EP0944388A4 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase

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Publication number
EP0944388A4
EP0944388A4 EP97921256A EP97921256A EP0944388A4 EP 0944388 A4 EP0944388 A4 EP 0944388A4 EP 97921256 A EP97921256 A EP 97921256A EP 97921256 A EP97921256 A EP 97921256A EP 0944388 A4 EP0944388 A4 EP 0944388A4
Authority
EP
European Patent Office
Prior art keywords
substituted
unsubstituted
alkyl
ylmethyl
aryl
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Withdrawn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
EP97921256A
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German (de)
English (en)
Other versions
EP0944388A2 (fr
Inventor
Neville J Anthony
Christopher Dinsmore
Robert P Gomez
John H Hutchinson
John S Wai
Theresa M Williams
Ian M Bell
Mark W Embrey
Thorsten E Fisher
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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Publication date
Priority claimed from GBGB9609981.7A external-priority patent/GB9609981D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0944388A2 publication Critical patent/EP0944388A2/fr
Publication of EP0944388A4 publication Critical patent/EP0944388A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D401/02—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • C07D401/02—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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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 conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termiria.t.kl by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R.
  • Mutated ras genes are found in marry- 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 involve ⁇ ⁇ th 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 57(9:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
  • farnesyl-protein transferase or geranylgeranyl-protein transferase which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
  • 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.
  • Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol Chem., 265: 14701 - 14704 (1990); Schafer et al, Science, 249: 1 133- 1139 (1990); Manne et al, Proc. Natl Acad. Sci USA, 37:7541 -7545 (1990)).
  • Inhibition of farnesyl 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 farnesyl-protein transferase
  • FPP farnesyl 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 farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. 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.
  • farnesyl-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 farnesyl-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 piperidine-containing compounds which inhibit the farnesyl-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 farnesyl transferase inhibitors and methods for their production are further contained in this invention.
  • the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula A:
  • Rla and R lb are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R ⁇ 0 ⁇ , R ⁇ lS(0) m -, Rl0C(O)NR ⁇ 0., (R 10) 2 N- C(O)-, CN, N ⁇ 2, (R 1 0) 2 N-C(NRl )_, R10 C (O)-, N3, -N(RlO)2, or R 1 l ⁇ C(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Ci -Cfj alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R i OO-, R
  • Rlc is selected from: a) hydrogen, b) 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, R ⁇ O-, R U S(0) m -, RlOC(0)NRlO-, (R10) 2 N-C(O)-, CN, (R!0) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, and Rl 1 OC(O)-NR10-, and c) unsubstituted or substituted aryl;
  • 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, unsubstituted or
  • substituted heterocycle OR 10, O O wherein the substituted group is substituted with one or more of:
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR6a, S(0)R6a, S ⁇ 2R 6a , 2) C3-6 cycloalkyl,
  • 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(CORI O)- ;
  • R4 and R ⁇ are independently selected from H and CH3;
  • 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) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, 1 e) o
  • R6 and R ⁇ may be joined in a ring;
  • R7 and R ⁇ a may be joined in a ring;
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R I OQ-, Rl lS(0) m -, Rl0C(O)NRl0.
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOo, Rl lS(0)m-, R 1 0 C(O)NRl0-, (Rl0) 2 NC(O)-, R 10 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, (Rl0)2NC(O)-, Rl0 2 N-C(NRlO)-, CN, Rl ⁇ c( ⁇ )-, N3, -N(Rl0)2, or Rl l ⁇ C(O)
  • RlO is independently selected from hydrogen, C ] -Cl4 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • R 1 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl
  • R 2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of:
  • aryl or heterocycle unsubstituted or substituted with: a) Cl -4 alkyl, b) (CH2)pOR6 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Ci-4 alkyl, h) SR6a, S(0)R6a, S ⁇ 2R 6a ,
  • 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 1 is a bond, n is 0 and A ⁇ is S(0)m;
  • W is a heterocycle
  • Y is selected from: a) hydrogen, b) RlOo-, Rl l S(0)m-, R10C(O)NR10-, (R10) 2 N-C(0)-, CN, N02, (R 10 )2N-C(NRl )-, R12C(0)-, RI OOC(O)-, N3, F, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) unsubstituted or substituted C 1 -C6 alkyl wherein the substitutent on the substituted C1 -C alkyl is selected from unsubstituted or substituted aryl, R!0O-, Rl C(O)NRl0-, (RlO) 2 N-C(0)-, RlOC(O)- and Rl QC(O)-;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1 ; t is 0 or 1 ; u is 4 or 5; and v is 0, 1 or 2;
  • Rla and R b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C] 0 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, Rl o-, Rl lS(0) m -, R1 C(O)NR 10-, (RlO) 2 N- C(O)-, CN, N02, (Rl°)2N-C(NRlO)-, Rl0c(O)-, N3,
  • R n S(0) m -, Rl0C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, (Rl0) 2 N-C(NRl0)_, R10C(O)-, N3, -N(RlO) 2 , and Rl l ⁇ C(O)-NRl0- ;
  • Rlc is selected from: a) hydrogen, b) unsubstituted or substituted Cl-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 U S(0)m-, R 10 C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, (Rl ) 2 N-C(NRl )-, RlOc(
  • R2 and R ⁇ are independently selected from: H; unsubstituted or substituted C l-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or
  • substituted heterocycle ORlO, O O wherein the substituted group is substituted with one or more of:
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR6a, S(0)R6 s ⁇ 2R 6a ,
  • 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(CORl O). ;
  • R4 and R5 are independently selected from H and CH3;
  • R2, R3, R4 an( j R5 are optionally attached to the same carbon atom;
  • R6, R7 and R7 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) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO, e, ) 11
  • R6 and R7 may be joined in a ring; R7 and R7 may be joined in a ring;
  • R6 is selected from: C l-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, Rl o-, Rl l S(0) m -, R l C(0)NRlO-, (RlO) 2 NC(0)-, R!0 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or RH OC(O)NR 1 -, and c) C 1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, Rl 0
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R Oo-, Rl lS(0)m-, R 10 C(O)NRl0-, (R! 0) 2NC (O)-,
  • R is independently selected from hydrogen, C]-Cl4 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • R! 1 is independently selected from Cl-C6 alkyl and substituted or unsubstituted 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-C2O alkenyl, provided that V is not hydrogen if A 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 an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(0) m R 6a , or g) -C(0)NR6R7,
  • Rl a is independently selected from: hydrogen or C1 -C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R lO)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOo- and -N(R 10)2;
  • Rlc is selected from: a) hydrogen, b) 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 l S(0) m -, Rl0C(O)NRl0-, (RlO) 2 N-C(0)-, CN, (R10) 2 N-C(NR 10)-, R10C(O)-, RlO ⁇ C(O)-, N3, -N(R O)2, and R lOC(O)-NRl0-, and c) unsubstituted or substituted aryl;
  • R3, R4 and R ⁇ are independently selected from H and CH3;
  • R6, R7 and R a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R ⁇ a is selected from:
  • R8 is independently selected from: a) hydrogen, b) C l -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, CJ -C6 perfluoroalkyl, F,
  • RlO is independently selected from hydrogen, C1-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • R is independently selected from C1-C alkyl and substituted or unsubstituted aryl
  • Rl2 is selected from: H; unsubstituted or substituted Cl -8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of:
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR6a, S(0)R6a S02R 6a
  • 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) 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, 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 A ⁇ is S(0)m;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Y is selected from: a) hydrogen, b) R OO-, Rl lS(0) m -, R 10 C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, N02, (RlO)2N-C(NRlO)-, Rl2c(0)-, RlO ⁇ C(O)-, N3, F, -N(Rl )2, or RHOC(O)NR1 -, and c) unsubstituted or substituted C ] -C6 alkyl wherein the substitutent on the substituted C 1 -C6 alkyl is selected from unsubstituted or substituted aryl, RJOo-, R1 C(O)NR 1 °-, (RlO)2N-C(0)-, RlOC(O)- and Rl O ⁇ C(O)-;
  • Z is an unsubstituted or substituted group selected from aryl and heterocycle, wherein the substituted group is substituted with one or more of the following:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle,
  • Rla is independently selected from: hydrogen or C l -C6 alkyl
  • Ri is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(Rl0)2 or C2-C6 alkenyl, c) unsubstituted or substituted Cl -C6 alkyl wherein the substitutent on the substituted C 1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, Rl O- and -N(RlO)2;
  • Rlc is selected from: a) hydrogen, b) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R Oo-, Rl lS(0)m-, Rl°C(O)NRl0-, (RlO) 2 N-C(0)-, CN,
  • R3, R 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 R7 a re independently selected from:
  • R6 is selected from:
  • R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, Rl OO-, R10C(O)NR 10-, CN, N ⁇ 2, (RlO)2N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl substituted by Cl-C6 perfluoroalkyl, Rl°0-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, Rl o-, Rl lS(0) m -, R 1°C(0)NR 10-, CN, NO2, (R10) 2 N-C(NR10)-, RlOc(O)-, -N(Rl )2, or Rl OC(O)NRl0-, and c) C l -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, Rl O-, RHS(0) m -, R 10 C(O)NRl0-, CN, (Rl )2N-C(NRlO)-, RlOc(O)-, -N(Rl )2, or R1 1OC(O)NR10- ;
  • R lO is independently selected from hydrogen, C1 -C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • Rl 1 is independently selected from Cl-C6 alkyl and substituted or unsubstituted 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) 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, and 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)m,
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Z is an unsubstituted or substituted aryl , wherein the substituted aryl is substituted with one or more of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle,
  • R a is selected from: hydrogen or C1 -C6 alkyl
  • Ri is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R 10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or
  • Rlc is selected from: a) hydrogen, b) 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-, Rl lS(0) m -, Rl°C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, R lO ⁇ C(O)-, N3, -N(RlO)2, and Rl l ⁇ C(O)-NRl0-, and c) unsubstituted or substituted aryl;
  • R3 and R independently selected from H and CH3;
  • R 2 is selected from H; ORl°; T O ; or Cl -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R , R3 and R4 are optionally attached to the same carbon atom;
  • R6 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R6a is selected from:
  • R is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, Rl O-, R !0C(O)NR 1 -, CN, N ⁇ 2, (RlO) N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl substituted by C1 -C6 perfluoroalkyl, Rl° ⁇ -, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, R10C(O)-,
  • RI is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl;
  • R 2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl,
  • 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-C2O alkenyl, and provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A is a bond, n is 0 and A is S(0) m ;
