WO1998028980A1 - Inhibiteurs de farnesyl-proteine transferase - Google Patents

Inhibiteurs de farnesyl-proteine transferase Download PDF

Info

Publication number
WO1998028980A1
WO1998028980A1 PCT/US1997/023888 US9723888W WO9828980A1 WO 1998028980 A1 WO1998028980 A1 WO 1998028980A1 US 9723888 W US9723888 W US 9723888W WO 9828980 A1 WO9828980 A1 WO 9828980A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
rlo
unsubstituted
aryl
Prior art date
Application number
PCT/US1997/023888
Other languages
English (en)
Inventor
Steven D. Young
Neville J. Anthony
Robert P. Gomez
Lekhanh O. Tran
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9702212.3A external-priority patent/GB9702212D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97954798A priority Critical patent/EP1003374A1/fr
Priority to AU60139/98A priority patent/AU6013998A/en
Priority to CA002276081A priority patent/CA2276081A1/fr
Priority to JP53021498A priority patent/JP2002511054A/ja
Publication of WO1998028980A1 publication Critical patent/WO1998028980A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
  • Mutated ras genes (Ha-ras, Ki4a- ras, Ki4b-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 box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 370:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a 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., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol. Chem., 265:14701-14704 (1990); Schafer et al, Science, 249: 1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of farnesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase farnesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • Bisubstrate inhibitors and inhibitors of farnesyl-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 farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
  • farnesyl-protein trans- ferase 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, C2-C6 alkynyl, RlOO-, RHS(0) m -, R10C(O)NR10-,
  • R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-,
  • Rl lS(0)m- R 10 C(O)NRl0-, (RlO) 2 NC(0)-, RHC(0)0-, Rl0 2 N-C(NRlO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(RlO) 2 , or RHOC ⁇ NRlO-, 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,
  • 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-, (Rl0) 2 NC(O)-, (R 10 )2NS(O)2-,
  • R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, Rl lS(0) m -, R10C(O)NR10-, (R10) 2 NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0_, (R!0)2NC(0)-, R 1 02N-C(NR 1 0)-, CN, Rl ⁇ c( ⁇ )-,
  • 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;
  • R! 1 is independently selected from C1-C6 alkyl and aryl;
  • Rl2 is independently selected from hydrogen, Cl-C6 alkyl, C1-C aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • 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 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;
  • W is a heterocycle
  • Y is selected from: phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothienyl;
  • R is independently selected from: hydrogen, C3-C10 cycloalkyl, RIOO-, -N(RlO)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RiOO-, -N(R10) J 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) ;
  • R3, R4 and R5 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, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (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 heterocycl
  • R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and R11OC(O)-NR10- ;
  • 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, C2-C6 alkenyl,
  • R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO)2, and Rl l ⁇ C(O)-NRl0-; or
  • 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, C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C ⁇ perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10_,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
  • 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
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • 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-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)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 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 0-2 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, provided that Q is not
  • Y is selected from: phenyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothiophenyl;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(R 10 )2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -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, RlOO- and -N(RlO)2;
  • R3 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, Rl ⁇ 2N-C(NRiO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(Rl ) 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
  • R6d 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, C1-C6 perfluoroalkyl, Rl 2 0-,
  • 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) 2 NC(O)-, (R10) 2 NS(O)2-, CN,
  • R9a and R ⁇ b 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-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
  • Rl 2 is independently selected from hydrogen, C1-C alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • 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-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A is a bond, n is 0 and A 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 0-2 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, provided that Q is not
  • Y is selected from: phenyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothiophenyl;
  • 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-, -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, 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,
  • R6a, R6b 5 R6C 5 R6d an d R e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-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-,
  • Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R OO-, Rl0C(O)NRl0-, (R!0) 2 NC(O)-,
  • R9a 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-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, 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-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 A 1 is a bond, n is 0 and A 2 is S(0) m ;
  • n is independently 0, 1, 2, 3 or 4; p IS 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; and r is 0 to 5, provided that r is 0 when V is hydrogen;
  • 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;
