EP0891357A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase

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Publication number
EP0891357A1
EP0891357A1 EP97917829A EP97917829A EP0891357A1 EP 0891357 A1 EP0891357 A1 EP 0891357A1 EP 97917829 A EP97917829 A EP 97917829A EP 97917829 A EP97917829 A EP 97917829A EP 0891357 A1 EP0891357 A1 EP 0891357A1
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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.)
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Application number
EP97917829A
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German (de)
English (en)
Inventor
Neville J. Anthony
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 GBGB9617280.4A external-priority patent/GB9617280D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0891357A1 publication Critical patent/EP0891357A1/fr
Withdrawn legal-status Critical Current

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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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 confor ational 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 (H' ⁇ -ras, ⁇ &-ras, Ki4b-ra.v and N-ras) 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 3/0:583-586 (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., /. 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.
  • 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 prenylation.
  • 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 5,141 ,851 , University of Texas; N.E. Kohl et al., Science, 260: 1934- 1937 (1993); Graham, et al., J. Med. Chem., 37, 725 ( 1994)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
  • 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- 112930).
  • the present invention comprises biheteroaryl -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;
  • f(s) are independently N, and the remaining f s are independently CH;
  • Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • Rl0 2 N-C(NRl )_, CN, RlOC(O)-, N3, -N(Rl )2, and R11OC(O)-NR!0-;
  • R3, R4 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 ⁇ -, R 11 S(O)m-,R 10 C(O)NR 10 -, (R10) 2 NC(O)-, R 1] C(0)0-, Rl ⁇ 2N-C(NR ] 0)-, CN, N02, R 10 C(O)-, N3, -N(R!0) 2 , orRHOC(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C alkyl is selected from unsubstituted or substituted aryl, un
  • R6a, R6b ? R6C an£ j R6d 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, C.-C6 perfluoroalkyl, R 12 0-, R U S(0) m -, Rl c(0)NRlO-, (RlO) 2 NC(0)-, RUC(0)0-, Rl0 2 N-C(NRlO)_, CN, N02, R 10 C(O)-, N3,-N(RlO) 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 substitute
  • R7 is selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cj-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-C10 cycloalkyl,
  • R is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cj -C6 perfluoroalkyl, F, Cl, Br, Rl lO-, Rl lS(0) m -, R1 C(O)NR10-, (Rl ) 2 NC(0)-, R!0 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(Rl0)2, orRHOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, (Rl ) 2 NC(0)-, Rl 2N-C(NRl )-, CN, RlOc(O)-,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1-C alkyl and aryl
  • R 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 heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • V is selected from: a) hydrogen, b) heterocycle, 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, provided that V is not hydrogen if A* 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 R8 and to Al is through a substitutable ring carbon;
  • W is a heterocycle
  • 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;
  • f(s) are independently N, and the remaining fs are independently CH;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(RlO)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 lO) 2 , F or 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, Rl O- and -N(R lO) 2;
  • R , 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, Cl-C ⁇ perfluoroalkyl, Rl2o-, RllS(O) m -,R 10 C(O)NRl0-,(Rl0) 2N c(O)-,
  • R_a. j ⁇ 6b 5 R6C an ⁇ R6d 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 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-C6 perfluoroalkyl, F, Cl, RlOO-, Rl " ⁇ C(0)NRlO-, CN, NO2, (R10)2N-C(NR10)-, Rl C(O)-, -N(Rl0)2, orRllOC(O)NRl0-, an d c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, RlOC(0)NRlO-, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(Rl0)2, or Rl l ⁇ C(O)NRl0-; provided that when R& is heterocycle, attachment of R ⁇ to V is through a substitutable ring carbon;
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cj-C6 perfluoroalkyl, F, Cl, Rl lO-, Rl lS(0)m-, R1°C(0)NR10-, (R10) 2 NC(O)-, CN, N ⁇ 2, (R 10 )2N-C(NRl )-, R 10C(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) Cl -C6 alkyl unsubstituted or substituted by Cl -C6 perfluoroalkyl, F, Cl, RlOO-, Rl l S(0) m -, R10C(0)NR 10-, (R l ) 2 NC(0)-, CN, (R l0) N-C(NRl0)-, R lOc(O)-, -N(R 1 )2, or R 1 1