  • Y is selected from: a) hydrogen, b) RlOO-, Rl lS(0)m-, R !°C(O)NR 10-, (Rl0) 2 N-C(O)-, CN, N ⁇ 2, (RlO)2N-C(NRlO)-, R ! 2C(0)-, RlO ⁇ C(O)-, N3, F, -N(Rl )2, or Rl 10C(0)NR10-, c) unsubstituted or substituted C1 -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, Rl O-, R! 0C(O)NR10-, (RlO)2N-C(0)-, RlOC(O)- and RlO ⁇ C(O)-;
  • Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Cl -4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(0) m R6a, or
  • Rl a is selected from: hydrogen or C1-C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(RlO) 2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, Rl OO-, or
  • Rlc is selected from: a) hydrogen, b) 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-, Rl lS(0)m-, RlOC(0)NRlO-, (RlO) 2 N-C(0)-, CN, (RlO) 2 N-C(NRlO)-, Rl0c(O)-, RlO ⁇ C(O)-, N3,
  • R3 and R4 independently selected from H and CH3;
  • NR 6 R 7 R2 is selected from H; OR 10; O G r Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R , R3 and R4 are optionally attached to the same carbon atom;
  • R6 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R6 is selected from:
  • R is independently selected from: a) hydrogen, b) C l -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C ⁇ perfluoroalkyl, F, Cl, Rl O-, R1 C(O)NR 10-, CN, N02, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(Rl0)2, or Rl lOC(O)NRl0-, and c) C 1 -C ⁇ alkyl substituted by C l -C6 perfluoroalkyl, R 1 O-,
  • R ⁇ a is hydrogen or methyl
  • R O is independently selected from hydrogen, C1-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • R is independently selected from -C6 alkyl and substituted or unsubstituted 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) C] -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 A is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A is S(0) m ;
  • Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Cj-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO,
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl O-, -N(RlO)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlO ⁇ -, or
  • Rlc is selected from: a) hydrogen, b) unsubstituted or substituted Cl-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-, R lS(0)m-, Rl0C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, (R10) 2 N-C(NR10)-, R10C(O)-, RlOoC(O)-, N3, -N(RlO)2, and RUOC(O)-NR10-, and c) unsubstituted or substituted aryl;
  • R3 and R independently selected from H and CH3;
  • R is selected from H; OR ⁇ O ; O or Cl-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 3 and R4 are optionally attached to the same carbon atom;
  • R° R and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R6 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 l -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, RlOO-, R 1 C(O)NR 10-, CN, N ⁇ 2,
  • R O is independently selected from hydrogen, C1 -C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • Rl is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl
  • Rl2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of:
  • Y is selected from: a) hydrogen, b) RlOo-, Rl lS(0) m -, R 1°C(0)NR10-, (R 10 )2N-C(O)-, CN, N02, (R )2N-C(NRlO)-, R!
  • Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1 ) Cl-4 alkyl, unsubstituted or substituted with: a) C]-4 alkoxy, b) NROR7,
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(RlO) 2 or C2-C6 alkenyl, c) C1-C alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO) 2;
  • Rlc is selected from: a) hydrogen, b) 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-, R lS(0) m -, R 1°C(0)NR10-, (Rl0) 2 N-C(O)-, CN,
  • R3 and R independently selected from H and CH3;
  • R is selected from H; ORlO; O or C l -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6, R7 and R7a are independently selected from:
  • R6a is selected from:
  • R is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, R OO-, R!0C(O)NR 0-, CN, N02, (R10) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-, and c) C1 -C6 alkyl substituted by C1 -C perfluoroalkyl, R OO-, RlOC(0)NRlO-, (R10) 2 N-C(NR 10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or Rl lOC(0)NRlO-;
  • RlO is independently selected from hydrogen, C j-C l4 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl
  • 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 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 structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzoxazolidinonyl, benzoxazinonyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholiny
  • 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.
  • 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 substitutent(s) R2 and R3 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 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, NO2, CN, (C1 -C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C] -C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, iso
  • 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 Rib are independently selected from: hydrogen, -N(RlO) 2 , Rl c(0)NRlO- or unsubstituted or substituted C 1 -C6 alkyl wherein the substituent on the substituted C l -C alkyl is selected from unsubstituted or substituted phenyl, -N(Rl O) 2 , RlOo- and R ' 0C(O)NR10-.
  • Rla and R ⁇ b are independently selected from: hydrogen or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) 2 , RIO ⁇ - and R!OC(0)NR10-.
  • R is selected from: H, OR ,
  • 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 C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R6a is unsubstituted or substituted C1 -C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R 0 is hydrogen or methyl.
  • R9 is hydrogen.
  • RlO is selected from H, C1-C6 alkyl and substituted and unsubstituted benzyl.
  • Rl2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, suvbstituted aryl or substituted heterocycle is substituted with one or more of:
  • aryl or heterocycle unsubstituted or substituted with: a) Cl-4 alkyl, b) halogen, c) CN, d) perfluoro-Cl-4 alkyl,
  • Al and A2 are independently selected from: a bond, -C(O)NRl0-, -NR10C(O)-, O, -N(R10)-, -S(0)2N(R1 )- and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • ⁇ l is a bond
  • Y is selected from hydrogen, RlOO-, Rl0C(O)NRl0-, (Rl0) 2 N-C(O)-, R12C(0)-, Rl ⁇ C(O)-, -N(Rl ) 2 , and unsubstituted or substituted Cl-C6 alkyl. More preferably, Y is RlOO-, RlO ⁇ C(O)- and unsubstituted or substituted Cl-C6 alkyl.
