EP1793843A1 - Makrozyklische sh2-domäne bindende inhibitoren - Google Patents

Makrozyklische sh2-domäne bindende inhibitoren

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Publication number
EP1793843A1
EP1793843A1 EP05805719A EP05805719A EP1793843A1 EP 1793843 A1 EP1793843 A1 EP 1793843A1 EP 05805719 A EP05805719 A EP 05805719A EP 05805719 A EP05805719 A EP 05805719A EP 1793843 A1 EP1793843 A1 EP 1793843A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
aryl
compound
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05805719A
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English (en)
French (fr)
Inventor
Jr. Terrence R. Burke
Zhen-Dan Shi
Shinya Oishi
Fa Liu
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US Department of Health and Human Services
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US Department of Health and Human Services
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Publication of EP1793843A1 publication Critical patent/EP1793843A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to macrocyclic peptides, compositions comprising these peptides, and methods of using these peptides, e.g., in inhibiting SH2 domain-containing protein from binding with a phosphoprotein and in the prevention or treatment of a disease such as cancer in a mammal.
  • these enzymes catalyze the phosphorylation of specific tyrosine residues to form tyrosine phosphorylated residues.
  • this class of enzymes include the PDGF receptor, the FGF receptor, the HGF receptor, members of the EGF receptor family such as the EGF receptor, erb-B2, erb-B3 and erb-B4, the src kinase family, Fak kinase and the Jak kinase family.
  • the tyrosine-phosphorylated proteins are involved in a range of metabolic processes, from proliferation and growth to differentiation.
  • Protein-tyrosine phosphorylation is known to be involved in modulating the activity of some target enzymes as well as in generating specific complex networks involved in signal transduction via various proteins containing a specific amino acid sequence called an Src homology region or SH2 domain (see, e.g., Proc. Natl. Acad. ScL USA, 90, 5891 (1990)).
  • a malfunction in this protein-tyrosine phosphorylation through tyrosine kinase overexpression or deregulation is manifested by various oncogenic and (hyper-) proliferative disorders such as cancer, inflammation, autoimmune disease, hyper ⁇ proliferative skin disorders, such as psoriasis, and allergy/asthma.
  • SH2- and/or SH3- comprising proteins that play a role in cellular signaling and transformation include, but are not limited to, the following: Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, phosphoinositol-3 (PI-3) kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, Tyk2, especially Src, phospholipase c, phoshoinositol-3 (PI-3) kinase, Grb
  • Ri is a lipophile
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group
  • R 3 is hydrogen (unsubstituted), azido, amino, oxalylamino, carboxy alkyl, alkoxycarbonyl alkyl, aminocarbonyl alkyl, or alkyl carbonylamino; wherein the alkyl portion of any of the R 3 groups may be optionally substituted with a suitable substituent, for example, one or more selected from the group consisting of halo, hydroxy, carboxyl, amino, amino alkyl, alkyl, alkoxy, and keto, and any combination thereof;
  • R 6 is a linker; AA is an amino acid or fragment thereof; and n is 1 to 6; or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; pharmaceutical compositions thereof, and methods of use thereof.
  • Ri and Ri' are the same and are Ci-C 6 alkyl or Ri and Ri' together form a C 4 -C 8 cycloalkyl
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group
  • R 6 is a group having 1-6 carbon atoms, which may be optionally have a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci- C 6 alkoxy, and keto, and any combination thereof; and m is 1 or 2; [0012] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; pharmaceutical compositions thereof, and methods of use thereof.
  • Figure 1 depicts a method for preparing compounds 3 and 4. Reagents: (i)
  • Figure 2 depicts the formulas of compounds 3 and 4 in accordance with an embodiment of the invention and of open-chain compound 2.
  • Figure 3 depicts a solid-state method for preparing compound 9b, open-chain compound 2, and 15a-15c, 17a-17b, and 18a-18b.
  • Figure 4 depicts a reaction scheme to prepare compound 24 in accordance with an embodiment of the invention.
  • An aspect of the present invention is predicated on the concept that binding affinity for SH2 domain proteins can be envisioned to increase by a conformational constraint in a ligand.
