulfonyl" refers to an alkyl-S(=O)2- group in which alkyl is as defined above.
The alkyl group is preferably a CrC6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.
"Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C1-C6 alkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Aminoalkyl" means an NH2-alkyl- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. "Aminosulfonyl" means an NH2-S(=O)2- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C6-C18 aryl group.
"Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Arylalkyloxy" refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein. di-arylamino means a group of formula (aryl)2N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Arylheteroalkyl" means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Aryloxy" refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a C6-Ci8aryloxy, more preferably a C6-Ci0aryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Arylsulfonyl" means an aryl-S(=O)2- group in which the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
A "bond" is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.
"Carboxamide" refers to a group of the formula -C(=O)-NR2 wherein each R is independently H, alkyl, alkenyl, alkynyl, aryl or heteroaryl as defined herein.
"Cyclic group" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system. Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.
"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group.
"Cycloalkyl" refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.
"Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a CrCβcycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group.
If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a Ci-Cβcycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Haloalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyl group typically has the formula CnH(2n+i- m)Xm wherein each X is independently selected from the group consisting of F, Cl, Br and I. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
"Haloalkenyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I. "Haloalkynyl" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
"Halogen" represents chlorine, fluorine, bromine or iodine.
"Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group.
"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. The group may be a terminal group or a bridging group.
"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. "Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a Ci-Ci2heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Heterocyclic" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
"Heterocycloalkenyl" refers to a heterocycloalkyl as defined herein but containing at least one double bond. The group may be a terminal group or a bridging group.
"Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane. The group may be a terminal group or a bridging group.
"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Heterocycloalkylalkenyl" refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein. Preferably the heterocycloalkyloxy is a Cr C6heterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein. Preferably the heterocycloalkenyloxy is a C1-C6 heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Hydroxyalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group. A hydroxyalkyl group typically has the formula CnH(2n+i-x)(OH)x In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3.
"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a bridging group.
"Sulfinyl" means an R-S(=O)- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Sulfinylamino" means an R-S(=O)-NH- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Sulfonyl" means an R-S(=O)2- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Sulfonylamino" means an R-S(=O)2-NH- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.
Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms have the same atomic number as, but an atomic mass or mass number different from, the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
"Prodrug" means a compound that undergoes conversion to a compound of formula
(I) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by FJ. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule (Many examples of prodrugs for these and other functional groups, including amines, are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R.Oliyai, H. Maag and J Tilley; Springer, 2007).
The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
The term "functional equivalent" is intended to include variants of the specific receptor described herein. It will be understood that receptors may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given receptor isoform is different to the prototypical receptor; the molecule maintains biological activity as a receptor. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term "functional equivalent" are variants generated at the level of transcription.
In the methods and uses of the invention it is observed that certain of the compounds of the Formula (I), are more active than others and therefore it is desirable to use these compounds in the methods and uses of the present invention.
In the methods and uses of the invention a particularly useful subset of compounds of formula (I) are compounds of formula (Ia) as shown below.
Figure imgf000021_0001
Formula (Ia) wherein
R1, R2, R3, R5a, R5b, R6, X, Y and r are as defined above,
Z is a group of formula -(CR13R14)q-;
R4 is selected from the group consisting of H, optionally substituted d-C^alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, optionally substituted C1- C18heteroaryl, NR4aR4b, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20, SC(=O)R20, SO2R20, OR20, ONR16R17, OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17, and ONR16C(=NR17)NR18R19
R4a is selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted Ci- Cisheteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15a, SO2R15a, C(=O)H, -C(=NR15a)- NR16aR17a, and 0R15a,
R4b is selected from the group consisting of H, optionally substituted CrCi2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted
C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted d- Ciβheteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15a, or
R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
one of R4a and R4b when taken together with any R13 or R14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;
R13 and R14 are each independently selected from the group consisting of H, halogen, OH, Ci-Ci2alkyl, C6-Ci8aryl, Ci-Ci2hydroxyalkyl, Ci-Ci2haloalkyl, Ci-Ci2alkyloxy and d- Ci2haloalkyloxy, or when taken together with the carbon to which they are attached R13 and R14 form an optionally substituted C3-Ci2cycloalkyl, or an optionally substituted Ci-Ci2heterocycloalkyl group, or
one of R13 and R14 when taken together with one of R4a, and R4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
one of R13 and R14 when taken together with one of R15, R16, R17, R18, R19 or R20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
each R15, R15a, R16, R16a, R17, R17a, R18, R19 and R20 is independently selected from the group consisting of H, optionally substituted d-Ci2alkyl, optionally substituted C1-
Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2 heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ci8heteroaryl, or
any two of R15, R15a, R16, R16a, R17, R17a, R18, R19 and R20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
one of R15, R16, R17, R18, R19 and R20 when taken together with one of R13 and R14 and the atoms to w Vhi IiicOhI i t Uh iet/y y a αrieG a αtutαacυihed f iouri m i n a αin i
Figure imgf000023_0001
s ouuubostuitiuutiuedu c oyycoliiico
Figure imgf000023_0002
q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
or a pharmaceutically acceptable salt or prodrug thereof.
In the methods and uses of the invention a particularly useful subset of compounds of formula (I) are compounds where Y is a group of the formula -(CR9R10X1-. In one embodiment of the suitable compounds n is 1 and Y is -CR9R10-. In another embodiment of the suitable compounds n is 2 and Y is -CR9R10CR9R10-.
In one embodiment of the compounds suitable for use in the invention each R9 and R10 is independently selected from H and CH3. In one specific embodiment R9 and R10 are both H. Accordingly in one embodiment of the compounds suitable for use in the invention Y is -CH2-. In another embodiment of compounds suitable for use in the invention Y is - CH2CH2-. In yet an even further embodiment of compounds suitable for use in the invention Y is -C(CHs)2-. In one embodiment of the compounds suitable for use in the invention R2 is H or C-i-Cβ alkyl. In a specific embodiment R2 is H.
In one embodiment of the compounds suitable for use in the invention R3 is H or CrC6 alkyl. In a specific embodiment R3 is H.
In one embodiment of the compounds suitable for use in the invention X is selected from the group consisting of -C(=O)- and -(CR11R12)S-. In one specific embodiment X is - C(=O)-. In one embodiment of the compounds suitable for use in the invention X is - (CR11R12)S-, s is 1. In another embodiment of compounds suitable for use in the invention X is -(CR11R12)S-, s is 2. In one form of each of these embodiments R11 and R12 are each independently selected from the group consisting of H and C-i-Cβ alkyl. In a specific embodiment both R11 and R12 are H, and s is 1 such that X is -CH2-.
In one embodiment of the compounds suitable for use in the present invention R = - Z-R4, R2 = H, R3 = H, X = C(=O) and Y = CH2. This provides compounds of formula (Ib).
Figure imgf000024_0001
Formula (Ib)
wherein R1, R4, R5a, R5b, R6, Z and r are as defined above.
In one embodiment of the compounds suitable for use in the invention and in particular the compounds of formula (Ia) and (Ib) R4 is selected from the group consisting of H, Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, C3-
Ci2cycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted C-linked d-
Ciβheteroaryl, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20, SC(=O)R20, SO2R20, OR20,
ONR16R17, OCR17R18R20, 0C(=0)R 20 OC(=O)OR ,20 OC(=O)NR16R17, and ONR16C(=NRη')NR jη1b8RD19 In one specific embodiment R4 is optionally substituted Ci-Ciβheteroaryl. In another embodiment R4 is optionally substituted C3-Ci2cycloalkyl. In another embodiment R4 is Cr Ci2alkyl
In another specific embodiment R4 is C(=O)NR16R17.
In another specific embodiment R4 is C(=O)NR16R17 and R16 and R17, when taken together with the nitrogen atom to which they are attached, form an optionally substituted C2- Ci2heterocycloalkyl group. In specific embodiments R15 and R16 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, azepan-1-yl, morpholin-4-yl, and piperazin-1-yl.
In one embodiment of the compounds suitable for use in the invention R16 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
In one embodiment of the compounds suitable for use in the invention R17 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
In one embodiment of the methods and uses of the invention the compound of formula (Ib) used is one in which R4 = NR4aR4b. Accordingly a useful subset of compounds for use in the methods and uses of the present invention are compounds of formula (Ic):
Figure imgf000025_0001
Formula (Ic) wherein R1, R4a, R4b, R5a, R5b, R6, and Z are as defined above
In one embodiment of the compounds suitable for use in the invention, r is selected from the group consisting of 0, 1 , 2, 3, and 4. In one specific embodiment r is 0. In another specific embodiment r is 1. In yet a further specific embodiment r is 2. In yet a further specific embodiment r is 3. In an even further specific embodiment r is 4.
In the compounds of the invention Z is a group of formula -(CR13R14)q-. In one embodiment of the compounds suitable for use in the invention, and in particular the compounds of formula (I), formula (Ia), formula (Ib), and formula (Ic), R13 and R14 are independently selected from H and C1-C6 alkyl. In one embodiment R13 and R14 are each independently selected from H and CH3. In one specific embodiment R13 and R14 are both H. In yet another embodiment at least one of R13 and R14 when taken together with at least one of R4a and R4b and the atoms to which they are attached form an optionally substituted heterocycloalkyl group. In one embodiment Z is -(CH2)q-
In one embodiment of the compounds suitable for use in the invention q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5. In one specific embodiment q is 1. In another specific embodiment q is 2, in yet an even further specific embodiment q is 3, and in yet an even further specific embodiment q is 4.
In one form of the compounds suitable for use in the invention R4a is selected from the group consisting of H, -C(=N)NH2, -C(=N)N(CH3)2, -C(=N)NCH(CH3)2, -C(=O)CH3, - C(=O)cyclohexyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof. In one form of the compounds suitable for use in the invention R4b is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
In another form of the compounds suitable for use in the invention R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C2-Ci2heterocycloalkyl group, an optionally substituted C2-Ci2 heterocycloalkenyl group or an optionally substituted Ci-Ci8 heteroaryl group.
In a particular embodiment of the compounds suitable for use in the invention R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azepan-1-yl, azetidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
In one embodiment of the methods and uses of the invention, the compound of formula (I) is one in which one of R4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted C2-Ci2heterocycloalkyl group. In a particular embodiment one of R 4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, and piperazinyl.
In one embodiment of the methods and uses of the invention the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5R), as in formula (Id):
Figure imgf000027_0001
Formula (Id)
wherein R1, R4a, R4b, R5a, R5b, R6, and Z are as defined for formula (Ic).
In another embodiment of the methods and uses of the invention the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5S), as in formula (Ie):
Figure imgf000028_0001
Formula (Ie)
wherein R1, R4a, R4b, R5a, R5b, R6, A and Z are as defined for formula (Ic).
In one specific embodiment of the compounds suitable for use in the invention R1 is selected from the group consisting of an optionally substituted amino acid, optionally substituted C2-Ci2alkenyl, optionally substituted C6-Ci8aryl, optionally substituted CH2(C6- Ci8aryl), and optionally substituted Ci-Ci8heteroaryl.
In another specific embodiment of the compounds suitable for use in the invention R1- X is an optionally substituted amino acid.
In one specific embodiment of the compounds suitable for use in the invention R1 is optionally substituted C6-C18aryl. The C6-C18aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C6-C18aryl is a monocyclic moiety. In certain embodiments the C6-Ci8aryl is a bicyclic moiety.
In one specific embodiment of the compounds suitable for use in the invention R1 is optionally substituted CH2(C6-Ci8aryl). The C6-Ci8aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C6-Ci8aryl is a monocyclic moiety. In certain embodiments the C6-Ci8aryl is a bicyclic moiety.
In one specific embodiment R1 is an optionally substituted C6-Ci8aryl selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl. In another specific embodiment R1 is an optionally substituted CH2(C6-Ci8aryl) with the aryl group selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl. The moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl.
The substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee. Examples of suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro- phenyl, 3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 4- ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4- methyl-phenyl, 4-isopropyl-phenyl, 4-cyano-phenyl 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl, 4-t-butyl-phenyl, 2,4-dimethoxy-phenyl, and 3,4-methylenedioxy-phenyl.
When R1 is optionally substituted biphenyl the point of attachment of R1 to the remainder of the molecule may be at the 2-, 3- or 4- position relative to the point of attachment of the second phenyl ring. As such the biphenyl may be an optionally substituted biphen-2-yl, or an optionally substituted biphen-3-yl, or an optionally substituted biphen-4-yl. In general the optionally substituted biphenyl is an optionally substituted biphen-4-yl. The optionally substituted biphenyl may be substituted in any suitable position.
When R1 is optionally substituted naphthyl the point of attachment of R1 to the remainder of the molecule may be at the 1 or 2 position. As such the naphthyl may be an optionally substituted naphth-1-yl, or an optionally substituted naphth-2-yl. In general the optionally substituted naphthyl is an optionally substituted naphth-2-yl. The optionally substituted naphthyl may be substituted in any suitable position. Examples of suitable optionally substituted naphth-2-yls include, but are not limited to, 6-fluoro-naphth-2-yl, 6- bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 6- methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and 6-amino-naphth-2-yl. In one specific embodiment of the compounds suitable for use in the invention R1 is optionally substituted Ci-Ci8heteroaryl. The Ci-Ci8heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the Ci-Ci8heteroaryl is a monocyclic moiety. In certain embodiments the Ci-C-isheteroaryl is a bicyclic moiety. Examples of suitable heteroaryl moieties include, but are not limited to, indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3- yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophen-2-yl. These may also be optionally substituted as discussed above.
In one specific embodiment of the compounds suitable for use in the invention R1 is an optionally substituted C2-C12alkenyl. The optionally substituted alkenyl may contain one or more double bonds with each of the double bonds being independently in the E or Z configuration. In one embodiment of the invention the alkenyl contains a single double bond which is in the E configuration.
In one specific form of this embodiment R1 is an optionally substituted C2-Ci2alkenyl of the formula:
Figure imgf000030_0001
R is selected from the group consisting of H, halogen and optionally substituted d- Ci2 alkyl;
R1b and R1c are each independently selected from the group consisting of H, halogen, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ci8heteroaryl.
In one form of this embodiment R1a is H. In one form of this embodiment R1b is H. This provides compounds where R1 is of the formula:
Figure imgf000031_0001
In one embodiment of the compounds of the invention R1c is optionally substituted Ce- Ci8aryl. The C6-Ci8aryl may be monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C6-C18aryl is a monocyclic moiety. In certain embodiments the C6-C18aryl is a bicyclic moiety.
In one specific embodiment R1c is an optionally substituted C6-C18aryl selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl. The moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol- 1-yl, and 3,5-dimethyl-pyrazol-1-yl.
The substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee. Examples of suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro- phenyl, 3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 4- ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4- methyl-phenyl, 4-isopropyl-phenyl, 4-cyano-phenyl 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl, 4-t-butyl-phenyl, 2,4-dimethoxy-phenyl, and 3,4-methylenedioxy-phenyl.
In one embodiment of the compounds suitable for use in the invention R5a and R5b are independently selected from H and CrC6 alkyl. In one embodiment R5a and R5b are each independently selected from H and CH3. In one specific embodiment R5a and R5b are both H. In one embodiment of the compounds suitable for use in the invention R6 is an optiona allllyy ssuubbssttiittuutteedd aallkkyyll group. In one embodiment invention R6 is an optionally substituted alkyl group of the formula:
Figure imgf000032_0001
In one embodiment R is H.
In one embodiment R6a and R6c are each independently selected from the group consisting of H, optionally substituted CrC12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C6-Ci8aryl and optionally substituted Ci-Ci8heteroaryl.
In one embodiment R6a and R6c are each independently selected from the group consisting of optionally substituted CrC12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C6-Ci8aryl and optionally substituted Ci-Ci8heteroaryl.
In one embodiment R6a is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C1-C5 heteroaryl.
In one embodiment R6a is optionally substituted phenyl or optionally substituted C1- C18heteroaryl.
In one embodiment R6c is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C1-C5 heteroaryl.
In one embodiment R6c is methyl, ethyl, phenyl or optionally substituted C1-C5 heteroaryl. In one embodiment of the compounds suitable for use in the invention, r is 1 , R ,5a is H, and R5b is selected from the group consisting of optionally substituted carboxy and optionally substituted carboxamide.
In one form of this embodiment R6 is selected from the group consisting of H, optionally substituted d-C^alkyl, optionally C6-Ci8aryl, or optionally substituted d- Ciβheteroaryl. In a further form of this embodiment, the optionally substituted alky group is selected from the group consisting of an optionally substituted CH2(C6-C18aryl) group and an optionally substituted CH2(C1-C18heteroaryl) group.
In one embodiment of the invention the compound used is not a compound selected from the group consisting of
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide, N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide,
N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide,
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)acrylamide.