  • 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 or unsubstituted or substituted naphthyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, 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.
  • -N(RlO)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 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. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-29, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • Substituents R a and Rb, as shown in the Schemes, represent the substituents R2, R3 5 R4 ? anc j R5; substituent "sub” represents a suitable substitutent on the substituent Z.
  • the point of attachment of such substituents to a ring is illustrative only and is not meant to be limiting.
  • These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
  • a suitably substituted Boc protected isonipecotate I may be deprotonated and then treated with a suitably substituted alkylating group, such as a suitably substituted benzyl bromide, to provide the gem disubstituted intermediate III.
  • a suitably substituted alkylating group such as a suitably substituted benzyl bromide
  • Deprotection and reduction provides the hydroxymethyl piperidine IV which can be utilized is synthesis of compounds of the invention or which may be nitrogen-protected and methylated to give the intermediate V.
  • the protected piperidine intermediate III can be deprotected and reductively alkylated with aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or l-trityl-4- imidazolylacetaldehyde, to give products such as VI.
  • aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or l-trityl-4- imidazolylacetaldehyde
  • the trityl protecting group can be removed from VI to give VII, or alternatively, VI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole VIII.
  • the deprotected intermediate Ilia can also be reductively alkylated with a variety of other aldehydes, such as IX, as shown in Scheme 3.
  • 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 with trifluoroacetic acid in methylene chloride to give the final compound XI.
  • 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. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
  • the intermediate Ilia can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures shown in Scheme 4, 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 piperidine Ilia in the presence of condensing reagents such as 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
  • EDC 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide
  • Scheme 4a illustrates the reductive alkylation of intermediate IV to provide a 4-cyanobenzylimidazolyl substituted piperidine.
  • the cyano moiety may be selectively oxidized with sodium borate to provide the corresponding amido compound of the instant invention.
  • Scheme 4c alternative preparation of the methyl ether intermediate V and the alkylation of V with a suitably substituted imidazolylmethyl chloride to provide the instant compound.
  • Preparation of the homologous l-(imidazolylethyl)pi ⁇ eridine is illustrated in Scheme 4d.
  • the piperidine Ilia is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 5, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 5, 6).
  • 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 6), or tertiary amines.
  • the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperidine such as XXXII (Scheme 7). Treating XXVII with l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. 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.
  • a nucleophile such as a thiol
  • piperidine Ilia can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, as shown in Scheme 8, 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.
  • Scheme 9 illustrates the synthesis of the instant compounds wherein the moiety Z is attached directly to the piperidine ring.
  • the piperidone XLII is treated with a suitably substituted phenyl Grignard reagent to provide the gem disubstituted piperidine XLIII.
  • Deprotection provides the key intermediate XLIV.
  • Intermediate XLIV may be acetylated as described above to provide the instant compound XLV (Scheme 10).
  • Scheme 1 1 the protected piperidine XLIII may be dehydrated and then hydroborated to provide the 3- hy droxy piperidine XLVI.
  • This compound may be deprotected and further derivatized to provide compounds of the instant invention (as shown in Scheme 12) or the hydroxyl group may be alkylated, as shown in Scheme 11, prior to deprotection and further manipulation.
  • the dehydration product may also be catalytically reduced to provide the des-hydroxy intermediate XL VIII, as shown in Scheme 13, which can be processed via the reactions illustrated in the previous Schemes.
  • Schemes 14 and 15 illustrate further chemical manipulations of the 4-carboxylic acid functionality to provide instant compounds wherein the substituent Y is an acetylamine or sulfonamide moiety.
  • Scheme 16 illustrates incorporation of a nitrile moiety in the 4-position of the piperdine of the compounds of formula A.
  • the hydroxyl moiety of a suitably substituted 4-hydroxypiperidine is substituted with nitrile to provide intermediate IL, which can undergo reactions previously described in Schemes 1-8.
  • Scheme 17 illustrates the preparation of several pyridyl intermediates that may be utilized with the piperdine intermediates such as compound I in Scheme 1 to provide the instant compounds.
  • Scheme 18 shows a generallized reaction sequence which utilizes such pyridyl intermediates.
  • Compounds of the instant invention wherein ⁇ l is a carbonyl moiety may be prepared as shown in Scheme 19.
  • Intermediate L may undergo subsequent reactions as illustrated in Schemes 1-8 to provide the instant compounds.
  • Preparation of the instant compounds wherein ⁇ l is sulfur in its various oxidation states is shown in Scheme 20.
  • Intermediates LI-LIV may undergo the previously described reactions to provide the instant compounds.
  • Scheme 21 illustrated preparation of compounds of the formula A wherein Y is hydrogen.
  • suitably substituted isonipecotic acid may be treated with N,0-dimethylhydroxylamine and the intermediate LV reacted with a suitably substituted phenyl Grignard reagent to provide intermediate LVI. That intermediate may undergo the reactions previously described in Schemes 1-8 and may be further modified by reduction of the phenyl ketone to provide the alcohol LVII.
