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  • 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
  • C07D401/10—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 aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P13/00—Drugs for disorders of the urinary system
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
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  • 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
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  • 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
  • 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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  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • 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
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

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-ras, Ki4b-ras 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 570:583-586 (1984)).
• this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
• the Ras protein is one of several proteins that are known to undergo post-translational farnesyl- ation.
• Other 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., /. 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 famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol. Chem., 265:14701-14704 (1990); Schafer et al, Science, 249:1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, ⁇ 7:7541-7545 (1990)).
• Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
• direct inhibition of famesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
• FPTase farnesyl-protein transferase
• FPP farnesyl diphosphate
• Ras protein substrates
• Bisubstrate inhibitors and inhibitors of famesyl-protein transferase that are non-competitive with the substrates have also been described.
• the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
• Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
• deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
• the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
• farnesyl-protein trans- f erase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
• the present invention comprises bicyclic compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
• 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:
• Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom;
• Rl and R ⁇ are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
• R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl,
• R6a, R6b ? R6C ? R6d mc ⁇ R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
• 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,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NRl0-, (RlO)2NC(0)-, RHS(O)2NR10-,
• N3, -N(RlO)2, or R11OC(O)NR10- and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R!0Q-, R ⁇ S(0) m -.
• R 10 C(O)NRl0-, (Rl0)2NC(O)-, Rl !S(O)2NRl0-, (Rl0) 2 NS(O)2-, R 10 2N-C(NR10)_, CN, RlOC(O)-, N3, -N(RlO)2, or Rl0 ⁇ C(O)NH-;
• R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) ⁇ r, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, R10 2N _C(NR1 )-, CN, N0 2 , RlOC(O)-, N3, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
• RlO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N-(unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-Cl-C6 alkyl, acetylamino-Cl-C6 alkyl, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• RU is independently selected from C1-C6 alkyl and aryl
• Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
• Rl3 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
• 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 A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m.
• W is a heterocycle
• Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl or sulfonyl moiety adjacent to the nitrogen atom attached to Y;
• f(s) are independently N, and the remaining f s are independently CH, wherein Y is attached to Q through a carbon atom;
• Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(RlO)2, F or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, Rl lC(0)0-, -N(RlO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 O- and -N(RlO) 2;
• R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C -C6 alkenyl, C -C6 alkynyl, halogen, C1-C6 perfluoroalky
• R ⁇ a ⁇ 6b ? R6C ? R6d an d Roe are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
• 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,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOo-, R10C(O)NR10-, (Rl0)2NC(O)-, R 1 lS(O)2NRl0-, (R 10 )2NS(O)2-, CN,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
• RIO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N-(unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-Cl-C6 alkyl, acetylamino-Cl-C6 alkyl, ⁇ henyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• RU is independently selected from C1-C6 alkyl and aryl
• Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trif uoroethyl;
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl,
• W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
• Q is a 5 or 6 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0-1 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl or sulfonyl moiety adjacent to the nitrogen atom attached to Y;
• f(s) are independently N, and the remaining f s are independently CH, wherein Y is attached to Q through a carbon atom;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(RlO) 2 , F or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, Rl C(0)0-,
• R3 and R4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
• R 6a , R 6 , 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, C 2 -C6 alkenyl,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-,
• R9 and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
• RlO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N-(unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-C ⁇ -C6 alkyl, acetylamino-Cl-C6 alkyl, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• Rl is independently selected from C1-C6 alkyl and aryl
• R 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0)m.
• Q is a 5 or 6 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0- 1 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl or sulfonyl moiety adjacent to the nitrogen atom attached to Y; from 1-2 of f(s) are independently N, and the remaining f s are independently CH;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(R1°)2, F or C1-C6 alkyl, wherein Y is attached to Q through a carbon atom;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, Rl lC(0)0-, -N(R 10)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO- and -N(RlO) 2 ;
• R3 and R4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
• 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,
• R 10 C(O)-, N3, -N(R10) 2 , or Rl l ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02,
• Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RIOO-, R10C(O)NR!0-, (R10)2N-C(NR10)-, R10C(O)-, -N(RlO)2, or Rl 10C(0)NR10-;
• R9 and R b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
• RIO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N- (unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-C ⁇ -C6 alkyl, acetylamino-Cl-C6 alkyl, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• Rl 1 is independently selected from C1-C6 alkyl and aryl
• Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0) m ;
• the inhibitors of famesyl-protein transferase are illustrated by the formula D:
• f(s) are independently N, and the remaining f s are independently CH;
• g is selected from N and CH;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, Rl°0-, -N(RlO) 2 , F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-,
• R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, R!0 2 N-C(NR10)-, CN, N0 2 , RlOC(O)-, N3, -N(RlO) 2 , or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycl
• R4 is selected from H, halogen, C1-C6 alkyl and CF3;
• R 6a , R 6b , R 6c , R 6d and 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, C1-C6 perfluoroalkyl, R12 0 -, Rl lS(0)nr.
