AU6953298A - A method of treating cancer - Google Patents

A method of treating cancer Download PDF

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AU6953298A
AU6953298A AU69532/98A AU6953298A AU6953298A AU 6953298 A AU6953298 A AU 6953298A AU 69532/98 A AU69532/98 A AU 69532/98A AU 6953298 A AU6953298 A AU 6953298A AU 6953298 A AU6953298 A AU 6953298A
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alkyl
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AU724216B2 (en
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Mark E. Duggan
George D. Hartman
David C. Heimbrook
Allen I. Oliff
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Merck and Co Inc
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Description

WO 98/44797 PCT/US98/06823 TITLE OF THE INVENTION A METHOD OF TREATING CANCER BACKGROUND OF THE INVENTION 5 The present invention relates to methods of treating cancer using a combination of a compound which is an integrin antagonist and a compound which is a inhibitor of farnesyl-protein transferase. Osteoclasts are multinucleated cells of up to 400 Rm in diameter that resorb mineralized tissue, chiefly calcium carbonate and 10 calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at 15 least two physiological states. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and acid to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory 20 or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone. Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration. The most abundant integrin in 25 osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or av33, thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to av33 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that avP3 ligands can be used 30 effectively to inhibit osteoclast mediated bone resoption in vivo in mammals. - 1 - WO 98/44797 PCT/US98/06823 A second integrin vitronectin receptor, avP5, has also been identified. A monoclonal antibody for xv15 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model. See M.C. Friedlander, et al., Science 5 270, 1500-1502, 1995, which is incorporated by reference herein in its entirety. Two collagen receptor integrins, (xlpl and u231, have also been proposed to mediate VEGF-induced mitogenesis in a mouse Matrigel implant model. See D.R. Senger, et al, Proc. Natl. Acad. Sci 94, 13612-13617, 1997, which is incorporated by reference herein in its 10 entirety. Additionally, axv33 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after corrective surgery on the heart valve), artherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (formation of 15 new blood vessels). Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine, 12th ed., 1991). xvP3 20 antagonists, which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth and metastasis. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)). Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a class of post-translational 25 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, 30 Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC. Three post-translational processing steps have been described for proteins having a C-terminal CaaX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon (geranylgeranyl) isoprenoid to the Cys residue, proteolytic cleavage of the last 3 amino acids, and methylation -2- WO 98/44797 PCT/US98/06823 of the new C-terminal carboxylate (Cox, A. D. and Der, C. J. (1992a). Critical Rev. Oncogenesis 3:365-400; Newman, C. M. H. and Magee, A. I. (1993). Biochim. Biophys. Acta 1155:79-96). Some proteins may also have a fourth modification: palmitoylation of one or two Cys 5 residues N-terminal to the farnesylated Cys. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxy methylation follows prenylation of proteins terminat ing with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61, 355-386). For all of the prenylated proteins, addition of the isoprenoid 10 is the first step and is required for the subsequent steps (Cox, A. D. and Der, C. J. (1992a). Critical Rev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current Opinion Cell Biol. 4:1008-1016). Three enzymes have been described that catalyze protein prenylation: farnesyl-protein transferase (FPTase), geranylgeranyl 15 protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). These enzymes are found in both yeast and mammalian cells (Clarke, 1992; Schafer, W. R. and Rine, J. (1992) Annu. Rev. Genet. 30:209-237). Each of these enzymes selectively uses farnesyl diphosphate or geranyl 20 geranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate. FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gln or Ala. For FPTase, CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme. The enzymological characterization of these 25 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'Hara, 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). 30 The prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CaaX Cys acceptors so that the proteins can no longer -3- WO 98/44797 PCT/US98/06823 be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic "proof of principle" indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins. 5 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. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is 10 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)). 15 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 271:810-812). Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and 20 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 25 utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famrnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). 30 Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modi fications 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-Aaal-Aaa 2 -Xaa" -4- WO 98/44797 PCT/US98/06823 box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depend ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein 5 transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). Direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects 10 than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Other farnesylated 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. 15 Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above. Inhibitors of farnesyl-protein transferase (FPTase) have 20 been described in two general classes. The first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme. 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. 25 (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (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 30 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 -5- WO 98/44797 PCT/US98/06823 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 5 1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of H-ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in H-ras 10 transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995). Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the 15 rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. A pharmaceutically effective combination of an integrin 20 antagonist and a farnesyl-protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells that are less susceptable to treatment by an integrin antagonist or a farnesyl-protein transferase inhibitor when administered alone. 25 SUMMARY OF THE INVENTION 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 an integrin antagonist and a farnesyl protein transferase inhibitor. Preferably a selective 30 integrin antagonist and a selective famrnesyl protein transferase inhibitor are used in such a combination. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of treating cancer 35 which is comprised of admininstering to a mammalian patient in need -6- WO 98/44797 PCT/US98/06823 of such treatment an effective amount of a combination of an integrin antagonist and a farnesyl-protein transferase inhibitor. The present method of treating cancer by simultaneously inhibiting farnesyl-protein transferase and binding to either or both of the evP3 integrin and avP5 5 integrin offers advantages over previously disclosed methods which utilize a prenyl-protein transferase inhibitor or an integrin antagonist alone, in that the inhibitory activity of the instant combination of inhibitors against FPTase or integrin activity can be varied by formulation depending on the nature of the cancer cells to be treated. 10 Any compound which acts as an integrin antagonist and any compound which inhibits famrnesyl protein transferase can be used in the instant method. Preferably the compounds utilized in the instant combination are a selective integrin antagonist and a selective farnesyl-protein transferase inhibitor. When practicing the present method the integrin 15 antagonist and the inhibitor of farnesyl-protein transferase may be administered either sequentially in any order or simultaneously. It is anticipated that the therapeutic effect of the instant compositions may be achieved with smaller amounts of either or both of the integrin antagonist and farnesyl-protein transferase inhibitor than 20 would be required if such an integrin antagonist and a selective farnesyl protein transferase inhibitor were administered alone, thereby avoiding any non-mechanism-based adverse toxicity effects which might result from administration of an amount of the integrin antagonist or farnesyl protein transferase inhibitor sufficient to achieve the same therapeutic 25 effect. It is also anticipated that the instant compositions will achieve a synergistic therapeutic effect or will exhibit unexpected therapeutic advantage over the effect of either of the component compounds if administered alone. As used herein the term an integrin antagonist refers to 30 compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the evP3 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the cvp5 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the exv33 integrin and the avI5 integrin, or -7- WO 98/44797 PCT/US98/06823 which antagonize, inhibit or counteract the activity of the particular integrin or integrins expressed on capillary endothelial cells. The term also refers to a combination of a selective antagonist of the xv133 integrin and a selective antagonist of the cv35 integrin. The term also 5 refers to antagonists of the o1 131P and x23 1 integrins. The term farnesyl protein transferase (FPTase) 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. 10 The terms selective and selectively as used herein refer to the antagonistic activity of the particular compound against either an integrin or integrins or the inhibitory activity of the compound against FPTase activity. Preferably, a selective compound exhibits at least 20 times greater activity against either an single integrin, a group of 15 integrins or all of the integrins which have been demonstrated as being important for angiogenesis when comparing its activity against other integrins. Such integrins which have been demonstrated as being important for angiogenesis include, but are not limited to, av133, av35, xalpl and x2p131 integrins. More preferably the selectivity is at least 100 20 times or more. As used herein, a selective FPTase inhibitor may also be an inhibitor of geranylgeranyl-protein transferase. The extent of selectivity of the two or more inhibitors that comprise the method of the instant invention effects the advantages that the method of treatment claimed herein offers over previously disclosed 25 methods of using a single integrin antagonist or FPTase inhibitor for the treatment of cancer. In particular, use of two independent pharmaceutically active components that have complementary, essentially non-overlapping activities allows the person utilizing the instant method of treatment to independently and accurately vary the 30 inhibitory activity of the combination without having to synthesize a single drug having a particular pharmaceutical activity profile. The term "synergistic" as used herein means that the effect achieved with the methods and compositions of this invention is greater than the sum of the effects that result from methods and compositions -8- WO 98/44797 PCT/US98/06823 comprising the FPTase inhibitor and integrin antagonist separately and in the amounts employed in the methods and compositions hereof. The preferred therapeutic effect provided by the instant composition is the treatment of cancer and specifically the inhibition 5 of cancerous tumor growth and/or the regression of cancerous tumors. 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. More particularly, such cancers include histiocytic lymphoma, lung 10 adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small cell lung cancers and neurological tumors. Other therapeutic effects provided by the instant composi tion include inhibiting: bone resorption mediated by osteoclast cells, restenosis, artherosclerosis, diabetic retinopathy, macular degeneration 15 and angiogenesis in animals, preferably mammals, especially humans. The instant composition may also be useful for preventing or treating osteoporosis. Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone 20 metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical 25 compositions described above. The composition of this invention is also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by 30 mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the instant composition to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder. -9 WO 98/44797 PCT/US98/06823 The composition of the instant invention is also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995). 5 The instant composition may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)). The pharmaceutical composition of this invention may be 10 administered to mammals, preferably humans, either alone or, prefer ably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharma ceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including 15 the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. For oral use of a chemotherapeutic combination according to this invention, the selected combination or compounds may be administered, for example, in the form of tablets or capsules, or as 20 an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral 25 use, the active ingredients are combined with emulsifying and suspend ing agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and 30 buffered. For intravenous use, 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 - 10 - WO 98/44797 PCT/US98/06823 being treated. For example, the instant combinations may be useful in combination with other known anti-cancer and cytotoxic agents. If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range 5 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. 10 The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the combinations of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous 15 solutions comprising compounds of this invention and pharmacologic ally 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. When a combination according to this invention is 20 administered into a human subject, 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. In one exemplary application, a suitable amount of an 25 integrin antagonist(s) and a farnesyl-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 30 about 40 mg/kg of body weight per day. A particular therapeutic dosage that comprises the instant composition includes from about 0.01mg to about 500mg of an integrin antagonist and from about 0.01mg to about 500mg of a farnesyl-protein transferase inhibitor. Preferably, the dosage comprises from about 1mg to about 100mg of an - 11 - WO 98/44797 PCT/US98/06823 integrin antagonist and from about Img to about 100mg of a farnesyl protein transferase inhibitor. The integrin antagonist component of the instant invention may be selected from the following: 5 (a) a compound of the formula I-a: X-Y-Z-Aryl-A-B wherein: Aryl is a 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R 8 and R 9 ; 10 X is selected from
NR
2
NR
1
NR
2 II II 2 3
-NR
1
R
2 , -NR -C-R 3 , -C-NR 2
R
3 , -NR'-C-NR 3
R
4 , NR'
NR
2 II 1II 3 R -aryl-NR'R 2 , -aryl-C-NR 2
R