  • Compounds of the instant invention wherein ⁇ l is an amine moiety may be prepared as shown in Scheme 22.
  • the N-protected 4-piperidinone may be reacted with a suitably substituted aniline in the presence of trimethylsilylcyanide to provide the 4-cyano-4- aminopiperidine LVIII.
  • Intermediate LVIII may then be converted in sequence to the corresponding amide LIX, ester LX and alcohol LXI.
  • Intermediates LIX-LXI can be deprotected and can then undergo the reactions previously described in Schemes 1 -8 to provide the compounds of the instant invention.
  • R CH , CH CH
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and the 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 alFASEB 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 corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried corn 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.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-protein transferase
  • 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 farnesyl 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 the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step A l-Triphenylmethyl-4-(hydroxymethyl)-imidazole.
  • Step B l-Triphenylmethyl-4-(acetoxymethyl)-imidazole.
  • the alcohol from Step A (260 mmol, prepared above) was suspended in pyridine (500 ml).
  • Acetic anhydride (74 ml, 780 mmol) was added dropwise, and the reaction was stirred for 48 hrs during which it became homogeneous.
  • the solution was poured into EtOAc, washed sequentially with water, 5% aqueous HCl solution, saturated aqueous NaHC ⁇ 3, solution, and brine, the organic extracts were dried (Na2S ⁇ 4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
  • Step C 1 -(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide
  • the filtrate was concentrated in vacuo to a volume (100 m), reheated at 60 °C for another 2hrs, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500ml), and warmed to 60 °C. After 2hrs, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
  • Step D l -(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole
  • 3: 1 THF/water (1.5 1) at 0 °C lithium hydroxide monohydrate (18.9 g, 450 mmol).
  • EtOAc EtOAc
  • 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 E 1 -(4-Cvanobenzyl -5-imidazole carboxaldehyde.
  • DMSO 500ml
  • S ⁇ 3-pyridine complex 40.5 g, 254 mmol
  • the reaction was poured into EtOAc, washed with water and brine, dried (Na2S04), and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure without further purification.
  • Step F N-t-Butoxycarbonyl-4- (3-methylphenyl)-4-hydroxy piperidine.
  • Step G 4-(3-Methylphenyl)-4-hydroxypiperidine hydrochloride.
  • Step H N- ⁇ [l-(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl ⁇ -4-(3- methylphenyl)-4 hydroxy piperidine.
  • 4-(3-methylphenyl)-4-hydroxypiperidine hydrochloride 457mg, 2.00mmol
  • the aldehyde from step E 508mg, 2.41 mmol
  • 3 A molecular sieves 2.0 g
  • sodium cyanoborohydride (2.20 ml of a I M solution in THF, 2.20 mmol).
  • the pH was adjusted to 5 by addition of acetic acid and the reaction stirred under argon for 48hrs at room temperature.
  • Step A N-t-Butoxycarbonyl isonipecotic acid.
  • Step B N-t-Butoxycarbonyl isonipecotic acid methyl ester
  • N-t-butoxycarbonyl isonipecotic acid methyl ester (lO.lg 41.8 mmol) in 140 ml of dry THF at -78°C was added LDA (59 ml of a 1.0 M solution in THF , 59 mmol) over 15 min.
  • LDA 59 ml of a 1.0 M solution in THF , 59 mmol
  • the resulting orange solution was stirred at -78°C for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs.
  • the reaction was quenched with saturated aqueous NH4CI, diluted with H2O, and extracted with EtOAc.
  • Step D 4-(2-Methylbenzyl)-isonipecotic acid methyl ester hydrochloride salt.
  • Step E N- ⁇ [ 1 -(4-Cy anobenzyl)- 1 H-imidazol-5-y ljmethy 1 ⁇ -4-(2- methylbenzyPisonipecotic acid methyl ester.
  • Step A 1 H-Imidazole-4- acetic acid methyl ester hydrochloride.
  • Step B 1 -(Triphenylmethyl)- 1 H-imidazol-4-y lacetic acid methyl ester.
  • Step C [l-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester.
  • Step D ri -(4-Cyanobenzyl)-lH-imidazol-5-yllacetic acid.
  • Step E N- ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-y llacety 1 ⁇ -4-(3- methylphenyl)-4 hvdroxy piperidine.
  • Step A 1 -(4 Cvanobenzyl)-5-nitro- 1 H-imidazole.
  • Step B l-(4 CyanobenzyP-5- amino- lH-imidazole hydrochloride.
  • Step C N- ⁇ 1 -(4 Cyanobenzyl)- 1 H-imidazol-5-yl-aminocarbony 1 ⁇ - 4-(2-methylbenzyl) isonipecotic acid methyl ester.
  • Step A 2- ⁇ l-(Triphenylmethyl)-lH-imidazol-4-yl ⁇ -2-(4- cyanobenzyP-acetic acid methyl ester.
  • Step B 2- ⁇ 1 -(Triphenylmethyl)- lH-imidazol-4-yl ⁇ -2-(4- cyanobenzyP-acetic acid.
  • Step C 2(R,S)- ⁇ 1 -(Triphenylmethyl)- 1 H-imidazol-4-yl ⁇ -2-(4- cyanobenzyl)-acetyl-4-(2-methylbenzyl) isonipecotic acid methyl ester.
