US20140194383A1 - Monomers capable of dimerizing in an aqueous solution, and methods of using same - Google Patents

Monomers capable of dimerizing in an aqueous solution, and methods of using same Download PDF

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US20140194383A1
US20140194383A1 US14/110,056 US201214110056A US2014194383A1 US 20140194383 A1 US20140194383 A1 US 20140194383A1 US 201214110056 A US201214110056 A US 201214110056A US 2014194383 A1 US2014194383 A1 US 2014194383A1
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substituted
group
monomer
unsubstituted
alkyl
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Francis Barany
Maneesh Pingle
Donald E. Bergstrom
Sarah F. Giardina
Lee Daniel Arnold
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Cornell University
Purdue Research Foundation
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Cornell University
Purdue Research Foundation
Coferon Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • protein-protein interactions For example, signaling pathways are used by cells to generate biological responses to external or internal stimuli.
  • a few thousand gene products control both ontogeny/development of higher organisms and sophisticated behavior by their many different cell types. These gene products can work in different combinations to achieve their goals and often do so through protein-protein interactions.
  • Such proteins possess modular protein domains that recognize, bind, and/or modify certain motifs. Protein-protein and protein-nucleic acid recognition often function through protein interactions domains, for example, such as the SH2, SH3, and PDZ domains. These protein-interaction domains may represent a meaningful area for developing targeted therapies.
  • Other macromolecular interactions that may serve as potential targets for effective therapies include protein-nucleic acid interactions, protein-carbohydrate interactions, and protein-lipid interactions.
  • Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media.
  • such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer).
  • Contemplated monomers may include a ligand moiety (e.g. a pharmacophore for the target biomolecule), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • a ligand moiety e.g. a pharmacophore for the target biomolecule
  • linker element e.g. a pharmacophore for the target biomolecule
  • a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g
  • a first monomer capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media is provided.
  • the first monomer is represented by the formula:
  • the second monomer has a boronic acid or oxaborole moiety capable of binding with the Z 1 moiety of Formula I to form the multimer.
  • a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof comprises administering to the patient thereof an amount of a first monomer as described above and an amount of a boronic acid or oxaborole monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.
  • a therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer is provided.
  • the multimer is represented by the formula:
  • a method of modulating two or more target biomolecule domains substantially simultaneously comprises contacting an aqueous composition comprising said biomolecule domains with a first monomer represented by:
  • said first monomer and said second monomer forms a dimer that binds to the first target biomolecule domain and the second target biomolecule domain.
  • a method of treating a disease associated with two or more target biomolecule domains in a patient in need thereof comprises administering to said patient a first monomer represented by:
  • X 2 is a second ligand moiety capable of binding to a second target biomolecule domain, wherein upon administration, said first monomer and said second monomer forms a dimer in vivo that binds to the first target biomolecule domain and the second target biomolecule domain.
  • a first monomer capable of forming a biologically useful dimer when in contact with a second monomer in vivo is provided.
  • the first monomer is represented by the formula:
  • a therapeutic dimerized compound formed from the dimerization in an aqueous media of a first monomer is provided.
  • the first monomer is represented by:
  • X 3 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 3 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • X 4 is a second ligand moiety capable of binding to a second target biomolecule
  • Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • a method of treating a disease associated with two or more target biomolecule domains in a patient in need thereof comprises administering to said patient two or more monomers each independently selected from the group represented by:
  • X 3 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 3 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • X 4 is a second ligand moiety capable of binding to a second target biomolecule
  • Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • Z 3 is as shown below, wherein upon administration, said first monomer and said second monomer forms a dimer in vivo that binds to the first target biomolecule domain and the second target biomolecule domain.
  • a first monomer capable of forming a biologically useful trimer when in contact with a second monomer and a third monomer in an aqueous media is provided.
  • the first monomer is represented by the formula:
  • FIG. 1A shows an x-ray co-crystal structure of a multimer bound to adjacent subunits of mast cell beta-tryptase-II, according to an embodiment.
  • the cationic aminomethyl-phenyl-piperidine moieties of the multimer are bound in the pharmacophoric pockets of the tryptase subunits, and the linker elements are joined by a cyclic tetrahedral sp 3 boronate diester linkage;
  • FIG. 1B shows the chemical structure of the multimer bound to tryptase in FIG. 1A , according to an embodiment
  • FIG. 2A shows dose response curves for T2 & T35 monomers and for T2 and T35 combined in a 1:1 ratio of T2:T35, according to an embodiment
  • FIG. 2B shows a reaction scheme for the formation of the 1:1 multimer in FIG. 2A , according to an embodiment
  • FIG. 3 shows the tryptase-bound state of the 1:1 multimer of T2:T35 shown in FIG. 1A , according to an embodiment
  • FIG. 4A shows an x-ray co crystal structure of a multimer bound to adjacent subunits of mast cell beta-tryptase, according to an embodiment.
  • the cationic aminomethyl-phenyl-piperidine moieties of a 1:1 T27:T10 multimer are bound in the pharmacophoric pockets of the tryptase subunits, and the multimer is joined by a cyclic planar sp 2 boronic acid diester linkage;
  • FIG. 4B shows a reaction scheme for the formation of the 1:1 multimer in FIG. 4A , according to an embodiment
  • FIG. 5A shows an x-ray co-crystal structure of a T92+T35 heterodimer at pH5.5 and pH6.5 bound to tryptase, according to an embodiment.
  • the structure confirms the sp 3 state of the phenolic-hydroxamate/boronate complex bound to tryptase under both conditions;
  • FIG. 5B shows a reaction scheme for the formation of the 1:1 multimer in FIG. 5A , according to an embodiment
  • FIG. 6A shows an x-ray co-crystal structure of a T55 homodimer bound to tryptase, according to an embodiment.
  • the cationic aminomethyl-phenyl-piperidine moieties of the multimer are bound in the pharmacophoric pockets of the tryptase subunits, and the monomers are joined by a covalent spiroketal linkage;
  • FIG. 6B shows a reaction scheme for the formation of the 1:1 multimer in FIG. 6A , according to an embodiment.
  • Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media.
  • such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer).
  • Contemplated monomers may include a ligand moiety (e.g. a pharmacophore moiety), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
  • contemplated monomers may be separate or separatable in a solid or in an aqueous media under one set of conditions, and when placed in an aqueous media having one or more biomolecules, with another (e.g., under a different set of conditions), can 1) form a multimer through the linker on each monomer; and either: 2a) bind to the biomolecule in two or more locations (e.g.
  • protein domains through each ligand moiety of the respective monomer or 2b) bind to two or more biomolecules through each ligand moiety of the respective monomer.
  • disclosed monomers may interact with another appropriate monomer (i.e. a monomeric pair) in an aqueous media (e.g., in vivo) to form a multimer (e.g. a dimer) that can bind to two separate target biomolecule domains (e.g. protein domains).
  • the ligand moiety of a contemplated monomer may be a pharmacophore or a ligand moiety that is e.g., capable of binding to a biomolecule, such as for example, a protein, e.g. a specific protein domain, a component of a biological cell such as ribosome (composed of proteins and nucleic acids), or an enzyme active site (e.g. a protease, such as tryptase).
  • the linker element comprises a functional group capable of forming a chemical bond with another linker element.
  • the linker moiety may also serve as a signaling entity or “reporter,” and in some instances the assembly of two or more linkers can produce a fluorescent entity or fluorophore with properties distinct from the individual linker moiety.
  • a plurality of monomers, each comprising a linker element may react to form a multimer connected by the linker elements.
  • the multimer may be formed in vivo.
  • the multimer may have enhanced properties relative to the monomers that form the multimer. For example, in certain embodiments, the multimer may bind to a target with greater affinity than any of the monomers that form the multimer. Also described are methods of making the compositions and methods of administering the compositions.
  • a plurality of monomers may assemble to form a multimer.
