EP0820445A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase

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Publication number
EP0820445A1
EP0820445A1 EP96909851A EP96909851A EP0820445A1 EP 0820445 A1 EP0820445 A1 EP 0820445A1 EP 96909851 A EP96909851 A EP 96909851A EP 96909851 A EP96909851 A EP 96909851A EP 0820445 A1 EP0820445 A1 EP 0820445A1
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EP
European Patent Office
Prior art keywords
substituted
aryl
unsubstituted
alkyl
heterocycle
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Withdrawn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
EP96909851A
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German (de)
English (en)
French (fr)
Inventor
Neville J. Anthony
Terrence M. Ciccarone
Robert P. Gomez
John H. Hutchinson
Theresa M. Williams
Christopher J. Dinsmore
Gerald E. Stokker
George D. Hartman
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
Original Assignee
Merck and Co Inc
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Publication date
Priority claimed from US08/600,728 external-priority patent/US5856326A/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0820445A1 publication Critical patent/EP0820445A1/en
Withdrawn legal-status Critical Current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
    • C07D233/64—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
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
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    • 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
    • C07D403/06—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 only aliphatic carbon atoms
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links

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 (Ha-ras, Ki4a-ras, Ki4b-r ⁇ s and N-r ⁇ s) 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 ⁇ l, Nature 37(9:583-586 (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 famesylation.
  • farnesylated proteins include the Ras-related GTP- binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown 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: 1133-1139 (1990); Manne et al, Proc. Natl Acad. Sci USA, 57:7541-7545 (1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of farnesyl- 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
  • 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: 1934-1931 (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).
  • an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit famesyl-protein transferase and thus, the post-translational famesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
  • the present invention comprises peptidomimetic piperazine-containing compounds which inhibit the famesyl-protein transferase.
  • the instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity.
  • chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production are further contained in this invention.
  • 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:
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RK>0-, Rl lS(0) m -, R 10 C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, N02, (RlO)2N-C(NRl )., RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or RH ⁇ C(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-
  • R2 and R ⁇ are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • R2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR O)- ;
  • R4 and R ⁇ are independently selected from H and CH3;
  • R2, R3, R4 nd R5 are optionally attached to the same carbon atom;
  • R6, R7 and R ⁇ a are independently 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,
  • R6 and R ⁇ may be joined in a ring;
  • R7 and R?a may be joined in a ring;
  • R6a is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 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, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 1 lS(0) m -,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIOO, Rl lS(0) m -, R10C(O)NR10-, (Rl0)2NC(O)-, Rl 2 N-C(NRlO)-, CN, N0 2 , Rl0c(O)-, RlO ⁇ C(O)-, N3,
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • 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 A is a bond, n is 0 and A ⁇ is S(0) ;
  • W is a heterocycle
  • Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RlOO-, RHS(0) m -, R 10 C(O)NRl0., CN(Rl0) 2 NC(O)-, Rl 2N-C(NRlO)-, CN, N ⁇ 2, Rl C(O)-, Rl ⁇ C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, Rl lS
  • R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • unsubstituted or substituted heterocycle wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, b) (CH 2 )pOR6 d) halogen, e) CN,
  • R2 and R ⁇ are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(C0R1°)- ;
  • R 4 is selected from H and CH3;
  • R2, R3 and R4 are optionally attached to the same carbon atom;
  • R6, R7 and R ⁇ a are independently 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,
  • R6 and R ⁇ may be joined in a ring; R7 and R ⁇ may be joined in a ring; R ⁇ a is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 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, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRl )-, CN,
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R U S(0) m -, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, RIO 2 N- C(NRlO)-, CN, N0 2 , RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, (RlO)2NC(0)-, R!0 2 N-C(NR10)-, CN, RlOC(O)-, Rl ⁇ C(O)-, N3, -N(Rl )2, or R
  • Rl is independendy selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
  • RU is independently selected from Cl-C6 alkyl and aryl
  • G is H2 or O
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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 is S(0) m ;
  • W is a heterocycle
  • Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl,
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RlOO-, RHS(0) m -, R1°C(0)NR10-, (RlO)2NC(0)-, Rl 2N-C(NRl )-, CN, N02, Rl°C(0)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or RHOC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, R lS(0)m-, Rl°C(O
  • R and R ⁇ are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • R2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ;
  • R4 is selected from H and CH3;
  • R2, R3 and R4 are optionally attached to the same carbon atom;
  • R6, R7 and R7a are independently 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,
  • R6 and R7 may be joined in a ring; R7 and R7 may be joined in a ring; R6a is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 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, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RUS(0) m -, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0c(O)NRl0-, (RlO) 2 NC(0)-, R10 2 N-C(NR10)-, CN, N02, Rl°C(0)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, R1 C(O)NR10-, (Rl0)2NC(O)-, Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(
  • RlO is independendy selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • 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 a heteroatom selected from O, S, and N, and e) C2-C2O 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 A2 is S(0) m ;
  • W is a heterocycle
  • Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl,
  • Rla is independently selected from: hydrogen or C1-C6 alkyl
  • Rib is independendy selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(Rl°)2 or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO- and -N(RlO) 2 ;
  • R3, R4 and R ⁇ are independently selected from H and CH3;
  • R2 is H; O or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6, R7 and R7a are independently selected from:
  • R ⁇ a is selected from:
  • R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C ⁇ perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N0 2 , (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0c(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-;
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl S(0) m -, R10C(O)NR10-, CN, N ⁇ 2, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (R10) 2 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or RHOC(O)NR10- ;
  • RU is independently selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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 Al is a bond, n is 0 and A2 is S(0)m;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Y is mono- or bicyclic aryl, or mono- or bicyclic heterocycle, unsubstituted or substituted with one or more of: a) Cl-4 alkyl, b) Cl-4 alkoxy, c) halogen, or d) NR6R7 ;
  • Rla is independently selected from: hydrogen or Cl-C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R OO-, -N(RlO)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO- and -N(RlO) ; R3 and R4 are independently selected from H and CH3; ⁇ .NR 6 R 7
  • R is H; O or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6, R7 and R7 are independently selected from:
  • R ⁇ a is selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, NO2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or
  • Rl lOC(O)NRl0- and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 10 ⁇ -, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or R1 1OC(O)NR1 -;
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R10C(0)NR10-, CN, N02, (RlO)2N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or RH ⁇ C(O)NRl0-, and c) C 1 -C ⁇ alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, R10C(O)-, RlO ⁇ C(O)-, -N(RlO)2, or RHOC(0)NR10-
  • RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 2 Q alkenyl, and 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 A2 is S(0)m;
  • G is H2 or O
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0)mR 6 , or g) -C(0)NR6R7, 2) aryl or heterocycle,
  • u is 4 or 5;
  • 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, Rl, R2 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 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.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl 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 11- 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 structure.