Specific compounds suitable for use in the methods and uses of the invention include the following:
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0004
Figure imgf000036_0003
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
(233) (234)
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In order to assist the reader the names of compounds suitable for use in the invention as discussed above are as follows:
(100) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(101 ) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide (102) N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
(103) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 6-bromo-N-methyl-2-naphthamide (104) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-bromo-2-naphthamide
(105) N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
(106) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3-(4- chlorophenyl)acrylamide
(107) N-((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)-2-(naphthalen-2-yl)ethyl)acetamide
(108) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (109) (S)-methyl 2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(naphthalen-1- yl)acetamido)methyl)-2-oxo-1 ,4-diazepan-1 -yl)-3-(1 H-indol-3-yl)propanoate
(1 10) N-(((3R,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(1 11 ) N-(((3R,5R)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(1 12) N-(((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(113) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide (1 14) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoxaline-2-carboxamide
(1 15) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)isoquinoline-3-carboxamide
(116) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-2-carboxamide
(1 17) (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(2-(naphthalen-1 - yl)ethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(1 18) N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)biphenyl- 4-carboxamide (1 19) N-(((3S,5S)-3-(4-aminobutyl)-1-benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide (120) (5S,9aS)-5-(4-aminobutyl)-7-benzhydryl-2-(biphenyl-4-ylmethyl)tetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(121 ) N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide (122) N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
(123) (5S,9aS)-5-(4-aminobutyl)-7-benzhydryl-2-(naphthalen-2-ylmethyl)tetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(124) N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide
(125) 1-(3-((5S,9aS)-7-benzhydryl-2-(biphenyl-4-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
(126) N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide (127) N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
(128) N-(((3S,5R)-1-benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(129) N-(((3S,5R)-1-benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide
(130) 1-(3-((5S,9aR)-7-benzhydryl-2-(biphenyl-4-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
(131 ) N-(((3S,5R)-1-benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide (132) 1-(3-((5S,9aR)-7-benzhydryl-2-(naphthalen-2-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
(133) N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(134) N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide
(135) N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
(136) 1-(3-((5R,9aR)-7-benzhydryl-2-(naphthalen-2-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine (137) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (138) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(139) (5S,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 - ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione (140) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(141 ) (5S,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 - ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione (142) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(143) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
(144) N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (1451 ) N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(146) (5R,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1- ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(147) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(148) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(149) (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 - ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione (150) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(151 ) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
(152) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1-naphthamide
(153) N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-1-yl)acetamide
(154) N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (155) N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide (156) (5S,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2- ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(157) N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (158) N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
(159) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(160) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(161 ) (5S,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2- ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(1620) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (163) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
(164) N-(((3S,5R)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-1-yl)acetamide
(165) N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(166) N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(167) (5R,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2- ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione (168) N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(169) N-(((3R,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(170) N-(((3R,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
(171 ) (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2- ylmethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
(172) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)benzamide (173) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)cyclohexanecarboxamide (174) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-phenoxybenzamide
(175) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-4-phenoxybenzamide (176) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1 H-indole-2-carboxamide
(177) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-phenylpropanamide
(178) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dimethylbenzamide
(179) 4-tert-butyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)benzamide
(180) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2,4-dimethoxybenzamide (181 ) 2-cyclohexyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)acetamide
(182) N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(2-(guanidinooxy)ethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(183) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)acrylamide
(184) propyl (R)-1-((3R,5R)-1-(2-(1 H-indol-3-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)-2-phenylethylcarbamate
(185) (R)-N-((S)-1-((3S,5S)-1-(2-(1 H-indol-3-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)-2-phenylethyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide (186) N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(187) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 6-bromo-2-naphthamide
(188) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
(189) N-(((3S,5S)-3-(3-(3,3-dimethylguanidino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(190) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-p-tolylacrylamide (191 ) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-fluorophenyl)acrylamide (192) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 6-fluoro-2-naphthamide
(1934) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide (194) N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
(195) N-(((3S,5S)-3-(3-guanidinopropyl)-1 -(naphthalen-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(196) N-(((3S,5S)-1 -((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(197) (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(198) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 5-(4-chlorophenyl)furan-2-carboxamide (199) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 4-(1 H-pyrrol-1-yl)benzamide
(200) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 5-(4-chlorophenyl)isoxazole-3-carboxamide
(201 ) N-(((3S,5S)-1 -(2-cyclohexylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(202) N-(((3S,5S)-1 -(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(203) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (204) 1-(3-((1 R,5S,9aS)-7-(2-(1 H-indol-3-yl)ethyl)-1 ,2-dibenzyl-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
(205) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-fluorophenyl)-N-methylacrylamide
(206) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan- 5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(207) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1- yl)propyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(208) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1- yl)propyl)-1 ,4-diazepan-5-yl)methyl)acrylamide (209) N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide (210) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(211 ) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(2-(naphthalen-2-yl)ethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (212) (E)-N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
(213) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1-ylmethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(214) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1- ylmethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(215) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
(216) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide (217) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(218) N-(((3S,5S)-1-((S)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(219) N-(((3S,5S)-1-(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(220) N-(((3S,5S)-1-((R)-2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(221 ) (S)-2-amino-N-((R)-1-((3S,5R)-3-(3-guanidinopropyl)-1-(2-(naphthalen-2-yl)ethyl)-2- oxo-1 ,4-diazepan-5-yl)-2-phenylethyl)-3-phenylpropanamide (222) (S)-2-amino-N-((R)-1-((3S,5S)-3-(3-guanidinopropyl)-1-(2-(naphthalen-2-yl)ethyl)-2- oxo-1 ,4-diazepan-5-yl)-2-phenylethyl)-3-phenylpropanamide
(223) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3-(4- chlorophenyl)acrylamide
(224) (E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
(225) N-(3-((2S,7S)-4-(2,2-diphenylethyl)-3-oxo-7-(((E)-3-p-tolylacrylamido)methyl)-1 ,4- diazepan-2-yl)propyl)cyclohexanecarboxamide
(226) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(2-phenoxy-2-phenylethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (227) N-(((3S,5S)-1 -(2-ethylbutyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide (228) N-(((3S,5S)-1 -((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(229) 3,4-dichloro-N-(2-((3S,5R)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)ethyl)benzamide (230) N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
(231 ) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
(232) (S)-2-((5S,9aS)-2-(4-fluorobenzyl)-5-(3-guanidinopropyl)-3,6-dioxotetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-7(8H,9H,9aH)-yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(233) (S)-2-((3S,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(234) (S)-2-((3S,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide (235) (S)-2-((3S,5R)-5-((4-fluorobenzylamino)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(236) (S)-2-((3S,5R)-5-((N-(4-fluorobenzyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(237) N-(((3S,5S)-1 -(3-chloro-5-fluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(238) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((1-phenylcyclohexyl)methyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(239) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide (240) N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(241 ) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(242) 4-fluoro-N-(((3R,5R)-3-(3-guanidinopropyl)-1-((S)-1-(methylamino)-3-(naphthalen-2- yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)benzamide
(243) 4-fluoro-N-(((3R,5S)-3-(3-guanidinopropyl)-1-((S)-1-(methylamino)-3-(naphthalen-2- yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)benzamide
(244) (S)-2-((3R,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide (245) (S)-2-((3R,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-(2-(4- fluorophenyl)acetamido)propyl)-2-oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2- yl)propanamide (246) (S)-2-((3R,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-(2-(4- fluorophenyl)acetamido)propyl)-2-oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2- yl)propanamide
(247) (S)-2-((3R,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(248) 3,4-dichloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(249) N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (250) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(piperidin-1-ylmethyl)-1 ,4- diazepan-5-yl)methyl)acrylamide
(251 ) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(piperidin-1-yl)propyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(252) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(phenylamino)propyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(253) N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
(254) N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide (255) (E)-N-(((3S,5S)-3-(aminomethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
(256) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1-ylmethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(257) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1- ylmethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(258) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-3,4- dichlorobenzamide
(259) (E)-N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-3- (4-chlorophenyl)acrylamide (260) 6-chloro-N-(((3S,5S)-1 -(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(261 ) 6-chloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(262) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-3-(4-isopropylphenyl)acrylamide
(263) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-isopropylphenyl)acrylamide (264) (E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(265) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(2,4-dimethylphenyl)acrylamide (266) (E)-3-(2,4-difluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(267) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(2,4-difluorophenyl)acrylamide
(268) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)acrylamide
(269) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrolidin-1-yl)ethyl)-1-(2,2- diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
(270) 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (271 ) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(272) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(273) (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
(274) 5-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
(275) 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidin-1-yl)propyl)-1-((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (2768) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidin-1-ylmethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(277) 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(3-(piperidin-1 -yl)propyl)-1 A- diazepan-5-yl)methyl)-2-naphthamide
(278) (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)propan-2-yl)-3-(4-chlorophenyl)acrylamide
(279) (E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)propan-2-yl)acrylamide
(280) 6-chloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (281 ) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)benzamide (282) 6-chloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(283) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-6- chloro-2-naphthamide (284) (E)-N-(((3S,5S)-3-((1 H-imidazol-1-yl)methyl)-1-(2,2-diphenylethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(285) N-(((3S,5S)-3-(2-(benzyl(methyl)amino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(286) 3,4-dichloro-N-(((3S,5S)-3-(2-(methyl(pentyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
(287) (S)-6-chloro-N-((2-oxo-1-(2-phenylbutyl)-3-(piperidin-4-yl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
(288) (S)-6-chloro-N-(3-(1-isopentylpiperidin-4-yl)-2-oxo-1-(2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (289) 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(290) 3,4-dichloro-N-(((3S,5S)-3-(2-(3,5-dimethylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)benzamide
(291 ) 3,4-dichloro-N-(((3S,5S)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)-2-oxo-1-((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)benzamide
(292) 1-(2-((2S,7S)-7-((3,4-dichlorobenzamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)ethyl)piperidine-4-carboxylic acid
(293) N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide (294) 3,4-dichloro-N-(((3S,5S)-3-(2-((S)-2-methylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)benzamide
(295) N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(296) N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(297) 6-chloro-N-((3-(1-ethylpiperidin-4-yl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(298) (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1-(2,2-diphenylethyl)-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-2-one (299) 6-chloro-N-(((3S,5S)-3-(2-guanidinoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (300) 6-chloro-N-(((3S,5S)-3-(2-(3-methylguanidino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(301 ) (S)-2-amino-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1- (methylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propanamide
(302) (S)-2-((3S,5R)-5-((2-(4-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(303) (R)-2-amino-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1- (methylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propanamide
(304) (S)-2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(naphthalen-1-yl)acetamido)methyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(305) N-(((3S,5S)-3-(2-aminoethyl)-1 -((R)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide (306) N-(((3S,5S)-3-(2-aminoethyl)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide
307) (E)-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1-(methylamino)-3- (naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
(308) 3,4-dichloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
(309) 3,4-dichloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
(310) (S)-2-((3S,5R)-5-((3-(4-fluorophenyl)propanamido)methyl)-3-(3-guanidinopropyl)-2- oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide (31 1 ) N-(((3S,5S)-3-(2-amino-2-methylpropyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(312) N-(((3R,5R)-3-(2-amino-2-methylpropyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(313) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
(314) 3,4-dichloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(315) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 6-chloro-2-naphthamide (316) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (317) 6-chloro-N-(((3S,5S)-3-(2-methyl-2-(piperidin-1-yl)propyl)-2-oxo-1-((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(318) (E)-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1-(methylamino)-3- (naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide (319) N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(320) N-(((3S,5S)-3-(2-aminoethyl)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(321 ) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(322) 6-chloro-N-(((3S,5S)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(323) (S)-2-amino-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1- (methylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propanamide
(324) (R)-2-amino-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1- (methylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propanamide
(325) (S)-2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(4-methoxyphenyl)acetamido)methyl)-2- oxo-1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(326) (S)-2-((3S,5R)-3-(3-guanidinopropyl)-2-oxo-5-((3-phenylpropanamido)methyl)-1 ,4- diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(327) (S)-2-((3S,5R)-5-((3-(4-chlorophenyl)propanamido)methyl)-3-(3-guanidinopropyl)-2- oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide (328) (E)-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1-((S)-1-(methylamino)-3- (naphthalen-2-yl)-1-oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
(329) 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
(330) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylguanidino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(331 ) 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(332) 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide (333) N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide (334) 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
(335) (S)-2-((3S,5R)-5-((2-(2,4-dichlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2- oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide (336) (S)-2-((3S,5R)-5-((2-(2,4-dichlorophenyl)acetamido)methyl)-3-(3-(3-(2-(2,4- dichlorophenyl)acetyl)guanidino)propyl)-2-oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2- yl)propanamide
(337) (S)-2-((3S,5R)-5-((2-(3-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide (338) (S)-2-((3S,5R)-5-((2-(3-chlorophenyl)acetamido)methyl)-3-(3-(3-(2-(3- chlorophenyl)acetyl)guanidino)propyl)-2-oxo-1 ,4-diazepan-1-yl)-N-methyl-3-(naphthalen-2- yl)propanamide
(339) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide (340) 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
(341 ) 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)benzamide
(342) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(343) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1- yl)ethyl)-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(344) 6-chloro-N-(((3S,5S)-1 -((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)-2-naphthamide (345) 6-chloro-N-(((3S,5S)-1-(2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(346) N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(347) N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide
(348) N-(((3S,5R)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
(349) N-(((3S,5R)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide (350) N-(((3R,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (351 ) N-(((3R,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(1 H-indol-3-yl)acetamide
(352) N-(((3R,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide (353) N-(((3R,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1 H-indole-3-carboxamide
(354) N-(((3R,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(355) N-(((3R,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
(356) N-(((3R,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide
(357) (S)-methyl 2-((3S,5R)-5-((2-(4-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)- 2-0X0-1 ,4-diazepan-1 -yl)-3-(naphthalen-2-yl)propanoate (358) (S)-2-((3S,5R)-3-(3-aminopropyl)-5-((2-(4-chlorophenyl)acetamido)methyl)-2-oxo-1 ,4- diazepan-1-yl)-N-methyl-3-(naphthalen-2-yl)propanamide
(359) N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(360) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylureido)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 A- diazepan-5-yl)methyl)-2-naphthamide
(361 ) benzyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)- 1 ,4-diazepan-2-yl)acetate
(362) benzyl 3-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)- 1 ,4-diazepan-2-yl)propanoate (363) 4'-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)biphenyl-2-carboxamide
(364) 6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacetamido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(365) 6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1-((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(366) 6-chloro-N-(((3S,5S)-3-(guanidinomethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(367) N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,4-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide (368) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide (369) 6-chloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(370) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((R)-2-(thiophen-3-yl)butyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide (371 ) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((S)-2-(thiophen-3-yl)butyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
(372) N-(((3S,5S)-3-(2-aminoethyl)-1 -(2-ethyl-2-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
(373) 6-chloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(374) 6-chloro-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
(375) 6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide (376) 6-chloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
(377) 3,4-dichloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)benzamide
(378) N-(3,4-dichlorobenzyl)-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acetamide
(379) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-(2,3,5-trichlorobenzyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(380) 6-chloro-N-(((3S,5S)-3-(2-(1 -methylethylsulfonamido)ethyl)-2-oxo-1 -((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2-naphthamide (381 ) butyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)ethylcarbamate
(382) (S)-6-chloro-N-((3-(1 -isopropylpiperidin-4-yl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
(383) 6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(384) 5-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
(385) N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-6-methoxy-2-naphthamide (386) 6-chloro-N-(((3R,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (387) 6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
(388) 6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide (389) 6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
As stated previously the compounds of formula (I) are modulators of the MC3R and / or MC4R and therefore may be used to modulate the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof by exposing MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof to a compound of the invention. This can occur in vitro in assays where the modulation of MC3R and / or MC4R activity is desirable, however it is typically more beneficial when utilised in modulation of MC3R and / or MC4R activity in a patient. The amount of modulation provided by the compounds of the invention will vary from compound to compound and will also be affected by the amount of compound administered. The modulation can consist of upregulation or downregulation. In one embodiment the amount of upregulation or downregulation is at least 10%. In another embodiment the amount of upregulation or downregulation is at least 20%. In an even further embodiment the amount of upregulation or downregulation is at least 50%.
Accordingly the methods of the present invention may be used in the treatment of any condition in which modulation of the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof would lead to a beneficial effect on that condition. As such the compounds suitable for use in the present invention may be used in methods of preventing or treating a condition associated either directly or indirectly with the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof in a mammal wherein an MC3R and / or MC4R modulating amount of the compound of the invention is administered to the mammal. One condition associated with MC3R and / or MC4R activity is metabolic syndromes and conditions related thereto. In one embodiment of the method the condition is selected from the group consisting of obesity, eating disorders, and diabetes. In a more specific embodiment the eating disorder is selected from the group consisting of cachexia, anorexia, weight gain and weight loss. In another specific embodiment the condition is Type Il diabetes. Another condition associated with MC3R and / or MC4R activity is sexual dysfunction. In one embodiment the sexual dysfunction is selected from the group consisting of erectile dysfunction and female sexual dysfunction. In one specific embodiment the condition is erectile dysfunction. The modulation of MC3R and / or MC4R may involve upregulation or downregulation. For example, downregulation of MC4R leads to increased food intake and weight gain and can thus be used in the treatment of cachexia. In another example, upregulation of MC4R leads to weight loss and can thus be used in the treatment of obesity. In another example, upregulation of MC4R leads penile erection and can thus be used in the treatment of erectile dysfucntion.
The methods of the invention may also be useful in prevention or treatment of a number of conditions that relate to biological processes controlled by MC3R and / or MC4R, such as diseases related to inflammation, depression, anxiety and addiction.
Due to their impact on metabolism the compounds of formula (I) may also find application in treatments where reduced weight is desirable such as in dieting. The compounds may thus be used in methods of reducing the weight a mammal, the method comprising administering an effective amount of a compound of formula (I).
The compounds of formula (I) may be used in the treatment of conditions in any species in which MC3R and / or MC4R is present, most typically mammals. Examples of species in which MC3R and / or MC4R are found and hence species in which the compounds may be used include humans, rats, mice, dogs, and rhesus monkey. In a specific embodiment the mammal is a human.
Administration of compounds within Formula (I) to a patient such as humans can be by topical administration, by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
In using the compounds of formula (I) they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995) for further information. The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of formula (I), while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. The compositions are prepared in manners well known in the art.
A compound of formula (I) is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the invention, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. Representative dosage forms will generally contain between from about 1 mg to about 500 mg of a compound of the invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. Compounds of the present invention may also be formulated for topical delivery in formulations such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches. For example, these topical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of a compound of the invention.
The compounds of formula (I) may be used or administered in combination with one or more additional drug (s), either concurrently or sequentionally. The compounds of the present invention may be used in combination with one or more other pharmaceutically-active compounds, such as other metabolism altering, sexual dysfunction, anti-inflammatory, antianxiety, or antiaddiction medications. These components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
Pharmaceutical compositions suitable for use in the invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
For topical administration, the active agent may be in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. Alternatively, the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle. Alternately, a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Methods for producing formulations for topical administration are known in the art.
The compositions used for topical administration typically contain a pharmaceutically acceptable carrier which may be any vehicle that is toxicologically and pharmaceutically acceptable. Typical pharmaceutically acceptable carriers that can be used in compositions of the present invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propylene glycol, polyethlyene glycol, fragrances, gel-producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, "Tweens," sorbitol, methyl cellulose, petrolatum, a mineral oil (vaseline oil), which may be any petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil, pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peach kernel oil, poppyseed oil, pine oil, castor oil, soya oil, safflower oil, coconut oil, hazelnut oil, grapeseed oil, avocado oil, soy oil, sweet almond oil, calophyllum oil, castor oil, olive oil, sunflower oil, or animal oils such as whale oil, seal oil, menhaden oil, halibut liver oil, cod liver oil, cod, tuna, turtle tallow, horse's hoof, sheep's foot, mink, otter, marmot oil and the like; synthetic oils such as silicon oil such as dimethylpolysiloxane; alkyl and alkenyl esters of fatty acids, such as isopropyl esters of myristic, palmitic and stearic acids and fatty esters which are solid at room temperature; waxes such as lanolin wax, candelilla wax, spermaceti, cocoa butter, karite butter, silicon waxes, hydrogenated oils which are solid at room temperature, sucro-glycerides, oleates, myristates, linoleates, stearates, paraffin, beeswax, carnauba wax, ozokerite, candelilla wax, microcrystalline wax; fatty alcohols such as lauryl, cetyl, myristyl, stearyl, palmityl and oleyl alcohols; polyoxyethylated fatty alcohols; and wax esters, lanolin and its derivatives, perhydrosqualene and saturated esters, ethyl palmitate, isopropyl palmitate, alkyl myristates such as isopropyl myristate, butyl myristate and decyl myristate, hexyl stearate, triglyceride esters, triglycerides of octanoic and decanoic acid, cetyl ricinoleate, stearyl octanoate (Purcellin oil), fatty acids, polyhydric alcohols, polyether derivatives, fatty acid monoglycerides, polyethylene gylcol, propylene glycol, alkyl ethoxy ether sulfonates, ammonium alkyl sulfates, fatty acid soaps, and hydrogenated polyisobutene, and mixtures of waxes and oils.
The compositions for topical administration may be formulated in numerous forms. However, the composition may often take the form of an aqueous or oily solution or dispersion or emulsion or a gel or a cream. An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
The oil phase of water-in-oil or oil-in-water emulsions may comprise for example: a) hydrocarbon oils such as paraffin or mineral oils; b) waxes such as beeswax or paraffin wax; c) natural oils such as sunflower oil, apricot kernel oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esters such as isopropyl palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such as cetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearyl alcohol); g) polypropylene glycol or polyethylene glycol ethers, eg PPG-14 butyl ether; or h) mixtures thereof.
Emulsifiers used may be any emulsifiers known in the art for use in water-in-oil or oil- in-water emulsions. Known cosmetically acceptable emulsifiers include: a) sesquioleates such as sorbitan sesquioleate, available commercially for example under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of derivatives of natural oils such as the polyethoxylated ester of hydrogenated castor oil available commercially for example under the trade name Arlacel 989 (ICI); c) silicone emulsifiers such as silicone polyols available commercially for example under the trade name ABIL WS08 (Th. Goldschmidt AG); d) anionic emulsifiers such as fatty acid soaps e.g. potassium stearate and fatty acid sulphates e.g. sodium cetostearyl sulphate available commercially under the trade name Dehydag (Henkel); e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); f) sorbitan esters, for example the emulsifiers available commercially under the trade name Span (ICI); g) ethoxylated sorbitan esters, for example the emulsifiers available commercially under the trade name Tween (ICI); h) ethoxylated fatty acid esters such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); i) ethoxylated mono-, di-, and triglycerides, for example the emulsifiers available commercially under the trade name Labrafil (Alfa Chem.); j) non-ionic self-emulsifying waxes, for example the wax available commercially under the trade name Polawax (Croda); k) ethoxylated fatty acids, for example, the emulsifiers available commercially under the trade name Tefose (Alfa Chem.); I) methylglucose esters such as polyglycerol-3 methyl glucose distearate available commercially under the name Tegocare 450 (Degussa Goldschmidt); or m) mixtures thereof.
Gels for topical administration may be aqueous or non-aqueous. Aqueous gels are preferred. The gel will contain a thickening agent or gelling agent in order to give sufficient viscosity to the gel. A variety of thickening agents may be used according to the nature of the liquid carrier and the viscosity required and these are recited hereinafter. A particularly suitable thickener is a copolymer of acryloyl dimethyl tauric acid (or a salt thereof), preferably a copolymer of that monomer with another vinylic monomer. For example, the thickening agent is a copolymer of a salt of acryloyl dimethyl tauric acid with another vinylic monomer. The salt may be a salt of a Group I alkali metal, but is more preferably an ammonium salt. Examples of suitable copolymer thickening agents are: i) Ammonium acryloyl dimethyl taurate I vinyl pyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyl taurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).
The composition may additionally comprise other components which will be well known to those skilled in the art such as emollients, humectants, emulsion stabilising salts, preservatives, chelating agents or sequestering agents (sequestrants), abrasives, antioxidants, stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumes and colourings.
The topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.
SYNTHESIS OF COMPOUNDS FOR USE IN THE INVENTION
The general synthetic route to the compounds for use in the invention proceeds through the key intermediate A, produced as outlined in Schemes 1 or 2.
In Scheme 1 , an amino acid derivative V-N(R2)- Y-CO2H (V = R1X or an amine protecting group P1) is converted to a Weinreb amide via activation of the carboxyl group and amidation with Λ/-methyl methoxyamine. Addition of a vinyl Grignard reagent produces the aminoalkyl vinyl ketone, which undergoes conjugate addition by the R6-(CR5aR5b)rNH2 amine component
(shown as WNH2 for simplicity). The resulting secondary amine is acylated under standard peptide coupling conditions with the protected amino acid, P2-NHCH(U)-CO2H, where U represents either the final R side chain, a protected final side chain R-P3, or a precursor that requires chemical modification to form the final R side chain. Deprotection of the P2 protecting group is followed by intramolecular reductive amination of the ketone using standard reduction conditions, such as H2/Pd catalyst, NaBH4, NaBH3CN, or NaBH(OAc)3, forming key intermediate A. If Y = CH2 or CH2CH2, A is formed as the predominant diastereomer. If V = R1X and U = R, A is the final product.
Scheme 1: Synthesis of Intermediate A via Intramolecular Reductive Amination
Figure imgf000077_0001
V amidation
R
Figure imgf000077_0002
2 Y O^ W-NH2 - coupling agent - OH
Figure imgf000077_0003
where U= R, a protected form thereof or a precursor thereof, V = P1 or R1X, and W = R6(CR5aR5b)r- Final product if V = R1X, U = R In Scheme 2, an alternate route to the desired intermediate A begins with the same Weinreb amide formation, vinyl Grignard addition, and amine conjugate addition. At this point, the secondary amine is protected with an amine protecting group P4. The ketone is then reductively aminated with a protected amino ester, H2NCH(U)-CO2P5, producing a mixture of diastereomers that are carried through the next reaction steps. The ring system is generated by deprotection of the P4 and P5 protecting groups, followed by amide bond formation using standard peptide coupling reagents. Alternatively, the P4 protecting group is removed and cyclization achieved by thermal or base-induced cyclization with the P5- protected ester. The cyclization produces a mixture of two diastereomers, A and B, from which the preferred diastereomers A can be separated by chromatography.
Scheme 2: Synthesis of Intermediate A via Intermolecular Reductive Amination
V.
Figure imgf000078_0001
1) P4 and P5 deprotection
2) intramolecular
Figure imgf000078_0002
amide formation A B separate desired isomer A by chromatography where U= R, a protected form thereof or a precursor thereof, V = P1 or R1X, and W = R6(CR5aR5b)r- final product if V = R1X, U = R
The key intermediate A may be the final product if U = R and V = R1X, but otherwise is converted into the final product as illustrated in Schemes 3, 4 and 5. In Scheme 3, where V = R1X, the final product is obtained by modification of the U side chain, such as removal of a P3 protecting group, or removal of a P3 protecting group followed by further chemical modification.