  • the multimer may be used for a variety of purposes. For example, in some instances, the multimer may be used to perturb a biological system. As described in more detail below, in some embodiments, the multimer may bind to a target biomolecule, such as a protein, nucleic acid, or polysaccharide. In certain embodiments, the multimer may be used as a pharmaceutical.
  • the multimer may form in vivo upon administration of suitable monomers to a subject.
  • the multimer may be capable of interacting with a relatively large target site as compared to the individual monomers that form the multimer.
  • a target may comprise, in some embodiments, two protein domains separated by a distance such that a multimer, but not a monomer, may be capable of binding to both domains essentially simultaneously.
  • contemplated multimers may bind to a target with greater affinity as compared to a monomer binding affinity alone.
  • a contemplated multimer may advantageously exhibit enhanced properties relative to the monomers that form the multimer.
  • a multimer may have improved binding properties as compared to the monomers alone.
  • a multimer may have improved signaling properties.
  • the fluorescent properties of a multimer may be different as compared to a monomer.
  • the fluorescent brightness of a multimer at a particular wavelength may be greater than the fluorescent brightness at the same wavelength of the monomers that form the multimer.
  • a difference in signaling properties between the multimer and the monomers that form the multimer may be used to detect formation of the multimer.
  • detection of the formation of the multimer may be used to screen monomers, as discussed in more detail below.
  • the multimers may be used for imaging or as diagnostic agents.
  • a multimer may be a homomultimer (i.e., a multimer formed from two or more essentially identical monomers) or may be a heteromultimer (i.e., a multimer formed from two or more substantially different monomers).
  • a contemplated multimer may comprise 2 to about 10 monomers, for example, a multimer may be a dimer, a trimer, a tetramer, or a pentamer.
  • a monomer may comprise a ligand moiety, a linker element, and a connector element that associates the ligand moiety with the linker element.
  • the linker element of a first monomer may combine with the linker element of a second monomer.
  • the linker element may comprise a functional group that can react with a functional group of another linker element to form a bond linking the monomers.
  • the linker element of a first monomer may be substantially the same as the linker element of a second monomer.
  • the linker element of a first monomer may be substantially different than the linker element of a second monomer.
  • the ligand moiety may be a pharmacophore.
  • the ligand moiety (e.g., a pharmacophore) may bind to a target molecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
  • the IC 50 of the first monomer against a first target biomolecule and the IC 50 of the second monomer against a second target biomolecule may be greater than the apparent IC 50 of a combination of the monomers against the first target biomolecule and the second target biomolecule.
  • the combination of monomers may be any suitable ratio.
  • the ratio of the first monomer to the second monomer may be between 10:1 to 1:10, in some embodiments between 5:1 and 1:5, and in some embodiments between 2:1 and 1:2.
  • the ratio of the first monomer to the second monomer may be essentially 1:1.
  • the ratio of the smaller of the IC 50 of the first monomer and the second monomer to the apparent IC 50 of the multimer may be at least 3.0.
  • the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 10.0. In some embodiments, the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 30.0.
  • the apparent IC 50 resulting from an essentially equimolar combination of monomers against the first target biomolecule and the second target biomolecule is at least about 3 to 10 fold lower, at least about 10 to 30 fold lower, at least about 30 fold lower, or at least about 40 to 50 fold lower than the lowest of the IC 50 of the second monomer against the second target biomolecule or the IC 50 of the first monomer against the first target biomolecule.
  • the affinity of the multimer for the target biomolecule(s) are less than 1 ⁇ M, in some embodiments less than 1 nM, in some embodiments less than 1 ⁇ M, in some embodiments less than 1 fM, and in some embodiments less than 1 aM, and in some embodiments less than 1 zM.
  • Affinities of heterodimerizing monomers for the target biomolecule can be assessed through the testing of the respective monomers in appropriate assays for the target activity or biology because they do not typically self-associate.
  • the testing of homodimerizing monomers may not, in some embodiments, afford an affinity for the monomeric or dimeric state, but rather the observed effect (e.g. IC 50 ) is a result of the monomer-dimer dynamics and equilibrium, with the apparent binding affinity (or IC 50 ) being e.g., a weighted measure of the monomer and dimeric inhibitory effects upon the target.
  • the pH of the aqueous fluid in which the multimer forms may be between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
  • the multimer may be stable in an aqueous solution having a pH between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
  • the aqueous solution may have a physiologically acceptable pH.
  • the ligand moiety may be capable of binding to a target and at least partially disrupting a biomolecule-biomolecule interaction (e.g., a protein-protein interaction). In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-nucleic acid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-lipid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-polysaccharide interaction. In some embodiments, the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.
  • a biomolecule-biomolecule interaction e.g., a protein-protein interaction
  • the ligand moiety may be capable of binding to a target and at least partially disrupt
  • the linker element may be capable of generating a signal.
  • the linker element may be capable of fluorescing.
  • the linker element may have greater fluorescence when the monomer to which it is attached is part of a multimer as compared to when the monomer to which it is attached is not part of a multimer.
  • the fluorescent brightness of a linker element may increase by at least 2-fold, in some embodiments by at least 5-fold, in some embodiments by at least 10-fold, in some embodiments by at least 50-fold, in some embodiments by at least 100-fold, in some embodiments by at least 1000-fold, and in some embodiments by at least 10000-fold.
  • a linker element in a multimer may have a peak fluorescence that is red-shifted relative to the peak fluorescence of the linker element in a monomer. In other embodiments, a linker element may have a peak fluorescence that is blue-shifted relative to the peak fluorescence of a linker element in a monomer.
  • a first monomer may be capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media, for example, when the first and second monomer are different and form e.g. a heteromultimer in aqueous media.
  • the first monomer can represented by the formula:
  • X 1 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
  • Z 1 is a first linker selected from the group consisting of:
  • the second monomer has a boronic acid or oxaborole moiety capable of binding with the Z 1 moiety of Formula I to form the multimer.
  • a 1 may be selected from the group consisting of C 1 -C 3 alkylene optionally substituted with one, two, or three halogens, or —C(O)—.
  • Z 1 may be
  • R 2 independently for each occurrence, is selected from H, C 1-4 alkyl, or two R 1 moities taken together form a 5- or 6-membered cycloalkyl or heterocyclic ring, wherein R 3 is H, or
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be a monosaccharide or a disaccharide.
  • Z 1 may be selected from the group consisting of
  • X is selected from O, S, CH, NR′, or when X is NR′, N may be covalently bonded to Y of formula I;
  • R′ is selected from the group consisting of H and C 1-4 alkyl
  • R 5 , R 6 , and R 7 are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or a mono- or bicyclic heterocyclic optionally substituted with amino, halo, hydroxyl, oxo, or cyano; and
  • AA is a 5-6 membered heterocyclic ring optionally substituted by C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′, or —S—C 1-4 alkyl.
  • Z 1 may be
  • Z 1 may be
  • X may be nitrogen.
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • Z 1 may be
  • the second monomer may be X 2 —Y 2 —Z 2 (Formula II), wherein Z 2 is the boronic acid or oxaborale moiety, and wherein X 2 is a second ligand moiety capable of binding to a second target biomolecule, and Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 .
  • X 1 and X 2 may be the same. In other instances, X 1 and X 2 may be different.
  • first target biomolecule and the second target biomolecule may be different. In other embodiments, the first target biomolecule and the second target biomolecule may be the same.
  • Z 2 of the second monomer may be selected from the group consisting of:
  • R 8 is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —COOH; or —CONHR′;
  • a 1 is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • Q is selected from the group consisting of substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • AA independently for each occurrence, is phenyl, aryl, or a 5-7 membered heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, C 1-4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 2-4 alkenyl; C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —NR 2 ′′′, wherein R′′′ is independently selected from the group consisting of H and C 1-4 alkyl; —COOH; —CONHR′; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and
  • R′ is H or C 1-4 alkyl.
  • R 8 and the substituent comprising boronic acid may be ortho to each other, and R 8 may be —CH 2 NH 2 .
