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EP1064289A1 - Heterozyclische inhibitoren von signal-transduction, sie enthaltende zusammensetzungen - Google Patents

Heterozyclische inhibitoren von signal-transduction, sie enthaltende zusammensetzungen

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Publication number
EP1064289A1
EP1064289A1 EP99912685A EP99912685A EP1064289A1 EP 1064289 A1 EP1064289 A1 EP 1064289A1 EP 99912685 A EP99912685 A EP 99912685A EP 99912685 A EP99912685 A EP 99912685A EP 1064289 A1 EP1064289 A1 EP 1064289A1
Authority
EP
European Patent Office
Prior art keywords
compound
substituted
unsubstituted
aliphatic
nrr
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Withdrawn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
EP99912685A
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English (en)
French (fr)
Inventor
John L. Buchanan
Regine Bohacek
Chi B. Vu
George P. Luke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ariad Pharmaceuticals Inc
Original Assignee
Ariad Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Ariad Pharmaceuticals Inc filed Critical Ariad Pharmaceuticals Inc
Publication of EP1064289A1 publication Critical patent/EP1064289A1/de
Withdrawn legal-status Critical Current

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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • A—HUMAN NECESSITIES
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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    • 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
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65318—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
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    • 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
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
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    • 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
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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    • 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
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
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    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • This invention concerns a new class of compounds which have a broad range of useful biological and pharmacological activities.
  • these compounds are useful for inhibiting intracellular signal transduction, especially intracellular signal transduction mediated by one or more molecular interactions involving a phosphotyrosine-contaimng protein
  • This invention also relates to pharmaceutical compositions containing the compounds and prophylactic and therapeutic methods involving pharmaceutical and veterinary administration of the compounds.
  • Cellular signal transduction i.e., the se ⁇ es of events leading from extracellular events to intracellular sequelae, is an aspect of cellular function in both normal and disease states.
  • Numerous proteins that function as signal transducing molecules have been identified, including receptor and non-receptor tyrosine kinases, phosphatases and other molecules with enzymatic or regulatory activities. These molecules generally demonstrate the capacity to associate specifically with other proteins to form a signaling complex that can alter cell activity.
  • Signaling proteins often contain domam(s) of conserved sequence which constitute catalytic domains such as kinase or phosphatase domains, or serve as non-catalytic modules that direct protein 'protein or other inter- or intramolecular interactions du ⁇ ng signal transduction.
  • Such domains include among others, Src homology 2 ("SH2") and phosphotyrosine interaction (“PI”) domains.
  • SH2 and PI domains recognize, i.e., bind to, proteins containing characteristic peptide sequences which include one or more phosphorylated tyrosine (“pTyr”) residues.
  • Src tyrosine kinases reveals that each family member contains an N-terminal membrane anchor, a poorly conserved "unique" region of 40-70 ammo acids, a Src homology 3 (SH3) domain of about sixty ammo acids capable of protein-protein interactions with prolme- ⁇ ch sequences and a Src homology 2 (SH2) domain composing about 100 ammo acid residues which mediates binding of the Src family member of phosphotyrosme-(pTyr) containing peptides and proteins (reviewed in Superti-Furga, FEBS Lett. 369 62-66 (1995).
  • SH3 Src homology 3
  • SH2 Src homology 2
  • SH2 domains including, e.g., ZAP-70, Syk, She, Tsk, Btk, VAV, Grb2, Crk, STATs
  • PI domam-contammg proteins see WO 97/39326 and references cited therein
  • SH2 domain binding specificity is thought to be influenced significantly by the specific ammo acids located carboxy-terminal to the pTyr residue.
  • the pp60c-src, Fyn, Lck and Fgr SH2 domains prefer the sequence pTyr-Glu-Glu-Ile.
  • Many signaling pathways which play cntical roles in disease processes are mediated by the binding of a phosphotyrosine-contaming protein or protein domain with an SH2 or other protein receptor for a tyrosme-phosphorylated domain.
  • Pharmaceutical agents which interfere with signaling mediated by such molecules e.g., which interfere with the formation or stability of such signaling complexes, may be used for precise intervention in these complex biological processes in order to treat or prevent the diseases or pathological effects mediated by such signaling.
  • Such interference may be achieved through a vanety of mechanisms, including competitive inhibition of a phosphotyrosine-contaming ligand with its receptor (e.g., with an SH2-conta ⁇ n ⁇ ng protein), inhibition of phosphorylation of the tyrosine residue of such a ligand, inhibition of activation of a kinase which catalyzes the phosphorylation of a ligand in a signaling pathway, etc.
  • a vanety of mechanisms including competitive inhibition of a phosphotyrosine-contaming ligand with its receptor (e.g., with an SH2-conta ⁇ n ⁇ ng protein), inhibition of phosphorylation of the tyrosine residue of such a ligand, inhibition of activation of a kinase which catalyzes the phosphorylation of a ligand in a signaling pathway, etc.
  • This invention concerns compounds of Formula I, or pharmaceutically acceptable derivatives thereof:
  • G is -O-, -S- or -NR-
  • each occurrence of M is an independently selected, substituted or unsubstituted, methylene moiety, and any M-M' moiety may be electronically saturated or unsaturated and/or may be part of a 3-8-membered ring.
  • M moieties include -CH 2 -, -CHF-, — CF 2 -,
  • n is independently 0, 1, 2, 3, 4 or 5 (in many embodiments n is 0, 1 or 2);
  • each m is independently 0, 1 or 2;
  • J and K are independently selected from the group consisting of -APO.RR , -OPO RR , -ASO 3 R, -OSO 3 R, -ACO 2 R, -A-tetrazole, -ASO 2 NRR', -(M) NRR' and -(M) n OR;
  • Z is a halogen (i.e., F, Cl, Br or I);
  • R 7 and R 8 are independently R, -CN, -NO 2 , Z, J, -A(M) aliphatic, -G(M) aliphatic ,
  • Each occurrence of R represents hydrogen or an aliphatic, heteroahphatic, aryl, heteroaryl, (aryl)al ⁇ phat ⁇ c-, or (heteroaryl)a phat ⁇ c- moiety, each of which (other than hydrogen) may be substituted or unsubstituted, e.g , with any of the va ⁇ ous substituents listed, illustrated or otherwise disclosed herein. While each occurrence of "R” withm a given compound is thus independently selected, where multiple R groups are depicted m the same figure or moiety, the va ⁇ ous R groups are generally marked R, R', R" and so on, as a reminder that they may be the same or different.
  • n M groups m a "M_" moiety may be the same or different from one another.
  • q is an integer from 1 to 8, and in many embodiments is 1, 2 or 3,
  • R is hydrogen, al ⁇ phat ⁇ c.-(M) -cycloaliphatic, -(M) -aryl, or -(M) -heterocyclic, each of which, other than H, may be substituted or unsubstituted (including, e g. moieties such as -(M) n CO 2 R, -(M) n C(O)NRR', -(M) n Z, -(M) n CN, -(M) n tetrazole, etc.),
  • R is hydrogen or substituted or unsubstituted aliphatic, which is optionally covalently linked with R to form a ⁇ ng, or R or R are covalently linked either to B or a substituent of B to form a 4 - 10- membered, saturated or unsaturated, ring, or to the N depicted in Formula I above to form a 5, 6 or 7-membered, saturated or unsaturated, ring;
  • X is:
  • R 3 is hydrogen, R(CO)NR'-, RR'N(CO)NR"-, R'SO 2 NR- R'CSNR- RR''NCSNR"-, RR''NS0 2 NR"-, R'OCONR- RR'N- or
  • R is hydrogen, aliphatic (which may be branched, unbranched or cyclic), cycloaliphatic-(M) n - aryl-(M) n - heterocyclic-(M) n -, RSO 2 (M n )- , (CO 2 R)(M) n - or (RR'N-CO)(M) n , where the aliphatic, cycloaliphatic, aryl and heterocyclic groups are substituted or unsubstituted;
  • HET is a heterocyclic moiety
  • R 9 , R 10 and R 11 are independently -(M) Z, -(M) R, -(M) n GR, -(M) n WR,
  • SR -CHO, -COR, -COOH (or amide, ester, carbamate, urea, oxime or carbonate thereof), -NH 2 (or substituted amine, amide, urea, carbamate or guanidino derivative therof), halo, trihaloalkyl, cyano, -SO 2 -CF 3 , -OSO 2 F, -OS(O) 2 R, -SO 2 -NHR, -NHSO 2 R, sulfate, sulfonate, aryl and heteroaryl moieties.