Scheme 3: V = R1X
Figure imgf000079_0001
Ar V = R1X
R5a R 5b W= Λ J,^ r R6
In Scheme 4, where V = P1, the final product is obtained by removal of the P1 protecting group followed by introduction of the R1X substituent. If U = R, this produces the final product. Alternatively, the U side chain is then modified to produce the final R group as in Scheme 3.
Scheme 4I V = P1
Figure imgf000079_0002
A: V = P> U R
W
Figure imgf000079_0003
RVΛΎΛ._ΛW
In Scheme 5, where V = P1, the final product is obtained by first modifying the U side chain to produce the final R group as in Scheme 3. This is followed by removal of the P1 protecting group followed by introduction of the R1X substituent. Scheme Sr V = P1
Figure imgf000080_0001
Ar V
=
Figure imgf000080_0002
with R1X
It is also possible to modify the W substituent, if desired, during these reaction sequences.
Examples
The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other than those described below, may be prepared using the following described reaction schemes as discussed above or appropriate variations or modifications thereof. All starting materials described in the Examples below are commercially available or readily synthesized by those skilled in the art.
Instrumentation
HPLC analyses were carried out on an Agilent 1100 Series Purification System with a Phenomenex Synergi 4μ Max-RP 8OA, 50 x 2.00 mm analytical HPLC column, with peak detection by UV. The standard analysis employed a 1 mL/min flow rate of 0.05% trifluoroacetic acid (TFA) in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water
(Solvent B), using a gradient of 5% B (initial) to 95% B over 9 min. Mass spectra were run on an Applied Biosystems MDS Sciex API 2000 LC/MS/MS triple quadrupole mass spectrometer and analyzed by ion spray mass spectrometry (ISMS). Preparative scale HPLC was carried out on a Waters Delta Prep 3000 HPLC system with peak detection by UV (Waters model
486 tunable absorbance detector), using Phenomenex Luna 10μ C5 100A, 250 x 21.20 mm
(20 mg scale), Phenomenex Luna 15μ C8(2) 100A, 250 x 30.00 mm (50 mg scale), or
Phenomenex Luna 15μ C8(2) 100A, 250 x 50.00 mm (100 mg scale) HPLC columns. The solvent system employed various gradients of 0.05% TFA in water (Solvent A) and 0.05%
TFA in 90:10 acetonitrile:water (Solvent B). The following examples 1 to 7 provide general synthetic procedures that may be followed in order to carry out the transformations described in schemes 1 to 5. In order to make different end products using these procedures it is necessary to either vary a variable group on the starting material or to vary a variable group on one of the reagents depending upon the nature of the reaction. It will be apparent to a skilled addressee from a reading of the general procedures how to vary either the starting material or the reagents used in the procedure to produce differing end products. In addition depending upon the starting materials and the reagents it may be necessary and/or desirable to make slight modifications to the described general procedures in order to provide the most facile synthesis of the desired end product.
Example 1 - General Procedure - Weinreb Amide Formation
Figure imgf000081_0001
1 2
BOP reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) is added to a stirred solution of the amino acid (1 ) (100 mmol) in dichloromethane (DCM) (100 ml_). The solution is then stirred at room temperature for 10 mins, before addition of a premixed solution of Λ/,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol) followed by stirring at room temperature overnight. The DCM is then removed by rotary evaporation and the residue taken up in ethyl acetate (EtOAc) (200 ml_). The organic phase is then washed with 1 N HCI (3 x 100 ml_), H2O (3 x 100 ml_), saturated NaHCO3 aqueous solution (3 x 100 ml.) and brine (1 x 10 ml_). The organic phase is then dried (MgSO4) and the EtOAc removed to give the Weinreb amide (2) as a white solid or an oil.
Example 2 - General Procedure - Vinyl Grignard Addition to Weinreb Amide to Form α,β-unsaturated ketones of formula (3)
Figure imgf000081_0002
2 3
To the Weinreb amide (2) (15 mmol) in DCM (10 ml.) at O0C is added vinyl magnesium bromide (45 mmol) in THF (45 ml_). The reaction is stirred for 2 hrs and monitored by HPLC. The reaction is then quenched by adding it to a mixture of ice and 1 M
HCI (200 ml_). The aqueous mixture is extracted with DCM (3x 100 ml.) and the organic layers combined and washed with 1 M HCI (2x 200 ml.) and H2O (3x 100 ml_). The organic phase is dried (MgSO4) to provide a solution of the α,β-unsaturated ketone (3). The α,β- unsaturated ketone (3) may be isolated by rotary evaporation or it may be used in solution without further purification. If the intention is to use the α,β-unsaturated ketone (3) in solution the volume is reduced to 100 ml. by rotary evaporation and stored for later use.
Example 3 General Procedure - Conjugate Addition of Amine to α,β-unsatu rated ketones of formula (3) to produce compounds of formula (4)
. ,
Figure imgf000082_0001
To the amine W-NH2 (7.4 mmol) in DCM (10 ml.) is added a solution of the α,β- unsaturated ketone (3) (5.7 mmol) in DCM (50 ml_). The solution is stirred at room temperature for 15 mins, or until analysis indicates that all of (3) has been consumed. The solution of compound (4) is immediately used without purification for the subsequent reaction.
Example 4 General Procedure - Acylation of Aminoketone (4)
Figure imgf000082_0002
5
The amine acid P2-NHCH(U)-CO2H (15 mmol) and DIC (15 mmol) is added to a solution of DCM containing 10 mmol of the conjugate addition adduct 4. The reaction is stirred at room temperature overnight. The DCM is removed by rotary evaporation and the residue is then subjected to column chromatography on silica gel using petroleum spirit:EtOAc to give 5.
As an alternative, the DIC may be replaced with HATU (15 mmol) and DIPEA (15 mmol). The reaction is stirred at room temperature overnight. The DCM is removed by rotary evaporation and the residue is taken up in EtOAc (100 ml_). The organic layer is washed with saturated sodium bicarbonate solution (2 x 100 ml_), saturated ammonium chloride solution (2 x 100 ml.) and brine (2 x 100 ml_). The organic phase is dried and the solvent removed under reduced pressure. The residue is subjected to column chromatography on silica gel using petroleum etheπEtOAc to give 5. Example 5 General Procedure - P2 Deprotection and Cyclization
Figure imgf000083_0001
The procedure adopted for the removal of the P2 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
P2 = Fmoc: To compound 5 (2 mmol) in DCM (3 ml.) is added diethylamine (20 mmol). The reaction is stirred at room temperature for 1 hr. The DCM and diethylamine is then removed by rotary evaporation. DCM (5 ml.) and sodium triacetoxyborohydride (3 mmol) are then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO4) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.
P2 = Boc: To compound 5 (2 mmol) in DCM (3 ml.) is added TFA (3 ml.) and the reaction stirred at room temperature for 2 hrs. The DCM and TFA are then removed by rotary evaporation. DCM (5 ml.) and sodium triacetoxyborohydride (3 mmol) is then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO4) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.
P2 = Cbz: A mixture of crude 5 (1 mmol) and 5% Pd/C (200 mg) in 2-propanol (15 ml.) is shaken at room temperature under hydrogen (30 psi) for 24 hrs. The mixture is then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give a crude product. Purification by flash chromatography on silica gel (100% EtOAc) may be used to give A. Example 6 General Procedure - P1 Deprotection and Derivatization with R1X
Figure imgf000084_0001
The procedure adopted for the removal of the P1 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
Deprotection, P1 = Cbz:
To the cyclised product A (1 mmol) in methanol (5 ml.) is added catalytic Pd/C. The reaction is stirred under a hydrogen atmosphere overnight. The reaction mixture is filtered through Celite and the methanol removed by rotary evaporation to give the free amine. The amine may be used in the next reaction without purification.
Deprotection, P1 = Boc:
To the cyclised product A (1 mmol) in DCM (1 ml.) is added TFA (1 mL) and the reaction stirred at room temperature for 2 hrs. The solvent is removed by rotary evaporation to give the amine TFA salt, which may be used in the next reaction without purification.
Deprotection, P1 = Alloc:
To the cyclised product A (1 mmol) in DCM (6 ml.) is added 1 ,3-dimethylbarbituric acid (0.2 mmol) and palladium tetrakis triphenylphosphine (10 mg). The reaction is evacuated and stirred at room temperature for 1 hr. The DCM is removed under reduced pressure to give the crude free amine, which may be used in the next reaction without purification.
Derivatisation with R1X when X = C(=O):
To the free amine (1 mmol) in DCM (5 ml.) is added DIPEA (1 mmoL), BOP reagent (1.5 mmol) and acid component R1CC^H (1.5 mmol). The reaction is stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gives the purified adduct. Example 7 General Procedure - U Modification via P3 Deprotection and Dialkylation with Dibromide
Figure imgf000085_0001
A 7
The procedure adopted for modification of U via deprotection and derivatization will vary depending on the exact nature of the U group. As will be appreciated by a skilled addressee a large number of modifications are possible, and a skilled worker in the art will readily be able to determine an appropriate procedure for the conversion into a desired R group. Nevertheless in order to assist the reader, one general modifcation procedure commonly employed for a number of the following examples is provided.
P3 = Boc:
To the protected amine (1 mmol) in DCM (5 ml.) is added TFA (5 ml.) and the reaction stirred at room temperature for 2 hrs. DCM (20 ml.) is added and the solution is washed with saturated sodium bicarbonate solution (20 ml_), dried (MgSO4) and evaporated to give the crude amine. To the crude amine is added DMF (0.5 ml_), potassium carbonate (50 mg) and 1 ,5-dibromopentane (5 mmol). The reaction mixture is stirred at room temperature for 1.5 hrs, after which DCM (20 ml.) is added, the organic layer washed with saturated sodium bicarbonate solution (20 ml.) and H2O (20 ml_), dried (MgSO4) and evaporated. The residue may be purified by preparative HPLC to give the piperidinyl product. The purified product is isolated as the TFA salt, but is readily converted into the free base via neutralisation with aqueous NaHCOs and extraction into an organic solvent, or further converted into the HCI salt by acidification with 1 N HCI.
Example 8 - Synthesis of Compound 8 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2- naphthamide
Figure imgf000085_0002
8
N- (2- (methoxy (methyl)amino) - 2-oxoethyl)-2-naphthamide
To a mixture of 2-naphthoic acid (5.8 g, 33.7 mmol), 2-amino-Λ/-methoxy-Λ/- methylacetamide (GIy Weinreb amide; prepared from Boc-Gly Weinreb amide 15 following the alternative procedure of Example 26) (3.8 g, 32.1 mmol) and DIPEA (12.0 ml_, 68.9 mmol) in DCM (70 ml.) was added BOP (14.9 g, 33.7 mmol) in one portion at room temperature. The resulting mixture was stirred for 1 hr then saturated NaHCO3 aqueous solution was added. The organic layer was washed with brine (5 x 60 ml.) and 1 N HCI (2 x 30 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was used in the next reaction without further purification.
Example 9 - Synthesis of Compound 9 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2- naphthamide
Figure imgf000086_0001
9
N-(2-oxobut-3-enyl)- 2-naphthamide
To a solution of 8 (3.5 g, 12.85 mmol) in dry THF (10 ml.) was added a solution of vinylmagnesium bromide in THF (1 M, 31 ml.) slowly at O0C. After addition, the resulting mixture was stirred at room temperature for 1 hr then was poured into an icy 1 N HCI solution (50 ml_). The aqueous layer was extracted with DCM (3 x 80 ml.) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product. MS (ESI) 240 (M+1 ); HPLC fR 5.46 min.
Example 10 - Synthesis of Compound 10 N-(4-(3,5-dichlorobenzylamino)-2-oxobutyl)-2- naphthamide
Figure imgf000086_0002
10
N-(4-(3,5-dichlorobenzylamino)- 2-oxobutyl)-2-naphthamide
To a solution of 3,5-dichlorobenzylamine (12 mg, 0.068 mmol) in DCM (0.2 ml.) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 ml_) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction. MS (ESI) 415 (M+1 ); HPLC fe 6.00 min. Example 11 - Synthesis of Compound 11 (S)-N-(4-(5-(3-Pbf-guanidino)-2-(Fmoc-amino)- N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide
Figure imgf000087_0001
11
(S)-N-(4-(5-(3-Pbf-guanidino)-2-(Fmoc-amino)- N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide
To a solution of freshly prepared aminoketone 10 in DCM (2 ml.) was added Fmoc-L- Arg(Pbf)-OH (53 mg, 0.082 mmol) followed by DIC (12.5 μl, 0.082 mmol) at room temperature. The resulting mixture was stirred for 2 hrs then the solvent was removed under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc to give the desired product 11 as a white solid. It was used in the next step without further purification. MS (ESI) 1045 (M+1 ); HPLC fe 9.99 min.
Example 12 - Synthesis of Compound 12 (S)-N-(4-(5-(3-Pbf-guanidino)-2-amino-N-(3,5- dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide
Figure imgf000087_0002
12
(S)-N-(4-(5-(3-Pbf-guanidino)-2-amino-N- (3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide
Diethylamine (0.5 ml.) was added to Fmoc-protected 11 (56 mg, 0.054 mmol) at room temperature and the resulting mixture was stirred for 30min. The excess amount of the diethylamine was removed under reduced pressure to give the desired free amine 12. It was used in the next step without further purification. MS (ESI) 823 (M+1 ); HPLC fe 7.49 min. Example 13 - Synthesis of Compound 13 N-(((3S,5S)-3-(3-(3-Pbf-guanidino)propyl)-1- (3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000088_0001
N-(((3lSr,5lSr)-3-(3-(3-Pbf-guanidino)propyl)-l-
(3,5-dichlorobenzyl)-2-oxo-l,4-diazepan-5-yl)methyl)-
2-naphthamide
The amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 ml.) was cyclized by addition of NaBH(OAc)3 (40mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hrs, followed by addition of saturated NaHCO3 aqueous solution (3 ml_). The aqueous layer was extracted with DCM (3 x 3 ml.) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc then EtOAc/IPA (9:1 ) to give the desired product 13 as a white solid. It was used in the next step without further purification. MS (ESI) 807 (M+1 ); HPLC fR 7.75 min.
Example 14 - Synthesis of Compound 100 N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3- guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000088_0002
7V-(((35',55)-l-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)- 2-oxo-l,4-diazepan-5-yl)methyl)-2-naphthamide
A solution of TFA/DCM (2:1 ) (1 ml.) with 5% H2O was added to 13 at room temperature and the resulting mixture was stirred for 4 hrs. The solvents were removed under reduced pressure and the residue was purified by prep HPLC (100% H2O to MeCN/H2O 9:1 , gradient) to give 100 (7.6 mg) as a white solid (TFA salt). The overall yield (from 9) was ca. 18%. MS (ESI) 556.2 (M+1 ); HPLC fe 5.74 min. Example 15 - Synthesis of Compound 14 benzyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate
Figure imgf000089_0001
14 benzyl 2-
(methoxy(methyl)amino)-2- oxoethylcarbamate
To Cbz-glycine (10 g, 47.8 mmol, Aldrich) in DCM (100 ml.) was added BOP reagent (21.5 g, 48.6 mmol) and DIPEA (6.5 ml_, 46.0 mmol). After stirring at room temperature for
10 mins, N,O-dimethylhydroxylamine hydrochloride (4.9 g, 50.2 mmol) and DIPEA (6.5 ml_,
46.0 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue taken up in EtOAc (100 ml_). The organic phase was washed with H2O (3x 100 ml_), saturated sodium bicarbonate solution (3x 100 ml_), H2O (3x 100 ml_), 1 M HCI (3x 100 ml_), brine (3x 100 ml_). The organic phase was dried (MgSO4) and the EtOAc removed to give the Weinreb amide 14 as a white solid (7.78 g,
64%).
Example 16 - Synthesis of Compound 15 benzyl 2-oxobut-3-enylcarbamate
Figure imgf000089_0002
15 benzyl 2-oxobut-3- enylcarbamate
To the Weinreb amide 14 (3.89 g, 15.42 mmol) in DCM (1 OmL) at O0C was added vinyl magnesium bromide (45 mmol) in THF (45 ml_). The reaction was stirred for 2 hrs and monitored by HPLC. The reaction was added to a mixture of ice and 1 M HCI (200 mL). The aqueous mixture was extracted with DCM (3x 100 mL) and washed with 1 M HCI (2x 20OmL) and H2O (3x 10OmL). The organic phase was dried (MgSO4) and the volume reduced to 100 mL by rotary evaporation. The α,β-unsaturated ketone 15 was stored and used in solution without purification. Example 17 - Synthesis of Compound 16 (S)-9-fluorenylmethyl 10-(2,2-diphenylethyl)- 2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8- ylcarbamate
Figure imgf000090_0001
16
GS>9-flιiorenylmethyl 10-(2,2-diphenylethyl)-2,2-dimethyl-18- phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8- ylcarbamate To 2,2-diphenylethylamine (0.95 g, 7.4 mmol) in DCM (10 ml.) was added the αβ- unsaturated ketone 15 (5.7 mmol) in DCM (75 ml_). After stirring at room temperature for 15 mins, Fmoc-L-2,4-diaminobutyric acid(Boc)-OH (2.4 g, 8.55 mmol) and DIC (0.87 ml_, 5.6 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ) to give 16 (1.5 g, 31%)
Alternatively, to 2,2-diphenylethylamine (0.97 g, 7.4 mmol) in DCM (20 ml.) was added the α,β -unsaturated ketone 15 (5.95 mmol) in DCM (4OmL). After stirring at room temperature for 15 mins, Fmoc-L-2,4-diaminobutyric acid(Boc)-OH (2.4 g, 8.55 mmol), DIPEA (2.5 ml.) and HATU (2.3 g, 6.0 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was taken up in EtOAc (100 ml_). The organic layer was washed with saturated sodium bicarbonate solution (2x 100 ml_), saturated ammonium chloride solution (2x 100 ml.) and brine (2x 100 ml_). The organic phase was dried and the solvent removed under reduced pressure. The residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (3:1 to 1 :1 to 0:1 ) to give 16 (0.86 g, 17%). Example 18 - Synthesis of Compound 17 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)- 5-(benzyloxycarbonylaminomethyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000091_0001
17 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-
(benzyloxycarbonylaminomethyl)- 1 -(2,2-diphenylethyl)- 1 ,4-diazepan-2-one
To Compound 16 (1.5 g, 1.8 mmol) in DCM (3 ml.) was added diethylamine (1.5 ml_, 14.5 mmol). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 ml_), sodium triacetoxyborohydride
(0.4 g, 1.9 mmol) was added, and the reaction was stirred overnight at room temperature.
The organic phase was washed with saturated sodium bicarbonate solution (25 ml_), dried
(MgSO4) and the DCM removed to give the cyclised product 17, which was used in the next step without purification.
Example 19 - Synthesis of Compound 18 (3S,5S)-3-(2-te/t-butoxycarbonylaminoethyl)- 5-aminomethyl-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000091_0002
18
(3S,5S)-3-(2-ter^butoxycarbonylaminoethyl)-5- aminomethyl- 1 -(2,2-diphenylethyl)- 1 ,4-diazepan-2-one
To the cyclised product 17 in methanol (5 ml.) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 18 (0.7 g, 83% from 16).
Example 20 - Synthesis of Compound 216 (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2- diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
Figure imgf000092_0001
216
(£)-N-(((35,55)-3-(2-aminoethyl)-l-(2,2-diphenylethyl)-2-oxo-l,4- diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
To the amine 18 (0.06 g, 0.13 mmol) in DCM (5 ml.) was added DIPEA (0.10 ml_), BOP reagent (0.06 g, 0.13 mmol) and 4-chlorocinnamic acid (0.03 g, 0.16 mmol). The reaction was stirred at room temperature overnight. TFA (1 mL) was added and the reaction stirred at room temperature for 1 hrs. Rotary evaporation and preparative HPLC gave 216 (0.058 g, 84%). MS (ESI) 531.4 (M+1 ); HPLC fR min 5.89
Example 21 - Synthesis of Compound 19 (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2- diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
Figure imgf000092_0002
(£)-3-(4-cMorophenyl)-_V-(((3S,5S)-l-(2,2- diphenylethyl)-2-oxo-3-(2-(piperidin- 1 -yl)ethyl)- 1 ,4- diazepan-5-yl)methyl)acrylamide
To the amine 216 (£)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2- aminoethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide (21 mg, 0.05 mmol) in DMF (0.25 mL) was added K2CO3 (5 mg) and 1 ,5-dibromopropane (0.066 mL, 0.5 mmol). The reaction mixture was left at room temperature for 4 hrs. The solvent was removed under high vacuum, and the residue purified by preparative HPLC to give 8 mg (-30%) of 19 as the TFA salt. MS (ESI) 599.4 (M+1 ); HPLC fR min 6.31
Example 22 - Synthesis of Compound 20 (S)-9-fluorenylmethyl 10-(2-phenylbutyl)-2,2- dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-δylcarbamate
Figure imgf000093_0001
20
(5)-9-f luorenylmethyl 10-(2-phenylbutyl)-2,2-dimethyl- 18-phenyl- 4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8- ylcarbamate
To 2-phenylbutylamine hydrochloride (0.26 g, 1.4 mmol) in DCM (10 ml.) and DIPEA (0.25 ml_, 1.8 mmol) was added the α,β-unsaturated ketone 15 (1.06 mmol) in DCM (20 ml_). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (0.7 g, 1.56 mmol) and DIC (0.25 ml_, 1.61 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ), providing Compound 20 as a mixture of diastereomers (0.17 g, 21 %).
Example 23 - Synthesis of Compound 21 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)- 5-(benzyloxycarbonylaminomethyl)-1-(2-phenylbutyl)-1 ,4-diazepan-2-one
Figure imgf000094_0001
21
(3S,5S)-3-(2-ter^butoxycarbonylaminoethyl)-5-
(benzyloxycarbonylaminomethyl)- l-(2-phenylbutyl)- 1 ,4-diazepan-2-one
To Compound 20 (0.17 g, 0.2 mmol) in DCM (3 ml.) was added diethylamine (1.5 ml_). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 ml.) and sodium triacetoxyborohydride (0.1 g, 0.47 mmol) were added and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO4) and the DCM removed to give the cyclised product 21 as a mixture of diastereomers (0.11 g, 100%).
