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  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/57—Nitriles
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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
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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
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/70—One oxygen atom
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  • 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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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
• Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
• Ras In the inactive state, Ras is bound to GDP.
• Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
• the GTP- bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
• Mutated ras genes (Ha-r ⁇ s, Ki4a-r ⁇ , Ki4b-r ⁇ _. and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
• Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
• the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature J/0.583-586 (1984)).
• this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
• the Ras protein is one of several proteins that are known to undergo post-translational famesyl- ation.
• famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesyl ⁇ ated proteins of unknown stmcture and function in addition to those listed above.
• FPTase famesyl-protein transferase
• FPP famesyl diphosphate
• Ras protein substrates
• Bisubstrate inhibitors and inhibitors of famesyl-protein transferase that are non-competitive with the substrates have also been described.
• the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
• Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851 , University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
• deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
• 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. It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 1 12 Al ).
• famesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 1 12930).
• the present invention comprises novel biaryl-containing compounds which inhibit the famesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.
• the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras.
• the inhibitors of famesyl-protein transferase are illustrated by the formula A:
• Rla and Rl° are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0) m -, R10C(0)NR10_, Rl lC(0)0-, (Rl0)2NC(O)-, R10 2 N-C(NR10)-, CN, N ⁇ 2, RlOC(O)-, N3,-N(RlO)2,orRllOC(0)NRlO-, c) unsubstituted or substituted C l -Co alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RllS(O) m -,Rl0C
• R-, R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, RlOC(0)NRlO-, (Rl0) 2 NC(O)-, Rl lC(0)0-, Rl0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , orRHOC(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl -C ⁇ alkyl is selected from unsubstituted or substituted aryl
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl -C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, R10C(O)NR10-, (RlO) 2 NC(0)-, R H C(0)0-,
• Rl0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or RHOC(O)NRl0-, c) unsubstituted C 1 -Co alkyl , d) substituted Cl -C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0 -, Rl lS(0) m -, R 1 l S(O) m NRl0-, (R l°)2NS(0) m -.
• R 7 is selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycleC3-Cl ⁇ cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, R l ⁇ (OJm-, R !0C(O)NR 10-, (RlO)2NC(0)-, Rl 2 N-C(NRlO)-, CN, N ⁇ 2, R 1°C(0)-, N3, -N(R ] 0)2, or R 1 1 OC(0)NR 10-, and c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R IOO-, R 1 1 S
• R9 is independently selected from: a) hydrogen. b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, halogen Rl lO-, Rl lS(0) m - .
• R 10 C(O)NRl0-, (Rl0)2NC(O)-, Rl°2N-C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C 1 -Co alkyl unsubstituted or substituted by C l -Co perfluoroalkyl, F, Cl, Br, Rl O-, RHS(0) m -, R!0C(O)NR10_, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRl )_, CN, Rl C(O)-, N3, -N(Rl ) 2) or Rl 10C(0)NR10- ;
• Rl is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl 2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• Rl3 is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, -CH2N(RlO)2, benzyl and aryl;
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O 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 A is a bond, n is 0 and A 2 is S(0)m . provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
• W is a heterocycle
• Rla is independently selected from: hydrogen, C3-C10 cycloalkyl, R10 O _, -N(RlO)2, F or Cl-C ⁇ alkyl;
• Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, Rl O-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R ⁇ O- and -N(RlO) 2 ;
• R 2 , R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R! C(O)NR10-, (Rl ) 2 NC(0)-, Rl0 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 ,
• R°A R6b ? ROC 5 Rod an d R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, Rl C(0)NRlO-, (RlO) 2 NC(0)-, R10 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(RlO) , orRHOC(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl; d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted
• -CH CH-CH2-, -(CH2)4- and -(CH2)3-;