  • R lO is independently selected from hydrogen, C . -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R l 1 is independently selected from Cl -C6 alkyl and aryl;
  • R l2 is independently selected from hydrogen, Cl -C6 alkyl, Cl -C6 aralkyl, -C substituted aralkyl, Cl -C6 heteroaralkyl, -C substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl -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) 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) and V is not hydrogen if A 1 is a bond, n is 0 and A2 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 selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridiny
  • 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; from 1-2 of f(s) are independently N, and the remaining fs are independently CH;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(Rl )2, For C1-C6 alkyl;
  • R2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, Rl0 ⁇ -,-N(R 10)2,
  • 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,
  • Rl0 2 N-C(NRlO)-, CN,N02, Rl°C(0)-, N3, -N(RlO) 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 aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, Rl lS(0)m-, Rl0C(O)NRl0-, (RlO) 2 NC(0)-,
  • Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and R11OC(O)-NR10- ; provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R ⁇ or R to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
  • R6a ? R6b ? R6C anc j R6d 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 ⁇ -, Rl lS(0) m -, R10C(0)NR1 -, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)_, CN, N02, Rl°C(0)-, N3, -N(Rl0)2,
  • 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, N ⁇ 2, (R 10 )2N-C(NRlO)-,
  • R ⁇ an d R ⁇ b re independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen
  • R IO is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R 1 is independently selected from Cl -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 heteraryl, C] -C6 perfluoroalkyl,
  • 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) C1 -C2O 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 is S(0) m ; provided that when V is heterocycle, attachment of V to R and to A l 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;
  • f(s) are independently N, and the remaining f s are independently CH;
  • R l is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(R l O)2, F or C 1 -C6 alkyl;
  • R2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R lOO-, -N(RlO) 2 , F or C2-C6 alkenyl, c) unsubstituted or substituted Cl -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) ;
  • 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, C_-C6 perfluoroalkyl,
  • R110C(0)-NR10- provided that when R or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
  • R 6b , R 6c and R 6 ⁇ 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, R120-, Rl lS(0) m -, Rl0c(O)NRl0-, CN(Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN,N02, Rl°C(0)-, N3,-N(RlO) 2 , orRll ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted Cl -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, NO2, (R1°)2N-C(NR10)_, R 1 °C(0)-, -N(R 10)2, or R 11 OC(0)NR 10-, an d c) C1-C6 alkyl substituted by Cl-C ⁇ perfluoroalkyl, Rl°0-,
  • R9a an d R ⁇ b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
  • 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-C alkyl, -C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • 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) C l -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 A l is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)m. provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula D: 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;
  • f(s) are independently N, and the remaining f s are independently CH;
  • 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, R lOO-, -N(R 1°)2, F or C2-C6 alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R l°0-, or
  • 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, R12 0 -, RllS(0)m-, Rl0C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , orRll ⁇ 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 aryl, unsubstituted or substituted heterocyclic,
  • R10 N-C(NR10 , CN, RlOc(O)-, N3, -N(RlO) 2 , and R11OC(O)-NR10- ; provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
  • R is selected from H, halogen, -C6 alkyl and CF3;
  • R 6a , R 6 b, R6c and R 6d 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 ⁇ -, Rl lS(0) m -, R!0C(O)NR10-, (Rl0) 2 NC(O)-, R10 2 N-C(NR10)_,CN, N ⁇ 2, Rl°C(0)-, N3,-N(R10) 2 , orRll ⁇ C(O)NRl0-, c) unsubstituted Cl -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsub
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C]-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
  • R9 and R ⁇ b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RlO i 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 heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m .