  • R 12 is independently selected from -(M) Z, -(M) R, -(M) GR, -(M) n WR, -(M) n WGR, and -(M) n W-COR;
  • R 14 is R;
  • U and W are independently -CO-, -CS-, -M-, -SO-, or -SO 2 -.
  • One subgenus includes compounds in which at least one R 4 moiety is H and at least one R moiety is either H or NH 2 .
  • Compounds of the latter sort include those in which X is
  • R comprises a substituted or unsubstituted, lower (i.e., containing 1 - 8 carbon atoms) aliphatic or alkoxyl group, or is a substituted or unsubstituted -(M) ⁇ -aryl or -(M) n -heterocyclic (including e.g., substituted and unsubstituted phenyl or benzyl group, or a homolog and heterocyclic analog thereof, including e.g., 2-naphthyl, 3-indolyl, and 1- imidazolyl);
  • R comprises -(M) n CH 3 , -(M) ⁇ aryl, -(M) ⁇ heterocyclic, -(M) n CN, -(M) n COOR, where n is 0, 1, 2, 3, 4, or 5.
  • n is 0, 1, 2, 3, 4, or 5.
  • R is a substituted or unsubstituted methyl, ethyl, n-propyl, l-propyl, n-butyl, sec- butyl, t- butyl, n-pentyl, sec- pentyl, l-pentyl, cyclo pentyl, etc. or benzyl moiety.
  • R comp ⁇ ses -(CH,.) CH., -(CH 2 )(CH 2 ) n aryl, -(CH 2 )(CH 2 ) n heterocycl ⁇ c, -(CH 2 )(CH 2 ) n CN or -(CH 7 )(CH 2 ) n COOR, where n again is 0, 1, 2, 3, 4, or 5.
  • R 5 comp ⁇ ses -CH 2 CN, -(CH 2 )CO 2 R, -(CH 2 ) 2 CO ? R,
  • R is H, lower alkyl or benzyl and those in which R 5 comp ⁇ ses -O-(subst ⁇ tuted or unsubstituted lower alkyl or benzyl).
  • Another subgenus of interest includes amides of the formula:
  • R1 R where R 4 is hydrogen, substituted or unsubstituted aliphatic (which may be branched, unbranched or cyclic), substituted or unsubstituted aryl-(M) n -, substituted or unsubstituted heterocychc-(M) n -, or (CO 2 R)(M) n -.
  • R 4 is hydrogen, substituted or unsubstituted aliphatic (which may be branched, unbranched or cyclic), substituted or unsubstituted aryl-(M) n -, substituted or unsubstituted heterocychc-(M) n -, or (CO 2 R)(M) n -.
  • R 4 is -(M) (CO)OR, -(M) n SO 2 R, -(M) (C0)NRR', or -(M) (tetrazole), including, for example, compounds in which R 4 is -CH 2 COOR, -CH 2 SO 2 R, -CH 2 (CO)NRR', or
  • Simple members of this subgenus are those in which the R group(s) of R is (are independently) H, lower alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tbutyl, etc.) or benzyl.
  • R group(s) of R is (are independently) H, lower alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tbutyl, etc.) or benzyl.
  • Another subgenus includes ureas of the formula: r R 14
  • R 1 , R 2 , R 4 , R 14 , Y and m are defined as above.
  • R 4 may be simply H or may be a more complex R moiety such as are noted above.
  • Another subgenus includes amides of the formula: R 14
  • R moieties are H. Also, in many compounds of interest, R is H.
  • One subgenus of interest includes compounds of Formula I, including the examples described or illustrated above, in which m is 1, R 1 is H, and R 2 comprises H, -(M) H,
  • R 1 is H
  • R 2 is methyl, ethyl, i-propyl, n-propyl, n-butyl, isobutyl, n-amyl, sec-amyl, isoamyl, substituted benzyl, -CH 2 -(3-indolyl), -CH 2 -(4-imidazolyl), -CH 2 CH 2 COOR,
  • R ⁇ and R ⁇ are independently selected, substituted or unsubstituted lower aliphatic groups, usually of 1 - 8 contiguous carbon atoms, or R and R are covalently linked to each other to form a ring, which may be a substituted or unsubstituted, aliphatic or heterocyclic ring or ring system (e.g. a bicyclic moiety), generally containing 3 - 10 annular atoms.
  • q is an integer from 1 to 8:
  • Another subgenus includes compounds of Formula I, including the examples described or illustrated above, in which m is 2, and each of R 1 , R 1 ', R 2 , and R 2 ' is independently selected from H, -(M) n H, -(M) n -(substituted or unsubstituted lower alkyl), -(M) n -(substituted or unsubstituted aryl), -(M) n -(substituted or unsubstituted heterocyclic), -(M) -COOR and -(M) (CO)NRR .
  • each of R ⁇ R ⁇ R 2 , and R 2 ' is H.
  • R and R is methyl, ethyl, i-propyl, n-propyl, n-butyl, isobutyl, n-amyl, sec-amyl, isoamyl, substituted benzyl, -CH 2 -(3-indolyl), -CH 2 -(4-imidazolyl), -CH 2 CH 2 COOR, -CH 2 CH 2 CONH 2 ,
  • R 1 , R 1 ' , R 2 , and R 2' is methyl, ethyl, i-propyl, n-propyl, n-butyl, isobutyl, n-amyl, sec-amyl, isoamyl, substituted benzyl, -CH 2 -(3-indolyl),
  • R 1 , R 1' , R 2 , and R 2' are covalently linked to form a ring, which as in other cases, may be a substituted or unsubstituted, aliphatic or heterocyclic ring or ring system (e.g. a bicyclic moiety), generally containing 4 - 10 annular atoms.
  • a ring which as in other cases, may be a substituted or unsubstituted, aliphatic or heterocyclic ring or ring system (e.g. a bicyclic moiety), generally containing 4 - 10 annular atoms.
  • Compounds containing 3-, 5- and 6-membered rings are illustrated by the following formulas:
  • One subgenus of compounds of this invention i.e., of compounds of Formula I. including among others the members of the various illustrative classes of compounds noted above, includes those compounds of Formula I in which m is 0:
  • R comprises -OR, -APO 3 RR , -OPO RR , -ASO R, -OSO3R, -ACO 2 R, -A-tetrazole, -ASO 2 NRR', -ACOCF3, -C(R)(J)(K) or -C(Z)(J)(K); and, R 7 and R 8 are independently H, -CN, -NO , halogen, J,
  • R comprises -OR, -APO 3 RR', -OPO 3 RR', -ACO 2 R, -ACOCF 3 , or -C(R)(J)(K);
  • A comprises -M m - (e.g., -CH 2 - -CF 2 - -CHF- , -CHOH-, -CH 2 CF 2 - etc), -GM- (e.g.
