EP0891339A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase

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Publication number
EP0891339A1
EP0891339A1 EP97917830A EP97917830A EP0891339A1 EP 0891339 A1 EP0891339 A1 EP 0891339A1 EP 97917830 A EP97917830 A EP 97917830A EP 97917830 A EP97917830 A EP 97917830A EP 0891339 A1 EP0891339 A1 EP 0891339A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
unsubstituted
aryl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97917830A
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German (de)
English (en)
Inventor
Neville J. Anthony
Robert P. Gomez
Steven D. Young
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
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Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Priority claimed from GBGB9617278.8A external-priority patent/GB9617278D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0891339A1 publication Critical patent/EP0891339A1/fr
Withdrawn legal-status Critical Current

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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 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 ⁇ -Aaa ⁇ -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 C15 or C20 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 famesyl ⁇ ated 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
  • famesyl-protein 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
  • 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;
  • Rl and R ⁇ are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl0 ⁇ , Rl l S(0) m -, R10C(O)NR 10_, Rl lC(0)0-, (R lO) 2 NC(0)-, RK ⁇ N- NRlO)-, CN, N02, R lOc(O)-, N , -N(Rl )2, or RH ⁇ C(0)NR lO-, c) unsubstituted or substituted C1 -C alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl.
  • R3, R and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl2 ⁇ -, R 1 !C(0)0-, Rl lS(0) m -, Rl0C(O)NR l0-, (Rl0) 2 NC(O)-,
  • R6a 5 R6b 5 R6C ⁇ R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3- 0 cycloalkyl, C2-C6 alkenyl,
  • Ri is( ⁇ ) m -, RIOC(0)NR10-, (R10) 2 NC(O)-, R H C(0)O-,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-C 10 cycloalkyl,
  • R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl,
  • RlO is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1 -C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0) m ; provided that when V is heterocycle, attachment of V to R8 and to A 1 is through a substitutable ring carbon;
  • W is a heterocycle
  • X is not O, -C(0)NR7-, -C(0)0-, -C(0)NR7C(0)-, -S(O)2N(Rl0)- or -NR7-;
  • a is N or C
  • 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;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, RIOO-, -N(RlO)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(Rl°)2,
  • C2-C6 alkenyl c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO- and -N(RlO)2;
  • R3, R4 and R5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C perfluoroalkyl, R 12Q-, Rl l S(0)m-, R 10 C(O)NRl0-, (R 10) 2 NC(O)-, R l0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, c) unsubstituted C l -C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or
  • R6a ⁇ 6b ? R6C ? R6d a nd R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl2o-, Rl l S(0) m -, R 10C(0)NR10-, (RlO) 2 NC(0)-, Rl ⁇ 2N-C(NRl )-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, c) unsubstituted C1 -C6 alkyl; d) substituted C l -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from un
  • Rl ⁇ 2N-C(NRlO)., CN, R l C(O)-, N3, -N(RlO) 2 , and R l lOC(O)-NR l 0-; or
  • R is selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RIOO-, Rl0c(O)NRl0-, CN, N02, (R 10 )2N-C(NR 10 )-, R l C(O)-, -N(RlO)2, or RHOC(O)NR 10-, and c) C1-C6 alkyl substituted by C1 -C6 perfluoroalkyl, R 10 O-, R!0C(O)NR 10-, (R10)2N-C(NR 1°)-, R!°C(0)-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Rl lO-, Rl lS(0) m -, R !0C(O)NR 10-, (R10) 2 NC(O)-, CN, N02, (Rl°)2N-C(NRlO)-, RlOC(O)-, -N(R 10 )2, or Rl lOC(0)NRlO-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, R lOO-, Rl lS(0) m -, R I 0 C(O)NR l0-, (R lO)2NC(0)-, CN, (RlO)2N-C(NR l°)-, R lOC(O)-, -N
  • RIO is independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from Cl -C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, Cl-C6 alkyl, Cl -C6 aralkyl, Cl -C6 substituted aralkyl, -C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0) m ; provided that when V is heterocycle, attachment of V to R$ and to Al is through a substitutable ring carbon; W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazohnyl, pyridinyl
  • a is N or C
