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WO1997036875A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase Download PDF

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Publication number
WO1997036875A1
WO1997036875A1 PCT/US1997/005383 US9705383W WO9736875A1 WO 1997036875 A1 WO1997036875 A1 WO 1997036875A1 US 9705383 W US9705383 W US 9705383W WO 9736875 A1 WO9736875 A1 WO 9736875A1
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Prior art keywords
substituted
alkyl
unsubstituted
cyanobenzyl
imidazole
Prior art date
Application number
PCT/US1997/005383
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English (en)
Inventor
Neville J. Anthony
Gerald E. Stokker
Robert P. Gomez
Kelly M. Solinsky
John S. Wai
Theresa M. Williams
Steven D. Young
John H. Hutchinson
Wasyl Halczenko
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Priority claimed from GBGB9617257.2A external-priority patent/GB9617257D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US09/155,663 priority Critical patent/US6080870A/en
Priority to JP9535553A priority patent/JP2000504024A/ja
Priority to AU24325/97A priority patent/AU716123B2/en
Priority to EP97920031A priority patent/EP0891333A1/fr
Publication of WO1997036875A1 publication Critical patent/WO1997036875A1/fr

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    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/57—Nitriles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—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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    • C07D417/02—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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP- bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem.
  • Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
  • the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
  • the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310.583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational farnesyl- ation.
  • farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown stmcture and function in addition to those listed above.
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described.
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851 , University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med.
  • CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity.
  • transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-1 12930).
  • the present invention comprises novel biaryl-containing compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions
  • the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula A:
  • R 1a and R 1b are independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 2 , R 3 , R 4 and R 5 are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 8 is independently selected from:
  • heterocycleC 3 -C 10 cycloalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NH-, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 10 OC(O)NH-;
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-,
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, -CH 2 N(R 10 ) 2 , benzyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • W is a heterocycle
  • n is independently 0, 1, 2, 3 or 4;
  • p is independently 0, 1, 2, 3 or 4;
  • q 0, 1, 2 or 3;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • R 1a is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2 ;
  • R 2 , R 3 , R 4 and R 5 are independently selected from:
  • substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 12 O-, R 11 S(O) m -, R 11 S(O) m NR 10 -, (R 10 ) 2 NS(O) m -,
  • -CH CH-CH 2 -, -(CH 2 ) 4 - and -(CH 2 ) 3 -; provided that when R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d or R 6e to the phenyl ring is through a substitutable heterocycle ring carbon;
  • R 7 is selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 8 is independently selected from:
  • R 9 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, -CH 2 N(R 1 0 ) 2 , benzyl and aryl;
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl,
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
  • n is independently 0, 1, 2, 3 or 4;
  • q 0, 1, 2 or 3;
  • p is independently 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • Rla is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 ,For C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2;
  • R 2 and R 3 are independently selected from:
  • substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 11 S(O) m NR 10 -, (R 10 ) 2 NS(O) m -, R 13 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -; any two of R 6a , R 6b , R 6c , R 6d and R 6e on adjacent carbon atoms are combined to form
  • R 8 is independently selected from:
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, -CH 2 N(R 10 ) 2 , benzyl and aryl;
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl,
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • n 0, 1 or 2;
  • n is independently 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
  • R 1a is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2 ;
  • R 2 and R 3 are independently selected from:
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN(R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
  • substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 11 S(O) m NR 10 -, (R 10 ) 2 NS(O) m -,
  • R 8 is independently selected from:
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • Rl3 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, -CH 2 N(R 10 ) 2 , benzyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • n 0, 1 or 2;
  • n is independently 0, 1, 2, 3 or 4;
  • p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond
  • r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
  • R 1a is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 3 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ;
  • R 6a , R 6b ; R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 2 , R 6a , R 6b , R 6c , R 6d or R 6e is
  • R 8 is independently selected from:
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aralkyl, C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • a 1 is selected from: a bond, -C(O)-, O, -N(R 1 0 )-, or S(O) m ;
  • n is 0 or 1 ; provided that n is not 0 if A 1 is a bond, O,
  • n 0, 1 or 2;
  • p 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
  • R 1a is independently selected from: hydrogen, R 10 O-, -N(R 10 ) 2 , F, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • R 2 is selected from:
  • R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 3 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ;
  • R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 8 is independently selected from:
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • n 0 or 1