  • each R and R' is H, or substituted or unsubstituted lower alkyl or substituted or unsubstituted benzyl; and, R 7 and R 8 are independently H, J, -A-(M) n substituted or unsubstituted aliphatic, -(M) n COCF 3 , -(M) n OH, -(M) n COOR,
  • R 6 comprises -OH, -PO RR ' , -OPO RR ' ,
  • -CF 2 CO 2 R -CH 2 SO 3 R, -CF 2 SO 3 R, -CH 2 COCF 3 , -CF 2 COCF 3> -CH(PO 3 RR') 2 , -CH(OH)(PO 3 RR'), -CH(NH 2 )(PO 3 RR'), -CH(CO 2 R) 2 , -CF(CO 2 R) 2 ,
  • R 6 is -NRM m CO R' are illustrated by compounds in which R is H, -M m CO 2 R', -M m SO 0 R" or another substituted or unsubstituted lower aliphatic moiety. In some such compounds, one or more
  • -CH(PO 3 RR')(SO 3 R"), -CH(PO 3 RR')(SO 2 NH 2 ), -CH(SO 2 NH 2 ) 2 , or -CH(SO 3 RR') 2 moiety is H.
  • one or more of those R groups is -(M) m -CH 2 Z, -(M) m -CHZ 2 , -(M) m -CZ 3 , -R 15 , -M-O-CO-OR 15 or -M-O-CO-R 15 , where Z is halogen and R 15 is substituted or unsubstituted lower aliphatic, aryl or heterocyclic.
  • R is methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, benzyl or substituted benzyl
  • M is CH 2 , CHR (e.g. CHCH 3 etc.) and the like. Further illustrations include -CH 2 -O-CO-OEt, -CH(Me)-O-CO-OEt, -CH 2 - O-CO-t-butyl, etc.
  • R and R are both H.
  • R is J, -A-(M) (substituted or unsubstituted aliphatic, aryl or heterocyclic),
  • R 8 is H.
  • R is lower alkyl, lower alkenyl, -OH,
  • -CH 2 PO 3 RR', -CF 2 PO 3 RR', -OCH 2 CO 2 R, -NHCH 2 CO 2 R, -CH 2 CO 2 R, -CF 2 CO 2 R, -SO 3 R, -CH 2 SO 3 R, or -CF 2 SO 3 R is H.
  • one or more of those R groups is -(M) m -CH 2.Z, -(M) m -CHZ 2, -(M) m -CZ, 3, -R 15 , -M-O-CO-OR 15 or -M-O-CO-R 15 ,
  • Z is halogen and R is substituted or unsubstituted lower aliphatic, aryl or
  • R is methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, benzyl or substituted benzyl
  • M is CH 2 , CHR (e.g. CHCH 3 etc.) and the like.
  • R 6 comp ⁇ ses -APO RR ' (e.g., -OPO H ) and R 7 is
  • R and R are independently selected from J and K.
  • R is -C(R)(J)(K).
  • Illustrative compounds of this subgenus include those in which R 6 is -CH(J)(K) and those m which R 6 is -C(R)(PO R'R'')(K). The latter compounds are illustrated by embodiments in which none, one, two or three of the R groups of the -C(R)(PO R'R'')(K) moiety are H.
  • compounds of this invention which contain a moiety J, e.g., compounds of Formula I m which R is -C(R)(J)(K), include among others embodiments in which one or both of R and R' (e.g., of a -PO RR ' moiety) are R 15 ,
  • Z is halogen and R is substituted or unsubstituted lower aliphatic, aryl or heterocyclic (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, benzyl or substituted benzyl), and M is CH 2 , CHR (e.g. CHCH 3 etc.) and the like.
  • R is substituted or unsubstituted lower aliphatic, aryl or heterocyclic (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, benzyl or substituted benzyl)
  • M is CH 2 , CHR (e.g. CHCH 3 etc.) and the like.
  • each of R 9 , R 10 and R 11 is independently Z, R, -GR, -COR, -CO 2 R, or
  • -(M) n W-NRR' and R 12 is independently selected from -(M) Z, -(M) R, -(M) GR, -(M) n WR , and -(M) n WGR.
  • one or more of the R, R' and R" groups of R >9 , D R10 and R »11 comprise a halo, hydroxy, aliphatic, amino, amido or sulfonamido moiety.
  • one or more of R , R , R , and R is a substituted aliphatic moiety containing at least one substituent selected from substituted or unsubstituted cycloaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COR, -CO 2 R, -CO-NRR', and -OR.
  • substituents selected from substituted or unsubstituted cycloaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COR, -CO 2 R, -CO-NRR', and -OR.
  • R , R , R , and R comprises -(M) (cycloaliphatic), n
  • R 12 is -(M) OR, n is 1 or greater.)
  • R 11 , and R 12 comprise methyl, -(CH ) R 13 where q is 1-8 13
  • R comprises methyl; i-propyl; i-butyl; t-butyl; cycloaliphatic; phenyl; substituted phenyl; naphthyl; substituted naphthyl; a 5, 6 or 7-membered heterocyclic ring or a bicyclic heterocylic moiety.
  • R 12 comprises a formyl group on a ring nitrogen.
  • Possible substituents on the R, R' and R" groups include, among others, halo, hydroxy, alkyl, amino, amido and sulfonamido moieties. Other potential substituents are as disclosed elsewhere herein, including in the numerous specific examples.
  • Compounds of particular interest include those in which B is selected from the following:
  • compounds of particular interest include those compounds of Formula I, including those of the various subgenera and examples herein, which have the following structures:
  • R and R each comp ⁇ se an independently selected, substituted or unsubstituted lloowweerr aalliipphhaattiicc mmooiieettyy,, aanndd RR aanndd RR aarree eeaacchh iinnddependently selected from H. and a substituted or unsubstituted lower aliphatic moiety.
  • R and R are independently selected from H; linear, branched or cyclic lower aliphatic; -(CH 2 ) n COOR; -(CH 2 ) n CONRR ⁇ -(CH 2 ) n cycloahphat ⁇ c (substituted or unsubstituted); -(CH 2 ) n aryl (substituted or unsubstituted) or -(CH 2 ) n heterocycl ⁇ c (substituted or unsubstituted).
  • R comp ⁇ ses a linear, branched or cyclic lower aliphatic, -(CH ) 2 COOR, -(CH 2 ) 2 aryl (substituted or unsubstituted) or -(CH 2 ) 2 heterocychc
  • R comp ⁇ ses a linear, branched or cyclic lower aliphatic; and R and R are independently selected from H; linear, branched or cyclic lower aliphatic; -(CH 2 ) 2 COOR, -(CH 2 ) 2 CONH 2 ; -(CH 2 )cycloal ⁇ phat ⁇ c (substituted or unsubstituted); -(CH 2 )aryl (substituted or unsubstituted) or -(CH 2 )heterocycl ⁇ c
  • Thiazoles of Formula II may be useful as inhibitors of cellular signaling mediated by Src or Src family kinases, and thus may be useful in treating diseases such as osteoporosis and other bone resorptive disorders in patients in need thereof.
  • Such compounds may be used for example as immunosuppressants in patients who are going to receive, or have received, an organ or tissue transplant or in patients suffering an autoimmune disorder.
  • R 1 and R 5 each comprise an independently selected, substituted or unsubstituted lower aliphatic moiety, and R comprises H or a substituted or unsubstituted lower aliphatic moiety.
  • R comprises a linear, branched or cyclic lower aliphatic, -(M) n aliphatic (which may be substituted or unsubstituted), -(M) n COOR, -(M) n OR, -(M) n aryl (which may be substituted or unsubstituted) or -(CH 2 ) n heterocyclic (which may be substituted or unsubstituted);
  • R comprises a linear, branched or cyclic lower aliphatic; and R comprises H; linear, branched or cyclic lower aliphatic; -(M) COOR;
  • M is CH 2 .
  • R comprises a linear, branched or cyclic lower aliphatic, -(CH-) 2 COOR, -(CH 2 )aryl (substituted or unsubstituted) or -(CH 2 )heterocyclic (substituted or unsubstituted);
  • R comprises a linear, branched or cyclic lower aliphatic (substituted or unsubstituted); and R comprises H; linear, branched or cyclic lower aliphatic; -(CH 2 ) 2 COOR; -(CH 2 ) 2 CONH 2 ; -(CH 2 )cycloaliphatic (substituted or unsubstituted);
  • Oxadiazoles of Formula HI may be useful as inhibitors of cellular signaling mediated by Src or Src family kinases, and thus may be useful in treating diseases such as osteoporosis and other bone resorptive disorders in patients in need thereof.