  • R l is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOo, -N(R lO)2, F or C 1 -C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R lOO-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C l -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl O- and -N(RlO)2;
  • R3 and R4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, Rl 0-, Rl lS(0) m -, RlOC(0)NRlO-, (RlO) 2 NC(0)-, Rl0 2 N-C(NR lO)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, c) unsubstituted C l -C6 alkyl, d) substituted Cl -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substitute
  • R6a, R6b, R6C, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R!0C(O) R10-, (R10) 2 NC(O)-, Rl ⁇ 2N-C(NRlO)-, CN,N02, R 10 C(O)-, N3,-N(RlO) 2 , orRH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted
  • Rl ⁇ 2N-C(NRl )., CN, RlOC(O)-, N3, -N(RlO) 2 , and RllOC(O)-NRl0-;or
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R OO-, R10C(O)NR10_, CN, N02, (R 10 )2N-C(NRlO)-,
  • RlOC(O)-, -N(RlO)2, or Rl 10C(0)NR10- and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R i0 O-, R!0C(O)NR10-, (R10) 2 N-C(NR10)-, RlOC(O)-, -N(RlO)2, or Rl 1OC(O)NR10- ; provided that when R ⁇ is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
  • R9a and R ⁇ b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
  • RlO is independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R 1 is independently selected from C1 -C alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, C1 -C6 heteroaralkyl, C1 -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl -C perfluoroalkyl,
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazohnyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A l is a bond, n is 0 and A 2 is S(0)m; provided that when V is heterocycle, attachment of V to R$ and to Al is through a substitutable ring carbon;
  • n 0, 1 or 2; : 8
  • a is N or C
  • 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 l is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(R 10)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R l°0-, -N(Rl ) 2 , F or C2-C6 alkenyl, c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R lOO- and -N(RlO) 2;
  • R3 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, Rl lS(0)m-, R1°C(0)NR10-, CN(Rl ) NC(0)-,
  • R6a ? R6b 5 R6C 5 R6d and R6e ar e independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3- 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, RllS(0)m-, R ,0 C(O)NRl0-, CN(R10)?NC(0)-, R10 2 N-C(NR10)-, CN,N02, R 10 C(O)-, N3, -N(Rl ) 2 , orRllOC(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted ary
  • RHOC(O)-NR1 - provided that when R°a, R6b ? R6C ? R6d 0 r R6e i s unsubstituted or substituted heterocycle, attachment of R6a, R6b 5 6 C ? R ⁇ d or R6e to 0 is through a substitutable ring carbon;
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, RlOO-, R!
  • R9a and R ⁇ b are independently hydrogen, -C6 alkyl, trifluoromethyl and halogen;
  • Rl is independently selected from hydrogen, -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R l 1 is independently selected from Cl -C6 alkyl and aryl;
  • R l 2 is independently selected from hydrogen, Cl -C6 alkyl, Cl -C6 aralkyl, -C6 substituted aralkyl, Cl -C6 heteroaralkyl, Cl -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazohnyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0) m ; provided that when V is heterocycle, attachment of V to R ⁇ and to Al is through a substitutable ring carbon;
  • a is N or C
  • 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 l is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(RlO) 2 , F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(RlO) 2;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -C6 perfluoroalkyl, Rl 2 O-, Rl l S(O) m -, R 10 C(O)NRl0-, (R l0) 2 NC(O)-,
  • R 4 is selected
  • R 6a , R6b ? R6C 5 R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, Rl 2 0-, Rl lS(O) m -, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, R l0 2 N-C(NRlO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0_, c) unsubstituted C1-C6 alkyl, d) substituted C l -C6 alkyl wherein the substituent on the substituted C1-C alkyl is
  • R ⁇ d or R6e to Q is through a substitutable ring carbon
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1 -C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, RlOO-, RlOC(0)NRlO-, CN, N02, (R lO)2N-C(NRlO)-, RlOc(O)-, -N(R lO) 2 , or R l l ⁇ C(O)NR l0-, and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, RlOO-, R l0c(O)NR l0-, (R 10) 2 N-C(NR 10)-, R lOc(O)-, -N(R lO)2, or Rl l ⁇ C(O)NRl0- ; provided that when R8 is heterocycle,
  • R9a and R b are independently hydrogen, halogen, CF3 or methyl