  • the conformational constraint is believed to lead to certain advantages, e.g., a reduction in binding entropy penalty.
  • Binding of natural pTyr-containing ligands to Grb2 SH2 domains takes place in a ⁇ -bend fashion, with key interactions occurring in a pTyr binding pocket as well as in a proximal pocket which ligates the amino acid side chain of a pY+2 Asn residue.
  • the present invention provides a novel platform which is expected provide enhanced binding outside the pTyr pocket.
  • the present invention provides, in an embodiment, compounds of formula (I):
  • R] can be a lipophile
  • R 2 in combination with the phenyl ring, can be a phenylphosphate mimic group or a protected phenylphosphate mimic' group
  • R 3 can be, for example, hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Cj-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of any of the R 3 groups may be optionally substituted, e.g., with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof;
  • R 6 is a linker;
  • AA is an amino acid or fragment thereof, and the amino acid can be natural or synthetic; and n can be any
  • the linker R 6 connects the ⁇ -carbon (shown as 1 in formula I) of the pTyr mimetic to the carbon (shown as 2 in formula I) adjacent to the amino group (NH) of the first amino acid.
  • the bond connecting the linker to the linking sites can have any suitable configuration (R, S, or R/ S).
  • Ri can be any suitable lipophile, e.g., a hydrophobic or nonpolar group, such as an alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, aryl alkoxy, alkylaryl, alkyloxy aryl, arylalkyl, alkylamino, arylalkylamino, alkenylamino, arylamino, aryloxy alkyl, heterocyclyl, heterocyclyloxy, aryl heterocyclyl alkyl, heterocyclyl alkoxy, aryl heterocyclyl, aryl heterocyclyloxy, alkyl arylalkyl, alkoxy arylalkyl, and alkoxy arylalkoxy, and any combination thereof, optionally substituted or in combination with one or more groups such as alkyl, keto, ester, amino, aminocarbonyl, ureido, hydroxyl, and any combination thereof, optionally substituted or in combination
  • Electron rich groups such as aromatic ring systems such as naphthyl, biphenyl, anthracenyl, and fluorenyl, can be part of examples of Ri in accordance with an embodiment of the invention.
  • the alkyl portion can have 1-6 carbon atoms
  • the aryl portion can have 6-14 carbon atoms
  • alkenyl and alkynyl portions can have 2-6 carbon atoms
  • the heterocyclyl portion can have 3-7 ring atoms including at least one of N, S, and O.
  • a phenylphosphate mimic group can be one that has the functional property of the phosphorylated end of tyrosine-phosphorylated sequences, e.g., it can replicate the interaction of phenylphosphate with proteins. The interaction may involve any number of mechanisms, including geometry, size, and/or charge.
  • a protected phenylphosphate mimetic is a phenylphosphate mimic that contains a protecting group that releases the mimetic, e.g., in a biological environment, such as due to chemical or enzymatic hydrolysis.
  • the protecting groups can be esters or amides.
  • the present invention also provides pharmaceutically acceptable salts of the above compounds including alkali or amine salts.
  • the acidic groups, e.g., carboxylic, phosphoric, or phosphonic groups, of the compound may be converted to salts known to those skilled in the art, for example, a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium salt.
  • an alkali metal e.g., sodium or potassium
  • alkaline earth metal e.g., calcium
  • ammonium salt e.g., sodium or potassium
  • amino acid (AA) may be selected from the group consisting of glycine, alanine, valine, norvaline, leucine, iso-leucine, norleucine, ⁇ -amino n-decanoic acid, serine, homoserine, threonine, methionine, cysteine, S-acetylaminomethyl-cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenylalanine, 4- nitrophenylalanine, 4-chlorophenylalanine, 4- carboxyphenylalanine, ⁇ -phenylseri ⁇ e, ⁇ -hydroxyphenylalanine, phenylglycine, ⁇ - naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic
  • the invention provides compounds of formula (Ia)
  • R 4 and R 5 independently, are hydrogen, Ci-C 6 alkyl, C 4 -C 8 cycloalkyl, or heterocyclyl, or R 4 and R 5 together form a C 4 -C 8 cycloalkyl or a heterocyclyl; Rj-R 3 and R 6 being as described above.