  • 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, isodiiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazoly
  • heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
  • the substituted group intended to mean a substituted Cl -8 alkyl, substituted C 2 -8 alkenyl, substituted C 2 -8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R2 and R ⁇ are selected.
  • the substituted Cl -8 alkyl, substituted C3-6 alkenyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • substituted aryl is intended to include the aryl group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH 2 , N(Cl -C6 alkyl)2, N ⁇ 2, CN, (Cl -C ⁇ alkyl)0-, -OH, (Cl-C6 alkyl)S(0) m -, (Cl -C6 alkyl)C(0)NH-, H 2 N-C(NH)-, (Q -C6 alkyl)C(O)-, (Cl -C6 alkyl)OC(O)-, N3,(C l-C6 alkyl)OC(0)NH- and C1 -C20 alkyl.
  • cyclic moieties When R2 and R ⁇ are combined to fo ⁇ n - (CH 2 )u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties may optionally include a heteroatom(s).
  • heteroatom-containing cyclic moieties include, but are not limited to:
  • Rla and R b are independently selected from: hydrogen, -N(R °) 2 , Rl0c(O)NR 10 - 0 r unsubstituted or substituted C1 -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) 2 , RlOO- and
  • R is selected from: H, RW , ⁇ ° Re ,
  • R3 is selected from: hydrogen and Cl-C6 alkyl.
  • R4 and R ⁇ are hydrogen.
  • R6, R7 and R7a is selected from: hydrogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R6a i s unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R9 is hydrogen or methyl.
  • R a is hydrogen.
  • RlO is selected from H, -C6 alkyl and benzyl.
  • a l and A2 are independently selected from: a bond, -C(O)NR l0-, -NR IOC(O)-, O, -N(R 10)-, -S(0) 2 N(R 10 and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Y is unsubstituted or substituted phenyl.
  • Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Z is unsubstituted or substituted 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.
  • p is 1 , 2 or 3.
  • s is 0.
  • t is 1.
  • the substitutent (R ⁇ )r- V - A l (CRl a 2)nA (CRla 2 )n - is not H.
  • any substituent or variable e.g., Rl , R , n, etc.
  • -N(Rl0) 2 represents -NHH, -NHCH3, -NHC2H5, etc.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily 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.
  • Boc-protected amino acids I available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
  • dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
  • the product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III.
  • acid for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride
  • Reduction of in with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V.
  • the N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h.
  • the product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme 2).
  • the intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX.
  • 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 (Scheme 3).
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
  • the product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
  • the final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII.
  • the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as 1 -trityl-4- imidazolyl-carboxaldehyde or 1 -trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4).
  • the trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII.
  • the intermediate VIII can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
  • Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
  • the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
  • the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
  • the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8).
  • the aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIII.
  • piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX.
  • R' is an aryl group
  • XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL.
  • the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
  • various side chains can be inco ⁇ orated into the piperazine.
  • the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
  • the imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV.
  • Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI.
  • Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
  • N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
  • the resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
  • Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form - (CH 2 )u -.
  • 1- aminocyclohexane-1 -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2.
  • the piperazine intermediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9.
  • the aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16.
  • the product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII.
  • Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI.
  • intermediate LXXXII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXXIII.
  • Intermediate LXXXII may also be oxidized to provide the carboxylic acid on intermediate LXXXIV, which can be utilized form an ester or amide moiety.
  • Amino acids of the general formula LXXXVI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 18 starting with the readily prepared imine LXXXV.
  • 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 al.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.
  • 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.
  • 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 immunological, 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 die 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 l-Benzyl-3(S)-n -butylpiperazine-2.5-dione
  • Step B 4-Benzyl-l -ten -butoxycarbonyl-2(S)-n -butylpiperazine
  • Step C ⁇ -tert -Butoxycarbonyl-2(S)- « -butylpiperazine
  • Step B The product from Step B (3.75 g, 11.3 mmol) was dissolved in methanol (75 mL) in a Parr bottle, and the vessel purged with argon. To this was added 10 % palladium on carbon (0.80 g) and the reaction hydrogenated under 60 psi hydrogen for 24 h. The catalyst was removed by filtration through Celite, and the filtrate evaporated in vacuo to give the title compound as an oil.
  • Step D l-tert -Butoxycarbonyl-2(S)-n -butyl-4-(l-naphthoyl)- piperazine l-tert -butoxycarbonyl-2(S)-n -butylpiperazine (0.325 g, 1.34 mmol), 1 -hydroxybenzotriazole (HOBT) (0.203 g, 1.34 mmol) and l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (EDC • HCl) (0.254 g, 1.34 mmol) were added to dry, degassed dimethylformamide (7 mL).
  • HOBT 1 -hydroxybenzotriazole
  • EDC • HCl l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride
  • the pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred for 2 h.
  • the dimethylformamide (DMF) was distilled in vacuo. and the residue partitioned between ethyl acetate and water.
  • the organic phase was washed with 2% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate.
  • the tide compound was obtained as a thick oil.
  • Step E 2(S)-n -Butyl-4-(l-naphthoyl)piperazine hvdrochloride
  • the product from Step D was dissolved in ethyl acetate, cooled to -40°C under nitrogen, and the solution saturated with HCl(g). The solution was warmed to 0°C for 30 min, and then purged with nitrogen. The solvent was removed in vacuo. The product was evaporated from ethyl acetate three times. The tide compound was obtained as a white solid.
  • Step F 2.3-(_7t,?-tgrt-Butoxycarbonylamino)propanoic acid
  • Diaminopropanoic acid monohydrochloride (2.86 g, 0.0204 mol) was suspended in 1 : 1 water-dioxane (100 mL) containing triethylamine (5.97 mL, 0.0204 mol). BOC-ON (11.0 g, 0.0448 mol) was added along with additional triethylamine to adjust the pH to 9.5. The reaction was stirred under nitrogen overnight at 20°C. The clear solution was diluted with water and extracted with diethyl ether (5 x 100 mL). The aqueous solution was adjusted to pH 1 with cold 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride, then dried over magnesium sulfate. The resulting foam (5.46 g) was crystallized from ethyl acetate to give the title compound as a white solid.
  • Step G N-Methoxy-N-methyl-2,3-( ? «-terf-butoxycarbonyl- amino)proprionamide
  • Step H 2.3-(,?.s-rert-Butoxycarbonylamino)propanal
  • Lithium aluminum hydride (0.384 g, 10.14 mmol) was suspended in diethyl ether (20 mL) and cooled to -45°C under nitrogen.
