WO1997045412A1 - Procede de traitement du cancer - Google Patents

Procede de traitement du cancer Download PDF

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Publication number
WO1997045412A1
WO1997045412A1 PCT/US1997/008992 US9708992W WO9745412A1 WO 1997045412 A1 WO1997045412 A1 WO 1997045412A1 US 9708992 W US9708992 W US 9708992W WO 9745412 A1 WO9745412 A1 WO 9745412A1
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WIPO (PCT)
Prior art keywords
methionine
pyrrolidin
substituted
unsubstituted
aryl
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PCT/US1997/008992
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English (en)
Inventor
David C. Heimbrook
Allen I. Oliff
Steven M. Stirdivant
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9612913.5A external-priority patent/GB9612913D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9542869A priority Critical patent/JP2000508335A/ja
Priority to AU32151/97A priority patent/AU3215197A/en
Priority to EP97927776A priority patent/EP0934270A1/fr
Publication of WO1997045412A1 publication Critical patent/WO1997045412A1/fr

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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a method of treating cancer using a compound which has MEK inhibiting activity and a compound which has famesyl protein transferase inhibiting activity.
  • the Ras protein is 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. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).
  • Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al, Science 277 :810-812).
  • Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
  • the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
  • the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 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 C 15 or C20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational modification.
  • Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et ai, Cell, 62:81 -88 (1990); Schaber et al, J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al., Science, 249:1133-1 139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)).
  • 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 ai, have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • FPTase farnesyl-protein transferase
  • the first class includes analogs of famesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
  • FPP famesyl diphosphate
  • 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. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 55:732-736 (1991)).
  • 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., 7. Med. Chem., 37, 725 (1994)).
  • Ki-Ras can be farnesylated or geranylgeranylated in vitro (James et al, J. Biol. Chem. 270, 6221-6226 (1995)). This effect may contribute to the resistance of certain cell lines containing activated Ki-ras- to treatment with farnesyl- protein transferase inhibitors (E.C. Lerner et al., J. Biol. Chem. 270, 26770-26773 (1995); G. James et al, Proc. Natl. Acad. Sci. 93, 4454- 4458 (1996)).
  • MEK inhibiting compounds in general inhibit the phosphorylation of threonine and tyrosine residues on ERK which occurs naturally in the Map kinase pathway as a result of many diverse extracellular stimuli.
  • Many oncogenes and growth factors including ras , raf, epidermal growth factor and platelet-derived growth factor, activate the MEK signal transduction pathway.
  • cancers where the MEK pathway is implicated therefore include cancers where these oncogenes and growth factors are proposed to play a role, including cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. More particularly, such examples include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. More particularly, such cancers include pancreatic and breast carcinoma.
  • a MEK inhibiting compound and a famesyl protein transferase (FPTase) inhibitor are used in the present invention to inhibit the growth of cancer cells that are resistant to inhibition by FPTase
  • a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an amount of a MEK inhibiting compound and an amount of a famesyl protein transferase inhibiting compound which are effective to treat cancer.
  • the present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a MEK inhibiting compound and an effective amount of a famesyl protein transferase inhibiting compound.
  • a MEK inhibiting compound Any compound which inhibits MEK and any compound which inhibits famesyl protein transferase can be used.
  • MEK inhibiting is used in the general sense to relate to compounds which antagonize, inhibit or counteract the activity of the MEK cascade or the proteins produced in response thereto.
  • the term is used to refer to compounds which inhibit or antagonize the activity of the enzyme Map/Erk kinase, or the gene coding Map/Erk kinase.
  • famesyl protein transferase inhibiting compound is likewise used in the general sense and refers to compounds which antagonize, inhibit or counteract the activity of the gene coding famesyl protein transferase or the protein produced in response thereto.