  • 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(RlO)2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(RlO) 2 ;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12 0 -, Rl lS(0)m-, R10C(0)NR10-, (RlO) 2 NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, N02, R 10 C(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-C alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
  • R4 is selected from H, halogen, C1-C6 alkyl and CF3;
  • R6a ? R6b ? R6C ? R6d an d R6 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, R12O-, Rl lS(0) m -, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, N ⁇ 2, 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 unsubstitute
  • 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-, (Rl0)2NC(O)-, CN, N ⁇ 2, (R1°)2N-C(NR10)-,
  • R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RlO is independently selected from hydrogen, C1-C6 alkyl, amino- Cl-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, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
  • n is 0 or 1; provided that n is not 0 if A is a bond, O, -N(RlO)- or S(0) m ; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; and r is 0, 1 or 2;
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E: wherein:
  • f(s) are independently N, and the remaining f s are independently CH;
  • 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-, -N(RlO)2,
  • C2-C6 alkenyl c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(RlO) 2 ;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, R10C(O)NR10-, (RlO) 2 NC(0)-,
  • R4 is selected from H, halogen, C1-C alkyl and CF3;
  • R6a 5 R6b 5 R6C 5 R6d and R6e ar e 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, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (R10)2NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, NO2, 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, un
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle,
  • R9a an d R9b a re 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;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, Cl-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;
  • f(s) are independently N, and the remaining f s are independently 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(RlO)2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, Rl°0-, or -N(Rl°)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, R12O-, Rl lS(0)m-, R1°C(0)NR1 -, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, N ⁇ 2, R 10 C(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,
  • R4 is selected from H, halogen, CH3 and CF3;
  • R6a, R6b ? 6C 9 R6d 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, C1-C6 perfluoroalkyl, R12Q-, Rl lS(0) m -, R 10 C(O)NRl0-, (R10) 2 NC(0)-, R10 2 N-C(NR10)-, CN, N ⁇ 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
  • 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-,
  • R9a 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, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl; RU is independently selected from Cl-C6 alkyl and aryl;
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, Rl°0-, -N(R1°)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 alkenyl, Rl°0-, or -N(RlO) 2 ;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
  • R4 is selected from H, halogen, CH3 and CF3;
  • R 6a , R6 , R6C 5 R6d 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-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, (Rl0) 2 NC(O)-, R10 2 N-C(NR10)-, CN, N ⁇ 2, Rl°C(0)-, 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 substitute
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle,
  • R9a 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, phenyl-Cl-C6 alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
  • RU is independently selected from Cl-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • a 1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
  • n 0, 1 or 2;
  • the preferred compounds of the instant invention are selected from:
  • 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 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 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. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, 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) R ⁇ , R4 ? R5 a nd R6a-e ar e selected.
  • substituted Cl-8 alkyl, substituted C3- 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,
  • 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.
  • 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.
  • fused ring moieties may be further substituted by the remaining R 6a , R 6 , R6 C ? R6d and/or R 6e as defined hereinabove.
  • Rl and R 2 are independently selected from: hydrogen, RHC(0)0-, -N(R10)2, R1°C(0)NR10-, RlOO- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO)2, R 10 O- and R10C(O)NR10-.
  • R 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.
  • R5 is hydrogen
  • R6 , R6b ? R6C ? R6d an d R 6e are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl,
  • R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle,
  • R9 is hydrogen, halogen or methyl.
  • R O is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl, aryl and substituted aryl.
  • RlO is selected from H, Cl-C6 alkyl and benzyl.
  • Al and A 2 are independently selected from: a bond, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-
  • 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, R 2 , 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 synthe- sized 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, palmoic, 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 1-17, 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 1-8 illustrate synthesis of the instant bicyclic compounds which incorporate a preferred benzylimidazolyl sidechain.
  • a bicyclic intermediate that is not commercially available may be synthesized by methods known in the art.
  • a suitably substituted pyridinonyl alcohol 2 may be synthesized starting from the corresponding isonicotinate 1 according to procedures described by Boekelhiede and Lehn (J. Org. Chem., 26:428-430 (1961)).
  • the alcohol is then protected and reacted under Ullmann coupling conditions with a suitably substituted phenyl iodide, to provide the intermediate bicyclic alcohol 3.
  • the intermediate alcohol 3 may converted to the corresponding bromide 4.
  • the bromide 4 may be coupled to a suitably substituted benzylimidazolyl 5 to provide, after deprotection, the instant compound 6.
  • Schemes 2-4 illustrate methods of synthesizing related or alcohol intermediates, which can then be processed as described in Scheme 1.
  • Scheme 2 illustrates preparation of a pyridyl- pyridinonyl alcohol and thienylpyridinonyl alcohol starting with the suitably substituted halogenated heterocycles.