  • N-Methoxy-N-methyl-2,3-(A>t5-tert-butoxycarbonylamino)- proprionamide (2.07 g, 5.96 mmol) in 1:1 ether-tetrahydrofuran (60 mL) was added at such a rate so as to keep the reaction temperature less than -35°C.
  • the reaction was allowed to warm to 5°C, then cooled to -45°C and quenched with a solution of potassium hydrogen sulfate (3.08 g, 22.6 mmol) in water (20 mL).
  • the cmde product was chromatographed on silica gel with 40-50% ethyl acetate in hexane, and the tide compound was isolated as a foam (Rf 0.30, 50% ethyl acetate in hexane).
  • Step J l-(2,3-Diaminopro ⁇ - 1 -yl)-2(S)-butyl-4-( 1 - naphthoyDpiperazine trihvdrochloride
  • Trifluoroacetic acid 25 mL was added to a solution of 1- [(2,3-bw-t ⁇ ?rt-butoxycarbonylamino)prop- 1 -yl]-2(S)-butyl-4-( 1 - naphthoyDpiperazine (2.13 g, 3.75 mmol) in dichloromethane (75 mL). After 25 min at 20°C, the solvent was evaporated and the residue partitioned between chlorform and 20% aqueous sodium hydroxide. The organic layer was washed with saturated brine and dried over magnesium sulfate. The free base of the title compound was obtained as a yellow gum (1.72 g).
  • Step A l-[(2-Amino-3-te ⁇ butoxycarbonylaminoprop-l-yl]-2(S)- butyl-4-( 1 -naphthoyDpiperazine
  • Step B l-(3-tert-Butoxycarbonylamino-2-(2- naphthylmethylamino)prop-l-yl)-2(S)-butyl-4-(l- naphthovDpiperazine
  • Step C l-(3-Amino-2-(2-naphthylmethylamino)prop-l-yl)-2(S)- butyl-4-( 1 -naphthoyDpiperazine trihvdrochloride
  • the tide compound was prepared according to the procedure described in Example 4, except using p-nitrobenzylbromide (0.043 g, 0.199 mmol) and 2(S)-butyl-l-[5-(3- triphenylmethylimidazol)]methyl-4-(l -naphthoyDpiperazine (123 mg, 0.199 mmol) in acetonitrile (2 mL).
  • the cmde product was treated with triethylsilane (0.127 mL, 0.80 mmol) and trifluoroacetic acid (2 mL) in dichloroethane (4 mL).
  • Preparative HPLC (95-5% solvent A) provided the title compound as a white solid.
  • Step A 2(S)-Butyl-4-( 1 -naphthoyl)- 1 -vinylsulfonylpiperazine
  • Chloroethylsulfonylchloride (0.038 mL, 0.314 mmol) was added to a solution of 3(S)-butyl-l-(l -naphthoyDpiperazine (0.095 g, 0.285 mmol) and dusopropylethylamine (0.119 mL, 0.685 mmol) in dichloromethane (3 mL). The reaction was stirred ovemight under nitrogen, quenched with saturated sodium bicarbonate and extracted into ethyl acetate. After drying with magnesium sulfate, the title compound was isolated.
  • Step B 2(S)-Butyl-l-[2-(l-imidazolyl)ethyl]sulfonyl-4-(l- naphthoyPpiperazine ditrifluoroacetate
  • Imidazole (0.043 g, 0.627 mmol) was added to sodium hydride (60% dispersion in oil, 0.024 g, 0.598 mmol) suspended in dimethylformamide (2 mL). The reaction was cooled to 0°C under nitrogen, and 2(S)-butyl-4-(l -naphthoyl)- 1-vinylsulfonylpiperazine (0.011 g, 0.29 mmol) in dimethylformamide (5 mL) was added. The reaction was stirred at 20°C ovemight. The dimethylformaide was removed in vacuo and the residue dissolved in ethyl acetate.
  • Step A 2(R)-Butyl-4-(l-naphthoyl)-l-[4-(l- triphenylmethylimidazolyllmethyl-piperazine
  • the organic layer was washed with saturated brine, and dried over magnesium sulfate.
  • the cmde product was purified by chromatography on silica gel with 30% ethyl acetate in hexane followed by 5% methanol in chloroform, to obtain the title compound.
  • Step B 2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( 1 - naphthoyDpiperazine ditrifluoroacetate
  • Triethylsilane 1.0 mL, 11.80 mmol
  • Step A l-(2(R)-r-Butyoxycarbonylamino-2-formylethyl)-2(S)- butyl-4-( 1 -naphthoyDpiperazine
  • oxalyl chloride 1.36 mL, 14.9 mmol
  • dichloromethane 35 mL
  • dimethylsulfoxide 2.30 mL, 32.4 mmol
  • methylene chloride 7 mL
  • Step B l-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(l - naphthoyDpiperazine ditrifluoroacetate
  • the cmde product was chromatographed on silica gel with 25% ethyl acetate in hexane followed by 5% methanol in chloroform.
  • the purified product was dissolved in methylene chloride (7 mL) and treated with trifluoroacetic acid (3.5 mL). After 45 min, the solvents were removed in vacuo and the residue purified by preparative HPLC (95-40% solvent A). Two isomers were separated. After lyophilization, the title compound was isolated as diastereomer A (retention time 8.405 min, gradient 100-50% solvent A over 15 min), FAB ms (m+1) 566, Anal. Calc.
  • Step A l.(3S)-Dibenzylpiperazine-2.5-dione
  • the title compound was prepared according to the procedure described in Example 1, Step A, except using Boc-L- phenylalanine (12.8 g, 48.2 mmol), ethyl N-benzylglycinate (9.32 g, 48.2 mmol) and dicyclohexylcarbodiimide (96.5 mL 0.5 M in dichloromethane, 48.2 mmol).
  • Boc-L- phenylalanine 12.8 g, 48.2 mmol
  • ethyl N-benzylglycinate 9.32 g, 48.2 mmol
  • dicyclohexylcarbodiimide 96.5 mL 0.5 M in dichloromethane, 48.2 mmol.
  • the cmde diketopiperazine was triturated with hexane to give the title compound as a white powder.
  • Step B 1 -tert -Butoxycarbonyl-2(S)-.(S).4-dibenzylpiperazine
  • the title compound was prepared according to the procedure described in Example 1, Step B, except using 1,3(S)- dibenzylpiperazine-2,5-dione (5.01 g, 17.1 mmol) and lithium aluminum hydride (2.33 g, 61.4 mmol), followed by di-tert -butyl dicarbonate (4.02 g, 18.4 mmol).
  • the cmde product was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate in hexane. The title compound was obtained as a white solid.