  • Oxadiazoles of Formula III are further illustrated by the following types of compounds:
  • M is CH 2 .
  • R moieties are illustrated by the following:
  • one set of illustrative compounds of particular interest include those of the following sorts of structures:
  • Such oxadiazoles may be useful as inhibitors of cellular signaling mediated by ZAP-70 or ZAP- 70 family kinases, and thus may be useful in treating or preventing an inflammatory response in patients in need thereof.
  • Such compounds may be used for example as immunosuppressants in patients who are going to receive, or have received, an organ or tissue transplant or in patients suffering an autoimmune disorder.
  • Another set of illustrative oxadiazoles of particular interest include the following types of compounds:
  • R 6 comprises -PO 3 RR', -OPO 3 RR', -OSO 2 NRR', -(CH 2 )PO 3 RR ⁇ ⁇ -(CF 0 )PO RR' or -CRJK; and R comprises R (including among others, H, alkyl, alkenyl, etc.) -CN, amido, acylamino, J (e.g. -CO 2 R), or -CHO.
  • R comprises -PO 3 RR', -OPO 3 RR', -OSO 2 NRR', -(CH 2 )PO 3 RR ⁇ ⁇ -(CF 0 )PO RR' or -CRJK
  • R comprises R (including among others, H, alkyl, alkenyl, etc.) -CN, amido, acylamino, J (e.g. -CO 2 R), or -CHO.
  • J e.g. -CO 2 R
  • R comprises -OPO RR' or -(CF )PO RR' and R is H.
  • R groups including R', R", etc
  • R comprises -(M) -CH Z
  • R is substituted or unsubstituted lower aliphatic, aryl or heterocyclic.
  • R is methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, benzyl or substituted benzyl
  • M is CH 2 , CHR (e.g. CHCH 3 etc.) and the like.
  • SH2 domains of current interest include those of a Src, Fyn, Lck. Yes, Blk. Lyn, Fgr, Hck, Yrk, ZAP-70, Syk, STAT or Abl protein.
  • compositions comprising a compound of this invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable excipients.
  • Compounds of this invention can be administered to cells or to animals, preferably a mammal in need thereof, as a method for inhibiting SH2-mediated signal transduction therein.
  • the SH2-mediated signal transduction is mediated by a PDGF receptor protein, EGF receptor protein,
  • HER2/Neu receptor protein 20 HER2/Neu receptor protein, fibroblast growth factor receptor protein, focal adhesion kinase protein, pl30 protein, or p68 protein.
  • Cases in which a mammal may be m need of inhibition of SH2-med ⁇ ated signaling include cases in which the mammal has a prohferative disease, cancer, restenosis, osteoporosis, inflammation, allergies, or cardiovascular disease.
  • admimste ⁇ ng a therapeutically effective amount of the composition to the mammal, preferably to a human patient will constitute treating or preventing the prohferative disease, cancer, restenosis, osteoporosis, inflammation, allergic reaction, or cardiovascular disease in the recipient or a method for causing lmmunosuppression in the recipient.
  • prefened compounds of this invention include any of the foregoing compounds which yield an observable IC 50 value, when tested against an SH2 domain of interest and a pTyr-containmg peptide ligand (or mimic thereof) for that SH2 domain, of 50 ⁇ M or better, preferably 5 ⁇ M or better, more preferably 1 ⁇ M or better, and even more preferably, 500 nM or better, as determined by any scientifically valid measure, especially when the SH2 domain is from a Src, Fyn, Lck, Yes, Blk, Lyn, Fgr, Hck, Yrk, ZAP, Syk, STAT or Abl protein.
  • a pharmaceutical composition may be prepared containing a compound of this invention (including a pharmaceutically acceptable de ⁇ vative thereof) together with one or more pharmaceutically acceptable excipients.
  • a compound of this invention may be administered to a mammal in need thereof, preferably a human patient, as a method for inhibiting SH2-med ⁇ ated signal transduction m the recipient mammal.
  • the compound may be selected based on its ability to specifically bind to an SH2 domain, e.g of Src, ZAP-70, Syk, or STAT 6, etc., or on its ability to inhibit a signal transduction pathway mediated by an SH2 domam-contaming protein.
  • Such use of an approp ⁇ ately selected compound of this invention thus provides a method for inhibiting SH2-med ⁇ ated signal transduction which is mediated by a PDGF receptor protein, EGF receptor protein, HER2/Neu receptor protein, fibroblast growth factor receptor protein, focal adhesion kinase protein, pi 30 protein, or p68 protein.
  • Use of a compound of this invention may be particularly advantageous m cases in which the mammal has a prohferative disease, cancer, restenosis, osteoporosis, inflammation, allergies, or cardiovascular disease.
  • a therapeutically effective amount of a compound of this invention preferably in the form of a pharmaceutical composition, provides a method for
  • this invention provides a novel class of compounds useful as inhibitors of signal transduction pathways mediated by the interaction of protein receptors for phosphotyrosine-contaming proteins, such as proteins containing one or more SH2 domains, with their phosphotyrosine-contaming hgands.
  • Compounds of this invention comp ⁇ se those of Formula I, set forth above, and are illustrated in part by the va ⁇ ous classes, subgenera and subsets of compounds noted above, and by the va ⁇ ous subgenera and species disclosed elsewhere herein.
  • the compound may be m the form of an individual enantiomer, diastereomer or geomet ⁇ c isomer, or may be in the form of a mixture of stereoisomers.
  • pharmaceutically acceptable de ⁇ vatives of the foregoing compounds, where the phrase "pharmaceutically acceptable de ⁇ vative" denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or de ⁇ vative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise desc ⁇ bed herein, or a metabolite or residue thereof, preferably one which is a signal transduction inhibitor.
  • Pharmaceutically acceptable de ⁇ vatives thus include among others pro-drugs.
  • a pro-drug is a de ⁇ vative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal w vivo yielding the parent molecule as the pharmacologically active species
  • An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest.
  • Pro-drugs of a va ⁇ ety of compounds, and mate ⁇ als and methods for denvatizmg the parent compounds to create the pro-drugs are known and may be adapted to the present invention.
  • aliphatic as used herein includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyc c, or polycychc aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • alkyl, other aliphatic, alkoxy and acyl groups preferably contain 1-8, and m many cases 1- 6, contiguous aliphatic carbon atoms.
  • Illustrative aliphatic groups thus include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, allyl, n- butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl,
  • Aliphatic, heteroaliphatic, aryl and heterocyclic substituents may themselves be substituted or unsubstituted (e.g. mono-, di- and tri-alkoxyphenyl; methylenedioxyphenyl or ethylenedioxyphenyl; halophenyl; or -phenyl-C(Me) 2 -CH 2 -O-CO-[C3-C6] alkyl or alkylamino). Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples which follow.
  • alkyl includes both straight, branched and cyclic alkyl groups.
  • alkenyl alkynyl
  • alkynyl alkynyl
  • the language “alkyl”, “alkenyl”, “alkynyl” and the like encompasses both substituted and unsubstituted groups.
  • alkyl refers to groups usually having one to eight, preferably one to six carbon atoms.
  • alkyl may refer to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, and the like.
  • Suitable substituted alkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl and the like.
  • alkenyl refers to groups usually having two to eight, preferably two to six carbon atoms.
  • alkenyl may refer to prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like.
  • alkynyl which also refers to groups having two to eight, preferably two to six carbons, includes, but is not limited to, prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like.
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in
  • heteroaliphatic refers to aliphatic moieties which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., m place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched or cyclic and include heterocycles such as morpho no, pyrro dinyl, etc.