  • Scheme 3 illustrates preparation of the intermediate bromide 9 wherein the preferred pyridinone is replced by a saturated lactam.
  • Acylation of a suitably substituted aniline 7 with a suitably substituted brominated acyl chloride provides the acylated intermediate 8.
  • Closure of the lactam ring provides the intermediate alcohol, which is converted to the bromide as described above.
  • Scheme 4 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
  • a readily available 4-substituted imidazole 10 may be selectively iodinated to provide the 5-iodoimidazole 11. That imidazole 11 may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 12. Intermediate 12 can then undergo the alkylation reactions that were described hereinabove.
  • Scheme 5 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker.
  • the amine 14 may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
  • Scheme 8 illustrates incorporation of an acetyl moiety as the (CR 2 2) ⁇ X(CR 2 2)p linker of the instant compounds.
  • the suitably substituted acetyl pyridine 21 is converted to the corresponding pyridinone and undergoes the Ullmann reaction with a suitably substituted phenyl iodide.
  • the acetyl is then brominated to provide intermediate 22.
  • Reaction with the imidazolyl reagent 5 provides, after deprotection, the instant compound 23.
  • the intermediates whose synthesis are illustrated in the Schemes, and other pyridinonecarbocyclic and pyridinonehetero- cyclic 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 9, to incorporate the aryl- pyridinone moiety.
  • a suitably substituted 4-(bromo)pyridine is converted to the corresponding pyridinone 24 as described above and the pyridinone is coupled to a suitably substituted phenyl iodide as previously described above.
  • the resulting bromide 25 is treated with zinc(0) and the resulting zinc bromide reagent 26 is reacted with an aldehyde to provide the C-alkylated instant compound 27.
  • Compound 27 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 28.
  • the compound 28 may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine 28 can further be selectively protected to obtain 29, which can subsequently be reductively alkylated with a second aldehyde to obtain compound 30. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole 31 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 32 in Scheme 10, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 10, 11).
  • 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 34.
  • the fully deprotected amino alcohol 35 can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as 36 (Scheme 11), or tertiary amines.
  • the Boc protected amino alcohol 33 can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as 37 (Scheme 12). Treating 33 with 1 , l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine 37. The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product 38 .
  • a nucleophile such as a thiol
  • the arylpyridinone reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as 40, as shown in Scheme 13.
  • R' is an aryl group
  • 40 can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce 41.
  • the amine protecting group in 40 can be removed, and O-alkylated phenolic amines such as 42 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 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 d ⁇ .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 famesyl 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 immuno- logical, 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 3 4- (tert-buty 1-dimethy 1- silanyloxymethyl)- 1 -phenyl- 1 H- pyridin-2-one
  • Step 4 4-Hydroxymethyl- 1 -phenyl- 1 H-pyridin-2-one
  • Step 6 4-( 1 -Trityl- 1 H-imidazol-4-ylmethyl)-benzonitrile
  • Step 2 4-(4-Bromophenyloxy )- 1 -trityl- 1 H-imidazole
  • Step 3 4-[5-(4-Bromophenoxy)imidazol- 1 -ylmethyl]- 1 -(6-chloro- pyrazin-2-yl)- 1 H-pyridin-2-one A mixture of 4-(4-bromophenyloxy)-l -trityl- 1 H-imidazole
  • Step 4 4-[5-(4-Bromophenoxy)imidazol- 1 -ylmethyl]- 1 -(6-cyano- pyrazin-2-yl)- 1 H- ⁇ yridin-2-one
  • Step 1 4-(tert-butyl-dimethyl-silanyloxymethyl)- 1-(3- chlorophenyl)- 1 H-pyridin-2-one
  • Step 2 4-Hydroxymethyl- 1 -(3-chlorophenyD- 1 H-pyridin-2-one
  • Step 4 1 - (3 -chloro-pheny l)-4- [hy droxy- ( 1 -trityl- 1 H-imidazol-4- yl)-methyll-lH-pyridin-2-one
  • trityl-4-iodoimidazole 3.5 lg, 8.04 mmol
  • CH 2 C1 2 50 ml
  • ethyl- magnesium bromide 2.81 ml of a 3M solution in diethylether, 8.43 mmol
  • the aldehyde from step 3 (1.79g, 7.66 mmol) in CH 2 C1 2 (50ml) was added and the reaction was stirred a furthur 18 hrs at room temperature.
  • Step 5 Thiocarbonic acid 0-[[l-(3-chloro-phenyl)-2-oxo-l,2- dihydro-pyridin-4-yll-(l-trityl-lH-imidazol-4-yl)-methyl] ester O-phenyl ester
  • DMAP 1.34, 11.0 mmol
  • phenylthiochloroformate 694 ⁇ l, 5.522 mmol
  • Step 6 1 -(3-Chloro-phenyl)-4-( 1 -trityl- 1 H-imidazol-4-ylmethyl)- lH-pyridin-2-one
  • Step 7 4- ⁇ 5-[ 1 -(3-Chloro-phenyl)-2-oxo- 1 ,2-dihydro-pyridin-4- ylmethyl]-imidazol- 1 -ylmethyl ⁇ -2-methoxy-benzonitrile
  • l-(3-Chloro-phenyl)-4-(l -trityl- 1H- imidazol-4-ylmethyl)-lH-pyridin-2-one (272 mg, 0.527 mmol) from step 6 and 4-hydroxymethyl-2-methoxy-benzonitrile (90.3 mg, 0.55 mmol) in CH 2 C1 2 cooled to -78C over dry ice/acetone bath was added
  • N,N-diisopropylethylamine (192 ⁇ l, 1.1 mmol) and trifluoromethane- sulfonic anhydride(93 ⁇ l, 0.55mmol).
  • the reaction was allowed to slowly warm to room remperature and stirred overnight.
  • the reaction was diluted with methanol (10 mL), heated to reflux for 2 h, cooled and the solvent evaporated in vacuo.
  • the residue was partitioned between sat. Na 2 C0 3 (20ml) and CH 2 Cl 2 (2x50ml). The organic extracts were dried (MgS0 4 ) and evaporated in vacuo.
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-W-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H1-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31°C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al. , Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al. , Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%).
  • the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the ly sates cleared by centrifugation at 100,000 x g for 45 min.
  • 1 ml lysis buffer 1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
  • the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
  • IP buffer 20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
  • the cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Abstract

