WO1997036881A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase Download PDF

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Publication number
WO1997036881A1
WO1997036881A1 PCT/US1997/005514 US9705514W WO9736881A1 WO 1997036881 A1 WO1997036881 A1 WO 1997036881A1 US 9705514 W US9705514 W US 9705514W WO 9736881 A1 WO9736881 A1 WO 9736881A1
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substituted
alkyl
unsubstituted
aryl
hydrogen
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PCT/US1997/005514
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English (en)
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Neville J. Anthony
Robert P. Gomez
Steven D. Young
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Merck & Co., Inc.
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Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Priority claimed from GBGB9617278.8A external-priority patent/GB9617278D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9535590A priority Critical patent/JP2000509371A/ja
Priority to AU26058/97A priority patent/AU716381B2/en
Priority to EP97917830A priority patent/EP0891339A1/fr
Publication of WO1997036881A1 publication Critical patent/WO1997036881A1/fr

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    • 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
    • C07D233/56—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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/02—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
    • C—CHEMISTRY; METALLURGY
    • 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.
  • 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
  • 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 570:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 1 5 or C 20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational farnesyl- ation.
  • famesylated 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 famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
  • Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol Chem., 265:14701-14704 (1990); Schafer et al, Science, 249:1133-1 139 (1990); Manne et al, Proc. Natl Acad. Sci USA, 87:7541-7545 (1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of famesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase famesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • Bisubstrate inhibitors and inhibitors of famesyl-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 prenyl- ation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent
  • 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 arylheteroaryl-containing compounds which inhibit the famesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula A:
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R 1 and R 2 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 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 12 O-, R 1 1 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 1 1 OC(O)-NR 10 .;
  • R 6a , R 6b , R 6c , R6d and R 6e are independently selected from:
  • R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c , R 6d or R 6e to Q is through a substitutable ring carbon;
  • R7 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:
  • cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F,
  • R 10 O- R 1 1 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:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • 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
  • V is selected from: a) hydrogen
  • 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
  • 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.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
  • R 1 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 2 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 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 1 2 O-, R 1 1 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 1 1 OC(O)-NR 10 -;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • -CH CH-CH 2 -, -(CH 2 ) 4 - and -(CH 2 ) 3 -;
  • R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c , R 6d or R 6e to Q is through a substitutable 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 selected from:
  • R 10 perfluoroalkyl, F, Cl, R 10 O-, R 1 1 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 1 1 OC(O)NR 10 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • 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 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, imidazohnyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
  • X isoquinolinyl
  • n 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.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
  • R 1 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 2 is independently selected from:
  • R 3 and R 4 are independently selected from:
  • 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,
  • -CH CH-CH 2 -, -(CH 2 ) 4 - and -(CH 2 ) 3 -;
  • R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c , R 6d or R 6e to Q is through a substitutable ring carbon;
  • 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, benzyl, 2,2,2-trifluoroethyl 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 heteroaryl, C 1 -C 6 perfluoroalkyl,
  • 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 is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • X is not -C(O)NR 10 -, -NR 10 - or O; m is 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.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
  • R 1 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 2 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 3 and R 4 are independently selected from: a) hydrogen,
  • R 10 2 N-C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 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 1 1 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 1 1 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 1 1 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 1 1 OC(O)-NR 10 -; provided that when R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c , R 6d or R 6e to Q
  • 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, benzyl,
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • V is selected from: a) hydrogen
  • 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;
  • X is not -C(O)NR 10 -, -NR 10 - or O; m is 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.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula D:
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • R 10 O-, or -N(R 10 ) 2;
  • R 3 is 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 1 1 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 1 1 OC(O)-NR 10 -; R 4 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:
  • R 6a , R 6b , R 6c , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c ,
  • R 6d or R 6e to Q is through a substitutable ring carbon
  • R 8 is independently selected from:
  • aryl, substituted aryl, heterocycle C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and
  • 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, benzyl,
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • a 1 is selected from: a bond, -C(O)-, O, -N(R 10 )-, or S(O) m ;
  • n 0, 1 or 2;
  • p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula E:
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R 1 is independently selected from: hydrogen, R 10 O-, -N(R 10 ) 2 , F,
  • R 2 is independently selected from:
  • R 3 is 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 1 1 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 1 1 OC(O)-NR 10 -;
  • R 4 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 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 1 2 O-, R 1 1 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 1 1 OC(O)-NR 10 -;
  • R 6a , R 6b , R 6C , R 6d or R 6e is unsubstituted or substituted heterocycle, attachment of R 6a , R 6b , R 6c , R 6d or R 6e to Q is through a substitutable ring carbon;
  • R 8 is independently selected from: a) hydrogen
  • 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, benzyl,
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • X is not -C(O)NR 10 -, -NR 10 - or O; n is 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
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • R 3 is 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 1 2 O-, R 1 1 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 1 1 OC(O)-NR 10 -;
  • R 4 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:
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl,
  • p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • a is C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that at least one of b, c, d or e is independently N, NH, O or S; R 1 is independently selected from: hydrogen, R 10 O-, -N(R 10 ) 2 , F,
  • R 2 is independently selected from:
  • R 3 is 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 l 2 0-, R 1 1 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)-, N3, -N(R 10 ) 2 , and R 1 1 OC(O)-NR 10 -;
  • R 4 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:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • 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 heteroaryl, C 1 -C 6 perfluoroalkyl,
  • a l is selected from: a bond, -C(O)-, O, -N(R 10 )-, or S(O) m ; m is 0, 1 or 2; and
  • n 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • the preferred compounds of this invention are as follows:
  • 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. Also, 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, famesyl, 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 aroyl and aralkyl, 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, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to
  • 1 1 -membered bicyclic 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.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazohnyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,
  • pyridazinyl pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
  • 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,
  • the substituted group intended to mean a substituted C 1 -8 alkyl, substituted C 2-8 alkenyl, substituted C 2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R 3 , R 4 , R 5 and R 6a-e are selected.
  • the substituted C 1 -8 alkyl, substituted C 3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl- sulfonyl 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
  • the moiety designated by the following structure represents an aromatic 5-membered heterocyclic ring and includes the following ring systems:
  • aromatic 5-membered heterocyclic ring is selected from:
  • Lines drawn into the ring systems from substituents means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
  • the substituent illustrated by the structure is a simplified representation of a phenyl ring having five (5)
  • fused ring moieties may be further substituted by the remaining R 6a , R6b, R 6c , R 6d and/or R 6e as defined
  • R 1 and R 2 are independently selected from: hydrogen, R 1 1 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 !0C(O)NR 10 -.
  • R 3 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 1 1 OC(O)-NR 10 -.
  • R 4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C 1 -C 6 alkyl.
  • R 5 is hydrogen
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
  • R 12 O-, R 1 1 S(O) m -, CN, NO 2 , R 10 C(O)- or -N(R 10 ) 2 , c) unsubstituted C 1 -C 6 alkyl;
  • -CH CH-CH 2 -, -(CH 2 ) 4 - and -(CH 2 ) 3 -.
  • R 8 is independently selected from: a) hydrogen, and
  • R 9 is hydrogen, halogen, CF 3 or methyl.
  • R 10 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 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 )- and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • W is selected from imidazohnyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, 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 10 ) 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 -25, 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 3 , R 6 and R 8 as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d , R 6e and R 8 ; although only one such R 6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
  • Schemes 1 - 15 illustrate synthesis of the instant arylhetero- aryl compound which incorporate a preferred benzylimidazolyl side- chain.
  • a arylheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art.
  • a phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
  • Scheme 2 illustrates the analogous s eries of arylheteroaryl alcohol forming reactions starting with the halogenated heteroarylaldehyde.
  • 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 arylheteroaryl component of the instant compounds, as shown in Scheme 5.
  • a zinc bromide adduct such as phenyl zinc bromide, may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the
  • the heteroaryl halide, phenyl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
  • the sequence of coupling reactions may be modified such that the aryl-heteroaryl bond is formed last.
  • a suitably substituted imidazole may first be alkylated with a heteroarylmethyl halide to provide intermediate VII.
  • Intermediate VII can then undergo Suzuki type coupling to a suitably substituted heteroaryl boronic acid.
  • Scheme 7 illustrates the synthesis of a thiazole containing instant compound from the acyclic precursors. Further substitution on the thiazole ring may be accomplished as illustrated in Scheme 7a.
  • Schemes 8 and 9 illustrate synthetic strategies that utilize the nucleophilicity of an imidazolyl moiety in the arylheteroaryl.
  • the commercially available 4-phenylimidazole may be reacted with a suitably substituted imidazolyl methyl halide to provide the instant compound VIII. If a particular substituted aryl imidazole is not commercially available, it may be synthesized as illustrated in Scheme 9.