  • Step C 2(S)-Benzyl- 1 -tert -butoxycarbonylpiperazine
  • the tide compound was prepared according to the procedure described in Example 1, Step C, except using l-tert - butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and
  • Step D 2(S)-Benzyl- l-tert -butoxycarbonyl-4-(l- naphthoyPpiperazine
  • Step E 2(S)-Benzyl-4-( 1 -naphthoyl)- 1 -[4-( 1 - triphenylmethylimidazolyllmethyl-piperazine
  • Step F 2(S)-Benzyl- 1 -imidazolyl-4-methyl-4-( 1 - naphthoyDpiperazine ditrifluoroacetate
  • Triethylsilane (0.300 mL, 1.89 mmol) was added to a solution of 2(S)-benzyl-4-(l -naphthoyl)- l-[4-(l- triphenylmethylimidazolyljmethyl-piperazine (0.310 g, 0.472 mmol) in dichloromethane (5 mL), followed by trifluoroacetic acid (5 mL).
  • Step A 1 -[( 1 -Aziridinyl)methyl]-2(S)-butyl-4-( 1 -naphthoyD ⁇ piperazine ⁇
  • Step B l-(2(R)-Amino-3-(3-benzylthio) ⁇ ropyl)-2(S)-butyl-4-(l- naphthoyDpiperazine ditrifluoroacetate l-[(l-Aziridinyl)methyl]-2(S)-butyl-4-(l- naphthoyDpiperazine (0.050 g, 0.142 mmol) was retluxed for 18h with benzyl mercaptan (0.100 mL, 0.852 mmol) and triethylamine (0.200 mL) in methanol (4 mL).
  • Step A N-Methyl-N-methoxy-2-( 1 -triphenylmethyl- 1 H-imidazol-4- yPacetamide
  • 4-imidazoleacetic acid (1.04g, 6.40 mmol) and triphenylmethyl bromide (2.48 g, 7.68 mmol) in dimethylformamide (40 ml) was added triethylamine (4.46 ml, 32 mmol) and the suspension allowed to stir for 18 hours at room temperature.
  • Step C 2(S)-Butyl- 1 - [(4-imidazolyl)ethyl]-4-( 1 - naphthoyDpiperazine ditrifluoroacetate
  • Step A Preparation of lH-Imidazole-4- acetic acid methyl ester hydrochloride To a solution of lH-imidazole-4-acetic acid hydrochloride
  • Step B Preparation of 1- (Triphenylmethyl)- lH-imidazol-4-ylacetic acid methyl ester
  • methylene chloride 200ml
  • triethylamine 17.7 ml, 127 mmol
  • triphenylmethyl bromide 16.4g, 50.8 mmol
  • the resulting precipitate was collected by filtration and combined with the previous 2 precipitates in methanol (100 ml) and heated to reflux for 30m. After this time, the solvent was removed in vacuo and the resulting residue was partioned between methylene chloride(200 ml) and sodium bicarbonate (100 ml).
  • Step D Preparation of 2- [1 -(Naphth-2-ylmethyl)-lH-imidazol-5- yllacetic acid hydrochloride
  • Step E Preparation of 2(S)-Butyl- l-[(l-(naphth-2-ylmethyl)-lH- imidazol-5-yl)acetyl]-4-( 1 -naphthoyDpiperazine dihvdrochloride To a solution of the product from Step D (100 mg,
  • Step A Preparation of N-Methyl-N-methoxy-2-[l-(naphth-2- ylmethyl)-lH-imidazol-5-yl)1acetamide
  • Step B Preparation of 2-[l-(Naphth-2-ylmethyl)(lH-imidazol-5- vDlacetaldehyde
  • Step C Preparation of 2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH- imidazol-5-yl)ethyl]-4-( 1 -naphthoyDpiperazine ditrifluoroacetate
  • Step A N-Boc-O-Benzylserine-(N'-Methoxy) methyl amide
  • N-Boc-O-Benzylserine (Bachem; 5.0g, 16.9 mmol) and HOBT (2.29g, 16.9 mmol) were dissolved in dry DMF (100 mL) under argon. To this solution was added N,0-dimetiiylhydroxyl amine hydrochloride (1.98 g, 20.3 mmol) and then, at 0°C, EDC hydrochloride (3.56 g, 18.6 mmol). 4-Methylmorpholine was added to bring the pH to -7 (4.5 mL) and the mixture was strrred at room temperature for 3h. The solution was diluted with EtoAc and poured into 0.5N HCl. After extraction with EtoAc (twice), the organic layers - I l l -
  • Step B N-Boc-O-Benzyl-serine aldehyde
  • Step C l-(2(R)-N-Boc-Amino-3-benzyloxy propyl)-2(S)-butyl-4- (1-naphvthoyl) piperazine A solution of the piperazine hydrochloride from Example
  • Step E (1.7 g, 574 mmol) in CH2CI2 (25 mL) was adjusted to pH 6 using Et3N then freshly ground and activated 4 A sieves were added followed by sodium triacetoxyborohydride (4.85 g, 22.9 mmol).
  • the aldehyde from Step B (2.08g, 747 mmol) dissolved in 20 mL CH2CI2 was added dropwise at 0°C over 20 min. then the mixture was sitrred at room temperature for 16 h. After this time, the mixture was filtered through celite, diluted with EtoAc and washed successively with H2O, KHSO4, solution, NaHC03 solution and then brine.
  • the benzyl ether from Step C (700 mg, 1.25 mmol) was dissolved in 20 mL MeOH with 150 ⁇ L of acetic acid and then 20% Pd(OH)2 on carbon (500 mg) was added and the mixture hydrogenated at 50 psi for 16 hr. After filtration through celite, the solvent was removed and the residue was chromatographed on silica gel (EtoAc/hexane 1:1 then 5% MeOH/EtoAc) to give the title compound as an oil.
  • Step E l-(2(R)-Amino-3-hydroxy propyl)-2(S)-butyl-4-(l- naphythoyPpiperazine bis trifluoroacetate salt
  • Step A D.L-N-Boc-ortho-tyrosine methyl ester
  • the tide compound was prepared as a crystalline solid from D,L-orthotyrosine (Sigma) in two steps ((Boc)2 ⁇ /K2C ⁇ 3 in THF/H20 followed by diazomethane in EtOAc).
  • Step B 3-(2-Hvdroxyphenyl)-2-(N-Boc-Amino)propanol
  • Step D 3-(2-Benzyloxyphenyl)-2-(N-Boc-amino)propanol
  • Step E 1 -(2-N-Boc- Amino-3-(2-benzyloxyphenyl)propyl)-2(S)- butyl-4-( 1 -naphthoyDpiperazine
  • Step F l-(2-A nino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-
  • Step A l-(2-N-Boc-Amino-3-(2-hydroxyphenyl)propyl)-2(S)- butyl-4-( 1 -naphthoyDpiperazine
  • Step B l-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(l- naphthoyDpiperazine bis trifluoroacetate salt, diastereomer
  • Step D l-[3-(4-i ⁇ m Iazolyl)propyl]-2(S)-butyl-4-(l-naphthoyl)- piperazine bis trifluoroacetate salt
  • the title compound was prepared from 2(S)-n-butyl-l-[5- (3 -triphenylmethylimidazolyl)methyl]-4-(l -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-cyanobenzylbromide (0.041 g, 0.21 mmol) according to the procedure described in Example 4.