  • examples of Ri can include Ci-C 6 alkyl carbonyl, C 6 - C 14 aryl carbonyl, C 6 -Ci 4 aryl C 1 -C 6 alkyl carbonyl, C 6 -Ci 4 aryl Ci-C 6 alkylamino carbonyl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -C 14 aryl heterocyclyl C 1 -C 6 alkyl, C 6 -Ci 4 aryl heterocyclyl C 1 - C 6 alkyl carbonyl, Ci-C 6 alkylaminocarbonyl, C 2 -C 6 alkenyl aminocarbonyl, C 6 -C 14 arylaminocarbonyl, Ci-C 6 alkoxy Ci-C 6 alkyl, Ci-C 6 alkoxy Ci-C 6 alkyl carbonyl, C 6 -Cj 4 aryloxy Ci-C 6 alkyl, C 6 -Ci 4
  • examples of R 2 can include hydroxyl, carboxyl, formyl, carboxy Ci-C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy Ci-C 6 alkyloxy, dicarboxyhalo Ci-C 6 alkyl, dicarboxyhalo Ci-C 6 alkyloxy, phosphono, phosphono
  • R 3 in any of the embodiments can be, for example, hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of any of the R 3 groups may be optionally substituted, e.g., with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • R 4 and R 5 are hydrogen, Ci-C 6 alkyl, C 4 -C 8 cycloalkyl, or heterocyclyl, or R 4 and R 5 together form a C 4 -C 8 cycloalkyl, e.g., cyclohexyl, or a heterocyclyl.
  • R 6 in any of the embodiments can be a substituted or unsubstituted group having
  • 1-6 carbon atoms for example, a hydrocarbyl group, such as an unsaturated hydrocarbyl group, optionally further having a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • a hydrocarbyl group such as an unsaturated hydrocarbyl group, optionally further having a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • Rj can be Ci-C 6 alkyl carbonyl, C 6 -C] 4 aryl carbonyl, C 6 -Ci 4 aryl Ci-C 6 alkyl carbonyl, C 6 -Ci 4 aryl Ci-C 6 alkylamino carbonyl, C 6 -Ci 4 aryl heterocyclyl Ci-C 6 alkyl carbonyl, Ci-C 6 alkylaminocarbonyl, C 2 -C 6 alkenylaminocarbonyl, C 6 -C] 4 arylamino carbonyl, Ci-C 6 alkoxy Ci-C 6 alkyl carbonyl, C 6 -C] 4 aryloxy Ci-C 6 alkyl carbonyl, or C 6 -Ci 4 aryl Cj-C 6 alkoxy Ci-C 6 alkyl carbonyl, wherein the aryl portion may be unsubstituted or substituted, e.g., with a
  • R 2 can be hydroxyl, carboxyl, formyl, carboxy Ci-C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy Ci-C 6 alkyloxy, dicarboxyhalo C]-C 6 alkyl, dicarboxyhalo Cj-C 6 alkyloxy, phosphono, phosphono Ci-C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, or phosphoryl Ci-C 6 alkoxy, wherein the alkyl or alkoxy portion may be optionally substituted with a substituent, e.g., selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • a substituent e.g., selected from the group consisting of halo
  • R 3 can be hydrogen (unsubstituted), azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, and Ci-C 6 alkylcarbonylamino; wherein the alkyl portion of R 3 may be optionally substituted with a substituent, e.g., selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • a substituent e.g., selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • R 4 and R 5 independently, can be hydrogen
  • R 6 can be a C 2 -C 6 alkenylenyl or alkynylenyl group, specifically alkenylenyl, any of which may be optionally substituted, e.g., with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and keto, and any combination thereof.
  • Ri-R 6 are together as described in paragraphs [0027]-
  • Ri can be C 6 -Cu aryl Ci-C 6 alkylamino carbonyl, for example, Cio aryl Ci-C 6 alkylamino carbonyl, such as naphthyl methylamino carbonyl, e.g., 1 -naphthyl methylamino.
  • R 2 can be phosphono
  • Ci-C 6 alkyl optionally substituted with a substituent, e.g., selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto, and any combination thereof; particularly, R 2 can be phosphonomethyl.