• R 10 C(O)NRl0-, (R 10 )2NC(O)-, R10 2N _C(NR10)-, CN, N0 2 , RlOC(O)-, N3, -N(RlO) , or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl,
• R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and Rl lOC(O)-NRl0-; or
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02,
• Rl lOC(O)NRl0- and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, RIOO-, R10C(O)NR1°-, (R10)2N-C(NR10)-, RlOc(O)-, -N(RlO)2, or RHOC(O)NR10- ;
• R9a and R b are independently hydrogen, ethyl, cyclopropyl or methyl
• RIO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N- (unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-Cl-C6 alkyl, acetylamino-Cl-C6 alkyl, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl; RU is independently selected from C1-C6 alkyl and aryl;
• Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
• Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
• n is 0 or 1; provided that n is not 0 if Al is a bond, O,
• the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
• f(s) are independently N, and the remaining f s are independently CH;
• g is selected from N and CH;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(R1°) 2 , F or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R OO-, -N(RlO) 2 ,
• R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
• RHOC(O)NR10- c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, R12 0 -, Rl lS(0) m -, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and R11OC(O)-NR10- ;
• R4 is selected from H, halogen, C1-C6 alkyl and CF3;
• R6a ? R6b ? R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 N-C(NRlO)-, CN, N0 2 , RlOC(O)-, N3, -N(RlO) , or Rl lOC(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N ⁇ 2, (R 10 )2N-C(NRlO)-, RIO O)-, -N(RlO) 2 , or
• R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
• R O is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N-(unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl)2-amino-Cl-C6 alkyl, acetylamino-Cl-C6 alkyl, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• Rl 1 is independently selected from C1-C6 alkyl and aryl
• R 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
• f(s) are independently N, and the remaining f s are independently CH;
• g is selected from N and CH;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(R*0) 2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, Rl°0-, or -N(R 10 ) 2 ;
• R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, R1°C(0)NR10-, (Rl0) 2 NC(O)-, R10 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C
• Rl0 2 N-C(NRlO)., CN, RlOC(O)-, N3, -N(RlO) 2 , and Rl l ⁇ C(O)-NRl0-;
• R4 is selected from H, halogen, CH3 and CF3;
• R6a ? R6b ⁇ R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, N0 2 , RlOC(O)-, N3, -N(RlO) , or Rl l ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C -C6 alkenyl, C 2 -C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N0 , (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RIOO-, Rl0c(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(RlO) 2 , O ⁇ RHOC(O)NR10- ;
• R9 and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
• RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
• R 1 is independently selected from C1-C6 alkyl and aryl
• Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
• f(s) are independently N, and the remaining f s are independently CH;
• g is selected from N and CH;
• Rl is selected from: hydrogen, C3-C10 cycloalkyl, R OO-, -N(RlO)2, F or C1-C6 alkyl;
• R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 or alkenyl;
• R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl0-, (R10) 2 NC(O)-, R10 2 N-C(NR10)-, CN, N02, Rl°C(0)-, N3, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10
• R4 is selected from H, halogen, CH3 and CF3;
• R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
• R10 2 N-C(NR10)-, CN, N0 , RlOC(O)-, N3, -N(RlO) 2 , or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
• R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle,
• C1-C6 alkyl C 2 -C6 alkenyl, C 2 -C6 alkynyl, -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR1 -, CN, N0 , (RlO) N-C(NRlO)-, RlOC(O)-, -N(RlO) 2 , or
• R a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
• RlO is independently selected from hydrogen, C1-C6 alkyl, amino- C1-C6 alkyl, N-(unsubstituted or substituted benzolyl)- amino-Cl-C6 alkyl, (C1-C6 alkyl) 2 -amino-Cl-C6 alkyl, acetylamino-Cl-C6 alkyl, ⁇ henyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
• Rl is independently selected from C1-C6 alkyl and aryl
• Rl is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
• Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
• n 0, 1 or 2;
• Preferred compounds of the invention are: 4- ⁇ 3-[4-(-2-Oxo-2-H-pyridin-l-yl)benzyl]-3-H-imidazol-4- ylmethyl]benzonitrile
• 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, R 2 etc.
• its definition on each occurence is independent at every other occurence.
• combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
• alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
• cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
• examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like. "Alkynyl” groups include those groups having the specified number of carbon atoms and having one triple bonds.
• alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
• Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
• aryl and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
• aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
• heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable 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
• the substituted group is intended to mean a substituted Cl_8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4 ? R5 a nd R6a-e are selected.
• substituted Cl-8 alkyl, substituted C3_6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
• substituted aryl substituted heterocycle
• substituted cycloalkyl are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0) m -, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, iso
• Lines drawn into the ring systems from substituents means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
• fused ring moieties may be further substituted by the remaining R 6a , R6b, R6C ? R6d a nd or R6e as defined hereinabove.
• Y represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
• Y is the moiety designated by the following structure
• the Y is selected from phenyl and pyridyl. More preferably Y is the moiety designated by the following structure
• the Y is selected from phenyl, pyrazine and pyridyl.
• Rl and R 2 are independently selected from: hydrogen, RHC(0)0-, -N(RlO)2, R 10 C(0)NR10-, R10( or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) 2 , Rl°0- and R10C(O)NR10-.
• R3 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-,
• R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1-C6 alkyl.
• R ⁇ is hydrogen
• R 6a , R6b, R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R12Q-, Rl ls(0) m -, CN, N ⁇ 2, Rl°C(0)- or -N(RlO) 2 , c) unsubstituted C1-C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, Rl 2 0-, RHS(0) m -,
• R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 perfluoroalkyl, RlOO- or
• R9 is hydrogen, halogen or methyl.
• RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl, aryl and substituted aryl.
• RlO is selected from H, C1-C6 alkyl and benzyl.
• a and A 2 are independently selected from: a bond, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(0) 2 N(R10)- and
• V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl and pyridyl.
• W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
• n and r are independently 0, 1, or 2.
• s is 0.
• t is 1.
• any substituent or variable e.g., Rl, R2, R9 ; n, etc.
• -N(RlO) 2 represents -NHH, -NHCH3, -NHC 2 H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
• the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
• such conventional non- toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
• the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
• the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
• Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-19, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
• Schemes 1-11 illustrate synthesis of the instant bicyclic compounds which incorporate a preferred benzylimidazolyl side chain.
• a bicyclic intermediate that is not commercially available may be synthesized by methods known in the art.
• a suitably substituted pyridinone 1 may be reacted under coupling conditions with a suitably substituted iodobenzyl alcohol to provide the intermediate alcohol 2.
• the intermediate alcohol 2 may converted to the corresponding bromide 3.
• the bromide 3 may be coupled to a suitably substituted benzylimidazolyl 4 to provide, after deprotection, the instant compound 5.
• Schemes 2-4 illustrate methods of synthesizing related or analogous key alcohol intermediates, which can then be processed as described in Scheme 1.
• Scheme 2 illustrates pyridinonyl- pyridyl alcohol forming reactions starting with the suitably substituted iodonicotinate 6.
• Scheme 3 illustrates preparation of the intermediate alcohol 9 wherein the terminal lactam ring is saturated.
• Acylation of a suitably substituted 4-aminobenzyl alcohol 7 with a suitably substituted brominated acyl chloride provides the bisacylated intermediate 8.
• Closure of the lactam ring followed by saponifi- action of the remaining acyl group provides the intermediate alcohol.
• Preparation of the homologous saturated lactam 10 is illustrated in Scheme 4.
• Scheme 5 illustrates the synthesis of the alcohol intermediate 13 which incorporates a terminal pyrazinone moiety.
• the amide of a suitably substituted amino acid 11 is formed and reacted with glyoxal to form the pyrazine 12, which then undergoes the Ullmann coupling to form intermediate 13.
• Scheme 6 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
• a readily available 4-substituted imidazole 14 may be selectively iodinated to provide the 5-iodoimidazole 15. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 16. Intermediate 16 can then undergo the alkylation reactions that were described hereinabove.
• Scheme 7 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the bicyclic moiety via an alkyl amino, sulfonamide or amide linker.
• the 4-aminoalkylimidazole 17, wherein the primary amine is protected as the phthalimide is selectively alkylated then deprotected to provide the amine 18.
• the amine 18 may then react under conditions well known in the art with various activated bicyclic moieties to provide the instant compounds shown.
• Compounds of the instant invention wherein the Al(CR 2)nA 2 (CRl2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 8.
• the suitably substituted phenol 19 may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole 20.
• the intermediate 21 can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
• Scheme 10 illustrates incorporation of an acetyl moiety as the (CR 2 2) ⁇ X(CR 2 2)p linker of the instant compounds.
• the readily available methylphenone 25 undergoes the Ullmann reaction and the acetyl is brominated to provide intermediate 26.
• Reaction with the imidazolyl reagent 4 provides, after deprotection, the instant compound 27.
• R 9b is j — , Nal, NaHCOa TrCI, NEt,
• inco orated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group.
• the intermediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized can be coupled with a variety of aldehydes.
• the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid.
• Knochel chemistry may be utilized, as shown in Scheme 11 , to incorporate the arylpyridinone moiety.
• a suitably substituted 4-(bromo)iodobenzene is coupled to a suitably substituted pyridinone 1 as previously described above.
• the resulting bromide 28 is treated with zinc(O) and the zinc bromide reagent 29 is reacted with an aldehyde to provide the C-alkylated instant compound 30.
• Compound 30 can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoro- acetic acid in methylene chloride to give the final compound 31.
• the compound 31 may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
• the product diamine 31 can further be selectively protected to obtain 32, which can subsequently be reductively alkylated with a second aldehyde to obtain 33. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole 34 can be accomplished by literature procedures.
• the arylpyridinone zinc bromide reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as 35 in Scheme 12, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 12, 13).
• the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as alkyl lithium reagents, to obtain secondary alcohols such as 37.
• the fully deprotected amino alcohol 38 can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as 39 (Scheme 13), or tertiary amines.
• the Boc protected amino alcohol 36 can also be utilized to synthesize 2-aziridinylmethylaryl ⁇ yridinone such as 40 (Scheme 14). Treating 36 with 1 , 1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine 40. The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product 41.
• the arylpyridinone 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 43, as shown in Scheme 15.
• R' is an aryl group
• 43 can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce 44.
• the amine protecting group in 43 can be removed, and O-alkylated phenolic amines such as 45 produced.
• the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
• Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neuro- fibromin (NF-1), neu, ser, 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 al.FASEB Journal, 2: A3160 (1988)).
• the instant compounds may also be useful for the treatment of fungal infections.
• the instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels.
• the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
• the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
• carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
• useful diluents include lactose and dried com starch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
• sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
• the total concentration of solutes should be controlled in order to render the preparation isotonic.