Example 24 - Synthesis of Compound 22 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)- 5-(aminomethyl)-1 -(2-phenylbutyl)-1 ,4-diazepan-2-one
Figure imgf000094_0002
22 (3S,5S)-3-(2-ter^butoxycarbonylaminoethyl)-5-
(aminomethyl)- l-(2-phenylbutyl)- 1 ,4-diazepan-2-one
To the cyclised product 21 (0.11 g) in methanol (5 ml.) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 22 as a mixture of diastereomers (0.11 g, 100%).
Example 25 - Synthesis of Compound 101 (3S,5S)-3-(2-aminoethyl)-5-(Λ/-2- naphthamidomethyl)-1-(2-phenylbutyl)-1 ,4-diazepan-2-one
Figure imgf000095_0001
101
(3S,5S)-3-(2-aminoethyl)-5-(2- naphthamidomethyl)- 1 -(2-phenylbutyl)- 1 ,4-diazepan-2-one
To the amine 22 (0.02 mg, 0.05 mmol) in DCM (1 mL) was added DIPEA (0.1 ml_, 0.7 mmol), BOP reagent (0.02 mg, 0.045 mmol) and 2-naphthoic acid (0.015 mg, 0.09 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 ml.) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave 101 as a mixture of diastereomers (13.4 mg, 57%). MS (ESI) 473.4 (M+1 ); HPLC fR 5.59 min
Example 26 - Synthesis of Compound 23 allyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate
Figure imgf000095_0002
23 allyl 2-(methoxy(methyl)- amino)-2-oxoethylcarbamate
To Alloc-glycine (1.45 g, 9.1 mmol) in DCM (20 mL) was added BOP reagent (3.3 g, 7.46 mmol) and DIPEA (1.5 mL, 10.7 mmol). After stirring at room temperature for 10 mins, N,O-dimethylhydroxylamine hydrochloride (0.8 g, 8.2 mmol) and DIPEA (1.5 mL, 10.7 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue taken up in EtOAc (100 mL). The organic phase was washed with H2O (3x 100 mL), saturated sodium bicarbonate solution (3x 50 mL), H2O (3x 50 mL), 1 M HCI (3x 50 mL), brine (3x 50 mL). The organic phase was dried (MgSO4) and the EtOAc removed to give the Weinreb amide 23 as a white solid (0.43 g, 23%).
Alternatively, fe/t-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate 34 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 ml.) and TFA (3 ml.) were stirred at room temperature 1 hr. The solvent was removed under reduced pressure, followed by addition of
DCM (20 ml.) and then DIPEA until basic. The solution of 2-amino-Λ/-methoxy-Λ/- methylacetamide (GIy Weinreb amide) was cooled to 0° C and allyl chloroformate added (1.4 ml_, 13.2 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was neutralised with 1 M HCI and extracted with EtOAc. The EtOAc was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ), providing 23 (0.86 g, 66%).
Example 27 - Synthesis of Compound 24 allyl 2-oxobut-3-enylcarbamate
Figure imgf000096_0001
24 allyl 2-oxobut-3- enylcarbamate
To the Weinreb amide 23 (0.43 g, 2.1 mmol) in DCM (5 ml.) at 0° C was added vinyl magnesium bromide (10 mmol) in THF (10 ml_). The reaction was stirred for 2 hrs and monitored by HPLC. The reaction was added to a mixture of ice and 1 M HCI (100 ml_). The aqueous mixture was extracted with DCM (3x 50 ml.) and washed with 1 M HCI (2x 100 ml.) and H2O (3x 50 ml_). The organic phase was dried (MgSO4) and the volume reduced to 50 ml. by rotary evaporation. The α,β -unsaturated ketone 24 was stored and used in solution without further purification.
Example 28 - Synthesis of Compound 25 (S)-9-fluorenylmethyl 10-(3,5-dichlorobenzyl)- 2,2-dimethyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8-ylcarbamate
Figure imgf000097_0001
25
(5>9-fluorenylmethyl 10-(3,5-dichlorobenzyl)-2,2-dimethyl- 4,9,13, lβ-tetraoxo-SJV-dioxa-SJOJS-triazaiscos-lQ-en-δ- ylcarbamate
To 3,5-dichlorobenzylamine (0.49 g, 2.8 mmol) in DCM (5 ml.) was added the α,β- unsaturated ketone 24 (2.12 mmol) in DCM (10 ml_). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 ml_, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ), providing compound 25 (0.48 g, 22%).
Example 29 - Synthesis of Compound 26 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)- 5-(allyloxycarbonylaminomethyl)-1-(3,5-dichlorobenzyll)-1 ,4-diazepan-2-one
Figure imgf000097_0002
26
(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-
(allyloxycarbonylaminomethyl)- 1 -(3 ,5 -dichlorobenzyl)- 1 ,4-diazepan-2-one
To Compound 25 (0.48 g, 0.63 mmol) in DCM (3 ml.) was added diethylamine (1.5 ml_). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 ml_), sodium triacetoxyborohydride (0.2 g, 0.94 mmol) was added, and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO4) and the DCM removed to give the cyclised product 26 (0.24 g, 72%).
Example 30 - Synthesis of Compound 27 (3S,5S)-3-(2-te/ϊ-butoxycarbonylaminoethyl)- 5-aminomethyl-1-(3,5-dichlorobenzyl)-1 ,4-diazepan-2-one
Figure imgf000098_0001
27 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5- arainomethyl- 1 -(3 ,5 -dichlorobenzyl)- 1 ,4-diazepan-2-one
To the cyclised product 26 (0.24 g, 0.45 mmol) in DCM (3 ml.) was added 1 ,3- dimethylbarbituric acid (13 mg, 0.08 mmol) and palladium tetrakis triphenylphosphine (5 mg). The reaction was evacuated and stirred and room temperature for 1 hr. The DCM was removed under reduced pressure to give the crude product 27 (0.15 g. 75%) which was used in the next reaction without purification.
Example 31 - Synthesis of Compound 102 (3S,5S)-3-(2-aminoethyl)-5-(2- naphthoylaminomethyl)-1 -(3,5-dichlorobenzyl)-1 ,4-diazepan-2-one
Figure imgf000098_0002
102
(3S,5S)-3-(2-aminoethyl)-5-(2- naphthoylaminomethyl)- 1 -(3,5-dichlorobenzyl)-
1 ,4-diazepan-2-one
To the amine 27 (0.05 mg, 0.1 1 mmol) in DCM (1 ml.) was added DIPEA (0.1 ml_, 0.7 mmol), BOP reagent (0.05 mg, 0.1 1 mmol) and 2-naphthoic acid (0.04 mg, 0.23 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 ml.) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave 102 (48 mg, 90%). MS (ESI) 499.3 (M+1 ); HPLC fR 5.77 min
Example 32 - Synthesis of Compound 28 (3S,5S)-3-(2-tert- butoxycarbonylaminopropyl)-5-[benzyloxycarbonyl(methylamino)methyl]-1-(2,2 diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000099_0001
28
(3S,5S)-3-(2-tert-butoxycarbonylaminopropyl)-
5-[benzyloxycarbonyl(methylamino)methyl]- l-(2,2-diphenylethyl)-l,4-diazepan-2-one
Prepared from Cbz-Sar, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc) according to the procedures of Examples 15-18.
Example 33 - Synthesis of Compound 29 (3S,5S)-3-(2-tert- butoxycarbonylaminopropyl)-5-(methylamino)methyl-1-(2,2-diphenylethyl)-1 ,4 diazepan-2-one
Figure imgf000099_0002
29
(3lSr,55r)-3-(2-?ert-butoxycarbonylaminopropyl)-
5-(methylamino)methyl- l-(2,2-diphenylethyl)-l,4-diazepan-2-one The cyclised product 28 (1.9 g) was dissolved in methanol (10 mL) with catalytic Pd/C and hydrogenated under a hydrogen atmosphere (40 psi) overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 29 (1.86 g, 97%).
Example 34- Synthesis of Compound 103 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2- diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naphthamide
Figure imgf000100_0001
103 iV-(((35,55)-3-(3-aminopropyl)-l-(2,2- diphenylethyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)-6- bromo-./V-methyl-2-naphthamide
The amine 29 was coupled with 6-bromo-2-naphthoic acid then deprotected with TFA according to Example 20. Rotary evaporation and preparative HPLC gave 103 (7.8 mg). MS (ESI) 629.4 (M+1 ); HPLC fR 6.27 min.
Example 35 - Synthesis of Compound 30 (3S,5S)-3-(te/t-butoxycarbonylaminopropyl)- 5-(6-bromo-2-naphthamidomethyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000100_0002
(3S,5S)-3-(ter^butoxycarbonylaminopropyl)-5-(6- bromo-2-naphthamidomethyl)- l-(2,2-diphenylethyl)-l,4-diazepan-2-one
Prepared from 2,2-diphenylethylamine, Fmoc-L-Orn(Boc) and 6-bromo-2-naphthoic acid according to the procedures of Examples 17-20, without the TFA deprotection step of Example 20. Example 36 - Synthesis of Compound 104 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2- diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
Figure imgf000101_0001
104 iV-(((35,55)-3-(3-aminopropyl)-l-(2,2- diphenylethyl)-4-methyl-2-oxo- 1 ,4-diazepan-5- yl)methyl)-6-bromo-2-naphthamide
Compound 30 (20.8 mg) was dissolved in DMF (1 ml.) and treated with methyl iodide (6 μl_) at room temperature for 1 week. Additional methyl iodide (0.5 ml.) and K2CO3 were added and the reaction left at room temperature for an additional 2 days. TFA (2 ml.) was added and the reaction stirred at room temperature for 2h. Rotary evaporation followed by evaporation under high vacuum then preparative HPLC gave 104 (8.5 mg). MS (ESI) 629.3 (M+1 ); HPLC fR 6.22 min.
Example 37 - Synthesis of Compound 31 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2- diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000101_0002
31 iV-(((35',55)-3-(3-aminopropyl)-l-(2,2-diphenylethyl)-2-oxo-l,4- diazepan-5-yl)methyl)-2-naphthamide Obtained from 9, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc) according to
Examples 10-13. The Boc group was removed under standard conditions to give the free amine. MS(ESI) 535 (M+1 ); HPLC fR 5.78 min Example 38 - Synthesis of Compound 32 N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3- (piperidin-1-yl)propyl)-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000102_0001
32
N-(((35,55)-l-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-l- yl)propyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
The amine 31 (0.79 g, 1.48 mmol), 1 ,5-dibromopentane (0.2 ml_, 1.48 mmol) and K2CO3 (0.79 g) in DMF (1 1 ml.) was stirred at room temperature for 4 h. The resulting mixture was diluted with ethylacetate (30 ml_), washed with H2O (5 x 30 ml_), brine (10 ml.) and dried over MgSO4. Purification by preparative HPLC yielded 32 (0.23 g, 25%) MS(ESI) 603.3 (M+1 ); HPLC fR 6.04 min
Example 39 Synthesis of Compound 33 tert-butyl
(methylamino)(methylthio)methylenecarbamate i
Figure imgf000102_0002
33 tert-butyl (methylamino)(methylthio)- methylenecarbamate
DIAD (2.7 mL, 13.8 mmol) was added to a stirred mixture of thiopseudourea (2.0 g, 6.9 mmol), PPh3 (3.6g, 13.8 mmol), and MeOH (0.55 mL, 13.8 mmol) in dry THF (5 mL) at 00C under nitrogen. Stirring continued at 00C for 3 h then at room temperature for 16 h. The solvent was removed under reduced pressure and the resulting residue was re-dissolved in EtOAc, washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL), and dried over MgSO4. Purification by silica gel chromatography using 20% EtOAc in petroleum ether as eluent gave 33 (1.63 g, 78%) as a colourless oil. MS(ESI) 305 (M+1 ); HPLC fR 7.97 min. Example 40 - Synthesis of Compound 105 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3- methylguanidino)propyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000103_0001
105 iV-(((3S,5S)-l-(2,2-diphenylethyl)-3-(3-(3- methylguanidino)propyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)-2- naphthamide
A mixture of Compound 31 (10 mg, 0.019 mmol), guanylating agent 33 (56.9 mg, 0.19 mmol) and DIPEA (6.6 μl_, 0.038 mmol) in DCM (5 ml.) was stirred at room temperature for 16 h. TFA (5 ml.) was added, and the resulting mixture was stirred at room temperature for 30 min. Solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC to give 105 (0.53 mg, 4.7%) as a white solid. MS(ESI) 591.3 (M+1 ); HPLC fe 5.94 min
Example 41 - Synthesis of Compound 34 tert-butyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate (Boc-Gly Weinreb amide)
Figure imgf000103_0002
34 tert-butyl 2-(methoxy(methyl)amino)- 2-oxoethylcarbamate
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 mL), H2O (3 x 120 mL), saturated NaHCO3 aqueous solution (3 x 120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 34 as a white solid (20 g, 80%), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min. Example 42 - Synthesis of Compound 35 tert-butyl 2-oxobut-3-enylcarbamate
Figure imgf000104_0001
35 tert-butyl 2-oxobut-3 -enylcarbamate
At 00C a solution of vinylmagnesium bromide in THF (184 ml_, 1 M) was added in one portion to Weinreb amide 34 (20 g, 91.6 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 h, and poured into a 1 N HCI/ice mixture (400 ml_). The aqueous mixture was extracted with DCM (5 x 100 ml_), the combined DCM extract was washed with 1 N HCI (2 x 100 ml_), saturated NaHCC>3 aqueous solution (100 ml.) and brine (100 ml_), then dried over MgSO4. Solvent was removed under reduced pressure gave the ketone 35 (12.9 g, 76%) as a pale yellow oil, which was used in the next step without further purification. MS(ESI) 186 (M+1 ); HPLC fR 4.19 min.
Example 43 - Synthesis of Compound 36 tert-butyl 4-(2,2-diphenylethylamino)-2- oxobutylcarbamate
Figure imgf000104_0002
36 tert-butyl 4-(2,2-diphenylethylamino)-2-oxobutylcarbamate To a stirred solution of 2,2-diphenylethylamine (0.33 g, 1.66 mmol) in DCM (10 ml.) was added α.β-unsaturated ketone 35 (0.31 g, 1.66 mmol) at room temperature. Stirring continued for 2 h; the crude reaction mixture of 36 was used in the next step without purification. MS(ESI) 383 (M+1 ); HPLC fR 5.98 min
Example 44 - Synthesis of Compound 37 (S)-9-fluorenylmethyl 1-phenyl-10-(2,2- diphenylethyl)-18,18-dimethyl-4,9,13,16-tetraoxo-2,17-dioxa-4,10,15-triazanonadecan-8- ylcarbamate
Figure imgf000105_0001
(S)-9-f luorenylniethyl 1 -phenyl- 10-(2,2-diphenylethyl)-
18,18-dimethyl-4,9,13,16-tetraoxo-2,17-dioxa-4,10,15- triazanonadecan-8-ylcarbamate
To a stirred mixture of Fmoc-L-Orn(Cbz)-OH (1.78 g, 3.65 mmol), DIPEA (0.64 ml_, 3.65 mmol) and HATU (1.39 g, 3.65 mmol) in DCM (10 ml.) was added a solution of amine 36 at room temperature. Stirring continued for 3 h, the reaction mixture was washed with saturated NaHCOs aqueous solution (20 ml.) and brine (20 ml_), and dried over MgSO4. The solvent was removed under reduced pressure, with the crude 37 used in the next step without further purification. MS(ESI) 853 (M+1 ); HPLC fR 9.90 min.
Example 45 - Synthesis of Compound 38 (S)-(9H-fluoren-9-yl)methyl 7-((4-(tert- butoxycarbonylamino)-3-oxobutyl)(2,2-diphenylethyl)carbamoyl)-3-methyl-1 ,3- diazepane-1 -carboxylate
Figure imgf000105_0002
38
(S>(9H-fluoren-9-yl)methyl 7-((4-(/ert- butoxycarbonylamino)-3-oxobutyl)(2,2- diphenylethyl)carbamoyl)-3 -methyl- 1,3- diazepane- 1 -carboxylate
A mixture of 37 (136 mg, 0.159 mmol) and Pd/C (20 mg) in ethanol (5 ml.) was shaken under H2 at 30 psi for 16 h, then filtered, concentrated under reduced pressure to give the crude amine (90 mg, 78%). The amine (90 mg, 0.125 mmol) was treated with excess formaldehyde solution in H2O (37 mmol) in MeOH (5 mL) followed by sodium triacetoxyborohydride (23.5 mg, 0.375 mmol). After 1 h, the reaction mixture was washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude material was used in the next step without further purification. MS(ESI) 745 (M+1 ); HPLC ; HPLC fR 7.83 min.
Example 46 - Synthesis of Compound 39 (S)-(9H-fluoren-9-yl)methyl 7-((4-(2- naphthamido)-3-oxobutyl)(2,2-diphenylethyl)-carbamoyl)-3-methyl-1 ,3-diazepane-1- carboxylate
Figure imgf000106_0001
39
(S)-(9H-fluoren-9-yl)methyl 7-((4-(2- naphthamido)-3-oxobutyl)(2,2- diphenylethyl)carbamoyl)-3-methyl- 1,3- diazepane- 1 -carboxylate
Compound 38 (8 mg, 0.011 mmol) was treated with 1 :1 v/v trifluoacetic acid/DCM mixture (2 mL) for 30 min at room temperature. The mixture was concentrated under reduced pressure, re-dissolved in DCM (5 mL), washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL), dried over MgSO4 and filtered. The filtrate was then treated with a mixture of 2-naphthoic acid (1.8 mg, 0.011 mmol), DIPEA (5.7 μL, 0.033 mmol) and BOP (4.8 mg, 0.011 mmol) in DCM (1 mL) with stirring at room temperature. After 3 h, the reaction mixture was washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude material was used in the next step without further purification. MS(ESI) 799 (M+1 ); HPLC fR 7.90 min. Example 47 - Synthesis of Compound 106 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3- (methylamino)propyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-naphthamide
Figure imgf000107_0001
106
N-(((3S,5S)-l-(2,2-diphenylethyl)-3-(3-(methylamino)propyl)-2- OXO- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide
To a stirred solution of 39 (0.01 1 mmol) in DCM (5 ml.) was added diethylamine (5 ml.) at room temperature. The reaction was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in DCM (5 ml.) followed by addition sodium triacetoxyborohydride (5 mg, 0.08 mmol) at room temperature. Stirring continued for 1 h, with the resulting mixture washed with saturated NaHCOs aqueous solution (10 ml.) and brine (10 ml_), dried over MgSO4, filtered and concentrated. Purification by preparative HPLC yielded 106 (0.21 mg) as a white solid. MS(ESI) 549.3 (M+1 ); HPLC fR 5.93 min
Example 48 - Synthesis of Compound 40 (S)-2-(allyloxycarbonylamino)-3-(naphthalen- 2-yl)propanoic acid
Figure imgf000107_0002
40
((S)-2-(allyloxycarbonylamino)-3-(naphthalen-2- yl)propanoic acid To a stirred mixture of L-3-(2-naphthyl)alanine hydrochloride (5.0 g, 19.8 mmol),
Na2CO3 (7.3 g, 69.3 mmol) and 1 ,4-dioxane (30 mL) in H2O (50 mL) was added allylchloroformate (2.1 mL, 19.8 mmol) at 00C. The resulting mixture was stirred for 16 h then concentrated under reduced pressure. The residue was diluted with ethylacetate (50 mL), and at 00C acidified to pH 2. The aqueous phase was extracted with ethylacetate (3 x 20 mL), the combined organic phase was washed with H2O (50 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 40 as a colourless oil (5.8 g, 97%), which was used in the next step without further purification. HPLC fe 6.60 min. Example 49 - Synthesis of Compound 41 (S)-allyl 1-(methoxy(methyl)amino)-3- (naphthalen-2-yl)-1-oxopropan-2-ylcarbamate
Figure imgf000108_0001
41
(S)-aHyl l-(methoxy(methyl)amino)-3- (naphthalen-2-yl)- 1 -oxopropan-2-ylcarbamate
To a stirred mixture of the acid 40 (5.84 g, 19.5 mmol), DIPEA (3.7 ml_, 2.09 mmol) and BOP (8.63 g, 19.5 mmol) in DCM (10 ml.) was added a pre-mixed solution of N,O- dimethylhydroxylamine hydrochloride (1.9 g, 19.5 mmol) and DIPEA (7.3 ml_, 41.6 mmol) in
DCM (10 ml.) at room temperature. Stirring continued for 16 h the reaction mixture was washed with 1 N HCI (3 x 60 ml_), H2O (3 x 60 ml_), saturated NaHCO3 aqueous solution (3 x
60 ml.) and brine (60 ml_), dried over MgSO4. Purification by silica gel chromatography using 20% ethylacetate in petroleum ether as eluent gave 41 (4.83 g, 71%) as a colourless oil. MS
(ESI) 343 (M+1 ); HPLC fR 7.07 min.