3 , -aryI-NR'-C-NR 3 R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from 15 N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 , R 2 , R 3 and R 4 , or a 9- to 10-membered polycyclic ring system, wherein one or 20 more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 , R 2 , R 3 and R 4 ; 25 Y is selected from CO-8 alkylene, C3-10 cycloalkyl, CO-8 alkylene-NR 10-CO-CO-8 alkylene, - 12 - WO 98/44797 PCT/US98/06823 CO-8 alkylene-CONR 10 -CO-8 alkylene, CO-8 alkylene-O-CO-8 alkylene, CO-8 alkylene-NR10-CO-8 alkylene, CO-8 alkylene-S(0)0-2-CO-8 alkylene, 5 CO-8 alkylene-SO2-NR10-CO-8 alkylene, CO-8 alkylene-NR 10-S 02-CO-8 alkylene, CO-8 alkylene-CO-CO-8 alkylene, (CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, 10 (CH2)0-6 aryl-CO-NR10-(CH2)0-6, (CH2)0-6 arylNRO10CO(CH2)0-6, or OH I
(CH
2
)
0 -8CH (CH 2 )0o- 8 15 Z and A are each independently selected from O II 12
(CH
2 )m, (CH 2 )mO(CH 2 )n, (CH 2 )mNR 11
"(CH
2 )n,(CH 2 )mNR 1 " CNR 2
(CH
2
)
n O O O
(CH
2 )m CNR 11
(CH
2
)
n,
(CH
2 )mNR 11 " (CH 2 )n,(CH 2 )m (CH 2 )n, S
(CH
2 )m(CH 2 )n, (CH 2 )mSO 2
(CH
2 )n, (CH 2 )mS(CH 2 )n,
(CH
2 )mSO(CH 2 )n, (CH 2 )mSO 2
NR
1 1
(CH
2 )n,
(CH
2 )mNR 11
SO
2
(CH
2 )n, (CH 2 )mCR 1 "=CR12(CH 2 )n, or
(CH
2 )mCC- (CH 2 ), where m and n are each independently an integer from 0 to 6; - 13 - WO 98/44797 PCT/US98/06823 B is O II C-R13 R6 R 7 where p is an integer from 1 to 3; 5 R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 1 0, R 1 1 and R 12 are each independently selected from hydrogen, halogen, C 1-10 alkyl, 10 aryl CO-8 alkyl, amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, C1-6 dialkylamino CO-8 alkyl, 15 aryl CO-6 alkylamino CO-6 alkyl, C 1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C1-4 alkoxy CO-6 alkyl, hydroxycarbonyl CO-6 alkyl, 20 C1-4 alkoxycarbonyl CO-6 alkyl, hydroxycarbonyl CO-6 alkyloxy, hydroxy C1-6 alkylamino CO-6 alkyl or hydroxy CO-6 alkyl; 25 R 6 is selected from hydrogen, fluorine, C1-8 alkyl, hydroxyl, - 14 - WO 98/44797 PCT/US98/06823 hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C1-6 alkyloxy, C1-6 alkylcarbonyl, 5 aryl C0-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, 10 aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, C0-6 dialkylamino CO-6 alkyl, C 1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, 15 C1-8 alkyloxycarbonylamino CO-8 alkyl, aryl CO-8 alkyloxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino C0-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, C0-8 alkylaminocarbonylamino CO-6 alkyl, 20 aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, 25 C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, or aryl CO-6 alkylthiocarbonylamino CO-6 alkyl; wherein the alkyl or N atoms may be unsubstituted or 30 substituted with R 5 ;
R
7 is selected from hydrogen, CO-6 alkylamino CO-6 alkyl, - 15 - WO 98/44797 PCT/US98/06823 CO-6 dialkylamino CO-6 alkyl, aryl CO-6 alkyloxycarbonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl and aryl CO-6 alkylcarbonylamino CO-6 alkyl; 5 C7-20 polycyclyl CO-8 alkylsulfonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylcarbonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylaminosulfonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylaminocarbonylamino CO-6 alkyl or C7-20 polycyclyl CO-8 alkyloxycarbonylamino CO-6 alkyl; 10 wherein the polycyclyl may be unsubstituted or substituted with R 14 , R 15 , R 16 and R1 7 ; and wherein any of the alkyl groups may be unsubstituted or subsituted with R 14 and R15; 15 R 13 is selected from hydroxy, C1-8 alkyloxy, aryl CO-6 alkyloxy, C1-8 alkylcarbonyloxy C 1-4 alkyloxy, 20 aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy, Ci1-6 dialkylaminocarbonylmethyloxy, aryl C1-6 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid 25 is as the free acid or is esterified by C1-6 alkyl; and R1 4 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, oxo, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, 30 C1-3 acylamino Ci1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1-6 alkyl, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl - 16 - WO 98/44797 PCT/US98/06823 C 1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)q, C1-8 alkylaminocarbonyl, C1-8 dialkylaminocarbonyl, C1-8 alkyloxycarbonylamino, 5 C1-8 alkylaminocarbonyloxy or C1-8alkylsulfonylamino; (b) a compound of the formula I-b: O O 6 R 7 0
R
5
C-R
1 o I \ NH
X-(CH
2 )j- C -(CH 2 )-N
N
9 H / R8R 9 I-b wherein X is selected from
NR
2 10 - -NR4 -- Ar or NR Ar Ar is a 4- to 10-membered mono- or polycyclic aromatic or non aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S and wherein the mono- or polycyclic aromatic or non aromatic ring system is either unsubstituted or substituted with R 1 , R 2 , 15 R 3 and R 4 ;
R
1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C1-8 alkyl, halogen, aryl C0-8 alkyl, oxo, thio, amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, 20 C1-6 dialkylamino CO-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C1-4 alkoxy C0-8 alkyl, carboxy CO-8 alkyl, C1-4 alkoxycarbonyl CO-8 alkyl, carboxy CO-8 alkoxy, hydroxy CO-8 alkyl or C3-8 cycloalkyl CO-6 alkyl; 25
R
5 is selected from hydrogen, C1-6 alkyl, CO-6 alkylaryl, aryl or - 17 - WO 98/44797 PCT/US98/06823 C3-8 cycloalkyl CO-6 alkyl;
R
6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, fluorine, C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy 5 CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, CO-8 alkyl 10 SO2NR 3 -CO-8 alkyl, aryl CO-8 alkoxycarbonylamino CO-8 alkyl, aryl CO-8 alkyl-SO2NR 3 -CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino C0-6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylamino 15 sulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, aryl CO-6 alkyl thiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl CO-6 alkyl, 20 C3-8 cycloalkyl CO-6 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy or C3-8 cycloalkyl CO-6 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R 1 and R 2 ; 25 R 10 is selected from hydroxyl, C1-8 alkoxy, aryl CO-6 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy CI1-4 alkoxy, C1-6 dialkylaminocarbonylmethoxy, aryl C1-6 dialkylaminocarbonylmethoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of 30 the amino acid is as the free acid or is esterified by C1-6 alkyl; and each n is independently an integer from 0 to three; - 18 - WO 98/44797 PCT/US98/06823 provided that when R 5 is hydrogen and X is Ar and Ar is a 6-membered monocyclic non-aromatic ring system containing one nitrogen atom and
R
6 and R 7 are each hydrogen, and R 8 is selected from hydrogen or C1-6 alkyl, and R 10 is selected from hydroxyl, C1-8 alkoxy, C1-8 5 alkylcarbonyloxy C1-4 alkoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified with C 1-6 alkyl, then R 9 is selected from fluorine, hydroxyl, hydroxy C1-6 alkyl, carboxy-CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 10 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, aryl CO-8 alkoxycarbonyl amino CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkyl carbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, 15 CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylamino carbonylamino CO-6 alkyl, CO-8 alkylaminosulfonylamino CO-6 alkyl, aryl C0-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonyl 20 amino CO-6 alkyl, aryl CO-6 alkylthiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl CO-6 alkyl, C3-8 cycloalkyl CO-6 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy or C3-8 cycloalkyl CO-6 alkylamino carbonylamino; wherein any of the alkyl groups may be unsubstituted 25 or substituted with R 1 and R 2 ; and provided further that when R 5 is hydrogen and X is Ar and Ar is - H 2 N N- 0 N [Iz N- , ND/ , \'/ or and R 6 , R 7 and R 8 are each hydrogen, and R 10 is selected from 30 hydroxyl and C1-8 alkoxy, then R 9 is selected from fluorine, C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy C0-6 alkyl, - 19 - WO 98/44797 PCT/US98/06823 C 1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C 1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino 5 CO-6 alkyl, CO-8 alkyl-SO2NR 3 -CO-8 alkyl, aryl CO-8 alkoxycarbonyl amino CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylamino-sulfonylamino 10 CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino-CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl-CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl-CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, aryl CO-6 alkyl-thiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl CO-6 alkyl, C3-8 cycloalkyl CO-6 15 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl-CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy orC3-8 cycloalkyl CO-6 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R 1 and R 2 ; 20 (c) a compound of the formula I-c: O 8 R R 9
X-Y-Z-(CH
2 n-C -N CO 2
R
12 H 1 1OR R 11 I-c wherein X is selected from N, R 1
NR
2 || I
-C-NR
1
R
2 -NR--C-NR'
R
2 25 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from - 20 - WO 98/44797 PCT/US98/06823 N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 , or a 9- to 10-membered polycyclic ring system, wherein one or 5 more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 and R 2 ; 10 Y is selected from
R
3 R3 0 0 -- N (C H ) -- " -( H2) --- - -C -( H2 ' " -- -N -(C H)3 II
-N-C-(CH
2 )- -S(O)q-(CH 2 )E , - O-(CH 2 ); or -(CH 2 )r ;
R
3 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 15 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R 5 , R 6 and R 7 ; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is a 5-11 20 membered nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected 25 from R 4 , R 5 , R 6 and R 7 ;
R
1 , R 2 , R 4 , R 5 , R 13 and R 14 are each independently selected from hydrogen, halogen, CI1-10 alkyl, C3-8 cycloalkyl, aryl, - 21 - WO 98/44797 PCT/US98/06823 aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C 1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, 5 hydroxycarbonyl C1-6 alkyl, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C 1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)q, C1-8 aminocarbonyl, 10 C1-8 dialkylaminocarbonyl, Ci1-8 alkyloxycarbonylamino, C1-8 alkylaminocarbonyloxy or C1-8 alkylsulfonylamino;
R
3 is selected from hydrogen, 15 aryl, -(CH2)p-aryl, hydroxyl, C1-5 alkoxycarbonyl, aminocarbonyl, 20 C3-8 cycloalkyl, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, hydroxycarbonyl C1-6 alkyl, 25 C1-8 alkyl, aryl C1-6 alkyl, C1-6 alkylamino C1-6 alkyl, aryl C1-6 alkylamino C1-6 alkyl, C1-6 dialkylamino C1-6 alkyl, 30 C1-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, - 22 - WO 98/44797 PCT/US98/06823 arylcarbonyl, aryl C1-6 alkylcarbonyl, C1-8 alkylaminocarbonyl, aminosulfonyl, 5 C1-8 alkylaminosulfonyl, arylaminosulfonylamino, aryl C1-8 alkylaminosulfonyl, C1-6 alkylsulfonyl, arylsulfonyl, 10 aryl C 1-6 alkylsulfonyl, aryl C 1-6 alkylcarbonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, or aryl C1-6 alkylthiocarbonyl, 15 wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R14;
R
6 , R 7 , R 8 , R 9 , R 10 and R 1 1 are each independently selected from hydrogen, 20 aryl, -(CH2)p-aryl, halogen, hydroxyl, C1-8 alkylcarbonylamino, 25 aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-8 alkylaminocarbonyl, C1-6 alkylcarbonyloxy, 30 C3-8 cycloalkyl, oxo, amino, C1-6 alkylamino, amino C1-6 alkyl, - 23 - WO 98/44797 PCT/US98/06823 arylaminocarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, 5 hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C 1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, C1-5 alkylcarbonylamino, aryl C1-5 alkoxy, 10 C 1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino carbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, amino C1-3 alkyl, arylamino carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-4 alkyl, hydroxycarbonyl, or 15 hydroxycarbonyl C 1-5 alkyl, -(CH2)s C=-CH, -(CH2)s C-C-C1-6 alkyl, -(CH2)s C=C-C3-7 cycloalkyl, -(CH2)s C-C-aryl, 20 -(CH2)s C-C-C1-6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH C1-6 alkyl, -(CH2)s CH=CH-C3-7 cycloalkyl, -(CH2)s CH=CH aryl, 25 -(CH2)s CH=CH C1-6 alkylaryl, -(CH2)s SO2C1-6 alkyl, -(CH2)s SO2C1-6 alkylaryl, C1-6 alkoxy, aryl C1-6 alkoxy, 30 aryl C1-6 alkyl, C1-6 alkylamino C1-6 alkyl, arylamino, arylamino C1-6 alkyl, aryl C1-6 alkylamino, - 24 - WO 98/44797 PCT/US98/06823 aryl C1-6 alkylamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, C1-6 dialkylamino, 5 C1-6 dialkylamino C1-6 alkyl, C 1-6 alkylaminocarbonyloxy, C1-8 alkylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, 10 aryl Ci1-6 alkylsulfonylamino, aryl C 1-6 alkylsulfonylamino C 1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, 15 aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, 20 aryl C 1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C 1-6 alkyl, C1-8 alkylaminocarbonylamino, C1-8 alkylaminocarbonylamino C1-6 alkyl, 25 arylaminocarbonylamino C1-6 alkyl, aryl C1-8 alkylaminocarbonylamino, aryl Ci1-8 alkylaminocarbonylamino Ci1-6 alkyl, aminosulfonylamino C1-6 alkyl, C1-8 alkylaminosulfonylamino, 30 C1-8 alkylaminosulfonylamino C1-6 alkyl, arylaminosulfonylamino C1-6 alkyl, aryl C1-8 alkylaminosulfonylamino, aryl C1-8 alkylaminosulfonylamino C 1-6 alkyl, C1-6 alkylsulfonyl, - 25 - WO 98/44797 PCT/US98/06823 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl CI1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, 5 C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, 10 C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C 1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, 15 C1-8 alkylaminocarbonyl C1-6 alkyl, arylaminocarbonyl Ci1-6 alkyl, aryl C1-8 alkylaminocarbonyl, or aryl C1-8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with 20 R 13 and R1 4 ; and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R 1 1 are attached is itself attached to no more than one heteroatom; 25 R 12 is selected from hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, 30 hydroxy, C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, Ci1-8 alkylcarbonyloxy Ci1-4 alkoxy, - 26 - WO 98/44797 PCT/US98/06823 aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or C1-8 dialkylaminocarbonylmethyleneoxy; 5 m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and 10 s is an integer from 0 to 3; (d) a compound of the formula I-d: X-Y-Z-Ring-A-B 15 I-d wherein: Ring is a 4- to 10-membered mono- or polycyclic aromatic or 20 nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, and either unsubstituted or substituted with R 2 7 and
R
2 8 ; X is selected from 25
NR
2
NR
2
NR
2 II II II
-NR
1
R
2 , -NR 1
-C-R
3 , -C-NHR 4 , -NR 1
-C-NR
3
R
4 NR'
NR
2 II 2 31I 3 4 -aryl-NR'R 2 , -aryl-C-NR 2
R
3 , -aryl-NR'-C-NR 3 R or a 4- to 10- membered mono- or polycyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms 30 selected from N, O and S and either unsubstituted or substituted - 27 - WO 98/44797 PCT/US98/06823 with R 13 , R 14 , R 15 or R16; Y is selected from CO-8 alkylene, 5 C3-10 cycloalkyl, CO-8 alkylene-NR 5 -CO-CO-8 alkylene, CO-8 alkylene-CONR 5 -CO-8 alkylene, CO-8 alkylene-O-CO-8 alkylene, CO-8 alkylene-NR 5 -CO-8 alkylene, 10 CO-8 alkylene-S(O)0-2-CO-8 alkylene, CO-8 alkylene-SO2-NR 5 -CO-8 alkylene, CO-8 alkylene-NR 5 -SO2-CO-8 alkylene, CO-8 alkylene-CO-CO-8 alkylene, (CH2)0-6 aryl(CH2)0-6, 15 (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NR 5 -(CH2)0-6, (CH2)0-6 aryl-NR 5 -CO-(CH2)0-6, or OH I
(CH
2 )0-.
8 CH (CH 2 )0-8. 20 Z is selected from - 28 - WO 98/44797 PCT/US98/06823 0
(CH
2 )m, (CH 2 )mO(CH 2 )n, (CH 2 )mNR 6
(CH
2 )n, (CH2)mNR6 CNR 7(CH2)n 0 0 0 II 11 II
(CH
2 )mCNR 6
(CH
2 )n, (CH 2 )mNR 6
C(CH
2 )n, (CH 2 )mC(CH 2 )n, S 0
(CH
2 )m (CH 2 )n, (CH 2 )mSO 2
(CH
2 )n, (CH2)mS(CH2)n,
(CH
2 )mSO(CH 2 )n, (CH 2 )mSO 2
NR
6
(CH
2 )n, (CH 2 )mNR 6
SO
2
(CH
2 )n,
(CH
2 )mCR 6
=CR
7
(CH
2 )n, or (CH 2 )mC -C - (CH 2 )n; where m and n are each independently an integer from 0 to 6; A is selected from O 2 II a
(CH
2 )qO(CH 2 )p, (CH 2 )qNR 2 9
(CH
2 )p, (CH2)qNR 29 CNR (H2) p 0 0 0 O o o II II II
(CH
2 )qCNR 2 9
(CH
2 )p, (CH 2 )qNR 2 9
C(CH
2 )p, (CH 2 )qC(CH 2 )p, s 0 II II 5 (CH2)qC(CH2)p, (CH2)qSO2(CH2)p,
(CH
2 )qS(CH2)p, (CH2)qSO(CH 2 )p, (CH 2 )qSO 2
NR
2 9
(CH
2 )p, (CH 2 )qNR 29 SO2(CH 2 )p
(CH
2 )qCR 2 9
=CR
30
(CH
2 )p or (CH2)qC--C-(CH 2 )p; where p and q are each independently an integer from 0 to 6; - 29 - WO 98/44797 PCT/US98/06823 B is selected from O R 8 II 0 or(CH 2
)
0
.