  • Cancers which are treatable in accordance with the inven ⁇ tion described herein include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic, mammary and salivary carcinomas, colorectal carcinoma, exocrine pancreatic carcinoma and myeloid leukemias. Examples of compounds which inhibit MEK are as follows:
  • famesyl protein transferase inhibiting compounds include the following:
  • Rla and R l D are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 O-, R l lS(0) m -, R 1 0C(O)NR 10 -, CN, N02, (R 10 )2N-C(NR 10 )-, R 10 C (O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, or Rl l ⁇ C(O)NR 10 -, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 ⁇ -, Rl lS(0) m -, R 10C(O)NR 10-, CN, (R10) 2 N-C(NR 10
  • R 2 and R3 are independently selected from: H; unsubstituted or substituted Ci -8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
  • substituted group is substituted with one or more of:
  • aryl or heterocycle unsubstituted or substituted with: a) Cl -4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen,
  • R 2 and R3 are attached to the same C atom and are combined to form (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ; R4 and R5 are independently selected from H and CH3;
  • R 2 , R3, R ⁇ and R ⁇ are optionally attached to the same carbon atom;
  • R6, R7 and R?a are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R6 and R ⁇ may be joined in a ring;
  • R7 and R?a may be joined in a ring;
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R l OO-, R ⁇ S(0) m -, R 10 c(O)NR 10 -, CN, NO2, R 10 c(O)-, R lO ⁇ C(O)-, N3, -N(Rl O) 2 , or Rl lOC(O)NR 10.
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(0)m-, R 10 C(O)NR 10 -, CN, N ⁇ 2, (R 10 )2N-C-(NR 10 )., R 10 c(O
  • R 10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from Cl -C ⁇ alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(0)m and V is no. hydrogen if Al is a bond, n is 0 and A 2 is S(0) m ;
  • W is a heterocycle
  • RK Rib, RIO, Rl l , m , R2, R3, R6, R7, p , R7a, u> R8, Al, A2, V, W, X, n, p, r, s, t and u are as defined above with respect to formula (11-a);
  • R4 is selected from H and CH3;
  • R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0)n ⁇ -, R 10 C(O)NR l0-, CN, N ⁇ 2,
  • G is H2 or O
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1 ) Cl -4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R6, or g) -C(0)NR6R7,
  • Rla, Ri b, RlO, Rl l , m, R2, R3, R6, R 7, p , u , R 7a, R8, A l , A2, V, W, X, n, r and t are as defined above with respect to formula (Il-a);
  • R 4 is selected from H and CH3; and any two of R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • Cl -4 alkyl unsubstituted or substituted with: a) Cl -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0)mR 6 , or g) -C(0)NR6R7,
  • s 1 ;
  • R 1 1 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R 2 a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 O-, Rl lS(0) m -, R 10 C(O)NR 10 -, CN, N3, (R 10 )2N-C(NR 10 )-, R 10 c(O)-, R lO ⁇ C(O)-, -N(R lO)2, or Rl lOC(O)NR 10 -, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 O-, Rl lS(0)m-, R10C(O)NR10-, CN, N ⁇ 2, (R 10 )2N-C(NR 10 )-, R 10 c(O)-, R lO ⁇ C(O)-, N3, N(R 10 ) 2 , or Rl lOC
  • R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R lO) 2 , N02, Rl°0-, Rl lS(0) m -, R 1°C(0)NR 10-,
  • R3 and R4 are combined to form - (CH2)s - ;
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(R 10 ) 2 , N02, Rl°0-, RHS(0)m-, R 10 C(O)NR l0-, CN, (R l O) 2 N-C(NR 10 )-, R lOc(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 ) 2 , Rl 1OC(O)NR10- and C1 -C20 alkyl,
  • R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
  • R7b i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cyclo
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(0)m-, R 10 C(O)NRl 0-, CN, N ⁇ 2, R 1 0 2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, N3, -N(R lO)2, or Rl lOC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R l 1 S(0) m -, R 10 C(0)NH-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,
  • R 10 is independently selected from H, Cl -C6 alkyl, benzyl, substituted aryl and Cl -C6 alkyl substituted with substituted aryl;
  • Z is independently H2 or O
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl,
  • R2a and R2b are independently selected from: a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 O-, RH S(0) m -, R!0C(O)NR10-, CN, N3, (R 10 )2N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, -N(Rl O)2, or
  • R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,
  • R3 and R4 are combined to form - (CH2)s - ;
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C l -C20 alkyl, C2-C2O alkenyl, C3-C 10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(R 10 )2, N02, R 1 0 O-, RHS(0)m-, Rl°C(0)NR 10 -, CN, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, R1 1OC(O)NR10- and C1 -C20 alkyl, and d)
  • R5a and R5b are combined to form - (Cll2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R6 is a) substituted or unsubstituted Cl -Ctf alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl,