  • RlO is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1 -C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, C1 -C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1 -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • Al is selected from: a bond, -C(O)-, O, -N(RlO)-, or S(0) m ;
  • n is 0 or 1 ; provided n is not 0 if Al is a bond, O, -N(R 10)-, or
  • the inhibitors of famesyl-protein transferase are illustrated by the formula E: wherein:
  • a is N or C
  • 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;
  • Rl is independently selected from: hydrogen, RlOO-, -N(Rl ) 2 , F, C3-C 10 cycloalkyl or Cl-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R l0 ⁇ -, -N(R 10)2,
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1 -C6 perfluoroalkyl,
  • R4 is selected from H, halogen, C1-C6 alkyl and CF3;
  • R6a 5 R6b, R6C, Rod and R°e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C perfluoroalkyl, Rl2 ⁇ -, Rl lS(0) m -, R10C(0)NR10-, (Rl0) 2 NC(O)-, R l0 2 N-C(NRl0)-, CN, NO2, Rl°C(0)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0_, c) unsubstituted C 1 -C6 alkyl , d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl0c(O)NRl0-, CN, N02, (R1°)2N-C(NR10)-, RlOC(O)-, -N(Rl0)2,orRH ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0c(O)NRl0-, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or Rl 1OC(O)NR! - ; provided that when R8 is heterocycle, attachment of R$ to V is through a substitutable ring carbon
  • R a and R b are independently hydrogen, halogen, CF3 or methyl;
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • a is N or C
  • 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 l is independently selected from: hydrogen, C3-C10 cycloalkyl or C1 -C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, Rl O-, -N(RlO)2 or F, c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, Rl O-, or -N(Rl )2;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl2( R l l S(0) m -, R !
  • R4 is selected from H, halogen, CH3 and CF3;
  • R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, halogen, C1-C perfluoroalkyl, R12O, Rl lS(0) m -, Rl C(O)NRl -, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(Rl ) 2 , orRH ⁇ C(O)NRl0-, c) unsubstituted C 1 -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted
  • R9 and R9b are independently hydrogen, halogen, CF3 or methyl
  • Rl is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, Cl-C ⁇ substituted aralkyl, C1 -C heteroaralkyl, C1 -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl,
  • 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;
  • Rl is independently selected from: hydrogen, Rl O-, -N(Rl ) 2 , F, C3-C10 cycloalkyl or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl°0-, or -N(Rl O) 2 ;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl0-, (R 10) 2 NC(O)-, R l0 2 N-C(NRlO)-, CN, N02, Rl°C(0)-, N3, -NCR!
  • Rl lOC(O)NRl0- c) unsubstituted C 1 -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R l 2 0-, Rl lS(0) m -, R1 C(O)NR -, (RlO) 2 NC(0)-, R1 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and Rl lOC(O)-NRl0-;
  • R 4 is selected from H, halogen, CH3 and CF3;
  • R6a 5 R6b, R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, Ri c ⁇ NR O-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRl0)-, CN, NO2, R l°C(0)-, N3, -N(R 10) 2 , or Rl lOC(O)NRl0-, c) unsubstituted C 1 -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substitute
  • R9 and R9b are independently hydrogen, halogen, CF3 or methyl
  • R I is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1 -C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, C1 -C6 heteroaralkyl, C1 -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C6 perfluoroalkyl,
  • a l is selected from: a bond, -C(O)-, O, -N(Rl°)-, or S(0) m ;
  • n 0, 1 or 2;
  • 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 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 hetero ⁇ cyclic 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, mo holinyl, naphthyridinyl, oxadiazolyl
  • 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
  • R ⁇ , R4, R5 an d R6a-e the term "the substituted group” intended to mean a substituted Cl -8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R ⁇ , R , R5 an d R 6a"e are selected.
  • substituted Cj -8 alkyl, substituted C3-6 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, CF3, NH2, N(Cl-C6 alkyl)2, N ⁇ 2, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0) m -, (C1 -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C 1-C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3,(Cl -C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl
  • 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.