  • n 0, 1 or 2;
  • p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
  • R 1a is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • R 2 is selected from:
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
  • R 3 is selected from H, halogen, CH 3 and CF 3 ;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;or any two of R 6a .
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • n 0, 1 or 2;
  • p 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • R 1a is independently selected from: hydrogen, R 10 O-, -N(R 10 ) 2 , F, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • R 2 is selected from:
  • R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and
  • R 3 is selected from H, halogen, CH 3 and CF 3 ;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • a 1 is selected from: a bond, -C(O)-, O, -N(R 1 0 )-, or S(O) m ; m is 0, 1 or 2; and
  • n 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, R 1 a , R 1b etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
  • Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro- naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to
  • heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable stmcture. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
  • heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
  • the substituted C 1 -8 alkyl, substituted C 3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
  • substituted aryl substituted heterocycle
  • substituted cycloalkyl are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6 alkyl)S(O) m -, (C 1 -C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, (C 1 -C 6
  • Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
  • fused ring moieties may be further substituted by the remaining R 6a , R 6b , R 6c , R 6d and/or R 6e as defined
  • R 1a and R 1b are independently selected from: hydrogen, R 11 C(O)O-, -N(R 10 ) 2 , R 10 C(O)NR 10 -, R 10 O- or unsubstituted or substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10 ) 2 , R 10 O- and R 10 C(O)NR 10 -.
  • R 2 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 3 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C 1 -C 6 alkyl.
  • R 4 and R 5 are hydrogen.
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • R 12 O-, R 11 S(O) m -, CN, NO 2 , R 10 C(O)- or -N(R 10 ) 2 , c) unsubstituted C 1 -C 6 alkyl;
  • R 8 is independently selected from:
  • R 9 is hydrogen, halogen, CF 3 or methyl.
  • R 1 0 is selected from H, C 1 -C 6 alkyl and benzyl.
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 1 0 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 1 0 )- and -N(R 1 0 )S(O) 2 -.
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrohdinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • n and r are independently 0, 1 , or 2.
  • s is 0.
  • t is 1.
  • any substituent or variable e.g., R 1 a , R 9 , n, etc.
  • -N(R 1 0 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • Substituents R 2 , R 6 and R 8 as shown in the Schemes, represent the substituents R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d and R 8 ; although only one such R 2 , R 6 or R 8 is present in the intermediates and products of the schemes, it is
  • Schemes 1- 13 illustrate synthesis of the instant biaryl compound which incorporate a preferred benzylimidazolyl sidechain.
  • a biaryl intermediate that is not commercially available may be synthesized by methods known in the art.
  • a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4-bromobenzoic acid, to provide the biaryl carboxylic acid II.
  • the acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
  • Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1.
  • Scheme 2 illustrates the analogous series of biaryl alcohol forming reactions starting with the halogenated biarylaldehyde.
  • Scheme 3 illustrates the reaction wherein the "terminal" phenyl moiety is employed in the Suzuki coupling as the halogenated reactant.
  • Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 4.
  • Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biaryl component of the instant compounds, as shown in Scheme 5.
  • a suitably substituted zinc bromide adduct may be coupled to a suitably substituted aryl halide in the presence of nickel (II) to provide the biheteroaryl VII.
  • the aryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
  • Scheme 6 illustrates the preparation of a suitably substituted biphenylmethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
  • biaryl intermediates having a suitably substituted alkyl moiety on the carbon adjacent to the eventual point of attachment to the rest of the instant compounds is illustrated in Scheme 6a.
  • a suitably substituted biaryl carboxylic acid is first converted to the amide and then the phenyl lithium is prepared and reacted in situ with a suitably substituted alkanal to provide the hydroxyalkane side- chain.
  • the amide is then converted sequentially to the hydroxymethyl- biaryl Ilia or bromomethylbiaryl intermediates which may then be utilized in reactions that have been previously described or will be described below.
  • a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
  • Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
  • Scheme 8 illustrates synthesis of an instant compound wherein a non-hydrogen R 9b is incorporated in the instant compound.
  • a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
  • Scheme 9 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker.
  • the 4-aminoaIkylimidazole XII wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII.
  • the amine XIII may then react under conditions well known in the art with various activated biaryl moieties to provide the instant compounds shown.
  • N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
  • the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
  • Scheme 1 1 illustrates an analogous series of reactions wherein the (CR 1b 2 ) p X(CR 1 b 2 ) p linker of the instant compounds is oxygen.
  • a suitably substituted haloaryl alcohol such as
  • Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl.
  • the intermediate XVII can then be coupled to a second aryl moiety by Suzuki chemistry to provide the instant compound.
  • a 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n linker is a substituted methylene may be synthesized by the methods shown in Scheme 12.
  • the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX.
  • Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1 ) provides the instant compound XX. If other R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
  • Grignard chemistry may also be employed to form a substituted alkyl linker between the biaryl and the preferred W