  • Z 2 of the second monomer may be selected from the group consisting of:
  • Z 2 of the second monomer may be selected from the group consisting of:
  • Z 2 of the second monomer may be selected from the group consisting of:
  • R 8 is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —COOH; or —CONHR′;
  • AA independently for each occurrence, is a 5-7 membered heterocyclic ring having one, two, or three heteroatoms, or phenyl, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 2-4 alkenyl; C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —NR 2 ′′′, wherein R′′′ is independently selected from the group consisting of H and C 1-4 alkyl; —COOH; —CONHR′; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and
  • R′ is H or C 1-4 alkyl.
  • a first monomer may be capable of forming a biologically useful dimer or multimer when in contact with a second monomer in vivo, wherein the first and second linkers are the same (e.g. forming a homodimer or homomultimer) wherein the first monomer is represented by the formula:
  • X 3 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 3 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • X 4 is a second ligand moiety capable of binding to a second target biomolecule
  • Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • Z 3 is selected from the group consisting of:
  • a first monomer may be capable of forming a biologically useful trimer when in contact with a second monomer and a third monomer in an aqueous media, wherein the first monomer is represented by the formula:
  • X 2 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ;
  • Z 2 is a first linker selected from the group consisting of:
  • the second monomer and the third monomer each have a boronic acid moiety capable of binding with the Z 2 moiety of Formula II to form the trimer.
  • R 8 and the substituent comprising boronic acid may be ortho to each other, and R 8 may be —CH 2 NH 2 .
  • Z 2 of the first monomer may be selected from the group consisting of:
  • Z 2 of the first monomer may be selected from the group consisting of:
  • a monomer may be capable of reacting with one or more other monomers to form a multimer.
  • a first monomer may react with a second monomer to form a dimer.
  • a first monomer may react with a second monomer and a third monomer to form a trimer.
  • a first monomer may react with a second monomer, a third monomer, and a fourth monomer to form a tetramer.
  • each of the monomers that form a multimer may be essentially the same.
  • each of the monomers that form a multimer may be substantially different.
  • at least some of the monomers that form a multimer may be essentially the same or may be substantially different.
  • the linker element of a first monomer and the linker element of a second monomer may be substantially different.
  • the connector element of a first monomer and the connector element of a second monomer may be substantially different.
  • the ligand moiety (e.g., a pharmacophore) of a first monomer and the ligand moiety (e.g., a pharmacophore) of the second monomer may be substantially different.
  • formation of a multimer from a plurality of monomers may be irreversible. In some embodiments, formation of a multimer from a plurality of monomers may be reversible.
  • the multimer may have an oligomer or dimer dissociation constant between 10 mM and 1 nM, in some embodiments between 1 mM and 100 nM, in some embodiments between 1 mM and 1 mM, and in some embodiments between 500 mM and 1 mM.
  • the multimer may have a dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 mM, in some embodiments less than 100 mM, in some embodiments less than 50 mM, in some embodiments less than 1 mM, in some embodiments less than 100 nM, and in some embodiments less than 1 nM.
  • a first monomer and a second monomer may form a dimer in aqueous solution.
  • the first monomer may form a biologically useful dimer with a second monomer in vivo.
  • molecular self-assembly may be directed through noncovalent interactions, e.g., hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, electrostatic, and/or electromagnetic interactions.
  • pi-pi and pi-cation interactions can be used to drive multimerization.
  • van der Waals and electromagnetic forces are other interactions that can help to drive multimerization.
  • acid/base pairs and donor-acceptor pairs e.g., amide and/or sulfonamide pairs, can be employed to help direct self-assembly.
  • use of hydrophobic interactions can be used for multimerization targeting a membrane-bound protein.
  • metal coordination might be used when the target itself incorporates the metal, but could also be used in other scenarios.
  • a therapeutic multimer compound (e.g. a heteromultimer) may be formed from the multimerization in an aqueous media of a first monomer represented by:
  • X 1 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
  • Z 1 is a first linker selected from the group consisting of: a)
  • a therapeutic dimerized compound may be formed from the dimerization in an aqueous media of a first monomer represented by:
  • X 3 is a first ligand moiety capable of binding to a first target biomolecule
  • Y 3 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • X 4 is a second ligand moiety capable of binding to a second target biomolecule
  • Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 3 ;
  • Z 3 is selected from the group consisting of:
  • a monomer may comprise a connector that joins the ligand moiety with the linker element.
  • such connectors do not have significant binding or other affinity to an intended target.
  • a connector may contribute to the affinity of a ligand moiety to a target.
  • a connector element may be used to connect the linker element to the ligand moiety.
  • the connector element may be used to adjust spacing between the linker element and the ligand moiety.
  • the connector element may be used to adjust the orientation of the linker element and the ligand moiety.
  • the spacing and/or orientation the linker element relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target.
  • connectors with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a multimer to its target biomolecule.
  • connectors with restricted degrees of freedom are preferred to promote cellular permeability of the monomer.
  • the connector element may be used for modular assembly of monomers.
  • a connector element may comprise a functional group formed from reaction of a first and second molecule.
  • a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a linker element.
  • the connector element may comprise a spacer having a first functional group that forms a bond with a ligand moiety and a second functional group that forms a bond with a linker element.
  • Contemplated connecters may be any acceptable (e.g. pharmaceutically and/or chemically acceptable) bivalent linker that, for example, does not interfere with multimerization of the disclosed monomers.
  • linkers may be substituted or unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl, sulfone, phosphate, ester, carbamate, or amide.
  • Contemplated connectors may include polymeric connectors, such a polyethylene glycol or other pharmaceutically acceptable polymers.
  • contemplated connectors may be a covalent bond or a bivalent C 1-10 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three or four methylene units of L are optionally and independently replaced by cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, —C( ⁇ NR)—, phenyl, or a mono or bicyclic heterocycle ring.
  • a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length.
  • a connecter group is from about 6 ⁇ to about 15 ⁇ in length.
  • contemplated monomers and multimers may be administered to a patient in need thereof.
  • a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof is provided.
  • the method comprises administering to the patient thereof an amount of the first monomer and an amount of a boronic acid monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.
  • a first monomer and a second monomer may be administered substantially sequentially. In other embodiments, the first monomer and the second monomer are administered substantially simultaneously. In some embodiments the monomers may be administered, sequentially or simultaneously, by different routes of administration. In still further embodiments, a first monomer and a second monomer may be administered after forming a multimer.
  • a method of modulating two or more target biomolecule domains is provided.
  • a first ligand moiety may bind to a first domain and a second ligand moiety may bind to a second domain.
  • a multimer comprising the first and second ligand moieties may be form prior to binding the first and second domains. In other embodiments, the multimer may form after one and/or two of the monomers bind the first and second domains.
  • the target biomolecule may be a protein. In other embodiments, the target biomolecule may be nucleic acid. In some cases, the ligand moiety may be a pharmacophore.
  • a multimer may be used to inhibit or facilitate protein-protein interactions.
  • a multimer may be capable of activating or inactivating a signaling pathway.
  • a multimer may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the multimer does not bind the target protein.
  • monomers may be chosen such that a multimer formed from the monomers binds to at least two regions of a target molecule.
  • protein-protein and protein-nucleic acid recognition often work through protein interaction domains, such as the SH2, SH3, and PDZ domains.
  • protein interaction domains such as the SH2, SH3, and PDZ domains.
  • SH2 domains are miniature receptors for protein regions containing a phosphorylated tyrosine.
  • SH2 domains may be found in proteins that act as, or play a role in, for example, adaptors, scaffolds, kinases, phosphatases, ras signaling, transcription, ubiquitination, cytoskeletal regulation, signal regulation, and phospholipid second messenger signaling.
  • SH3 domains bind peptide loops with the motif RXXK or PXXP.
  • Many proteins have both SH2 and SH3 domains, which act as “receptors” to bind one or more protein partners.
  • Coferons may be designed to inhibit binding of a phosphotyrosine protein to its cognate SH2 domain.