  • Scheme 10 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 1 1 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the arylheteroaryl via an alkyl amino, sulfonamide or amide linker.
  • the 4-aminoalkylimidazole 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 arylheteroaryl moieties to provide the instant compounds shown.
  • a 1 (CR 1 2 ) n A 2 (CR 1 2 ) n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 12.
  • N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
  • the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
  • Scheme 13 illustrates an analogous series of reactions wherein the (CR 2 2 ) p X(CR 2 2 ) p linker of the instant compounds is oxygen.
  • a suitably substituted haloheteroaryl alcohol such as 4-bromo-2-thienol
  • methyl N-(cyano)methanimidate is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI.
  • 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 suitably substituted phenyl boronic acid by Suzuki chemistry to provide the instant compound.
  • a bishalogenated five membered heteroaryl such as 2,4-dibromothiophene
  • a suitably substituted imidazolyl aldehyde and acteyla- tion may undergo metal halogen exchange followed by reaction with a suitably substituted imidazolyl aldehyde and acteyla- tion to form a regioisomeric mixture of the acetyl intermediates.
  • the halogenated regioisomeric mixture may be chromatographically separated at this stage, if convenient.
  • Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized can be coupled with a variety of aldehydes, as shown in Scheme 16.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid.
  • Metal halogen exchange chemistry (Scheme 15) may be employed when manipulating the aldehydes.
  • Grignard chemistry may be utilized, as shown in Scheme 16.
  • Suzuki coupling provides, for example, the pyrrole containing
  • biheteroaryl XXI Reaction of the intermediate XXI with a Grignard reagent provides the N-pyrrylmagnesium derivative XXIa, which is then reacted with an aldehyde to provide the C-alkylated instant compound XXII.
  • the product XXII 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 XXIIa.
  • the final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • Scheme 17 illustrates the use of in situ formation of a lithium anion of a suitably substituted N-alkyl pyrrole to provide the C-alkylated compound of the instant invention.
  • the arylheteroaryl subunit is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 18, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 18, 19).
  • 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.
  • 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 19), or tertiary amines.
  • the Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 20). Treating XXVIII with 1 ,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIV .
  • a nucleophile such as a thiol
  • arylheteroaryl subunit 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 21.
  • 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.,
  • NF-1 neurofibromin
  • neu neu
  • scr abl
  • lck lck
  • fyn neurofibromin
  • 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 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 combination 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. If formulated as a fixed dose, such combination
  • 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 famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • the chemical content of the assay mixtures may be determined by well known immuno- logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective 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
  • 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 famesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl 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 B 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester
  • Step D 5-[1 -(4-Cyanobenzyl)-1H-imidazolyl]ethanol
  • Step F 1- ⁇ [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl ⁇ -4- phenyl-imidazole bis hydrochloride salt
  • Step A 1 -Triphenylmethyl-4-(hydroxymethyl)imidazole
  • Step A The alcohol from Step A (260 mmol, prepared above) was suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCl solution, sat. aq. NaHCO 3 , solution, and brine. The organic extracts were dried, (Na 2 SO 4 ), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction. Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide
  • Step D 1-(4-Cyanobenzyl)-5-(hvdroxymethyl)imidazol
  • Step C To a solution of the acetate from Step C (50.4 g, 150 mmol) in 3: 1 THF/water (1.5 L) at 0 °C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After 1 hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO 3 and brine. The solution was then dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
  • Step E 1 -(4-Cyanobenzyl)-5-(chloromethyl)imidazole
  • Step F 1- ⁇ [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl ⁇ -4- phenyl imidazole bis hydrochloride salt
  • Step B 1- ⁇ [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl ⁇ -4-(2- methyl)phenyl)imidazole bis hydrochloride salt
  • Step B 1 -(3-Phenyl-5-isoxazolylmethyl)-5-(4- cyanobenzyl)imidazole hydrochloride salt
  • Step A 4-[5-(Aminocarbonylmethyl)imidazol-1 - ylmethyl]benzonitrile
  • Step B 1-(4-Cyanobenzyl)-1H-imidazol-5-yl]aminothio- carbonylmethyl
  • Step C 1-(4-Cyanobenzyl)-5-(4-phenyl-thiazol-2- ylmethyl)imidazole hydrochloride salt
  • Step B 1 -(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2- ylmethy l)imidazole hydrobromide salt
  • Step B 1 -(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2- ylmethyl)imidazole hydrochloride salt
  • the minor component was isolated: (3- ⁇ 4-[4-(3-chlorophenyl)-thiazol- 2-yl]-3-H-imidazol-4-yl)acetonitrile, hydrochloride.
  • Step A 1 -o-Tolyl-propan-1-one
  • Step B 2-Bromo- 1 -o-tolyl-propan- 1 -one
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine- N'-(2-e thane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-famesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [ 3 H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorpora- tion of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the cell line used in this assay is a v-ras line derived from either Rat1 or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717. ( 1991 ). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %).
  • the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine semm and 400 mCi[ 35 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the ly sates cleared by centrifugation at 100,000 x g for 45 min.
  • 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 m
  • the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfamesylated ras proteins are compared to IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appro- priate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Abstract