1 -C- R 12
R
8
R
9 Ro R;
R
1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 17 , R 18 , R 19 , R 2 0 , R 2 1 , R 2 2 , R 2 3 , R 24 ,
R
2 5 , R 2 6 , R 2 7 , R 2 8 , R 29 and R 3 0 are each independently selected from 5 hydrogen, halogen, C 1-10 alkyl, aryl CO-8 alkyl, amino CO-8 alkyl, 10 C1-3 acylamino CO-8 alkyl, C1-6 alkylamino C0-8 alkyl, C1-6 dialkylamino CO-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, 15 hydroxy C1-6 alkylamino C0-8 alkyl, C1-4 alkoxy CO-6 alkyl, carboxy CO-6 alkyl, C1-4 alkoxycarbonyl CO-6 alkyl, carboxy CO-6 alkyloxy, 20 hydroxy C1-6 alkylamino CO-6 alkyl, hydroxy CO-6 alkyl,
NR
17
NR
18
R'
19 , or NR18 -NR1 7 NR1 9
R
20
R
8 , R 9 , R 10 , and R 1 1 are each independently selected from - 30 - WO 98/44797 PCT/US98/06823 hydrogen, fluorine, C1-8 alkyl, hydroxyl, 5 hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C1-6 alkyloxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, 10 C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, 15 CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, C1-8 alkyloxycarbonylamino CO-8 alkyl, 20 aryl CO-8 alkyloxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, 25 C0-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, 30 aryl CO-6 alkylcarbonyl CO-6 alkyl, C 1-6 alkylthiocarbonylamino CO-6 alkyl, or aryl CO-6 alkylthiocarbonylamino CO-6 alkyl wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R 2 1 and - 31 - WO 98/44797 PCT/US98/06823
R
2 2 (e.g., any amino group such as -NH- can be substituted with
R
2 1 to be -NR 2 1-);
R
12 is selected from 5 hydroxy, C1-8 alkyloxy, aryl C0-6 alkyloxy, C 1-8 alkylcarbonyloxy C 1-4 alkyloxy, aryl CO-8 alkylcarbonyloxy C1-4 alkyloxy, 10 C1-6 dialkylaminocarbonylmethyloxy, aryl C1-6 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1-6 alkyl; and 15
R
13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, C 1-10 alkyl, aryl CO-8 alkyl, 20 oxo, thio, amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino C0-8 alkyl, 25 C1-6 dialkylamino C0-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C 1-4 alkoxy CO-6 alkyl, 30 carboxy CO-6 alkyl, C1-4 alkoxycarbonyl CO-6 alkyl, carboxy CO-6 alkyloxy, hydroxy C1-6 alkylamino CO-6 alkyl, hydroxy CO-6 alkyl, - 32 - WO 98/44797 PCT/US98/06823
NR
23
NR
2 4
R
2 5 , or NR24
-NR
23
NR
2 5
R
26 provided that Ring is not a 6-membered monocyclic aromatic ring; 5 provided further that when Ring is thiophene, then X is selected from Ri13 R 1 , R13 N N N N N H H N N R13~~ __C.- \l3
N
13 RN N or N
R
1
R
1
R
1 provided further that when Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, 10 indole, benzothiazole, benzoxazole, SS S S or then X is selected from - 33 - WO 98/44797 PCT/US98/06823
R
13
R
1 3 RI3 S R 13N N , N , N N 'N N H H R13 R13N N N N N or N R R
R
1 and the pharmaceutically acceptable salts thereof. In one embodiment of the invention is the compound wherein Y is selected from 5 CO-8 alkylene, C3-10 cycloalkyl, CO-8 alkylene-NR 5 -CO-CO-8 alkylene, CO-8 alkylene-CONR 5 -CO-8 alkylene, CO-8 alkylene-O-CO-8 alkylene, 10 CO-8 alkylene-NR 5 -CO-8 alkylene, CO-8 alkylene-S(O)0-2-CO-8 alkylene, CO-8 alkylene-SO2-NR 5 -CO-8 alkylene, CO-8 alkylene-NR 5 -SO2-CO-8 alkylene, CO-8 alkylene-CO-CO-8 alkylene, 15 (CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NH-(CH2)0-6, or OH I
(CH
2 )0- 8 CH (CH 2 )0-8 20 Z is (CH2)m where m is an integer from 0 to 3; preferably, m is zero; and all other variables are as defined above; (e) a compound of the formula I-e: - 34 - WO 98/44797 PCT/US98/06823 O O 6 R R 7 X-Y-Z-C-CH- -N 0 2 Rio 8 R R 9 I-e wherein X is selected from
N
- R 1 N R 2 II
-C-NR
2
R
3 -NRI- C-NR 3
R
4 a 5- or 6-membered monocyclic aromatic or nonaromatic ring 5 system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 , or a 9- to 10-membered polycyclic ring system, wherein one or 10 more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 ; 15 Y is selected from
R
5 O , I I -(CH)-N-(CH2) -(CH2r-C-(CH2 , 0 0 II II -(CH20C-N-(CH2)E -(CH2)-N-C-(CH2)m
R
5
R
5
-(CH
2 ),-S(O)q-(CH 2 )- -(CH 2 )- O-(CH 2
)
R 13 Rs5 - (CH2n-- (CH2)m- or -(CH 2 )rN-(CH 2
)--N-(CH
2
)
- 35 - WO 98/44797 PCT/US98/06823 Z is absent or is a 4- to 11-membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a 5 carbon or nitrogen atom with one or more groups independently selected from R 14 , R 15 , R 16 and R 17 ; preferably, Z is not a 6-membered monocyclic aromatic ring system;
R
1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 16 and R 17 are each 10 independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, 15 Cl1-4 alkoxy, Ci1-4 alkoxy C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci1-6 alkyl, C 1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy or hydroxy C1-6 alkyl; 20 R 6 , R 7 , R 8 , R 9 , R1 4 and R 15 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, 25 C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-8 alkylaminocarbonyl, 30 C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-6 alkylamino, - 36 - WO 98/44797 PCT/US98/06823 amino C1-6 alkyl, arylaminocarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl, 5 aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C 1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, 10 C 1-5 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino carbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, amino C1-3 alkyl, arylamino carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, 15 aminocarbonyl C1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C1-5 alkyl, -(CH2)r C=-CH, -(CH2)r C-C-C1-6 alkyl, -(CH2)r CEC-C3-7 cycloalkyl, 20 -(CH2)r C-C-aryl, -(CH2)r C=C-C1-6 alkylaryl, -(CH2)r CH=CH2, -(CH2)r CH=CH C1-6 alkyl, -(CH2)r CH=CH-C3-7 cycloalkyl, 25 -(CH2)r CH=CH aryl, -(CH2)r CH=CH Ci1-6 alkylaryl, -(CH2)r SO2C1-6 alkyl, -(CH2)r SO2C1-6 alkylaryl, C1-6 alkoxy, 30 aryl C1-6 alkoxy, aryl C1-6 alkyl, C1-6 alkylamino C1-6 alkyl, arylamino, arylamino C1-6 alkyl, - 37 - WO 98/44797 PCT/US98/06823 aryl C1-6 alkylamino, aryl C1-6 alkylamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, 5 C1-6 dialkylamino, C1-6 dialkylamino C1-6 alkyl, C 1-6 alkylaminocarbonyloxy, C1-8 alkylsulfonylamino, C 1-8 alkylsulfonylamino C1-6 alkyl, 10 arylsulfonylamino CI1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C 1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino Ci1-8 alkyl, 15 aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, 20 arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C 1-6 alkyl, C1-8 alkylaminocarbonylamino, 25 C1-8 alkylaminocarbonylamino C1-6 alkyl, arylaminocarbonylamino C1-6 alkyl, aryl C1-8 alkylaminocarbonylamino, aryl Ci1-8 alkylaminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, 30 C 1-8 alkylaminosulfonylamino, C 1-8 alkylaminosulfonylamino C 1-6 alkyl, arylaminosulfonylamino CI1-6 alkyl, aryl Ci1-8 alkylaminosulfonylamino, aryl C1-8 alkylaminosulfonylamino C1-6 alkyl, - 38 - WO 98/44797 PCT/US98/06823 C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C 1-6 alkylsulfonyl, 5 aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C 1-6 alkyl, aryl C1-6 alkylcarbonyl, 10 aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, 15 aryl C1-6 alkylthiocarbonylamino C 1-6 alkyl, C1-8 alkylaminocarbonyl C1-6 alkyl, arylaminocarbonyl C1-6 alkyl, aryl CI1-8 alkylaminocarbonyl, or aryl C1-8 alkylaminocarbonyl C1-6 alkyl, 20 wherein any of the alkyl groups may be unsubstituted or substituted with
R
1 1 and R 12 ; and provided that the carbon atom to which R 6 and R 7 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; 25
R
10 is selected from hydrogen, C1-8 alkyl, aryl, 30 aryl C1-8 alkyl, aryl C1-6 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy C1-4 alkyl, Ci1-8 alkylaminocarbonylmethylene, or - 39 - WO 98/44797 PCT/US98/06823 C1-8 dialkylaminocarbonylmethylene; m, n and r are each independently an integer from 0 to 3; p is an integer from 1 to 4; and 5 q is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof. Specific examples of compounds that are integrin 10 antagonists include the following: 4-(2-Guanidoethyloxy)phenylcarbonyl-2(S)-benzyloxycarbonylamino-f alanine, 4-(2-Guanidoethyloxy)phenylcarbonyl-2(S)-phenylsulfonylamino- 15 alanine, 2(S)-Phenylsulfonylamino-3-[4-(4-guanidobutyloxy)phenyl]-propionic acid, 20 2(S)-(N-Benzyloxycarbonylamino)-3-[4-(5-guanidopentyloxy)phenyl] propionic acid, 4-(3-Guanidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-0 alanine, 25 4-(3-Formamidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-P alanine, 3-Methoxy-4-(3-guanidinopropyloxy)benzoyl-2(S)-phenylsulfonyl 30 amino-P-alanine, 3-Methoxy-4-(3-aminopropyloxy)benzoyl-2(S)-phenylsulfonylamino-f alanine, 35 3-(3-Guanidinopropyloxy)benzoyl-2(S)-phenylsulfonylamino-0-alanine, - 40 - WO 98/44797 PCT/US98/06823 4-[2-(N-Phenylguanidino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 3-alanine, 5 4-[2-(N,N-Dimethylguanidino)ethyloxy]benzoyl-2(S)-phenylsulfonyl amino- P-alanine, 4-(Guanidinophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-3 alanine, 10 4-[2-(Guanidino)ethyloxymethyl]benzoyl-2(S)-phenylsulfonylamino-3 alanine, 3-[2-(Guanidino)ethylaminocarbonyl]benzoyl-2(S)-phenylsulfonyl 15 amino- P-alanine, 4-[2-(2-Aminothiazol-4-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino P-alanine t-butyl ester, 20 4-[2-(2-Aminothiazol-4-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino P-alanine, 4-[2-(N-(2-Imidazolin-2-yl)aminoethyloxy]benzoyl-2(S)-phenylsulfonyl amino-0-alanine, 25 2(S)-Phenylsulfonylamino-3-[4-(4-(N-imidazolin-2-yl)aminobutyloxy) phenyl]propionic acid, 4-[2-[N-[Cis-3a,4,5,6,7,7a-Hexahydro- 1H-benzimidazol-2-yl] amino] 30 ethyloxybenzoyl-2(S)-phenylsulfonylamino--alanine, 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino P-alanine, - 41 - WO 98/44797 PCT/US98/06823 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S) phenylsulfonylamino-3-alanine, 4-[2-(2-Aminothiazol-4-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino-0 5 alanine t-butyl ester, 4-[2-(2-Aminothiazol-4-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino-0 alanine, 10 4-[2(S)-(N-(2-Imidazolin-2-yl)amino)propyloxy]benzoyl-2(S)-phenyl sulfonylamino-f-alanine, 4-[2-(Imidazol-2-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino- P-alanine, 15 4-[2-(Thiazol-2-ylamino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-I alanine, 4-[ 2 -(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-benzyloxycarbonyl amino- -alanine, 20 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S) benzyloxycarbonylamino-p-alanine, Methyl 2(S)-benzoylamino-3-[4-(4-pyrimidin-2-ylaminobutyloxy) 25 phenyl]propionate, 2(S)-Benzoylamino-3-[ 4 -(4-pyrimidin-2-ylamino)butyloxy)phenyl] propionic acid, 30 2(S)-Benzoylamino-3-[4-(4-(3,4,5,6-tetrahydropyrimidin-2-ylamino) butyloxy)phenyl]propionic acid, 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N-methyl-N-phenyl sulfonylamino-p-alanine t-butyl ester, - 42 - WO 98/44797 PCT/US98/06823 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N-methyl-N-phenyl sulfonylamino-o-alanine, 5 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N methyl-N-phenylsulfonylamino-3-alanine, 4-[2-(N-(5,6-Dihydro-4-keto- 1 (H)-pyrimidin-2-yl)amino)ethyloxy] benzoyl-2(S)-phenylsulfonylamino-0-alanine, 10 4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-3 alanine t-butyl ester, 4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-
P
15 alanine, 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino- f alanine, 20 4-[2-(2-Aminopyridin-6-yl)ethyloxy]benzoyl-2(S)-phenyl sulfonylamino-p-alanine t-butyl ester, 4-[2-(2-Aminopyridin-6-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 3-alanine, 25 4-[2-(Indol-2-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-0-alanine methyl ester, 4-[2-(Indol-2-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-P1-alanine, 30 4-[2-( 1H-Imidazo[4,5-6]pyridin-2-yl)ethenyl]benzoyl-2(S)-phenyl sulfonylamino-3-alanine t-butyl ester, 4-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)ethenyl]benzoyl-2(S)-phenyl 35 sulfonylamino-p3-alanine, - 43 - WO 98/44797 PCT/US98/06823 4-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)ethyl]benzoyl-2(S)-phenyl sulfonylamino- -alanine, 5 4-[2-(1,8-Naphthyidin-7-yl)ethenyl)benzoyl-2(S)-phenylsulfonylamino P-alanine t-butylester, 4-[2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl]benzoyl-2(S) phenylsulfonylamino-3-alanine t-butyl ester, 10 4-[2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7yl)ethyl]benzoyl-2(S) phenylsulfonylamino-f-alanine, 4-[2-(1,8-Naphthyridin-7-yl)ethenyl]benzoyl-2(S)-phenylsulfonyl 15 amino-p-alanine ethyl ester, 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7-yl)ethyl]benzoyl-2(S) phenylsulfonylamino-p-alanine ethyl ester, 20 4-[2-(1,2,3,4-Tetrahydro-l1,8 naphthyridin-7-yl)ethyl]benzoyl-2(S) [1 (S) 10-camphorsulfonylamido] P3-alanine ethyl ester, 4-[2-(1,2,3,4-Tetrahydro- 1,8 naphthyridin-7-yl)ethyl]benzoyl-2(S) [i1(S) 10-camphorsulfonylamido] P-alanine, 25 4-[(3-Aminoisoquinolin- 1 -yl)ethynyl]benzoyl-2(S)-phenylsulfonamido P-alanine ethyl ester, 4-[(3-Aminoisoquinolin-1-yl)ethynyl]benzoyl-2(S)-phenylsulfonamido 30 P-alanine trifluoroacetate, 4- [2-(3-Aminoisoquinolin- 1-yl)ethyl]benzoyl-2(S)-phenylsulfonamido P-alanine trifluoroacetate, - 44 - WO 98/44797 PCT/US98/06823 4-[3-[N-( 1H-Benzimidazo-2-yl)amino]propoxy]benzoyl-2(S) phenylsulfonylamino-p-alanine t-butyl ester, and 4- [3- [N-( 1H-Benzimidazol-2-yl)amino]propoxy]benzoyl-2(S) 5 phenylsulfonylamino-p-alanine. O O NH N N 2 H
H
2 N H H H'NHSO2 NH O O H N - CO2H
H
2 MN N-- N N H H H SH\O C0 2 H N N N N O O CO2 O 0 H / N H H NHSO2 - N N NH
NHSO
2 - 45 - WO 98/44797 PCT/US98/06823 o o C0 2 H N N N N H H NHCO 2
CH
2 \ / o o
CO
2 H N N N NH H SO H HHNHSO20 2-Oxo-3- [2-(5,6,7, 8-tetrahydro [1, 8]-naphthyridin-2-yl)ethyl]piperidin 1-yl-acetyl-3(S)-pyridin-3-yl- p3-alanine ethyl ester; 5 2-Oxo-3- [2-(5,6,7, 8-tetrahydro [1,8] -naphthyridin-2-yl)ethyl]piperin 1-yl-acetyl-3 (S)-pyridin-3-yl- p-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2 yl)ethyl]pyrrolidin- 1 -yl)acetyl-3 (S)-alkynyl- P3-alanine ethyl ester; 10 2-Oxo-3 (S)- [2-(5,6,7,8-tetrahydro [1,8 ]-naphthyridin-2 yl)ethyl]pyrrolidin- 1-yl)acetyl- 3 (S)-alkynyl- p-alanine; 2-Oxo-3 (S)- [2-(5,6,7,8-tetrahydro [1, 8 8]-naphthyridin-2-yl)ethyl] 15 pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl- 3-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-p3-alanine; 20 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]pyrrolidin- 1 -yl)acetyl- 3 (S)-alkynyl- 1-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-3-alanine; 25 - 46 - WO 98/44797 PCT/US98/06823 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2-yl)ethyl] pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-0-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 5 yl)ethyl]pyrrolidin- 1-yl)acetyl-3 (S)-pyridin-3-yl- p-alanine; Ethyl 2-oxo-3- [2-(5,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yl)ethyl] tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl- p-alanine; 10 2-Oxo-3-[2-(5,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl- p-alanine; Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro [1,8]naphthyridin-2 yl)ethyl]imidazolidin-l-yl-acetyl-3(S)-pyridin-3-yl-f-alanine; 15 2-Oxo-3-[2-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl } ethyl] imidazolidin- 1 -yl-acetyl-3(S)-pyridin- 3 -yl- -alanine; Ethyl 2-oxo-3(R)- [2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2 20 yl)ethyl]pyrrolidin-l-yl)acetyl-3(R)-(2-ethylindol-3-yl)-0-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2 yl)ethyl]pyrrolidin-l-yl)acetyl-3(R)-(2-ethylindol-3-yl)-3-alanine; 25 Ethyl 3-(S)-(2- { 2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2 ylmethyl)-amino]-pyrrolidin-1-yl }-acetylamino)-3-(S)-pyridin-3-yl propionic acid; 3-(S)-(2- { 2-Oxo-3- [(5,6,7,8-tetrahydro- [1,8]naphthyridin-2-ylmethyl) 30 amino]pyrrolidin- 1 -yl } -acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-(S)-(2- { 2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl) amino] -pyrrolidin- 1 -yl } -acetylamino)- 3- (S)-quinolin- 3 -yl-propionic acid; - 47 - WO 98/44797 PCT/US98/06823 3- { 2-[6-Oxo- 1-(5,6,7,8-tetrahydro- [ 1,8]naphthyridin-2-ylmethyl) hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino }-3-(S) pyridin-3-yl-propionic acid; 5 3- { 2- [6-Oxo- 1- (5,6,7,8-tetrahydro- [1,8]naphthyridin-2-ylmethyl) hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino }-3-(S) pyridin-3-yl-propionic acid; 10 [6-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)naphthylen-2-yl] carbonyl-2(S)-phenylsulfonylamino-0-alanine ethyl ester; [6-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)naphthylen-2-yl] carbonyl-2(S)-phenylsulfonylamino-0-alanine; 15 6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S) phenylsulfonylamino-p-alanine ethyl ester; 6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)-carbonyl-2(S) 20 phenylsulfonylamino- -alanine; 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidin- 1 -yl-carbonyl 2(S)-phenylsulfonylamino-p-alanine t-butyl ester; 25 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidin- 1 -yl-carbonyl 2(S)-phenylsulfonylamino-p3-alanine; 6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S) phenylsulfonyl-p-alanine ethyl ester; 30 6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S) phenylsulfonyl-p-alanine; - 48 - WO 98/44797 PCT/US98/06823 6-[(1,4,5,6-Tetrahydropyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl carbonyl-2(S)-phenylsulfonylamino-0-alanine; Ethyl 3(S)-pyridin-3-yl-3- { 2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 5 2-yl)propylcarbamoyl]acetylamino } propionate; 3(S)-pyridin-3-yl-3- { 2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2 yl)propylcarbamoyl]acetylamino }propionic acid; 10 3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl-0-alanine ethyl ester; 3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl-3-alanine; 15 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl--alanine ethyl ester; 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl 20 malonyl-3(S)-pyridin-3-yl-f-alanine; 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidinyl-malonyl-3(S) pyridin-3-yl-3-alanine ethyl ester; or 25 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidinyl-malonyl-3(S) pyridin-3-yl- p-alanine; or the pharmaceutically acceptable salts and optical isomers thereof. Compounds which are described as antagonists of the ovP3 receptor and may therefore be useful in the present invention, and 30 methods of synthesis thereof, can be found in the following pending applications and publications, which are herein incorporated by reference: - 49 - WO 98/44797 PCT/US98/06823 PCT Patent Pub. Nos. WO96/00574; WO 96/00730; WO 96/26190; WO 96/37492; EPO Patent Publication Nos. EP 0,578,083; EP 0,711,770; EP 0,727,425; EP 0,546,548. Compounds which are antagonists of the av33 receptor and 5 are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following pending publications, which is herein incorporated by reference: PCT Patent Pub. Nos. WO95/32710. Examples of farnesyl protein transferase inhibiting 10 compounds and in particular selective farnesyl protein transferase inhibiting compounds include the following: (a) a compound represented by formula (II-a) through (II-c): - 50 - WO 98/44797 PCT/US98/06823 (R )r R9 R2 R3 V- A'(CRla 2 )nA 2 (CRla 2
)
n -Wt- (CRlb 2 )pX/ N Y
R
4
R
5 (1-a) (R 8 )r R9 R2 G V - A'(CRla 2 )nA 2 (CR la 2 )n -\W - (CRlb 2 )P, N N-Z r/ t X \) J
R
3
R
4 (Il-b)
(R
8 )r 9 R2 R 3 A'(CRla 2 )nA 2 (CRla 2
)
n W - (CRib 2 )p N N-Z t X * '/ ( s G (ll-c) R wherein with respect to formula (II-a): (R ) r R9 R2 R 3 Hi 0 V - A'(CRla 2 )nA 2 (CRla 2
)
n -Vb W- (CR1b 2 )P /N y t X /U\ Y / -s\
R
4
R
5 (Il-a) 5 or a pharmaceutically acceptable salt thereof, Rla and R l b are independently selected from: - 51 - WO 98/44797 PCT/US98/06823 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR1 0 -, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, R10OC(O)-, N3, 5 N(R 10 )2, or R11 OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, CN,
(R
10 )2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, 10 N(R 10 )2, or R 1 1 0C(O)-NR 10 -;
R
2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted 15 aryl, unsubstituted or substituted heterocycle,
R
6
R
7 or
R
6 O O wherein the substituted group is substituted with one or more of: 20 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR 6 , c) (CH2)pNR 6
R
7 , d) halogen, 25 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , - 52 - WO 98/44797 PCT/US98/06823 5)
-NR
6
R
7 R6 6) - N
R
7 O 0 R6 7)
I
6 -N NRR 7 a O 0 8) -0
NR
6
R
7 O 0 9) -O. OR 6 O 0 10) NR 6
R
7 O 0 11) -SO 2
-NR
6
R
7
R
6 12) -N-SO 2
-R
7 , 5 13) R 6 , or O 0 14) -- OR 6 or O
R
2 and R 3 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 10 moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)- ; - 53 - WO 98/44797 PCT/US98/06823
R
4 and R 5 are independently selected from H and CH3; and any two of
R
2 , R 3 , R 4 and R 5 are optionally attached to the same carbon atom;
R
6 , R 7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 5 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, 10 c) halogen, d) HO, e) "" R 0 f) -SO 2
R
1 , or g) N(R 1 0 )2; or 15 R 6 and R 7 may be joined in a ring;
R
7 and R 7 a may be joined in a ring;
R
8 is independently selected from: 20 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-,
R
1 1 S(O)m-, R10C(O)NR 10 -, CN, NO2, R 10 2N-C(NR 10 )-, R10OC(O)-, R10OC(O)-, N3, -N(R10)2, or 25 R 1 10
OC(O)NR
10 -, and c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R 10 0C(O)-, 30 N3, -N(R 10 )2, or R 10 0C(O)NH-; - 54 - WO 98/44797 PCT/US98/06823
R
9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, 5 R 10 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, CN, NO2,
(R
10 )2N-C-(NRO10)-, R10C(O)-, R 10 0C(O)-, N3, N(R 10 )2, or R 1 1
OC(O)NR
10 -, and c) C1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, CN, 10 (R 10 )2N-C(NR 1 0)-, RO10C(O)-, R 10 0C(O)-, N3, N(R10)2, or R 1 1
OC(O)NR
10 -;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; 15
R
1 1 is independently selected from C1-C6 alkyl and aryl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(0)2N(R 10 )-, 20 N(R 10 )S(O)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, 25 c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 30 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; - 55 - WO 98/44797 PCT/US98/06823 X is -CH2-, -C(=O)-, or -S(=O)m-; Y is aryl, heterocycle, unsubstituted or substituted with one or 5 more of: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6
R
7 , c) C3-6 cycloalkyl, 10 d) aryl or heterocycle, e) HO, f) -S(O)mR 6 , or g) -C(O)NR 6
R
7 , 2) aryl or heterocycle, 15 3) halogen, 4) OR 6 , 5) NR 6
R
7 , 6) CN, 7) NO2, 20 8) CF3; 9) -S(O)mR 6 , 10) -C(O)NR 6
R
7 , or 11) C3-C6 cycloalkyl; 25 mis 0, 1 or 2; n is 0, 1, 2, 3 or4; p is 0, 1, 2, 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; 30 t is 0 or 1; and u is 4 or 5; with respect to formula (II-b): - 56 - WO 98/44797 PCT/US98/06823
(R
8 )r R9
R
2 G I(I a b II))NI b---N4 V - Al(CRa 2 )nA 2 (CRla 2 )n -\W - (CRb 2 )p, Nl N-Z t X I -e
R
3
R
4 (Il-b) or a pharmaceutically acceptable salt thereof, Rla, Rlb, R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, R 7 a, u, R 8 , A 1 , A 2 , V, W, X, 5 n, p, r, s, t and u are as defined above with respect to formula (II-a);
R
4 is selected from H and CH3; and any two of R 2 , R 3 and R 4 are optionally attached to the same 10 carbon atom; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, 15 R 1 1 S(O)m-, R 10
C(O)NR
10 -, CN, NO2, (R10)2N-C-(NR10)-, R10C(O)-, R 10 0C(O)-, N3, N(R10)2, or R 1 1
OC(O)NR
10 -, and c) C 1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, CN, 20 (R 10 )2N-C(NR 1 0)-, R10C(O)-, R 10 0C(O)-, N3, N(R10)2, or R 11OC(O)NR10-; G is H2 or O; 25 Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: - 57 - WO 98/44797 PCT/US98/06823 a) C1-4 alkoxy, b) NR 6
R
7 , c) C3-6 cycloalkyl, d) aryl or heterocycle, 5 e) HO, f) -S(O)mR 6 , or g) -C(O)NR 6
R
7 , 2) aryl or heterocycle, 3) halogen, 10 4) OR 6 , 5) NR 6
R
7 , 6) CN, 7) NO2, 8) CF3; 15 9) -S(O)mR 6 , 10) -C(O)NR 6
R
7 , or 11) C3-C6 cycloalkyl; with respect to formula (II-c):
(R
8 )r R9R3 III A'(CRa 2 )nA 2 (CROa 2 )n W - (CR b 2 )p\ ,N N-Z ( t X l- / s -G 20 (Il-c) R4 or a pharmaceutically acceptable salt thereof, Rla, Rlb, R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, u, R 7 a, R 8 , A 1 , A 2 , V, W, X, n, r and t are as defined above with respect to formula (II-a); 25
R
4 is selected from H and CH3; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom; - 58 - WO 98/44797 PCT/US98/06823 G is O; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, 5 arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6
R
7 , 10 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 , or g) -C(O)NR 6
R
7 , 15 2) aryl or heterocycle, 3) halogen, 4) OR 6 , 5) NR 6
R
7 , 6) CN, 20 7) NO2, 8) CF3; 9) -S(O)mR 6 , 10) -C(O)NR 6
R
7 , or 11) C3-C6 cycloalkyl; 25 and s is 1; 30 (b) a compound represented by formula (II-d): - 59 - WO 98/44797 PCT/US98/06823 R6a-e R 3
(R
8 )r R 9 9 )q V - A'(CRla 2 )nA 2 (CRla 2
)
n W - (CRib 2
)
p - X -(CRib2) p
R
4 t II-d wherein: RIa and R1b are independently selected from: 5 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -,
R
1 1 C(O)O-, (R10)2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, 10 c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-,
R
1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-, R 10 2N 15 C(NRO10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 lOC(O) NR10-;
R
2 , R 3 , R 4 and R 5 are independently selected from: a) hydrogen, 20 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, R 1 1 C(O)O-, - 60 - WO 98/44797 PCT/US98/06823
R
10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C 1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the 5 substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and 10 R11OC(O)-NR10-;
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 15 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R 1 1 C(O)O-,
R
10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR10-, 20 c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 25 R 12 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 1 0C(O)-NR10-; any two of R6a, R6b, R 6 C, R6d and R6e on adjacent carbon atoms are 30 combined to form a diradical selected from -CH=CH-CH=CH-, CH=CH-CH2-, -(CH2)4- and -(CH2)3-; - 61 - WO 98/44797 PCT/US98/06823
R
7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, 5 b) aryl or heterocycle, c) halogen, d) HO, e) ] R" 0 f) -SO 2
R
11 g) N(R 1 0 )2 or 10 h) C1-4 perfluoroalkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, 15 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-,
R
1 0C(O)NR 1 0-, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, and c) C 1-C6 alkyl unsubstituted or substituted by aryl, 20 cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R
10 0-, R 1 1 S(O)m-, R 10 C(O)NH-, (R 10 )2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, RO10C(O)-, N3, -N(R 10 )2, or R10OC(O)NH-; 25 R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, - 62 - WO 98/44797 PCT/US98/06823
(R
10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NRO10-, and c) C1 -C6 alkyl unsubstituted or substituted by C1 -C6 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, 5 RO10C(O)NRO 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, R10OC(O)-, N3, -N(R 10 )2, or R 1 1OC(O)NR10-;
R
10 is independently selected from hydrogen, C 1-C6 alkyl, 2,2,2 trifluoroethyl, benzyl and aryl; 10
R
1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C1 -C6 substituted aralkyl, C1-C6 heteroaralkyl, 15 C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, 20 -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R 10 )-, S(O)2N(R 10 )-, -N(R 10 )S(O)2- or S(O)m; V is selected from: a) hydrogen, 25 b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and 30 e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; - 63 - WO 98/44797 PCT/US98/06823 W is a heterocycle; X is a bond, -CH=CH-, O, -C(=0)-, -C(O)NR 7 -, -NR 7 C(O)-, -C(O)O-, -OC(O)-, -C(O)NR 7 C(O)-, -NR 7 -, -S(O)2N(R 10 )-, 5 N(R 10 )S(O)2- or -S(=O)m-; mis 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; 10 qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1; (c) a compound represented by formula (II-e): f 2
R
3 f- f (R 8 )r (R 9 )q5 V - A(CRla 2 )nA 2 (CRa 2 ) -W - (CR1b2 p -X -(CRb2" p R V~~ (-R b)(C 2) 2) 2)p 2 )p 15 II-e wherein: Rl a , Rib, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-d); 20 from 1-3 of f(s) are independently N, and the remaining fs are independently CR 6 ; and each R 6 is independently selected from: 25 a) hydrogen, - 64 - WO 98/44797 PCT/US98/06823 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-, R 1 1 C(0)O-, 5 R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted Ci1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or 10 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R10)2NC(O)-,
R
10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-; or 15 any two of R 6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, (CH2)4- and -(CH2)3-; 20 (d) a compound represented by formula (II-f):
R
6 a-e Q
R
3
((
8 )rf V - A'(CR'2)nA2(CR'2)n- W - (CR 2 2 )p - X -(CR 2 2 )p RI II-f wherein: - 65 - WO 98/44797 PCT/US98/06823
R
3 , R 4 , R 5 , R6a-e, R 7 , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p, q, rand t are as previously defined with respect to formula (II-d); from 1-2 of f(s) are independently N, and the remaining fs are 5 independently CH; and R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, 10 C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-,
R
1 1 C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2,
R
1 0C(O)-, N3, -N(R 10 )2, or R lOC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from 15 unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
10 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 1 OC(O)-NR10-; 20 (f) a compound represented by formula (II-g): g-9 g ,
R
3 (R 8) rC 9f (R)r (R) V - A'(CR 1 2)nA2(CR'2)n - (CR22)p- X -(CR22 R II-g wherein: - 66- WO 98/44797 PCT/US98/06823
R
3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-d); from 1-2 of f(s) are independently N, and the remaining fs are 5 independently CH; from 1-3 of g(s) are independently N, and the remaining g's are independently CR 6 ; 10 R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, R 1 1 S(O)m-, R 10
C(O)NR
10 -,
R
1 lC(0)O-, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, NO2, 15 R 10 C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, c) unsubstituted or substituted C1 -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 20 R1 0 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-; and each R 6 is independently selected from: 25 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R11 S(O)m-, R 10 C(O)NR1 0 -, (R 10 )2NC(O)-, R 11C(O)O-, 30 R 10 2N-C(NRO10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or - 67 - WO 98/44797 PCT/US98/06823 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1S(O)m-, R 10 C(O)NR10-, (R 1 0)2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and 5 RllOC(O)-NR 10 -; or any two of R 6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, (CH2)4- and -(CH2)3-; 10 (g) a compound represented by formula (II-h):
R
2 O R'NH N
N
Rc S H 3V" H HS R II-h wherein Rc is selected from: Rs
OR
6 and n 00 15 O RI 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 20 hydrocarbons of 1 to 6 carbon atoms;
R
2 and R3 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine - 68 - WO 98/44797 PCT/US98/06823 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 5 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 10 atoms;
R
5 is selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino 15 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 20 which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH2OH or -CH2CH2CH2OH; 25 R 6 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; 30 T is O or S(O)m; m is 0, 1 or 2; n is 0, 1 or 2; - 69 - WO 98/44797 PCT/US98/06823 (h) a compound represented by formula (II-i):
R
2 a
R
2 b R lb , N-(CR 2p-ii
R
3 II-i wherein: 5 R1a and RIb are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 0-, 10 R 9 S(O)m-, R 8
C(O)NR
8 -, CN, NO2, (R 8 )2N-C(NR 8 )-,
R
8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9
OC(O)NR
8 -, c) CI1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 15 alkenyl, C2-C6 alkynyl, R 8 0-, R 9 S(O)m-, R 8
C(O)NR
8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9
OC(O)-NR
8 -; R2a, R2b and R 3 are independently selected from: 20 a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R
8 0-, R 9 S(O)m-, R 8
C(O)NR
8 -, CN, N3, (R 8 )2N-C(NR 8
)
, R 8 C(O)-, R 8 OC(O)-, -N(R 8 )2, or R 9