  • monomers and multimers may be designed so one ligand moiety binds one motif (i.e. SH2), and a second ligand moiety binds a second motif (i.e. SH3), either on the same or different proteins.
  • linker elements may be used to bring together two pharmacophores on the same target to: (i) bind the target with higher affinity; (ii) exhibit a stronger inhibition than either pharmacophore alone; (iii) exhibit greater activation than either pharmacophore alone; or (iv) create a binding entity covering a larger surface area of the target, making it harder for the organism/cell/virus to develop resistance to the drug via point mutations.
  • a multimer may target a tryptase.
  • a multimer may be used to treat conditions activated by a tryptase, such as mast cell mediated inflammatory conditions (e.g. asthma).
  • mast cell mediated inflammatory conditions e.g. asthma
  • Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation.
  • Leukocytes containing IgE receptors notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, arylsulfatase B, chymase, and tryptase,
  • Human mast cell ⁇ -tryptase-II is a tetrameric serine protease that is concentrated in mast cell secretory granules.
  • the enzyme is involved in IgE-induced mast cell degranulation in an allergic response and is potentially a target for the treatment of allergic asthma, rhinitis, conjunctivitis and dermatitis.
  • Tryptase has also been implicated in the progression of renal, pulmonary, hepatic, testicular fibrosis, chronic obstructive pulmonary disease (COPD), and inflammatory conditions such as ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, and various other mast cell-related diseases.
  • multimers may be used to treat such diseases.
  • Tryptase is stored in the mast cell secretory granules and is the major protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilatory and bronchodilatory neuropeptides and modulation of bronchial responsiveness to histamine.
  • tryptase inhibitors may be useful as anti-inflammatory agents for treatment of inflammatory disease and may also be useful in treating or preventing allergic rhinitis, inflammatory bowel disease, psoriasis, ocular or vernal or ulcerative conjunctivitis, dermatological conditions (e.g., psoriasis, eczema, or atopic dermatitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis, hematoid arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or gouty arthritis), rheumatoid spondylitis, interstitial lung disease, chronic obstructive pulmonary disease, and diseases of joint cartilage destruction.
  • dermatological conditions e.g., psoriasis, eczema, or atopic dermatitis
  • arthritis e.g., rheumatoid arthritis, osteoarthritis, hema
  • tryptase inhibitors may be useful in treating or preventing fibrotic conditions, for example, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hepatic fibrosis, renal fibrosis, testicular, and hypertrophic scars.
  • tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture.
  • tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.
  • tryptase inhibitors may be useful in the treatment or prevention of arthritis, periodontal disease, diabetic retinopathy, a condition relating to atherosclerotic plaque rupture, anaphylactic ulcerative colitis, and tumor growth.
  • tryptase inhibitors may be useful in the treatment of anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections.
  • a variety of antibiotics elicit their antibacterial activity by binding to the bacterial ribosome and inhibiting protein synthesis. Many of these antibiotics bind the peptidyl transferase center of the ribosome (P site).
  • a multimer may bind to two or more sites on the ribosome. For example, a first pharmacophore of a multimer may bind to the peptidyl transferase center of the ribosome (i.e., the P site) and a second multimer may bind to site adjacent to the P site.
  • Linezolid an oxazolidinone antibiotic, is believed to bind adjacent to the binding site for Sparsomycin.
  • target protein families are provided in Table 1 below. Also provided in Table 1 are endogenous ligands, agonists, and antagonists that bind to the protein families. Examples of detection assays are also provided in Table 1, which may be used in a screening assay to detect activation and/or inhibition of the target protein.
  • Table 2 Provided in Table 2 are non-limiting examples of domains that can bind a ligand, proteins that contain the domains, known inhibitors, and K D values of binding partners (i.e., ligands). Examples of detection assays are also provided in Table 2, which may be used in a screening assay to find ligands for the domains.
  • a pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects.
  • identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
  • pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high-throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
  • pharmacophores may be derived from traditional approaches such as fragment based drug design and structure based drug design.
  • any pharmacophore including pre-existing pharmacophores such as approved drugs are amenable to be designed as monomers through the incorporation of the appropriate linker elements and connector elements.
  • previously approved drugs that have poor efficacy due to a low affinity for a first macromolecular target may be utilized as a pharmacophore component of a first monomer which when combined with a pharmacophore of a second monomer that also binds the first macromolecular target or a second macromolecular target that interacts with the first macromolecular target results in enhanced binding and, in some cases, higher efficacy.
  • previously approved drugs that have low efficacy as a result of size, molecular weight or other physicochemical attributes that reduce the cellular uptake of the drug may be amenable to being converted into one or more monomers that bear the appropriate pharmacophoric elements, such that each monomer has physicochemical attributes that allow for increased cellular uptake.
  • a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
  • the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
  • compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
  • Treatment can be continued for as long or as short a period as desired.
  • the compositions may be administered on a regimen of, for example, one to four or more times per day.
  • a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
  • a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
  • the present disclosure provides pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl
  • compositions 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, 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, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • 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
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples 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 and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may 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
  • enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising monomers, dimers, and/or multimers, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins
  • kits are provided containing one or more compositions each including the same or different monomers.
  • Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • Such kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • compositions that include a second active agent, or administering a second active agent.
  • compositions that include a second active agent, or administering a second active agent.
  • the compounds, as described herein may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —SCN; —SR x ; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —OR x , —C(O)R
  • the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • acyl refers to a moiety that includes a carbonyl group.
  • an acyl group may have a general formula selected from —C(O)R x ; —CO 2 (R x ); —C(O)N(R x ) 2 ; —OC(O)R x ; —OCO 2 R x ; and —OC(O)N(R x ) 2 ; wherein each occurrence of R x independently includes, but is not limited to, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —SCN; —SR x ; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH;
  • aryl and “heteroaryl,” as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH
  • heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
  • heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C 2-6 alkenyl, and C 3-4 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
  • alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C 3-6 alkenyloxy.
  • alkenyloxy groups include, but are not limited to allyloxy, butenyloxy, etc.
  • alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O—).
  • exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C 1-6 alkoxy, and C 2 -C 6 alkoxy, respectively.
  • exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • alkoxycarbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O—C(O)—).
  • exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C 1-6 alkoxycarbonyl.
  • Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
  • alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
  • exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
  • alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)—).
  • exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C 1-6 alkylcarbonyl groups.
  • Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C 2-6 alkynyl, and C 3-6 alkynyl, respectively.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • carbonyl refers to the radical —C(O)—.
  • carboxylic acid refers to a group of formula —CO 2 H.
  • cyano refers to the radical —CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O—).
  • cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C 3-6 cycloalkyl or C 4-6 cycloalkyl and derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
  • halo or halogen as used herein refer to F, Cl, Br, or I.
  • heterocyclylalkoxy refers to a heterocyclyl-alkyl-O-group.
  • heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl-group.
  • heterocyclyloxy refers to a heterocyclyl-O— group.
  • heteroaryloxy refers to a heteroaryl-O— group.
  • hydroxy and “hydroxyl” as used herein refers to the radical —OH.
  • oxo refers to the radical ⁇ O.
  • connector refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a pharmacophore.
  • Contemplated connectors are generally hydrolytically stable.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.
  • “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
  • the compounds are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers.
  • the enantiomers and diastereomers may be designated by the symbols “(+),” “( ⁇ ).” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.”
  • cis represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
  • Individual enantiomers and diasteriomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using steroselective chemical or enzymatic reagents.
  • Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 10 B, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound may have one or more H atom replaced with deuterium.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1-8 )alkyl, (C 2-12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl (C 1-6 )alkoxycarbonyloxymethyl, N—(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, ⁇ -amino(C 1-4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , —P(O)(O(C 1 -C 6 )alkyl) 2 or
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyakyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • synthetic procedures known in the art.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated.
  • the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed.
  • Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Lz-NA-19 (S)-N-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin-5-yl)methyl)-3,4- dihydroxybenzamide 19.
  • Lz-NA-20 (S)-2-(3,4-dihydroxyphenyl)- N-((3-(3-fluoro-4-morpholino- phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide 20.
  • Lz-NA-21 (S)-N-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin-5-yl)methyl)-2,3- dihydroxybenzamide 21.
  • Lz-NA-22 (S)-2-(2,3-dihydroxyphenyl)- N-((3-(3-fluoro-4-morpholino- phenyl)-2-oxooxazolidin-5- yl)methyl)acetamide 22.
  • Lz-NA-23 (S)-N-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin- 5-yl)methyl)-3-hydroxy-4- (hydroxymethyl)benzamide 23.
  • Lz-NA-24 (S)-N-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin- 5-yl)methyl)-4-hydroxy-3- (hydroxymethyl)benzamide 24.
  • Lz-NA-27 (S,E)-3-(3,4-dihydroxyphenyl)- N-((3-(3-fluoro-4-morpholino- phenyl)-2-oxooxazolidin-5- yl)methyl)acrylamide 25.
  • Lz-NA-28 (S)-3-(3,4-dihydroxyphenyl)-N- ((3-(3-fluoro-4- morpholinophenyl)- 2-oxooxazolidin-5- yl)methyl)propanamide 26.
  • Lz-NA-34 (S,E)-4-(3-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin-5-yl) methylamino)-3-oxoprop- 1-enyl)-2- hydroxy-N-methoxybenzamide 27.
  • Lz-NA-36 (S,E)-5-(3-((3-(3-fluoro-4- morpholinophenyl)-2- oxooxazolidin-5-yl) methylamino)-3-oxoprop-1- enyl)-2-hydroxybenzamide 28.
  • Lz-NA-12 (S)-3-(3-fluoro-4- morpholinophenyl)-5-((2-oxo- 2,3-dihydro-1H-pyrrol-1- yl)methyl)oxazolidin-2-one Fluorfenicol analogues 29.
  • NAFFLA- 19 N-((1S)-3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)phenyl)propan-2- yl)-3,4-dihydroxybenzamide 30.
  • NAFFLA- 20 2-(3,4-dihydroxyphenyl)-N-((1S)- 3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)phenyl)propan-2- yl)acetamide 31.
  • NAFFLA- 21 N-((1S)-3-fluoro-1-hydroxy- 1-(4-(methylsulfonyl) phenyl)propan-2-yl)- 2,3-dihydroxybenzamide 32.
  • NAFFLA- 22 2-(2,3-dihydroxyphenyl)-N-((1S)- 3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)phenyl)propan-2- yl)acetamide 33.
  • NAFFLA- 23 N-((1S)-3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)propan-2-yl)-3- hydroxy-4-(hydroxymethyl) benzamide 34.
  • NAFFLA- 27 (E)-3-(3,4-dihydroxyphenyl)-N- ((1S)-3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)phenyl)propan-2- yl)acrylamide 35.
  • NAFFLA- 28 3-(3,4-dihydroxyphenyl)-N-((1S)- 3-fluoro-1-hydroxy-1-(4- (methylsulfonyl)phenyl)propan-2- yl)propanamide 36.
  • NAFFLA- 34 4-((E)-3-((1R,2S)-3-fluoro- 1-hydroxy-1-(4-(methylsulfonyl) phenyl)propan-2-ylamino)-3- oxoprop-1-enyl)-2-hydroxy-N- methoxybenzamide 37.
  • NAFFLA- 35 4-((E)-3-((1R,2S)-3-fluoro-1- hydroxy-1-(4-(methylsulfonyl) phenyl)propan-2-ylamino)-3- oxoprop-1-enyl)-2- hydroxybenzamide 38.
  • NAFFLA- 36 5-((E)-3-((1R,2S)-3-fluoro-1- hydroxy-1-(4-(methylsulfonyl) phenyl)propan-2-ylamino)-3- oxoprop-1-enyl)-2- hydroxybenzamide 39.
  • NAFFLA- 37 N 1 -((1R,2S)-3-fluoro-1-hydroxy- 1-(4-(methylsulfonyl) phenyl)propan-2-yl)-4- hydroxy-N 3 - methoxyisophthalamide Tryptase targets Method-A 40.
  • Target-31 ((2-(4-(3-(aminomethyl)phenyl) piperidine-1- carbonyl)-1H-indol-5- yl)(hydroxy)boryl)holmium 41.
  • Target-62 3′-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl) biphenyl-2-ylboronic acid 42.
  • Target-64 5-(2-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-2-oxoethyl)- 2-fluorophenylboronic acid 43.
  • Target-35 3′-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)biphenyl- 3-ylboronic acid 44.
  • Target-11F 8-(4-(5-(aminomethyl)-2- fluorophenyl)piperidine-1- carbonyl)naphthalen-2- ylboronic acid 45.
  • Target-58 4-(2-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-2-oxoethyl)- 3-fluorophenylboronic acid 46.
  • Target-57 3-(2-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-2-oxoethyl)- 4-fluorophenylboronic acid 47.
  • Target-35F 3′-(4-(5-(aminomethyl)-2- fluorophenyl)piperidine-1- carbonyl)biphenyl-3-ylboronic acid 48.
  • Target-33 (E)-4-(3-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3-oxoprop- 1-enyl)phenylboronic acid 49.
  • Target-34 (E)-3-(3-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3-oxoprop- 1-enyl)phenylboronic acid 50.
  • Target-37 4-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl) benzo[b]thiophen-2-ylboronic acid 51.
  • Target-31 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)- 1H-indol-4-ylboronic acid 52.
  • Target-62 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)- 1H-indol-6-ylboronic acid 53.
  • Target-64 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)benzo [b]thiophen-4-ylboronic acid Tryptase targets Method-B 54.
  • Target-32 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)- 1H-indol-4-ylboronic acid 55.
  • Target-59 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)- 1H-indol-6-ylboronic acid 56.
  • Target-56 2-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)benzo [b]thiophen-4-ylboronic acid Tryptase targets Method-C 57.
  • Target-28 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(2,3- dihydroxyphenyl)methanone 58.
  • Target-27-F (4-(5-(aminomethyl)-2- fluorophenyl)piperidin-1-yl)(6,7- dihydroxynaphthalen-1- yl)methanone 59.
  • Target-68 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(2,3,4- trihydroxyphenyl)methanone 60.
  • Target-69 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3,4,5- trihydroxyphenyl)methanone 61.
  • Target-77 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(2,4,5- trihydroxyphenyl)methanone 62.
  • Target-78 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3-chloro-4,5- dihydroxyphenyl)methanone 63.
  • Target-43 (E)-1-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3-(3,4,5- trihydroxyphenyl)prop-2-en-1- one 64.
  • Target-70 N-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenyl)- 2,3-dihydroxybenzamide 65.
  • Target-71 N-(3-(4-(aminomethyl)phenyl) piperidine-1-carbonyl)phenyl)- 3,4-dihydroxybenzamide 66.
  • Target-97 4-(2-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-2-oxoethyl)- 6,7-dihydroxy-2H-chromen- 2-one 67.
  • Target-100 3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-6,7- dihydroxy-2H-chromen-2-one 68.
  • Target-102 3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-7,8- dihydroxy-2H-chromen-2-one Tryptase targets Method-D 69.
  • Target-101 3-(2-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-2-oxoethyl)-7,8- dihydroxy-4-methyl-2H- chromen-2-one Tryptase targets Method-E 70.
  • Target-74 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3-hydroxy-4- (hydroxymethyl)phenyl) methanone 71.
  • Target-65 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(4-hydroxy-3- (hydroxymethyl)phenyl) methanone 72.
  • Target-40 (E)-1-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-3-(4-hydroxy-3- (hydroxymethyl)phenyl)prop- 2-en-1-one 73.