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloal
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-Q0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl Oo-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl l S(0) m -, R10C(O)NR10-, CN, N ⁇ 2, (R 10 )2N-C-(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 ) 2 , or Rl l ⁇ C(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 O-, RH S(0) m -, Rl 0 C(O)NR 10 -, CN,
  • R 10 is independently selected from H, C1 -C6 alkyl, benzyl, substituted aryl and C1 -C6 alkyl substituted with substituted aryl;
  • Rl 2 is hydrogen or C1 -C6 alkyl
  • Rl3 is C1 -C6 alkyl
  • Z is independently H2 or O
  • Rl l, V, W, m, n, p and r are as defined above with respect to formula
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 O-, Rl lS(0)m-, R !0C(O)NR 10-, CN, N3, (R 10 )2N-C(NR 10 )-, R 10 c(O)-, R I 0 OC(O)-, -N(R 10 ) 2 , or
  • R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R lO)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R! 0C(O)NR 10-,
  • R3 and R4 are combined to form - (CH2)s - ;
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cyclo
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R l Oo-, R ⁇ S(0)m-, R 10 C(0)NR l O-, CN, N02, Rl°2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 ) 2 , or Rl lOC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R l lS(0) m -, R 10 C(0)NH-
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,
  • R 10 is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
  • Rl 2 is hydrogen or C1 -C6 alkyl
  • Rl3 is C1-C6 alkyl
  • Z is independently H2 or O
  • Rl l, V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 1 a and R 1 b are independently selected from : a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 O-, R l ⁇ (O ⁇ -, R 10 C(O)NR 10 -, CN, N02, (R 1°)2N-C(NR 10)-, R 10 c(O)-, R 10 ⁇ C(O)-, N3,
  • R2a and R 2 b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 O-, RHS(0) m -, R !0C(O)NR10-, CN, N3, (R 10 ) 2 N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, -N(R 10 )2, or Rl lOC(O)NR 10 -, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 O-, RHS(0) m -, R 10 C(O)NR 10 -, CN, N ⁇ 2, (R 10 ) 2 N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 ) 2 or R1 10C(0)NR 1°-,
  • R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C2O alkenyl,
  • R3 and R4 are combined to form - (CH2)s - ;
  • X-Y is
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloal
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(0) m -, R 10C(O)NR 10-, CN, N02, Rl ⁇ 2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, N3, -N(R 10) 2 , or Rl l ⁇ C(O)NR 10 -, and c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(0) m -, R 10 C(0)NH-
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl,
  • R 10 is independently selected from H, C1 -C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
  • Rl 2 is hydrogen or C1 -C6 alkyl
  • Rl3 is C1 -C6 alkyl
  • Z is independently H2 or O
  • Rla, Rib, R8, R9, RIO, Rl l, Al, A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R2 or R3 are combined with R6 to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 10 ⁇ -,
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10 ) 2 , N ⁇ 2, R 10 O-, Rl l S(0) m -, R10C(O)NR 10-,
  • R6 is independently selected from hydrogen or Cl -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R 8, R9, RIO, Rl 1 , Al , A 1 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
  • C3-C10 cycloalkyl, aryl or heterocyclyl group wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, Rl°0-, Rl l S(0)m-, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, RH OC(O)NR 10- and C1 -C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or
  • R2 and R3 are combined to form - (CH2)s - ;
  • R2 or R3 are combined with R ⁇ to fo ⁇ n a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by alkenyl, R 10 O-, Rl l S(0) m -, R 10 C(O)NR l0 ⁇ , CR N3, (R1°)2N-C(NR 10)-, R 10 C(O)-, Rl°OC(0)-, -N(R 10 )2, or RHOC(O)NR 10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, Rl l S(0) ⁇ r, R 10 C(O)NR 10 -, CN, N02, (R l O)2N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R10) 2 or R l l ⁇ C(O)NR 10 -, and d) C1
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, R 10 O-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10)2N-C(NR10)-, R 10 c(O)-, R 10 ⁇ C(O)-,
  • R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R6 is independently selected from hydrogen or C1 -C6 alkyl
  • Rl 2 is a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from:
  • Rl3 is independently selected from hydrogen and C1-C6 alkyl
  • Rl4 is independently selected from C1 -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • R la, Rib, R8, R9, RIO, Rl 1 , Al , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C l -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, Rl°0-, Rl lS(0) m -, R1°C(0)NR 10-, CN, (R 10 )2N-C(NR lO)-, R l Oc(O)-, R 10 ⁇ C(O)-,