• the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
• the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
• the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF- 1 , restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
• the instant compounds may also be useful in combination with other inhibitors of parts of the signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
• the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity.
• compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection.
• composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
• a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
• Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
• the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
• FPTase famesyl-protein transferase
• 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.
• FPTase for example a tetrapeptide having a cysteine at the amine terminus
• farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
• the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.
• 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 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 1 4-Iodobenzyl alcohol Methyl 4-iodobenzoate (5g, 19.07 mmol) was suspended in THF (100 mL). LiBH 4 (40 mmol) was added slowly, via syringe.
• Step 2 4-(-2-Oxo-2-H-pyridin- 1 - vDbenzyl alcohol
• Step 4 4-(l-Trityl-lH-imidazol-4-ylmethyl)-benzonitrile
• a suspension of activated zinc dust (3.57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 20°C.
• the suspension was cooled to 0°C and ⁇ -bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added drop wise over a period of 10 minutes.
• Step 5 4- ⁇ 3-[4-(2-Oxo-2-H-pyridin-l-yl)benzyl]-3-H-imidazol-4- ylmethyllbenzonitrile
• Step 4 l-(4-Bromomethyl-phenyl)-piperidin-2-one l-(4-Hydroxymethyl-phenyl)-piperidin-2-one (200mg,
• Step 5 4- ⁇ 3-[4-(2-Oxo-piperidin- l-yl)benzyl]-3-H-imidazol-4- ylmethyllbenzonitrile
• D-alanine amide(7.5 g, 60.2 mmol) was suspended in MeOH (lOOmL). H 2 0 (10 mL) was added to dissolve the solid. The solution was cooled to -30°. Glyoxal (72.2 mmol, 8.28 mL of 40% weight solution) was added in one portion. 12.5 N NaOH (12 mL) was added dropwise over 20 minutes. The resulting mixture was stirred at -30° for 40 minutes then at room temperature for another 3 hours. The reaction mixture was placed in refrigerator overnight. The yellow suspension was cooled to 0° and then treated with concentrated HCI (15 mL) followed by NaHC0 3 (12.3g). The resulting neutral mixture was filtered through a frit.
• Step 4 l-(4-Bromomethyl-phenyl)-3-methyl-lH-pyrazin-2-one
• the pyrazinone intermediate from Step 3 (430 mg, 1.99 mmol) was dissolved in CH 2 C1 2 and added to a yellow suspension of NBS (531 mg, 2.98 mmol) and Me 2 S (0.248 mL, 3.38 mmol) at -20°.
• the sulfoxium salt was formed at 0° then cooled to -20° before the addition of alcohol. After addition of the alcohol, the reaction mixture was stirred at 0° for several hours and then the cooling bath was allowed to expire overnight.
• the light brown solution was poured into H 2 0 and extracted with CHC1 3 (3x).
• Step 5 4- ⁇ 3-[4-(3-Methyl-2-oxo-2-H-pyrazin-l-yl)-benzyl-3-H- imidazol-4-y lmethy 1 ⁇ -benzonitrile
• Step 6 l-(4-Bromomethyl-3-methoxy-phenyl)-lH-pyridin-2-one
• Step 7 4- ⁇ 3-[2-Methoxy-4-(2-oxo-2-H-pyridin-l-yl)-benzyl]-3-H- imidazol-4-ylmethyl ⁇ -benzonitrile
• Step 2 l-(4-Bromomethyl-phenyl)-5-chloro-lH-pyridin-2-one
• Step 1 5'-Methyl- ⁇ .2'1bipyridinyl-2-one 2-Pyridinone (l.OOg, 10.5 mmol), 2-bromo-5-methyl- pyridine (1.81g, 10.5 mmol), Copper (0.013g, 0.20 mmol) and K 2 C0 3 (1.60g, 11.6 mmol) were heated at 180°C for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHC0 3 . The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried
• Step 3 4-[l-(2-Oxo-2H-[l,2 , ]bipyridinyl-5'-ylmethyl)-lH- imidazol-2-ylmethyn-benzonitrile
• Step 3 4-[l-(5-Chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)- lH-imidazol-2-ylmethyn -benzonitrile hydrochloride
• the bromide from Step 2 (0.750g, 2.50 mmol) and the 4-(l-trityl-lH-imidazol-4-ylmethyl)-benzonitrile (1.06g, 2.50 mmol) in CH 3 CN (10 mL) were heated at 60°C. The reaction was cooled to room temperature and the solids collected by filtration and washed with EtOAc (lOmL).
• Step 1 2-B romo (5 -hy droxy methy Dpy ridine
• Step 2 5'-Hydroxymethyl-6-methyl- ⁇ .2'1bipyridinyl-2-one 2-bromo(5-hydroxymethyl)pyridine (3.00g, 15.95 mmol),
• 6-methylpyridone (2.08g, 19.14 mmol), Copper (2.64, 19.14 mmol) and K 2 C0 3 (.635g, lO.Ommol) were heated at 140°C for 3 hrs.