  • Target-44 (4-(3- (aminomethyl)phenyl)piperidin- 1-yl)(7-hydroxy-6- (hydroxymethyl)naphthalen-1- yl)methanone Tryptase targets Method-F 74.
  • Target-75 4-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-2- hydroxybenzamide 75.
  • Target-75a 4-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-2-hydroxy- N-methoxybenzamide 76.
  • Target-66 5-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)- 2-hydroxybenzamide 77.
  • Target-86 (E)-5-(3-(4-(3-(aminomethyl) phenyl)piperidine-1-yl)-3-oxoprop- 1-enyl)-2-hydroxybenzamide 78.
  • Target-92 5-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-2- hydroxy-N-methoxybenzamide Tryptase targets Method-H 79.
  • Target-72 3-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 2-hydroxy-2-methylpropanoic acid 80.
  • Target-73 3-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 2-hydroxy-2-phenylpropanoic acid 81.
  • Target-76 (E)-4-(3-(4-(3-(aminomethyl) phenyl)piperidin-1- yl)-3-oxoprop-1-enyl)- 2-hydroxybenzamide 82.
  • Target-76a (E)-4-(3-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)- 3-oxoprop-1-enyl)-2- hydroxy-N-methoxybenzamide 83.
  • Target-81 3-(5-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-1H-indol- 1-yl)-2-hydroxy-2- methylpropanoic acid 84.
  • Target-82 3-(6-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-1H- indol-1-yl)-2-hydroxy-2- methylpropanoic acid 85.
  • Target-83 3-(5-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-1H- indol-1-yl)-2-hydroxy-2- phenylpropanoic acid 86.
  • Target-84 3-(6-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)-1H- indol-1-yl)-2-hydroxy-2- phenylpropanoic acid 87.
  • Target-103 3-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 2-cyclopentyl-2- hydroxypropanoic acid Tryptase targets Method-I 88.
  • Target-53 3-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 1-((3S,4R)-3,4- dihydroxypyrrolidin-1- yl)propan-1-one 89.
  • Target-29 2-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 1-((3S,4R)- 3,4-dihydroxypyrrolidin-1- yl)ethanone 90.
  • Target-30 2-(4-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenoxy)- 1-((3S,4R)-3,4- dihydroxypyrrolidin-1-yl) ethanone Tryptase targets Method-J 91.
  • Target-78- Spiro (5-(aminomethyl)-2H- spiro[benzofuran-3,4′-piperidine]- 1′-yl) (3-chloro-4,5- dihydroxyphenyl)methanone 93.
  • Target-2 Spiro (5-(aminomethyl)-2H-spiro [benzofuran-3,4′- piperidine]-1′-yl)(3,4- dihydroxyphenyl)methanone 94.
  • Target-36 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(4-(1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-5- yl)phenyl)methanone 97.
  • Target-36- meta (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3-(1-hydroxy-1,3- dihydrobenzo[c][1,2]oxoborol-5- yl)phenyl)methanone Tryptase targets 98.
  • Target-21 N-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenyl)- 2-(1-hydroxycyclobutyl)-2- oxoacetamide 99.
  • Target- 21-diol N-(3-(4-(3-(aminomethyl)phenyl) piperidine-1-carbonyl)phenyl)- 2-hydroxy-2-(1- hydroxycyclobutyl)acetamide 100.
  • Target-22 2-(3-(4-(3-(aminomethyl)phenyl) piperidine-1- carbonyl)phenoxy)-1-(1- hydroxycyclobutyl)ethanone 101.
  • Target-42 (E)-1-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3-(3- hydroxy-2-(hydroxymethyl) phenyl)prop-2-en-1-one 102.
  • Target-14 (E)-3-(4-(3-(aminomethyl) phenyl)piperidine-1- carbonyl)styrylboronic acid 105.
  • Target- 24 cis (Z)-1-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3- (3,4-dihydroxyphenyl)prop-2- en-1-one 106.
  • Target-25b (4-(3-(aminomethyl)phenyl) piperidin-1-yl) (3-((3S,4R)-3,4- dihydroxypyrrolidin-1- yl)phenyl)methanone 107.
  • Target- 26 diol c is (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3-((3R,4R)-3,4- dihydroxypyrrolidine-1- carbonyl)phenyl)methanone 108.
  • Target-41 (E)-1-(4-(3-(aminomethyl) phenyl)piperidin-1-yl)-3-(3- hydroxy-4-(hydroxymethyl) phenyl)prop-2- en-1-one 109.
  • Target-67 (4-(3-(aminomethyl)phenyl) piperidin-1-yl)(3-(3,4-dihydroxy- 3,4-dimethylpyrrolidin-1- yl)phenyl)methanone 110.
  • Target-41 gem dimethyl (E)-1-(4-(3-(aminomethyl)phenyl) piperidin-1-yl)-3-(3-hydroxy- 4-(2-hydroxypropan-2- yl)phenyl)prop-2-en-1-one 111.
  • CF1 4-(aminomethyl)-N-(4-(2- ((3S,4S)-3,4- dihydroxypyrrolidin-1-yl)-2- oxoethyl)benzyl)benzamide hydrochloride 112.
  • CF5 (4-(3-(aminomethyl) phenyl)piperidin-1-yl)(3,4- dichlorophenyl)methanone 115.
  • CF6 4-(aminomethyl)-N-(4-(2- ((3R,4R)-3,4- dihydroxypyrrolidin-1-yl)-2- oxoethoxy)benzyl)benzamide hydrochloride 116.
  • CF7 (R)-4-(aminomethyl)-N-(4-(2-(3- hydroxy-4-oxopyrrolidin-1-yl)-2- oxoethoxy)benzyl)benzamide hydrochloride 117.
  • CF10 (S)-4-(aminomethyl)-N-(4-(3-(3- hydroxy-4-oxopyrrolidin-1-yl)-3- oxopropoxy)benzyl)benzamide hydrochloride 118.
  • CF13 N-(4-(aminomethyl)benzyl)-4-(2- (2,3-dihydroxypropanamido)acetyl) piperazine-1-carboxamide hydrochloride 120.
  • CF15 (5-(aminomethyl)-2H- spiro[benzofuran-3,4′- piperidine]-1′-yl)(4-(2,3- dihydroxypropoxy)phenyl) methanone hydrochloride 121.
  • CF17 1-(3-(4-(3-(aminomethyl) phenyl)piperidine-1-carbonyl) phenyl)-3-(3,3,3-trifluoro- 2-hydroxypropyl)urea hydrochloride 122.
  • CF20 N-(4-(aminomethyl)benzyl)- 4-(2-(3-hydroxy-2- oxopropanamido)acetyl) piperazine-1- carboxamide
  • Stock solutions of recominbant human tryptase, beta, from lung were made at 30 ⁇ M, in solution with 50 ⁇ M heparin sulfate and 1 M NaCl.
  • Monomer tryptase inhibitor stock solutions were made at 50 mM in DMSO.
  • Test substance plates were made at 1.2 ⁇ the final concentration in assay buffer (50 mM HEPES, 150 mM NaCl, 100 ⁇ M EDTA, pH 7.4, 0.02% Tween-20). A final concentration of 1 nM tryptase was used. When required, test substances were diluted in water immediately before use in 10-fold serial dilutions.
  • the release of fluorescent AMC was immediately measured every 30 seconds over 15-30 minutes at an excitation wavelength of 367 nm, monitoring emission at 468 nm on a Spectramax M5 (Molecular Devices) microplate reader.
  • the Softmax Pro (Molecular Devices) and Graphpad prism software were used to determine V max , and concentration-response curve IC 50 s, respectively.
  • Combinations of monomeric test substances were typically tested in a 1:1 ratio initially, and those displaying IC 50 's>4 ⁇ lower than that of the most potent monomeric component were often retested with a range of ratios of manomeric concentrations.
