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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/005—Enzyme inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
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  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
  • C07D309/30—Oxygen atoms, e.g. delta-lactones
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—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 combination of a compound which is a inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a inhibitor of farnesyl-protein transferase.
• the invention further relates to a method of treating cancer using a combination of a compound which is a selective inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a selective inhibitor of farnesyl-protein transferase.
• Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a new class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. ( 1990). FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins.
• Prenylated proteins share characteristic C-terminal sequences including CaaX (C, Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC.
• Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. Proteins terminating with a XXCC or XCXC motif are modified by geranylgeranylation on the Cys residues and do not require an endoproteolytic processing step. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxymethylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61 , 355-386).
• FPTase farnesyl-protein transferase
• GGPTase-I geranylgeranyl- protein transferase type I
• Rab GGPTase geranylgeranyl-protein transferase type-II
• FPTase and GGPTase-I are ⁇ / ⁇ heterodimeric enzymes that share a common subunit; the ⁇ subunits are distinct but share approximately 30% amino acid similarity (Brown, M. S. and Goldstein, J. L. (1993). Nature 366, 14-15; Zhang, F. L., Diehl, R. E., Kohl, N. E., Gibbs, J. B., Giros, B., Casey, P. J., and Omer, C. A. (1994). J. Biol. Chem. 269, 3175-3180).
• GGPTase-II has different ⁇ and ⁇ subunits and complexes with a third component (REP, Rab Escort Protein) that presents the protein substrate to the ⁇ / ⁇ catalytic subunits.
• REP Rab Escort Protein
• Each of these enzymes selectively uses famesyl diphosphate or geranylgeranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate.
• FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
• CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
• GGPTase-II modifies XXCC and XCXC proteins; the interaction between GGPTase-II and its protein substrates is more complex, requiring protein sequences in addition to the C-terminal amino acids for recognition.
• the enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., O ⁇ ara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., and Gibbs, J. B., J. Biol. Chem., 266: 17438 (1991 ), U.S. Pat. No. 5,470,832).
• 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.
• 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 al., Cell, 62:81 -88 (1990); Schaber et al., J. Biol. Chem., 265: 14701 -14704 (1990); Schafer et al., Science, 249:1 133-1 139 (1990); Marine et al., P oc. Natl. Acad. Sci USA, 87:7541 -7545 (1990)).
• 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 ai, Nature J7(J: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 1 5 or C2 0 isoprenoid, respectively.
• N- Ras and K-Ras proteins' sequences do not exhibit the absolute substrate specificity for farnesyl-protein transferase that is found for the H-Ras C-terminus sequence, which allows N-Ras and K-Ras proteins to be processed bygeranylgeranyl-protein transferase as well (Moores, S. L. et al., J. Biol. Chem., 266:17438 ( 1991 ) and James, G. et al., J. Biol. Chem., 270:6221 -6226 (1995)).
• 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.
• famesylated proteins include the Ras-related GTP-binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 ( 1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
• GGTase-I Protein geranylgeranyltransferase type-I transfers a geranylgeranyl group from the prenyl donor geranylgeranyl diphosphate to the cysteine residue of substrate proteins containing a C-terminal CAAX -motif in which the "X" residue is leucine or phenyl- alanine (Clark, 1992; Newman and Magee, 1993).
• GGTase-I gamma subunits of brain heterotrimeric G proteins and Ras-related small GTP-binding proteins such as RhoA, RhoB, RhoC, CDC42Hs, Racl , Rac2, R-Ras, TC21 , Rapl A and RaplB (Newman and Magee, 1993; Cox and Der, 1992a).
• the proteins RhoA, RhoB, RhoC, Racl , Rac2 and CDC42Hs have roles in the regulation of cell shape (Ridley, A. J. and Hall, A. (1992). Cell 70:389-399; Ridley, A. J., Paterson, H. F., Johnston, C.
• Rho and Rac proteins transmit intracellular signals initiated by growth factors and by Ras protein (Prendergast, G. C. and Gibbs, J. B. (1993). Adv. Cancer Res. 62, 19-64; Ridley and Hall, 1992; Ridley et al., 1992).