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R6 to fo ⁇ n a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1 °0-,
  • R6 is independently selected from hydrogen or C1 -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R8, R9, RIO, Rl l , A l , A 2 , V, W, m, n, p, and r are as defined above with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl,
  • C3-C10 cycloalkyl, aryl or heterocyclyl group wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, Rl°0-, Rl lS(0) m -, R!0C(O)NR10_, CN, (R 10 )2N-C(NR 10 )-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, R! 1 OC(O)NR10- and C1 -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R2 or R3 are combined with R ⁇ to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R l O()-, RHS(0) m -, R!0C(O)NR 10-, CN, N3, (R10) 2 N-C(NR 10)-, R 10 C(O)-, R 10 ⁇ C(O)-, -N(R 10 )2, or RH ⁇ C(O)NR 10 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, Rl lS(0) m -, R 10 C(0)NR lO-, CN, N ⁇ 2, (R 10 ) 2 N-C(NR 10 )-, R 10 c(O)-, R lO ⁇ C(O)-, N3, -N(R 10 )2 or RHOC(O)NR10-, and d) C1-C
  • R6 is independently selected from hydrogen or C1 -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R8, R9, RIO, Rl 1 , Al , A*, V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, Rl°0-, Rl l S(0) m -, Rl 0 C(O)NR l0-,
  • R2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R6 to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 10 O-, R u S(0)m-, Rl°C(O)NR 10 -, CN, N3, (Rl°)2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, -N(R 10 ) 2 , or RH ⁇ C(O)NR 10 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, Rl l S(0) m -, R 10 C(O)NR 10 -, CN, NO2,
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
  • R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R6 is independently selected from hydrogen or C1-C6 alkyl;
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R8, R9, RIO, Rl l, Al , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 ) 2 , N02, Rl°0-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-,R10C(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, RllOC(O)NR 10 - and C1-C20 alkyl, and d) C1
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R6 to fo ⁇ n a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, Rl°0-, RllS(0) m -, R10C(O)NR!0-, CN, N3, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, -N(R10) 2 , OI RHOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, RllS(0) m -, R ⁇ C ⁇ NR 1 ⁇ -, CN, N02,
  • R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
  • C3-C10 cycloalkyl, aryl or heterocycle group wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N ⁇ 2, Rl°0-, Rl lS(0)m-, R! 0C(O)NR10-, CN, (R 10)2N-C(NR 10)-, R 10 c(O)-, R lO ⁇ C(O)-, N3, -N(R 10 )2, Rl lOC(O)NR 10 - and Q-C20 alkyl, d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or
  • R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R6 is independently selected from hydrogen or C1 -C6 alkyl
  • Rl 2 is a) substituted or unsubstituted C1 -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1 ) aryl,
  • Rl3 is independently selected from hydrogen and C1-C6 alkyl
  • Rl4 is independently selected from C1 -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R8, R9, RIO, RI 1, A l , A*, V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 )2, N02, Rl°0-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-, R 10 c(O)-, R 10 ⁇ C(O)-, N3, -N(R 10 )2, Rl lOC(O)NR 10 - an d C1 -C20 alkyl, and d
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R6 to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R l°0-, R n S(0) m -, Rl °C(O)NR 10 -, CN, N3, (R 1°)2N-C(NR 10)-, R 10 C(O)-, R 10 ⁇ C(O)-, -N(R 10 )2, or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, R 1 !S(0) m -, Rl°C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR lO)-, Rl °C(0)-, Rl °OC(0)-, N3, -N(Rl°)2, or RH OC(O)NR 10-, and d) C1
  • R6 is independently selected from hydrogen or C1 -C6 alkyl;
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla, Rib, R8, R9, RIO, Rl l , Al , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C] -C20 alkyl, C2-C2O alkenyl,
  • R2 and R3 are combined to form - (CH2)s - ;
  • R2 or R3 are combined with R6 to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R lOO-, Rl lS(O) m -, R 10 C(O)NR l0-, CN, N3, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, R 10 ⁇ C(O)-, -N(R lO)2, or R l lOC(O)NR 10 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R lOO-, Rl lS(0) m -, R ! 0C(O)NR 10-, CN, N02,
  • R6 is independently selected from hydrogen or C1 -C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Raf Specific compounds which antagonize Raf include the following: 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid tert-buty ⁇ ester;
  • Examples of compounds which antagonize or inhibit famesyl protein transferase include the following:
  • MEK inhibiting compounds an example of a published MEK inhibiting compound is PD-098059, published in JL Biol. Chem. 270: 27489 (1995) and J. Biol. Chem. 270: 13585 (1995), inco ⁇ orated herein by reference.
  • heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic or stable 8- to 1 1 -membered bicyclic or stable 1 1 -15 membered tricyclic heterocycle 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, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, mo ⁇ holinyl, naphthyridinyl, oxadiazol
  • Substituted alkyl, aryl and heteroaryl, and the substituted portions of aralkyl, aralkoxy, heteroaralkyl, heteroaralkoxy and like groups are substituted with from 1 -3 groups selected from the group consisting of: halo, hydroxy, cyano, acyl, acyiamino, aralkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino, alkylamino, dialkylamino, and sulfonylamino.
  • substituted aryl substituted heterocycle
  • substituted cycloalkyl are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Q -C6 alkyl)2, N ⁇ 2, CN, (Ci -C ⁇ alkyl)0-, -OH, (C1 -C6 alkyl)S(0)m-, (C1 -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3,(Ci -C6 alkyl)OC(0)NH- and C1-C2O alkyl.
  • heterocycloalkyl and “heterocyclyl” refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S(0)y or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. When three heteroatoms are present in the heterocycle, they are not all linked together.
  • heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidine-2- one, piperidine-2-one and the like.
  • Acyl as used herein refers to -C(0)Ci- 6 alkyl and -C(O)- aryl.
  • Acylamino refers to the group -NHC(0)Ci-6 alkyl and -NHC(0)aryl.
  • Aralkoxy refers to the group -OC i-6 alkylaryl.
  • Alkylsulfonyl refers to the group -SO2C1-6 alkyl.
  • Alkylsulfonylamino refers to the group -NHS02Ci-6alkyl.
  • Arylsulfonylamino refers to the group -NHS02aryl.
  • Alkylaminocarbonyl refers to the group -C(0)NHC ⁇ _ 6 alkyl.
  • Aryloxy refers to the group -O-aryl.
  • Aralkoxy refers to the group -O-Ci -6 alkylaryl.
  • Sulfonylamino refers to the group -NHSO3H.
  • Halo means Cl, F, Br and I selected on an independent basis.
  • the ring may also be heterocyclic as defined above.
  • amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
  • the compounds used in the present method 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.
  • named amino acids are understood to have the natural "L" stereoconfiguration
  • cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
  • a cyclic amine moiety include, but are not limited to, the following specific structures:
  • substitution on the cyclic amine moiety by R ⁇ a and R2b may be on different carbon atoms or on the same carbon atom.
  • cyclic moieties are formed.
  • examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties as described hereinabove for R3 and R4 are formed.
  • such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
  • any substituent or variable e.g., R lO, Z, n, etc.
  • -N(R 10 )2 represents -NHH, -NHCH3, -NHC2H5, etc.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
  • the compounds of formulas (Il-a) through (Il-k) can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below.
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
  • Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
  • the famesyl transferase inhibitors of formula (Il-a) through (ITc) can be synthesized in accordance with reaction schemes 1 -16, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • Substituents R a and Rb, as shown in the Schemes, represent the substituents R ⁇ , R3, R4, and R ; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
  • These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.
  • Boc -protected amino acids I available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethylformamide.
  • dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethylformamide.
  • the product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III.
  • acid for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride
  • Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V.
  • the N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h.
  • the product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII.
  • intermediate VIII (Scheme 2).
  • Intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX, prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 3).
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as dichloroethane, methanol or dimethylformamide.
  • the product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
  • the final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to the cyclized product such as the dihydroimidazole XV, can be accomplished by literature procedures.
  • the trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII.
  • the intermediate VIII can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
  • Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
  • the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
  • the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
  • the protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8). Treating XXVII with l ,l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXXII.
  • the aziridine reacts in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
  • Piperazine VIII can be reacted with an aldehyde derived from an amino acid, such as an O-alkylated tyrosine, to obtain compounds such as XXXIX.