• Step 4 4-[3-(6-Methyl-2-oxo-2-H-[l,2']bipyridinyl-5'-ylmethyl)-
• Step 2 3.5.-Dibromo-5'-methyl- ⁇ .2'lbipyridinyl-2-one
• Step 3 5'-Bromomethyl-3.5-dibromo-[T.2'lbipyridinyl-2-one
• Step 4 4-[l-(3,5-Dibromo-2-oxo-2H-[l,2']bi ⁇ yridinyl-5'- ylmethyl)- 1 H-imidazol-2-ylmethyl]-benzonitrile hydrochloride
• Step 2 4-[l-(3-Bromo-2-oxo-2H-[l,2']bi ⁇ yridinyl-5'-ylmethyl)- lH-imidazol-2-ylmethyll-benzonitrile hydrochloride
• the bromide from Step 1 (0.161g, 0.465 mmol) and the 4-(l-trityl-lH-imidazol-4-ylmethyl)-benzonitrile (0.198g, 0.465 mmol) in CH 3 CN (2.5 mL) were heated at 60°C for 18 hrs.
• the reaction was cooled to room temperature and the solids collected by filtration and washed with EtOAc.
• the solid was suspended in methanol (20 mL) and heated at reflux for 1 hr, cooled and the solvent evaporated in vacuo.
• the hydrobromide salt was partitioned between sat. NaHC0 3 and CH 2 C1 2 and extracted with CH 2 C1 2 .
• the organic extracts were dried (Na 2 S0 4 ) and evaporated in vacuo.
• the residue was chromatographed (silica gel, MeOH: CH 2 C1 2 3:97 to 4:96 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid.
• Step 3 4- [ 1 -(5-Bromo-2-oxo-2H- [ 1 ,2 * ]bipyridinyl-5 '-ylmethyl)-
• Step 2 4-[l-(5-Cyano-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)-lH- imidazol-2-ylmethyll-benzonitrile
• Step 1 5'-Methyl-3.5-dichloro-ri.2'lbipyridinyl-2-one
• Step 2 4-[l-(3,5-Dichloro-2-oxo-2H-[l,2']bipyridinyl-5'- ylmethyl)-lH-imidazol-2-ylmethyll-benzonitrile
• the title compound was prepared according to the procedures described in Steps 3 to 4, Example 13 using 5'-methyl- 3,5-dichloro[l,2']bipyridinyl -2-one from step 1.
• Step 2 Acetic acid (4-cyano-phenyl)-(l-trityl-lH-imidazol-4-yl)- methyl ester
• acetic anhydride 0.641 ml 68.0 mmol
• Step 3 (R,S)4-[l-(5-Chloro-2-oxo-2H-[l,2']bipyridinyl-5'- y lmethy D- 1 H-imidazol-2-ylacetoxymethyn -benzonitrile
• the bromide from Example 10 Step 2 (0.500g, 1.67 mmol) and the 4-(l-trityl-lH-imidazol-4-ylacetoxymethyl)-benzonitrile (0.807 g, 1.67 mmol) in CH 3 CN (2 mL) were heated at 60°C for 20 hrs.
• Step 4 (R,S) 4- ⁇ [3-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'- ylmethyl)-3H-imidazol-4-yll-hydroxy-methyl ⁇ -benzonitrile
• aqueous lithium hydoxide 0.763ml, 0.763 mmol
• Example 18 To a solution of the alcohol from Step 4 Example 18 (0.0564g, 0.135 mmol) in CH 2 C1 2 (3 ml) at 0°C was added diethylamino- sulfur trifluoride (0.018ml, 0.14 mmol) and the reaction was stirred for 1 hour and then allowed to warm to room temperature. The reaction was partitioned between CH 2 C1 2 and NaHC0 3 and the organic extracts were washed with brine, dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH 2 C1 2 3:97 to 5:95 gradient elution) to afford the free base of the title compound which was converted to its hydrochloride salt..
• Step 1 (R,S) 4-[Methoxy-(l-trityl-lH-imidazol-4-yl)-methyl]- benzonitrile To a solution of the alcohol from Step 1 Example 18
• Step 2 (R,S) 4- ⁇ [3-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'- ylmethyl)-3H-imidazol-4-yll-methoxy-methyl ⁇ -benzonitrile
• Example 18 To a solution of the alcohol from Step 1, Example 18 (0.600g, 1.35 mmol) in CH 2 C1 2 (10 ml) at 0°C was added diethylamino- sulfurtrifluoride (0.268 ml, 2.02 mmol) and the reaction was stirred for 1 hour and then allowed to warm to room temperature. The reaction added to butanol (10ml) and stirred at room temperature for 18hrs and then the solvent was evaporated in vacuo. The residue was partitioned between CH 2 C1 2 and Na 2 C0 3 and the organic extracts were washed with brine, dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH 2 C1 2 20:80) to afford the title compound.
• Step 2 (R,S)4-[l-(5-Chloro-2-oxo-2H-[l,2']bipyridinyl-5'- ylmethyl)-lH-imidazol-2-ylbutyloxy-methyll-benzonitrile
• the title compound was prepared according to the procedures described in Step 3, Example 10 using the imidazole from step 1.