• Rho and Rac proteins were required by Ras and growth factors to change cell shape, a biological parameter indicative of cellular transformation and cancer.
• Activated forms of Rho and Rac proteins have also been shown to cause cellular transformation in cell culture (Symons, M., Current Opinion Biotechnology, 6:668-674 (1995)). Since Rho and Rac proteins require geranylgeranylation for function, an inhibitor of GGPTase-I would block the functions of these proteins and be useful as an anticancer agent.
• Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes.
• 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, 88:132-136 (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 ai, Science, 26(9: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
• Mammalian cells express four types of Ras proteins (H-, N, K4A-, and K4B-Ras) among which K-Ras4B is the most frequently mutated form of Ras in human cancers.
• Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras -transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260: 1934- 1937 (1993) and G.L. James et al., Science, 260: 1931-1942 ( 1993).
• a pharmaceutically effective combination of geranylgeranyl-protein transferase-type I inhibitor and a famesyl- protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells that are less susceptable to treatment by one of the selective inhibitors when administered alone.
• a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a combination of a geranylgeranyl- protein transferase-type I inhibitor and a famesyl protein transferase inhibitor.
• a selective geranylgeranyl-protein transferase- type I inhibitor and a selective famesyl protein transferase inhibitor are used in such a combination.
• FIG. 1 Autoradiograph of the 13% acrylamide gel chromatography of the immunoprecipitates from Assay Set No. 1.
• Assays that are illustrated include in vivo prenylation inhibition by a selective FPTase inhibitor (Compound 5), a selective geranylgeranyl- protein transferase-type I inhibitor (Compound 1 ) and a non-selective inhibitor (Compound 7).
• the intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.
• 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 combination of a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl- protein transferase inhibitor.
• the present method of treating cancer by simultaneously inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase-type I offers advantages over previously disclosed methods utilizing prenyl-protein transferase inhibitors, in that the inhibitory activity of the instant combination of inhibitors against FPTase and/or GGTase can be varied by formulation depending on the nature of the cancer cells to be treated.
• variable inhibitory potency combinations are useful in treatment of human cancers associated with the K-Ras4B and N-Ras mutated forms of Ras whose processing are not blocked by a potent selective FPTase inhibitor alone.
• Any compound which inhibits geranylgeranyl-protein transferase-type I and any compound which inhibits famesyl protein transferase can be used in the instant method.
• the compounds utilized in the instant combination are a selective geranylgeranyl-protein transferase-type I inhibitor and a selective farnesyl-protein transferase inhibitor.
• geranylgeranyl-protein transferase- type I inhibiting compound refers to compounds which antagonize, inhibit or counteract the activity of the gene coding geranylgeranyl- protein transferase-type I or the protein produced in response thereto.
• famesyl protein transferase inhibiting compound likewise refers to compounds which antagonize, inhibit or counteract the activity of the gene coding farnesyl-protein transferase or the protein produced in response thereto.
• a geranylgeranyl-protein transferase-type I inhibitor may be distinquished from a farnesyl-protein transferase inhibitor by having greater inhibitory activity against geranylgeranyl- protein transferase-type I than against farnesyl-protein transferase.
• a farnesyl-protein transferase inhibitor may be distinquished from a geranylgeranyl-protein transferase-type I inhibitor by having greater inhibitory activity against farnesyl-protein transferase than against geranylgeranyl-protein transferase-type I.
• selective as used herein refers to the inhibitory activity of the particular compound against geranylgeranyl-protein transferase-type I activity when compared to the inhibitory activity of the compound against farnesyl-protein transferase activity.
• a compound is considered a selective inhibitor of geranylgeranyl-protein transferase-type I, for example, when its in vitro activity, as assessed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound against farnesyl-protein transferase in that assay.
• a compound is considered a selective inhibitor of farnesyl-protein transferase, for example, when its in vitro farnesyl- protein transferase inhibitory activity, as assessed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound against geranylgeranyl-protein transferase-type I in that assay.