  • Step D 2(R,S)-N ⁇ -2- ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]-2-(4- cyanobenyl) ⁇ acetyl-4-(2-methylbenzyl)-isonipecotic acid methyl ester.
  • Step A 2- [l-(Naphth-2-ylmethyl)-lH-imidazol-5-yI)]acetic acid methyl ester.
  • 2-(bromomethyl)- naphthalene was added to a solution of the product of example 4 step B (4.36g, 11.4 mmol) in acetonitrile (70 ml) and 2-(bromomethyl)- naphthalene and heated to 55°C for 4hr. The reaction was cooled to room temperature and the resulting white precipitate was collected by filtration. The filtrate was concentrated to 30 ml and heated at 55°C for 18 hr. After this time, the reaction was cooled to room temperature and the resulting white precipitate collected by filtration.
  • the filtrate was concentrated to 10 ml volume and heated to 55°C for 1 hr.
  • the reaction was cooled to room temperature and diluted with ethyl acetate (25 ml).
  • the resulting precipitate was collected by filtration and combined with the previous 2 precipitates in methanol (100 ml) and heated to reflux for 30 min. After this time, the solvent was removed in vacuo and the resulting residue was partitioned between methylene chloride (200 ml) and saturated sodium bicarbonate solution (100 ml).
  • the organic layer was evaporated to dryness in vacuo and the residue purified by chromatography (Si ⁇ 2, gradient elution, 0-6% methanol in methylene chloride) to provide the title compound as an off white solid.
  • Step B 2-[l-(Naphth-2-ylmethyl)-lH-imidazol-5-yl]acetic acid hydrochloride.
  • Step C N- ⁇ [ 1 -(Na ⁇ hth-2-ylmethyl)- lH-imidazol-5-yl]acetyl ⁇ -4-(2- methylbenzyPisonipecotic acid methyl ester.
  • the title compound was prepared using the procedure from example 4 step E, substituting 4-(2-methylbenzyl)-isonipecotic acid methyl ester hydrochloride for 4-(3-methylphenyl)-4- hydroxypiperidine hydrochloride and the acid from step B.
  • Step A N-t-butoxycarbonyl isonipecotic acid benzyl ester.
  • Step B N-t-Butoxycarbonyl-4-(2-methylbenzyl) isonipecotic acid benzyl ester.
  • Step C N-t-Butoxycarbonyl-4-hydroxymethyl-4-(2-methylbenzyl) piperidine.
  • Step D N-t-Butoxycarbonyl-4-methoxymethyl-4-(2- methylbenzyPpiperidine
  • Step E 4-Methoxymethyl-4-(2-methylbenzyl)-piperidine hydrochloride salt.
  • Step F N- ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-y ljmethyl ⁇ -4- methoxymethyl-4-(2-methylbenzyl) piperidine.
  • the title compound was prepared using the procedure from example 1 step H using 4-methoxymethyl-4-(2-methylbenzyl) piperidine hydrochloride.
  • the title compound was prepared using the procedure from example 4 step E using 4-hydroxymethyl-4-(2-methylbenzyl) piperidine hydrochloride (which was obtained from treatment of N-t- butoxycarbonyl-4-hydroxymethyl-4-(2-methylbenzyl) piperidine with gaseous HCl in EtOAc and evaporation of solvent.
  • Step A 5-[l -(4-cyanobenzyl)-lH-imidazolyl]ethanol.
  • Step B 5-(-l-(4-CyanobenzyP-imidazolyI)ethylmethanesulfonate.
  • Step C N- ⁇ [l-(4-Cyanobenzyl)-lH-imidazol-5-yl]ethyl ⁇ -4-(2- methylbenzyPisonipecotic acid methyl ester.
  • Step A N-t-Butoxycarbonyl-4-(3-methylphenyl)-piperid-3-ene.
  • Step B s-N-t-Butoxycarbonyl-4- (3-methylphenyl)-3 hydroxy piperidine
  • Step C trans-4- (3-Methylphenyl)-3 hydroxypiperidine hydrochloride.
  • Step D N- ⁇ [l-(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl ⁇ -trans-4- (3-methylphenyl)-3 hydroxy piperidine.
  • Step A fra ⁇ s-N-t-Butoxycarbonyl-4- (3-methylphenyl)-3- methoxy piperidine
  • Step B trans-4- (3-Methylphenyl)-3 methoxy piperidine hydrochloride.
  • Step C N- ⁇ [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-y ljmethyl ⁇ -trans-4- (3-methylphenyl)-3-methoxy piperidine.
  • the title compound was prepared by the procedure in example 1 step H using trans-4- (3-methylphenyl)-3 methoxy piperidine hydrochloride.
  • Step A £ ⁇ ms-N-t-Butoxycarbonyl-4- (3-methylphenyl)-3 benzyloxy piperidine.
  • Step B trans-4- (3-Methylphenyl)-3-benzloxypiperidine hydrochloride.
  • Step C N- ⁇ [l -(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl ⁇ -trans-4- (3-methylphenyl)-3-benzyloxy piperidine.
  • Step A 3-(2-hydroxyphenyl)-2-(N-t-butoxycarbonyl- amino)propanol
  • Step B 3-(2-Tetradecyloxyphenyl)-2(R,S)-(N-t-butoxycarbonyl- amino)propanol.