Example 50 - Synthesis of Compound 42 (S)-allyl 1-(naphthalen-2-yl)-3-oxopent-4-en-2- ylcarbamate
Figure imgf000108_0002
42
(S^-allyl 1 -(naphthalen-2-yl)-3-oxopent-4-en-2- ylcarbamate
At 0° C a solution of vinylmagnesium bromide in THF (1 1.5 ml_, 1 M) was added in one portion to Weinreb amide 41 (1.58 g, 4.62 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 h, and poured into a 1 N HCI/ice mixture (50 ml_). The aqueous mixture was extracted with DCM (3x 20 ml_), the combined DCM extract was washed with 1 N HCI (50 ml_), saturated NaHCO3 aqueous solution (50 ml.) and brine (20 ml_), dried over MgSO4. Solvent was removed under reduced pressure producing the product 42 (1.14 g, 80%), which was used in the next step without further purification. MS(ESI) 310 (M+1 ); HPLC fR 7.51 min. Example 51 - Synthesis of Compound 43 (S)-allyl 5-(2,2-diphenylethylamino)-1- (naphthalen-2-yl)-3-oxopentan-2-ylcarbamate
Figure imgf000109_0001
(5)-allyl 5 -(2,2-diphenylethylamino)- 1 - (naphthalen-2-yl)-3-oxopentan-2-ylcarbamate
To a stirred solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) in DCM (55 ml.) was added the vinyl ketone 42 (0.71 g, 2.3 mmol) in one portion. Stirring continued for 2 h, with the reaction mixture used in the next step without purification. MS(ESI) 507 (M+1 ); HPLC fR 7.22 min.
Example 52 - Synthesis of Compound 44 (S)-allyl 5-(Λ/-(Boc-L-Arg(Cbz)2) 2,2- diphenylethylamino)-1-(naphthalen-2-yl)-3-oxopentan-2-ylcarbamate
Figure imgf000109_0002
44
(S)-allyl 5-(N-(Boc-L-Arg(Cbz)2) 2,2- diphenylethylamino)- 1 -(naphthalen-2-yl)-3- oxopentan-2-ylcarbamate
To a stirred solution of the amine adduct 43(2.3 mmol) was added a mixture of Boc- Arg(Cbz)2-OH (1.25 g, 2.3 mmol), DIPEA (0.8 ml_, 4.6 mmol) and HATU (0.87 g, 2.3 mmol) in DCM (15 ml.) at room temperature. Stirring continued for 16 h, after which the reaction mixture was washed with saturated NaHCO3 aqueous solution (3x 20 ml.) and brine (10 ml.) then dried over MgSO4. Purification by silica gel chromatography using 20% ethylacetate in petroleum ether as eluent gave 44 as a colourless oil (708 mg, 30% over 3 steps). MS(ESI) 1031 (M+1 ); HPLC fR 10.80 min.
Example 53 - Synthesis of Compound 45 allyl (S)-1-((3S,5RS)-1-(2,2-diphenylethyl)-3- (bis Cbz 3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)-2-(naphthalen-2- yl)ethylcarbamate
Figure imgf000110_0001
allyl (S)-I -((35,5RS)- l-(2,2-diphenylethyl)-3-(bis Cbz 3- guanidinopropyl)-2-oxo- 1 ,4-diazepan-5-yl)-2-(naphthalen-2- yl)ethylcarbamate
To a stirred solution of acyclic intermediate 44 (0.48 g, 0.47 mmol) in DCM (5 ml.) was added TFA (5 ml.) at room temperature. Stirring continued for 30 min, after which the mixture was diluted with DCM (20 ml.) then washed with saturated NaHCO3 aqueous solution (3 x 20 ml.) and brine (10 ml_), and dried over MgSO4. To the resulting solution was added sodium triacetoxyborohydride (0.2 g, 0.94 mmol) with stirring at room temperature, after 30 min the mixture was washed with saturated NaHCO3 aqueous solution (3 x 20 ml.) and brine (10 ml_), then dried over MgSO4. The crude 45, a mixture of diastereomers at the diazepan-2-one C5, was used in the next step without further purification. MS(ESI) 915 (M+1 )
Example 54 - Synthesis of Compound 46 bis (Cbz) 1-(3-((2S,7RS)-7-((S)-1-amino-2- (naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1 ,4-diazepan-2-yl)propyl)guanidine
Figure imgf000111_0001
46 bis (Cbz) l-(3-((25,7R5)-7-((5)-l-amino-2-(naphthalen-2-yl)ethyl)- 4-(2,2-diphenylethyl)-3-oxo-l,4-diazepan-2-yl)propyl)guanidine
A mixture of compound 45 (36 mg, 0.039 mmol), 1 ,3-dimethylbarbituric acid (7.4 mg, 0.047 mmol) and Pd(PPh3)4 in DCM (5 ml.) was stirred at room temperature under vacuum for 4 h. The resulting mixture was used in the next step without further purification. MS(ESI) 832 (M+1 )
Example 55 - Synthesis of Compounds 107 and 47 N-((S)-1-((3S,5S)-1-(2,2- diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)-2-(naphthalen-2- yl)ethyl)acetamide and N-((S)-1 -((3S,5R)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2- oxo-1 ,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide
Figure imgf000111_0002
107 47
N-((5>l-((3S,5S>l-(2,2-diphenylethyl)-3-(3- N-((5)-l-((35,5Λ)-l-(2,2-diphenylethyl)-3-(3- guanidinopropyl)-2-oxo- 1 ,4-diazepan-5-yl)-2- guanidinopropyl)-2-oxo- 1 ,4-diazepan-5-yl)-2-
(naphthalen-2-yl)ethyl)acetamide (naphthalen-2-yl)ethyl)acetamide
A solution of the amine 46 (0.09 mmol) in DCM (5 ml.) was treated with acetic anhydride (8.6 μl_, 0.09 mmol) with stirring at room temperature. After 3 h the mixture was concentrated, re-dissolved in EtOAc, washed with saturated NaHCO3 aqueous solution (10 ml.) and brine (10 ml_), dried over MgSO4, then concentrated under reduced pressure. The residue was dissolved in MeOH (10 ml_), Pd/C (5 mg) was added, and the solution shaken under H2 at 20 psi for 16 h. The reaction was filtered, concentrated and purified by preparative HPLC to give the minor diastereomer 107 (3 mg) and the major diastereomer 47 (6 mg) as white solids. 107: MS(ESI) 606.4 (M+1 ); HPLC fR 6.033 min, 47: MS(ESI) 606.3 (M+1 ); HPLC fR 6.046 min
Example 56 - Synthesis of Compounds 48 and 49 (S)-2-acetamido-N-((S)-1-((3S,5S)-1- (2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)-2-(naphthalen-2- yl)ethyl)-3-(1 H-imidazol-5-yl)propanamide and (S)-2-acetamido-N-((S)-1-((3S,5R)-1-(2,2- diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)- 3-(1 H-imidazol-5-yl)propanamide
Figure imgf000112_0001
(5)-2-acetamido-.V-((5)-l -((35,55)- 1 -(2,2- (5)-2-acetamido-.V-((5)-l -((35,5R)-I -(2,2- diphenylethyl)-3-(3-guanidinopropyl)-2-oxo- diphenylethyl)-3-(3-guanidinopropyl)-2-oxo- l,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)- l,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-
3-(lH-imidazol-5-yl)propanamide 3 -( 1 H -imidazol- 5 -yl)propanamide
To a stirred mixture of Ac-L-Ηis-OΗ (33.6 mg, 0.156 mmol), DIPEA (1 12.5 μL, 0.312 mmol) and BOP (68.8 mg, 0.156 mmol) in DMF (1 mL) was added the amine 46 (0.039 mmol) at room temperature. Stirring continued for 16 h, then the reaction mixture was diluted with DCM/Η2O mixture (10 mL, 1 :1 v/v), and the aqueous phase was extracted with DCM (3 x 5 mL). The combined DCM extracts were washed with saturated NaHCO3 aqueous solution (3 x 20 mL) and brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was re-dissolved in MeOH (5 mL), and Pd/C (20 mg) was added. The resulting mixture was shaken under H2 at 30 psi for 16 h, then was filtered, concentrated and purified by preparative HPLC to give the minor diastereomer 48 (1.9 mg) and the major diastereomer 49 (0.9 mg) as white solids. 48: MS(ESI) 743.4 (M+1 ); HPLC fR 5.489 min 49: MS(ESI) 743.4 (M+1 ); HPLC fR 5.555 min Example 57 - Synthesis of Compounds 50 and 51 1-(3-((2S,7S)-7-(N-R1 (R)-1-amino-2- (naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1 ,4-diazepan-2-yl)propyl)guanidine
Figure imgf000113_0001
50, 51
1-(3-((2SJS)-I-(N-Rl (#)-l-amino-2-(naphthalen-2- yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo- 1 ,4-diazepan-2- yl)propyl)guanidine
Compounds 50 and 51 were prepared in the same fashion as Compounds 107 and 48 using the procedures described in Examples 48-56, but with D-(2-naphthyl)alanine hydrochloride as the starting material.
Figure imgf000113_0003
Examples 58-66: Synthesis via Scheme 2: Preparation of all Four Diastereomers of N- ((1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide 52
Figure imgf000113_0002
_V-((l-(2,2-diphenylethyl)-3-(3- guanidinopropyl)-2-oxo- 1 ,4-diazepan-5- yl)methyl)-2-naphthamide Example 58 - Synthesis of Compound 53 2,2-dimethyl-10-(2,2-diphenylethyl)-4,7,11- trioxo-3,12-dioxa-5,10-diazapentadec-14-ene
Figure imgf000114_0001
53
2,2-dimethyl-10-(2,2-diphenylethyl)-4,7,l l- trioxo-3 , 12-dioxa-5 , 10-diazapentadec- 14- ene
2,2-diphenylethylamine (3g) was added to Boc-vinylketone 35 (2.8g) as in Example 43. To the crude adduct 36 was added Alloc-CI (1.6 mL) and the reaction stirred until TLC indicated consumption of the secondary amine. THE solvent was evaporated and the residue purified by column chromatography (SiO2 gel, pet. ether/EtOAc) to give 3.2 g (57%) of 53.
Example 59 Synthesis of Compound 54 (S)-allyl 2-amino-5- (benzyloxycarbonylamino)pentanoate L-H-Orn(Cbz)-Oallyl
Figure imgf000114_0002
54
(5r)-allyl 2-amino-5- (benzyloxycarbonylamino)pentanoate
H-L-Orn(Cbz)-OH (6.66g, 25 mmol), allyl alcohol (17.56 mL, 25 mmol) and p-TsOH (5.7g, 30 mmol) were dissolved in benzene (200 mL) and refluxed under Dean-Stark conditions for 5h. The majority of the solvent was then distilled off, with the remainder removed under vacuum. The resulting solid was recrystallized from DCM, filtered and dried to give 11.19g (94%) of the tosylate salt. To obtain the free amine the solid was dissolved in DCM, washed with sat. NaHCO3, the aqueous layer washed with DCM (3x), and the organic layers dried over MgSO4 and evaporated to dryness. Example 60 Synthesis of Compound 55 (R)-allyl 2-amino-5-
(benzyloxycarbonylamino)pentanoate D-H-Orn(Cbz)-Oallyl
Figure imgf000115_0001
55
(R)-allyl 2-amino-5- (benzyloxycarbonylamino)pentanoate
H-D-Orn(Cbz)-OH (6.66g, 25 mmol) was converted into 10.93 g (91%) of the tosylate salt of 55 as in Example 59, then converted into the free amine.
Example 61 - Synthesis of Compound 56 (2R)-allyl 5-(benzyloxycarbonylamino)-2-(10-
(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7- ylamino)pentanoate
Figure imgf000115_0002
56
(2R)-allyl 5-(benzyloxycarbonylamino)-2-(10-(2,2- diphenylethyl)-2,2-dimethyl-4,l l-dioxo-3,12-dioxa-
5,10-diazapentadec-14-en-7-ylamino)pentanoate
The protected aminoketone 53 (746 mg, 1.6 mmol), D-Orn(Cbz)-Oallyl 55 (538 mg,
1.76 mmol) and NaBH(OAc)3 (678 mg, 3.2 mmol) in a minimum volume of DCM were stirred for 24 h. A drop of AcOH was added just before workup, at which point saturated NaHCO3 was added, extracted with DCM (3x), and the organic extracts combined and washed with saturated NaHCO3 and H2O, dried over MgSO4, and evaporated to dryness. The product was purified by column chromatography (SiO2 gel, pet. ether/EtOAc) to give 890 mg (74%) of 56 as a mixture of diastereoisomers.
Example 62 - Synthesis of Compound 57 (2S)-allyl 5-(benzyloxycarbonylamino)-2-(10-
(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7- ylamino)pentanoate
Figure imgf000116_0001
57
(2S)-al\y\ 5-(benzyloxycarbonylamino)-2-(10-(2,2- diphenylethyl)-2,2-dimethyl-4,l l-dioxo-3,12-dioxa-
5,10-diazapentadec-14-en-7-ylamino)pentanoate
Protected aminoketone 53 and L-Orn(Cbz)-Oallyl 54 (592 mg, 1.93 mmol) were converted into a mixture of the set of diasteromers 57 (925 mg, 76%) following the procedures of Example 61.
Example 63 - Synthesis of Compounds 58 and 59 (3R,5S)-5-(N-Boc aminomethyl)-3-(N- Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one and (3R,5R)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000117_0001
58 59
(3R, 5S)S-(N -Boc aminomethyl)-3-(N- (3tf,5tf)-5-(N-Boc aminomethyl)-3-(N-
Cbz 3-aminopropyl)-l-(2,2- Cbz 3-aminopropyl)-l-(2,2- diphenylethyl)- 1 ,4-diazepan-2-one diphenylethyl)- 1 ,4-diazepan-2-one
The Alloc/allyl protected derivative 56 (840 mg, 1.1 1 mmol) was dissolved in a minimum of DCM. 1 ,3-Dimethylbarbituric acid (346 mg, 2.22 mmol) and catalytic Pd(PPh3)4 were added, and the reaction degassed under vacuum, sealed and stirred overnight. The reaction was diluted to 50 ml. with DCM, DIPEA (430 mg, 3.33 mmol) and BOP (540 mg, 1.22 mmol) were added, and the reaction stirred for 30 min. The DCM was removed under vacuum and the residue taken up in EtOAc, washed (saturated NaHCOs, H2O, saturated NaCI), dried (MgSO4) and evaporated to dryness (TLC: EtOAc, 2 spots, Rf 0.33 and 0.57). The two diasteromeric products were separated by column chromatography (SiO2 gel, pet. ether/EtOAc) to give 362 mg of the earlier eluting (3R,5S) isomer 58, and 342 mg of the later eluting (3R,5R) isomer 59.
Example 64 - Synthesis of Compounds 96 and 97 (3S,5R)-5-(N-Boc aminomethyl)-3-(N- Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one and (3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000118_0001
60 61
(3R, 5S)S-(N -Boc aminomethyl)-3-(N- (3tf,5tf)-5-(N-Boc aminomethyl)-3-(N-
Cbz 3-aminopropyl)-l-(2,2- Cbz 3-aminopropyl)-l-(2,2- diphenylethyl)- 1 ,4-diazepan-2-one diphenylethyl)- 1 ,4-diazepan-2-one The (3S,5R) (312 mg) and (3S,5S) (331 mg) isomers were obtained from the L-Orn- derived acyclic material 57 (870 mg) following the procedure of Example 63.
Example 65 - Synthesis of Compounds 62-65 5-(N-Boc aminomethyl)-3-(N,N'-Cbz2 3- guanidinopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
Figure imgf000118_0002
62-65
The Orn Cbz group of 58 was removed by hydrogenation (H2, 30 psi) over catalytic Pd/C in methanol overnight. The solution was filtered through Celite and evaporated to give a solid. A solution of the resulting amine (187 mg, 0.39 mmol) in DCM was mixed with a solution of the guanylating reagent CbzNHC(=NCbz)NHTf (196 mg, 0.43 mmol) in DCM. TEA (43 mg, 0.43 mmol) was added, and the reaction stirred overnight. The solution was diluted with DCM, washed (KHSO4, sat. NaHCO3, brine), dried (MgSO4) and evaporated to dryness, then purified by flash chromatography over SiO2 using hexanes/EtOAc as eluent, to give (3R,5S) 62 (182 mg, 59%). The other isomers 59-61 were converted in a similar manner to give: 63 (3R,5R): 171 mg (68%) from 148 mg of amine, 64 (3S,5S): 80 mg (65%) from 72 mg of amine, 65 (3S,5R):142 mg (58%) from 144 mg of amine
Example 66 - Synthesis of Compounds 66-69
66 N-(((3R,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
67 N-(((3R,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
68 N-(((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
69 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
Figure imgf000119_0001
7V-(((3i?,5S>l-(2,2-diphenylethyl)-3-(3- 7V-(((3i?,5i?)-l-(2,2-diphenylethyl)-3-(3- guanidinopropyl)-2-oxo-l,4-diazepan-5- guanidinopropyl)-2-oxo-l,4-diazepan-5- yl)methyl)-2-naphthamide yl)methyl)-2-naphthamide
Figure imgf000119_0002
68 69
7V-(((3,S,5i?)-l-(2,2-diphenylethyl)-3- 7V-(((35,55)-l-(2,2-diphenylethyl)-3-(3-
(3-guanidinopropyl)-2-oxo-l ,4- guanidinopropyl)-2-oxo-l,4-diazepan-5- diazepan-5-yl)methyl)-2-naphthamide yl)methyl)-2-naphthamide The Boc derivative 63 (180 mg) in DCM (1 ml.) was treated with TFA (1 ml.) for 20 ml_. The solvent was removed by evaporation, a solution of NaHCOs was added, and extracted 3x with DCM. The dichoromethane solution was dried over MgSO4, filtered and evaporated to dryness. A portion (56 mg, 0.086 mmol) of the crude deprotected amine in DCM was stirred with 2-naphthoic acid (16 mg), DIPEA (60 uL) and BOP (42 mg) for 30 min. MeOH was added and the reaction stirred overnight. The reaction was filtered, then purified by flash chromatography over SiO2 using petroleum ether/EtOAc as eluent, to give the (3R,5R) isomer (43 mg, 94%). The other isomers were converted in a similar manner to give the protected derivatives: (3R,5S): 41 mg (85%) from 60 mg 62, (3S,5R): 27 mg (70%) from 40 mg 65 , and (3S,5S): 13 mg (74%) from 20 mg 64
Each compound was dissolved in dioxane:MeOH and hydrogenated over catalytic Pd/C under 30 psi H2 overnight. The solution was filtered through Celite and evaporated to give a solid. 66 (3R,5S): 27mg (96%) from 41 mg, 67 (3R,5R): 25mg (85%) from 43 mg, 68 (3S,5R): 11 mg (quantitative) from 13 mg, and 69 (3S,5S): 3 mg (73%) from 6 mg.
Figure imgf000120_0002
Example 67 - Synthesis of Compound 70 6-chloro-2-naphthoic acid
Figure imgf000120_0001
70
6-chloro-2 -naphthoic acid
A suspension of 6-bromo-2-naphthoic acid (3.0 g, 11.47 mmol), CuCI (1 1.7 g, 114.64 mmol) and CuI (2.19 g, 1 1.50 mmol) in degassed DMF (45 ml.) was heated to reflux under argon in dark for 4 hrs. After cooling to room temperature, the solution was decanted into H2O (200 ml.) and the resulting mixture was extracted with EtOAc (2 x 500 ml_). The combined organic layers were then washed with H2O (4 x 500 ml.) followed by brine (1 x 500 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to dryness. The residue was trituated with CH3CN and the solid obtained was then re-crystallized from EtOAc to give the pure product 70 (2.2 g, 93%) as a off-white solid. HPLC fe 6.47 min. Example 68 - Synthesis of Compound 71 (S)-2-phenylbutanol
Figure imgf000121_0001
71
To a suspension of sodium borohydride (2.36 g, 62.4 mmol) in THF (50 ml.) was added a solution of (S)-2-phenylbutyric acid (4.27 g, 26.0 mmol) in THF (40 ml.) slowly at O0C. The mixture was stirred until the evolution of gas ceased. A solution of iodine (6.60 g, 26.0 mmol) in THF (40 ml.) was then added slowly at 0 0C. After addition, the resulting mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction solution was then slowly poured into a 1 N HCI solution (280 ml.) and the resulting mixture was diluted with EtOAc (250 ml_). The aqueous layer was extracted with EtOAc (150 ml. x 3) and the combined organic layers were then washed with saturated NaHCO3 (aq), 0.5 M Na2S2O3 (aq) and brine. This organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (Petroleum etheπEtOAc 4:1 ) gave the desired product 71 as a colorless oil in quantitative yield. HPLC fR 5.24 min.
Example 69 - Synthesis of Compound 72 (S)-1-mesyloxy2-phenylbutane
Figure imgf000121_0002
To a mixture of 71 (3.9 g, 26.0 mmol) and triethylamine (5.5 ml_, 39.5 mmol) in DCM (90 ml.) was added a solution of methanesulfonyl chloride (4.47 g, 39.0 mmol) in DCM (30 ml.) slowly at O0C. After addition, the resulting mixture was allowed to warm to room temperature and stirred for 2 hrs. 1 N HCI (70 ml.) was then added to the above mixture and the aqueous layer was extracted with DCM (1 x 70 ml_). The combined organic layers were washed with brine (150 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product 72 as a colorless oil. This crude product was used in the next step without further purification. HPLC fe 6.48 min.
Example 70 - Synthesis of Compound 73 (S)-1-azido-2-phenylbutane
Figure imgf000121_0003
A suspension of 72 (5.93 g, 26.0 mmol) and sodium azide (5.7 g, 78.0 mmol) in DMF (60 ml.) was heated at 850C for 3 hrs. After cooling to room temperature, the mixture was diluted with H2O (200 ml.) and extracted with EtOAc (250 ml_). The organic layer was then washed with H2O (4 x 150 ml.) followed by brine (150 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (100% petroleum ether as the eluent) gave the pure product 73 (4.03 g, 88%) as a colorless oil. HPLC fe 7.67 min.
Example 71 - Synthesis of Compound 74 (S)-2-phenylbutylamine
Figure imgf000122_0001
A mixture of 73 (4.0 g, 22.8 mmol) and Lindlar's catalyst (1.5 g) in EtOAc (50 ml.) was shaken at room temperature under H2 (40 psi) over-night. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the crude product 74 (3.4 g, 100%) as a light yellowish oil. This crude product was used for the conjugate addition reactions without further purification. MS (ESI) 150 (M+1 ); HPLC fe 1.84 min.