  • a substituent e.g., selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto, and any combination thereof; particularly, R 2 can be phosphonomethyl.
  • R 3 can be carboxy Ci-C 6 alkyl, e.g., carboxymethyl.
  • R 6 can be allyl
  • Ri and R 1 ' are the same and are Ci-C 6 alkyl or Ri and R 1 ' together form a C 4 -C 8 cycloalkyl
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group
  • R 6 is a group having 1-6 carbon atoms, which may be optionally have a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, C 1 - C 6 alkoxy, and keto, and any combination thereof; and m is 1 or 2; or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; and specifically, compounds wherein m is 1.
  • R 1 and Ri' together form a C 4 -C 8 cycloalkyl, e.g., cyclohexyl.
  • R 2 is hydroxyl, carboxyl, formyl, carboxy C 1 -C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy Ci-C 6 alkyloxy, dicarboxyhalo Ci-C 6 alkyl, dicarboxyhalo Ci-C 6 alkyloxy, phosphono, phosphono C 1 -C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, and phosphoryl Ci-C 6 alkoxy, carboxy Ci-C 6 alkylamino, oxalylamino, RSO 2 NH- wherein R can be Ci-C 6 alkyl, halo Cj-C 6 alkyl, C 6 -C 14 aryl, C 6 -Ci 4 aryl Ci-C 6 alkyl, or trifluoro Ci-
  • Ci-C 6 alkyl Ci-C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, or phosphoryl
  • alkyl and alkoxy portions may be optionally substituted with a substituent selected from the group Consisting of halo, hydroxy, carboxyl, amino, amino Ci-
  • R 2 is hydroxyl, carboxyl, formyl, carboxy Ci-C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy Ci-C 6 alkyloxy, dicarboxyhalo Ci-C 6 alkyl, dicarboxyhalo
  • Ci-C 6 alkyloxy phosphono, phosphono Ci-C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, or phosphoryl Ci-C 6 alkoxy.
  • R 2 is phosphonomethyl
  • R 4 and R 5 together form a C 4 -C 8 cycloalkyl, particularly cyclohexyl.
  • R 6 is a C 2 -C 6 alkenylenyl or C 2 -C 6 alkynylenyl group, which may optionally have a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-
  • R 3 is carboxy Ci-C 6 alkyl, e.g., carboxy methyl.
  • aryl refers to an aromatic moiety such as phenyl, naphthyl, anthracenyl, and biphenyl.
  • heterocyclyl refers to a 3-7 membered ring comprising one or more heteroatoms such as O, N, and S, and optionally carbon and/or hydrogen.
  • heterocyclyl groups include pyridyl, piperidinyl, piperazinyl, pyrazinyl, pyrolyl, pyronyl, pyronyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, tetrahydrothiophenyl, purinyl, pyrimidinyl, thiazolyl, thiazolidinyl, thiazolinyl, oxazolyl, tetrazolyl, tetrazinyl, morpholinyl, thiophorpholinyl, quinolinyl, and isoquinolinyl.
  • aryl and heterocyclyl moieties may be fused, as in aryl heterocyclyl, such as, e.g., indole, isoindole, benzimidazole, quinoline, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, carbazolyl, benzodioxolyl, and the like.
  • aryl heterocyclyl such as, e.g., indole, isoindole, benzimidazole, quinoline, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, carbazolyl, benzodioxolyl, and the like.
  • alkyl, alkoxy, or alkylamino groups can be linear or branched.
  • aryl group When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, hydroxy, or alkoxy, the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available atoms (e.g., carbon atoms) bearing a hydrogen, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10-position, taking, for the purpose of illustration, the 1 -position as the point of attachment of the aryl group.
  • halo refers to fluorine, chlorine, bromine, or iodine.
  • the present invention further provides a composition comprising a pharmaceutically acceptable carrier and an effective (e.g., therapeutically or prophylactically effective) amount of at least one of the compounds described above.
  • the present invention further provides a method of inhibiting an SH2 domain from binding with a phosphoprotein comprising contacting a sample or substance containing an SH2 domain with a compound of the present invention.