• R5, R ⁇ a, ROb ? ROC, Rod or R6e is unsubstituted or substituted heterocycle, attachment of R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d or R°e t0 the phenyl ring is through a substitutable heterocycle ring carbon;
• R7 is selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, R10(3-, R10C(O)NR10-, CN, N ⁇ 2, (R1°)2N-C(NR10)_, Rl C(O)-, -N(Rl0) 2 ,orRllOC(O)NRl0-, and c) C l -Co alkyl substituted by C l -Co perfluoroalkyl , R 1 °0- , Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOc(O)-,
• R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, Rl lO-, Rl lS(0) m -, R!0C(O)NR1 -, (RlO) 2 NC(0)-, CN, N ⁇ 2, (Rl°)2N-C(NRl0)-, RlOC(O)-, -N(R!0) 2 , or RllOC(O)NRl0-, and c) C 1 -Co alkyl unsubstituted or substituted by C 1 -Co perfluoroalkyl, F, Cl, RlOO-, R 1 lS(0) m -, R!0C(O)NR10_, (Rl0) 2 NC(O)-, CN, (Rl )2N-C(NRl )_, RIOC(O)-, -N(R 10)
• RI is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• R 2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• Rl i independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, -CH2N(R O) 2 , benzyl and aryl;
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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 2 is S(0) m ; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
• W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
• Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(RlO) 2 , F or C l -C ⁇ alkyl;
• R l b is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, Rl°0-, -N(RlO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl -C ⁇ alkyl wherein the substituent on the substituted C l -Co alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R l O- and -N(R lO) 2;
• R 2 and R 3 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 5 -
• Rod and R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, R12O-, RllS(0) m -, Rl0c(O)NRl0-, (Rl0) 2 NC(O)-, Rl ⁇ 2N-C(NRl° CN, N ⁇ 2, Rl°C(0)-, N3, -N(RlO) 2 , orRllOC(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C ⁇ perfluoroalkyl, F, Cl, Rl O-, Rl0c(O)NRl0-, CN, NO2, (R 10 )2N-C(NR lO)-,
• R9a and R ⁇ b are independently hydrogen, Cl -C ⁇ alkyl, trifluoromethyl and halogen;
• R lO is independently selected from hydrogen, Cl -C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl -C ⁇ alkyl and aryl
• Rl 2 is independently selected from hydrogen, Cl -C ⁇ alkyl, Cl -C ⁇ aralkyl, -C6 substituted aralkyl, Cl -C ⁇ heteroaralkyl, C l -C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl -C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• R l3 is independently selected from hydrogen, Cl -C ⁇ alkyl, 2,2,2- trifluoroethyl, -CH2N(Rl )2, benzyl and aryl;
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m . provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
• R la is independently selected from: hydrogen, C3-C10 cycloalkyl, R lOO-, -N(RlO)2, F or C l-C ⁇ alkyl;
• Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3- 0 cycloalkyl, Rl°0-, -N(R lO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the substituent on the substituted C l -Co alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R l O- and -N(R*0)2;
• R 2 and R3 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl,
• Roa, R6b ? R6C 5 Rod an d R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 1 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl !S(0)m-, R!0C(O)NR10-, CN(RlO) 2 NC(0)-, Rl0 2 N-C(NRl )-,CN,N ⁇ 2, Rl°C(0)-, N3, -N(RlO)2, orRHOC(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubsti
• -CH CH-CH2-, -(CH2)4- and -(CH2)3-;
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, RlOO-, Rl0c(O)NRl0-, CN, N02, (R 10 )2N-C(NRlO)., R 1 0 C(O)-, -N(R 10)2, or R 11 OC(0)NR 10., and c) Cl-C ⁇ alkyl substituted by Cl-C ⁇ perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (R!0) 2 N-C(NR10)_, RlOc(O)-, -N(Rl0)2, or Rl lOC(O)NRl0- ; provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
• R ⁇ a and R ⁇ b are independently hydrogen, Cl-C ⁇ alkyl, trifluoromethyl and halogen;
• RlO is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl 2 is independently selected from hydrogen, C]-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl,
• Rl3 is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, -CH2N(Rl0)2, benzyl and aryl;
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A is S(0) and V is not hydrogen if A is a bond, n is 0 and A 2 is S(0)m. provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
• Rla is independently selected from: hydrogen, C3-C10 cycloalkyl or Cl-C ⁇ alkyl;
• Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(R10)2, F or C2-C6 alkenyl, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3- 0 cycloalkyl, C2-C6 alkenyl, R 10 O-. or
• R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, Rl°C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 N-C(NRlO)-, CN, N02, Rl°C(0)-, N3,-N(RlO)2, orRllOC(O)NRl0-, c) unsubstituted C l -Co alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloal
• R3 is selected from H, halogen, Cl-C ⁇ alkyl and CF3;
• R6a, R6b ; R6C 5 Rod an d R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, RllS(0) m -, R10C(O)NR10-, (R10) 2 NC(O)-, Rl0 N-C(NRl )-, CN, N02, Rl°C(0)-, N3, -N(Rl ) 2 , orRll ⁇ C(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsub
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, RIOO, R10C(O)NR10-, CN, N ⁇ 2, (R1°)2N-C(NR10)-, Rl°C(0)-, -N(Rl0) 2 ,orRll ⁇ C(O)NRl0-, and c) C l -Co alkyl substituted by C 1 -Co perfluoroalkyl, R 1 °0-, Rl0c(O)NRl0-, (RlO) 2 N-C(NRlO)_, RlOc(O)-, -N(RlO)2, or Rl lOC(O)NRl0-; or provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
• R9 and R ⁇ are independently hydrogen, halogen, CF3 or methyl
• R O is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl 2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, Cl-C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• a 1 is selected from: a bond, -C(O)-, O, -N(R10)_, 0 r S(0) m ;
• n is 0 or 1 ; provided that n is not 0 if A is a bond, O,
• the inhibitors of farnesyl-protein transferase are illustrated by the formula E: wherein:
• Rla is independently selected from: hydrogen, Rl O-, -N(RlO)2, F, C3-C10 cycloalkyl or Cl-C ⁇ alkyl;
• Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3- 0 cycloalkyl, RlOO-, -N(RlO)2, F or C2-C6 alkenyl, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(RlO) 2 ;
• R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, RllS(0) m -, Rl0c(O)NRl0-, (RlO) 2 NC(0)-,
• R3 is selected from H, halogen, Cl-C ⁇ alkyl and CF3;
• R6a, R6b. R6C, Rod an d Roe are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, R12O-, Rl lS(0) m -, Rl0c(O)NRl0-, (Rl0) 2 NC(O)-, Rl ⁇ 2N-C(NRlO)-, CN, N02, Rl°C(0)-, N3,-N(Rl0)2, orRl ⁇ C(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, un
• -CH CH-CH2-, -(CH2)4- and -(CH2)3-;
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C ⁇ perfluoroalkyl, F, Cl, R OO-, R10C(O)NR10-, CN, N02, (RlO) 2 N-C(NR O)-, RlOc(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C l -Co alkyl substituted by C l -Co perfluoroalkyl, R OO-, RlOC(0)NRlO-, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(Rl0)2, or Rl lOC(O)NRl0- ; provided that when R8 is heterocycle, attachment of R8 to V is through
• R9 and R9 are independently hydrogen, halogen, CF3 or methyl
• RlO i independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl 2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl,
• R la is independently selected from: hydrogen, C3-C10 cycloalkyl or Cl-C ⁇ alkyl;
• Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3- 0 cycloalkyl, Rl°0-, -N(R10)2 or F, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, Rl OO-, or -N(RlO) 2 ;
• R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl -C ⁇ perfluoroalkyl,
• R3 is selected from H, halogen, CH3 and CF3;
• Rod an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C ⁇ alkynyl, halogen, Cl -C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl _, (Rl0) 2 NC(O)-, R l0 2 N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , or R HOC(O)NRl0-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted C l -Co alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted
• R 2 , R6 , R6b R6C, Rod or R6e j s unsubstituted or substituted heterocycle, attachment of R 2 , R6a, R6b ? R6C ? Rod or R ⁇ e t0 the phenyl ring is through a substitutable heterocycle ring carbon;
• R and R9b are independently hydrogen, halogen, CF3 or methyl;
• R O is independently selected from hydrogen, Cl-C ⁇ alkyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, Cl-C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• Rla is independently selected from: hydrogen, RlOO-, -N(R l )2, F, C3-C10 cycloalkyl or Cl -C ⁇ alkyl;
• R ib is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R l°0-, or -N(RlO) 2 ;
• R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl,
• R 12 ( 3-, Rl lS(0)m-, R 10 C(O)NR l0.. (Rl0) 2 NC(O)-, R 10 2 N-C(NR10)-, CN, N02, Rl°C(0)-, N3, -N(RlO) 2 , or RHOC(0)NRlO-, c) unsubstituted Cl-C ⁇ alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, R l0 2 N-C(NRlO)-, CN, RlOC(O)-, N3,
• R is selected from H, halogen, CH3 and CF3;
• R6a, R6b ? 6C, Rod an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, R 1 2 0-, R 11 S(0) m - .
• -CH CH-CH2-, -(CH2)4- and -(CH2)3-;
• R9a and R b are independently hydrogen, halogen, CF3 or methyl
• Rl is independently selected from hydrogen, Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
• Rl 1 is independently selected from Cl-C ⁇ alkyl and aryl
• Rl2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, Cl-C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• Al is selected from: a bond, -C(O)-, O, -N(R 10)_, or S(0) m ;
• n 0, 1 or 2;
• the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
• any variable e.g. aryl, heterocycle, R l a , Rib etc.
• its definition on each occurence is independent at every other occurence.
• combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
• alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
• cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
• examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• Alkenyl include those groups having the specified number of carbon atoms and having one or several double bonds.
• alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
• Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
• Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
• aryl and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydro- naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
• heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined hetero ⁇ cyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable stmcture.
• heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
• heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
• heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
• substituted Cl _8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl ⁇ sulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
• substituted aryl substituted heterocycle
• substituted cycloalkyl are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl -C ⁇ alkyl)2, N02, CN, (Cl-C ⁇ alkyl)0-, -OH, (Cl-C ⁇ alkyl)S(0)m-, (Cl -C ⁇ alkyl)C(0)NH-, H2N-C(NH)-, (Cl -C ⁇ alkyl)C(O)-, (Cl -C ⁇ alkyl)OC(O)-, N3 C1 -C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl
• Rla and Rib are independently selected from: hydrogen, RHC(0)0-, -N(RlO) 2 , R!0C(O)NR10-, Rl0 O - or unsubstituted or substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) 2 , RlOO- and R!0C(O)NR10-.
• R 2 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, CN, N ⁇ 2, Rl°C(0)- or-N(RlO) 2 , c) unsubstituted C 1 -Co alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, Rl lS(0) m -, R1°C(0)NR10-, (RlO) 2 NC(0)-,
• Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and RllOC(O)-NRl0-.
• R3 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C ⁇ alkyl.
• R and R ⁇ are hydrogen.
• R&A R6b, ROC, Rod an d R°e are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl 2 0-, Rl lS(0) ⁇ r, CN, N ⁇ 2, Rl°C(0)- or -N(RlO) , c) unsubstituted C 1 -Co alkyl; d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, Rl 2 0-, Rl lS(0) m -, Rl0c(O)-or-N(Rl°)2;or
• R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C l -C ⁇ perfluoroalkyl or CN.
• R9 is hydrogen, halogen, CF3 or methyl.
• RlO is selected from H, Cl -C ⁇ alkyl and benzyl.
• Al and A 2 are independently selected from: a bond, -C(O)NR l0_, -NR I OC(O)-, O, -N(R 10)-, -S(O)2N(R 1 ). and
• V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
• W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrohdinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
• n and r are independently 0, 1 , or 2.
• s is 0.
• t is 1.
• V - A 1 (CR 1 a 2 ) n A 2 (CR 1 (CR 1 b 2 ) p - X -(CR 1 2 )- p is selected from:
• any substituent or variable e.g., R l a, R9 ? n , etc.
• -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 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 1-22, 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.
• Substituents R 2 , R ⁇ and R ⁇ as shown in the Schemes, represent the substituents R 2 , R , R , 5 ? R6a, R6b, R6C, R 6d and R 8 ; although only one such R 2 , R6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
• Schemes 1- 13 illustrate synthesis of the instant biaryl compound which incorporate a preferred benzylimidazolyl sidechain.
• a biaryl intermediate that is not commercially available may be synthesized by methods known in the art.
• a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4-bromobenzoic acid, to provide the biaryl carboxylic acid II.
• the acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
• Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1.
• Scheme 2 illustrates the analogous series of biaryl alcohol forming reactions starting with the halogenated biarylaldehyde.
• Scheme 3 illustrates the reaction wherein the "terminal" phenyl moiety is employed in the Suzuki coupling as the halogenated reactant.
• Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 4.
• Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biaryl component of the instant compounds, as shown in Scheme 5.
• a suitably substituted zinc bromide adduct may be coupled to a suitably substituted aryl halide in the presence of nickel (II) to provide the biheteroaryl VII.
• the aryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
• Scheme 6 illustrates the preparation of a suitably substituted biphenyl ethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
• biaryl intermediates having a suitably substituted alkyl moiety on the carbon adjacent to the eventual point of attachment to the rest of the instant compounds is illustrated in Scheme 6a.
• a suitably substituted biaryl carboxylic acid is first converted to the amide and then the phenyl lithium is prepared and reacted in situ with a suitably substituted alkanal to provide the hydroxyalkane side- chain.
• the amide is then converted sequentially to the hydroxymethyl- biaryl Ilia or bromomethylbiaryl intermediates which may then be utilized in reactions that have been previously described or will be described below.
• a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
• Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
• Scheme 8 illustrates synthesis of an instant compound wherein a non-hydrogen R j s incorporated in the instant compound.
• a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
• Scheme 9 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker.
• the 4-aminoaIkylimidazole XII wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII.
• the amine XIII may then react under conditions well known in the art with various activated biaryl moieties to provide the instant compounds shown.
• Scheme 1 1 illustrates an analogous series of reactions wherein the (CRlb2)pX(CRl D 2)p linker of the instant compounds is oxygen.
• a suitably substituted haloaryl alcohol such as , is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI.
• Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl.
• the intermediate XVII can then be coupled to a second aryl moiety by Suzuki chemistry to provide the instant compound.
• Grignard chemistry may also be employed to form a substituted alkyl linker between the biaryl and the preferred W (imidazolyl) as shown in Scheme 13. Similar substituent manipulation as shown in Scheme 12 may be performed on the fully functionahzed compound which incorporates an R l b hydroxyl moiety.
• V - A 1 (CR 1 a 2 ) n A 2 (CR - (CR 1 b 2 ) p -X incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group.