La présente invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase), et la farnésylation de la protéine oncogène Ras. L'invention concerne également des compositions chimiothérapiques qui renferment les composés de la présente invention, les procédés permettant d'inhiber la farnésyl-protéine transférase, et la farnésylation de la protéine oncogène Ras.
PCT/US1997/023888 1996-12-30 1997-12-22 Inhibiteurs de farnesyl-proteine transferase WO1998028980A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97954798A EP1003374A1 (fr) 1996-12-30 1997-12-22 Inhibiteurs de farnesyl-proteine transferase
AU60139/98A AU6013998A (en) 1996-12-30 1997-12-22 Inhibitors of farnesyl-protein transferase
CA002276081A CA2276081A1 (fr) 1996-12-30 1997-12-22 Inhibiteurs de farnesyl-proteine transferase
JP53021498A JP2002511054A (ja) 1996-12-30 1997-12-22 ファルネシル蛋白トランスフェラーゼ阻害薬

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3399196P 1996-12-30 1996-12-30
US60/033,991 1996-12-30
GB9702212.3 1997-02-04
GBGB9702212.3A GB9702212D0 (en) 1997-02-04 1997-02-04 Inhibitors of farnesyl-protein transferase

Publications (1)

Publication Number Publication Date
WO1998028980A1 true WO1998028980A1 (fr) 1998-07-09

Family

ID=26310926

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/023888 WO1998028980A1 (fr) 1996-12-30 1997-12-22 Inhibiteurs de farnesyl-proteine transferase

Country Status (5)

Country Link
EP (1) EP1003374A1 (fr)
JP (1) JP2002511054A (fr)
AU (1) AU6013998A (fr)
CA (1) CA2276081A1 (fr)
WO (1) WO1998028980A1 (fr)