  • the present invention discloses the use of above compounds in the manufacture of a medicament for the treatment of a condition that responds to the inhibition of phosphoprotein binding to an SH2 domain of a mammal.
  • the present invention further provides the use of the above compounds in medicine.
  • the compounds can find use as an SH2 domain binding inhibitor.
  • SH2 domain-containing proteins are Grb2, Shp2, and STAT3 proteins.
  • the pharmaceutically acceptable (e.g., pharmacologically acceptable) carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants; lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention alone or in combination with other suitable components can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and non ⁇ aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3- dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adj
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanutj soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient involution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants. The quantity of surfactant in such formulations typically ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art; see, e.g., Pharmaceutics and Phannacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4 th ed., pages 622-630 (1986).
  • the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, 1 creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the present invention provides for a wide range of responses.
  • the dosages range from about 0.001 to about 1000 mg/kg body weight of the animal being treated/day.
  • Preferred dosages range from about 0.01 to about 10 mg/kg body weight/day, and further preferred dosages range from about 0.01 to about 1 mg/kg bqdy weight/day.
  • Embodiments of the compounds have the advantage that they are stable to or in presence of enzymes encountered during in vivo use. Embodiments of the compounds can find use in in vitro and in vivo applications.
  • the compounds can find use as molecular probes as well as in assays to identify, isolate, and/or quantitate receptor or binding sites in a cell or tissue.
  • the compounds also can find use in vivo for studying the efficacy in the treatment of various diseases or conditions involving SH2 domains.
  • the present invention further provides a method of preventing or treating a disease, state, or condition in a mammal by the use of the compounds of the present invention.
  • the method involves preventing a disease, state, or condition.
  • the method involves treating an existing disease, state, or condition.
  • the method involves inhibition of SH2 domain binding with a phosphoprotein.
  • the SH2 domain may involve one or more of the following proteins: Shp2, STAT3, Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, PI-3 kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, and Tyk2, especially Grb2, Shp2, and STAT3.
  • GAP GTPase-activating protein
  • Grb2 is an adaptor protein with N- and C-terminal src homology 3 (SH3) domains and a central src homology 2 (SH2) domain.
  • SH3 domain can bind to phosphoT.yr residues of receptors or other adaptor proteins, such as SHC.
  • the SH3 domains bind the Ras exchange factor SOS, but can also bind to other adaptor proteins such as GABl' and GAB2.
  • Grb2 is involved in activation of Ras but can also play a role in other signaling pathways in mammalian cells.
  • Shp2 is a tyrosine phosphatase that is recruited into tyrosine kinase signaling pathways through binding of its two amino-terminal SH2 domains to specific phosphotyrosine motifs.
  • Shp2 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
  • Shp2 contains two tandem Src homology-2 domains, which function as phosphotyrosine binding domains and mediate the interaction with its substrates.
  • Shp2 is widely expressed in most tissues and plays a regulatory role in various cell-signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration..
  • STATs Signal Transducers and Activators of Transcription
  • JAK kinases transcription factors that are phosphorylated by JAK kinases in response to cytokine activation of a cell surface receptor tyrosine kinases.
  • the STATs dimerize and are localized to the nucleus where they activate transcription of cytokine-responsive genes.
  • Cytokines that activate STAT3 include growth hormone, IL-6 family cytokines, and G-CSF.
  • STAT3 induces progression through the cell cycle, prevents apoptosis and upregulates oncogenes, such as c-myc and bcl-X and may play a role in oncogenesis.
  • STAT3 has been shown to play a critical role in hematopoiesis. The importance of STAT3 is underscored by the failure of mice lacking STAT3 to survive embryogenesis.
  • Crosstalk from pathways other than JAK kinases also leads to phosphorylation and activation of STAT3 as indicated by a role of mTOR (mammalian target of rapamycin, or p70 S6 kinase) and MAP kinase pathways in STAT3 activation and signaling.
  • the method of treatment or prevention of a diseases comprises administering to the mammal one or more compounds of the present invention.
  • the disease, state, condition can be a cancer, e.g., a breast cancer or an ovarian cancer, or a tumor such as a solid tumor, e.g., a brain tumor, a prostate tumor, and the like, leukemia including chronic myelocytic leukemia, lymphoma, an autoimmune disease, an inflammatory disease, a metabolic disease, diabetes, obesity, or cardiovascular disease.