  • Monomers with the potential to form heterodimers were evaluated in an in vitro Transcription and Translation assay (TnT assay) using the commercially available E. coli S30 Extract System for Circular DNA kit (Promega Catalog #L1020) according to the manufacturers instructions with minor modifications. Monomers were tested independently to determine individual IC 50 values. Pairs of monomers with the potential to form heterodimers were assayed at concentrations that ranged about their individual IC25 values.
  • Each reaction uses 2 ⁇ l (250 ng/ ⁇ l) of the pBESTlucTM DNA based circular luciferase plasmid (Promega Catalog #L492A), with 4 ⁇ l of complete amino acid mix (Promega Catalog #L4461), 13 ⁇ l of S30 Premix Without Amino Acids (Promega Catalog #L512A), 5 ⁇ l of S30 Extract (Promega Catalog #L464A), monomers at the appropriate concentration, and nuclease free water in a total volume of 35 ⁇ l. Assays were carried out in Costar 96 well white round bottom plates.
  • Assay plates were setup with a master mix consisting of S30 extract and water, followed by the addition of compound, with the final addition of a master mix consisting of the plasmid, amino acid mix, and the S30 Premix. Plates were incubated at 37° C. for one hour followed by addition of 35 ⁇ l of the Bright-Glo Luciferase Reagent (Promega Catalog #E2620). After removal of 35 ⁇ l of the reaction mixture, the luminescence was recorded immediately in the Spectramax M5 plate reader (Molecular Devices). The data was plotted to generate dose-response curves using GraphPad Prism.
  • IC 50 ranges are provided for various exemplary monomers against tryptase.
  • the prefix “Target,” as used elsewhere in the Examples, has been shortened to “T.”
  • “Target-14” has been shortened to “T14.”
  • A” refers to an IC 50 range of 0.1 nM to 1 ⁇ M
  • B refers to an IC 50 range of 1 ⁇ M to 10 ⁇ M
  • C refers to an IC 50 range of 10 ⁇ M to 65 ⁇ M.
  • T116SPIRO (1:10); T117; T131SPIRO; T56; T156; T35F; T10; T109SPIRO; T35SPAM; T35; T133SPIRO.
  • T35SPIRO T107; T147; T107SPIRO; T155SPIRO; T132SPIRO; T31; T34; T32; T37; T154; T143; T59; T62; T54BASPIRO; T57; T64; T12; T144; T58; T33SPAM; T33; T11F; T54BA.
  • T142EXOANTI T142ENDOSYN; T98; T100; T77; T9; T8
  • IC 50 ratios are provided for various exemplary monomer pairs against tryptase.
  • the IC 50 ratio is calculated by dividing the smallest monomer IC 50 value chosen from between monomer 1 and monomer 2 by the apparent IC 50 value for an essentially equimolar combination of monomer 1 and monomer 2.
  • T the prefix “Target,” as used elsewhere in the Examples, has been shortened to “T.”
  • T100 the prefix “Target,” as used elsewhere in the Examples, has been shortened to “T.”
  • AA refers to an IC 50 ratio of 30 or greater
  • BB refers to an IC 50 ratio of 10-30
  • CC refers to an IC 50 ratio of 3-10.
  • This compound was synthesized by oxidation of (S)—N-((3-(4-(2,5-dihydro-1H-pyrrol-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide by osmium tetroxide as in the reaction scheme below (see Scheme 3).
  • Florfenicol amine was synthesized from commercially available florfenicol by the procedure reported in the literature (WO2005/85266). Coupling & subsequent demethylation reactions were carried out as per the general procedure described earlier for similar analogues of Linezolid.
  • Boronate ester form step-2 was dissolved in mix of Water and solvents like THF/methanol/Acetone that are miscible in water. To this, lithium hydroxide was added and mixture was stirred at room temperature and monitored by TLC & LCMS till maximum starting was consumed (6-12 hrs required) THF was then concentrated and reaction mass was extracted with ethyl acetate and water. Organic layer was washed with water and combined aq. washings were acidified with 2N HCl and extracted with ethyl acetate. Ethyl acetate extract was dried over sodium sulphate and concentrated in vacuum to get crude product. In most of the cases products were sufficient pure to be used for the next step. The details of compounds synthesized by above method are as below.
  • TFA salts were converted to hydrochloride salts by stirring with 2N HCl for 30 min under nitrogen atmosphere followed by lyophilization.
  • Non commercial aryl/hetero aryl carboxy boronic acids were synthesized from corresponding aryl halo carboxylic acids by reaction with LDA & Tri alkyl borate followed by hydrolysis as per method described in the literature (US-patent application 2008/306082; 2008 example 20B)
  • TFA salts were converted to hydrochloride salts by stirring with 2N HCl for 30 min under nitrogen atmosphere followed by lyophilization.
  • Desired halo aryl carboxylic acids were first coupled with tert-butyl 3-(piperidin-4-yl)benzylcarbamate and coupled products were reacted with bis pinacolato diborane to get boronate esters which were hydrolyzed to corresponding boronic acids.
  • step-1 was converted boronate ester by reacting with Bis Pinacolato Borane in presence of Potassium acetate DPPF-PdCl 2 .DCM by heating in 1,4-dioxane/Dimethyl sulfoxide for 12 hrs. R.M was then concentrated in vacuum and residue was purified by column chromatography.
  • step-2 Products of step-2 were stirred with trifluoro acetic acid in dichloromethane at room temp. Reaction mass was then concentrated in vacuum and used for next step without purification.
  • the details of compounds synthesized are as below in Table 19.
  • Desired dimethoxy analogues of carboxylic acids were first coupled with tert-butyl 3-(piperidin-4-yl)benzylcarbamate and coupled products were de-methylated using boron tribromide.
  • 6,7-dimethoxy-2-oxo-2H-chromene-3-carboxylic acid & 7,8-dimethoxy-2-oxo-2H-chromene-3-carboxylic acid required for target—100 & 102 were prepared by the reaction of Meldrums acid with 2-hydroxy-4,5-dimethoxybenzaldehyde or 2-hydroxy-3,4-dimethoxybenzaldehyde in water at 75° C. for 2 hrs. Precipitated products were sufficient pure to be used for the next step.
  • Required aldehydes for this were prepared from corresponding trimethoxy benzaldehydes by demethylation using AlCl 3 in benzene ( JOC, 54, 4112, 1989)
  • Target-69 BBr 3 (3 eq) DCM (85 vol), R.T. 2 hrs, 23.6% Mol. Wt:- 342.38 M.I.
  • Desired carboxylic acid (A) was coupled with tert-butyl 3-(piperidin-4-yl)benzylcarbamate followed by deprotection of Boc functionality.
  • step-4 Products were purified by column chromatography over silica gel using methanol (0-5%) in Chloroform.
  • Boc deprotection of the products from step-1 was carried out by stirring it with hydrochloric acid in presence of co-solvent like methanol or dioxane at room temperature. Solvents were then evaporated and residue was purified by reverse phase preparative HPLC. Products were isolated as TFA salts. Details of the compounds synthesized are as below in Table 26.
  • step-1 products Protection of step-1 products was carried out using 2,2-dimethoxy propane by refluxing in acetone in presence of catalytic p-toluene sulfonic acid. Reaction was monitored by LCMS and after completion of reaction solvents were distilled and crude product obtained was purified by column chromatography using ethyl acetate (0-10%) in hexane. The details of compounds synthesized are as below in Table 27.
  • step-2 products were carried out as per procedure described in Method-A (step-3).
  • step-3 hydrolysis of corresponding cyano compound (G-44) was carried out using ethanolic potassium hydroxide under reflux to get mixture of acid and corresponding amide. This mixture was used for next step without purification.
  • the details of compounds synthesized are as below in Table 28.
  • Boc and isopropylidine deprotection of the compounds was carried out by stirring with Methanolic HCl or Trifluoro acetic acid in dichloromethane at room temperature. Reactions were monitored by LCMS and after reaction completion, reaction mass was concentrated and residue was purified by reverse phase preparative HPLC. Products were isolated as TFA salts. The details of compounds synthesized are as below in Table 30.