OC(O)NR
8 -, c) unsubstituted or substituted aryl, unsubstituted or 25 substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 8 0-,
R
9 S(O)m-, R 8
C(O)NR
8 -, CN, NO2,
(R
8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3,
-N(R
8 )2, halogen or R 9
OC(O)NR
8 -, and - 70 - WO 98/44797 PCT/US98/06823 d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; 5 R 4 and R 5 are independently selected from: a) hydrogen, and b) (R6 )r R7 z I R Z ) )A V - A'(CRa 2 )nA 2 (CRla 2
)
n W - (CRlb 2 ) ( U 10 R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 15 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8
C(O)NR
8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, N(R 8 )2, or R 9
OC(O)NR
8 -, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 20 unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br,
R
8 0-, R 9 S(O)m-, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8
C(O)
, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; 25 R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8
C(O)NR
8 -, CN, NO2,
(R
8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or 30 R 9
OC(O)NR
8 -, and - 71 - WO 98/44797 PCT/US98/06823 c) C 1-C6 alkyl unsubstituted or substituted by C 1-C6 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8
C(O)NR
8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NRS-; 5
R
8 is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C 1-C6 aralkyl and substituted or unsubstituted aryl; 10 R 9 is independently selected from C1-C6 alkyl and aryl;
R
10 is independently selected from hydrogen, C 1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; 15
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 8 -, -NR 8 C(O)-, O, -N(R 8 )-, S(O)2N(R 8 )-, -N(R 8 )S(O)2-, or S(O)m; 20 V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are 25 replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 30 W is a heterocycle; - 72 - WO 98/44797 PCT/US98/06823 Y is selected from: a bond, -C(RO10)=C(RO10)-, -C-C-, -C(O)-, -C(R10) 2-, -C(OR10)R10-, -CN(R 10 )2R 10-, -OC(RO10) 2 -, -NR 10
C(R
10 )2-,
-C(R
10 )20-, -C(R 10 )2NR 10 -, -C(O)NR10-, -NR10OC(O)-, O, NC(O)R10-, -NC(O)OR10-, -S(O)2N(R 10 )-, -N(R 10 )S(O)2-, or 5 S(O)m; Z is H2 or O; m is 0, 1 or 2; 10 nis 0, 1,2, 3 or4; pis 0, 1, 2, 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; and u is 0 or 1; 15 (e) a compound represented by formula (II-m):
R
6 a-e Q
R
3
(R
8 )r ( 9 )q Y V - A 1
(CR
1 2 )nA 2
(CR'
2 )n - W - (CR 2 2 )p - X -(CR 2 2 )p Rs
R
4 II-m wherein: Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises 20 a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom attached to Y; - 73 - WO 98/44797 PCT/US98/06823 Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom; 5 R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 0 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, 10 RlIC(0)0-, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R10OC(0)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted or substituted CI1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, 15 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
10 0-, R 11 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(0)-,
R
10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NR
10 -; 20 R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, 25 R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, R 1 1 C(0)O-,
R
10 2N-C(NR 10 )-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the 30 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, - 74 - WO 98/44797 PCT/US98/06823
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 1 0)2NC(O)-,
R
10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 1 0C(O)-NR 10 -; 5 R 6 a, R6b, R 6 C, R6d and R 6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, 10 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R11C(O)O-,
R
10 2N-C(NR 10 )-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 11
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, 15 d) substituted C1-C6 alkyl wherein the substituent on the substituted CI1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 2 0-,
R
1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-, 20 R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR10)-, CN,
R
1 0C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NRO10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 25 CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 30 a) C1-4 alkoxy, b) aryl or heterocycle, - 75 - WO 98/44797 PCT/US98/06823 c) "
R
11 O 0 d) - SO 2
R
1 1 e) N(R 10 )2 or f) C1-4 perfluoroalkyl; 5 R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, 10 R10C(O)NR10-, (R 10 )2NC(O)-, R 1 1 S(O)2NR 10 -,
(R
10 )2NS(O)2-, R 10 2N-C(NR 10 )-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 11
OC(O)NRO
10 -, and c) Ci1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 15 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R
1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR10)-, CN, R10OC(O)-, N3, -N(R 10 )2, or R 10 0C(O)NH-; 20 R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,
R
10 0-, R 11 S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or 25 R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -,
(R
10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, N(R10)2, or R 1 1OC(O)NR10-; - 76 - WO 98/44797 PCT/US98/06823
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 5 R 11 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, CI1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, 10 heteroaryl, substituted heteraryl, Ci1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R
13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C 1-C6 acyl; 15
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -CEC-, -C(0)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, S(O)2N(R 10 )-, -N(R10)S(0)2-, or S(O)m; 20 V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are 25 replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 30 W is a heterocycle; - 77 - WO 98/44797 PCT/US98/06823 X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR 7 -, -NR 7 C(0)-, -C(O)O-, -OC(0)-, -C(O)NR 7 C(0)-, -NR 7 -, -S(O)2N(R 10 )-, N(R 10 )S(0)2- or-S(=O)m-; 5 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and 10 t is 0 or 1; (f) a compound represented by formula (II-n):
R
6 a-e Y
R
3 (8)r Q(R9) V - A'(CR' 2 )nA 2
(CR'
2 )n - W - (CR 2 2 )p - X -(CR 2)p R 5 t R4 II-n wherein: 15
R
1 , R 2 , R 3 , R 4 , R 5 , R6a-e, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , A 1 , A 2 , V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-m); 20 Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or - 78 - WO 98/44797 PCT/US98/06823 sulfonyl moiety adjacent to the nitrogen atom attached to Y, provided that Q is not O 0 0 0-1 0-1 0 or 0-1 0 0 5 Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom; 10 or a pharmaceutically acceptable salt or disulfide thereof. Examples of compounds which selectively inhibit farnesyl protein transferase include the following: 15 2(S)-Butyl-l1-(2,3-diaminoprop-1-yl)- 1-(1-naphthoyl)piperazine; 1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 20 2(S)-Butyl-1- { 5- [1-(2-naphthylmethyl)]-4,5-dihydroimidazol } methyl-4 (1-naphthoyl)piperazine; 1- [5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1 -naphthoyl)piperazine; 25 1- { 5- [1-(4-nitrobenzyl)]imidazolylmethyl } -2(S)-butyl-4-( 1 naphthoyl)piperazine; - 79 - WO 98/44797 PCT/US98/06823 1-(3-Acetamidomethylthio-2(R)-aminoprop- 1 -yl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 5 2(S)-Butyl- 1- [2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine; 2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( 1 -naphthoyl)piperazine; 2(S)-Butyl-4-(1-naphthoyl)- 1-(3-pyridylmethyl)piperazine; 10 1-2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1 naphthoyl)piperazine; 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl) 15 piperazine; 2(S)-Benzyl-l1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine; 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1 20 naphthoyl)piperazine; 1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1 naphthoyl)piperazine; 25 2(S)-Butyl- 1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine; 2(S)-Butyl- 1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine; 2(S)-Butyl-1-[(1-naphth-2-ylmethyl)- 1H-imidazol-5-yl)acetyl]-4-(1 30 naphthoyl)piperazine; 2(S)-Butyl- 1-[(1-naphth-2-ylmethyl)- 1H-imidazol-5-yl)ethyl]-4-(1 naphthoyl)piperazine; - 80 - WO 98/44797 PCT/US98/06823 1-(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine; 1- (2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine; 5 1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 10 1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine; 2(S)-n-Butyl-4-(2,3-dimethylphenyl)-1-(4-imidazolylmethyl) piperazin-5-one; 15 2(S)-n-Butyl- 1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3 dimethylphenyl)piperazin-5-one; 1-[I1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl) 20 2(S)-(2-methoxyethyl)piperazin-5-one; 2(S)-n-Butyl-4-(1-naphthoyl)- 1-[1-(1-naphthylmethyl)imidazol-5 ylmethyl]-piperazine; 25 2(S)-n-Butyl-4-(1-naphthoyl)- 1-[ 1-(2-naphthylmethyl)imidazol-5 ylmethyl]-piperazine; 2(S)-n-Butyl- 1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 30 2(S)-n-Butyl- 1-[1 -(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; - 81 - WO 98/44797 PCT/US98/06823 2(S)-n-Butyl- 1-[1 -(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 2(S)-n-Butyl- 1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1 5 naphthoyl)piperazine; 2(S)-n-Butyl- 1-[1 -(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 10 1- [1 -(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1 naphthoyl)piperazine; 2(S)-n-Butyl-4-(1-naphthoyl)- -[1 -(4-trifluoromethylbenzyl)imidazol 5-ylmethyl]-piperazine; 15 2(S)-n-Butyl- 1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)-piperazine; 2(S)-n-Butyl- 1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1 20 naphthoyl)-piperazine; 1-[1-(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1 naphthoyl)-piperazine; 25 2(S)-n-Butyl-4-(1-naphthoyl)- 1- [1-(2-phenylethyl)imidazol-5-ylmethyl] piperazine; 2(S)-n-Butyl-4-(1-naphthoyl)- 1-[1-(4-trifluoromethoxy)imidazol-5 ylmethyl]piperazine; 30 1- { [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl } -2(S)-n-butyl-4-(1 naphthoyl)piperazine; (S)-1 -(3-Chlorophenyl)-4- [1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2 35 (methanesulfonyl)ethyl]-2-piperazinone; - 82 - WO 98/44797 PCT/US98/06823 (S)- 1 -(3-Chlorophenyl)-4-[ 1-(4-cyanobenzyl)-5-imidazolylmethyl]-5- [2 (ethanesulfonyl)ethyl]-2-piperazinone; 5 (S)- 1-(3-Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2 (ethanesulfonyl)methyl]-2-piperazinone; (S)- 1- (3-Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl] -5- [N ethyl-2-acetamido]-2-piperazinone; 10 (±)-5-(2-Butynyl)- 1-(3-chlorophenyl)-4- [1 -(4-cyanobenzyl)-5 imidazolylmethyl]-2-piperazinone; 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2 15 piperazinone; 5(S)-Butyl-4-[1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]- 1-(2,3 dimethylphenyl)-piperazin-2-one; 20 4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]- 1-(3 chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one; 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2 methylphenyl)piperazin-2-one; 25 4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)- 1-(3 chlorophenyl)piperazin-2-one; 4-[3-(4-Cyanobenzyl)pyridin-4-yl]-1 -(3-chlorophenyl)-5(S)-(2 30 methylsulfonylethyl)-piperazin-2-one; 4-[5-(4-Cyanobenzyl)- 1-imidazolylethyl]-1 -(3-chlorophenyl)piperazin 2-one; 35 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-homoserine lactone, - 83 - WO 98/44797 PCT/US98/06823 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-homoserine, 5 2(S)-[2(S)- [2(R)-Amino-3-mercapto]propylamino-3 (S) methyl]pentyloxy-2-methy 1-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine, 10 2(S)-[2(S)-[2(R)-Amino-3-mercapto)propylamino-3(S) methyl]pentyloxy-4-pentenoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] 15 pentyloxy-4-pentenoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxypentanoyl-homoserine lactone, 20 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S) methyl] pentyloxypentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]5 pentyloxy-4-methylpentanoyl-homoserine lactone, 25 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-4-methylpentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S) 30 methyllpentyloxy-3-methylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-methylbutanoyl-homoserine, - 84 - WO 98/44797 PCT/US98/06823 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] 5 pentyloxy-3-phenylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, 10 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, 15 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S)-methyl] 20 pentyloxy-3-phenylpropionyl-methionine methyl ester, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine, 25 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester (Compound 5), 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) 30 methyl]pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 6), 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, - 85 - WO 98/44797 PCT/US98/06823 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-naphth-2-yl-propionyt-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] 5 pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone methyl ester, 10 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) 15 methyllpentyloxy-3-methybutanoyl-methionine methyl ester. 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-methybutanoyl-methionine, 20 Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino 3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-homoserine, 25 Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino 3(S)methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole 30 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole - 86 - WO 98/44797 PCT/US98/06823 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole 5 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 10 1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 15 1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 20 1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 25 1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 30 1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole - 87 - WO 98/44797 PCT/US98/06823 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4 methylimidazole 5 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole 5-(4-Cyanophenyloxy)- 1-(2'-methyl-4-biphenylmethyl)-imidazole 10 5-(4-Biphenyloxy)- 1-(4-cyanobenzyl)-imidazole 5-(2'-Methyl-4-biphenoxy)- 1-(4-cyanobenzyl)-imidazole 15 5-(4-(3',5'-dichloro)biphenylmethyl)- 1-(4-cyanobenzyl)imidazole 1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4 20 cyanophenyl)methylimidazole 1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy- 1-(4-cyanophenyl) methylimidazole 25 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl) methylimidazole 30 1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy- 1-(4-cyanophenyl) methylimidazole 35 1-(4-Cyanobenzyl)-5-(1-hydroxy- 1-(4-biphenyl)-methyl imidazole - 88 - WO 98/44797 PCT/US98/06823 1-(4-Cyanobenzyl)-5-(1-oxo- 1-(4-biphenyl)-methyl imidazole 5 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl) imidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy- 1-(3-biphenyl)methyl-imidazole 10 5-(2-[1,1'-Biphenyl]vinylene)- 1-(4-cyanobenzyl)imidazole 1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4 15 phenylbenzene 1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole 1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole 20 1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole N- { 1-(4-Cyanobenzyl)- 1H-imidazol-5-yl)methyl }-5-(pyrid-2-yl)-2 25 amino-pyrimidine N,N-bis(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene N,N-bis(4-Imidazolemethyl)amino-4-[(3-carboxyphenyl)oxy]benzene 30 N,N-bis(4-Imidazolemethyl)amino-3-[(3-carbomethoxyphenyl) oxy]benzene N,N-bis(4-Imidazolemethyl)amino-4-[(3-carbomethoxyphenyl) oxy]benzene 35 - 89 - WO 98/44797 PCT/US98/06823 N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3 carboxyphenyl)oxy]benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3 5 carbomethoxyphenyl)oxy]benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzene 10 N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenylthio)benzene