• a selective compound exhibits at least 20 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition. More preferably the selectivity is at least 100 times or more.
• the extent of selectivity of the two inhibitors that comprise the method of the instant invention effects the advantages that the method of treatment claimed herein offers over previously disclosed non-selective inhibitors of prenyl -transferase enzymes.
• use of two independent inhibitor components that have complementary, essentially non-overlapping inhibitory activities allows the person utilizing the instant method of treatment to independently and accurately vary the inhibitory activity of the combination without having to synthesize a single drug having a particular GGTase-type I/FPTase inhibitory profile.
• Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, lymphatic system,pancreas, rectum, stomach, larynx, liver and lung, and chronic myelogenous leukemia. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma and small cell lung cancers.
• the pharmaceutical composition 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 combination or compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
• carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
• useful diluents include lactose and dried com starch.
• aqueous suspensions are required for oral use, the active ingredients are 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 combinations 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 combinations may be useful in combination with other known anti-cancer and cytotoxic agents.
• combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
• Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
• the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutical ly effective amount of the combinations of this invention, with or without pharmaceutically acceptable carriers or diluents.
• suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo- gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection.
• 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 a geranylgeranyl-protein transferase-type I inhibitor and a famesyl- protein transferase inhibitor are administered to a mammal undergoing treatment for cancer.
• Administration occurs in an amount of each type of inhibitor of 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.
• Rl and R2 are independently selected from: a) C2 - C alkyl; b) C2 - C8 alkenyl; c) C2 - C8 alkynyl; d) substituted Cl - C8 alkyl; e) aryl; f) substituted aryl; g) heteroaryl; h) substituted heteroaryl; and i) the side chain of a naturally occurring amino acid;
• R3 is selected from alkyl, alkenyl and alkynyl of 1 to 6 carbon atoms, either branched or straight chain, which is unsubstituted or substituted with a phenyl group;
• X-Y is
• Z is H2 or O; or the pharmaceutically acceptable salts or disulfides thereof.
• famesyl protein transferase inhibiting compounds and in particular selective famesyl protein transferase inhibiting compounds include the following:
• Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
• R ⁇ and R ⁇ are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
• R2 and R ⁇ 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 J O)- ;
• R4 and R ⁇ are independently selected from H and CH3;
• R ⁇ , R3, R4 a nd R5 are optionally attached to the same carbon atom;
• R6, R7 anc j R7a are independently selected from: H; Ci -4 alkyl, C -6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
• R8 i independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOo-, RHs(0)m-, R 10 C(O)NRl0-, CN, NO2,
• RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
• Rl 1 is independently selected from C]-C6 alkyl and aryl;
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C] -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A l is a bond, n is 0 and A 2 is S(0)m;
• W is a heterocycle
• Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
• 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)mPA or g) -C(0)NR6R7, 2) aryl or heterocycle,
• Rla, Rib, R10, Rl l , m , R2, R3, R 6, R7, p , R7a , u , RX , A l , V , W, X, n, p, r, s, t and u are as defined above with respect to formula (Il-a);
• R4 is selected from H and CH3;
• R 2 , R3 and R 4 are optionally attached to the same carbon atom;
• R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, 1 ⁇ (O , R 10 C(0)NR10_, CN, N02, (R10) N-C-(NR10) . ,R10C(O)-, RIOOC(O)-, N3, -N(R10) 2 , O ⁇ R11OC(O)NR10., an d c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(0) m -, R!