  • Desired Carbmethoxy hydroxy benzaldehyde was dissolved in Acetonitrile and aq solution of di-sodium hydrogen phosphate & 30% hydrogen peroxide was then added and reaction mass cooled to 0° C. Aq. solution of Sodium chlorite was added to the reaction mass drop wise and reaction mass was allowed to warm to room temperature. Stirring continued at room temperature and reaction was monitored by LCMS till maximum starting was consumed. Reaction mass was then concentrated, residue was acidified with aq. HCl and product extracted in ethyl acetate. Ethyl acetate extract dried over sodium sulfate and concentrated to get the crude product which was sufficient pure for the use in next step. The details of the compounds synthesized are as below in Table 31.
  • step-1 Products from step-1 were converted to desired amides either by conversion to acid chloride and subsequent reaction with ammonia/desired amine or by coupling reaction using EDCI-HOBT in DMF followed by usual work-up as described in method-A (step-4.) Crude products were purified by column chromatography over silica gel using methanol (0-30%) in chloroform.
  • step-2 Hydrolysis of step-2 products was carried out as per general procedure followed in method-A (step-3) crude products were used for next step unless specified.
  • step-3 products Coupling reactions of step-3 products with tert-butyl 3-(piperidin-4-yl)benzylcarbamate were carried out as per general procedure followed in method-A (step-4) Crude products
  • Step-4 products Boc deprotection of Step-4 products was carried out by stirring with Aq. hydrochloric acid-methanol or methanolic HCl at room temperature. Crude products were purified by reverse phase preparative HPLC and isolated as TFA salts.
  • Alfa hydroxy carboxylic acids were synthesized by reacting desired epoxide with tert-butyl 3-(1-(3-hydroxybenzoyl)piperidin-4-yl)benzyl carbamate in presence of base to yield Alfa hydroxy carboxylic esters that were hydrolyzed and de-protected to get the title compounds (Scheme-1).
  • Hydroxy ester from step-2 was hydrolyzed to acid following general procedure in method-A, step3.
  • Compounds were purified by column chromatography over silica gel using methanol (1-15%) in chloroform. The details of the compounds synthesized are as below in Table 38.
  • Boc deprotection of the step-3 products was carried out by stirring with methanolic HCl at room temperature. Reactions were monitored by LCMS and after reaction completion, solvents were evaporated in vacuum and residue was purified by reverse phase preparative HPLC to get the products as TFA salts.
  • the details of the compounds synthesized are as below in Table 39.
  • Meta/para hydroxy benzoic acid was coupled with tert-butyl 3-(1-(3-hydroxybenzoyl)piperidin-4-yl)benzylcarbamate. Coupled product was reacted with ethyl bromo acetate/methyl acrylate in presence of base to yield corresponding O-Alky product with aliphatic ester functionality which was hydrolyzed and coupled with cis-pyrrolidine diol (e.g. as shown in EP1961750 & WO2009/61879) the coupled products were de-protected to yield the title compounds.
  • step-1 Product from step-1 was dissolved in methyl acrylate. To this catalytic hydroquinone was added as polymerization inhibitor followed by sodium metal. Reaction mass was then refluxed for 48 hrs and monitored by LCMS. After consumption of maximum starting, the reaction mass was concentrated and the residue was purified by column chromatography over neutral alumina using Methanol (0-10%) in dichloromethane.
  • Spiro key intermediate (E) was synthesized from 2H-spiro[benzofuran-3,4′-piperidine]-5-carbonitrile (US 2009/0163527, & B.org. Med. Chem. Lett. 2008, 18, 2114-2121.) through the reaction sequence described in the scheme below.
  • Residue was diluted with water ( ⁇ 20 volumes) and extracted with ethyl acetate. Ethyl acetate extract was dried over sodium sulphate and concentrated to get the crude product which was purified by column chromatography over silica gel using ethyl acetate (0-40%) in hexane to get the pure product.
  • step-1 & 2 Procedure described in method-C, step-1 & 2 was followed for Target-78-spiro & and Procedure as per method-A, step-4 & 9 was followed for Target-2 spiro.
  • Target-2 Spiro 1) tert-butyl ((2H-spiro [benzofuran-3,4′-piperidin]- 5-yl)methyl)carbamate (1.1 eq.), EDCI (1.5 eq.), DMAP (1.2 eq.), DMF (10 vol), RT, 12 h, Yield - 60% 2) TFA (3 eq) DCM (25 vol), R.T. 4 hrs, Yield - 51% Mol. Wt:- 354.40 M.I.
  • step-3 product Dibenzoyl peroxide & N-bromo succinamide were added.
  • the resulting mixture was heated to 75° C. and reaction was monitored by LCMS. After consumption of maximum starting the reaction mixture was diluted with water and extracted with dichloromethane. Organic phase was again washed with water followed by brine, and dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product.
  • the crude product was purified by column chromatography over silica gel using 1-5% ethyl acetate in hexane. The details of the compounds synthesized are as below in Table 52.
  • Step-4 product To a stirred solution of Step-4 product in acetonitrile, trifluoro acetic acid and water were added and mixture was heated to 91° C. and monitored by LCMS. After maximum starting was consumed, The reaction mixture was concentrated and residue obtained was diluted with water and extracted with ethyl acetate. Concentration of ethyl acetate layer yielded crude product which was purified by column chromatography over silica gel using 10-35% ethyl acetate in hexane.
  • step-5 product lithium hydroxide, THF & water was heated to 60° C. Reaction was monitored by LCMS till maximum starting was consumed. The reaction mixture was concentrated and diluted with water. pH of the reaction mass was then adjusted to ⁇ 2 using Conc. HCl. Precipitated product was filtered, washed with water and dried in vacuum oven. The details of the compounds synthesized are as below in Table 54.
  • Step 3 Synthesis of benzyl 3-(1-(3-aminobenzoyl)piperidin-4-yl)benzylcarbamate
  • Step 4 Synthesis of benzyl 3-(1-(3-(2-cyclobutylideneacetamido)benzoyl)piperidin-4-yl)benzylcarbamate
  • Step 5 Synthesis of benzyl 3-(1-(3-(2-hydroxy-2-(1-hydroxycyclobutyl)acetamido)benzoyl)piperidin-4-yl)benzylcarbamate
  • Reaction mixture was quenched with 10% aqueous sodium bisulphite solution and stirred for ⁇ 1 h at room temperature. Aqueous layer was extracted with ethyl acetate, dried over sodium sulphate. Crude product obtained was purified by column chromatography (silica 60-120 mesh, ethyl acetate/n-hexane) afforded semi solid.
  • Step 7 Synthesis of N-(3-(4-(3-(aminomethyl)phenyl)piperidine-1-carbonyl)phenyl)-2-(1-hydroxycyclobutyl)-2-oxoacetamide
  • triphenyl phosphine (0.56 g, 2.25 mmol) was allowed to stir at ⁇ 20° C.
  • DIAD (0.45 g, 0.44 mL, 2.25 mmol) was added. Yellow precipitate was observed in the reaction mixture.
  • Methyl 3-hydroxybenzoate (0.26 g, 1.73 mmol) in 3 mL THF was added dropwise to the reaction mixture and stirred for 10-15 min.
  • Step 4 Synthesis of tert-butyl 3-(1-(3-(2-cyclobutylidene ethoxy)benzoyl)piperidin-4-yl)benzylcarbamate
  • Step 5 Synthesis of tert-butyl 3-(1-(3-(2-cyclobutylideneethoxy)benzoyl)piperidin-4-yl)benzylcarbamate
  • Step 4 product (0.23 g, 0.47 mmol), OsO 4 (4% aqueous solution, 0.012 mL, 18.5 ⁇ mol) was added and stirred for 10 min at room temperature. Then NMO (50% aqueous solution, 0.13 mL, 0.56 mmol) was added and allowed to stir at room temperature overnight.
  • OsO 4 4% aqueous solution, 0.012 mL, 18.5 ⁇ mol

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