  • fused ring moieties may be further substituted by the remaining R° a , R6b, R6C ? R6d and/or R 6e as defined hereinabove.
  • Rl and R 2 are independently selected from: hydrogen, R l lC(0)0-, -N(RlO)2, R 10 C(O)NRl0-, Rl°0- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted -C6 alkyl is selected from unsubstituted or substituted phenyl, -N(Rl ) 2 , Rl O- and R ! C(O)NR10-.
  • R ⁇ is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, -C6 perfluoroalkyl, R l 2 0-, CN, N02, Rl°C(0)- or -N(Rl O) 2) c) unsubstituted C 1 -C alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, R12 0 -, Rl l S(0)m-, R!0C(O)NR 0-, (RlO) 2 NC(0)-, R l0 N-C(NRl )-, CN, RlOc(O)-, N3, -N(RlO)
  • R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1 -C6 alkyl.
  • R ⁇ is hydrogen.
  • R 6a , R 6 b, R6C, R6d an d R6e are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1 -C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, CN, NO2, Rl°C(0)- or -N(RlO) 2 , c) unsubstituted C 1 -C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, R l 2 0-, Rl lS(0) m -, R l C(0)- or -N(RlO) 2 ; or
  • R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C 1 -C6 perfluoroalkyl or CN .
  • R is hydrogen, halogen, CF3 or methyl.
  • Rl is selected from H, C1 -C6 alkyl and benzyl.
  • a l and A 2 are independently selected from: ⁇ bond, -C(O)NRl0-, -NR10C(O)-, O, -N(R 10)-, -S(0)2N(Rl )- 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. It is intended that the definition of any substituent or variable (e.g., R la, R , n> e tc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
  • -N(R l0)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that 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.
  • 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.
  • Schemes 1 - 15 illustrate synthesis of the instant arylhetero- aryl compound which inco ⁇ orate 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.
  • 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 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 inco ⁇ orates a suitably protected hydroxyl functionality as illustrated in Scheme 4.
  • Negishi chemistry (Or ⁇ . 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
  • 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. Similar strategies may be utilized to prepare other bisheteroatom moieties.
  • 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 R9b i s inco ⁇ orated 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 inco ⁇ orate 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.
  • Al (CR l 2)nA 2 (CR l2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 12.
  • the suitably substituted phenol XIV may be reacted with methyl 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)pX(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 XV ⁇ 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 Svntheses. 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.
  • 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.
  • 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 ⁇ ?.#. 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).
  • the aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIV .
  • 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., neurofibromin (NF-1 ), neu, scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit famesyl- protein transferase and the famesylation 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)).
  • Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • 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 vimses (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. American Journal of Pathology, 142: 1051 -1060 (1993) and B. Cowley, Jr. et ⁇ .FASEB Journal, 2:A3160 (1988)).
  • 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 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 altematively 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 administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
  • suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo ⁇ gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. 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 FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quanti- tating the enzyme.
  • 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 A lH-Imidazole-4-acetic acid methyl ester hydrochloride
  • Step B l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester
  • Step D 5-f 1 -(4-Cyanobenzyl)- 1 H-imidazolyl lethanol To a stirred solution of the ester from example step C,
  • Step E 5-( 1 -(4-Cyanobenzy l)-imidazoly Dethylmethanesulfonate
  • a solution of 5-[ l-(4-cyanobenzyl)-lH-imidazolyl] ethanol (0.500 g, 2.20 mmol) in CH2CI2 (6 mL) at 0°C was treated with Hunig's base (0.460 mL, 2.64 mmol) and methanesulfonyl chloride (0.204 mL, 2.64 mmol).
  • Step F 1 - ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]ethy 1 ⁇ -4- phenyl -imidazole bis hydrochloride salt
  • sodium hydride (14.2mg, 60% dispersion in mineral oil, 0.356 mmol) in DMF (0.30 mL) at 0°C was added 4-phenylimidazole (48.8mg, 0.339 mmol), and stirred for 20 minutes.