La présente invention se rapporte à des composés inhibant la farnésyl-protéine transférase (FTase) et à la farnésylation de la protéine oncogène Ras. L'invention se rapporte également à des compositions chimiothérapeutiques contenant ces composés et à des procédés d'inhibition de la farnésyl-protéine transférase et de la farnésylation de la protéine oncogène Ras.
PCT/US1997/005514 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase WO1997036881A1 (fr)

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JP9535590A JP2000509371A (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
AU26058/97A AU716381B2 (en) 1996-04-03 1997-04-01 Inhibitors of farnesyl-protein transferase
EP97917830A EP0891339A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase

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US1459296P 1996-04-03 1996-04-03
US60/014,592 1996-04-03
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GBGB9613462.2A GB9613462D0 (en) 1996-06-27 1996-06-27 Inhibitors of farnesyl-protein transferase
US2234096P 1996-07-24 1996-07-24
US60/022,340 1996-07-24
GBGB9617278.8A GB9617278D0 (en) 1996-08-16 1996-08-16 Inhibitors of farnesyl-protein transferase
GB9617278.8 1996-08-16

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WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6942836B2 (en) 2001-10-16 2005-09-13 Applera Corporation System for filling substrate chambers with liquid
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
DE102008057344A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057364A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057343A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
DE102009041241A1 (de) 2009-09-11 2011-08-04 Bayer Schering Pharma Aktiengesellschaft, 13353 Substituierte Aryl-Verbindungen und ihre Verwendung
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
DE102009041242A1 (de) 2009-09-11 2011-12-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8686007B2 (en) 2011-04-22 2014-04-01 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
WO2016202935A1 (fr) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
US9556166B2 (en) 2011-05-12 2017-01-31 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9834542B2 (en) 2013-03-15 2017-12-05 Bristo-Myers Squibb Company LXR modulators
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US9850262B2 (en) 2013-11-12 2017-12-26 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10351568B2 (en) 2010-01-28 2019-07-16 President And Fellows Of Harvard College Compositions and methods for enhancing proteasome activity
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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US7511061B2 (en) 1999-11-15 2009-03-31 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
JP2003514804A (ja) * 1999-11-15 2003-04-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ファルネシルトランスフェラーゼ阻害剤としてのトリアゾール類
JP4883862B2 (ja) * 1999-11-15 2012-02-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ファルネシルトランスフェラーゼ阻害剤としてのトリアゾール類
WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
US7592356B2 (en) 1999-11-15 2009-09-22 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company 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
US6942836B2 (en) 2001-10-16 2005-09-13 Applera Corporation System for filling substrate chambers with liquid
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8080666B2 (en) 2003-07-22 2011-12-20 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8207198B2 (en) 2005-01-20 2012-06-26 Pfizer Inc. Substituted triazole derivatives as oxytocin antagonists
US9023872B2 (en) 2005-01-20 2015-05-05 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US10150752B2 (en) 2005-01-20 2018-12-11 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US9394278B2 (en) 2005-01-20 2016-07-19 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
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US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
US9233956B2 (en) 2008-05-06 2016-01-12 Novartis Ag Benzene sulfonamide thiazole and oxazole compounds
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US8415345B2 (en) 2008-05-06 2013-04-09 Glaxo SmithKline LLC Benzene sulfonamide thiazole and oxazole compounds
US8642759B2 (en) 2008-05-06 2014-02-04 Glaxosmithkline Llc Benzene sulfonamide thiazole and oxazole compounds
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CA2249639A1 (fr) 1997-10-09

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