• biaryl Grignard reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI.
• Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII.
• the final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
• the product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures. If the biaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme
• the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16).
• the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXX.
• organometallic reagents such as Grignard reagents
• the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXII (Scheme 16), or tertiary amines.
• the Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiaryl such as XXXIII (Scheme 17). Treating XXVIII with l ,l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIV .
• a nucleophile such as a thiol
• the biaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 18.
• R' is an aryl group
• XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI.
• the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
• Schemes 19-22 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
• 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 fa esyl- protein transferase and the famesylation of the oncogene protein Ras.
• the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
• Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
• the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
• a component of NF-1 is a benign proliferative disorder.
• the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related vimses (J.S. Glenn et al. Science, 256: 1331-1333 (1992).
• the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
• the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142: 1051-1060 (1993) and B. Cowley, Jr. et ⁇ LFASEB 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 combina- tion 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 vimses 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 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 the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
• a series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• Step A l -Trityl-4-(4-cvanobenzvD-imidazole
• Step B 1 -(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydochloride salt
• Step A 3-(Bromomethy ⁇ biphenyl
• N-bromosuccinimide (2.124 g, 1 1.93 mmol)
• AIBN 50 mg, 0.30 mmol
• additional AIBN was added (50 mg, 0.30 mmol) and the mixture refluxed for 16 hours.
• the reaction was cooled, filtered, and the solvent evaporated in vacuo.
• the residue was chromatographed (Silica gel, 5% EtOAc in hexanes) to afford the title compound as a white solid.
• Step B 1 -(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetate salt
• Step A l -(4-Cvanobenzyl)-5-aminoethylimidazole
• NG.pivaloyloxymethyl-Na-phthaloylhistaminel (4.55 g, 12.8 mmol) and a-bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL) and heated at 55°C for 4 hours, cooled to room temperature, filtered and the imidazolium salt retained as a white solid .
• the filtrate was evaporated in vacuo to a volume of 30 mL and heated at 55°C for 16 hours. The solution was cooled and the white solid collected by filtration. The solids were combined, and dissolved in ethanol (50 mL).
• Step B l- ( 4-Cvanobenzyl ) -5- ( 4'-phenylbenzamido)ethyl-imidazole
• Step C 1 -(2'-Trif_uoromethyl-4-biphenylmethyl)-5-(4- cvanobenzvDimidazole hydrochloride salt
• Step B l -(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt
• Step B 4-(2'-Bromophenyl)benzyl alcohol
• Step C 1 -(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)- imidazole hydrochloride salt
• Step B l-(Bromomethyl)-2-chloro-4-biphenyl
• Step C 1 -(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)- imidazole hvdrobromide salt.
• Step A Methyl 4-(3 , .5'-Bis-trifluoromethylphenyl)benzoate
• Step B 1 -(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4- cyanobenzyl) imidazole hydrochloride salt
• Step B l-Trityl-4-iodo-5-methylimidazole
• Step C l -Trityl-4-(4-cyanobenzyl)5-methylimidazole
• Step D 1 -(2'-Trifluoromethyl-4-biphenylmethy l)-5-(4- cyanobenzyl)-4-methylimidazole hydrochloride salt
• the resultant mixture was stirred at 120°C for 2 hours, cooled, and the reaction product partitioned between methylene chloride (500 mL) and aqueous sodium hydroxide (1 M, 500 mL). The aqueous layer was separated and extracted with methylene chloride (3 x 100 mL). The organic extracts were combined, washed with brine (100 mL), dried (K2CO3), and the solvent evaporated in vacuo. The residue was purified by chroma ⁇ tography (Silica gel, 3:7 acetone in CHCI3) to afford the title compound as a white powder.
• Step B 4-(4-Cvanophenyloxy)- 1 -trityl-imidazole
• Step C l -(4-Biphenylmethyl)-5-(4-cvanophenyloxy)-imidazole
• the hydrochloride salt was obtained by treatment of a solution of the imidazole in acetonitrile with aq. HCI and evaporation of the solvents in vacuo.
• the title compound was prepared as white solid using the protocol described in example 17 - step B, using 4-(4-bromophenyloxy) imidazole.