N-Butyl-N-[1-(4-cyanobenzyl)-5-imidazolemethyl]amino-4 (phenoxy)benzene 15 N- [1- (4-Cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzene N-(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene 20 4- { 3-[4-(-2-Oxo-2-H-pyridin- 1 -yl)benzyl]-3-H-imidazol-4 ylmethyl]benzonitrile 4- { 3- [4-3-Methyl-2-oxo-2-H-pyridin- 1 -yl)benzyl]-3-H-imidazol-4 25 ylmethyl]benzonitrile 4- { 3-[4-(-2-Oxo-piperidin- 1 -yl)benzyl]-3-H-imidazol-4 ylmethyl]benzonitrile 30 4- { 3-[3-Methyl-4-(2-oxopiperidin- 1 -yl)-benzyl]-3-H-imidizol-4 ylmethyl } -benzonitrile (4- { 3- [4- (2-Oxo-pyrrolidin- 1 -yl)-benzyl] -3 H-imidizol-4-ylmethyl } benzonitrile 35 - 90 - WO 98/44797 PCT/US98/06823 4- { 3-[4-(3-Methyl-2-oxo-2-H-pyrazin- 1-yl)-benzyl-3-H-imidizol-4 ylmethyl } -benzonitrile 4- { 3- [2-Methoxy-4-(2-oxo-2-H-pyridin- 1 -yl)-benzyl] -3-H-imidizol-4 5 ylmethyl I -benzonitrile 4- { 1- [4- (5-Chloro-2-oxo-2H-pyridin- 1 -yl)-benzyl]- 1H-pyrrol-2 ylmethyl I -benzonitrile 10 4-[1-(2-Oxo-2H- [ 1,2']bipyridinyl-5'-ylmethyl)- 1H-pyrrol-2-ylmethyl] benzonitrile 4- [1-(5-Chloro-2-oxo-2H- [ 1,2']bipyridinyl-5'-ylmethyl)- 1H-pyrrol-2 ylmethyl]-benzonitrile 15 4- [3-(2-Oxo- 1 -phenyl- 1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4 ylmethyl]benzonitrile 4- { 3-[1-(3-Chloro-phenyl)-2-oxo- 1,2-dihydropyridin-4-ylmethyl]-3H imidazol-4-ylmethyl } benzonitrile 20 or a pharmaceutically acceptable salt, disulfide or optical isomer thereof. Compounds which are described as inhibitors of farnesyl protein transferase and may therefore useful in the present invention, 25 and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incorporated by reference: WO 95/32987 published on 7 December 1995; U. S. Pat. No. 5,420,245; 30 European Pat. Publ. 0 618 221 ; European Pat. Publ. 0 675 112 ; WO 95/08542; WO 95/11917; WO 95/12612; 35 WO 95/12572; - 91 - WO 98/44797 PCT/US98/06823 WO 95/10514; WO 95/10515; WO 95/10516; WO 95/24612; 5 WO 95/34535; WO 96/22278; WO 96/24611; WO 96/24612; WO 96/05168; 10 WO 96/05169; WO 96/00736 and U.S. Pat. No. 5,571,792 granted on November 5, 1996; WO 96/17861; WO 96/33159; 15 WO 96/34850; WO 96/34851; WO 96/30017; WO 96/30018; WO 96/30362; 20 WO 96/30363; WO 96/31111; WO 96/31477; WO 96/31478; WO 96/31501; and 25 U. S. Pat. No. 5,532,359 granted on July 2, 1996. Compounds which are inhibitors of farnesyl-protein transferase and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, 30 pending applications and publications, which are herein incorporated by reference: U. S. Pat. No. 5,238,922 granted on August 24, 1993; - 92 - WO 98/44797 PCT/US98/06823 U. S. Pat. No. 5,340,828 granted on August 23, 1994; U. S. Pat. No. 5,480,893 granted on January 2, 1996; 5 U. S. Pat. No. 5,352,705 granted on October 4, 1994; U. S. Pat. No. 5,504,115 granted on April 2, 1996; U. S. Pat. No. 5,536,750 granted on July 16, 1996; 10 U. S. Pat. No. 5,504,212 granted on April 2, 1996; U. S. Pat. No. 5,439,918 granted on August 8, 1995; 15 WO 94/10138 (May 11, 1994); USSN 08/968,025 filed on October 29, 1992 and USSN 08/143,943 filed on October 27, 1993 ; WO 95/00497 (January 5, 1995); USSN 08/080,028 filed on June 18, 1993 and USSN 08/237,586 filed on May 11, 1994; 20 U. S. Pat. No. 5,576,293 granted on November 19, 1996 U. S. Pat. No. 5,468,733 granted on November 21, 1995 25 WO 96/06609 (March 3, 1996) and USSN 08/298,478 filed on August 24, 1994 ; U. S. Pat. No. 5,585,359 granted on December 17, 1996 30 U. S. Pat. No. 5,523,456 granted on June 4, 1996; WO 96/10035 (April 4, 1996); USSN 08/315,161 filed on September 29, 1994; USSN 08/399,282 filed on March 6, 1995; USSN 472,077 filed on June 6, 1995 and USSN 08/527,972 filed on September 14, 35 1995 - 93 - WO 98/44797 PCT/US98/06823 U. S. Pat. No. 5,571,835 granted on November 5, 1996; U. S. Pat. No. 5,491,164 granted on February 13, 1996; 5 WO 96/10034 (April 4, 1996); USSN 08/314,974 filed on September 29, 1994; USSN 08/526,244 filed on September 21, 1995 WO 96/30014 (October 3, 1996); USSN 08/412,621 filed on March 29, 1995 and USSN 08/448,865 filed on May 24, 1995; 10 U. S. Pat. No. 5,578,629 granted on November 26, 1996; WO 96/34010 (October 31, 1996); USSN 08/412,828 filed on March 29, 1995; USSN 08/600,794 filed on February 13, 1996 15 WO 96/30343 (October 3, 1996); USSN 08/412,829 filed on March 29, 1995; and USSN 08/470,690 filed on June 6, 1995; and USSN 08/600,728 filed on February 28, 1996; WO 96/31525 (October 10, 1996); USSN 08/412,626 filed on March 29, 1995; USSN 08/600,792 filed on February 13, 1996; 20 U. S. Pat. No. 5,534,537 granted on July 9, 1996; WO 96/37204 (November 28, 1996); USSN 08/449,038 filed on May 24, 1995; USSN 08/648,330 filed on May 15, 1996; WO 96/39137 (December 12, 1996); USSN 08/468,160 filed on June 6, 25 1995; USSN 08/652,055 filed on May 23, 1996; USSN 08/729,265 filed on October 10, 1996; USSN 08/749,254 filed on November 15, 1996; 30 USSN 60/010,798 filed on January 30, 1996; USSN 08/ , filed on January 21, 1997; USSN 60/010,799 filed on January 30, 1996; USSN 08/ , filed on 35 January 21, 1997; - 94 - WO 98/44797 PCT/US98/06823 USSN 60/010,860 filed on January 30, 1996; USSN 08/ , filed on January 21, 1997; 5 USSN 60/011,081 filed on January 30, 1996; USSN 08/ , filed on January 21, 1997; USSN 60/010,798 filed on January 30, 1996; USSN 08/ , filed on January 21, 1997; 10 USSN 60/014,587 filed on April 3, 1996; USSN 60/014,589 filed on April 3, 1996; 15 USSN 60/014,592 filed on April 3, 1996; USSN 60/014,593 filed on April 3, 1996; USSN 60/014,594 filed on April 3, 1996; 20 USSN 60/014,668 filed on April 3, 1996; USSN 60/014,775 filed on April 3, 1996; 25 USSN 60/014,776 filed on April 3, 1996; USSN 60/014,777 filed on April 3, 1996; USSN 60/014,791 filed on April 3, 1996; 30 USSN 60/014,792 filed on April 3, 1996; USSN 60/014,793 filed on April 3, 1996; - 95 - WO 98/44797 PCT/US98/06823 USSN 60/014,794 filed on April 3, 1996; USSN 60/014,798 filed on April 3, 1996; 5 USSN 60/014,774 filed on April 3, 1996; USSN 60/022,332 filed on July 24, 1996; USSN 60/022,340 filed on July 24, 1996; 10 USSN 60/022,341 filed on July 24, 1996; USSN 60/022,342 filed on July 24, 1996; 15 USSN 60/022,558 filed on July 24, 1996; USSN 60/022,582 filed on July 24, 1996; USSN 60/022,586 filed on July 24, 1996; 20 USSN 60/022,587 filed on July 24, 1996; USSN 60/022,647 filed on July 24, 1996; 25 USSN 60/032,126 filed on December 5, 1996; USSN 60/032,428 filed on December 5, 1996; USSN 60/032,578 filed on December 5, 1996; 30 USSN 60/032,579 filed on December 5, 1996; USSN 60/ 033,990, filed on December 30, 1996; and - 96 - WO 98/44797 PCT/US98/06823 USSN 60/033,991, filed on December 30, 1996; All patents, publications and pending patent applications identified are hereby incorporated by reference. 5 With respect to the compounds of formulas I-a through I-e the following definitions apply: The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, 10 etc.). The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range. The term "alkynyl" shall mean straight or branched chain 15 alkynes of two to ten total carbon atoms, or any number within this range. The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 20 cyclooctyl). The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C1-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.). 25 The term "aryl," as used herein, refers to a mono- or polycyclic system composed of 5- and 6-membered aromatic rings containing 0, 1, 2, 3 or 4 heteroatoms chosen from N, O or S and either unsubstituted or substituted with one or more groups selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, 30 amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-5 alkoxycarbonyl, - 97 - WO 98/44797 PCT/US98/06823 C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl or C1-5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, benzimidazolyl, 5 indolyl, thienyl, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups selected from hydrogen, halogen, C1-10l alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, 10 C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, 15 di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is unsubstituted, mono-, di- or tri-substituted with one to three of the above-named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents. 20 Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aryl CO-8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., C1-10) shall refer independently to the number of carbon atoms in an alkyl or 25 cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. The CO-m or Cl-m designation where 30 m may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl - 98 - WO 98/44797 PCT/US98/06823 include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine. When substituent Y, B, R 1 to R 2 8 includes the definition CO (e.g., aryl CO-8 alkyl), the group modified by CO is not present in 5 the substituent. Similarly, when any of the variables m, q, r or s is zero, then the group modified by the variable is not present; for example, when s is zero, the group "-(CH2)s C-CH" is "-C-CH". The term "halogen" shall include iodine, bromine, chlorine and fluorine. 10 The term "oxy" means an oxygen (0) atom. The term "thio" means a sulfur (S) atom. The term "oxo" shall mean =O. The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound 15 can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of 20 attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to O II -C1-6 alkyl-NH-C-Cl 1 5 alkyl. With respect to the compounds of formulas II-a through II-n the following definitions apply: 25 The term "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 30 include cyclopentyl and cyclohexyl. - 99 - WO 98/44797 PCT/US98/06823 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 5 carbon atoms, and interrupted by from 1-4 heteroatoms selected from O, S and N. The term "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 10 carbon to carbon double bond is present, and up to four non aromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl, iso propenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2 15 butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is 20 provided. The term "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 25 include ethynyl, propynyl and butynyl. As described above with respect to alkyl, 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 30 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. - 100 - WO 98/44797 PCT/US98/06823 Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups. With regard to the farnesyl transferase inhibitors, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon 5 ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like. The term "heteroaryl" refers to a monocyclic aromatic 10 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 15 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. Examples of this type 20 are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydro imidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below. With regard to the farnesyl transferase inhibitors, the term 25 heterocycle or heterocyclic, as used herein, represents a stable 5- to 7 membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 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 30 including any bicyclic group in which any of the above-defined hetero cyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, - 101 - WO 98/44797 PCT/US98/06823 benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, 5 imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2 oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, 10 pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. Preferably, heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, 15 piperidyl, pyridyl and pyrrolidinyl. With regard to the farnesyl transferase inhibitors, the terms "substituted aryl", "substituted heterocycle" and "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 20 F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)O-, OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH- and C1-C20 alkyl. In the present method, amino acids which are disclosed are 25 identified both by conventional 3 letter and single letter abbreviations as indicated below: Alanine Ala A Arginine Arg R 30 Asparagine Asn N Aspartic acid Asp D Asparagine or Aspartic acid Asx B Cysteine Cys C 35 Glutamine Gln Q - 102 - WO 98/44797 PCT/US98/06823 Glutamic acid Glu E Glutamine or Glutamic acid Glx Z Glycine Gly G 5 Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M 10 Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W 15 Tyrosine Tyr Y Valine Val V The compounds used in the present method may have 20 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. Unless otherwise specified, named amino acids are understood to have the natural "L" stereoconfiguration 25 With respect to the farnesyl-protein transferase inhibitors of the formulas II-d and II-f,the substituent illustrated by the structure R 6a-e is a simplified representation of a phenyl ring having five (5) substituents (hydrogens and/or non-hydrogens) and may also be 30 represented by the structure - 103 - WO 98/44797 PCT/US98/06823
R
6 b
R
6a R6c R6d
R
6 e With respect to the farnesyl-protein transferase inhibitors of the formulas II-d and II-f, the moiety described as R 6a-e 5 where any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following structures: I It is understood that such fused ring moieties may be further substituted 10 by the remaining R 6 a, R6b, R 6 c, R6d and/or R 6 e as defined hereinabove. With respect to the farnesyl-protein transferase inhibitors of the formulas II-e and II-g, the moieties designated by the following structures //f, f f 9,,~ f 15 - 104 - WO 98/44797 PCT/US98/06823 represent an aromatic 6-membered heterocyclic ring and includes the following ring systems:
R
6
R
6 N 6 R6 N \ N N N S6 R 6 R6 N R6
R
6
R
6
R
6
R
6
R
6 O N R 6 RFl 6 R6 R 6 N R 6 N H NI N HN NH N N N N NN O
R
6
R
6
R
6 0 N N 6 N HN NH R6 R6 N\ )F 0
R
6 6
R
6 wherein R 6 is as defined hereinabove. 5 With respect to the farnesyl-protein transferase inhibitors of the formulas II-e and II-g, the moieties designated by the following structures f ff f% ,,g9 g .f ,9g fg where any two of R 6 on adjacent carbon atoms are combined to form a 10 diradical selected from -CH=CH-CH=CH-, -CH=CH-CH-, -(CH2)4- and -(CH2)4- include, but are not limited to the following structures: - 105 - WO 98/44797 PCT/US98/06823 N N t - I NN II I NN It is understood that such fused ring moieties may be further substituted by the remaining R 6 s as defined hereinabove. With respect to the farnesyl-protein transferase inhibitors 5 of the formulas II-f and II-g, the moiety designated by the following structure f// f f / /f represents an aromatic 6-membered heterocyclic ring and includes the following ring systems: - 106 - WO 98/44797 PCT/US98/06823 N N N%\ NNN zz~o 0 N N N"N HN NH 0 wherein it is understood that one of the ring carbon atoms is substituted with
R
6 a-e g g Q , , or g g 5 respectively. With respect to the fatnesyl-protein transferase inhibitors of the formula II-m, the substituent illustrated by the structure represents a 4, 5, 6 or 7 membered heterocyclic ring which comprises 10 a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom attached to Y and includes the following ring systems: - 107 - WO 98/44797 PCT/US98/06823 00 nNN _N NNH O O S R 1 3 N 0 \X N H \NyNH O o\o 0\\ S O OS OS * N XI 0 o 0 0 0 _X-N N , N N It is understood that such rings may be substituted by R 6 a , R6b, R 6 c, R6d and/or R 6 e as defined hereinabove. With respect to the farnesyl-protein transferase inhibitors 5 of the formula II-m, the moiety described as
R