  • the present invention further provides a method of enhancing the therapeutic effect of a treatment rendered to a mammal comprising administering a compound in conjunction with the treatment.
  • the inhibitor can be used in any suitable manner, for example, prior to, simultaneous with, or post- administration of the therapeutic agent. Synergistic effects are observed when the SH2 domain binding inhibitor is used in combination with other treatments known to those skilled in the art.
  • the inhibitor enhances the cytotoxicity of the chemotherapeutic treatments. Cancer treatment is particularly suitable for this combination treatment.
  • the cancer may involve any number of mechanisms.
  • a majority of human breast cancers are dependent upon activation of the Ras signaling pathways through activation of growth factor receptor as the means to achieve continuous cellular proliferation.
  • the cancer may involve overexpression of Her-2/neu.
  • the cancer can be mediated through BCR-AbI or the expression of erbB-2 receptor.
  • therapeutic agents affecting Grb2 function at its SH2 domain may interrupt the flow of signal transduction to the Ras pathway and thus result in reversal of the cancer phenotype.
  • the therapeutic treatment can include chemotherapy, radiation therapy, and/or a biological therapy.
  • chemotherapy include the use of cancer treatment agents such as alkylating agents, hormonal agents, antimetabolites, natural products, and miscellaneous agents.
  • cancer treatment agents include paclitaxel, 5- fluoruracil, and doxorubicin.
  • biological therapy include the use of a protein such as an antibody (monoclonal or polyclonal) or a recombinant protein.
  • An example of an antibody is herceptin, which is targeted for inhibiting the erbB-2 receptor.
  • the enhancement of the therapeutic effect comprises blocking of a cell survival factor in the mammal and/or triggering, e.g., enhancing or speeding up, of cell apoptosis.
  • the treatment can be carried out in vivo and/or in vitro.
  • the Grb2 SH2 binding inhibitors are effective in inhibiting the association or binding of Grb2 with activated receptor PTKs. Interaction of native Grb2 protein with phosphotyrosinylated proteins including receptor PTKs can be monitored by immunoprecipitating Grb2 and detecting the amount of phosphotyrosinylated proteins which are coprecipitated using anti-phosphotyrosine Western Blotting.
  • the compounds of the present invention can be prepared by any suitable method, for example, a method that advantageously utilizes C-terminal allylglycine amides, for example, compound 1 in Figure 1 in a method involving ring closing metathesis (RCM) reaction of allylglycines onto a ⁇ -vinyl-containing residue; see, e.g., Figures 1-3.
  • RCM ring closing metathesis
  • For examples of RCM reactions see, Gao et al., Org. Lett. 2001, 3, 1617-1620; Reichwein et al., Angew. Chem., Int. Ed. 1999, 38, 3684-3687, J. Org. Chem., 2000, 65, 6187-6195; and J. Org.
  • the RCM reaction advantageously allows ring closure with retention of desired functional groups, e.g., phenylphosphate functionality or the chemical (e.g., a lipophile comprising a carbonyl group) functionality at or near the site of ring juncture(s).
  • desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., a lipophile comprising a carbonyl group) functionality at or near the site of ring juncture(s).
  • L- and D- allylglycines and many of the required terminal amines may be commercially available, thereby making the synthesis more readily accessible than certain other methods, for example, those involving the use of C-terminal 2-allyl-3-aryl-l-propanamides that lacked the ⁇ -carboxyl portion of allylglycine residues.
  • the preparation of multiple analogues may be made possible through the use of solid-phase chemistries.
  • This example demonstrates a method of preparing compounds in accordance with an embodiment of the invention.
  • HPLC separations were conducted using a Waters Prep LC4000 system with photodiode array detection and either a J-sphere ODS-H80 column (20 x 250 mm) with a solvent system consisting of 0.1% aqueous TFA (v/v, solvent A) / 0.1% TFA in MeCN (v/v, solvent B).
  • a solvent system consisting of 0.1% aqueous TFA (v/v, solvent A) / 0.1% TFA in MeCN (v/v, solvent B).