  • a mixture of the alcohol from Step A (218 mg, 0.82 mmol), tetradecyl bromide (170 ⁇ L, 0.9 mmol) and CsC03 (532 mg, 1.63 mmol) in DMF (8 mL) was stirred for 16 hs at room temperature under argon. The mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (MgS ⁇ 4), and concentrated in vacuo to give an oil. Purification by chromatography (Si ⁇ 2, 20% EtOAc in hexanes) gave the title compound as a solid.
  • Step C 3-(2-Tetradecyloxyphenyl)-2(R,S)-(N-t butoxycarbonylamino)propanal
  • Step D l-[2(R,S)-N-t-Butoxycarbonylamino-3-(2- tetradecyloxyphenyl)propyl] ⁇ 4-(2-methylbenzyl) isonipecotic acid methyl ester.
  • the aldehyde (138 mg, 0.30 mmol) obtained in Step C was dissolved in dichloroethane (2.5 ml) and treated with the piperidine hydrochloride from example 3 step D (75 mg, 0.27 mmol) and Et3N (37.8 ml, 0.27 mmol).
  • the solution was slurried with 4 A molecular sieves and stirred for 30 min at room temperature before adding sodium triacetoxyborohydride (172 mg, 0.81 mmol). After stirring for 18 hrs, the solution was filtered through celite. The filtrate was poured into EtOAc, washed with saturated NaHC ⁇ 3 solution, brine, dried (MgS ⁇ 4), and concentrated in vacuo to give an oil.
  • Step E l-[2(R,S)-Amino-3-(2-tetradecyloxyphenyl)propyl]-4-(2- methylbenzyl)isonipecotic acid methyl ester dihydrochloride salt
  • N-t-butoxycarbonylamine from Step D l-[2(R,S)-Amino-3-(2-tetradecyloxyphenyl)propyl]-4-(2- methylbenzyl)isonipecotic acid methyl ester dihydrochloride salt
  • Step A (S)-3-( 1 -Oxolauroyl)-4-(phenylmethyl-2-oxazolidinone. To a solution of (S)-4-Benzyloxazolidinone (8.85 g,
  • Step B Preparation of (S)-3-(l-Oxo-(S)-2-azidolauroyl)-4-
  • Step D Preparation of (S)-2-N-t-Butoxycarbonylaminolauric acid
  • a 3: 1 THF: water mixture under argon at 0°C , was added LiOH monohydrate (0.45g, 10.7 mmol).
  • the mixture was diluted with 0.5 M aqueous sodium bicarbonate and extracted with methylene chloride.
  • the aqueous portion was acidified with 3 M aqueous HCl and extracted with ethyl acetate.
  • the combined extracts were dried (MgS ⁇ 4) and concentrated in vacuo to afford the product as a viscous oil.
  • Step E N-2-(S)-t-Butoxycarbonylaminolauroyl-4-( 1 - napthylmethyl) isonipecotic acid methyl ester.
  • the title compound was prepared according to the procedure in example 10 using the acid prepared in step D.
  • Step F N-2-(S)- Aminolauroyl-4-( 1 -napthylmethyl)-isonipecotic acid methyl ester .
  • 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 [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester. To a solution of the product from Step B (8.00g,
  • Step D Preparation of [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid.
  • a solution of [l-(4-cyanobenzyl)-lH-imidazol-5-yljacetic 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 titled compound containing lithium chloride as a white solid.
  • Step E Preparation of l-(t-?7 -butoxycarbonyl)-4- 2- hydroxyphenyPaminolpiperidine
  • a 500 mL round bottom flask under inert atmosphere is charged with a magnetic stirring bar, 6.6 g (60 mmol) 2-aminophenol and 12 g (60 mmol) N-t-butyloxycarbonyl-4-piperidone.
  • the solids are suspended in 50 mL each 1 ,2-dichloroethane and glacial HOAc, treated with 1 g powdered 4A molecular sieves, and stirred at room temperature 30 min.
  • 12.8 g (60 mmol) NaBH(OAc)3 is added and the thick slurry stirred at room temperature 30 h.
  • the reaction mixture is diluted with 200 mL CH2CI2 and quenched slowly with saturated NaHC ⁇ 3 solution, approx 100 mL.
  • Step F Preparation of l-(ter/-butoxycarbonyl)-4-(benzoxaxolidin-
  • a 1-L round bottom flask under inert atmosphere is charged with a magnetic stirring bar, 16.8 g (57 mmol) of the aminoalcohol from Step E and 500 mL freshly distilled THF, and the flask immersed in an ice- water bath. Stirring is initiated and when the solution becomes homogeneous, 12 mL (69 mmol) N,N- diisopropylethylamine is added followed by 5.7 g (19.2 mmol) triphosgene in one portion. The reaction is stirred at 0°C 30 min and then the ice- water bath removed and the reaction allowed to stir 15 h, wherein a precipitate is formed.
  • reaction mixture is filtered, concentrated to an oil and partitioned between 400 mL EtOAc and 200 mL saturated Na2C ⁇ 3 solution. The layers are separated, the organic layer washed with 200 mL saturated Na2C03 solution, dried over MgS04, filtered and concentrated to an oil. Flash chromatography on silica (15 to 30 to 40% EtOAc in hexanes) provided 14.6 g (46 mmol, 80%) of the benzoxazolone as an amorphous solid.