Cited By (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
WO2002006233A1 (fr) * 2000-07-18 2002-01-24 Basf Aktiengesellschaft 1-aryl-4-halogenure d'alkyl-2-(1h)-pyridones et leur utilisation en tant qu'herbicides
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US6759404B2 (en) 2000-04-03 2004-07-06 Richard E. Olson Cyclic malonamides as inhibitors of aβ protein production
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7049324B1 (en) 1999-11-15 2006-05-23 Ashis Kumar Saha Triazoles as farnesyl transferase inhibitors
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7053088B2 (en) 2002-05-22 2006-05-30 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
US7144888B2 (en) 2002-08-08 2006-12-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
WO2008106692A1 (fr) 2007-03-01 2008-09-04 Novartis Vaccines And Diagnostics, Inc. Inhibiteurs de pim kinase et procédés de leur utilisation
WO2008144062A1 (fr) 2007-05-21 2008-11-27 Novartis Ag Inhibiteurs du csf-1r, compositions et procédés d'utilisation
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
US7511044B2 (en) 2004-02-11 2009-03-31 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7534798B2 (en) 2004-02-11 2009-05-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
US7659268B2 (en) 2005-11-08 2010-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7754739B2 (en) 2007-05-09 2010-07-13 Vertex Pharmaceuticals Incorporated Modulators of CFTR
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
WO2011115725A2 (fr) 2010-03-16 2011-09-22 Dana-Farber Cancer Institute, Inc. Composés d'indazole et leurs utilisations
US8039491B2 (en) 2005-12-28 2011-10-18 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2011163330A1 (fr) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
WO2012024170A2 (fr) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
US8124781B2 (en) 2007-12-07 2012-02-28 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
WO2012036997A1 (fr) 2010-09-16 2012-03-22 Schering Corporation Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk
WO2012058210A1 (fr) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. INHIBITION FACILITÉE PAR L'INTERFÉRENCE D'ARN DE L'EXPRESSION D'UN GÈNE AU MOYEN D'ACIDES NUCLÉIQUES INTERFÉRENTS COURTS (siNA)
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
WO2014100065A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituées en tant qu'inhibiteurs de hdm2
US8765747B2 (en) 2009-06-12 2014-07-01 Dana-Farber Cancer Institute, Inc. Fused 2-aminothiazole compounds
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
WO2016020864A1 (fr) 2014-08-06 2016-02-11 Novartis Ag Inhibiteurs de protéine kinase c et leurs procédés d'utilisation
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9758522B2 (en) 2012-10-19 2017-09-12 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9862688B2 (en) 2014-04-23 2018-01-09 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged janus kinase inhibitors and uses thereof
WO2018058022A1 (fr) 2016-09-26 2018-03-29 Merck Sharp & Dohme Corp. Anticorps anti-cd27
US10000483B2 (en) 2012-10-19 2018-06-19 Dana-Farber Cancer Institute, Inc. Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof
US10017477B2 (en) 2014-04-23 2018-07-10 Dana-Farber Cancer Institute, Inc. Janus kinase inhibitors and uses thereof
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
WO2018190719A2 (fr) 2017-04-13 2018-10-18 Aduro Biotech Holdings, Europe B.V. Anticorps anti-sirp alpha
US10112927B2 (en) 2012-10-18 2018-10-30 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10144730B2 (en) 2011-11-17 2018-12-04 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
WO2019094311A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
WO2019152642A1 (fr) 2018-02-01 2019-08-08 Merck Sharp & Dohme Corp. Anticorps bispécifiques anti-pd-1/lag3
US10550121B2 (en) 2015-03-27 2020-02-04 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
WO2020033282A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033284A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
US10702527B2 (en) 2015-06-12 2020-07-07 Dana-Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
CN111848521A (zh) * 2020-08-26 2020-10-30 韶远科技（上海)有限公司 一种2-取代-4-烷氧基咪唑化合物的制备方法
US10870651B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10906889B2 (en) 2013-10-18 2021-02-02 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
US11040957B2 (en) 2013-10-18 2021-06-22 Dana-Farber Cancer Institute, Inc. Heteroaromatic compounds useful for the treatment of proliferative diseases
US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4074051A (en) * 1971-12-08 1978-02-14 Minnesota Mining And Manufacturing Company 3-Pyrazolidinone derivatives
US4287195A (en) * 1978-07-14 1981-09-01 Janssen Pharmaceutica, N.V. Heterocyclic derivatives of [4-(piperazin-1-yl-phenyloxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazoles and 1H-1,2,4-triazoles
US4329470A (en) * 1981-05-04 1982-05-11 Merrell Dow Pharmaceuticals Inc. 5-(4-Phenyl 1-piperidinyl)methyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives
US4826835A (en) * 1985-10-23 1989-05-02 Rorer Pharmaceutical Corporation Pyridyl-pyridazinone and pyridyl-pyrazolinone compounds and their use in the treatment of congestive heart failure
US4914207A (en) * 1989-05-09 1990-04-03 Pfizer Inc. Arylthiazolylimidazoles
US5441970A (en) * 1991-04-05 1995-08-15 G. D. Searle & Co. Use of N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
US5478934A (en) * 1994-11-23 1995-12-26 Yuan; Jun Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL117580A0 (en) * 1995-03-29 1996-07-23 Merck & Co Inc Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
CA2249641A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4074051A (en) * 1971-12-08 1978-02-14 Minnesota Mining And Manufacturing Company 3-Pyrazolidinone derivatives
US4287195A (en) * 1978-07-14 1981-09-01 Janssen Pharmaceutica, N.V. Heterocyclic derivatives of [4-(piperazin-1-yl-phenyloxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazoles and 1H-1,2,4-triazoles
US4329470A (en) * 1981-05-04 1982-05-11 Merrell Dow Pharmaceuticals Inc. 5-(4-Phenyl 1-piperidinyl)methyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives
US4826835A (en) * 1985-10-23 1989-05-02 Rorer Pharmaceutical Corporation Pyridyl-pyridazinone and pyridyl-pyrazolinone compounds and their use in the treatment of congestive heart failure
US4914207A (en) * 1989-05-09 1990-04-03 Pfizer Inc. Arylthiazolylimidazoles
US5441970A (en) * 1991-04-05 1995-08-15 G. D. Searle & Co. Use of N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
US5478934A (en) * 1994-11-23 1995-12-26 Yuan; Jun Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS ON STN, DN:114:62092, AONO et al., "Preparation of Pyrazolones and Peroxylipid Formation Inhibitors and Collagenase Inhibitors Containing Them"; & JP,A,02 229 169. *
DATABASE CAPLUS ON STN, DN:126:31349, PAYNE et al., "Use of Pyrazolylpiperidine Derivatives as Alpha 1a Adrenergic Receptor Antagonists, for Treatment of Benign Prostatic Hypertrophy"; & WO,A,96 32938. *
See also references of EP1003374A4 *