  • the tide compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1 % TFA; 75%- 35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)- ⁇ -butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-(l -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-methyoxybenzylchloride (0.041 mL, 0.21 mmol) according to the procedure described in Example 4, with the addition of potassium iodide (100 mg) to the reaction mixture.
  • the title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the tide compound was prepared from 2(S)-n-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-bromo-2-methyl-2-butene (0.024 mL, 0.21 mmol) according to the procedure described in Example 4.
  • the tide compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 5%-95% acetonitrile/0.1% TFA; 95%-5% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)-n-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-fluorobenzylbromide (0.026 mL, 0.21 mmol) according to the procedure described in Example 4.
  • the title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%- 35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)- z-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-chlorobenzylchloride (0.034 mg, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture.
  • the title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)-w-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-bromobenzylbromide (0.053 mg, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture.
  • the title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-35% 0.1% aqueous TFA over 50 min.) and lyophilization. FAB ms (m+1) 545. Anal.
  • the title compound was prepared from 2(S)-n-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 4-phenylbenzylbromide (0.029 mL, 0.21 mmol) according to the procedure described in Example 4.
  • the tide compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%- 35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)-n-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-( 1 -naphthoyDpiperazine (0.124 g, 0.200 mmol) and 2-phenylethylbromide (0.029 mL, 0.21 mmol) according to the procedure described in Example 4, except with the addition of sodium iodide (120 mg) and refluxing for 12 h.
  • the tide compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0.1 % TFA; 70%- 35% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • the title compound was prepared from 2(S)-n-butyl-l-[5- (3-triphenylmethylimidazolyl)methyl]-4-(l-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-trifluoromethoxybenzylbromide (0.032 mL, 0.21 mmol) according to the procedure described in Example 4, except with the addition of sodium iodide (120 mg) and refluxing for 12 h.
  • the title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 35%-70% acetonitrile/0.1 % TFA; 65%-30% 0.1% aqueous TFA over 50 min.) and lyophilization.
  • Step A Preparation of lH-Imidazole-4- acetic acid methyl ester hydrochloride.
  • Step B Preparation of 1 -(Triphenylmethyl)- lH-imidazol-4-ylacetic acid methyl ester.
  • Step C Preparation of [ 1 -(4-cy anobenzyl)- 1 H-imidazol-5-yl] acetic acid methyl ester.
  • Step D Preparation of [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid A solution of [ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (100ml) and 1 M lithium hydoxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilised to afford the title compound containing lithium chloride as a white solid.
  • Step E Preparation of l- ⁇ [l-(4-cyanobenzyl)-lH-imidazol-5- yljacetyl ⁇ -2(S)- «-butyl-4-( 1 -naphthoyDpiperazine trifluoroacetate
  • Step A N-Methoxy-N-methyl 2(S)-(r_?rf-butoxycarbonylamino)- hexanamide
  • Step B 2(S)-(rgrr-Butoxycarbonylamino)hexanal
  • Step C N-(2,3-Dimethylphenyl)-2(S)-(tert-butoxycarbonylamino)- hexanamine
  • 2,3-Dimethylaniline (8.32 mL, 68.3 mmol) was dissolved in dichloroethane under nitrogen. Acetic acid was added to obtain pH 5, and sodium triacetoxyborohydride (17.2 g, 80.8 mmol) and cmshed molecular sieves (4 g) were added.
  • a solution of the product from Step B (13.3 g, 62.1 mmol) in dichloroethane (80 mL) was added slowly dropwise at 20°C. The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The aqueous layer was removed, die organic phase washed with saturated brine and dried over magnesium sulfate. Crystallization from hexane gave the tide compound.
  • Step D 4- rt-Butoxycarbonyl-5(S)-n-butyl- 1 -(2,3- dimethylphenyl)piperazin-2-one
  • Step E 5(S)-n-Butyl-l-(2,3-dimethylphenyl)-4-[4-(l- triphenylmethylimidazolvDmethyllpiperazin-2-one
  • ethyl acetate 50 mL
  • HCl gas was bubbled through for 15 min, and the reaction solution warmed to 0°C for 2h.
  • the solvent was removed in vacuo, and the resulting solid was dissolved in dichloroethane (20 mL).
  • Step F 5(S)-n-Butyl-l-(2,3-dimethylphenyl)-4-(4- imidazolylmethyl)piperazin-2-one ditrifluoroacetic acid salt
  • dichloromethane 6 mL
  • triethylsilane 0.254 mL
  • trifluoroacetic acid 2 mL
  • Step A N-Methoxy-N-methyl 4-benzyloxy-2(S)-(tert- butoxycarbonylamino)butanamide
  • the tide compound was obtained by lithium aluminum hydride reduction of the product of Step A using the procedure described in Example 39, Step B.
  • Step C N-(2,3-Dimethylphenyl)-4-(2-benzyloxyethyl)-2-(S)-(tert- butoxycarbonylamino)butanamine
  • the tide compound was prepared from the product of Step
  • Step D 5(S)-(2-Benzyloxyethyl)-4- rt-butoxycarbonyl- 1 -(2,3- dimethylphenyl)piperazin-2-one
  • the title compound was prepared from the product of Step
  • Step E 4-rert-Butoxycarbonyl- 1 -(2,3-dimethyl ⁇ henyl)-5(S)-(2- hvdroxyethyl)piperazin-2-one
  • Step D 4- rf-Butoxycarbonyl- 1 -(2,3-dimethylphenyl)-5(S)-(2- methoxyethyl)piperazin-2-one
  • Step G l-(2,3-Dimethylphenyl)-5(S)-(2-methoxyethyl)-4-[4-(l- triphenylmethylimidazolyl)methynpiperazin-2-one
  • the product from Step F (0.113 g, 0.312 mmol) was converted to the title compound according to the procedure described in Example 39, Step E, except using 30% trifluoroacetic acid in dichloromethane (10 mL) for 1 h for the initial deprotection. The volatiles were removed in vacuo, and the residue dissolved in dichloroethane. Triethylamine was added to obtain pH 5.