• Rla, R i b, R lO, Rl l , m , R2, R3, R6, R7, p, u , R 7a , R8, A l , A 2, 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;
• R 2 , R3 and R 4 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:
• R 1 J, 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,
• R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOo-, Rl lS(0) m -, RlOC(0)NRlO-, CN, N3, (R ]0 )2N- C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO) , or R11OC(O)NR10-, c) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, RlOo,
• R3 and R 4 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(R 1 )2, Rll ⁇ C(O)NRl0- and C1-C20 alkyl, and d) C1
• 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 -C20 alkyl, C2-C2O alkenyl,
• C1-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(CORlO)-; X-Y
• 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) Cl-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 cycloalkyl
• R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOo-, 1 ⁇ O)TM-, Rl0c(O)NRl0-, CN, NO2, R 10 2N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or
• R11OC(O)NR10- and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl°0-, Rl lS(0) m -, RlOC(0)NH-,CN, H2N-C(NH)-, RlOc(O)-, RlO ⁇ C(O)-,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl,
• RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
• Z is independently H2 or O
• R ' ! , W, m, n, p and r are as defined above with respect to formula (Il-a);
• R 1 and R 1 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOo-, Rl !S(0)m-, R10C(0)NR10-, CN,
• R10 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, orRH ⁇ C(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R ] lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, O ⁇ RUOC(O)-NR10-;
• R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOO-, R 1 lS(0) m -, R10C(O)NR10-, CN, N3,
• R3 and R 4 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-C20 alkenyl, C3-C]0 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0) m -, R10C(O)NR10-, CN, (R10) 2 N-C(NR10)-, Rl°C(0)-, RlO ⁇ C(O)-, N3, -N(RlO)2, Rl l ⁇ C(O)NRl0- and C1-C20 alkyl, and d) C1-C6 al
• R3 and R 4 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-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(CORlO)-; R°is a) substituted or unsubstituted C1-C8 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:
• 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-C] 0 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10
• R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-,
• R 11 S(0)m-, R 10c(O)NR 10-, CN, NO2, R l °2N-C(NR 10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or
• RllOC(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, RlOC(0)NH-, CN, H2N-C(NH)-, Rl°C(0)-, RlO ⁇ C(O)-,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,
• RlO 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
• R 13 is C1-C6 alkyl
• Z is independently H2 or O
• Rl 1, V, W, m, n, p and r are as defined above with respect to formula (H-a);
• Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
• R3 and R 4 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-C20 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 10C(O)NR 10-,
• R3 and R 4 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-C 10 cycloalkyl, and e) Cl -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 cycloalky
• R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(O)m-,R I0 C(O)NRl0-, CN, N ⁇ 2,Rl°2N-C(NRlO)-,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,
• RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
• Rl2 is hydrogen or C]-C6 alkyl
• Rl3 is Cl-C ⁇ alkyl
• Z is independently H2 or O
• R n , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
• Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RllS(0) m -, R!0C(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl 10C(0)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m -, R!°C(O)NR10-, CN, (Rl0)2N-C(NR 0)-, RlOc(O)-, RlO ⁇ C
• R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOo-, R lS(0)m-, R ] 0c(O)NRl0-, CN, N3, (R 10 )2N- C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, -N(Rl ) 2 , or
• RHOC(O)NR10 c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, NO2, (RlO) 2 N-C(NRlO , RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2 orRll ⁇ C(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C 10 cycloalkyl;
• R and R 4 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, NCR 10)2, N02, RlOO-, Rl lS(0) m -, R!0C(O)NR10-
• R3 and R 4 are combined to form - (CH2)s - ;
• R7a i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) Cl -C($ 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
• R 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 1 1 S(0)m-, R ] °C(0)NR 10-, CN, N ⁇ 2, R 1 °2N-C(NR ' )-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or RllOC(O)NRl0-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 OO-, R 11 S(0) m -,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl,
• RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
• Rl2 i hydrogen or C1-C6 alkyl
• Rl3 is C1-C6 alkyl
• Z is independently H2 or O
• Rla, Rib, R8, R9, R10, Rll, A l, A2, 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 C i -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , NO2, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, (Rl0) 2 N-C(NRl0)-,Rl0c(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and C1-C20 alky
• 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) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-
• 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N02, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-
• 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, R l b , R x , R y , R 1 , R 1 1 , A l , A2, 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 C ⁇ -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N ⁇ 2, Rl°0-, Rl lS(0)m-, Rl0c(O)NRl0-, CN, (R10)2N-C(NR1°)-, RlOC(O)-, RlO ⁇ C(O)-,
• R2 and R3 are combined to form - (CH2)s - ;