Cited By (133)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7304049B2 (en) 1998-12-24 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylaminobenzodiazepines as inhibitors of Aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7718795B2 (en) 1998-12-24 2010-05-18 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US7342008B2 (en) 1999-09-13 2008-03-11 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7423033B2 (en) 1999-09-13 2008-09-09 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of aβ protein production
US7112583B2 (en) 1999-09-13 2006-09-26 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
JP2003514804A (ja) * 1999-11-15 2003-04-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ファルネシルトランスフェラーゼ阻害剤としてのトリアゾール類
US7049324B1 (en) 1999-11-15 2006-05-23 Ashis Kumar Saha Triazoles as farnesyl transferase inhibitors
US7592356B2 (en) 1999-11-15 2009-09-22 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
US7511061B2 (en) 1999-11-15 2009-03-31 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
JP4883862B2 (ja) * 1999-11-15 2012-02-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ファルネシルトランスフェラーゼ阻害剤としてのトリアゾール類
WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US7053081B2 (en) 2000-04-03 2006-05-30 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of A-β protein production
US7528249B2 (en) 2000-04-03 2009-05-05 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of aβ protein production
US6759404B2 (en) 2000-04-03 2004-07-06 Richard E. Olson Cyclic malonamides as inhibitors of aβ protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US7390896B2 (en) 2000-04-03 2008-06-24 Bristol-Myers Squibb Pharma Corporation Cyclic malonamides as inhibitors of Aβ protein production
US7276496B2 (en) 2000-04-03 2007-10-02 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of Aβ protein protection
US7655647B2 (en) 2000-04-11 2010-02-02 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7498324B2 (en) 2000-04-11 2009-03-03 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7276495B2 (en) 2000-04-11 2007-10-02 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7390802B2 (en) 2000-04-11 2008-06-24 Bristol-Myers Squibb Pharma Corporation Substituted lactams as inhibitors of Aβ protein production
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7354914B2 (en) 2000-06-01 2008-04-08 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6958329B2 (en) 2000-06-01 2005-10-25 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of A-β protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US7456278B2 (en) 2000-06-01 2008-11-25 Bristol-Myers Squibb Pharma Corporation Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
WO2002006233A1 (fr) * 2000-07-18 2002-01-24 Basf Aktiengesellschaft 1-aryl-4-halogenure d'alkyl-2-(1h)-pyridones et leur utilisation en tant qu'herbicides
US7396831B2 (en) 2002-05-22 2008-07-08 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7053088B2 (en) 2002-05-22 2006-05-30 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7524874B2 (en) 2002-05-22 2009-04-28 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7148221B2 (en) 2002-08-08 2006-12-12 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7332511B2 (en) 2002-08-08 2008-02-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7144888B2 (en) 2002-08-08 2006-12-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US10626111B2 (en) 2004-01-30 2020-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8227469B2 (en) 2004-02-11 2012-07-24 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7511044B2 (en) 2004-02-11 2009-03-31 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7534798B2 (en) 2004-02-11 2009-05-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
US9394278B2 (en) 2005-01-20 2016-07-19 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US10150752B2 (en) 2005-01-20 2018-12-11 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US8207198B2 (en) 2005-01-20 2012-06-26 Pfizer Inc. Substituted triazole derivatives as oxytocin antagonists
US9023872B2 (en) 2005-01-20 2015-05-05 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
US7956052B2 (en) 2005-11-08 2011-06-07 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11084804B2 (en) 2005-11-08 2021-08-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7741321B2 (en) 2005-11-08 2010-06-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7973038B2 (en) 2005-11-08 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7659268B2 (en) 2005-11-08 2010-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9216969B2 (en) 2005-11-08 2015-12-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8039491B2 (en) 2005-12-28 2011-10-18 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
EP2805945A1 (fr) 2007-01-10 2014-11-26 MSD Italia S.r.l. Indazoles substitués d'amide en tant qu'inhibiteurs PARP de poly(ADP-ribose)polymérase
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