Example 72 - Synthesis of Compounds 75, 76, 270,383,386-389
270 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
383 6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan-
5-yl)methyl)-2-naphthamide
386 6-chloro-N-(((3R,5R)-2-oxo-1 -((R)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide 387 6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan-
5-yl)methyl)-2-naphthamide
388 6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
75 6-chloro-N-(((3S,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
76 6-chloro-N-(((3R,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
389 6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
Figure imgf000123_0001
Compounds 75, 76, 270, 383, and 386-389 were prepared following similar procedures as used to prepare Compounds 102-104 (Scheme 2 route). In addition, compounds 270, 383, 386 and 389 were prepared according to the Scheme 1 route.
Figure imgf000123_0002
Example 73 - Syntheses of Compounds 100-389.
Compounds 100-389, with substituents as identified in Table 2, were prepared as in the previous examples according to the routes identified in Schemes 1-5, as summarized in Table 3, with experimental properties summarized in Table 4. Table 2: Identity of Compounds
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000132_0002
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Example 74 - Human MC3R and MC4R Radioligand Binding Assay
Assessments of compound binding to human MC3R (hMC3R) and human MC4R (hMC4R) by displacement of an 125l-labeled NDP-MSH receptor ligand peptide were performed essentially as described in the data sheets produced by Perkin Elmer to accompany their frozen hMC3R membranes (Perkin Elmer catalog number RBXMC3M400UA) and their frozen hMC4R membranes (Perkin Elmer catalog number RBHMC4M400UA).
Alternatively, the frozen hMC3R and hMC4R plasma membranes were prepared as described below from transfected mammalian cells (prepared as in Example 76, using plasmid DNA containing the human MC3R or MC4R gene in a plasmid vector with a mammalian origin of replication.
Preparation of Frozen hMC3R and hMC4R Plasma Membranes: Adherent cells were washed with warm Hanks buffered saline solution (HBSS). 1 ml_ of cold HBSS was added to each flask and the cells were scraped off with a rubber policeman. The scraped cells were added to a 50 ml. tube on ice. The plates were then rinsed twice with 5 ml. cold HBSS and this was also added to the tube. The cells were centrifuged at 1000 x g for 5 mins in a bench top centrifuge and the supernatant was decanted. The remaining cell pellet was resuspended in 0.25 M sucrose. The cell suspension was centrifuged again as previously and the pellet resuspended in 5 ml. of 0.25 M sucrose containing protease inhibitors. The cells were homogenised by a 10 second pulse with an lka disperser followed by 30 seconds on ice. The homogenisation and ice incubation was repeated three times. The mixture was then centrifuged at 1260 x g for 5 mins. The supernatant was decanted into another centrifuge tube, to which a buffer containing 50 mM Tris, pH 7.4, 12,5 mM MgCI2, 5 mM EGTA and protease inhibitors was added to make the volume up to 30 ml_. This was centrifuged at 30,000 x g for 90 mins at 40C. The resulting pellet was resuspended in 1 ml. of the buffer above also containing 10% glycerol. Membranes were aliquoted into cryovials which were snap-frozen in a dry-ice/ethanol bath before being stored at -8O0C until required for use.
[125I] NDP-MSH: radiolabeled in house and purified by HPLC:
Na125I (0.5 mCi, 17.4 Ci/mg) was added to 50 μl_ sodium phosphate (50 mM, pH 7.4) in an eppendorf tube precoated with IODOGEN. After incubation for 10 mins the phosphate buffer containing the iodine was added to NDP-MSH (10 ul at 1 mg/ml_) in a separate eppendorf tube. This was incubated for a further 10 mins. The iodinated NDP-MSH was purified by HPLC on a Zorbax SB 300 column using solvent A: 0.05% TFA and solvent B: 90% acetonitrile 0.045% TFA with a linear gradient, 0-67% B over 60 mins. The 125I NDP-MSH eluted at 52 mins after the unlabeled starting material (48 min) and was counted and stored in the freezer. It was used within 48 hrs, as radioactive decay and ligand decomposition resulted in greatly reduced specific binding observed after 72 hrs.
Reagents:
Incubation buffer: 25 mM HEPES-KOH (pH 7.0), 1.5 mM CaCI2, 1 mM MgSO4, 0.1 M NaCI, 1 mM 1 ,10-phenanthroline, and 1 Complete™ protease inhibitor tablet/100 mL (Roche, catalog number 1873580) Perkin Elmer frozen hMC3 or hMC4 membranes: catalog number RBXMC3M400UA / RBHMC4M400UA, 0.4 mL/vial; 400 microassays/vial, 0.78 mg/mL protein concentration Vials of frozen membranes were thawed rapidly immediately before use, diluted with binding buffer and vortexed. Resuspended membranes were kept on ice until they were added to the wells of the plate.
Binding Protocol for 400 microassays per vial:
Assays were performed in 96 well polypropylene plates. Membranes (0.78 μg 40 μl_ of a 1 :40 dilution in incubation buffer) were added to [125I] NDP-MSH (0.84 nM; 2200 Ci/mmol) and test compounds in a total volume of 140 μl_. This was incubated for 1 hr at 37 0C. Non-specific binding was determined with 3 mM NDP-MSH. Plates were filtered using a Tomtec cell harvester with GF/A filters (Wallac) (presoaked in 0.6% polyethylenimine) and washed three times with 1.0 ml. ice-cold wash buffer (the above incubation buffer without 1 ,10- phenanthroline and Complete™ protease inhibitor tablet). The filters were dried in a 37 0C oven, placed in a sample bag and 5 ml. Betaplatescint (Wallac) was added. Prepared filters were counted in cassettes in a Microbeta Trilux (Wallac) for 1 min. Non-specific binding just under 5%. Data analysis was performed using GraphPad Prism 4, employing competition binding with a single site model and a fixed Hill coefficient. The following equation was used: Y = Bottom + (Top-Bottom)/1/10Λ(X-logEC5o), where X = log(concentration) and Y = binding to fit the data.
Example 75 - Activity of Selected Compounds: hMC3R and hMC4R binding
Representative compounds of the present invention were tested for binding in the hMC3R and hMC4R assays as in Example 74, as listed in Table 4. The compounds were tested as their trifluoroacetate or hydrochloride salts, or as their free base.
Table 4: Experimental Properties and MC3R/MC4R Radioligand Binding of Compounds x = <10μM; xx = < 1 μM; xxx = < 100 nM
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Example 76 - Inhibition or stimulation of cAMP signal in cells expressing human MC4R Transient transfection of mammalian cell lines:
The mammalian cell line, human embryonic kidney cells (HEK 293), were maintained in Dulbeccos Modified Eagle's medium (DMEM) with 5% fetal bovine serum, L- glutamine, high glucose and antibiotics/antimycotics. On the day prior to transfection, cells were passaged using trypsin/EDTA and seeded into 75 cm2 flasks so that they would be approximately 90% confluent the next day. The next day, the cell media was replaced with fresh antibiotic/antimycotic-containing DMEM. Approximately 100 μl of the transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA), was diluted in 1.0 ml. of serum and antibiotic/antimycotic-free OptiMEM in a sterile 15 ml. tube and incubated for 5 mins at room temperature. Following incubation, approximately 10-20 μg of plasmid DNA expressing the gene of interest (for example: Homo sapiens melanocortin 4 receptor) was diluted into the transfection mix and incubated for a further 30 mins at room temperature. The DNA/lipid solution was then added drop-wise to the media covering the cells while rocking the flask gently. 24 hrs post-transfection, the cells were passaged and seeded directly into two, 75cm2 flasks and left to recover. 48 hrs post transfection, cells were harvested for use in assays with cell dissociation solution.
Cyclic-Adenosine Monophosphate [cAMP] stimulation assay: HEK 293 cells transiently expressing the melanocortin MC4 receptor were suspended in stimulation buffer (Hanks buffered saline solution (HBSS), 0.1 % bovine serum albumin, protease inhibitors and 0.5 mM 3-lsobutyl-1 -methylxanthine) at 4 x 106 cells/mL. 5 μl of cells, plus the compounds/peptides as described below, were added to wells of a 384-well plate as soon as possible after resuspension.
To detect antagonist activity, test compounds at varying concentrations were diluted in stimulation buffer at four times concentrate and 2.5 μl was added to wells containing cells. 2.5 μl of a four times required concentration of NDP-MSH or alpha-MSH was added to all wells containing compounds. Negative control wells contained two times concentrated NDP-MSH or alpha-MSH alone without compound. The concentration of NDP-MSH or alpha-MSH employed was calculated to give a response equivalent to approximately 60% of the maximal stimulation.
To detect agonist activity, test compounds at varying concentrations were diluted in stimulation buffer at two times concentrate and 5 μl was added to wells containing cells. Positive control wells contained NDP-MSH or alpha-MSH alone (no compound) at two times concentrate. Basal level (of cAMP) control wells contained stimulation buffer only (no agonist or compounds). Known concentrations of cAMP (standards) in stimulation buffer were included on the plate, but no cells were added to these wells. The plate was then incubated for 30 mins at 37 0C with gentle shaking. After incubation, 10 μl of lysis buffer (10 % Tween 20, 1 M HEPES, 0.1 % BSA, protease inhibitors, ddH2O) was added to all wells to be measured. Detection of cAMP was then achieved using the Alphascreen cAMP kit (Perkin Elmer, USA), briefly described as follows. A dilution of 10 μl acceptor beads/mL of lysis buffer was prepared in low light conditions. 5 μl of diluted acceptor beads were added to each well to be measured, then the plate was incubated for 30 mins at room temperature, in the dark, with gentle shaking. In low light conditions, donor beads were diluted at 10 μl/mL of lysis buffer, to which 0.75 μl biotinylated cAMP/ml_ of lysis buffer was added. This mixture was allowed to incubate for 30 mins at room temperature (in the dark) before proceeding with the assay. Following incubation, 5 μl/mL of biotinylated cAMP/Donor bead mix were added per well in low light conditions and the plate was incubated in the dark, at room temperature, for a further hr. Plates were read on an Envision plate reader (Perkin Elmer) after 1 hr and ~16hrs incubation. cAMP concentration in the cells was determined by the use of a 'standard curve' generated from the output of known cAMP concentrations as described below.
Each assay plate contained a "standard curve" of known concentrations of cAMP, in
10 fold dilutions. This is an essential part of the assay as there is high inter-plate variability. The plates were read on an Envision multilabel plate reader fitted with Alphascreen technology and the raw data was imported into GraphPad Prism 4 software (GraphPad, USA) for analysis. A curve was fitted to the known concentrations using non-linear regression, specifically using a sigmoidal dose-response equation (Y = Bottom + (Bottom + (Top- Bottom)/1 + 1 ologEC50"x), where the equation shows the response as a function of the logarithm of concentration. X is the logarithm of peptide/compound concentration and Y is the response. Also considered in this equation are bottom plateau, top plateau of the curve and EC50 (effective concentration, 50%)
Example 77 - Activity of Selected Compounds: hMC4R agonism
Representative compounds of the present invention were tested for agonism of the hMC4R, as in Example 76, results are listed in Table 5. Table 5: Agonism of hMC4 by Selected Compounds
Figure imgf000154_0001
References
Adan, RAH. : Tiesjema, B.: Hiilebrand. JJ. G.; Ia Fieur, S. E.; Kas, MJ. H.; de Krom, M. Sm. J. Pharmacol 2008, 149, 815-827 "The MC4 Receptor and control of appetite''
Bόhm, M.: Luger. TA; Tobin, DJ.; Garaa-Borron, J. C, J, Invest. Dermatol, 20G8s 126, 1968- 1975 "Meianocortin Receptor Ugands: New Horizons for Skin Biology and Ciinical Dermatology'"
Bertile, F.; Raclot, T. Peptides 2006, 27, 291-300 "The meianocortin system during fasting" Butler, AA.; Kesterson, R.A.; Khong, K.; Cullen, MJ.; Pelleymounter, M.A.; Dekoning, J.; Baetscher, M.; Cone, R.D. Endocrinology 2000, 1141 , 3518-3521 "A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse" Butler, A.A. Peptides 2006, 27, 281-290 "The meianocortin system and energy balance" Catania, A.; Gatti, S.; Colombo, G.; Lipton, J. M. Pharmacol. Rev. 2004, 56, 1-29 "Targeting Meianocortin Receptors as a Novel Strategy to Control Inflammation".
Chaki, S.; Okuyama, S. Peptides 2005, 26, 1952-1964 "Involvement of melanocortin-4 receptor in anxiety and depression" Chaki, S.; Okubo, T. Curr. Top. Med. Chem. 2007, 7,1 145-1 151 "Melanocortin-4 Receptor
Antagonists for the Treatment of Depression and Anxiety Disorders" Chen, A.S.; Marsh, DJ.; Trumbauer, M. E.; Frazier, E.G.; Guan, X.-M.; Yu, H.; Rosenblum, C. I.; Vongs, A.; Feng, Y.; Cao, L.; Metzger, J. M.; Strack, A.M.; Camacho, R. E.; MeIMn, T.N.; Nunes, C. N.; Min, W.; Fisher, J.; Gopal-Truter, S.; Maclntyre, D. E.; Chen, H.Y.; Van der Ploeg, L. HT. Nature Genetics 2000, 26, 97-102 "Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass" Diamond, L. E.; Earle, D. C; Rosen, R.C.; Willett, M.S.; Molinoff, P. B. Int. J. Impotence Res. 2004, 16, 51-59 "Double-blind, placebo-controlled evaluation of the safety, pharmacokinetics properties and pharmacodynamic effects of intranasal PT-141 , a melanocortin receptor agonist, in healthy males and patients with mild to moderate erectile dysfucntion" Emmerson, PJ. ; Fisher, MJ. ; Yan, L.Z.; Mayer, J. P. Curr. Top. Med. Chem. 2007, 7, 1121-
1130 "Melanocortin-4 Receptor Agonists for the Treatment of Obesity" Foster, A.C.; Chen, C. Curr. Top. Med. Chem. 2007, 7,1 131-1 136 "Melanocortin-4 Receptor
Antagonists as Potential Therapeutics in the Treatment of Cachexia"
Gantz, I.; Konda, Y.; Tashiro, T.; Shimoto, Y.; Miwa, H.; Munzert, G.; Watson, SJ.; DeIVaIIe, J.; Yamada, T. J. Biol. Chem. 1993a, 268, 8246-8250 "Molecular cloning of a novel melanocortin receptor" Gantz, I.; Miwa, H.; Konda, Y.; Shimoto, Y.; Tashiro, T.; Watson, SJ.; DeIVaIIe, J.; Yamada, T. J. Biol. Chem. 1993b, 268, 15174-15179 "Molecular cloning, expression, and gene localization of a fourth melanocortin receptor"
Getting, SJ.; Christian, H. C; Lam, C.W.; Gavins, F. N. E.; Flower, RJ.; Schioth, H. B.; Perretti, M. J. Immunol. 2003, 170, 3323-3330 "Redundancy of a Functional Melanocortin 1 Receptor in the Anti-inflammatory Actions of Melanocortin Peptides: Studies on the
Recessive Yellow (e/e) Mouse Suggest an Important Role for Melanocortin 3 Receptor" Giuliani, D.; Mioni, C; Bazzani, C; Zaffe, D.; Botticelli, A. R.; Capolongo, S.; Sabba, A.; Galantucci, M.; lannone, A.; Grieco, P.; Novellino, E.; Colombo, G.; Tomasi, A.; Catania, A.; Guarini, S. Br. J. Pharmacol. 2007, 150, 595-603 "Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage"
Hall, J. E.; Brands, M.W.; Hildebrandt, D.A.; Kuo, J.; Fitzgerald, S. Brazilian J. Med. Biol. Res. 2000, 33, 605-618 "Role of sympathetic nervous system and neuropeptides in obesity hypertension"
Holder, J. R.; Bauzo, R.M.; Xiang, Z.; Haskell-Luevano, C. J. Med. Chem. 2002, 45, 3073- 3081 "Structure-Activity Relationships of the Melanocortin Tetrapeptide Ac-His-DPhe-
Arg-Trp-NH2 at the Mouse Melanocortin Receptors: Part 2 Modifications at the Phe Position"
Holder, J. R.; Marques, F. F.; Xiang, Z.; Bauzo, R. M.; Haskell-Luevano, C. Eur. J. Pharmacol. 2003, 462, 41-52 "Characterization of apliphatic, cyclic and aromatic N-terminally "capped" His-DPhe-Arg-Trp-NH2 tetrapeptides at the melanocortin receptors"
Hruby, VJ.; Cai, M.; Cain, J. P.; Mayorov, A.V.; Dedek, M. M.; Trivedi, D. Curr. Top. Med. Chem. 2007, 7, 1085-1097 "Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor"
Huszar, D.; Lynch, CA. ; Fairchild-Huntress, V.; Dunmore, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.; Kesterson, R.A.; Boston, B.A.; Cone, R.D.; Smith, FJ.; Campfield, L.A.; Burn,
P.; Lee, F. Ce// 1997, 88, 131-141 "Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice" Irani, B. G.; Haskell-Luevano, C. Peptides 2005, 26, 1788-1799 "Feeding effects of melanocortin ligands - A historical perspective"
King, S. H.; Mayorov, A.V.; Balse-Srinivasan, P.; Hruby, VJ. ; Vanderah, T. W.; Wessells, H. Curr. Top. Med. Chem. 2007, 7, 1 1 1 1 -1 1 19 "Melanocortin Receptors, Melanotropic Peptides and Penile Erection"
Lam, D. D.; Farooqi, I.S.; Heisler, L. K. Curr. Top. Med. Chem. 2007, 7, 1098-1 1 10
"Melanocortin Receptors as Targets in the Treatment of Obesity"
Lasaga, M.; Debeljuk, L.; Durand, D.; Scimonelli, T.N.; Caruso, C. Peptides 2008, 29, 1825- 1835 "Role of α-melanocyte stimulating hormone and melanocortin 4 receptor in brain inflammation"
MacNeil, DJ. ; Howard, A.D.; Guan, X, Fong, T.M.; Nargund, R.P.; Bednarek, M.A.; Goulet,
M.T.; Weinberg, D. H.; Strack, A.M.; Marsh, DJ.; Chen, H.Y.; Shen, C-P.; Chen, A.S.;
Rosenblum, C. I.; MacNeil, T.; Tota, M.; Maclntyre, E. D.; Van der Ploeg, L. H. T. Eur. J.
Pharmacol. 2002, 440, 141 -157 "The role of melanocortins in body weight regulation: opportunities for the treatment of obesity"
Marks, D. L.; Hruby, V.; Brookhart, G.; Cone, R.D. Peptides 2006, 27, 259-264 "The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)" Mazur, A.W.; Kulesza, A.; Mishra, R. K.; Cross-Doersen, D.; Russell, A.F.; Ebetino, F. H. Bioorg. Med. Chem. 2003, 77, 3053-3063 "Novel tetrahydropyran-based peptidomimetics from a bioisosteric transformation of a tripeptide. Evidence of their activity at melanocortin receptors"
Mutulis, F.; Mutule, I.; Liepinsh, E.; Yahorau, A.; Lapinsh, M.; Kopantshuk, S.; Veiksina, S.; Rinken, A.; Wikberg, J.E.S. Peptides 2005, 26, 1997-2016 "Λ/-Alkylated dipeptide amides and related structures as imitations of the melanocortins' active core" Nargund, R.P.; Strack, A.M.; Fong, T.M. J. Med. Chem. 2006, 49, 4035-4053 "Melanocotin-4
Receptor (MC4R) Agonists for the Treatment of Obesity"
Ploj, K.; Roman, E.; Kask, A.; Hyytia, P.; Schioth, H. B.; Wikberg, J. E. S.; Nylander, I. Brain Res. Bull. 2002, 59, 97-104 "Effects of melanocortin receptor ligands on ethanol intake and opioid peptide levels in alcohol-preferring AA rats" Schuler, S.; Ebling, FJ. P. Peptides 2006, 27, 301-309 "Role of melanocortin in the long-term regulation of energy balance: Lessons from a seasonal model"
Shadiack, A.M.; Sharma, S. D.; Earle, D. C; Spana, C; Hallam, TJ. Drug Disc. Today: Ther. Strat. 2006, 3, 605-61 1 "A role for melanocortin agonists in treating male and female sexual dysfucntion" Shadiack, A.M.; Sharma, S. D.; Earle, D. C; Spana, C; Hallam, TJ. Curr. Top. Med. Chem. 2007, 7, 1 137-1 144 "Melanocortins in the Treatment of Male and Female Sexual Dysfunction" Thorleifsson et al, Nature Genetics 2009, 41, 18-24 "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity" Tian, X.; Switzer, A.G.; Derose, S.A.; Mishra, R.K.; Solinsky, M. G.; Mumin, R.N.; Ebetino,
F. H.; Jayasinghe, L. R. Webster, M. E.; Colson, A.-O.; Crossdoersen, D.; Pinney, B. B.; Farmer, J.A.; Dowty, M. E.; Obringer, CM.; Cruze, C.A.; Burklow, M. L.; Suchanek, P.M.;
Dong, L; Dirr, M. K.; Sheldon, R.J.; Wos, J.A. J. Med. Chem. 2008, 51, 6055-6066
"Discovery of Orally Bioavailable 1 ,3,4-Trisubstituted 2-Oxopiperazine-Based
Melanocortin-4 Receptor Agonists as Potential Antiobesity Agents"
Todorovic, A.; Haskell-Luevano, C. Peptides 2005, 26, 2026-2036 "A review of melanocortin receptor small molecule ligands"
Ujjainwalla, F.; Sebhat, I. K. Curr. Top. Med. Chem. 2007, 7, 1068-1084 "Small Molecule
Ligands of the Human Melanocortin-4 Receptor" Voisey, J.; Carroll, L.; van Daal, A. Curr. Drug Targets 2003, 4, 586-597 "Melanocortins and their Receptors and Antagonists" Wessells, H.; Blevins, J. E.; Vanderah, T.W. Peptιdes 2005, 26, 1972-1977 "Melanocortinergic control of penile erection" Wikberg, J. E. S.; Muceniece, R.; Mandrika, I.; Prusis, P.; Lindblom, J.; Post, C; Skottner, A.