  • biaryl Grignard reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI.
  • Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII.
  • the final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
  • biaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXX.
  • organometallic reagents such as Grignard reagents
  • the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXII (Scheme 16), or tertiary amines.
  • Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiaryl such as XXXIII
  • the biaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 18.
  • R' is an aryl group
  • XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI.
  • the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1 ), neu, scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and the farnesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combina tion with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1 , restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
  • Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the
  • compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • pharmacologically acceptable carriers e.g., saline
  • the solutions may be introduced into a patient's blood-stream by local bolus injection.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-protein transferase
  • mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.
  • inhibitors of FPTase absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step A 1 -Trityl-4-(4-cyanobenzyl)-imidazole
  • Step B 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole
  • Step B 1-(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole
  • Step A 1 -(4-Cyanobenzyl)-5-aminoethylimidazole
  • N G -pivaloyloxymethyl-Na-phthaloylhistaminel (4.55 g, 12.8 mmol) and a-bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL) and heated at 55°C for 4 hours, cooled to room temperature, filtered and the imidazolium salt retained as a white solid .
  • the filtrate was evaporated in vacuo to a volume of 30 mL and heated at 55°C for 16 hours. The solution was cooled and the white solid collected by filtration. The solids were combined, and dissolved in ethanol (50 mL).
  • Step B 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole
  • Step B 4-(2'-trifluoromethylphenyl)benzyIalcohol
  • Step C 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4- cyanobenzyl)imidazole hydrochloride salt
  • the 4-biphenylethanol was prepared using the protocol described in example 5, step B and 4-biphenylacetic acid.
  • Step B 4-(2'-Bromophenyl)benzyl alcohol
  • Step C 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)- imidazole hydrochloride salt
  • Step C 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)- imidazole hydrobromide salt.
  • the imidazole was isolated by chromatography (Silica gel, 2-3% MeOH in CH2C12), and converted to the HCl salt by treatment with HCl gas in EtOAc and evaporation of the solvent in vacuo.
  • Step B 1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4- cyanobenzyl) imidazole hydrochloride salt
  • Step C 1 -Trityl-4-(4-cyanobenzyl)5-methylimidazole
  • Step D 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4- cyanobenzyl)-4-methylimidazole hydrochloride salt
  • Step B 4-(4-Cyanophenyloxy)-1-trityl-imidazole
  • Step C 1 -(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole
  • the hydrochloride salt was obtained by treatment of a solution of the imidazole in acetonitrile with aq. HCl and evaporation of the solvents in vacuo.
  • the title compound was prepared as white solid using the protocol described in example 17 - step B, using 4-(4-bromophenyloxy) imidazole.
  • Step C 5-(4-Bromophenyloxy)- 1 -(4-cyanobenzyl)-imidazole
  • the title compound was prepared as a white solid using the protocol described in example 5, step C using 4-cyanobenzyl alcohol and 4-(4-bromophenyloxy)-l -trityl-imidazole.
  • the title compound was purified by chromatography (Silica gel 3:7 acetone in CHCl 3 ).
  • the aqueous extract was separated, and extracted with CH 2 CI 2 .
  • the organic extracts were combined, dried (Na2SO 4 , filtered and evaporated in vacuo.
  • the residue was purified by chromatography (Silica gel, eluting with 3:7 acetone in CHCl 3 , and the trifluoroacate salt obtained by treatment of a solution of the imidazole in acetonitrile with aqueous TFA and evaporation of the solvents in vacuo.
  • Step B 4-(3',5'-Dichlorophenyl) benzyl bromide
  • Step C 1 -Trityl-4-(4-(3',5'-dichloro)-biphenylmethyl- imidazole
  • Step D 5-(4-(3'.5'-Dichloro)-biphenylmethyl)-1-(4-cyanobenzyl) imidazole hydrochloride salt
  • Step A 1 -Trityl-4-(1 -(R,S)-hydroxy-1-(4-cyanophenyl)
  • Step E 1 -(4-Cyanobenzyl)-5-imidazole carboxaldehyde
  • Step F 1-(4-Cyanobenzyl)-5-(1 -hydroxy-1-(4-biphenyl)-methyl imidazole
  • a Grignard reagent freshly prepared from 4-bromo- biphenyl (116 mg, 0.500 mmol) and magnesium turnings ( 18 mg, 0.73 mmol) in dry THF (0.50 mL) was added to a dry Argon-purged 3mL flask containing the 1-(4-cyanobenzyl)-5 -imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.2 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. aq.
  • a Grignard reagent freshly prepared from 4-bromo-2- fluorobiphenyl] (251 mg, 1 mmol) and magnesium turnings (36 mg, 1.45 mmol) in dry THF (1 mL) was added to a dry argon-purged 5mL flask containing 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (212 mg, 1 mmol) in dry THF (0.40 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. aq. NH 4 CI (10 mL) and distributed between EtOAc (100 mL) and H 2 O (50 mL). The organic phase was evaporated and the residue was chromatographed (Silica gel, 5% MeOH in CHCl 3 ) to afford the title compound.
  • a Grignard reagent freshly prepared from 3-biphenyl- bromide (116 mg, 0.50 mmol) and magnesium turnings (18 mg, 0.73 mmol) in dry THF (0.5 mL) was added to a dry Argon-purged 3 mL flask containing 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.20 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. NH 4 CI (5 mL) and distributed between EtOAc (50 mL) and H 2 O (50 mL). The organic phase was evaporated and the residue chromatographed (Silica gel, 5% MeOH in CHCl 3 ) to afford the title compound.
  • Step 2 Preparation of 1 -triphenylmethyl-4-(acetoxymethyl)-imidazole
  • the reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt.
  • the filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60°C for two hours, cooled to room temperature, and filtered again.
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60°C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60°C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid (50.4 g, 89% purity by HPLC) which was used in the next step without further purification.
  • Step 4 Preparation of 1 -(4-cvanobenzyl)-5-(hydroxymethyl)-imidazole