• Step C 5-(4-Bromophenyloxy)- 1 -(4-cyanobenzyl)-imidazole
• Step D 5-(4-Biphenyloxy)- 1 -(4-cyanobenzyl)-imidazole trifluoroacetate salt
• Step A 4-(3 , .5'-Dichlorophenyl) benzyl alcohol
• Step B 4-(3'.5'-Dichlorophenyl) benzyl bromide
• Step C 1 -Trityl-4-(4-(3'.5'-dichloro)-biphenylmethyl- imidazole
• Step D 5-(4-(3'.5'-Dichloro)-biphenylmethyl)- 1 -(4-cyanobenzyl) imidazole hydrochloride salt
• Step A 1 -Trityl-4-(l -(R,S)-hydroxy- 1 -(4-cyanophenyl) methylimidazole
• Step C l -(4-Biphenylmethyl)-5-(l-(R,S)-acetoxy- l -(4- cyanophenyPmethylimidazole hydrochloride salt
• Step A l-Triphenylmethyl-4-(hydroxymethyl)imidazole
• 4-(hydroxymethyl)imidazole hydrochloride 35.0 g, 260 mmol
• triethylamine 90.6 mL, 650 mmol
• Chlorotriphenylmethane 76.1 g, 273 mmol
• DMF 500 mL
• the reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water.
• the resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
• Step B l -Triphenylmethyl-4-(acetoxymethyl)imidazole
• Step C 1 -(4-Cyanobenzyl)-5-(acetoxymethy l)imidazole hydrobromide
• the filtrate was concentrated in vacuo to a volume 100 mL, then heated at 60°C for 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 methanol (500 mL), and warmed to 60 °C. After two hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Evaporation of residual solvent 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-CvanobenzvI)-5-(hvdroxymethyl)imidazole
• Li hydroxide monohydrate 18.9 g, 450 mmol
• the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHC ⁇ 3 and brine.
• the solution was then dried, (Na 2 S ⁇ 4) filtered, and concentrated in vacuo to provide the cmde product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
• Step E 1 -(4-Cyanobenzyl)-5 -imidazole carboxaldehyde
• Step F 1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- 1 -(4-biphenyl)-methyl imidazole
• a Grignard reagent freshly prepared from 4-bromo- biphenyl (116 mg, 0.500 mmol) and magnesium turnings ( 18 mg, 0.73 mmol) in dry THF (0.50 mL) was added to a dry Argon-purged 3mL flask containing the l-(4-cyanobenzyl)-5 -imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.2 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. aq. NH 4 C1 (5 mL) and distributed between EtOAc (50 mL) and H 2 0 (50 mL). The organic phase was evaporated in vacuo and the residue chromatographed (Silica gel, 5% MeOH in CHCI 3 ) to afford the title compound.
• a Grignard reagent freshly prepared from 3-biphenyl- bromide (116 mg, 0.50 mmol) and magnesium turnings (18 mg, 0.73 mmol) in dry THF (0.5 mL) was added to a dry Argon-purged 3 mL flask containing l -(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.20 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. NH4CI (5 mL) and distributed between EtOAc (50 mL) and H2O (50 mL).
• Step 1 Preparation of l -triphenylmethyl-4-(hydroxymethyl)-imidazole
• Step 2 Preparation of l -triphenylmethyl-4-(acetoxymethyl)-imidazole
• the product from Step 1 was suspended in 500 mL of pyridine. Acetic anhydride (74 mL) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCI soln. (2 x 1 L), sat. aq. NaHC ⁇ 3 , and brine, then dried (Na2SO_ ⁇ ), filtered, and concentrated in vacuo to provide the cmde product. The titled acetate product was isolated as a white powder (85.8 g) which was sufficiently pure for use in the next step.
• Step 3 Preparation of 1 -(4-cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide
• Step 4 Preparation of 1 -(4-cvanobenzyl)-5-(hvdroxymethyl)-imidazole
• Step 5 Preparation of 1 -(4-cyanobenzyl)-5-imidazole-carboxaldehvde
• Step 6 Preparation of l-[N-(l -(4-cyanobenzyl)-5- imidazolylmethyl)aminol-3-methoxy-4-phenylbenzene
• l-amino-3-methoxy-4-phenylbenzene in 1 ,2-dichloroethane at 0 °C was added 4A powdered molecular sieves and sodium triacetoxyborohydride.
• l -(4-Cyanobenzyl)-5-imidazole- carboxaldehyde was added, followed by 5 drops of acetic acid. The cooling bath was removed after 5 hours, and the reaction was stirred for another 15 hours.
• Step A 4-(2 > -trifluoromethylphenyl)benzaldehvde To a solution of 4-formylbenzeneboronic acid
• Step B l -(4-(2'-trifluoromethylpheny ⁇ phenyl)ethanol
• Step C 1 - ⁇ 1 -(4-(2'-trifluoromethylphenyl)phenyl)ethy 1 ⁇ -5-(4- cyanobenzyPimidazole hydrochloride salt
• Step A E-Ethyl -3-(4-(2'-trifluoromethylphenyl)phenyl)prop-2- enoate
• Step B Ethyl-3-(4-(2'-trifluoromethylphenyl)phenyl)- propionoate
• Step C 1 -(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4- cyanobenzyl) imidazole
• Step A 4-(2 , -Cyanophenyl)benzoic acid methyl ester.