  • R' is an aryl group
  • XXXIX can first be hydrogenated to unmask the phenol, and the amine group - I l l -
  • XXXDC deprotected with acid to produce XL.
  • the amine protecting group in XXXDC can be removed, and O-alkylated phenolic amines such as XLI produced.
  • N-Aryl piperazines can be prepared as described in Scheme 1 1.
  • An aryl amine XLV is reacted with bis -chloroethyl amine hydrochloride (XLVI) in refluxing n -butanol to furnish compounds XLVII.
  • the resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
  • Piperazin-5-ones can be prepared as shown in Scheme 12. Reductive amination of protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions. Ring closure is effected with a base, such as sodium hydride, in a polar aprotic solvent, such as dimethylformamide, to give LI. The carbamate protecting group is removed under acidic conditions, such as trifluoro ⁇ acetic acid in methylene chloride or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 3-9.
  • a base such as sodium hydride
  • a polar aprotic solvent such as dimethylformamide
  • the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
  • the imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV.
  • Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI.
  • Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
  • Access to alternatively substituted piperazines is described in Scheme 14.
  • N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
  • the resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
  • Reaction Scheme 15 provides an example of the synthesis of compounds wherein the substituents R ⁇ and R3 are combined to form - (CH2)u -•
  • 1 -aminocyclohexane-l -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2.
  • the piperazine inter ⁇ mediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9.
  • the aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16.
  • the product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII.
  • Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXX VI.
  • famesyl transferase inhibitors can also be synthesized in accordance with the general reaction schemes in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., in accordance with WO 96/10035 published on April 4, 1996, incorporated herein by reference. In addition to the disclosure contained therein, some alternative reactions are set forth below.
  • Step A l -triphenylmethyl-4-(hvdroxymethylVimidazole
  • 4-(hydroxymethyl)imidazole hydrochloride 35.0 g, 260 mmol
  • triethylamine 90.6 mL, 650 mmol
  • a white solid precipitated from the solution.
  • Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
  • Step B l-triphenylmethyl-4-facetoxymethv ⁇ -imidazole
  • Step C l -(4-cvanobenzvD-5-(acetoxymethv ⁇ -imidazole hydrobromide
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60°C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60°C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
  • Step D l -(4-cyanobenzylK5-(r ⁇ ydroxymethyl)-imidazole
  • Step E l -f4-cvanobenzylV5-irnidazolecarboxaldehvde
  • Step F (S)-2-(fm-butoxycarbonylammo)-N-methoxy-N-methyl-4-
  • Step G (S)-2-( ⁇ rNbutoxycarbonylamino)-4-(methylthio)butanal
  • a suspension of lithium aluminum hydride (5.02 g, 0.132 mol) in ether (500 mL) was stirred at room temperature for one hour.
  • the solution was cooled to -50°C under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min, maintaining the temperature below -40°C.
  • the reaction was warmed to 5°C, then recooled to -45°C. Analysis by tic revealed incomplete reaction.
  • the solution was re warmed to 5°C, stirred for 30 minutes, then cooled to -50°C.
  • Step H £S)-2-( ⁇ rr-butoxycarbonyIamino)-/V-(3-chlorophenyl)-4- (methylthio)butanamine
  • Step I (S)-4-(ter/-butoxycarbonyl)- 1 -(3-chlorophenyl)-5-[2-
  • Step J (S)-4-(terr-butoxy carbonyl)- 1 -(3-chlorophenyl)-5-f 2-
  • Step K (S)- 1 -(3-chlorophenyl)-5-[2-
  • Step L (S)-l-(3-chlorophenyl)-4-l l -(4- cyanobenzyl)imidazolylmethyl
  • Step A N-(3-chlorophenyl)ethylenediamine hydrochloride To a solution of 3-chloroaniIine (30.0 mL, 284 mmol) in 500 mL of dichloromethane at 0°C was added dropwise a solution of 4 N HCl in 1 ,4-dioxane (80 mL, 320 mmol HCl). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g, 282 mmol) was heated under nitrogen atmosphere at 160°C for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the crude diamine hydrochloride salt as a pale brown solid.