  • the inhibitors of famesyl-protein transferase are illustrated by the formula E:
  • 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;
  • f(s) are independently N, and the remaining fs are independently CH;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(R l0)2, F or C1 -C6 alkyl;
  • R is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R lOo-, -N(R lO) 2 , F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl°0-, 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, C1-C6 perfluoroalkyl, Rl2 ⁇ -, RllS(0) m -, R10C(O)NR10-, (RlO) 2 NC(0)-,
  • R4 is selected from H, halogen, -C6 alkyl and CF3;
  • R° ⁇ j ⁇ 6b 5 R6C anf j R6d re 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 ⁇ -, Rl lS(0) m -, R!0C(O)NR10_, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)_, CN, N ⁇ 2, Rl°C(0)-, N3,-N(Rl0)2, orRHOC(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
  • 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, N ⁇ 2, (RlO)2N-C(NRlO)-, RlOc(O)-, -N(RlO)2, orRllOC(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, RlOC(0)NRlO-, (R!0) 2 N-C(NR10)-, RlOc(O)-,
  • R a a nd R b a re independently hydrogen, ethyl, cyclopropyl 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, Cj-C6 aralkyl, C1-C substituted aralkyl, C1-C6 heteroaralkyl,
  • C1-C6 substituted heteroaralkyl aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • n is 0 or 1 ; provided that n is not 0 if Al is a bond, O, -N(R l0)-, or S(O) m ; m is 0, 1 or 2; and p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond or O;
  • 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;
  • f(s) are independently N, and the remaining fs are independently CH;
  • R l is independently selected from: hydrogen, C3-C10 cycloalkyl or C1 -C6 alkyl; R is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, Rl°0-, -N(R10) 2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, Rl O-, 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, C1-C6 perfluoroalkyl, Rl2 ⁇ -, RllS(O) m -,Rl0c(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN,N02, Rl°C(0)-, N3, -N(RlO) 2 , orR'lOC(O)NRl0-, c) unsubstituted C]-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,
  • R4 is selected from H, halogen, CH3 and CF3;
  • R6b 5 R6C a nd R6d 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 ⁇ -, RllS(0)m-,RlOC(0)NRlO-,(RlO) 2NC ( ⁇ )-, Rl0 2 N-C(NRlO)-,CN, N02, Rl°C(0)-, N3, -N(RlO)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 aryl, unsubstit
  • R and R b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from -C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, C]-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • 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;
  • f(s) are independently N, and the remaining fs are independently CH;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(RlO) 2 , F or C1 -C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl or heterocycle, c) Cl -C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R lOO-, or -N(R l O) 2 ;
  • R is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl -C ⁇ perfluoroalkyl, Rl2 ⁇ -, Rl lS(0) m -.
  • R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, Rl°2N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , or R l lOC(O)NRl0-, c) unsubstituted C l -Co alkyl, d) substituted Cl -C ⁇ alkyl wherein the substituent on the substituted Cl -C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
  • R 4 is selected from H, halogen, CH3 and CF3;
  • Rf5a. 0b 5 R6C an d R6d 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, Cl -C ⁇ perfluoroalkyl,
  • R9a and R9b a re independently hydrogen, ethyl, cyclopropyl or methyl
  • RlO is independently selected from hydrogen, Cl -C ⁇ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from Cl -C ⁇ alkyl and aryl
  • R l 2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl -C ⁇ aralkyl, Cl -C ⁇ substituted aralkyl, Cl -C ⁇ heteroaralkyl, Cl -C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C] -C ⁇ perfluoroalkyl,
  • a l is selected from: a bond, -C(O)-, O, -N(R 10)-, 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.
  • any variable e.g. aryl, heterocycle, R l , R etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of 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 include those groups having the specified number of carbon atoms and having one triple bonds.
  • alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
  • Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro- naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 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, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, 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
  • R5 and R6a-d 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) R3, R4 ? 5 a nd R6a-e ar e selected.
  • substituted Cl -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, (Cl -C ⁇ alkyl)0-, -OH, (Cl -C ⁇ alkyl)S(0)m-, (Cl -C ⁇ alkyl)C(0)NH-, H2N-C(NH)-, (Cl -C ⁇ alkyl) C(O)-, (Cl -C ⁇ alkyl)OC(O)-, N3,(Cl-C ⁇ alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazo
  • 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 aromatic 6-membered heterocyclic ring is a pyridyl ring.
  • aromatic 5-membered heterocyclic ring is selected from:
  • Rl and R2 are independently selected from: hydrogen, RHC(0)0-, -N(RlO) , R!0C(O)NR 10-, RlOO- or unsubstituted or substituted Cl -C ⁇ alkyl wherein the substituent on the substituted Cl -C ⁇ alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) 2 , RlOO- and R10C(O)NR 10_.