  • Step A l -Triphenylmethyl-4-(hydroxymethyl)imidazole
  • Step B l-Triphenylmethyl-4-(acetoxymethyl)imidazole
  • pyridine 500 mL
  • Acetic anhydride 74 mL, 780 mmol
  • the solution was poured into EtOAc, washed sequentially with water, 5% aq. HCI solution, sat. aq. NaHC03, solution, and brine.
  • the organic extracts were dried, (Na2S04), 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 l-(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. NaHC03 and brine. The solution was then dried (Na2S04), 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 l -(4-Cyanobenzyl)-5-(chloromethyl)imidazole
  • Step F 1 - ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]ethyl ⁇ -4- phenyl imidazole bis hydrochloride salt
  • Step A 4-(2-Methyl)phenyl imidazole
  • Step B 1 - ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]ethyl ⁇ -4-(2- methyDphenvDimidazole bis hydrochloride salt
  • Step B l -(3-Phenyl-5-isoxazolyJu ⁇ ethyl)-5-(4- cyanobenzyDimidazole hydrochloride salt
  • Step A 4-[5-(Aminocarbonylmethyl)imidazol- 1 - ylmethyllbenzonitrile
  • Step B l-(4-Cyanobenzyl)-lH-imidazol-5-yl]aminothio- carbonylmethyl
  • Step C 1 -(4-Cyanobenzy l)-5-(4-phenyl-thiazol-2- ylmethyPimidazole hydrochloride salt
  • Step A l-(2-Methyl)phenyl-2-bromoethanone
  • Step A l-(3-Chloro)phenyl-2-bromoethanone
  • Step B 1 -(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2- ylmethyDimidazole hydrochloride salt
  • Step A 1 -o-Tolyl-propan- 1 -one
  • Step B 2-Bromo- 1 -o-tolyl-propan- 1 -one
  • CH3C1 10 ml
  • THF 5 ml
  • 1 -o-tolyl-propan- 1 - one 318 mg, 2.14 mmol
  • pyridium bromide perbromide 735 mg
  • Step C 1 -((4-(2-methyl ⁇ henyl)-5-methylthiazole-2-ylmethyl)-5-
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-/V'-(2-e thane sulfonic acid) (HEPES), pH 7.4, 5 m MgCl2, 5 mM dithiothreitol (DTT), 100 mM [ 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 [3H]-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 inco ⁇ ora- tion of radioactivity in the presence of the test compound when compared to the amount of inco ⁇ oration in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et ah, 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 Ratl 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[35S]methionine (1000 Ci/rnmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM 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 MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM
  • 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 determine the percent inhibition of famesyl transfer to protein.
  • 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
  • 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.

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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.
EP97917830A 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase Withdrawn EP0891339A1 (fr)

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Application Number Priority Date Filing Date Title
US1459296P 1996-04-03 1996-04-03
US14592P 1996-04-03
GBGB9613462.2A GB9613462D0 (en) 1996-06-27 1996-06-27 Inhibitors of farnesyl-protein transferase
GB9613462 1996-06-27
US2234096P 1996-07-24 1996-07-24
US22340P 1996-07-24
GB9617278 1996-08-16
GBGB9617278.8A GB9617278D0 (en) 1996-08-16 1996-08-16 Inhibitors of farnesyl-protein transferase
PCT/US1997/005514 WO1997036881A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase

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JP4681548B2 (ja) 2003-07-22 2011-05-11 アステックス・セラピューティクス・リミテッド ３，４−ジ置換１ｈ−ピラゾール化合物および、そのサイクリン依存性キナーゼ（ｃｄｋ）およびグリコーゲン・シンセターゼ・キナーゼ−３（ｇｓｋ−３）調節剤としての使用
AP2007004047A0 (en) 2005-01-20 2007-06-30 Pfizer Ltd Substituted triazole derivatives as oxtocin antagonists
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
AR054425A1 (es) 2005-01-21 2007-06-27 Astex Therapeutics Ltd Sales de adicion de piperidin 4-il- amida de acido 4-(2,6-dicloro-benzoilamino) 1h-pirazol-3-carboxilico.
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UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
DE102009041242A1 (de) 2009-09-11 2011-12-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057364A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057344A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituierte Aryl-Verbindungen und ihre Verwendung
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AU2605897A (en) 1997-10-22

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