  • heterocycle refers to cyclic heteroaliphatic and heteroaryl groups and preferably three to ten ⁇ ng atoms total, mcludes, but is not limited to heteroaliphatic moieties such as oxetane, tetrahydrofuranyl, tetrahydropyranyl, azi ⁇ dme, azetidme, pyrrolidme, pipe ⁇ dme, morpho ne, piperazme and the like, and heteroaryl moieties as desc ⁇ bed below.
  • aryl and “heteroaryl” as used herein refer to stable mono- or polycychc, heterocyclic, polycychc, and polyheterocyc c unsaturated moieties havmg 3 - 14 carbon atom which may be substituted or unsubstituted.
  • Substituents include any of the previously mentioned substituents
  • Non-limiting examples of useful aryl ⁇ ng groups include phenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, t ⁇ alkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl, phenanthro and the like.
  • heteroaryl ⁇ ngs examples include 5-membered monocychc ⁇ ng groups such as thienyl, pyrrolyl, lmidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl and the like; 6-membered monocychc groups such as py ⁇ dyl, pyrazmyl, py ⁇ midmyl, py ⁇ dazinyl, t ⁇ azmyl and the like; and polycychc heterocyclic ⁇ ng groups such as benzo[b]th ⁇ enyl, naphtho[2,3-b]th ⁇ enyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, mdo zinyl, isoindolyl, indolyl, ind
  • the aryl or heteroaryl moieties may be substituted with one to five members selected from the group consisting of hydroxy, C1-C8 alkoxy, C1-C8 branched or straight-chain alkyl, acyloxy, carbamoyl, ammo, N-acylamino, mtro, halo, t ⁇ halomethyl, cyano, and carboxyl
  • Aryl moieties thus include, e.g phenyl; substituted phenyl bea ⁇ ng one or more substituents selected from groups including: halo such as chloro or fluoro, hydroxy, C1-C6 alkyl, acyl, acyloxy, C1-C6 alkoxy (such as methoxy or ethoxy, including among others dialkoxyphenyl moieties such as 2,3-, 2,4-, 2,5-, 3,4- or 3,5-d ⁇ methoxy or diethoxy phenyl or such
  • a "halo" substituent may be fluoro, chloro, bromo or iodo.
  • Compounds of this invention may be evaluated in a variety of assays to determine their relative ability to bind to a receptor for a pTyr-containing ligand, such as a protein containing one or more SH2 or PI domains, or to otherwise inhibit an intermolecular interaction mediated by such a domain. See e.g. US 5667980 (Pawson; competitive binding assays), PCT/US97/02635 (Rickles et al; cell-based assays) and PCT/US97/06746 (Lynch et al, FP assays). Compounds may also be evaluated for their selectivity of binding to one such receptor (or family of receptors) relative to another such receptor (or family of receptors).
  • a pTyr-containing ligand such as a protein containing one or more SH2 or PI domains
  • the compounds of this invention can be further evaluated by conventional methods for possible therapeutic applications, including evaluations of toxicological and pharmacological activity.
  • the compounds may further be evaluated for activity in inhibiting cellular or other biological events mediated by a pathway involving the molecular interaction of interest using a suitable cell-based assay or an animal model.
  • Cell-based assays and animal models suitable for evaluating inhibitory activity of a test compound with respect to a wide variety of cellular and other biological events are known
  • compounds which bind to an SH2 domain involved in the transduction of a signal leading to asthma or allergic episodes may be evaluated in a mast cell or basophil degranulation assay.
  • the inhibitory activity of a test compound identified as an SH2 inhibitor by the method of this invention with respect to cellular release of specific mediators such as histamine, leukotrienes, hormonal mediators and/or cytokines, as well as its biological activity with respect to the levels of phosphatidylinositol hydrolysis or tyrosine phosphorylation can be characterized with conventional in vitro assays as an indication of biological activity.
  • mediators such as histamine, leukotrienes, hormonal mediators and/or cytokines
  • histamine release can be measured by a radioimmunoassay using a kit available from AMAC Inc. (Westbrook, ME).
  • AMAC Inc. Westbrook, ME
  • Inhibitors of this invention may also be tested in an ex vivo assay, e.g., for their ability to block antigen-stimulated contraction of sensitized guinea pig tracheal strip tissue. Activity in this assay has been shown to be useful in predicting the efficacy of potential anti-asthma drugs.
  • compounds which bind to an SH2 or other domain of interest involved in the transduction of a signal involved in the initiation, maintenance or spread of cancerous growth may be evaluated in relevant conventional in vitro and in vivo assays. See e.g., Ishii et al., I. Antibiot.. XLII: 1877- 1878 (1989); and US Patent 5,206,249 (issued 27 April 1993).
  • Compounds which bind to a Src SH2 domain or which otherwise inhibit Src- mediated signaUng may be evaluated for activity in a variety of assays considered predictive of activity in treating or preventing osteoporosis.
  • assays include the various pit assays and calvaria assays, among others. Illustrative assays are described below.
  • MURINE CALVARIA ASSAY In osteoporosis, excessive bone resorption results in decreased bone density. In vivo and in vitro models of bone resorption are used to study the processes leading to osteoporosis. In vitro, fetal rat long bone and murine calvaria cultures are routinely used. Both models display similar responses to parathyroid hormone (PTH), a physiological modulator of bone reso ⁇ tion (Stern, P.H. and N.S. Krieger. Comparison of fetal rat limb bones and neonatal mouse calvaria: effects of parathyroid hormone and 1,25- dihydroxyvitamin D 3 . Calcif. Tissue Int. 35: 172-176, 1983).
  • PTH parathyroid hormone
  • Stern, P.H. and N.S. Krieger Comparison of fetal rat limb bones and neonatal mouse calvaria: effects of parathyroid hormone and 1,25- dihydroxyvitamin D 3 . Calcif. Tissue Int. 35: 172-176
  • the calvaria model of bone reso ⁇ tion can be successfully used to screen osteotropic compounds as has been previously shown (Green, J.R., K. Muller and K. Jaeggi. Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J. Bone Miner. Res. 9: 745-751, 1994.).
  • calvaria culture model tests the ability of anti-reso ⁇ tive compounds to prevent reso ⁇ tion (prophylactic model).
  • a second model tests the ability of these compounds to terminate ongoing reso ⁇ tion (therapeutic model). Cytotoxicity may be assessed in both models using a lactate dehydrogenase (LDH) assay.
  • LDH lactate dehydrogenase
  • DMEM Dulbecco's Modified Eagle's Medium
  • D-012 Dulbecco's Modified Eagle's Medium
  • a lx solution is prepared using ultrafiltered water.
  • a suitable media contains 15% heat inactivated horse serum (Sigma, H 1270).
  • 27 concentration is adjusted to 1.65 to 1.83 mM using 0.2 M CaCl 2 .
  • Penicillin (100 U/ml) and streptomycin (0.1 mg/ml) are added to the final media preparation.
  • Indomethacin is prepared to 0.5 mg/ml (1.397 x 10 M) in ethanol, and is added to an aliquot of DMEM to produce a final concentration of 0.5 ⁇ M.
  • Bovine parathyroid hormone (1-34) may be obtained from Bachem (PCAL 100).
  • PTH is solubilized in 0.1 % BSA and is then diluted in DMEM to produce a final concentration of 10 M PTH.
  • Ten-fold serial dilutions are performed down to 10 M.
  • CD-I mice may be obtained from Charles River and are subjected to parturition. Neonatal mice (4-6 days) are cleansed with betadine and then euthanized by decapitation. Adherent skin is cleared away from the skull, exposing the calvaria. The calvaria are dissected away from the skull using a 12B scalpel. Calvaria are immediately placed into a glass petri dish containing room temperature Tyrode's Salt Solution (Sigma, T-2397). The calvaria are trimmed free of cartilage and bisected with a scalpel along the sagital suture. After dissection of all calvaria, calvaria are transferred into 24 well plates containing 0.5 ⁇ M indomethacin (Sigma, 1-7378).