• 2-bromobenzonitrile l .OOg, 5.494 mmol
• THF 16.5 mL
• t-butyl lithium 6.46mL, of a 1.7M solution in pentane, 10.98 mmol.
• zinc chloride(5.494 mL, of a I M solution in THF, 5.494 mmol) was added. The reaction was stirred for 10 minutes at -78°C and then allowed to warm to 0°C and stirred for 1 hour.
• Step B 4-(2 , -Aminomethylphenyl)hvdroxymethylbenzene
• Step C 4-(2'-t-Butoxycarbonylaminomethylphenyl) hydroxymethylbenzene
• Step D 1 -(2'-N-t-Butoxycarbonylaminomethyl-4- biphenylmethyl)-5-(4-cyanobenzyl) imidazole
• the title compound was prepared using the protocol described in Example 5, step C using the product from step C.
• Step A Preparation of 4-trifluoromethylsulfonylyoxy-3- methylbenzaldehyde
• step A Following the procedure described for Example 13, step A, but using the product from step A above and 3-chlorobenzene- boronic acid as starting materials the title product was obtained.
• Step C Preparation of (3'-chlorophenyl)-3-methylbenzylalcohoI Following the procedure described for Example 7, step B, but using the product from step B above as starting material, the title product was obtained.
• Step D Preparation of l -(3'-chloro-2-methyl-4- biphenylmethyl)-4-(4-cyanobenzyl)imidazole hydrochloride salt
• step C Using the alcohol from step C and following the procedure described for Example 5, step C with a subsequent purification by silica gel chromatography (EtOAc then 2% MeOH in CHCI 3 ). The first eluted material afforded the title compound after treatment with HCI and Et2 ⁇ . Analysis calculated for C 2 H 2 oN 3 Cl «2.7HCl«0.3Et 2 0: C, 60.67; H, 4.99; N, 8.10;
• step D but collecting the later eluting material the title compound was obtained.
• Step B Preparation of 4-(3'-methoxyphenyl)-3-methyl- benzylalcohol Following the procedure described for Example 13, step A, but using the product from step A above and 3-methoxybenzene- boronic acid as starting materials the title product was obtained.
• Step C Preparation of 1 -(3'-methoxy-2-methyl-4- biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt
• Step A Preparation of l -chloro-5-fluoro-2-trifluoromethyl- sulfonylyoxybenzene
• Step B Preparation of l-(2'-Chloro-4'-fluoro-4-biphenylmethyl)- 5-(4-cyanobenzyl)imidazole hydrochloride salt Following the procedure described for Example 5, steps A-C, but using the product from step A above as starting material, the title product was obtained.
• Step A Preparation of 2-(2-methyl-2-propyl)- l -trifluoromethyl- sulfonylyoxybenzene Following the procedure described for Example 53, step
• Step B Preparation of l -(2'-(2-methyl-2-propyl)-4-biphenyl- methyP-5-(4-cyanobenzyPimidazole hydrochloride salt Following the procedure described for Example 5, steps
• Step B Preparation of l -allyloxy-4-(2 , -methylphenyPbenzene
• Step C Preparation of 2-allyl-4-(2-methylphenyl)phenol To a stirred solution of BCI 3 (I M in p-xylene; 6.7 mL,
• Step D Preparation of 2-aIlyl- l -benzyloxy-4-(2- methylphenyPbenzene
• step C Following the procedure of step B but using benzyl bromide, the phenol from step C was converted into the title compound
• Step E Preparation of l -benzyloxy-2-(3-hydroxypropyl)-4-(2'- methylphenvPbenzene
• 9-BBN 0.5 M in THF; 30.6 mL, 15 mmol
• the solution was treated with 30 H 2 ⁇ 2 lN NaOH and after 15 minutes, poured into water, and extracted with EtOAc (2x). The organic layers were washed with water, brine, dried and evaporated to give an oil. Chromatography on silica gel (hexane/EtOAc 4: 1 ) afforded the title compound as an oil.
• Step F Preparation of l -benzyloxy-2-(3-N-phthalimido-l -propyl)-
• Step G Preparation of 2-(3-N-phthalimido- l -propyl)-4-(2'- methylphenvPphenol
• Step H Preparation of l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride
• Step I Preparation of l -f l -(4-cyanobenzyl)imidazol-5-ylmethoxyJ-
• step B Following the procedure described for step B, but using the phenol from step G and 5-chloromethyl-l -(4-cyanobenzyl) imidazole hydrochloride from step H as starting materials, the title compound was obtained.