  • Step B -V-(ter/-butoxycarbonyl)-/V'-(3- chlorophenyOethylenediamine
  • Step A The amine hydrochloride from Step A (ca. 282 mmol, crude material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHC ⁇ 3 soln., cooled to 0°C, and ⁇ i-tert- butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without further purification.
  • Step C /V-[2-(re ⁇ -butoxycarbamoyl)ethylJ-N-(3-chlorophenyl)-2 I chloroacetamide
  • Step D 4-(/ ⁇ ?r/-butoxycarbonyl)- 1 -(3-chlorophenyl)-2- piperazinone
  • Step E l -(3-chlorophenyl)-2-piperazinone
  • Step F l-(3-chlorophenyl)-4-[l -(4-cyanobenzyl)imidazolylmethyl]-
  • Step A 2-Methoxybenzylglycine methyl ester
  • 2-Methoxybenzyl alcohol 53.5 g, 0.39 mol was dissolved in CH2CI2 (200 mL), treated with diisopropylethylamine (81 mL, 0.74 mol), cooled to 0°C. with stirring in an ice-CH3 ⁇ H bath under Ar, and treated dropwise with methanesulfonyl chloride (33 mL, 0.43 mol). After 0.5 hr, the reaction mixture was left to warm to ambient tempera- ture and stirred for 4 hr.
  • Step B N-[(2S)-(t-Butoxycarbonylpy ⁇ Olidinyl-methyl)-N-(2- methoxybenzyOglycine methyl ester
  • Step C N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2- methoxybenzyPglycine
  • Step D Methionine isopropyl ester hydrochloride N-(t-Butoxycarbonyl)methionine (25 g, 0.1 mol), isopropyl alcohol (1 1.8 mL, 0.15 mol), EDC (21.1 g, 0.1 1 mol), and 4-dimethyl- aminopyridine (DMAP) (1.22 g, 0.01 mol) were dissolved in CH2CI2 (400 mL) with stirring in an ice-water bath. After 2 h the bath was removed, and the solution was left to stir o.n. at RT.
  • DMAP 4-dimethyl- aminopyridine
  • N-(t-Butoxycarbonyl)methionine isopropyl ester (20.5 g, 0.07 mol) was dissolved in EtOAc (200 mL) with stirring and cooling to -20°C in a dry ice- acetone bath. HCl gas was bubbled into the solution for 10 min, the flask was stoppered and stirred for 1 h. Tic (EtOAc: hexane, 1 :3) indicates loss of starting material. Argon was bubbled through the soln for 5 min, then it was concentrated to dryness to give the title compound as a white solid.
  • Step E N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2- methoxybenzvPglvcyl-methionine isopropyl ester
  • Step F N-((2S)-PyrrolidinyImethyl )-N-(2-methoxybenzyl)-glycyl- methionine isopropyl ester bis hydrochloride
  • Step G N-[l -(lH-Imidazol-4-propionyl) pyrrolidin-2(S)- ylmethyl]-N-(2-methoxybenzyl)glycyl-methionine isopropyl ester
  • N-((2S)-Pyrrolidinylmethyl)-N-(2-methoxybenzyl)glycyl methionine isopropyl ester bis hydrochloride (0.800 g, 1.53 mmol), dissolved in DMF (30 mL), was treated with l H-imidazol-4-propionic acid (0.43 g, 3.05 mmol) (prepared by catalytic hydrogenation of urocanic acid in 20% acetic acid with Pd on carbon), and BOP reagent (1.35 g, 3.05 mmol).
  • the pH was adjusted to 7.5 with N-methyl- morpholine (0.756 mL, 6.89 mmol), and the mixture was stirred at ambient temperature for 18 h.
  • Step A Diethyl l -Acetyl-5-hydroxy-3-ethylpyrrolidine-2,2- dicarboxylate
  • Step B Diethyl 1 -Acetyl-3-ethylpyrrolidine-2.2-dicarbox ylate
  • diethyl l -acetyl-5-hydroxy-3-ethyl- pyrrolidine-2,2-dicarboxylate 287 g, 0.95 mol
  • triethylsilane 228 mL, 1.43 mol
  • CH2CI2 3 L
  • trifluoroacetic acid 7.35 mL, 9.53 mol
  • Step D N-[(/er/-Butyloxy)carbonyll-c/ ⁇ v:/ra/ ⁇ -3-ethylproline methyl ester
  • 3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.1 1 mol) was dissolved in CH3OH (200 mL), and the solution was saturated with HCl gas, then stirred at 23°C for 24 h. Argon was bubbled through the solution to remove excess HCl. The solution was treated with NaHC ⁇ 3 (>84 g) to a pH of 8, then di-/e/ /-butyl dicarbonate (25.1 g, 0.1 15 mol) dissolved in CH3OH (20 mL) was added slowly. After stirring for 18 h at 23°C, the mixture was filtered, the filtrate concentrated, and the residue triturated with EtOAc, filtered again, and concentrated to give the title compound as an oil.