6 a-e where any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes, but is not limited to, 10 the following structures: - 108 - WO 98/44797 PCT/US98/06823 I I 0 ON O0 N 0 N NN 0 -N 0' , N >~N o I N0 0 It is understood that such fused ring moieties may be further substituted by the remaining R 6 a, R6b, R 6 C, R6d and/or R6e as defined hereinabove. 5 With respect to the farnesyl-protein transferase inhibitors of the formula II-m, the substituent illustrated by the structure represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, 10 and wherein Y is attached to Q through a carbon atom and includes the following ring systems: - 109 - WO 98/44797 PCT/US98/06823 N N N N N N H H NN N N\N-z N N N N )N NS 0 0 j\ H H - 110 / HNNH HNJ NH NH - C -110 - WO 98/44797 PCT/US98/06823 With respect to the farnesyl-protein transferase inhibitors of the formula II-n, the substituent illustrated by the structure represents a 4, 5, 6 or 7 membered heterocyclic ring which comprises 5 a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom attached to Y and includes the following ring systems: H O N O- 0 0 0 0 H ~ H0 S NR13 NR30 0 0 H O O O O o11 0 1 0 0 0 0 00 SN-f- N-- - N j O O O O N-S S 10 0 o - 111 - WO 98/44797 PCT/US98/06823 With respect to the farnesyl-protein transferase inhibitors of the formula II-n, the substituent illustrated by the structure represents a 5-, 6- or 7-membered carbocyclic ring wherein from 0 to 5 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems: NN NN N N ~~0 -112- WO 98/44797 PCT/US98/06823 H H NH N With respect to the farnesyl-protein transferase inhibitors of the formula II-n, the moiety described as 5
R
6a -e 5K where any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH= CH-CH-, -(CH2)4- and -(CH2)4- includes, but is not limited to, the following structures: /10 - 113 N >.N S S\ 0 s NI HN" NH HN NH \ NH With respect to the farnesyl-protein transferase inhibitors of the formula Il-n, the moiety described as R 6 a-e where any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes, but is not limited to, the following structures: 10 -113 WO 98/44797 PCT/US98/06823 zN ~II It is understood that such fused ring moieties may be further substituted by the remaining R 6 a, R6b, R 6 C, R6d and/or R 6 e as defined 5 hereinabove. When R 2 and R 3 are combined to form - (CH2)u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: 10 In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: "I I 00 H 0 1 CORi o 15 - 114 - WO 98/44797 PCT/US98/06823 When R 6 and R 7 , R 7 and R7a, or are combined to form (CH2)u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: 5 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. For example, such conventional non-toxic salts include those 10 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, 15 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. It is intended that the definition of any substituent or variable (e.g., R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, 20 N(RO10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set 25 forth below. - 115 - WO 98/44797 PCT/US98/06823 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 5 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 utility of a compound as an avp3 antagonist may be demonstrated by the methodology known in the art, such as the assays 10 described in WO95/32710, published 7 December 1995. The compounds of formula (II-h) can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following 15 works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid 20 Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. Also useful in exemplifying syntheses of specific unnatural amino acid residues are European Pat. Appl. No. 0 350 163 A2 (particularly page 51-52) and J. E. Baldwin et al. Tetrahedron, 50:5049-5066 (1994). With regards to the synthesis of instant compounds containing a (P 25 acetylamino)alanine residue at the C-terminus, use of the commercially available NX-Z-L-2,3-diaminopropionic acid (Fluka) as a starting material is preferred. Abbreviations used in the description of the chemistry and in the Examples that follow are: 30 - 116 - WO 98/44797 PCT/US98/06823 Ac20 Acetic anhydride; Boc t-Butoxycarbonyl; DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP 4-Dimethylaminopyridine; 5 DME 1,2-Dimethoxyethane; DMF Dimethylformamide; EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; HOBT 1-Hydroxybenzotriazole hydrate; 10 Et3N Triethylamine; EtOAc Ethyl acetate; FAB Fast atom bombardment; HOOBT 3-Hydroxy- 1,2,2-benzotriazin-4(3H)-one; HPLC High-performance liquid chromatography; 15 MCPBA m-Chloroperoxybenzoic acid; MsCl Methanesulfonyl chloride; NaHMDS Sodium bis(trimethylsilyl)amide; Py Pyridine; TFA Trifluoroacetic acid; 20 THF Tetrahydrofuran. The compounds are useful in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharma 25 ceutical chemist. i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and 30 flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combina tion with pharmaceutically acceptable carriers. Pharmaceutically acceptable salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from 35 non-toxic inorganic or organic acids. Non-toxic salts include those - 117 - WO 98/44797 PCT/US98/06823 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, 5 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. 10 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 farnesyl transferase inhibitors of formula (II-a) 15 through (II-c) can be synthesized in accordance with Schemes 1-22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R, R a and Rb, as shown in the Schemes, represent the substituents R 2 , R 3 , R 4 , and R 5 ; 20 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 25 reactions described in the Schemes. Synopsis of Schemes 1-22: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for 30 the most part. In Scheme 1, for example, the synthesis of 2-alkyl substituted piperazines is outlined, and is essentially that described by J. S. Kiely and S. R. Priebe in Organic Preparations and Proceedings Int., 1990, 22, 761-768. Boc-protected amino acids I, available commercially or by procedures known to those skilled in the art, can - 118 - WO 98/44797 PCT/US98/06823 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 dimethyl 5 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. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected 10 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; a final acid 15 deprotection as previously described gives the intermediate VIII (Scheme 2). The intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from 20 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 trifluoro 25 acetic 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 30 group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures. Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as 1-trityl-4 imidazolyl-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give - 119 - WO 98/44797 PCT/US98/06823 products such as XVI (Scheme 4). 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. Alternatively, the intermediate VIII can be 5 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 10 the presence of condensing reagents such as 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV. If 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 15 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. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated 20 (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines. The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8). Treating XXVII with 1,1'-sulfonyldiimidazole and sodium 25 hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleo phile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII. In addition, the piperazine VIII can be reacted with 30 aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX. When R' is an aryl group, XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL. - 120 - WO 98/44797 PCT/US98/06823 Alternatively, the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced. Depending on the identity of the amino acid I, various side chains can be incorporated into the piperazine. For example when I 5 is the Boc-protected -benzyl ester of aspartic acid, the intermediate diketopiperazine XLII where n=1 and R=benzyl is obtained, as shown in Scheme 10. Subsequent lithium aluminum hydride reduction reduces the ester to the alcohol XLIII, which can then be reacted with a variety of alkylating agents such as an alkyl iodide, under basic conditions, for 10 example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether XLIV can then be carried on to final products as described in Schemes 3-9. N-Aryl piperazines can be prepared as described in Scheme 11. An aryl amine XLV is reacted with bis -chloroethyl amine hydro 15 chloride (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 Boc-protected amino aldehydes XLIX 20 (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 25 trifluoroacetic 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 30 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 - 121 - WO 98/44797 PCT/US98/06823 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 5 in Scheme 14. Following deprotection with trifluoroacetic acid, the 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. 10 Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R 2 and R 3 are combined to form - (CH2)u -. For example, 1-aminocyclohexane-1-carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined 15 in Schemes 1 and 2. The piperazine intermediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9. It is understood that reagents utilized to provide the substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and 20 readily available to provide other N-substituents on the piperazine. 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 25 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. Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane 30 in methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII. Scheme 17 illustrates the use of an optionally substituted homoserine lactone LXXIX to prepare a Boc-protected piperazinone LXXXII. Intermediate LXXXII may be deprotected and reductively - 122 - WO 98/44797 PCT/US98/06823 alkylated or acylated as illustrated in the previous Schemes. Alternatively, the hydroxyl moiety of intermediate LXXXII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXXIII. Intermediate 5 LXXXII may also be oxidized to provide the carboxylic acid on intermediate LXXXIV, which can be utilized form an ester or amide moiety. Amino acids of the general formula LXXXVI which have a sidechain not found in natural amino acids may be prepared by the 10 reactions illustrated in Scheme 18 starting with the readily prepared imine LXXXV. Schemes 19-22 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies 15 for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art. - 123
-
WO 98/44797 PCT/US98/06823 SCHEME 1 0 Ra Rb O-N OH PhCH 2
NHCHCO
2
C
2
H
5 HO0 0 DCC,
CH
2
CI
2 0 >' OA N N yC02C 2
H
5 H 0 Rb II R
R
a 1) HCI, CH 2
CI
2 LAH HN N 2) NaHCO 3 HN N THF, reflux H 2)RNaHCO3 b 0 Rb/ III IV
R
a Ra Boc20O 10% Pd/C o
CH
2
C,
2 N N H 2
CH
3 OH O N NH Rb \/ Rb V - VI - 124 - WO 98/44797 PCT/US98/06823 SCHEME 2 EDC-HCI, HOBT
R
a DMF BocN NH Rb CO 2 H vib '
R
b Ra HCI, EtOAc BocN N V~o Rb VII Ra HCI - N N 0 Rb VIII - 125
-
WO 98/44797 PCT/US98/06823 SCHEME 3 Boc NH IX Ra / Boc NH CHO HCI -N N NaBH(OAc)3 -Rb 0 Et 3 N, CICH 2
CH
2 CI VIII Ra / CF 3 C00 2 H Boc NH N N - O CH 2
CI
2 NHBoc Rb X Ra Boc 2 0
NH
2 N N 0 CH 2
CI
2 NH2 Rb CH22 / CHO Ra a BocNH N N4 NaHOA b Et3N, CICH2CH2 NHI-2 R C XII - 126 - WO 98/44797 PCT/US98/06823 SCHEME 3 (continued) Ra BocNH N N - CF 3
CO
2 H, CH 2
CI
2 ; - NH Rb NaHCO 3 NH R b \/ xiii Ra
NH
2 N N NC - NH Rb AgCN A \/ xiv Ra N N Rb XV - 127 - WO 98/44797 PCT/US98/06823 SCHEME 4 Ra ~~~ _NaBH(OAc) 3 / \ Et 3 N , CICH 2
CH
2 CI HCI -N N (CH 2 )CHO Rb N VIII N Tr Ra
(CH
2 _N NO N CRb N XVI Tr 1) Ar CH 2 X, CH 3 CN CF3CO0 2 H, CH 2
CI
2 2) CF 3 CO2H ,
CH
2
CI
2
(C
2
H
5
)
3 SiH
(C
2
H
5
)
3 SiH R\/ NN N0 (H2)nl\ Rb N H XVII Ra N N Ar (/ H2) nN 1 N Rb N XVIII - 128 -xv - 128 - WO 98/44797 PCT/US98/06823 SCHEME 5
N-CH
2
CO
2 H NCH 2 CO2CH 3
CH
3 0H N HCI N H H HCI XIX XX N CH 2 C02CH 3 1) ArCH 2 X CH 3 CN
(C
6 Hs) 3 CBr reflux
(C
2 Hs) 3 N N 2) CH 3 OH, reflux DMF Tr XXI Ar - N
-CH
2
CO
2
CH
3 2.5N HCI N aq N 550C XXII Ar-- N_.CH 2
CO
2 H N XXII XXIll- 129 - 129- WO 98/44797 PCT/US98/06823 SCHEME 5 (continued) Ar . N CH 2
CO
2 H Ra/ N + HCI-HN N 0 XXIII Rb VIII EDC- HCI HOBt DMF HCI Ar Ra N N No N R b XXIV - 130 - WO 98/44797 PCT/US98/06823 SCHEME 6 NaBH(OAc) 3 Ra Et 3 N , CICH 2
CH
2 CI HCI -N N BnO
R
b O Rb BocNH CHO VIII XXV Ra BnO N N - 20% Pd(OH) 2
H
2 O CH 3 0H NHBoc Rb CH 3 C00 2 H XXVI Ra HO N N CICOCOCI HOO N N DMSO CH 2
CI
2 NHBoc Rb (C 2
H
5
)
3 N XXVII - 131 - WO 98/44797 PCT/US98/06823 SCHEME 6 (CONTINUED) Ra 1.R'MgX 0 N N (C 2
H
5
)
2 0 OK O 2. TFA, H NHBoc Rb
CH
2
CI
2 XXVIII Ra HO N N 0 R' NH 2 Rb XXIX - 132
-
WO 98/44797 PCT/US98/06823 SCHEME 7 R / \ CF 3 C0 2 H HO N N O
CH
2 CI2 NHBoc Rb XXVII SR'CHO HO N N NaBH(OAc) 3
NH
2 Rb CICH 2
CH
2 CI XXX Ra HO N N ~~Ko NH Rb /
R'CH
2 XXXI - 133 - WO 98/44797 PCT/US98/06823 SCHEME 8 H H N-- o=N Ra N N HO N N -02 0 bNaH, DMF O 0 C NHBoc Rb XXVII Ra\/ R'SH N N (C2H 5
)
3 N A b CH 3 OH N Rb H XXXII Ra R'S N N 0
NH
2 Rb XXXIII - 134 - WO 98/44797 PCT/US98/06823 SCHEME 9 HO HO 1) Boc 2 0, K 2
CO
3 "
THF-H
2 0
H
2 N C0 2 H 2) CH 2
N
2 , EtOAc BocNH C02CH 3 XXXIV XXXV HO LiAIH 4
R'CH
2 X THF?0 Cs 2 00 3 0-200C BocNH
CH
2 0H DMF XXXVI
R'CH
2 0
R'CH
2 0 pyridine - SO 3 DMSO (C2Hs)3N BocNH CH 2 OH 2 BocNH CHO 200C XXXVII XXXVIII - 135 - WO 98/44797 PCT/US98/06823 SCHEME 9 (continued)
R'CH
2 0 + HCI - N N BocNH CHO b Rb XXXVIII VIII NaBH(OAc) 3
CICH
2
CH
2 CI
R'CH
2 O N N 0 ~O NHBoc Rb XXXIX HCI ETOAc 1) 20% Pd(OH) 2
CH
3 OH, CH 3
CO
2 H Ra 2) HCI, EtOAc R
R'CH
2 0 N N 0
NH
2 Rb XXLI HO N N NH 2 Rb XL - 136 - WO 98/44797 PCT/US98/06823 SCHEME 10
CO
2 R n( )o 1) LAH, Et 2 0 HN N 2) Boc20 0 XLII
R
6 0 HO
R
6 1 ( ) o nNaH, DMF -N N 0 N~N 0O XLIV XLIII 5 SCHEME 11 ArNH 2 Ra Rb XLV + CI ) 2 NH HCI - butanol ArN NH HCI Ra XLVI reflux R a Rb XLVII - 137 - WO 98/44797 PCT/US98/06823 SCHEME 12 > R a 0 Ra N- O - - N. N(CH 3
)OCH
3 HO J N OH CH 3
NHOCH
3 - HCI O N(CH)OCH H O H O EDC. HCI, HOBT XLVIII I DMF, Et 3 N, pH 7 LAH, Et 2 0 Ra HArCH 2
NH
2 _O N H NaBH(OAc) 3 H O
CICH
2
CH
2 CI XLIX pH 6 0 R a 1) BrCH 2 COBr > o- N NHCH 2 Ar EtOAc, H 2 0, NaHCO 3 H 2) NaH, THF, DMF L Ra 0 1) TFA, CH2CI 2
R
a 0 Ar HN N- O0 Ar LI O - 138
-
WO 98/44797 PCT/US98/06823 SCHEME 13 ArCHO + NH 2
CH
2
CH(OC
2
H
5
)
2 NaBH(OAc) 3 LII LIII O
R
a Ar CH 2
NHCH
2
CH(OC
2
H
5
)
2 >"O" N "OH I H O LIV LIV EDC. HCI, HOBT DMF, Et 3 N, pH 7 O.. R a Ar 6N HCI SN N
CH(OC
2
H
5
)
2 THF H O LV Ra 0 O O
H
2 10%Pd/C -N N CH 3 OH O Ar LVI
R
a 0 - N O \Ar LVII - 139 - WO 98/44797 PCT/US98/06823 SCHEME 14 Rb 1) CF 3
CO
2 H, CH 2
C
2 N NH ArCO 2 H V ,. ,-N NH 2)NaHCO 3 - EDC HCI \ / Ra HOBT, DMF LVIII Rb Rb N N 10% Pd / C HN R N4 HN N4 - Ra Ar H 2
CH
3 OH Ar
/R
a LIX LX L- 140X - 140 - WO 98/44797 PCT/US98/06823 SCHEME 15 u PhCH 2
NHCH
2
CO
2
C
2
H
5 DCC, CH 2
CI
2 BocNH CO 2 H LXI u a) TFA, CH 2
C
2 b) NaHC03 BocNH N
CO
2
C
2 H b) NaHCO 3 O LXII u\
H
2 O (CH 3
)
3 AI HN N sC22Hs S0CHCI 3 LXIII HN N LiAIH 4 HN N >HN N O' / THF LXIV LXV u Boc20 BocN N- H 2 Pd/C
CH
2
CI
2
CH
3 OH LXVI - 141 - WO 98/44797 PCT/US98/06823 SCHEME 15 (continued) coCI BocN NH NaHCO 3 EtOAc LXVII U O a) TFA, CH 2
CI
2 BocN N b) NaBH(OAc) 3 _ / / C(=O)H LXVIII N CPh 3 U 0 /\ O N HN TFA CH 2
C
2 /N\/ (C 2
H
5
)
3 SiH N Ph 3 LXIX U 0 NN \ N N/\/ N H *2 TFA LXX - 142 - WO 98/44797 PCT/US98/06823 SCHEME 16 R R ArNH 2 H BocNH CHO ArNBocNH Ar NaBH(OAc) 3
CICH
2
CH
2 CI XLIX LXXI O R CI "CI BocNH N-Ar EtOAc / H 2 0 NaHCO 3 CI O LXXII R NaH HCI BocN N-Ar DMF EtOAc O LXXIII - 143 - WO 98/44797 PCT/US98/06823 SCHEME 16 (continued) CHO R R N HCI-HN N-Ar C(Ph) 3 N N-Ar 0 NaBH(OAc) 3 N LXXIV CICH 2
CH
2 CI (Ph) 3 LXXIV pH56(Ph)3C pH 5-6 LXXV R Ar---- N -N N-Ar ArCH 2 X N
CH
3 CN O N e (Ph) 3 C X LXXVI R MeOH or Ar---\ N N-Ar TFA, CH 2 CI O
(C
2 Hs) 3 SiH N LXXVII - 144 - WO 98/44797 PCT/US98/06823 SCHEME 17 sub sub sub 1. Boc20, i-Pr 2 EtN s
H
2 N 2. DIBAL BocHN \ HCI O OH LXXIX OH sub ArNH 2 H ArNH 2 BocNH N ,Ar NaBH(OAc) 3
CICH
2
CH
2 CI LXXX HO sub o WF CI-" CI BocNH N-Ar EtOAc / H 2 0 NaHCO 3 CI O LXXXI HO sub Cs 2 00 3 S BocN N-Ar DMF O LXXXII - 145 - WO 98/44797 PCT/US98/06823 SCHEME 17 (continued) HO sub BocN N-Ar 0 1. (COCI)2, Et 3 N DMSO 1. MsCI, iPr 2 NEt LXXXII DM 2. NaCIO 2 , t-BuOH 2. NaSEt, DMF 2-Me-2-butene NaH 2
PO
4 EtS sub HO sub 0 BocN N-Ar BocN N-Ar 0 O LXXXIII LXXXIV - 146 - WO 98/44797 PCT/US98/06823 SCHEME 18 1. KOtBu, THF R 2
S/-CO
2 Et R 2 X >- CO 2 Et N H 2 N Ph 2. 5% aqueous HCI HCI LXXXV 1. Boc20, NaHCO 3
R
2
-CO
2 H BocHN 2. LiAIH 4 , Et 2 0 LXXXVI - 147 LXXXVI - 47 - WO 98/44797 PCT/US98/06823 REACTION SCHEME 19
CH
3 1) HNO 2 ,Br 2 CO 2
CH
3 C 2) KMnO 4
H
2 N N 3) MeOH,H' Br N R MgCI R0 2
H
3 ZnCI 2 ,N iCI 2 (Ph 3
P)