• Step 2 5'-Formyl-5-chloro-ri.2']bipyridinyl-2-one To a suspension of the dibromide from Step l(10.69g,
• Step 3 5-Chloro-5 '- [hydroxy-( 1 -trityl- 1 H-imidazol-4-yl)-methyl] ⁇ f 1.2'1bipyridinyl-2-one
• Step 4 Thiocarbonic acid 0-[(5-chloro-2-oxo-2H-[l,2']bipyridinyl-
• Step 5 5-chloro-5'-(l-trityl-lH-imidazol-4-ylmethyl)- ⁇ .2'1bipyridinyl-2-one
• tributyl tin hydride 0.159ml, 3.74 mmol
• AIBN 0.012g, 0.50 mmol
• Step 6 4-[5-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)- imidazol- 1 -ylmethyll-benzonitrile 4-Cyanobenzyl bromide (0.159 g, 0.813 mmol) and the imidazole from step 5 (0.430g, 0.813 mmol) in CH 3 CN (4 mL) were heated at 60°C for 18 hrs. The reaction was cooled to room temperature and the solvent evaporated in vacuo The residue was suspended in methanol (10 mL) and heated at reflux for 1 hr, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat.
• the compound was converted to its hydrochloride salt for storage.
• Step 2 5-Chloro-5 ' -(imidazol-4-ylmethyl)- r 1.2 ' lbipyridinyl-2-one
• 5-chloro-5'-(l-triphenylmethyl-lH- imidazol-4-ylmethyl)-[l,2']bipyridinyl-2-one from Example 23 step 5 (1.00 g, 1.89 mmol) in CH 2 C1 2 (15 mL) was added trifluoroacetic acid
• Step 3 5-Chloro-5'-(3-pyrazin-2-ylmethyl-3i7-imidazol-4- ylmethyl)-ri.2'lbipyridinyl-2-one (L-824.867) To a stirred solution of 5-chloro-5'-(imidazol-4-ylmethyl)-
• Step 2 5-hydroxymethyl-furan-2-carbonitrile
• a solution of the ester from step 1 (0.098g, 0.652 mmol), in ethanol (2.5 ml) at 0°C was treated with sodium borohydride (0.1 lg, 2.936mmol) and the reaction was stirred for 2 hrs.
• Saturated NH 4 C1 solution (1 ml) was added and the aqueous extracted with diethylether.
• the combined extracts were dried (MgS0 4 ) and evaporated in vacuo. The residue was chromatographed (silica gel, diethylether) to afford the title compound.
• Step 3 5-[5-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)- imidazol- 1 -ylmethy ⁇ -furan-2-carbonitrile
• Step 1 (R,S) Acetic acid (4-cyano-phenyl)-(l-trityl-lH-imidazol-4- yl)-methyl ester
• Step 3 To a solution of the alcohol from Example 23, Step 3 (2.29g, 4.20 mmol) in CH 2 C1 2 (50 ml) at 0°C was added pyridine (1.02 ml, 12.6 mmol) and acetic anhydride (0.595 ml 6.30 mmol) and the mixture stirred for 18 hr.. Saturated NaHC0 3 solution (50 ml) was added and the aqueous extracted with CH 2 C1 2 . The combined extracts were washed with water, dried (MgS0 4 ) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH 2 C1 2 3:97 to 4:96 gradient elution) to afford the title compound.
• Step 2 (R,S) Acetic acid (5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'- yl)-[3-(4-cyano-benzyl)-3H-imidazol-4-yll-methyl ester
• the title compound was prepared according to the procedures described in Step 6, Example 23 using the imidazole from step 1.
• Step 1 (R,S) 4- ⁇ 5-[(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-yl)- methoxy-methyl] -imidazol- 1 -ylmethyl ⁇ -benzonitrile
• Diethylaminosulfur- trifluoride (0.115 ml, 0.87 mmol) and triethylamine (0.121ml, 0.87 mmol) and the reaction was stirred for 1 hour at room temperature.
• the reaction mixture was partitioned between CH 2 C1 2 and water and the organic extracts were washed with Na 2 C0 3 , dried (Na 2 S0 4 ) and evaporated in vacuo
• the residue was dissolved in CH 2 C1 2 (6 ml) and added to methanol (10ml) and stirred at room temperature for 24 hrs and then the solvent was evaporated in vacuo.
• the residue was partitioned between CH 2 C1 2 and Na 2 C0 3 and the organic extracts were washed with brine, dried (Na 2 S0 4 ) and evaporated in vacuo.
• the residue was chromatographed (silica gel, MeOH: CH 2 C1 2 3:97) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid.
• Step 2 4-(4-Bromophenyloxy )- 1 -trityl- 1 H-imidazole
• Step 3 1 - ⁇ 4-[5-(4-Bromophenyloxy)imidazol- 1 -ylmethyl] - phenyl ) lH-pyridin-2-one
• a mixture of 4-(4-bromophenyloxy)-l -trityl- lH-imidazole (0.345 g, 0.72 mmol) and the bromide from Example 1, Step 3 (0.19 g, 0.72 mmol) in anhydrous acetonitrile (10 mL) was heated under reflux at 60°C for 24 h.
• the resultant solution was concentrated, and the residue dissolved in methanol.
• the methanolic solution was heated under reflux for 3 h, and concentrated under vacuum.
• the residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the titled compound.
• Step 4 l- ⁇ 4-[5-(4-Cyanophenyloxy)imidazol-l-ylmethyl]phenyl ⁇ - lH-pyridin-2-one
• Step 2 4-(4-Bromo-3-methoxy ⁇ henyloxy)-l -trityl- lH-imidazole Following the procedure as described in Example 31 -
• Step 2 substituting 4-(4-bromophenyloxy)imidazole with 4-(4-bromo- 3-methoxyphenyloxy)-imidazole.