  • R is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl2 ⁇ -, CN, N02, Rl°C(0)- or-N(RlO) 2 , c) unsubstituted C 1 -Co alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, RllS(0)m-, R10C(0)NR10-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and RllOC
  • R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C ⁇ alkyl.
  • R ⁇ is hydrogen.
  • R 6a , R6b, R6C and R6d are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl2 ⁇ -, R 1 !S(0) m -, CN, N ⁇ 2, Rl°C(0)- or -N(RlO) 2 , c) unsubstituted Cl-C ⁇ alkyl; d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, Rl ⁇ -, Rl lS(0) m -,
  • R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle,
  • R9 is hydrogen, halogen or methyl.
  • Rl° is selected from H, Cl-C ⁇ alkyl and benzyl.
  • Al and A2 are independently selected from: a bond, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)_, -S(0)2N(R10)_ and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • W is selected from imidazolinyl, 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.
  • f(s) are independently N, and the remaining f s are independently CH.
  • any substituent or variable e.g., Rl , R2, R9. n, etc.
  • -N(R 10)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 -22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • Schemes 1 - 13 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
  • a biheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art.
  • a suitably substituted thienyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
  • nicotinic acid such as nicotinic acid 6-triflate
  • the acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
  • Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1.
  • Scheme 2 illustrates the reaction wherein the "terminal" 5-membered heteroaryl 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 3.
  • Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 4.
  • a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the biheteroaryl VII.
  • the heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
  • Scheme 5 illustrates the preparation of a suitably substituted biheteroaryl alcohol starting from the halogenated methylpyridine.
  • a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
  • Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
  • Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b j s 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 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biheteroaryl via an alkyl amino, sulfonamide or amide linker.
  • the 4-amino- alkylimidazole 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 biheteroaryl moieties to provide the instant compounds shown.
  • Al (CR 2)nA2(CRl2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 10.
  • 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 1 1 illustrates an analogous series of reactions wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen.
  • a suitably substituted halopyridinol such as
  • Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl.
  • the intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound.
  • NC- __ ⁇ SCHEME 1 1
  • the intermediates whose synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized can be coupled with a variety of aldehydes.
  • 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.
  • Lithioheteroaryl chemistry may be utilized, as shown in Scheme 14, to incorporate the biheteroaryl moiety.
  • a suitably substituted biheteroaryl N-lithio reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI.
  • Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII.
  • the final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • 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.
  • the biheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 15, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as alkyl lithium 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 16), or tertiary amines.
  • the Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiheteroaryl such as XXXIII (Scheme 17). Treating XXVIII with 1 , l'-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
  • the biheteroaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 18.
  • R' is an aryl group
  • XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI.
  • the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1 ), neu, scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit 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 viruses (J.S. Glenn et al. Science, 256: 1331 -1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541-545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et ⁇ I.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.
  • Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutical ly 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.
  • 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 2-Trifluoromethanesulfonyloxy-5-pyridinecarboxylic acid
  • the aqueous extract is separated, and extracted with EtOAc.
  • the organic extracts are combined, washed with sat. aq. NaHC03 and 5% aq. Na2S2 ⁇ 3, dried, (Na2S04) and the solvent is evaporated in vacuo.
  • the residue is purified by chromatography to afford the title compound.
  • Step C 2- Thien-2-v ⁇ -5-hvdroxymethylpyridine To a solution of 2-(thien-2-yl)-5-pyridinecarboxylic acid
  • Step D l -(2-(Thien-2-yl) pyrid-5-ylmethyl)-5-(4- cvanobenzyl midazole
  • Step B l -Triphenylmethyl-4-(hydroxymethyl)imidazol
  • 4-(hydroxymethyI)imidazole hydrochloride 35.0 g, 260 mmol
  • triethylamine 90.6 mL, 650 mmol
  • a white solid precipitated from the solution.
  • Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
  • Step C l -Triphenylmethyl-4-(acetoxymethyl)imidazole
  • Step D 1 -(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hvdrobromide
  • Step E l -(4-Cyanobenzyl)-5-(hydroxymethyl)imidazole
  • Step D To a solution of the acetate from Step D (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 lhour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHC ⁇ 3 and brine. The solution was then dried (Na2S ⁇ 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 F l-f4-Cyanobenzyl)-5-(chloromethyl)imidazol
  • Step G N- ⁇ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yI)methyl ⁇ -5-(thien-
  • step F To a solution of the chloride from step F (500mg, 1.65 mmol) in DMF (10 mL) at 0°C is added sequentially, the amine from step A (292mg, 1.65 mmol) and sodium hydride (145mg, 60% dispersion in mineral oil, 3.62 mmol). Stirring is continued at 0°C for 1 hour and then at room temperature for 16 hours. The reaction is quenched with water (50 mL), and extracted with CH2CI2. The organic extracts are dried, (MgS04), and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM V-(2- hydroxy ethyl) piperazine-V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-farnesyl diphosphate ( HJ-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 [ ⁇ Hj-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 ⁇ oration 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 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 ⁇ M 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 compounds of the instant invention are tested for inhibitory activity against human FPTase by the assay described above.
  • 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 serum and 400 mCi[35s]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 MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupe ⁇ tin/2 mg/ml antipain/0.5 mM PMSF) and the lysates 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 leupe ⁇ tin/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 NaCI) 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 NaCI
  • 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 semm) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate 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 a nd comparisons are made.

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Abstract

La présente invention se rapporte à des composés inhibant la farnésyl-protéine tranférase (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.
EP97917829A 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase Withdrawn EP0891357A1 (fr)

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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
US2234296P 1996-07-24 1996-07-24
US22342P 1996-07-24
GBGB9617280.4A GB9617280D0 (en) 1996-08-16 1996-08-16 Inhibitors of farnesyl-protein transferase
GB9617280 1996-08-16
PCT/US1997/005512 WO1997036898A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase

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US6015817A (en) * 1996-12-05 2000-01-18 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6093737A (en) * 1996-12-30 2000-07-25 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5939439A (en) * 1996-12-30 1999-08-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6127390A (en) * 1997-10-02 2000-10-03 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
AU1612099A (en) * 1997-12-04 1999-06-16 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
EP1296978A2 (fr) 2000-06-30 2003-04-02 Bristol-Myers Squibb Company N-ureidoheterocycloaklyl-piperidines utilises comme modulateurs de l'activite du recepteur de la chimiokine
FR2819509B1 (fr) * 2001-01-18 2004-04-16 Servier Lab Nouveaux composes cycloheptene, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2819511A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes azepane, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6992087B2 (en) 2001-11-21 2006-01-31 Pfizer Inc Substituted aryl 1,4-pyrazine derivatives
US6964965B2 (en) 2002-04-26 2005-11-15 Pharmacia & Upjohn Substituted pyrazine derivatives
MXPA05012082A (es) 2003-05-09 2006-02-22 Pharmacia & Upjohn Co Llc Compuestos como antagonistas del receptor crf1.
US7244739B2 (en) 2003-05-14 2007-07-17 Torreypines Therapeutics, Inc. Compounds and uses thereof in modulating amyloid beta
DK2007752T3 (da) 2006-03-31 2010-11-15 Janssen Pharmaceutica Nv Benzimidazol-2-yl-pyrimidiner og -pyraziner som modulatorer af histamin H4-receptoren
UY30892A1 (es) 2007-02-07 2008-09-02 Smithkline Beckman Corp Inhibidores de la actividad akt
UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
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CA2756870A1 (fr) 2009-03-31 2010-10-07 Arqule, Inc. Composes indolo-pyridinone substitues
EP2560488B1 (fr) 2010-04-23 2015-10-28 Cytokinetics, Inc. Aminopyridines et aminotriazines, leurs compositions et leurs procédés d'utilisation
AR081626A1 (es) 2010-04-23 2012-10-10 Cytokinetics Inc Compuestos amino-piridazinicos, composiciones farmaceuticas que los contienen y uso de los mismos para tratar trastornos musculares cardiacos y esqueleticos
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AU2014225675B2 (en) 2013-03-06 2018-10-04 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor
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