• R2 or R3 are combined with R ⁇ to form a ring such that
• R4a, R4D, R7a and R7b are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by alkenyl, RlOo-,
• R 1 ⁇ (O , Rl0c(O)NRl0-, CN, N3, (RlO)2N-C(NRlO)-, R 10C(O)-, R 10 ⁇ C(O)-, -N(R 10) 2 , or R 11 OC(0)NR 10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOo-, R 1 ⁇ (OTM-, Rl0c(O)NRl0-, CN, NO2, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3,
• 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-C ] ⁇ cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R lO)2, N02, R 10 O-, R l lS(0)m-, R 1°C(0)NR 10., CN, (RlO)2N-C(NRl O)-, R l0 (O)-, R lO ⁇ C(O)-,
• R5a and R5b are combined to fo ⁇ n - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORl°)- ;
• R6 is independently selected from hydrogen or Cl -C6 alkyl
• R l2 is a) substituted or unsubstituted Cl -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from:
• Rl3 i independently selected from hydrogen and C1-C6 alkyl
• Rl 4 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;
• s is 4 or 5; tis 3, 4 or 5; and u is Oor 1;
• R'a, Rib, R8, R9, R10, R11, A l, 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 Cl -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,
• R2 and R3 are combined to form - (CH2)s - ;
• R2 or R3 are combined with R6 to form a ring such that
• R 4 a, R 4 b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1 Oo-, R 1 'SIO , R!°C(O)NR10-, CN, N3, (R1°)2N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, orRll ⁇ C(O)NRl0-, c)
• R6 is independently selected from hydrogen or C] -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, R i b, R8, R9, R 10, 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N02, Rl°0-, Rl lS(0)m-, R1°C(0)NR10-, CN, (R10)2N-C(NR10)-, Rl0c(O)-, RlO ⁇ C(O)-,
• 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) 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;
• Rl is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
• R2 and R3 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
• R 4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
• R5 is selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH20H or -CH2CH2CH2OH;
• R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
• Examples of compounds that selectively inhibit geranylgeranyl-protein transferase-type I include the following:
• Examples of compounds which selectively inhibit famesyl protein transferase include the following:
• alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
• substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
• Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and intermpted by from 1 -4 heteroatoms selected from O, S and N.
• alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non- aromatic (non-resonating) carbon-carbon double bonds may be present.
• alkenyl groups examples 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.
• Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
• alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
• Preferred alkynyl groups include ethynyl, propynyl and butynyl.
• the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
• Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
• Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
• the preferred aryl groups are phenyl and naphthyl.
• Aryl groups may likewise be substituted as defined below.
• Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
• aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
• aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
• heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
• the heteroaryl group is optionally substituted with up to three groups.
• Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
• this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.
• partially aromatic groups are tetrahydro- imidazof4,5-clpyridine, phthalidyl and saccharinyl, as defined below.
• 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, morpholinyl, naphthyridinyl, oxadiazoly
• 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(Cj -C6 alkyl)2, N ⁇ 2, CN, (CJ -C6 alkyl)0-, -OH, (C1 -C6 alkyI)S(0) m -, (Cl -C ⁇ alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3,(Cl -C6 alkyl) OC(0)NH- and C1-C20 alkyl.
• 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:
• R3 and R 4 are combined to form - (CH2)s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
• cyclic moieties as described hereinabove for R3 and R 4 are formed.
• such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
• 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.
• 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 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 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 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.
• DMAP 4-Dimethylaminopyridine
• DME 1,2-Dimethoxyethane
• compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
• Non-toxic salts include conventional non -toxic salts or quartemary 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 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 (II-c) can be synthesized in accordance with 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 R2, R3, R4 a nd R5; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
• 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 ( l -ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethyl- formamide.
• dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 ( l -ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethyl- formamide.
• 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 cyanoboro- hydride, in a solvent such as dichloroethane, methanol or dimethyl- formamide.
• 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 trifluoro- acetate, 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-aziridinylmethylpiperazine.s 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.
• a nucleophile such as a thiol
• 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 deprotected with acid to produce XL.