• the titled compound was isolated as white solid.
• Step 3 l- ⁇ 4-[5-(4-Bromo-3-methoxyphenyloxy)imidazol-l- ylmethyl] -phenyl ⁇ - 1 H-pyridin-2-one
• Step 4 1 - ⁇ 4- [5-(4-Cayno-3-methoxyphenyloxy)imidazol- 1 - ylmethyl]-phenyl ⁇ -lH-pyridin-2-one Following the procedure as described in Example 31 -
• Step 4 substituting l- ⁇ 4-[5-(4-bromophenyloxy)imidazol-l-ylmethyl]- phenyl ⁇ -lH-pyridin-2-one with l- ⁇ 4-[5-(4-Bromo-3-methoxyphenyl- oxy)imidazol-l-ylmethyl]-phenyl ⁇ -lH-pyridin-2-one, and the reaction mixture was heated at 80 °C for 48 h.
• IH NMR CDCI3 ⁇ 7.5-7.2 (m), 6.8 -6.2 (m), 5.01 (2H, s), 3.83 (3H, s).
• Step 1 4-(4-bromo-phenyl)-4,5,6,7-tetrahydro-3 -imidazo[4,5- clpyridine
• Step 2 4-(4-bromo-phenyl)-6,7-dihydro-4 -imidazo[4,5- ]pyridine-1.5-dicarboxylic acid di-terf-butyl ester
• Step 3 4-(4-cyano-phenyl)- 1 ,4,6,7-tetrahydro-imidazo[4,5- c]pyridine-5-carboxylic acid tert-butyl ester
• Step 4 3-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)-4-(4- cyano-phenyl)-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5- carboxylic acid tert-butyl ester
• Step 5 4-[3-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)- 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-4-yl]- benzonitrile
• Step 2 Preparation of methyl 3-hydroxy-4-iodobenzoate A solution of methyl 4-amino-3-hydroxybenzoate (79 g,
• Methyl 4-cyano-2-hydroxybenzoate (0.50 g, 2.82 mmol) was dissolved in dry THF (30 mL), treated with LiBH 4 (2.0 M solution in THF) (5.64 mL, 11.28 mmol), and heated at reflux for 18 hr. The reaction mixture was cooled to room temperature, poured into IN HCI solution and extracted with EtOAc (2x). Organics combined and dried (MgS0 4 ), filtered and concentrated to dryness to give the title compound which was used without further purification.
• Step 3 5-chloro-l-(5-hydroxymethyl-pyrazin-2-yl)-lH-pyridin-2- one
• a solution of the ester from step 2 (1.41g, 5.317 mmol), in CH 2 C1 2 and methanol (1:1 50 ml) at 0°C was treated with sodium borohydride (2.01g, 53.17mmol) and the reaction was stirred at room temperature for 18 hrs.
• the solvent was evaporated in vacuo and the residue was dissolved in EtOAc and sat. NaHC0 3 .
• the aqueous layer was extracted with EtOAc and the combined extracts were dried
• Step 4 l-(5-bromomethyl-pyrazin-2-yl)-5-chloro-lH-pyridin-2- one
• NBS 0.598g, 3.36 mmol
• CH 2 C1 2 l ⁇ ml
• methylsulfide 0.296ml, 4.035 mmol
• the slurry was cooled to -20°C and the alcohol from step 3 (0.532g, 2.24 mmol) was added followed by CH 2 C1 2 (10ml).
• the reaction was stirred at 0°C for 3 hrs and then at room temperature for 24 hrs.
• Step 5 4- ⁇ 3-[5-(5-Chloro-2-oxo-2H-pyridin-l-yl)-pyrazin-2- ylmethyll -3H-imidazol-4-ylmethyl ⁇ -benzonitrile
• Step 1 (2-Bromoethyl)carbamic acid tert-butyl ester
• 2-Bromoethylamine HBr (2.0 g, 9.76 mmol) was suspended in CH 2 C1 2 (50 ml). Boc 2 0 (2.1 g, 9.76 mmol) was added and the reaction mixture was cooled to 0°C. Et 3 N (1.4 ml, 9.76 mmol) was then added and the reaction stirred at 0°C for 5 min. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction was extracted with water (3x 10 mL), brine (10 mL), dried
• Step 3 [2-(2-cyano-5-hydroxymethyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester
• the reaction mixture stirred at -78°C for 1 hour and was then transferred to an ice bath and stirred at 0°C for another hour.
• the solvent was removed in vacuo.
• the residue was then dissolved in MeOH (4.5 ml) and heated to 60°C for 4 hours.
• the MeOH was then removed in vacuo and the residue treated with saturated NaHC0 3 and extracted with CH 2 C1 2 .
• the organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated.
• the residue was purified by flash chromatography with 0 to 4% MeOH(NH 4 OH 5%) in CH 2 C1 2 to yield the desired product.
• Step 1 4-Cyano-3-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester
• CF 3 S0 2 C1 (2.7 ml, 25.5 mmol) was added under argon atmosphere to diethylether (60 ml) and cooled to 0°C.
• CF 3 CH 2 OH (1.8 ml, 25.5 mmol) and Et 3 N (3 ml, 21.25 mmol) were then added dropwise.