Pharmacol. Res. 2000, 42, 393-420 "New Aspects on the Melanocortins and their
Receptors" Wskbcrq J E S Exp Opm Ther Patents 2001 , 1 1, 61-78 "Molanocortn receptors now opportunities m drug discovery" Wikberg J. E S., Mululis F Nature Rev. Drug Disc 2008s 7. 307-323 "Targeting meianocortin receptorb an approddi to treat weight disorders and sexual dysfunction" Wilier et al, Nature Genetics 2009, 41, 24-34 "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation"
The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

The Claims defining the Invention are as follows
1 A method of modulating the activity of a receptor selected from the group consisting of
MC3R and MC4R or a fragment, analogue or functional equivalent thereof comprising exposing the receptor or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):
Figure imgf000158_0001
Formula (I) wherein
Y is a group of formula -(CR9R1V;
X is selected from the group consisting -C(=O)-, -OC(=O)-, -NHC(=O)-,
-(CR11 R12)S! and -S(=O)2-;
R is an amino acid side chain group;
R1 is selected from the group consisting of H, optionally substituted d-C^alkyl, optionally substituted CH2(C6-Ci8aryl) optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted d-C^heteroalkyl, optionally substituted C3- d2cycloalkyl, optionally substituted C2-d2heterocycloalkyl, optionally substituted C6-d8aryl, and optionally substituted d-d8heteroaryl;
R2 and R3 are each independently selected from the group consisting of H, optionally substituted Ci-C12alkyl, optionally substituted C2-d2alkenyl, optionally substituted C2- d2alkynyl, optionally substituted d-d2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-d2heterocycloalkyl, optionally substituted C6-d8aryl, and optionally substituted d-d8heteroaryl, or R2 and R3 may be joined to form a linker between the two nitrogen atoms to which they are attached, wherein the linker is selected from the group consisting of -C(=O)-, -CH2-, -C(=O)CH2- and -CH2C(=O)- ;
R5a, R5b and R6 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted CrC12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted CrCi2 heteroalkyl, optionally substituted C1-C10 heteroalkenyl, optionally substituted C3-Ci 2cycloalkyl, optionally substituted C2-Ci2 heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted C1- C18heteroaryl, optionally substituted amino, optionally substituted carboxy, optionally substituted carboxamide, optionally substituted C^C^alkyloxy, and optionally substituted thio;
each R9 and R10 is independently selected from the group consisting of H, optionally substituted CrC12alkyl, optionally substituted C6-C18aryl, and optionally substituted C1- C18heteroaryl;
each R11 and R12 is independently selected from the group consisting of H, and optionally substituted CrC12alkyl;
n is an integer selected from the group consisting of 1 , 2, 3 and 4;
r is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
s is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
or a pharmaceutically acceptable salt or prodrug thereof.
2. A method according to claim 1 wherein the activity of the receptor or a fragment, analogue or functional equivalent thereof is modulated in a mammal, the method comprising administering a receptor modulating amount of a compound of formula (I) to the mammal.
3. A method of preventing or treating a condition associated with the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula (I) as described in claim 1 to the mammal.
4. A method according to any one of claims 2 to 3 wherein the mammal is a human.
5. A method according to any one of claims 1 to 3 wherein in the method the activity of the receptor is up-regulated.
6. A method according to any one of claims 1 to 3 wherein in the method the activity of the receptor is down-regulated.
7. A method according to claim 3 wherein the condition is selected from the group consisting of obesity, eating disorders, metabolic syndrome, diabetes, sexual dysfunction, anxiety, depression, inflammation, addiction and alcohol intake.
8. A method according to claim 3 wherein the condition is selected from the group consisting of cachexia, anorexia, weight gain, weight loss, Type Il diabetes, erectile dysfunction and female sexual dysfunction.
9. A method according to any one of claims 2 to 4, 7 and 8 wherein the compound is administered topically.
10. A method according to any one of claims 2 to 4, 7 and 8 wherein the compound is administered orally.
1 1 . A method according to any one of claims 2 to 4, 7 and 8 wherein the compound is administered parenterally.
12. A method according to any one of claims 2 to 4 and 7 to 1 1 wherein the compound of formula (I) is administered in combination with a second active agent.
13. A method according to any one of claims 1 to 12 wherein the compound of formula (I) is a compound of the formula (Ia):
Figure imgf000161_0001
Formula (Ia)
R1, R2, R3, R5a, R5b, R6, X, Y and r are as defined in claim 1 ;
Z is a group of formula -(CR13R14)q-;
R4 is selected from the group consisting of H, optionally substituted d-C12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C3-Ci 2cycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted C1- C18heteroaryl, NR4aR4b, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20, SC(=O)R20, SO2R20, OR20, ONR16R17, OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17, and ONR16C(=NR17)NR18R19
R is selected from the group consisting of H, optionally substituted d-C12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted C1- dsheteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15a, SO2R15a, C(=O)H, -C(=NR15a)- NR16aR17a, and 0R15a,
R4b is selected from the group consisting of H, optionally substituted d-d2alkyl, optionally substituted C2-d2alkenyl, optionally substituted C2-d2alkynyl, optionally substituted Ci-Ci2heteroalkyl, optionally substituted drd2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-d8aryl, optionally substituted C1- C18heteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=0)OR15a, or
R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or one of R4a and R4b when taken together with any R13 or R14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;
R13 and R14 are each independently selected from the group consisting of H, halogen, OH, Ci-Ci2alkyl, C6-Ci8aryl, Ci-Ci2hydroxyalkyl, CrCi2haloalkyl, Ci-Ci2alkyloxy and Ci- Ci2haloalkyloxy, or
when taken together with the carbon to which they are attached R13 and R14 form an optionally substituted C3-Ci2cycloalkyl, or an optionally substituted CrCi2heterocycloalkyl group, or
one of R13 and R14 when taken together with one of R4a, and R4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
one of R13 and R14 when taken together with one of R15, R16, R17. R18, R19 or R20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
each R15, R15a, R16, R16a, R17. R17a, R18, R19 and R20 is independently selected from the group consisting of H, optionally substituted CrCi2alkyl, optionally substituted Cr Ci2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-Ci2 heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted d-Ci8heteroaryl, or
any two of R15, R15a, R16, R16a, R17, R17a, R18, R19 and R20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
one of R15, R16, R17, R18, R19 and R20 when taken together with one of R13 and R14 and the atoms to which they are attached form an optionally substituted cyclic moiety;
q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
or a pharmaceutically acceptable salt or prodrug thereof.
14. A method according to any one of claims 1 to 13 wherein Y is CH2.
15. A method according to any one of claims 1 to 14 wherein R2 is H.
16. A method according to any one of claims 1 to 15 wherein R is H.
17. A method according to any one of claims 1 to 16 wherein Y is CH2, X is C(=O), R2 is H, R3 is H and R is a group of formula -Z-R4, resulting in a compound of the formula (Ib):
Figure imgf000163_0001
Formula (Ib)
wherein R , R , R , R , and r are as defined in claim 1 and Z and R are as defined in claim 13.
18. A method according to claim 13 or 17 wherein R4 = NR4aR4b.
19. A method according to any one of claims 1 to 18 wherein the compound is a compound of the formula
Figure imgf000163_0002
Formula (Id)
wherein R1, R5a, R5b, R6, Z, and r are as defined in claim 1 and R4a and R4b are as defined in claim 13 and the stereochemistry is as shown, or a pharmaceutically acceptable salt or prodrug thereof.
20 A method according to any one of claims 1 to 18 wherein the compound is a compound of the formula (Ie)
Figure imgf000164_0001
Formula (Ie)
wherein R1, R5a, R5b, R6, Z, and r are as defined in claim 1 and R4a and R4b are as defined in claim 13 and the stereochemistry is as shown, or a pharmaceutically acceptable salt or prodrug thereof.
21 . A method according to any one of claims 18 to 20 wherein R4a is selected from the group consisting of H, -C(=NH)NH2, -C(=NH)N(CH3)2, -C(=NH)NHCH(CH3)2, -C(=O)CH3, - C(=0)cyclohexyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 CH2CH2CH2CH3, -CH(CH3)CH2CH3 CH2CH(CH3)2 C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
22. A method according to any one of claims 18 to 21 R4b is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 CH2CH2CH2CH3, CH(CH3)CH2CH3 CH2CH(CH3)2 C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
23. A method according to any one of claims 18 to 20 wherein R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C2- Ci2heterocycloalkyl group, an optionally substituted C2-Ci2heterocycloalkenyl group or an optionally substituted CrCi8heteroaryl group.
24. A method according to claim 23 wherein R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C2- Ci2heterocycloalkyl group selected from the group consisting of piperidin-1 -yl, pyrrolidin-1 -yl, azepan-1 -yl, azetidin-1 -yl, piperazin-1 -yl, and morpholin-4-yl.
25. A method according to any one of claims 18 to 20 wherein one of R4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted C2-Ci2heterocycloalkyl group.
26. A method according to claim 25 wherein one of R4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted C2-Ci2heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, and piperazinyl.
27. A method according to any one of claims 13 to 26 wherein Z is selected from the group consisting of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, and -(CH2)5-.
28. A method according to any one of claims 1 to 27 wherein R1 is selected from the group consisting of optionally substituted C2-Ci2alkenyl, optionally substituted C6-Ci8aryl, optionally substituted CH2(C6-Ci8aryl), optionally substituted CH2(C6-Ci8aryl), and optionally substituted Ci-Cisheteroaryl.
29. A method according to any one of claims 1 to 28 wherein R5a and R5b are each independently selected from the group consisting of H, optionally substituted d-Ci2alkyl, optionally substituted C6-Ci8aryl, optionally substituted d-Ci8heteroaryl, optionally substituted carboxy and optionally substituted carboxamide.
30. A method according to any one of claims 1 to 29 wherein R6 is is selected from the group consisting of optionally substituted Ci-Ci2alkyl, optionally substituted C6-Ci8aryl and optionally substituted CrCi8heteroaryl.
31 . A method according to any one of claims 1 to 30 wherein r is 0.
32. A method according to any one of claims 1 to 30 wherein r is 1 .
33. A method according to any one of claims 1 to 30 wherein r is 2.
34. A method according to any one of claims 1 to 33 wherein in the compound of formula (I) each optional substituent is independently selected from the group consisting of: halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)Ra, -C(=O)ORa, C(=O)NRaRb, C(=NOH)Ra, C(=NRa)NRbRc, NRaRb, NRaC(=O)Rb, NRaC(=O)ORb, NRaC(=O)NRbRc, NRaC(=NRb)NRcRd, NRaSO2Rb,-SRa, SO2NRaRb, -0Ra OC(=O)NRaRb, OC(=O)Ra and acyl,
wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of H, Ci-Ci2 alkyl, CrCi2 haloalkyl, C2-Ci2 alkenyl, C2-Ci2 alkynyl, C1-C10 heteroalkyl, C3-Ci2 cycloalkyl, C3-Ci2 cycloalkenyl, CrCi2 heterocycloalkyl, CrCi2 heterocycloalkenyl, C6-Ci8aryl, d-dsheteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
35. A method according to any one of claims 1 to 34 wherein in the compound of formula (I) each optional substituent is independently selected from the group consisting of F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN.
36 Use of a compound of the formula (I):
Figure imgf000166_0001
Formula (I) wherein
Y is a group of formula -(CR9R1V;
X is selected from the group consisting -C(=O)-, -OC(=O)-, -NHC(=O)-,
-(CR11R12)S! and -S(=O)2-;
R is an amino acid side chain group;
R1 is selected from the group consisting of H, optionally substituted d-C12alkyl, optionally substituted CH2(C6-Ci8aryl), optionally substituted C2-C12alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted d-C12heteroalkyl, optionally substituted C3- Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Cisheteroaryl;
R2 and R3 are each independently selected from the group consisting of H, optionally substituted d-C12alkyl, optionally substituted C2-d2alkenyl, optionally substituted C2- Ci2alkynyl, optionally substituted d-Ci2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted d-d8heteroaryl, or
R2 and R3 may be joined to form a linker between the two nitrogen atoms to which they are attached, wherein the linker is selected from the group consisting of -C(=O)-, -CH2-, -C(=O)CH2- and -CH2C(=O)- ;
R5a, R5b and R6 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted d-C12alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C12alkynyl, optionally substituted CrCi2 heteroalkyl, optionally substituted C1-C10 heteroalkenyl, optionally substituted C3-Ci 2cycloalkyl, optionally substituted C2-Ci2 heterocycloalkyl, optionally substituted C6-C18aryl, optionally substituted C1- C18heteroaryl, optionally substituted amino, optionally substituted carboxy, optionally substituted carboxamide, optionally substituted d-C12alkyloxy, and optionally substituted thio;
each R9 and R10 is independently selected from the group consisting of H, optionally substituted d-C12alkyl, optionally substituted C6-C18aryl, and optionally substituted C1- C18heteroaryl; each R11 and R12 is independently selected from the group consisting of H, and optionally substituted d-C^alkyl;
n is an integer selected from the group consisting of 1 , 2, 3 and 4;
r is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
s is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
or a pharmaceutically acceptable salt or prodrug thereof in modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof.
37. Use of a compound of formula (I) as described in claim 36 in the preparation of a medicament for treating, preventing, or controlling a condition associated with the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal.
38. A use according to claim 37 wherein the mammal is a human.
39. A use according to claim 37 wherein the condition is selected from the group consisting of obesity, eating disorders, metabolic syndrome, diabetes, sexual dysfunction, anxiety, depression, inflammation, addiction and alcohol intake.
40. A use according to claim 37 wherein the condition is selected from the group consisting of cachexia, anorexia, weight gain, weight loss, Type Il diabetes, erectile dysfunction and female sexual dysfunction
41 . A use according to any one of claims 37 to 40 wherein the medicament is adapted to be administered topically.
42. A use according to any one of claims 37 to 40 wherein the medicament is adapted to be administered orally.
43. A use according to any one of claims 37 to 40 wherein the medicament is adapted to be administered parenterally.
44. A use according to any one of claims 37 to 43 wherein the medicament contains a second active agent.
45. A use according to any one of claims 36 to 44 wherein the compound of formula (I) is a compound of the formula (Ia):
Figure imgf000169_0001
Formula (Ia)
wherein R1 , Fr, Fr, Fra, FT, Fr, X, Y and r are as defined in claim 36;
Z is a group of formula -(CR13R14)q-;
R4 is selected from the group consisting of H, optionally substituted d-C^alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C3-Ci 2cycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted d- dsheteroaryl, NR4aR4b, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20, SC(=O)R20, SO2R20, OR20, ONR16R17, OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17, and ONR16C(=NR17)NR18R19
R is selected from the group consisting of H, optionally substituted d-d2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted d-d2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-d2heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted d- dsheteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15a, SO2R15a, C(=O)H, -C(=NR15a)- NR16aR17a, and 0R15a,
R is selected from the group consisting of H, optionally substituted d-d2alkyl, optionally substituted C2-d2alkenyl, optionally substituted C2-d2alkynyl, optionally substituted CrCi2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-C12heterocycloalkyl, optionally substituted C6-Ci8aryl, optionally substituted d- C18heteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=0)OR15a, or
R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
one of R4a and R4b when taken together with any R13 or R14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;
R13 and R14 are each independently selected from the group consisting of H, halogen,
OH, Ci-Ci2alkyl, C6-Ci8aryl, d-C^hydroxyalkyl, d-C^haloalkyl, d-d2alkyloxy and d- d2haloalkyloxy, or
when taken together with the carbon to which they are attached R13 and R14 form an optionally substituted drd2cycloalkyl, or an optionally substituted d-d2heterocycloalkyl group, or
one of R13 and R14 when taken together with one of R4a, and R4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
one of R13 and R14 when taken together with one of R15, R16, R17. R18, R19 or R20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
each R15, R15a, R16, R16a, R17. R17a, R18, R19 and R20 is independently selected from the group consisting of H, optionally substituted d-d2alkyl, optionally substituted d- d2heteroalkyl, optionally substituted C3-d2cycloalkyl, optionally substituted C2-d2 heterocycloalkyl, optionally substituted C6-d8aryl, and optionally substituted d-d8heteroaryl, or
any two of R15, R15a, R16, R16a, R17, R17a, R18, R19 and R20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
one of R15, R16, R17, R18, R19 and R20 when taken together with one of R13 and R14 and the atoms to which they are attached form an optionally substituted cyclic moiety;
q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5; or a pharmaceutically acceptable salt or prodrug thereof.
46. A use according to any one of claims 36 to 45 wherein Y is CH2.
47. A use according to any one of claims 36 to 46 wherein R2 is H.
48. A use according to any one of claims 36 to 47 wherein R3 is H.
49. A use according to any one of claims 36 to 48 wherein in the compound of formula (I) Y is CH2, X is C(=O), R2 is H, R3 is H and R is a group of formula -Z-R4, resulting in a compound of the formula (Ib):
Figure imgf000171_0001
Formula (Ib)
wherein R1, R5a, R5b, R6, and r are as defined in claim 36 and Z and R4 are as defined in claim 45.
50. A use according to claim 45 or 49 wherein R4 = NR4aR4b.
51 . A use according to any one of claims 36 to 50 wherein the compound of formula (I) is a compound of the formula (Id)
Figure imgf000172_0001
Formula (Id)
wherein R1, R5a, R5b, R6, Z, Y and r are as defined in claim 36 and R4a and R4b are as defined in claim 45 and the stereochemistry is as shown, or a pharmaceutically acceptable salt or prodrug thereof.
52. A use according to any one of claims 36 to 50 wherein the compound of formula (I) is a compound of the formula (Ie)
Figure imgf000172_0002
Formula (Ie)
wherein R1, R5a, R5b, R6, Z, Y and r are as defined in claim 36 and R4a and R4b are as defined in claim 45 and the stereochemistry is as shown, or a pharmaceutically acceptable salt or prodrug thereof.
53. A use according to any one of claims 50 to 52 wherein R4a is selected from the group consisting of H, -C(=NH)NH2, -C(=NH)N(CH3)2, -C(=NH)NHCH(CH3)2, -C(=O)CH3, - C(=0)cyclohexyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 CH2CH2CH2CH3, -CH(CH3)CH2CH3 CH2CH(CH3^ C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
54. A use according to any one of claims 50 to 53 wherein R4b is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 CH2CH2CH2CH3, CH(CH3)CH2CH3
CH2CH(CH3)2 C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
55. A use according to any one of claims 50 to 52 wherein R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C2-
Ci2heterocycloalkyl group, an optionally substituted C2-Ci2 heterocycloalkenyl group or an optionally substituted CrCi8 heteroaryl group.
56. A use according to claim 55 wherein in the compound of formula (I) R4a and R4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C2-Ci2heterocycloalkyl group selected from the group consisting of piperidin-1 -yl, pyrrolidin-1 -yl, azepan-1 -yl, azetidin-1 -yl, piperazin-1 -yl, and morpholin-4-yl.
57. A use according to any one of claims 50 to 52 wherein one of R4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted C2-Ci2heterocycloalkyl group.
58. A use according to claim 57 wherein one of R4a and R4b when taken together with the nitrogen atom to which it is attached and one of R13 and R14 and the carbon atom to which it is attached form an optionally substituted C2-Ci2heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, and piperazinyl.
59 A use according to any one of claims 45 to 58 wherein Z is selected from the group consisting Of -CH2-, -(CHg)2-, -(CH2)3-, -(CH2)4-, and -(CH2)5-.
60. A use according to any one of claims 36 to 59 wherein R1 is selected from the group consisting of optionally substituted C2-Ci2alkenyl, optionally substituted C6-Ci8aryl, optionally substituted CH2(C6-Ci8aryl), optionally substituted CH2(C6-Ci8aryl), and optionally substituted Ci-Ci8heteroaryl.
61 . A use according to any one of claims 36 to 60 wherein R5a and R5b are each independently selected from the group consisting of H, optionally substituted d-Ci2alkyl, optionally substituted C6-Ci8aryl, optionally substituted Ci-Ci8heteroaryl, optionally substituted carboxy and optionally substituted carboxamide.
62. A use according to any one of claims 36 to 61 wherein in the compound of formula (I) R6 is is selected from the group consisting of optionally substituted d-Ci2alkyl, optionally substituted C6-Ci8aryl and optionally substituted d-Ci8heteroaryl.
63. A use according to any one of claims 36 to 62 wherein r is 0.
64. A use according to any one of claims 36 to 62 wherein r is 1 .
65. A use according to any one of claims 36 to 62 wherein r is 2.
66. A use according to any one of claims 36 to 65 wherein in the compound of formula (I) each optional substituent is independently selected from the group consisting of: halogen,
=0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)Ra, -C(=O)ORa, C(=O)NRaRb, C(=NOH)Ra, C(=NRa)NRbRc, NRaRb, NRaC(=O)Rb, NRaC(=O)ORb, NRaC(=O)NRbRc, NRaC(=NRb)NRcRd, NRaSO2Rb,-SRa, SO2NRaRb, -0Ra OC(=O)NRaRb, OC(=O)Ra and acyl,
wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of H, Ci-Ci2 alkyl, d-Ci2 haloalkyl, C2-d2 alkenyl, C2-d2 alkynyl, d-Ci0 heteroalkyl, C3-d2 cycloalkyl, d-Ci2 cycloalkenyl, CrCi2 heterocycloalkyl, CrCi2 heterocycloalkenyl, C6-d8aryl, d-Ci8heteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
67. A use according to any one of claims 36 to 66 wherein in the compound of formula (I) each optional substituent is independently selected from the group consisting of F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN.