• Step B Preparation of 4-hydroxymethyl-biphenyI-3- carbaldehyde O -methyl -oxime
• Step C Preparation of 3-aminomethyl-biphenyl-4-methanol
• THF 15 mL
• BH 3 .THF I M in hexane; 8 mL, 8 mmol
• the solution was stirred at room temperature for 16 h then heated to reflux for 24 h.
• the solution was cooled to 0°C and IN NaOH (10 mL) was added slowly. After 1 h, the mixture was diluted with water, extracted withEtOAc (3x), washed with brine, dried and evaporated to give the title compound as an oil. This was used as such in the next step.
• Step D Preparation of 3-N-Boc-aminomethyl-biphenyl-4-methanol
• Step G Preparation l-(3-(N-Boc-am omethyl)-4-biphenylmethyl)-
• Finely grounded aminoacetonitrile hydrochloride (21 g) was stirred in a solution of chloroform (200 mL) saturated with ammonia gas for 10-15 minutes. The slurry was filtered through a plug of Celite. The filtrate was concentrated, and the residue distilled (36-40°C, 0.1 mmHg) to provide aminoacetonitrile as clear, colorless oil.
• Aminoacetonitrile (14 g) was added at a rate of 1 mL/min to a boiling mixture of trimethyl orthoacetate (200 mL), concentrated sulfuric acid (5 drops), and anhydrous sodium sulfate (20 g), with removal of distillate. The resultant mixture was heated for additional 30 minutes, filtered through Celite, and concentrated.
• Step C 5-(4-Bromophenyloxy)-l-(4-cyanobenzyl)-2- methylimidazole
• Step D 1 -(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4- yloxyVimidazole trifluoroacetate salt
• the title compound was prepared as a white solid using the protocol described in Example 19 - Step D, substituting 5-(4- bromo-phenyloxy)-l-(4-cyanobenzyl)imidazole with 5-(4- bromophenyl-oxy)- 1 -(4-cyanobenzyl)-2-methylimidazole, phenyl boronic acid with o-tolylboronic acid, and stirring the reaction mixture at 100 °C for 18 hours.
• Anal. Calcd for C25H21N3O-1.10 TFA-0.95 H 2 0:
• Step A 3-Cyano-4-methyl-2 , -trifluoromethylbiphenyl
• Step B 4-Bromomethyl-3-cyano-2'-trifluoromethylbiphenyl
• a mixture of 3-cyano-4-methyl-2'-trifluoromethyl- biphenyl (420 mg, 1.61 mmol), N-bromosuccinimide (286 mg, 1.61 mmol), AIBN ( 10 mg), and carbon tetrachloride (20 mL) was refluxed for 1 hour.
• the resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate in hexane (7.5 to 92.5 v/v). Collection and concentration of appropriate fractions provided the title compound.
• Step C 5-(4-Cyanobenzyl)- 1 -(3-cyano-2'- trifluoromethvlbiphenyl-4-ylmethyP-imidazole hydrochloride salt
• Step A N-Methoxy-N-methyl 2-(N-tert- butyloxycarbonylamino)-2-(biphenyl-4- ylmethvPacetamide
• Step B N-Methoxy-N-methyl 2-( (N-tert-butyloxycarbonyl)-(N-
• Step C 2-A_mino-5-(biphenyl-4-ylmethyl)- 1 -(4-bromobenzyl)- imidazole
• a cold (-40°C) slurry of LiAlH4 in anhydrous diethyl ether (50 mL) a solution of N-Methoxy-N-methyl 2-[(N- tert-butyloxy-carbonyl)-(N-4-bromobenzyl)aminol-2-(biphenyl-4- ylmethyl)acetamide (2.1 1 g, 3.82 mmol) in THF (10 mL) was added. The resultant mixture was stirred at -40 °C for 10 min. and allowed to warm up to 0°C.
• the mixture was then cooled back to -40°C, and quenched with aqueous KHSO4 solution with temperature of the mixture maintained below -30 °C.
• the resultant mixture was diluted with diethyl ether and stirred at room temp for 30 min.
• the ethereal solution was isolated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide a foamy product.
• Step D 2- Amino-5-(bipheny 1-4-ylmethyl)- 1 -(4- cy anobenzy 1 )imi dazo le A mix ⁇ re of 2-amino-5-(biphenyl-4-ylmethyl)-l -
• Step A N-Methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-
• Step B N-Methoxy-N-methyl 2-[(N-tert-butyloxycarbonyl)-(N- biphenyl-4-ylmethyPamino1-2-(4-bromobenzyl)acetamide
• the title compound was prepared as a white solid using the protocol described in Example 71 - Step B, substituting N-methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-
• Step C 2- Amino- 1 -(biphenyl-4-ylmethyl)-5-(4-bromobenzyl)- imidazole
• Step D 2-Amino- l -(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)- imidazole trifluoroacetate salt

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