  • Step E N-[(?er/-Butyloxy)carbonyl]-/ra/7 ⁇ -3-ethylproline and
  • N-[(/er/-Butyloxy)carbonyl]-/ra/2.v-3-ethylproline (15.5 g, 0.064 mol), S- ⁇ -methylbenzylamine (9.03 mL, 0.070 mol), HOBT (10.73 g, 0.70 mol), and N-mefhylmorpholine (8 mL, 0.076 mol) were dissolved in CH2CI2 (150 mL) with sitrring in an ice-H2 ⁇ bath, treated with EDC (13.4 g, 0.070 mol) stirred at 23°C for 48 h.
  • N-[(/w-Butyloxy) carbonyl-3(S)-ethyl-2(S)-proline was dissolved in EtOAc (50 mL) and the solution was saturated with HCl gas with cooling in an ice-H2 ⁇ bath. The solution was stoppered and stirred at 0 n C. for 3 hr. Argon was bubbled through the solution to remove excess HCl, and the solution was concentrated to dryness to give 3(S)-ethyl-2(S)-proline hydrochloride.
  • Step G N-(t-Buty loxycarbonyl)-pyrrolidin-2(S)-y Imethy 1J-3(S)- ethyl-proline
  • 3(S)-Ethyl-2(S)-proline hydrochloride (2.33 g, 0.013 mol) was dissolved in CH3OH (20 mL), treated with 3A molecular sieves (2 g) and KOAc (1.27 g, 0.013 mol) to adjust the pH of the reaction mixture to 4.5-5, then N-[(fer/-Butyloxy)carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) 59, [211 6287-95) (3.36 g, 0.017 mol) was added, and the mixture was stirred for 16 hrs at room temperature.
  • reaction mixture was filtered, quenched with aq satd NaHC ⁇ 3 (5 mL) and concentrated to dryness. The residue was extracted with CHCI3. The extract was dried (MgS04), filtered, and concentrated to give the title compound and inorganic salts.
  • Step H N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethylJ-3(S)- ethyl-prolyl methionine isopropyl ester
  • Step I Pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester hydrochloride
  • N-(t-butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-prolyl methionine isopropyl ester 1.38 g, 0.0028 mol
  • EtOAc 40 mL
  • EtOAc 40 mL
  • HCl gas saturated with HCl gas
  • Concentration to dryness gave pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl- prolyl methionine isopropyl ester hydrochloride.
  • Step K Preparation of l -(Triphenylmethyl)-l H-imidazol-4- ylacetic acid methyl ester
  • Step L Preparation of H -(4-Cyanobenzyl)- l H-imidazol-5-yllacetic acid methyl ester
  • the precipitated imidazolium salts were combined, suspended in methanol ( 100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHC ⁇ 3 (300ml) and CH2CI2 (300ml) and stirred at room temperature for 2 hr.
  • Step M Preparation of [ l -(4-cyanobenzyl)- l H-imidazol-5-yl]acetic acid

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Abstract

Procédé de traitement du cancer, qui consiste à administrer à un mammifère un composé qui inhibe la MEK et un composé qui inhibe la farnésyl-protéine transférase.
PCT/US1997/008992 1996-05-30 1997-05-27 Procede de traitement du cancer WO1997045412A1 (fr)

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JP9542869A JP2000508335A (ja) 1996-05-30 1997-05-27 癌の治療方法
AU32151/97A AU3215197A (en) 1996-05-30 1997-05-27 A method of treating cancer
EP97927776A EP0934270A1 (fr) 1996-05-30 1997-05-27 Procede de traitement du cancer

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US1867996P 1996-05-30 1996-05-30
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GBGB9612913.5A GB9612913D0 (en) 1996-06-18 1996-06-18 A method of treating cancer

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