  • Step H 4- [ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]- 1 -(2,3- dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one ditrifluoroacetic acid salt
  • Step A Preparation of l-triphenylmethyl-4-(hydroxymethyl)- imidazole
  • Step C Preparation of l-(4-cyanobenzyl)-5-(acetoxymethyl)- imidazole hvdrobromide
  • a solution of the product from Step B (85.8 g, 225 mmol) and ⁇ -bromo- / tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 °C for 20 hours, during which a pale yellow precipitate formed.
  • the reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt.
  • the filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60 °C for two hours, cooled to room temperature, and filtered again.
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 °C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 °C.
  • Step D Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)- imidazole
  • Step E Preparation of l-(4-cyanobenzyl)-5- imidazolecarboxaldehvde
  • Step F Preparation of (S)-2-(fert-butoxycarbonylamino)-.V- methoxy-N-methyl-4-(methylthio)butanamide
  • L-yV-Boc-methionine (30.0 g, 0.120 mol)
  • N.O- dimethylhydroxylamine hydrochloride (14.1 g, 0.144 mol)
  • EDC hydrochloride 27.7 g, 0.144 mol
  • HOBT HOBT (19.5 g, 0.144 mol) were st ⁇ red in dry DMF (300 mL) at 20°C under nitrogen. More N,0- dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) was added to obtain pH 7-8.
  • the solution was cooled to -50 °C under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min, maintaining the temperature below -40 °C.
  • the reaction was warmed to 5°C, then recooled to -45 °C. Analysis by tic revealed incomplete reaction.
  • the solution was rewarmed to 5 °C, stirred for 30 minutes, then cooled to -50 °C.
  • Step H Preparation of (S)-2-(rerf-butoxycarbonylamino)-/V-(3- chlorophenyl)-4-(methylthio)butanamine
  • Step I Preparation of (S)-4-(tert-butoxycarbonyl)-l-(3- chlorophenyl)-5-r2-(methylthio)ethvnpiperazin-2-one
  • a solution of the product from Step H (22.0 g, 63.8 mmol) in ethyl acetate (150 mL) was vigorously stirred at 0°C with saturated sodium bicarbonate (150 mL).
  • the DMF was distilled in vacuo, and the residue partitioned between ethyl acetate and water.
  • the organic phase was washed with saturated brine, and dried over sodium sulfate.
  • the cmde product was chromatographed on silica gel with 20-25% ethyl acetate in hexane to obtain the title compound.
  • Step J Preparation of (S)-4-(tert-butoxycarbonyl)-l-(3- chlorophenyl)-5-r2-(methanesulfonyl)ethvnpiperazin-2-one
  • methanol 300 mL
  • magnesium monoperoxyphthalate 54.9 g, 111 mmol
  • MeOH 210 mL
  • the ice bath was removed, and the solution was allowed to warm to room temperature. After 45 minutes, the reaction was concentrated in vacuo to half the original volume, then quenched by the addition of 2N Na2S2 ⁇ 3 soln.
  • Step K Preparation of (S)-l-(3-chlorophenyl)-5-[2- (methanesulfonyl)ethyllpiperazin-2-one
  • Step L Preparation of (S)-l-(3-chloro ⁇ henyl)-4-[l-(4- cyanobenzyl)-5-i__ ⁇ dazolylmethyl]-5-[2-(methanesulfonyl)- ethyll-2-piperazinone dihvdrochloride
  • amine from Step K 898 mg, 2.83 mmol
  • imidazole carboxaldehyde from Step E 897 mg, 4.25 mmol
  • 15 ,2-dichloroethane was added sodium triacetoxyborohydride (1.21 g, 5.7 mmol).
  • Step B Preparation of (S)-N-(tert-butoxycarbonyl)homoserine lactol
  • Step D Preparation of (S)- ⁇ [2-(t_ ⁇ butoxycarbonylamino)-4- hydroxybutyl1-2-chloro-N-(3-chlorophenyl)acetamide
  • the aniline derivative from Step C (5.29 g, 16.9 mmol) was dissolved in 60 mL of EtOAc and 60 mL of sat. NaHC ⁇ 3 soln., then cooled to 0 °C. With vigorous stirring, chloroacetyl chloride (1.48 mL. 18.5 mmol) was added dropwise.
  • Step E Preparation of (S)-4-(t-Tt-butoxycarbonyl)-l -(3- chlorophenyl)-5-(2-hydroxyethyl)piperazin-2-one
  • Step F Preparation of (S)-4-(tert-butoxycarbonyl)-l-(3- chlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]piperazin-2- one
  • Step G Preparation of (S)-4-(tert-butoxycarbonyl)-l-(3- chlorophenyl)-5-r2-(ethylthio)ethyl1piperazin-2-one
  • sodium ethanethiolate 1. g, 16.6 mmol
  • the reaction was poured into EtOAc, washed with sat. NaHC03 and brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the cmde product which was used in the next step without further purification.
  • Step H Preparation of (S)-4-(tert-butoxycarbonyl)-l -(3- chlorophenvP-5-r2-(ethanesulfonyl)ethyllpiperazin-2-one
  • methanol 50 mL
  • magnesium monoperoxyphthalate 11.6 g, 23.5 mmol
  • Step I Preparation of (S)-l-(3-chlorophenyl)-5-[2- (ethanesulfonvPethyllpiperazin-2-one
  • Step J Preparation of (S)-l-(3-chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-5-[2- (ethanesulfonyl)ethyl1-2-piperazinone dihydrochloride
  • a solution of the amine from Step I (480 mg, 1.45 mmol)
  • imidazole carboxaldehyde from Step E of Example 42 460 mg, 2.2 mmol
  • acetic acid 0.15 mL, 7.25 mmol
  • 10 mL of 1,2- dichloroethane was added sodium triacetoxyborohydride (615 mg, 2.9 mmol).
  • the reaction was stirred for 18 hours, then quenched at 0 °C with sat. NaHC03 solution.
  • the solution was poured into CH2O2, and the organic layer was washed with brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo.
  • the resulting product was purified by silica gel chromatography (2-5% MeOH:CHCl3), to give the desired product and less polar boron complex.
  • the latter compound was taken up in dichloromethane (1 mL) and benzene (5 mL), treated with n- propylamine (1 mL) for 18 hours, and concentrated in vacuo.
  • Step A Preparation of (S)-2-( r butoxycarbonylamino)-./V-(3- chlorophenvP-3-r(triphenylmethyl)thiol- 1 -propanamine
  • 3-chloroaniline 0.09 mL. 6.70 mmol
  • dichloromethane 30 mL of dichloromethane at room temperature
  • 1.2 g of cmshed 4A molecular sieves To a solution of cmshed 4A molecular sieves. Sodium triacetoxyborohydride (3.55 g, 16.7 mmol) was added, followed by dropwise addition of N- methylmorpholine to achieve a pH of 6.5.