  • the organic extract was dried (Na 2 SO 4 ), evaporated to an oil (203 mg), taken up in DMF (1 mL) and to this was added an HOBt active ester solution prepared by reacting N-Fmoc-L- asparagine (Novabiochem) (357 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol) and DIPCIDI (172 ⁇ L, 1.10 mmol) in DMF (3 mL), 15 minutes. The resulting cleat solution was stirred at room temperature to rapidly yield a thick white suspension. The suspension was diluted with DMF (4 mL) and stirring was continued at room temperature (overnight).
  • Novabiochem N-Fmoc-L- asparagine
  • HOBt 148 mg, 1.10 mmol
  • DIPCIDI 172 ⁇ L, 1.10 mmol
  • iV-Fmoc-Ac 6 C-L-Asn-L-AllylGly-(l-naphthyl)methyl amide 8a.
  • an HOBt active ester solution prepared by reacting N-Fmoc-l-aminocyclohexane carboxylic acid (N-Fmoc- Ac 6 C- OH) (Advanced ChemTech) (420 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol) and DIPCIDI (172 ⁇ L, 1.10 mmol) in DMF (3 mL), 10 minutes and the resulting solution was stirred at room temperature (overnight).
  • Fmoc-amino acids were coupled by treatment with 5 equivalents of Fmoc-amino acid and coupling reagents [HATU/HOAt for GIy and AllylGly for 6 h; (DIPCDI)/HOBt for Asn(Trt) for 2 h; DEPCDI/HOAt for Ac 6 C for 6 h] in DMF.
  • the pTyr mimetic 10 was poupled using DrPCDI/HOAt in DMF for 2 days at 50° C.
  • Peptides 18a and 18b may be converted to compounds 3 and 4, respectively, by an RCM reaction.
  • Preparation of 20 1-Chloro-l-cyanocyclohexane (J. Org. Chem. 1968, 33, 2211 - 2214).
  • phosphorus pentachloride 66.8 g, 0.32 mol
  • pyridine 34 mL, 0.42 mol
  • chloroform 300 mL, HPLC grade
  • reaction mixture was cooled to r.t, poured into crashed ice carefully, and the aqueous phase was extracted by ether (200 mL x 2), the combined organic phase was washed by water (200 mL x 3), sat. NaHCO 3 (100 mL), brine (100 mL), dried over anhydrous Na 2 SO 4 , after concentrated, the residue oil was distilled to afford 20 as a colorless liquid 28.6 in 95% yield.
  • Biosensor Analysis Binding experiments were performed on a Biacore S51 instrument (Biacore Inc., Piscataway NJ). AU Biotinylated Grb2 SH2 domain proteins (b- Grb2) were expressed and purified (Protein Expression Laboratory and The Protein Chemistry Laboratory, SAIC - Frederick). The b-Grb2 was immobilized onto carboxymethyl 5' dextran surface (CM5 sensor chip, Biacore Inc.) by amine coupling.
  • CM5 sensor chip Biacore Inc.
  • the lyophilized b-Grb2 was reconstituted in fifty percent DMSO in H 2 O to make a stock solution of lmg/mL and stored at -80° C
  • a l: 12.5 dilution of b-Grb2 was used for immobilization, by dilution in acetate buffer pH-5.0, with 5% DMSO.
  • IXPBS phosphate buffered saline, pH 7.4 was used as the running buffer.
  • An immobilization wizard was used to optimize the immobilization target.
  • 2500-5000 resonance units (RU) of protein were captured on the CM5 sensor chip.
  • Small molecules were serially diluted in running buffer to the concentrations (1.25 nM - 1500 nM) as indicated in each sensorgram and injected at 25 °C at a flow rate of 30 ⁇ L/min for 2 minutes. Varying concentrations of small molecules were injected in increasing concentrations, and every injection was performed in duplicate within each experiment. In order to subtract background noise from each data set, all samples were also run over an unmodified reference surface and random injections of running buffer were performed throughout every experiment ("double referencing"). Data were fit to a simple 1: 1 interaction model, using the global data analysis program CLAMP; Myszka et al., Trends Biochem. ScL 1998, 23, 149-150.

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