  • Step G Preparation of 4-(benzoxaxolidin-2-one-l-yl)piperidine hydrochloride
  • a 1-L round bottom flask is charged with a magnetic stirring bar, 14.6 g (46 mmol) benzoxazolone from Step F and 120 mL isopropanol.
  • 60 mL 8 N HCl is added, the reaction becomes homogeneous and it is stirred 15 h wherein a precipitate forms.
  • the reaction is concentrated by rotary evaporation and the solid dried azeotropically with 2 x 150 mL toluene and the resulting off white solid dried under vacuum to provide 11.5 g (45 mmol, 99%) of the amine hydrochloride salt.
  • Step H Preparation of 4-(benzoxaxolidin-2-one-l-yl)-l-[l-(4- cyanobenzyP-5-imidazolylacetynpiperidine hydrochloride To a solution of the acid from Step D (639 mg, 1.77 mmol), the amine hydrochloride salt from Step G (303 mg, 1.18 mmol), and HOOBT (295 mg, 1.81 mmol) in DMF (5 mL) was added EDC
  • Step A Preparation of 1 -ferr-butoxycarbonyM-l ⁇ - hydroxymethyPphenylaminolpiperidine
  • N-r-butoxycarbonyl-4-piperidinone (20 g, 100 mmol), 2- aminobenzyl alcohol (13 g, 110 mmol), and acetic acid (14 mL, 220 mmol) were dissolved in dry toluene (500 mL). The solution was refluxed under inert atmosphere with azeotropic removal of water for 16 h. The solution was cooled to ambient temperature and to it was added NaBH3CN (14 g, 220 mmol) and dry THF (200 mL). The reaction was stirred at ambient temperature for 24 h. The reaction was concentrated under reduced pressure and the residue was dissolved in EtOAc (750 mL).
  • the EtOAc layer was washed with saturated aqueous NaHC ⁇ 3 (4 x 500 mL) and brine (250 mL).
  • the EtOAc layer was dried (MgS ⁇ 4), filtered, and the solvent was removed under reduced pressure.
  • the residue was purified by pressurized silica gel column chromatography, using a gradient elution of 15-30% EtOAc-hexanes. The titled compound was obtained as a gum.
  • Step B Preparation of l-[(l-t-butyloxycarbonyl)piperidin-4-yl]- 1 ,2-dihvdro-4(H)-3.1 -benzoxazin-2-one
  • Step A (24 g, 78 mmol) was dissolved in dry THF (250 mL) and cooled to 0°C. To the solution was added diisopropylethylamine (41 mL, 240 mmol) and triphosgene (8.54 g, 28.8 mmol). The reaction was stirred at 0 C for lh, and then at ambient temperature for 72 h. Ether (250 mL) was added, the mixture was cooled to 0°C for 3 h and then filtered to remove the hydrochloride salt of DIEA. The filtrate solvents were removed under reduced pressure and the residue was dissolved in EtOAc (750 mL).
  • the EtOAc solution was washed with 5% aqueous citric acid (2 x 500 mL), water (250 mL), and saturated aqueous NaHC03 (2 x 500 mL).
  • the EtOAc layer was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was boiled in ether (ca. 200 mL) until the solid had dissolved. Cooling overnight gave the titled product as off-white crystals.
  • Step C Preparation of l-(4- ⁇ iperidinyl)-l ,2-dihydro-4(H)-3, l - benzoxazin-2-one hydrochloride
  • Step D Preparation of 4-(l,2-dihydro-4(H)-3,l-benzoxazin-2-one- l-yl)-l-[l-(4-cyanobenzyl)-5-imidazolylacetyl]piperidine hydrochloride
  • the acid from Step D of Example 25 (435 mg, 1.21 mmol)
  • the amine hydrochloride salt from Step C (215 mg, 0.796 mmol)
  • HOBT 168 mg, 1.24 mmol
  • EDC 233 mg, 1.22 mmol
  • triethylamine (0.66 ml, 4.8 mmol

Abstract

Cette invention a trait à des composés inhibant la farnésyl-protéine transférase (FTase) et la farnélysation de la protéine oncogène Ras. Cette invention a trait, de surcroît, à des compositions à usage chimiothérapeutique contenant les composés selon cette invention ainsi qu'à des procédés visant à inhiber la farnésyl-protéine transférase et la farnélysation de la protéine oncogène Ras.
EP97921256A 1996-04-03 1997-03-27 Inhibiteurs de la farnesyl-proteine transferase Withdrawn EP0944388A4 (fr)

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US1479196P 1996-04-03 1996-04-03
US14791P 1996-04-03
GBGB9609981.7A GB9609981D0 (en) 1996-05-13 1996-05-13 Inhibitors of farnesyl-protien transferase
GB9609981 1996-05-13
PCT/US1997/006487 WO1997038665A2 (fr) 1996-04-03 1997-03-27 Inhibiteurs de la farnesyl-proteine transferase

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WO1999038862A1 (fr) * 1998-02-02 1999-08-05 Lg Chemical Ltd. Inhibiteurs de farnesyl-transferases, ayant une structure piperidine, et procede de preparation correspondant
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EP0944388A2 (fr) 1999-09-29
AU715202B2 (en) 2000-01-20
WO1997038665A2 (fr) 1997-10-23

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