• the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
• N-Aryl piperazines can be prepared as described in Scheme
• Pipe razin-5 -ones can be prepared as shown in Scheme 12.
• Ring closure is effected with a base, such as sodium hydride, in a polar aprotic solvent, such as dimethylformamide, to give LI.
• a base such as sodium hydride
• a polar aprotic solvent such as dimethylformamide
• 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.
• the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
• the imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIU) 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.
• N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
• 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 LXXVI.
• the geranylgeranyl-protein transferase-type I inhibitors and certain of the famesyl transferase inhibitors can be synthesized in accordance with general Reaction Schemes A-E 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.
• Some key bond-forming and peptide modifying reactions are:
• Reaction B Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
• Reaction C Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.
• Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety.
• Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. Such reactions are equally useful when the - NHC(RA) - moiety of the reagents and compounds illustrated is replaced with the following moiety:
• R 4a , R 4b , R 7a and R 7b which can be substituted with R 4a , R 4b , R 7a and R 7b in accordance with structures (ll-d) through (Il-k).
• 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.
• RA and RB are R3, R4, R5a or R5b as previously defined; RC is R6 as previously defined or a carboxylic acid protecting group; XL is a leaving group, e.g., Br-, I- or MsO-; and Ry is defined such that R7b is generated by the reductive alkylation process.
• Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure.
• substituents R ⁇ a and R ⁇ b on the cyclic amine moiety are not shown.
• Step H of Scheme F the amino terminus sidechain, designated R ⁇ is incorporated using coupling reaction A and RxCOOH; the alkylation reaction C using R*CHO and a reducing agent; or alkylation reaction C using R ⁇ CH2XL.
• Such reactions as described in Step H are described in more detail in Reaction Schemes J-X hereinbelow.
• alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G.
• oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H.
• An aminoalcohol I is acylated with alpha-chloroacetyl chloride in the presence of trialkyl- amines to yield amide 2.
• a deprotonation reagent e.g., sodium hydride or potassium t-butoxide
• THF ethereal solvent
• R3 ⁇ L where XL is a leaving group such as Br, I- or Cl- in THF/DME (1 ,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amidej, affords 4, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4 ⁇ to give 5a or 5b, respectively, as a enantiomeric mixture.
• 5a . can be prepared from 3. via an aldol condensation approach. Namely, deprotonation of 3 with NaHMDS followed by the addition of a carbonyl compound RyRzCO gives the adduct 6.
• Dehydration of 6 can be effected by mesylation and subsequent elimination catalyzed by DBU (l ,8-diazabicyclo[5.4.0Jundec- 7-ene) or the direct treatment of 6 with phosphorus oxychloride in pyridine to give olefin 7. Then, catalytic hydrogenation of 7 yields 5a (wherein -CHRYR 2 constitutes R3). Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or aqueous HCI, produces acid 8a. Compound 8a is then derivatized with BOC-ON or BOC anhydride to give 8b.
• the aminoalcohol 1 is protected with trifluoroacetic anhydride and the blocked compound _L5 treated with diphenyl disulfide in the presence of tributylphosphine to provide the thioether 16.
• Chlorination of compound J_6 provides compound JJ7 which can be reacted with the appropriate carboxylic acid alcohol in the presence of silver perchlorate and tin (II) chloride, to afford the mixed acetal 18 .
• Removal of the phenylmercapto moiety with Raney nickel provides compound 19.
• Compound 19 is doubly deprotected, then selectively BOC protected to provide the acid 20, which undergoes the steps previously described for incorporating terminal amino acid.
• the thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I.
• Aminoalcohol 1 is derivatized with BOC2O to give 25.
• Mesylation of 25 followed by reaction with methyl alpha-mcrcaptoacetate in the presence of cesium carbonate gives sulfide 26.
• Removal of the BOC group in 26 with TFA followed by neutralization with di-isopropyl- ethylamine leads to lactam 27.
• Sequential alkylation of 27 with the alkyl halides R3 ⁇ and R ⁇ in THF/DME using NaHDMS as the deprotonation reagent produces 28.

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