  • Step B Preparation of (S)- ⁇ K2-(tert-butoxycarbonylamino)-3- ((triphenylmethyl)thio)propyl]-2-chloro-.V-(3- chlorophenvPacetamide
  • Step C Preparation of (S)-4-( rt-butoxycarbonyl)-l-(3- chlorophenyl)-5-[_?-(triphenylmemyl)thiomethyljpiperazin-
  • Step D Preparation of (S)-4-(terr-butoxycarbonyl)-l-(3- chlorophenyl)-5-(thiomethyl)piperazin-2-one
  • Step E Preparation of (S)-4-(t_?rt-butoxycarbonyl)-l -(3- chlorophenyl)-5-r(ethylthio)methvnpiperazin-2-one
  • Step F Preparation of (S)-4-( rt-butoxycarbonyl)-l-(3- chlorophenvP-5-r(ethanesulfonyl)methvnpiperazin-2-one
  • a solution of the sulfide from Step E (217 mg, 0.563 mmol) in 3 mL of MeOH at 0 °C was added a solution of magnesium monoperoxyphthalate (835 mg, 1.69 mmol) in 2 mL MeOH.
  • the reaction was stirred overnight, allowing it to warm to room temperature.
  • the solution was cooled to 0 °C, quenched by the addition of 4 mL 2N Na2S2 ⁇ 3 soln., then concentrated in vacuo.
  • Step G Preparation of (S)-l-(3-chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-5-[2- (ethanesulfonyl)methyll-2-piperazinone dihvdrochloride
  • TFA trifluoroacetic acid
  • the cmde product was taken up in methanol and injected onto a preparative HPLC column and purified with a mixed gradient of 15%-50% acetonitrile/0.1% TFA; 85%-50% 0.1% aqueous TFA over 60 minutes. After concentration in vacuo, the resultant product was partitioned between dichloromethane and aq. NaHC ⁇ 3 soln., and the aqueous phase was extracted with CH2CI2. The organic solution was washed with brine, dried (Na2S ⁇ 4), filtered, and concentrated to dryness to provide the product free base, which was taken up in CH2CI2 and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.
  • Step A Preparation of (S)-4-(tert-butoxycarbonyl)-l-(3- chlorophenyl)-5-r2-(oxo)ethyllpiperazin-2-one
  • the aqueous layer was acidified to pH 3 with 2.75 M KHSO4 soln., and extracted several times with EtOAc. The combined organic extracts were dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the titled carboxylic acid.
  • Step C Preparation of (S)-4-(tert-butoxycarbonyl)-5-[.V-eti ⁇ yl-2- acetamidol- 1 -(3-chlorophenyl)piperazin-2-one
  • Step D Preparation of (S)-l-(3-chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetamido]-
  • Step A Preparation of l-(methanesulfonyl)-2-butvne
  • Step B Preparation of ( ⁇ )-ethyl 2-[(phenylmethyl)imino]-4- hexynoate
  • Step C Preparation of ( ⁇ )-ethyl 2-[(tert-butoxycarbonyl)amino]-4- hexynoate
  • Step D Preparation of ( ⁇ )-2-[(tert-butoxycarbonyl)amino]-4- hexynoic acid
  • Step E Preparation of ( ⁇ )-2-(tert-butoxycarbonylamino)-./V- methoxy-N-methyl-4-hexynamide
  • Step F Preparation of ( ⁇ )-2-(tert-butoxycarbonylamino)-4-hexynal
  • Step G Preparation of ( ⁇ )-2-(tert-butoxycarbonylamino)-_V-(3- chlorophenyl)-4-butynamine
  • Step H Preparation of ( ⁇ )-/v/-[2-(tet -butoxycarbonylamino)-4- hexynyll-2-chloro- ⁇ -(3-chlorophenyl)acetamide
  • a solution of the product from Step G (1.68 g, 5.22 mmol) and triethylamine (1.20 mL, 8.61 mmol) in 15 mL of CH2CI2 was cooled to 0 °C. Chloroacetyl chloride (0.457 mL, 5.74 mmol) was added dropwise, and the reaction was maintained at 0 °C with stirring.
  • Step I Preparation of ( ⁇ )-4-(tert-butoxycarbonyl)-5-(2-butynyl)- l-(3-chlorophenyl)-2-piperazinone To a solution of the chloroacetamide from Step H (1.68 g,
  • Step J Preparation of ( ⁇ )-5-(2-butynyl)-l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone dihydrochloride
  • Step B Preparation of -V-(tert-butoxycarbonyl)-/V'-(3- chlorophenvPethylenediamine
  • Step A The amine hydrochloride from Step A (ca. 282 mmol, cmde material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHC03 soln., cooled to 0 °C, and di-tert- butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without further purification.
  • Step C Preparation of ⁇ [2-(t ⁇ rt-butoxycarbamoyl)ethyl]-/V-(3- chlorophenyl)-2-chloroacetamide
  • Step D Preparation of 4-(tert-butoxycarbonyl)-l-(3-chlorophenyl)- 2-piperazinone
  • Step E Preparation of l-(3-chlorophenyl)-2-piperazinone
  • Step F Preparation of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyn-2-piperazinone dihydrochloride
  • a solution of the amine from Step E (55.4 mmol, prepared above) in 200 mL of 1 ,2-dichloroethane at 0 °C was added 4A powdered molecular sieves (10 g), followed by sodium triacetoxyborohydride (17.7 g, 83.3 mmol).
  • the imidazole carboxaldehyde from Step E of Example 42 (11.9 g, 56.4 mmol) was added, and the reaction was stined at 0 °C.
  • Step B 4-Bromo- 1 -(4-cyanobenzyl)-2-methylimidazole-5- carboxaldehvde
  • reaction was stined at -10°C for 2 h, and a further 4 h at 20°C.
  • reaction was diluted with water and extracted with ethyl acetate.
  • Step C 1 -(4-C vanobenz yl)-2-methylimidazole-5 -carboxaldeh vde
  • Step A 4-(tert-Butyldimethylsilyloxymethyl)- 1 - triphenylmethylimidazole tert-Butyldimethylsilylchloride (2.83 g, 18.76 mmol) was added to a suspension of 4-hydroxymethyl-l-triphenylmethylimidazole (5.80 g, 17.05 mmol) in DMF (200 mL) containing imidazole (3.48 g, 51.1 mmol). After 15 min, a clear colorless solution was obtained which was stined at room temperature. When reaction was complete, the DMF was removed in vacuo and the residue patitioned between ethyl acetate and water.