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Abstract

L'invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase) et la farnésylation de la protéine oncogène Ras. Elle concerne également des compositions chimiothérapiques contenant ces composés et des procédés permettant d'inhiber la farnésyl-protéine transférase, ainsi que la farnésylation de la protéine oncogène Ras.
PCT/US1997/005383 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase WO1997036875A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US09/155,663 US6080870A (en) 1996-04-03 1997-04-01 Biaryl substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
JP9535553A JP2000504024A (ja) 1996-04-03 1997-04-01 ファルネシル―タンパク質トランスフェラーゼ阻害剤
AU24325/97A AU716123B2 (en) 1996-04-03 1997-04-01 Inhibitors of farnesyl-protein transferase
EP97920031A EP0891333A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US1459296P 1996-04-03 1996-04-03
US60/014,592 1996-04-03
GBGB9613462.2A GB9613462D0 (en) 1996-06-27 1996-06-27 Inhibitors of farnesyl-protein transferase
GB9613462.2 1996-06-27
US2258296P 1996-07-24 1996-07-24
US60/022,582 1996-07-24
GBGB9617257.2A GB9617257D0 (en) 1996-08-16 1996-08-16 Inhibitors of farnesyl-protein transferase
GB9617257.2 1996-08-16

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Cited By (12)

* Cited by examiner, † Cited by third party
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WO1999010317A1 (fr) * 1997-08-26 1999-03-04 Kumiai Chemical Industry Co., Ltd. Derives d'acide biarylalkylenecarbamique et bactericides a usage horticole et agricole
WO2001030764A1 (fr) * 1999-10-22 2001-05-03 Takeda Chemical Industries, Ltd. Alcools de phenyl-1-(1h-imidazol-4-yl) substitues en position 1, procede de preparation et utilisation de ces derniers
JP2001187784A (ja) * 1999-10-22 2001-07-10 Takeda Chem Ind Ltd １−置換フェニル−１−（１ｈ−イミダゾール−４−イル）アルコール類、その製造法および用途
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6984643B2 (en) 2002-07-02 2006-01-10 Roche Palo Alto Llc 2,5-substituted pyrimidine derivatives-CCR-3 receptor antagonists
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
WO2008077625A1 (fr) * 2006-12-22 2008-07-03 Laboratorios Del Dr. Esteve, S.A. Dérivés d'éthylamino-phényle à substitution hétérocyclyle, leur préparation et leur utilisation en tant que médicaments
EP2308852A1 (fr) 2005-08-21 2011-04-13 Abbott GmbH & Co. KG Composés 5-cycle-heteroaromates et leur utilisation en tant que partenaires de liaison des récepteurs 5-HT5
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity

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JP4750286B2 (ja) * 2001-01-10 2011-08-17 関東電化工業株式会社 反応活性な基を有する新規なビフェニル化合物の製造方法
BRPI0612925A2 (pt) * 2005-04-27 2010-12-07 Univ Florida Res Foudation Inc uso de um composto, composição farmacêutica e kit
JP5296109B2 (ja) * 2011-01-07 2013-09-25 関東電化工業株式会社 反応活性な基を有する新規なビフェニル化合物

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DE3145928A1 (de) * 1981-11-20 1983-06-01 Basf Ag, 6700 Ludwigshafen Substituierte benzylimidazoliumsalzue und diese enthaltende mikrozide
US5126342A (en) * 1990-10-01 1992-06-30 Merck & Co., Inc. Imidazole angiotensin ii antagonists incorporating acidic functional groups
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US4207324A (en) * 1978-05-15 1980-06-10 Takeda Chemical Industries, Ltd. 1,2-Di-Substituted-4-haloimidazole-5-acetic acid derivatives and their use
DE3145928A1 (de) * 1981-11-20 1983-06-01 Basf Ag, 6700 Ludwigshafen Substituierte benzylimidazoliumsalzue und diese enthaltende mikrozide
US5126342A (en) * 1990-10-01 1992-06-30 Merck & Co., Inc. Imidazole angiotensin ii antagonists incorporating acidic functional groups
US5559141A (en) * 1991-06-18 1996-09-24 Orion-Yhtyma Oy Selective aromatase inhibiting 4(5)-imidazoles
US5538987A (en) * 1992-07-28 1996-07-23 Istituto Luso Farmaco D'italia S.P.A. Imidazole ethers having a II antagonist activity

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999010317A1 (fr) * 1997-08-26 1999-03-04 Kumiai Chemical Industry Co., Ltd. Derives d'acide biarylalkylenecarbamique et bactericides a usage horticole et agricole
US8716323B2 (en) 1999-04-15 2014-05-06 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US9382219B2 (en) 1999-04-15 2016-07-05 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6979694B2 (en) 1999-04-15 2005-12-27 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8993567B2 (en) 1999-04-15 2015-03-31 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7091223B2 (en) 1999-04-15 2006-08-15 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7153856B2 (en) 1999-04-15 2006-12-26 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7189854B2 (en) 1999-04-15 2007-03-13 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2001030764A1 (fr) * 1999-10-22 2001-05-03 Takeda Chemical Industries, Ltd. Alcools de phenyl-1-(1h-imidazol-4-yl) substitues en position 1, procede de preparation et utilisation de ces derniers
JP2001187784A (ja) * 1999-10-22 2001-07-10 Takeda Chem Ind Ltd １−置換フェニル−１−（１ｈ−イミダゾール−４−イル）アルコール類、その製造法および用途
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US7323570B2 (en) 2000-11-30 2008-01-29 Abbott Laboratories Farnesyltransferase inhibitors
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
US6984643B2 (en) 2002-07-02 2006-01-10 Roche Palo Alto Llc 2,5-substituted pyrimidine derivatives-CCR-3 receptor antagonists
EP2308852A1 (fr) 2005-08-21 2011-04-13 Abbott GmbH & Co. KG Composés 5-cycle-heteroaromates et leur utilisation en tant que partenaires de liaison des récepteurs 5-HT5
US8921406B2 (en) 2005-08-21 2014-12-30 AbbVie Deutschland GmbH & Co. KG 5-ring heteroaromatic compounds and their use as binding partners for 5-HT5 receptors
WO2008077625A1 (fr) * 2006-12-22 2008-07-03 Laboratorios Del Dr. Esteve, S.A. Dérivés d'éthylamino-phényle à substitution hétérocyclyle, leur préparation et leur utilisation en tant que médicaments
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds

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AU2432597A (en) 1997-10-22
AU716123B2 (en) 2000-02-17
JP2000504024A (ja) 2000-04-04
EP0891333A1 (fr) 1999-01-20

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