WO2008106692A1 (fr) 2007-03-01 2008-09-04 Novartis Vaccines And Diagnostics, Inc. Inhibiteurs de pim kinase et procédés de leur utilisation
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US7754739B2 (en) 2007-05-09 2010-07-13 Vertex Pharmaceuticals Incorporated Modulators of CFTR
WO2008144062A1 (fr) 2007-05-21 2008-11-27 Novartis Ag Inhibiteurs du csf-1r, compositions et procédés d'utilisation
EP3103791A1 (fr) 2007-06-27 2016-12-14 Merck Sharp & Dohme Corp. Dérivés de4-carboxybenzylamino utilisés comme inhibiteurs de l'histone désacétylase
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
US10597384B2 (en) 2007-12-07 2020-03-24 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8124781B2 (en) 2007-12-07 2012-02-28 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
US9505784B2 (en) 2009-06-12 2016-11-29 Dana-Farber Cancer Institute, Inc. Fused 2-aminothiazole compounds
US8765747B2 (en) 2009-06-12 2014-07-01 Dana-Farber Cancer Institute, Inc. Fused 2-aminothiazole compounds
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
WO2011115725A2 (fr) 2010-03-16 2011-09-22 Dana-Farber Cancer Institute, Inc. Composés d'indazole et leurs utilisations
US8987275B2 (en) 2010-03-16 2015-03-24 Dana-Farber Cancer Institute, Inc. Indazole compounds and their uses
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US11052075B2 (en) 2010-04-07 2021-07-06 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
WO2011163330A1 (fr) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
EP3330377A1 (fr) 2010-08-02 2018-06-06 Sirna Therapeutics, Inc. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
EP4079856A1 (fr) 2010-08-17 2022-10-26 Sirna Therapeutics, Inc. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012024170A2 (fr) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
WO2012036997A1 (fr) 2010-09-16 2012-03-22 Schering Corporation Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk
WO2012058210A1 (fr) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. INHIBITION FACILITÉE PAR L'INTERFÉRENCE D'ARN DE L'EXPRESSION D'UN GÈNE AU MOYEN D'ACIDES NUCLÉIQUES INTERFÉRENTS COURTS (siNA)
EP3327125A1 (fr) 2010-10-29 2018-05-30 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
EP3766975A1 (fr) 2010-10-29 2021-01-20 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
US10144730B2 (en) 2011-11-17 2018-12-04 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
EP3919620A1 (fr) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Compositions d'acide nucléique interférent court (sina)
WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
US10787436B2 (en) 2012-10-18 2020-09-29 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10112927B2 (en) 2012-10-18 2018-10-30 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
USRE48175E1 (en) 2012-10-19 2020-08-25 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US9758522B2 (en) 2012-10-19 2017-09-12 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US10000483B2 (en) 2012-10-19 2018-06-19 Dana-Farber Cancer Institute, Inc. Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
WO2014100065A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituées en tant qu'inhibiteurs de hdm2
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
US10906889B2 (en) 2013-10-18 2021-02-02 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
US11040957B2 (en) 2013-10-18 2021-06-22 Dana-Farber Cancer Institute, Inc. Heteroaromatic compounds useful for the treatment of proliferative diseases
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10017477B2 (en) 2014-04-23 2018-07-10 Dana-Farber Cancer Institute, Inc. Janus kinase inhibitors and uses thereof
US9862688B2 (en) 2014-04-23 2018-01-09 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged janus kinase inhibitors and uses thereof
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
WO2016020864A1 (fr) 2014-08-06 2016-02-11 Novartis Ag Inhibiteurs de protéine kinase c et leurs procédés d'utilisation
EP3514151A1 (fr) 2014-08-06 2019-07-24 Novartis AG Inhibiteurs de protéine kinase c et leurs procédés d'utilisation
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
US10870651B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US10550121B2 (en) 2015-03-27 2020-02-04 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US10702527B2 (en) 2015-06-12 2020-07-07 Dana-Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
WO2018058022A1 (fr) 2016-09-26 2018-03-29 Merck Sharp & Dohme Corp. Anticorps anti-cd27
WO2018190719A2 (fr) 2017-04-13 2018-10-18 Aduro Biotech Holdings, Europe B.V. Anticorps anti-sirp alpha
WO2019094311A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2019152642A1 (fr) 2018-02-01 2019-08-08 Merck Sharp & Dohme Corp. Anticorps bispécifiques anti-pd-1/lag3
WO2020033284A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033282A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
CN111848521A (zh) * 2020-08-26 2020-10-30 韶远科技（上海)有限公司 一种2-取代-4-烷氧基咪唑化合物的制备方法