  • Step B 5- rt-Butyldimethylsilyloxymethyl- 1 -(4- cvanobenzvPimidazole
  • Step C 5-tert-Butoxydimethylsilyloxymethyl- 1 - [2-(4- cvanophenvP-2-propyl)l imidazole
  • a solution of lithium hexamethyldisilazide (4.61 mL, 1 M in THF) was added and the reaction stined at -78°C for 1 h, then warmed to -60°C over 30 min.
  • the reaction was cooled to -78°C, methyl iodide added (0.287 mL, 4.61 mmol), and stirring continued at -78°C for an additional 2 h, before warming to 0°C over 2 h. After 30 min, the reaction was cooled to -78°C, and lithium hexamethyldisilazide (4.61 mL, 1 M in THF) added. After 1 h, methyl iodide was added (0.287 mL, 4.61 mmol) and the reaction allowed to warm to room temperature ovemight. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase washed with saturated brine.
  • Tetra-N-butylammonium fluoride (2.99 mL, 1M in THF) was added to a solution of 5- rt-butoxydimethylsilyloxymethyl-l-[2-(4- cyanophenyl)-2-propyl)]imidazole (0.750 g, 2.72 mmol) in THF (10 mL). After 2 h at room temperature, the reaction was poured into ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic phase was extracted with saturated brine, and dried over magnesium sulfate. The cmde product was chromatographed on silica gel with 3% methanol in ethyl acetate. The title compound was obtained as a semi-solid.
  • Step E 1 -[2-(4-Cyanophenyl)-2-propyl)]imidazole-5- carboxaldehyde
  • Step F 4-[l-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]-l-
  • Step A N-(2-Methylphenyl)-2(S)-(tert-butoxycarbonylamino)- hexanamine
  • the tide compound was prepared according to the procedure described in Example 39, Step C, except using o-toluidine (0.32 mL, 3.00 mmol), 2(S)-(r_?rt-butoxycarbonylamino)hexanal (0.538, 2.50 mmol), sodium triacetoxyborohydride (0.795 g, 3.75 mmol) in dichloroethane (10 mL)
  • o-toluidine 0.32 mL, 3.00 mmol
  • 2(S)-(r_?rt-butoxycarbonylamino)hexanal 0.538, 2.50 mmol
  • sodium triacetoxyborohydride 0.795 g, 3.75 mmol
  • Step B 4-fert-Butoxycarbonyl-5(S)- «-butyl- l-(2- methylphenyl)piperazin-2-one
  • the title compound was prepared essentially according to the procedure described in Example 39, Step D, except using N-(2- methylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine (0.506 g, 1.65 mmol), chloroacetyl chloride (0.158 mL, 1.98 mmol) in ethyl acetate-saturated sodium bicarbonate at 0°C.
  • Step C 5(S)-n-Butyl-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]- 1 -(2-methylphenyl)piperazin-2-one dihydrochloride
  • Step A 4- rt-Butoxycarbonyl- 1 -(3-chlorophenyl)-5(S)-(2- fluoroethyl)-piperazin-2-one 4-tert-Butoxycarbonyl- 1 -(3-chlorophenyl)-5(S)-(2- methylsulfonyloxyethyl)- piperazin-2-one (0.433 g, 1.00 mmol) and fert-butylammonium fluoride (3.0 mL, 1M in THF) were stined at room temperature in acetonitrile (5 mL) for 72 h. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using 20% ethyl acetate in hexane. The tide compound was obtained as a thick oil.
  • Step B 4-[l-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2- fluoroethyl)-l-(3-chlorophenyl)piperazin-2-one dihydrochloride
  • the title compound was prepared according to the procedure described in Example 39, Step E, except using l-(3-chlorophenyl)-5(S)-(2- fluoroethyl)piperazin-2-one ditrifluoroacetic acid salt, l-(4- cyanobenzylimidazole)-5-carboxaldehyde (0.114 g, 0.54 mmol), and sodium triacetoxyborohydride (0.172 g, 2.25 mmol) in dichloroethane (5 mL).
  • the cmde product was injected onto a preparative HPLC column and purified with a mixed gradient of acetonitrile/0.1% TFA and 0.1% aqueous TFA.
  • Step A 3-(4-Cvanobenzyl)pyridin-4-carboxylic acid methyl ester
  • 4-cyanobenzyl bromide 625 mg, 3.27 mmol
  • dry THF 4mL
  • activated Zn dust; 250 mg
  • dry THF 2 mL
  • the ice-bath was removed and the slurry was stined at room temperature for a further 30 min.
  • 3-bromopyridin-4- carboxylic acid methyl ester 540 mg. 2.5 mmol
  • dichlorobis(triphenylphosphine)nickel II
  • Step B 3-(4-Cvanobenzyl)-4-(hvdroxymethyl)pyridine
  • the title compound was obtained by sodium borohydride (300 mg) reduction of the ester from Step A (415 mg) in methanol (5 mL) at room temperature. After stining for 4 h the solution was evaporated and the product was purified on silica gel, eluting with 2% methanol in chloroform to give the title compound. FAB ms (M+1) 225.
  • the title compound was obtained by activated manganese dioxide (l.Og) oxidation of the alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10 mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp 80-83°C.
  • Step D 4-[3-(4-Cyanobenzyl)pyridine-4-yl]- l-(3-chlorophenyl)-
  • Step A l-Trityl-4-(4-cvanobenzyl)-imidazole.
  • THF tetrahydrofuran
  • dibromoethane 0.315ml, 3.60mmol
  • the suspension was cooled to 0°C and ⁇ -bromo-p-tolunitrile (9.33g, 47.6mmol) in THF (100ml) was added dropwise over a period of 10 min.
  • Step B 1 -Methyl acetyl-5-(4-cvanobenzyl)-imidazole.
  • Step C l-Hydroxyethyl-5-(4-cvanobenzyl)-imidazole.
  • Step D 2-(-5-(4-Cvanobenzyl)-imidazolyPethyl methanesulfonate
  • methylene chloride 70ml
  • Hunigs base 0.489ml, 2.81 mmol
  • methane sulfonyl chloride 0.219ml, 2.81mmol
  • the reaction was quenched by addition of saturated NaHC ⁇ 3 solution (50ml) and the mixture extracted with methylene chloride (50ml), dried MgS04 and the solvent evaporated in vacuo.
  • Step E 4-[5-(4-Cyanobenzyl)- 1 -imidazolylethyl]- 1 -(3- chlorophenyPpiperazin-2-one.
  • a solution of 2-(-5-(4-cyanobenzyl)-imidazolyl)ethyl methanesulfonate (24 mg, 0.079 mmol) in DMF (0.2ml) was added to 3- (chlorophenyl)piperazin-2-one( 17.7mg, 0.084mmol), sodium iodide (50mg, 0.336mmol) and Hunigs base (0,0146ml, 0.084mmol).
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-W-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-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 incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid

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