68. A method according to any one of claims 1 to 35 or a use according to any one of claims 36 to 67 wherein the compound is selected from the group consisting of:
• N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
• N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-6- bromo-N-methyl-2-naphthamide • N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-bromo-2-naphthamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
• (E)-N-(((3S,5S)-3-butyl-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3-(4- chlorophenyl)acrylamide
• N-((S)-1 -((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)- 2-(naphthalen-2-yl)ethyl)acetamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide • (S)-methyl 2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(naphthalen-1 -yl)acetamido)methyl)- 2-0X0-1 ,4-diazepan-1 -yl)-3-(1 H-indol-3-yl)propanoate
• N-(((3R,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5R)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5R)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide • N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoxaline-2-carboxamide • N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)isoquinoline-3-carboxamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-2-carboxamide • (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(2-(naphthalen-1 - yl)ethyl)tetrahydro-1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)biphenyl-4- carboxamide
• N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2-(biphenyl- 4-yl)acetamide
• (5S,9aS)-5-(4-aminobutyl)-7-benzhydryl-2-(biphenyl-4-ylmethyl)tetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide • N-(((3S,5S)-3-(4-aminobutyl)-1 -benzhydryl-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
• (5S,9aS)-5-(4-aminobutyl)-7-benzhydryl-2-(naphthalen-2-ylmethyl)tetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide
• 1 -(3-((5S,9aS)-7-benzhydryl-2-(biphenyl-4-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
• N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide • N-(((3S,5S)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
• N-(((3S,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide
• 1 -(3-((5S,9aR)-7-benzhydryl-2-(biphenyl-4-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
• N-(((3S,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide • 1 -(3-((5S,9aR)-7-benzhydryl-2-(naphthalen-2-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine • N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (biphenyl-4-yl)acetamide • N-(((3R,5R)-1 -benzhydryl-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- (naphthalen-2-yl)acetamide
• 1 -(3-((5R,9aR)-7-benzhydryl-2-(naphthalen-2-ylmethyl)-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5S,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 -ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione • N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• (5S,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 -ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
• N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide • N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5R,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 -ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-1 -ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione • N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
• N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1 -naphthamide • N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-1 -yl)acetamide
• N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5S,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2-ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • N-(((3S,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5S,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2-ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
• N-(((3S,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-1 -yl)acetamide
• N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide
• (5R,9aR)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2-ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione • N-(((3R,5R)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5S)-3-(4-aminobutyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(biphenyl-4-yl)acetamide • (5R,9aS)-5-(4-aminobutyl)-2-(biphenyl-4-ylmethyl)-7-(naphthalen-2-ylmethyl)tetrahydro- 1 H-imidazo[1 ,5-d][1 ,4]diazepine-3,6(2H,5H)-dione
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)benzamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)cyclohexanecarboxamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-phenoxybenzamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-4-phenoxybenzamide • N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1 H-indole-2-carboxamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-phenylpropanamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dimethylbenzamide
• 4-tert-butyl-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)benzamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2,4-dimethoxybenzamide • 2-cyclohexyl-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,A- diazepan-5-yl)methyl)acetamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(2-(guanidinooxy)ethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)acrylamide
• propyl (R)-1 -((3R,5R)-1 -(2-(1 H-indol-3-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,A- diazepan-5-yl)-2-phenylethylcarbamate
• (R)-N-((S)-1 -((3S,5S)-1 -(2-(1 H-indol-3-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,A- diazepan-5-yl)-2-phenylethyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide • N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-6- bromo-2-naphthamide
• (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide • N-(((3S,5S)-3-(3-(3,3-dimethylguanidino)propyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,A- diazepan-5-yl)methyl)-2-naphthamide
• (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-p-tolylacrylamide
• (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-fluorophenyl)acrylamide
• N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-6- fluoro-2-naphthamide
• N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide • N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(3-guanidinopropyl)-1 -(naphthalen-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
• N-(((3S,5S)-1 -((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,A- diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
• N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-5- (4-chlorophenyl)furan-2-carboxamide • N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-4- (1 H-pyrrol-1 -yl)benzamide
• N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-5- (4-chlorophenyl)isoxazole-3-carboxamide
• N-(((3S,5S)-1 -(2-cyclohexylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-1 -(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphthamide
• (N-(((3S,5S)-3-(3-guanidinopropyl)-1 -(naphthalen-2-ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • 1 -(3-((1 R,5S,9aS)-7-(2-(1 H-indol-3-yl)ethyl)-1 ,2-dibenzyl-3,6-dioxooctahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-5-yl)propyl)guanidine • (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-fluorophenyl)-N-methylacrylamide
• (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan- 5-yl)methyl)-3-(4-fluorophenyl)acrylamide • (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1 - yl)propyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
• (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1 - yl)propyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
• N-(((3S,5S)-3-(3-guanidinopropyl)-1 -(naphthalen-1 -ylmethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(3-guanidinopropyl)-1 -(2-(naphthalen-2-yl)ethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • (E)-N-(((3S,5S)-3-(aminomethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3-(4-chlorophenyl)acrylamide
• N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(piperidin-1 -ylmethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(piperidin-1 -ylmethyl)- 1 ,4-diazepan-5-yl)methyl)acrylamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3,4- dichlorobenzamide
• (E)-N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3-(4-chlorophenyl)acrylamide • 3,4-dichloro-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
• N-(((3S,5S)-1 -((S)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphth amide
• N-(((3S,5S)-1 -(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-1 -((R)-2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphth amide
• (S)-2-amino-N-((R)-1 -((3S,5R)-3-(3-guanidinopropyl)-1 -(2-(naphthalen-2-yl)ethyl)-2- oxo-1 , 4-diazepan-5-yl)-2-phenylethyl)-3-phenylpropanamide • (S)-2-amino-N-((R)-1 -((3S,5S)-3-(3-guanidinopropyl)-1 -(2-(naphthalen-2-yl)ethyl)-2- oxo-1 , 4-diazepan-5-yl)-2-phenylethyl)-3-phenylpropanamide • (E)-N-(((3S,5S)-3-butyl-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-3-(4- chlorophenyl)acrylamide
• (E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide • N-(3-((2S,7S)-4-(2,2-diphenylethyl)-3-oxo-7-(((E)-3-p-tolylacrylamido)methyl)-1 ,A- diazepan-2-yl)propyl)cyclohexanecarboxamide
• N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1 -(2-phenoxy-2-phenylethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-1 -(2-ethylbutyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
• N-(((3S,5S)-1 -((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,A- diazepan-5-yl)methyl)-2-naphthamide
• 3,4-dichloro-N-(2-((3S,5R)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)ethyl)benzamide • N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
• (E)-N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acryl amide
• (S)-2-((5S,9aS)-2-(4-fluorobenzyl)-5-(3-guanidinopropyl)-3,6-dioxotetrahydro-1 H- imidazo[1 ,5-d][1 ,4]diazepin-7(8H,9H,9aH)-yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • (S)-2-((3S,5R)-5-((4-fluorobenzylamino)methyl)-3-(3-guanidinopropyl)-2-oxo-1 ,A- diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5R)-5-((N-(4-fluorobenzyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• N-(((3S,5S)-1 -(3-chloro-5-fluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1 -((1 -phenylcyclohexyl)methyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• 3,4-dichloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)methyl)benzamide • N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
• 4-fluoro-N-(((3R,5R)-3-(3-guanidinopropyl)-1 -((S)-1 -(methylamino)-3-(naphthalen-2-yl)- 1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)benzamide • 4-fluoro-N-(((3R,5S)-3-(3-guanidinopropyl)-1 -((S)-1 -(methylamino)-3-(naphthalen-2-yl)- 1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)benzamide
• (S)-2-((3R,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3R,5R)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-(2-(4- fluorophenyl)acetamido)propyl)-2-oxo-1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2- yl)propan amide
• (S)-2-((3R,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-(2-(4- fluorophenyl)acetamido)propyl)-2-oxo-1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2- yl)propan amide • (S)-2-((3R,5S)-5-((2-(4-fluorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• 3,4-dichloro-N-(((3S,5S)-1 -(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan- 5-yl)methyl)benzamide
• N-(((3S,5S)-1 -(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
• (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2-ethylbutyl)-2-oxo-3-(piperidin-1 -ylmethyl)-1 ,4- diazepan-5-yl)methyl)acrylamide
• N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1 -(3-oxo-2-phenyl-3-(piperidin-1 -yl)propyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1 -(3-oxo-2-phenyl-3-(phenylamino)propyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(aminomethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
• N-(((3S,5S)-3-(aminomethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide
• (E)-N-(((3S,5S)-3-(aminomethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3-(4-chlorophenyl)acrylamide
• 3,4-dichloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1 -ylmethyl)-1 ,A- diazepan-5-yl)methyl)benzamide • (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1 - ylmethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide • N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-3,4- dichlorobenzamide
• (E)-N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-3- (4-chlorophenyl)acrylamide • 6-chloro-N-(((3S,5S)-1 -(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamid
• 6-chloro-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)methyl)-2-naphthamide
• (E)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-3-(4-isopropylphenyl)acrylamide
• (E)-N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3-(4-isopropylphenyl)acrylamide
• (E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide • (E)-N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3-(2,4-dimethylphenyl)acrylamide
• (E)-3-(2,4-difluorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
• (E)-N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3-(2,4-difluorophenyl)acrylamide
• (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo- 1 ,4-diazepan-5-yl)methyl)acrylamide
• E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrolidin-1 -yl)ethyl)-1 -(2,2- diphenylethyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide • 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)methyl)-2-naphthamide
• 3,4-dichloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,A- diazepan-5-yl)methyl)benzamide
• (E)-3-(4-bromophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acrylamide
• 5-(4-chlorophenyl)-N-(((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide • 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidin-1 -yl)propyl)-1 -((S)-2-phenylbutyl)-1 ,A- diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(piperidin-1 -yl methyl)- 1 ,4-diazepan- 5-yl)methyl)-2-naphth amide
• 6-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(3-(piperidin-1 -yl)propyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan-5- yl)propan-2-yl)-3-(4-chlorophenyl)acrylamide
• (E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1 -(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)propan-2-yl)acrylamide
• 6-chloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 3,4-dichloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)benzamide
• 6-chloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-6- chloro-2-naphthamide
• (E)-N-(((3S,5S)-3-((1 H-imidazol-1 -yl)methyl)-1 -(2,2-diphenylethyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-3-(4-chlorophenyl)acrylamide
• N-(((3S,5S)-3-(2-(benzyl(methyl)amino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan- 5-yl)methyl)-3,4-dichlorobenzamide
• 3,4-dichloro-N-(((3S,5S)-3-(2-(methyl(pentyl)amino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
• (S)-6-chloro-N-((2-oxo-1 -(2-phenylbutyl)-3-(piperidin-4-yl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide • (S)-6-chloro-N-(3-(1 -isopentylpiperidin-4-yl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)- 2-naphthamide
• 3,4-dichloro-N-(((3S,5S)-3-(2-(3,5-dimethylpiperidin-1 -yl)ethyl)-2-oxo-1 -((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)benzamide
• 3,4-dichloro-N-(((3S,5S)-3-(2-(4-hydroxypiperidin-1 -yl)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
• 1 -(2-((2S,7S)-7-((3,4-dichlorobenzamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)ethyl)piperidine-4-carboxylic acid • N-(((3S,5S)-3-(2-(azepan-1 -yl)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide • 3,4-dichloro-N-(((3S,5S)-3-(2-((S)-2-methylpiperidin-1 -yl)ethyl)-2-oxo-1 -((S)-2- phenylbutyl)-1 ,4-diazepan-5-yl)methyl)benzamide
• N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-((3-(1 -ethylpiperidin-4-yl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1 -(2,2-diphenylethyl)-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-2-one
• 6-chloro-N-(((3S,5S)-3-(2-guanidinoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-(2-(3-methylguanidino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • (S)-2-amino-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 - (methylamino)-3-(naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propan amide
• (S)-2-((3S,5R)-5-((2-(4-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • (R)-2-amino-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 - (methylamino)-3-(naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propan amide
• (S)-2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(naphthalen-1 -yl)acetamido)methyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • N-(((3S,5S)-3-(2-aminoethyl)-1 -((R)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide
• (E)-3-(4-fluorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 -(methylamino)-3- (naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
• 3,4-dichloro-N-(((3S,5S)-1 -((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
• 3,4-dichloro-N-(((3S,5S)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)benzamide • (S)-2-((3S,5R)-5-((3-(4-fluorophenyl)propanamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • N-(((3S,5S)-3-(2-amino-2-methylpropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphth amide
• N-(((3R,5R)-3-(2-amino-2-methylpropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide • N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-3,4- dichlorobenzamide
• 3,4-dichloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)benzamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(3,5-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-6- chloro-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphth amide
• 6-chloro-N-(((3S,5S)-3-(2-methyl-2-(piperidin-1 -yl)propyl)-2-oxo-1 -((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide • (E)-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 -(methylamino)-3- (naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -((R)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphth amide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • (S)-2-amino-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 - (methylamino)-3-(naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propan amide
• (R)-2-amino-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 - (methylamino)-3-(naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5- yl)methyl)propanamide
• (S)-2-((3S,5R)-3-(3-guanidinopropyl)-5-((2-(4-methoxyphenyl)acetamido)methyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5R)-3-(3-guanidinopropyl)-2-oxo-5-((3-phenylpropanamido)methyl)-1 ,4- diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • (S)-2-((3S,5R)-5-((3-(4-chlorophenyl)propanamido)methyl)-3-(3-guanidinopropyl)-2- oxo-1 , 4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide • (E)-3-(4-chlorophenyl)-N-(((3S,5R)-3-(3-guanidinopropyl)-1 -((S)-1 -(methylamino)-3- (naphthalen-2-yl)-1 -oxopropan-2-yl)-2-oxo-1 ,4-diazepan-5-yl)methyl)acrylamide
• 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide • 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylguanidino)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphth amide
• 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5-yl)methyl)-2- naphthamide • (S)-2-((3S,5R)-5-((2-(2,4-dichlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2- oxo-1 , 4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5R)-5-((2-(2,4-dichlorophenyl)acetamido)methyl)-3-(3-(3-(2-(2,4- dichlorophenyl)acetyl)guanidino)propyl)-2-oxo-1 ,4-diazepan-1 -yl)-N-methyl-3- (naphthalen-2-yl)propanamide • (S)-2-((3S,5R)-5-((2-(3-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)-2-oxo- 1 ,4-diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• (S)-2-((3S,5R)-5-((2-(3-chlorophenyl)acetamido)methyl)-3-(3-(3-(2-(3- chlorophenyl)acetyl)guanidino)propyl)-2-oxo-1 ,4-diazepan-1 -yl)-N-methyl-3- (naphthalen-2-yl)propanamide • N-(((3S,5S)-3-(2-aminoethyl)-1 -(2-ethyl-3-methylbut-3-enyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-3,4-dichlorobenzamide
• 3,4-dichloro-N-(((3S,5S)-1 -(2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
• 3,4-dichloro-N-(((3S,5S)-1 -(2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)benzamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(2-ethyl-3-methylbut-3-enyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-1 -((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-1 -(2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide • N-(((3S,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide
• N-(((3S,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3S,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide
• N-(((3R,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5R)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(1 H-indol-3-yl)acetamide • N-(((3R,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)biphenyl-4-carboxamide
• N-(((3R,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-1 H-indole-3-carboxamide
• N-(((3R,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3R,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-(naphthalen-2-yl)acetamide
• N-(((3R,5S)-1 -(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)quinoline-3-carboxamide • (S)-methyl 2-((3S,5R)-5-((2-(4-chlorophenyl)acetamido)methyl)-3-(3-guanidinopropyl)- 2-0X0-1 ,4-diazepan-1 -yl)-3-(naphthalen-2-yl)propanoate
• (S)-2-((3S,5R)-3-(3-aminopropyl)-5-((2-(4-chlorophenyl)acetamido)methyl)-2-oxo-1 ,4- diazepan-1 -yl)-N-methyl-3-(naphthalen-2-yl)propanamide
• N-(((3S,5S)-3-(2-(azepan-1 -yl)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-6-chloro-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylureido)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• benzyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)acetate • benzyl 3-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)propanoate • 4'-chloro-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)biphenyl-2-carboxamide
• 6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacetamido)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-3-(guanidinomethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(2,4-dichlorobenzyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 3,4-dichlorobenzamide
• 3,4-dichloro-N-(((3S,5S)-1 -(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)benzamide
• 6-chloro-N-(((3S,5S)-1 -(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 -((R)-2-(thiophen-3-yl)butyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 -((S)-2-(thiophen-3-yl)butyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• N-(((3S,5S)-3-(2-aminoethyl)-1 -(2-ethyl-2-methylbutyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)- 6-chloro-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1 -((S)-2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4-diazepan- 5-yl)methyl)-2-naphth amide
• 3,4-dichloro-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1 ,4- diazepan-5-yl)methyl)benzamide
• N-(3,4-dichlorobenzyl)-N-(((3S,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 - yl)ethyl)-1 ,4-diazepan-5-yl)methyl)acetamide
• 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 -(2,3,5-trichlorobenzyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-3-(2-(1 -methylethylsulfonamido)ethyl)-2-oxo-1 -((S)-2-phenylbutyl)- 1 ,4-diazepan-5-yl)methyl)-2-naphthamide • butyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1 ,4- diazepan-2-yl)ethylcarbamate
• (S)-6-chloro-N-((3-(1 -isopropylpiperidin-4-yl)-2-oxo-1 -(2-phenylbutyl)-1 ,4-diazepan-5- yl)methyl)-2-naphthamide • 6-chloro-N-(((3S,5S)-2-oxo-1 -((R)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 5-(4-chlorophenyl)-N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)- 1 ,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
• N-(((3S,5S)-1 -(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1 -yl)ethyl)-1 ,4-diazepan-5- yl)methyl)-6-methoxy-2-naphthamide
• 6-chloro-N-(((3R,5R)-2-oxo-1 -((R)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3S,5R)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide • 6-chloro-N-(((3R,5S)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
• 6-chloro-N-(((3R,5R)-2-oxo-1 -((S)-2-phenylbutyl)-3-(2-(piperidin-1 -yl)ethyl)-1 ,4- diazepan-5-yl)methyl)-2-naphthamide
a pharmaceutically acceptable salt or prodrug thereof.
PCT/AU2009/000229 2009-02-27 2009-02-27 Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors WO2010096854A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/AU2009/000229 WO2010096854A1 (en) 2009-02-27 2009-02-27 Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/AU2009/000229 WO2010096854A1 (en) 2009-02-27 2009-02-27 Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors

Publications (1)

Publication Number Publication Date
WO2010096854A1 true WO2010096854A1 (en) 2010-09-02

Family

ID=42664923

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2009/000229 WO2010096854A1 (en) 2009-02-27 2009-02-27 Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors

Country Status (1)

Country Link
WO (1) WO2010096854A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013102047A1 (en) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
WO2019195756A1 (en) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions for treating kidney disease
EP4029513A1 (en) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Melanocortin-4 receptor agonists for the treatment of disorders characterised by pomc gene hypermethylation
WO2022247783A1 (en) * 2021-05-24 2022-12-01 中国科学技术大学 Use of melanocortin receptor mc5r
JP7288554B1 (en) 2020-06-09 2023-06-07 ファイザー・インク Spiro compounds and their use as melanocortin 4 receptor antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048913A1 (en) * 1998-03-24 1999-09-30 The University Of Queensland Peptide turn mimetics
WO2008017852A1 (en) * 2006-08-11 2008-02-14 Palatin Technologies, Inc. Diamine-containing, tetra- substituted piperazine compounds as melanocortin receptor modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048913A1 (en) * 1998-03-24 1999-09-30 The University Of Queensland Peptide turn mimetics
WO2008017852A1 (en) * 2006-08-11 2008-02-14 Palatin Technologies, Inc. Diamine-containing, tetra- substituted piperazine compounds as melanocortin receptor modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NOUVET, A ET AL.: "Convenient introduction of 2-(trimethylsilyl)ethylsulfonyl (SES) amino protection on different amino acids and its use in peptidomimetic chemistry", LETTERS IN PEPTIDE SCIENCE, vol. 6, no. 4, 1999, pages 239 - 242 *
NOUVET, A ET AL.: "Synthesis ofperhydrodiazepinones as new putative peptidomimetics", TETRAHEDRON, vol. 55, no. 15, 1999, pages 4685 - 4698, XP004223084, DOI: doi:10.1016/S0040-4020(99)00130-1 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013102047A1 (en) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US9845339B2 (en) 2011-12-29 2017-12-19 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US10167312B2 (en) 2011-12-29 2019-01-01 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP3539551A1 (en) 2011-12-29 2019-09-18 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US10954268B2 (en) 2011-12-29 2021-03-23 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP3988108A1 (en) 2011-12-29 2022-04-27 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US11702448B2 (en) 2011-12-29 2023-07-18 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP4029513A1 (en) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Melanocortin-4 receptor agonists for the treatment of disorders characterised by pomc gene hypermethylation
WO2019195756A1 (en) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions for treating kidney disease
JP7288554B1 (en) 2020-06-09 2023-06-07 ファイザー・インク Spiro compounds and their use as melanocortin 4 receptor antagonists
JP2023525394A (en) * 2020-06-09 2023-06-15 ファイザー・インク Spiro compounds and their use as melanocortin 4 receptor antagonists
WO2022247783A1 (en) * 2021-05-24 2022-12-01 中国科学技术大学 Use of melanocortin receptor mc5r

Similar Documents

Publication Publication Date Title
RU2555343C2 (en) Methods of modulating activity of mc5 receptor and treatment of conditions related to thereof
US20140128380A1 (en) Methods of modulating the activity of the mc1 receptor and treatment of conditions related to this receptor
WO2010096854A1 (en) Methods of modulating the activity of the mc3 and/or mc4 receptors and treatment of conditions related to these receptors
EP2257534B1 (en) 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists
US9340517B2 (en) Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor
AU2009219108B2 (en) 3-substituted-1,4-diazepan-2-one melanocortin-5 receptor antagonists
US8343958B2 (en) 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5-receptor antagonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09840607

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09840607

Country of ref document: EP

Kind code of ref document: A1