  • calvaria are thoroughly washed in indomethacin-free DMEM. Calvaria are then transferred to new wells containing various PTH concentrations, and are cultured for an additional 72 hours. Media samples (30 ⁇ l) are obtained every 24 hours and assayed for calcium and LDH activity.
  • the calvaria are washed free of indomethacin using DMEM. Calvaria are then transferred to new wells containing DMEM or various concentrations of PTH. After 24 hours calvaria are transferred into new wells
  • a commercially available diagnostic calcium assay (Sigma, No. 588-3), modified for use in a microtiter format, may be used to determine circulating serum calcium concentrations.
  • This colorimetric assay is dependent on the specific, high affinity complexation of calcium with arsenazo HI dye under acidic conditions, which occurs with 1:1 stoichiometry and absorbs at 600 nm (Bauer, P.J. Affinity and stoichiometry of calcium binding by Arsenazo HI. Anal Biochem, 110:61, 1981; Michaylova, V and P Ilkova. Photometric determination of micro amounts of calcium with Arsenazo HI. Anal Chim Acta, 53: 194, 1971). Magnesium has very low affinity for arsenazo HI.
  • Phosphate buffer is prepared in distilled water (0.26 M K 2 HPO 4 '3H 2 O, 0.26 M
  • Ten ⁇ l of media samples obtained from incubated calvaria are added to 96 well plates. Wells containing 10 ⁇ l of DMEM serve as blanks. To each well, 90 ⁇ l distilled water and 150 ⁇ l phosphate mix is added. 50 ⁇ l NADH is added using an eight channel pipette immediately before the plate is read on a microtiter plate reader at 340 nm. A kinetic assay is performed for 10 minutes, with a read interval of 20 seconds.
  • Parathyroid hormone (PTH) replacement in thyroparathyroidectomized (TPTX) rats is routinely used as an in vivo model of controlled bone reso ⁇ tion. Rats are the species of choice since the mechanisms of bone modeling in the rat resemble those in humans. In addition, hormones and pharmacologic agents have similar effects on both rat and human bone (Frost, H.M. and W.S.S. Jee. On the rat model of human osteopenias and osteoporoses. Bone and Mineral, 18: 227-236, 1992). Removal of the thyroid and parathyroid glands results in a rapid loss of parathyroid hormone (PTH) from the circulation.
  • PTH parathyroid hormone
  • mice Female Wistar rats (226-250 gm, Charles River) are fasted overnight and anesthetized with 0.15 ml of 1.2% tribromoethanol (TBE).
  • TBE tribromoethanol
  • the ventral neck area is shaved and swabbed with betadine and isopropanol.
  • a midline incision is made in the neck through the skin and superficial muscle layer, as well as in the stemohyoid muscle. Blunt dissection is performed to expose the thyroid gland.
  • the thyroid gland is carefully isolated from the trachea, thyrohyoid muscle, as well as adjacent nerves and blood vessels, using blunt dissection.
  • the thyroid gland is excised one lobe at a time. Cautery is performed for hemostasis.
  • Rats are fed at least 5 grams, but not more than 10 grams, of food Rats consuming less than 3.0 grams of food receive the nutritional supplement Nut ⁇ -Cal p.o. (Evsco; ⁇ 0.0033% calcium).
  • rats which are found to be hypocalcemic, based on day 2 serum calcium levels, are implanted with PTH-contammg Alzet mini-osmotic pumps (ALZA, model 2001D) which pumps at a rate of 1 ⁇ l/h.
  • the rats are anesthetized with ketarmne (50 mg/kg, l.p.) and acepromazine (1.67 mg/kg, ⁇ .p.).
  • the scapula region is shaved and prepared for surgery with betadine and isopropanol. A lateral incision of approximately 2 cm in length is made between the scapulae.
  • Bovme parathyroid hormone 1-34 (Bachem California, PCAL100) is prepared in vehicle (10 "3 N HCl, 0.15 M NaCl, 20 mg/ml cysteme ⁇ Cl) at the following concentrations: 0 156, 0.47, 1.56, 4.7, 15.6, and 156 ⁇ M.
  • Alzet mini-osmotic pumps are filled with the PTH solution and maintained in 37 » C saline for 4 hours p ⁇ or to implantation.
  • Rats are anesthetized by CO 2 from dry ice and daily blood samples are obtained via cardiac puncture using a 27 gauge needle. Baseline samples are taken just p ⁇ or to TPTX Daily samples are obtained m the morning. Samples are allowed to clot on their side for several hours and subsequently spun at lOOOxg for 15 minutes to obtain serum Serum is ahquoted and stored in the ref ⁇ gerator until assayed for serum calcium Serum calcium is measured (see above) daily for at least 7 days following TPTX.
  • Compounds of this invention which bind to an SH2 domain of interest may be used as biological reagents in assays as desc ⁇ bed herein for functional classification of a pTyr- bindmg domain (e g. SH2 or PI domain) of a particular protein, particularly a newly discovered protein. Families or classes of such proteins which bind to pTyr-contaimng hgands may now be defined functionally, with respect to ligand specificity Moreover, compounds of this invention can be used to inhibit the occurrence of biological events resulting from molecular interactions mediated by the protein of interest Inhibiting such
  • Such compounds would be useful, for example, in the diagnosis, prevention or treatment of conditions or diseases resulting from a cellular processes mediated by the binding of a pTyr-containing ligand with a receptor therefor.
  • a patient can be treated to prevent the occurrence or progression of osteoporosis or to reverse its course by administering to the patient in need thereof an SH2inhibitor which selectively binds Src SH2 or otherwise interferes with Src-mediated signaling.
  • Still other relevant applications include the prevention of interferon-, growth factor-, or cytokine-mediated diseases (e.g. inflammatory diseases) by targeting the interaction of STAT proteins with their pTyr-containing ligands or otherwise inhibiting their signal transduction pathways.
  • cytokine-mediated diseases e.g. inflammatory diseases
  • Agents that block the SH2 domains of ZAP-70 or otherwise inhibit ZAP-70-mediated signaling would be candidates for the treatment of immune-related disorders such as rejection of transplanted bone marrow, skin or other organs; rheumatoid arthritis; inflammatory bowel disease; and systemic lupus erythmatosis, and a variety of autoimmune diseases.
  • compounds of this invention which inhibit cellular signal transduction may be used in pharmaceutical compositions and methods for treatment or prevention in a subject in need thereof.
  • Such inhibitors can be used to treat or reduce the risk of the diseases or their pathological effects mediated by such interactions.
  • drugs that completely block one of the two ZAP SH2 domains should effectively prevent ZAP from associating with the activated TCR and thus block T cell activation.
  • a ZAP antagonist or inhibitor would specifically inhibit T cells and avoid the toxicity of the currently used immunosuppressive drugs, FK506 and cyclosporin, which target the more ubiquitously expressed protein, calcineurin. Since calcineurin is required for cellular activities in several tissues in addition to T cells, cyclosporin and FK506 cause side effects in the kidney and central nervous system which limit their application largely to patients with organ transplant rejection.
  • compositions of this invention can exist in free form or, where approp ⁇ ate, m salt form.
  • Pharmaceutically acceptable salts of many types of compounds and their preparation are well-known to those of skill in the art.
  • the pharmaceutically acceptable salts of compounds of this invention include the conventional non-toxic salts or the quaternary ammonium salts of such compounds which are formed, for example, from inorganic or organic acids of bases.
  • the compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an approp ⁇ ate organic solvent.
  • This invention also relates to pharmaceutical compositions comp ⁇ sing a therapeutically (or prophylactically) effective amount of the compound, and a pharmaceutically acceptable earner or excipient.
  • Car ⁇ ers include e g. saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, and are discussed in greater detail below.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffe ⁇ ng agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and car ⁇ ers such as t ⁇ glyce ⁇ des.
  • Oral formulation can include standard car ⁇ ers such as pharmaceutical grades of manmtol, lactose, starch, magnesium stearate, sodium saccha ⁇ ne, cellulose, magnesium carbonate, etc. Formulation may involve mixing, granulating and compressing or dissolving the ingredients as approp ⁇ ate to the desired preparation.