• the reaction mixture was stirred at 0°C for 0.5 hour.
• the reaction was cooled to -20°C to maximize ppt. of Et 3 N HCI.
• the mixture was filtered and washed with cold diethylether (1 x 20 mL). The filtrate was concentrated to approx.
• Step 4 4-[5-(5-Chloro-2-oxo-2H-[l,2 * ]bipyridinyl-5'-ylmethyl)- imidazol- 1 -ylmethyl]-2-(2,2,2-trifluoro-ethoxy)- benzonitrile
• Step 3 4-Bromomethyl-2-(2,2,2-trifluoro-ethoxy)-benzonitrile from Step 3 (200 mg, 0.68 mmol) and 5-chloro-5'-(l-trityl-lH- imidazol-4-ylmethyl)-[l,2']bipyridinyl-2-one from Example 23, Step 5 (360 mg, 0.68 mmol) were dissolved in CH 3 CN (3.5 ml) and heated to 60°C for 4 hours. The solvent was removed in vacuo and redissolved in MeOH (3.5 ml). The reaction mixture was heated to 60°C for 3 more hours. The solvent was removed in vacuo and the crude residue purified by flash chromatography [4% MeOH(5% NH 4 0H)/CH 2 C1 2 ) to yield the final product.
• Step 3 2-Benzyloxy-4- [5-(5-chloro-2-oxo-2H- [ 1 ,2']bipyridinyl-5'- ylmethyP-imidazol- 1 -ylmethyl] -benzonitrile
• Step 1 4-Cyano-3-phenethyloxy-benzoic acid methyl ester
• Step 3 4-[5-(5-Chloro-2-oxo-2H-[l,2 * ]bipyridinyl-5'-ylmethyl)- imidazol- 1 -ylmethyl] -2-phenethyloxy-benzonitrile
• the reaction mixture was stirred at -78°C for 1 hour and was then transferred to an ice bath and stirred at 0°C for another hour.
• the solvent was removed in vacuo.
• the residue was then dissolved in MeOH (2 ml) and heated to 60°C for several hours.
• the MeOH was then removed in vacuo and the residue treated with saturated aqueous NaHC0 3 (5 mL) and extracted with CH 2 C1 2 (2 x 10 mL).
• the organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated.
• the residue was purified by flash chromatography [4% MeOH(5% NH 4 OH)/CH 2 Cl 2 ] to yield the final product.
• Step 1 4-Cyano-3-(4-phenyl-butoxy)-benzoic acid methyl ester
• Step 3 4-[5-(5-Chloro-2-oxo-2H-[l,2']bipyridinyl-5 , -ylmethyl)- imidazol-l-ylmethyl1-2-(4-phenyl-butoxy)-benzonitrile
• 4-hydroxymethyl-2-(4- phenyl-butoxy)-benzonitrile from step 2 100 mg, 0.36 mmol
• Step 5 (188 mg, 0.36 mmol) in CH 2 C1 2 (2 ml) was added DIEA (136 ⁇ l, 0.78 mmol) followed immediately by the addition of Tf 2 0 (90 ⁇ l, 0.53 mmol).
• the reaction mixture stirred at -78 °C for 1 hour and was then transferred to an ice bath and stirred at 0°C for another hour.
• the solvent was removed in vacuo.
• the residue was then dissolved in MeOH (2 ml) and heated to 60°C for several hours.
• the MeOH was then removed in vacuo and the residue treated with saturated NaHC0 3 (5 mL) and extracted with CH 2 C1 2 (2 x 10 mL). The organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated.
• Step 3 (2.5 g, 14 mmol) was dissolved in THF (70 ml). LiBH 4 in THF
• Step 2 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy- benzonitrile
• Step 3 4-Hydroxymethyl-2-(3-phenyl-propoxy)-benzonitrile 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy- benzonitrile from step 2 (50 mg, 0.19 mmol) was dissolved in DMF (1 ml) and treated with phenylpropylbromide (29 ⁇ l, 0.19 mmol). Cs 2 C0 3
• Step 4 4-[5-(5-chloro-2-oxo-2H-[l,2']bipyridinyl-5'-ylmethyl)- imidazol- 1 -ylmethyl] -2- (3 -phenyl-propoxyVbenzonitrile
• a cooled solution (-78C 0 ) of 4-hydroxymethyl-2-(3- phenyl-propoxy)-benzonitrile from step 3 35 mg, 0.13 mmol
• Step 5 70 mg, 0.13 mmol) in CH 2 C1 2 (650 ⁇ l) was added DIEA (50 ⁇ l, 0.27 mmol) followed immediately by the addition of Tf 2 0 (33 ⁇ l, 0.19 mmol).
• the reaction mixture was stirred at -78°C for 1 hour and was then transferred to an ice bath and stirred at 0°C for another hour.
• the solvent was removed in vacuo.
• the residue was then dissolved in MeOH (650 ⁇ l) and heated to 60°C for 14 hours.
• the MeOH was then removed in vacuo and the residue treated with saturated NaHC0 3 (5 mL) and extracted with CH 2 C1 2 (2 x 10 mL). The organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated.
• Step 1 4-Cyano-3-methoxy-benzoic acid methyl ester

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• 1997
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  • 1997-12-22 CA CA002276150A patent/CA2276150A1/en not_active Abandoned

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