Also Published As

Publication number Publication date
EP1003374A4 (fr) 2000-05-31
CA2276081A1 (fr) 1998-07-09
AU6013998A (en) 1998-07-31
JP2002511054A (ja) 2002-04-09
EP1003374A1 (fr) 2000-05-31

Similar Documents

Publication Publication Date Title
US6093737A (en) Inhibitors of farnesyl-protein transferase
WO1998028980A1 (fr) Inhibiteurs de farnesyl-proteine transferase
US5872136A (en) Arylheteroaryl inhibitors of farnesyl-protein transferase
US6077853A (en) Inhibitors of farnesyl-protein transferase
US5854265A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
US5883105A (en) Inhibitors of farnesyl-protein transferase
US5854264A (en) Inhibitors of farnesyl-protein transferase
US5919785A (en) Inhibitors of farnesyl-protein transferase
US5880140A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
US5859012A (en) Inhibitors of farnesyl-protein transferase
US5939557A (en) Inhibitors of farnesyl-protein transferase
US5874452A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
EP0951285A1 (fr) Inhibiteurs de farnesyl-proteine transferase
WO1997036901A1 (fr) Inhibiteurs de transferase de farnesyl-proteine
CA2249665A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU715606B2 (en) Inhibitors of farnesyl-protein transferase
US5885995A (en) Inhibitors of farnesyl-protein transferase
CA2250353A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU2542597A (en) Inhibitors of farnesyl-protein transferase
WO1997036888A1 (fr) Inhibiteurs de farnesyl-proteine transferase
AU704792B2 (en) Inhibitors of farnesyl-protein transferase
WO1997036886A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU706314B2 (en) Inhibitors of farnesyl-protein transferase
US6001835A (en) Inhibitors of farnesyl-protein transferase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE GW HU ID IL IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997954798

Country of ref document: EP

ENP Entry into the national phase

Ref country code: CA

Ref document number: 2276081

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref document number: 2276081

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 60139/98

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1997954798

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997954798

Country of ref document: EP