  • the pharmaceutical earner employed may be, for example, either a solid or liquid
  • Illustrative solid earner include lactose, te ⁇ a alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stea ⁇ c acid and the like.
  • a solid earner can include one or more substances which may also act as flavo ⁇ ng agents, lub ⁇ cants, solubilizers, suspending agents, fillers, ghdants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating mate ⁇ al.
  • the earner is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a earner havmg the necessary compression properties in suitable proportions ,and compacted m the shape and size desired
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid earners include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dext ⁇ n, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrro dme, low melting waxes and ion exchange resins.
  • Illustrative liquid carriers include syrup, peanut oil, olive oil, water, etc. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carders are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compound can also be administered orally either in liquid or solid composition form.
  • the carrier or excipient may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate along or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • time delay material such as glyceryl monostearate or glyceryl distearate along or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • Tween 80 in PHOSAL PG-50 phospholipid concentrate with 1,2-propylene glycol, A. Nattermann & Cie. GmbH
  • PHOSAL PG-50 phospholipid concentrate with 1,2-propylene glycol, A. Nattermann & Cie. GmbH
  • a wide variety of pharmaceutical forms can be employed. If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampule or vial or nonaqueous liquid suspension.
  • a pharmaceutically acceptable salt of the compound may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic acid or citric acid.
  • an organic or inorganic acid such as a 0.3M solution of succinic acid or citric acid.
  • acidic derivatives can be dissolved in suitable basic solutions. If a soluble salt form is not available, the
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, polyoxyethylated fatty acids, fatty alcohols or glycerin hydroxy fatty acids esters and the like in concentrations ranging from 0-60% of the total volume.
  • Various delivery systems are known and can be used to administer the compound, or the various formulations thereof, including tablets, capsules, injectable solutions, encapsulation in liposomes, microparticles, microcapsules, etc.
  • Methods of introduction include but are not limited to dermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (as is usually preferred) oral routes.
  • the compound may be administered by any convenient or otherwise appropriate route, for example by infusion or bolus injection, by abso ⁇ tion through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • prefened routes of administration are oral, nasal or via a bronchial aerosol or nebulizer.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ease pain at the side of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Administration to an individual of an effective amount of the compound can also be accomplished topically by administering the compound(s) directly to the affected area of the
  • the compound is administered or applied in a composition including a pharmacologically acceptable topical carrier, such as a gel, an ointment, a lotion, or a cream, which includes, without limitation, such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
  • a pharmacologically acceptable topical carrier such as a gel, an ointment, a lotion, or a cream, which includes, without limitation, such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
  • Topical carriers include liquid petroleum, isopropyl palmitate, polyethylene glycol, ethanol (95%), polyoxyethylene monolaurate (5%) in water, or sodium lauryl sulfate (5%) in water.
  • Other materials such as anti-oxidants, humectants, viscosity stabilizers, and similar agents may be added as necessary.
  • Percutaneous penetration enhancers such as Azone may also be included.
  • the compound may be disposed within devices placed upon, in, or under the skin.
  • Such devices include patches, implants, and injections which release the compound into the skin, by either passive or active release mechanisms.
  • Materials and methods for producing the various formulations are well known in the art and may be adapted for practicing the subject invention. See e.g. US Patent Nos. 5,182,293 and 4,837,311 (tablets, capsules and other oral formulations as well as intravenous formulations) and European Patent Application Publication Nos. 0 649 659 (published April 26, 1995; illustrative formulation for IV administration) and 0 648 494 (published April 19, 1995; illustrative formulation for oral administration).
  • the effective dose of the compound will typically be in the range of about 0.01 to about 50 mg/kgs, preferably about 0.1 to about 10 mg/kg of mammalian body weight, administered in single or multiple doses.
  • the compound may be administered to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient.
  • the amount of compound which will be effective in the treatment or prevention of a particular disorder or condition will depend in part on the nature and severity of the disorder or condition, which can be determined by standard clinical techniques.
  • in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the precise dosage level should be determined by the attending physician or other health care provider and will depend upon well known factors, including route of administration, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; the use (or not) of concomitant therapies.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of
  • the invention Optionally associated with such contamer(s) can be a notice m the form presc ⁇ bed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration
  • Compounds of this invention can be prepared by convergent synthesis as illustrated in the following examples.
  • a carboxylic acid e.g., Ac-Tyr(PO3Bn2)- OH or Boc-Tyr(PO3Bn2)-OH, for example, is coupled with a heterocyclic amine using standard materials and methods for peptide coupling, including any necessary or desired protection and subsequent deprotection.
  • Compounds such as Compound ZZ1 can be prepared according to General Methods A-G, as exemplified by the following examples.
  • General Methods C and D exemplify typical coupling strategies, which can be modified with obvious standard manipulations and as shown here in General Methods A-G as well as in the following General Methods H-ZT.
  • thiazoles and oxazoles can be prepared via standard Hantzsch thiazole synthesis with alpha halo ketones and thioamides or amides.
  • Compounds such as Compound A can be prepared using thiazole formation Conditions A followed by Coupling Conditions C. Expe ⁇ mental details for the synthesis of Compound A are as follows
  • Bromomethyl ketone 2 can be prepared according to the procedure found in Hajos, Z G , Wachter, M P , Werblood, H. M.; Adams, R. E. J. Org. Chem 1984, 49, 2600.
  • the intermediate amide can be prepared according to the procedure found in Nozaki, S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1988, 61, 2647.
  • Thiazole 4 can be prepared according to Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473 and Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J. Synth. Commun. 1990, 20, 2235.
  • Compounds such as Compound B can be prepared using thiazole formation Conditions A followed by Coupling Conditions D. Experimental details for the synthesis of compound B are as follows:
  • Bromoketone 9 was prepared as bromoketone 2 except that TMSCI was used rather than the centrifugate from 1:1 Et3N-TMSCl. Flash chromatography (elution with 6:1 hexanes- Et2 ⁇ ) gave 1.8 g (50.2%) of a very volatile pale oil: Rf 0.38 (6:1 hexanes-Et2 ⁇ ).
  • Thiazole 10 can be prepared as shown for the preparation of thiazole 4. Flash chromatography (elution with 3:2 hexanes-Et2 ⁇ ) gave 0.95 g (80.5%) of a pale oil: Rf 0.50 (1:1 hexanes-Et2 ⁇ ).
  • Dibenzyl phosphate 12 can be prepared according to the procedure found in Silverberg, L. J.; Dillon, J. L.; Vemishetti, P. Tetrahedron Lett. 1996, 37, 111.
  • Compounds such as Compound C can be prepared using thiazole formation Conditions B followed by Coupling Conditions D. Experimental details for the synthesis of Compound C are as follows:
  • Thioamide 15 can be prepared following the procedure described for the preparation of thioamide 3 using the commercially available N-Cbz-glycinamide as the starting material. Flash chromatography (elution with 2:1 hexanes-EtOAc) provided 4.05 g (75.1%) of a white solid: Rf 0.50 (1: 1 hexanes-EtOAc). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 449 (M+H).
  • Coupling product 18 can be prepared as shown for the preparation of coupling product 6. Flash chromatography (elution with 10:1 CH2Cl2-MeOH) gave 260.7 mg (51.0%) of a pale oil: Rf 0.59 (9:1 CH2CI2 -MeOH).
  • Compounds such as Compound D can be prepared using thiazole formation Conditions A followed by Coupling Conditions C. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 496 (M+H).
  • Compounds such as Compound E can be prepared using thiazole formation Conditions B followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 854 (2M-H).
  • Compounds such as Compound F can be prepared using thiazole/oxazole formation Conditions B, substituting the appropriate keto amide for the bromo ketone and substituting toluene as solvent, followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 412 (M+H).
  • Compounds such as Compound G can be prepared using thiazole formation Conditions B followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 476 (M+H).
  • Compounds such as Compound H can be prepared using thiazole formation Conditions B followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 472 (M+H).
  • Compounds such as Compound I can be prepared using thiazole formation Conditions B followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 550 (M-H).
  • Compounds such as Compound J can be prepared using thiazole formation Conditions B followed by Coupling Conditions D with the appropriate side chain manipulations as shown in the following scheme. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 574 (M+CH3CN).
  • Compounds such as Compound K can be prepared using thiazole formation Conditions A followed by Coupling Conditions D. Compound K was isolated as a 60/40 mixture of diastereomers, presumably at the NHAc stereocenter. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 542 (M+H).
  • thiazoles, oxazoles and imidazoles can be prepared via the conesponding keto amides according to the cyclization conditions described in Gordon, T. D. et al. (Tetrahedron Lett. 1993. 34, 1901) as shown generically below.
  • Compounds such as Compound L can be prepared according to General Method E, followed by Coupling Conditions D. Experimental details for the synthesis of compound L are as follows:
  • Compound L can then be prepared using amine 27 according to Coupling Conditions D Electrospray Mass Spectrum (50/50 acetomt ⁇ le/water + 0.1% ammonium hydroxide) m/z 595 (M+H)
  • Compounds such as Compound M can be prepared using General Method E using the commercially available amino ketone followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0.1% ammonium hydroxide) m/z 476 (M+H).
  • Compounds such as Compound N can be prepared using General Method E followed by Coupling Conditions D. Compound N was isolated as a 60/40 mixture of diastereomers, presumably at the NHAc stereocenter. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 582 (M+H).
  • Compounds such as Compound O can be prepared using General Method E followed by Coupling Conditions D with the appropriate side chain manipulations as shown in the following scheme. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 500 (M+H).
  • Compounds such as Compound P can be prepared using General Method E using the commercially available amino ketone followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 546 (M-H).
  • Compounds such as Compound Q can be prepared using General Method E followed by Coupling Conditions D. Reverse phase HPLC resulted in the separation of two diastereomers, presumably at the NHAc stereocenter. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 566 (M+H).
  • Compounds such as Compound R can be prepared using General Method E followed by Coupling Conditions D with the appropriate side chain manipulations as shown in the following scheme. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 575 (M+H).
  • Compounds such as Compound S can be prepared using General Method E followed by Coupling Conditions D with the appropriate side chain manipulations included according to the following scheme using the aldehyde (30) described for the preparation of compound R. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 603 (M+H).
  • Compounds such as Compound T can be prepared using General Method E followed by Coupling Conditions D similar to the preparation of Compound O with the approp ⁇ ate side chain manipulations as shown in the following scheme. Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0.1% ammonium hydroxide) m/z 485 (M+H).
  • Compounds such as Compound W can be prepared using General Method E followed by Coupling Conditions D using the approp ⁇ ate am o alcohol as desc ⁇ bed m the preparation of Compounds U and R. Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0.1% ammonium hydroxide) m/z 542 (M+H).
  • Compounds such as Compound X can be prepared using General Method E followed by Coupling Conditions D with the approp ⁇ ate side chain manipulations as shown in the following scheme using the intermediate alcohol 29 found in the preparation of Compound R.
  • Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0.1% ammonium hydroxide) m/z 589 (M+H)
  • Compounds such as Compound Y can be prepared using amino alcohol 28, prepared using General Method E as found in the preparation of Compound U, followed by Coupling Conditions D with the appropriate side chain manipulations as shown in the following scheme. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 576 (M+H).
  • Compounds such as Compound Z can be prepared using General Method E followed by Coupling Conditions D along with the appropriate side chain manipulations as shown in the scheme shown for the preparation of Compound S. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 583 (M+H).
  • Compounds such as Compound AA can be prepared using General Method E followed by Coupling Conditions D with the approp ⁇ ate side chain manipulations analogous to those shown for the preparation of Compound L. Electrospray Mass Spectrum (50/50 acetomt ⁇ le/water + 0.1% ammonium hydroxide) m/z 637 (M-H).
  • Compounds such as Compound AB can be prepared using General Method E followed by Coupling Conditions D. Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0 1% ammonium hydroxide) m/z 512 (M+H).
  • Compounds such as Compound AC can be prepared using General Method E followed by Coupling Conditions D using the appropriate ammo alcohol as in the preparation of Compounds U and W. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 542 (M+H).
  • Compounds such as Compound AD can be prepared using General Method E followed by Coupling Conditions D similar to the preparation of Compound O with the approp ⁇ ate side chain manipulations as shown in the following scheme Electrospray Mass Spectrum (50/50 acetonit ⁇ le/water + 0.1% ammonium hydroxide) m/z 466 (M-H)
  • Compounds such as Compound AE can be prepared using General Method E followed by Coupling Conditions D as in the preparation of Compounds U and W, using the appropriate amino alcohol which can be prepared as shown in the scheme below. Electrospray Mass Spectrum (50/50 acetonitrile/water + 0.1% ammonium hydroxide) m/z 582 (M-H).
  • BocHN ' 1. 3 N HCI ⁇ -BuLi, DME 2. Boc-Ala-OSu -78 °C
  • Compounds such as Compound AF can be prepared using General Method E followed by Coupling Conditions D with side chain manipulations as shown for the preparation of
  • oxadiazoles can be prepared via cyclization of the appropriate O-acylamidoxime according to the method described in Borg et al. (J. Org. Chem. 1995, 60, 3112).
  • the required amidoxime can be prepared via the conesponding nitrile as shown below.
  • the resulting amine can then be further elaborated according to Coupling Conditions D.
  • Boc-Glu(OBn)-OSu 500 mg, 1.15 mmol was dissolved in 7 mL of ethylene glycol dimethyl ether along with 1.15 mmol of amidoxime 31. The resulting reaction mixture was stined at rt for 15 h. It was then concentrated under reduced pressure.
  • Compounds such as Compounds BA-BH can be prepared according to General Method F as exemplified above for the preparation of Compound BC.
  • Compounds such as Compounds CA-FBG and GA-GC can be prepared according to General Method F followed by Coupling Conditions D as exemplified below by the preparation of Compound CD.
  • Amidoxime 36 was prepared using the same procedure that was outlined for compound BC substituting isovaleronitrile. Amidoxime 36 (150 mg, 1.15 mmol) was then dissolved in 2 mL of DMF and 6 mL of CH 2 C1 along with Boc-Gln-OH (237 mg, 0.958 mmol). HOBT (176 mg, 1.15 mmol) and EDC-HCI (220 mg, 1.15 mmol) were added, followed by DIEA (0.25 mL, 1.44 mmol). The resulting reaction mixture was stined at rt for 8 h. It
  • Compounds such as Compounds CA-FBG can be prepared according to General Method G as exemplified above for the preparation of Compound CD.

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US6780609B1 (en) 1998-10-23 2004-08-24 Genome Therapeutics Corporation High bone mass gene of 1.1q13.3
US6770461B1 (en) 1998-10-23 2004-08-03 Genome Therapeutics Corporation High bone mass gene of 11q13.3
CA2345459A1 (en) * 1998-11-12 2000-05-18 Regine Bohacek Bicyclic signal transduction inhibitors, compositions containing them & uses thereof
CA2366932C (en) 1999-04-15 2009-08-25 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
JP2003518129A (ja) 1999-12-22 2003-06-03 メルク フロスト カナダ アンド カンパニー タンパク質チロシンホスファターゼ１ｂ（ｐｔｐ−１ｂ）のインヒビターとなるホスホン酸誘導体
WO2001046203A1 (en) 1999-12-22 2001-06-28 Merck Frosst Canada & Co. Phosphonic acid biaryl derivatives as inhibitors of protein tyrosine phosphatase 1b (ptp-1b)
WO2001046206A1 (en) * 1999-12-22 2001-06-28 Merck Frosst Canada & Co. Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1b (ptp-1b)
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