2
R
6 NaBH 4 (excess) CH 2 OH N
R
6
SO
3 Py, Et 3 N CHO DMSO N - 148 - WO 98/44797 PCT/US98/06823 REACTION SCHEME 20 1. EtO(CO)CI R 6 2.
R
6 Br MgCI COC/CO2CH 3 050 2 0H 3 Zn, CuCN 0 2
H
3 N 3. S, xylene, heat N
R
6
R
6 NaBH 4
SO
3 "Py, Et 3 N (excess) CH 2 OH DMSO CHO N N N
R
6 R 6
R
6 Br CO 2
CH
3 MgCI N / C0 2
CH
3 ZnCI 2 , NiCI 2 (Ph 3
P)
2 N
R
6
R
6 NaBH 4 SO 3 "Py, Et 3 N
SCH
2 OH CHO (excess) DMSO N N - 149 - WO 98/44797 PCT/US98/06823 REACTION SCHEME 21
CO
2
CH
3 Br 1. LDA, CO2 Br N 2. MeOH, H' N R6 R6 MgCI C2CH3 ZnCI 2 , NiCI 2 (Ph 3
P)
2 N
R
6 NaBH 4 (excess) CH 2 OH SO 3 "Py, Et 3 N DMSO N
R
6 CHO N - 150 - WO 98/44797 PCT/US98/06823 REACTION SCHEME 22
CO
2
CH
3 1. LDA, 00 2 Br N Br N 2. (CH 3
)
3 SiCHN 2
R
6 < Br R6 "N 0CO0H3 Zn, NiCI 2 (Ph 3
P)
2 N 0 2
H
3 R6 excess NaBH 4 SO 3 "Py, Et 3 N
CH
2 OH DMSO N DMSO R6 I N CHO The farnesyl transferase inhibitors of formula (II-d) can 5 be synthesized in accordance with Schemes 23-36, 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 - 151 - WO 98/44797 PCT/US98/06823 experimental procedures. Substituents R 2 , R 6 and R 8 , as shown in the Schemes, represent the substituents R 2 , R 3 , R 4 , R 5 , R6a, R6b, R 6 C, R6d and R 8 ; although only one such R 2 , R 6 or R 8 is present in the intermediates and products of the schemes, it is understood that the 5 reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents. The compounds referred to in the Synopsis of Schemes 23-36 by Roman numerals are numbered starting sequentially with I and ending with XXV. These reactions may be employed in a linear sequence 10 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 Schemes. Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon 15 Press (1995). Synopsis of Schemes 23-36: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the 20 most part. Schemes 23-35 illustrate synthesis of the compounds of the formula II-d which incorporate a preferred benzylimidazolyl sidechain. In Scheme 23, for example, a biaryl intermediate that is not commer cially available may be synthesized by methods known in the art. Thus, a suitably substituted phenyl boronic acid I may be reacted under Suzuki 25 coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4-bromobenzoic acid, to provide the biaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after 30 deprotection, the instant compound V. Schemes 24-27 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 23. Thus, Scheme 24 illustrates the analogous series of biaryl alcohol forming reactions starting with the halogenated biarylaldehyde. - 152 - WO 98/44797 PCT/US98/06823 Scheme 25 illustrates the reaction wherein the "terminal" phenyl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as 5 illustrated in Scheme 26. Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biaryl component of the instant compounds, as shown in Scheme 27. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted aryl halide in the presence of 10 nickel (II) to provide the biaryl VII. The aryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents. Scheme 28 illustrates the preparation of a suitably substituted biphenylmethyl bromide which could also be utilized in 15 the reaction with the protected imidazole as described in Scheme 1. As illustrated in Scheme 29, the sequence of coupling reactions may be modified such that the biphenyl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII. 20 Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid. Scheme 30 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole IX may be selectively 25 iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove. Scheme 31 illustrates synthesis of instant compounds that 30 incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkyl imidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well - 153 - WO 98/44797 PCT/US98/06823 known in the art with various activated biaryl moieties to provide the instant compounds shown. Compounds of the instant invention wherein the A 1 (CR 1 a2)nA 2 (CR la2)n linker is oxygen may be synthesized by 5 methods known in the art, for example as shown in Scheme 32. The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV. After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described 10 for the benzylimidazoles hereinabove. Scheme 33 illustrates an analogous series of reactions wherein the (CRlb2)pX(CRlb2)p linker of the instant compounds is oxygen. Thus, a suitably substituted haloaryl alcohol, such as, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. 15 Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a second aryl moiety by Suzuki chemistry to provide the instant compound. Compounds of the instant invention wherein the 20 A1 (CR1a2)nA 2 (CRl1a2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 34. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above 25 (in particular, Scheme 23) provides the instant compound XX. If other R1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Grignard chemistry may also be employed to form a substituted alkyl linker between the biaryl and the preferred W 30 (imidazolyl) as shown in Scheme 35. Similar substituent manipulation as shown in Scheme 34 may be performed on the fully functionalized compound which incorporates an R l b hydroxyl moiety. Scheme 36 illustrates reactions wherein the moiety - 154 - WO 98/44797 PCT/US98/06823
(R
8 ) R9 V - A'(CR 1 a 2 )nA 2 (CRla 2
)
n - (CRb 2 )p-X. incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group. Thus, the intermediates whose synthesis are illustrated in 5 Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid 10 (Scheme 14). Grignard chemistry may be utilized, as shown in Scheme 36, to incorporate the biaryl moiety. Thus, a suitably substituted biaryl Grignard reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then 15 deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be 20 reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures. Incorporation of other moieties via the appropriate aldehyde starting material may be performed as illustrated in Scheme 36 25 and the intermediates manipulated as illustrated above in Schemes 4-9. - 155
-
WO 98/44797 PCT/US98/06823 SCHEME 23 -R6
(HO)
2 B R HO
R
2 Pd(PPh 3
)
4 O R 6 LiAIH 4 HO
R
2 HO. I
R
2 III - 156 - WO 98/44797 PCT/US98/06823 SCHEME 23 (continued) Tr Tr N NiCI 2 (PPh 3
)
2 N N ZnBr \
R
8 /
R
8 IV R6
(CF
3
SO
2
)
2 0, -78-C HO \ R NEtiPr 2 -78C-20 R2 2qI, _78oC-20oC
CH
2
CI
2 rN RR N R6
R
2 /w V
R
8 - 157 - WO 98/44797 PCT/US98/06823 SCHEME 24 (HO)2B R N 2 Pd(PPh 3
)
4 O R2 R 2 O 0 NaBH 4 R6 HO \
R
2 5 SCHEME 25
B(OH)
2 B R6 Br MeO '
R
2 Pd(PPh 3
)
4 O 6 6 MeO LiAIH 4 R o R HO R2 - 158 - WO 98/44797 PCT/US98/06823 SCHEME 26 B(OH) 2 - R 6
R
3 SiO Br
R
2 Pd(PPh 3
)
4
R
6 IBu 4 NF
R
3 SiO
R
2
R
6 HO
R
2 Br R 3 SiO B r (HO) 2
B
R
R
2 Pd(PPh 3
)
4 Bu 4 NF
R
3 SiO
R
2 R6 HO\
R
2 159 - WO 98/44797 PCT/US98/06823 SCHEME 27 I -R6
R
3 SiO BrZn
R
2 NiCI 2 (PPh 3
)
2 R 6 R3SO Bu 4 NF
R
3 SiO\
R
2 R 6 VII HO\
R
2 Znl R6
R
3 SiO Br
R
2 NiC 2 (PPh 3
)
2 R6 Bu 4 NF
R
3 SiO
R
2 HO
R
2 160 - WO 98/44797 PCT/US98/06823 SCHEME 28 -L 6 R6 NBS, AIBN
H
3 C R 2 CC1 4 B
R
2 5 SCHEME 29 R2 T Br I L. N ii. MeOH reflux
R
8 N I (HO) 2 B Pd(PPh 3
)
4 R8 VIII
R
6 N R2 R8 -161 - WO 98/44797 PCT/US98/06823 SCHEME 30 H H N N R9 b Nal, NaHCO 3 ,12 R9b TrCI, NEt a , bII IX X Ix x Tr T N NI
R
9 b
R
9 b NiCl 2 (PPh 3
)
2 RN N ZnBr
R
8
R
8 R R6 Tr N
R
9 b N bR2 OTf i. -780C-20OC R ii. MeOH, reflux
R
8 R XI N..< " R6 N
R
9 b N\ RR' R2 - 162 - WO 98/44797 PCT/US98/06823 SCHEME 31 O0 ( i. Br NO 0 55oC,CH 3 CN N N ii. EtOH,80°C, NH 2
NH
2 O XII N N
NH
2
R
8 XIII N acylation, sulfonylation O R2 ----------- NR or alkylation N N N R8- H NI 0 06 </\ N/ R2 R6
NR
6 <- 163 N N RH I -163- WO 98/44797 PCT/US98/06823 SCHEME 32 \ OH i, Na, MeOH NC ii. 1200C XlV H3C o H Tr N TrCI, NEt 3 , N NC O NC XV XVI /R6 T R2 N i. -780C-200C N + ii. MeOH reflux NC O OTf XVI R jp-R 6 R2 N NC NC O - 164 - WO 98/44797 PCT/US98/06823 SCHEME 33 H IN BrOH i,Na, MeOH N Br ii. 1200C / \ 0
R
2 H3C- Br-\
R
2 XVI N "
R
8 TrCI, NEt 3 IN OTf I i. -780C-20°C Br O ii. MeOH reflux Br
R
2
B(OH)
2
R
8 Br O DMF, Pd(PPh 3
)
4
K
3
PO
4 , 8000
R
2 XVII
R
8 R/6 0
R
2 - 165 - WO 98/44797 PCT/US98/06823 SCHEME 34 Tr Tr N S EtMgBr N N O O 0 OH XVIII R8 R8 XIX
-
R
6 Tr N HO AC20, py N R 2 Ac
(CF
3
SO
2
)
2 0, -780C R8 NEtiPr 2
,CH
2
CI
2 R 6 N LiOH R 2 OAc
R
8 XX R 6 N-1 N
SOCI
2 R2 OH R 8 - 166 - WO 98/44797 PCT/US98/06823 SCHEME 34 (continued)
R
6 N1 N \R NH 3 , MeOH HNR2 Cl
R
8 +6 NN N R2 NH2 R8 R 6 R2 j OMe R6 - 167 - WO 98/44797 PCT/US98/06823 SCHEME 35
R
6 <I BrMg N R'
R
6 0
R
8 - 168 OH R8 - 168 - WO 98/44797 PCT/US98/06823 SCHEME 36
R
6 Boc NH R Boc NH CHO BrMg
R
2 R6 1. catalytic HO / hydrogenation Boc NH 2. CF 3
CO
2 H C0H 2 C1 2 NHBoc XXI R 2
R
6 Boc20
NH
2 CH2CI2
NH
2 XXII
R
2
R
6 CHO BocNH NaBH(OAc) 3
NH
2 Et 3 N , CICH 2
CH
2 C XXIII - 169 - WO 98/44797 PCT/US98/06823 SCHEME 36 (continued)
R
2 R6 BocNH~
CF
3
CO
2 H, CH 2 C1 2 ; - NH NaHCO 3 / \/ XXIV R 2
NH
2 NC - NH AgCN A
R
2 R6 NN XXV The farnesyl transferase inhibitors of formula (II-e) can 5 be synthesized in accordance with Schemes 37-52, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R 2 , R 6 and R 8 , as shown in - 170
-
WO 98/44797 PCT/US98/06823 the Schemes, represent the substituents R 2 , R 3 , R 4 , R 5 , R 6 and R 8 ; although only one such R 2 , R 6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple 5 substituents. The compounds referred to in the Synopsis of Schemes 37-52 by Roman numerals are numbered starting sequentially with I and ending with XXV. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to 10 synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. Aryl-aryl coupling 15 is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995). Synopsis of Schemes 37-52: 20 The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 37-51 illustrate synthesis of the instant arylheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 37, for example, a 25 arylheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted pyridyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4-bromobenzoic acid, to provide 30 the arylheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V. Schemes 38-41 illustrate other methods of synthesizing - 171
-
WO 98/44797 PCT/US98/06823 the key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 38 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the halogenated arylaldehyde. 5 Scheme 39 illustrates the reaction wherein the "terminal" heteroaryl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 40. 10 Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 41. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted aryl halide in the presence of nickel (II) to provide the arylheteroaryl VII. The 15 heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents. Scheme 42 illustrates the preparation of the suitably substituted arylheteroaryl methanol from the pyridyltoluene. Scheme 43 illustrates the preparation of the suitably 20 substituted pyrazinylaryl methanol starting with alanine. As illustrated in Scheme 44, the sequence of coupling reactions may be modified such that the arylheteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide 25 intermediate VIII. Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted heteroaryl boronic acid. Scheme 45 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole IX may be selectively 30 iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove. - 172 - WO 98/44797 PCT/US98/06823 Scheme 46 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the arylhetero aryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4 aminoalkylimidazole XII, wherein the primary amine is protected as 5 the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown. Compounds of the instant invention wherein the 10 A1 (CR 1 a2)nA 2 (CRl1a2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 47. The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV. After selective protection of one of the imidazolyl nitrogens, the 15 intermediate XVI can undergo alkylation reactions as described for the phenylmethylimidazoles hereinabove. Scheme 48 illustrates an analogous series of reactions wherein the (CRlb2)pX(CRlb 2 )p linker of the instant compounds is oxygen. Thus, a suitably substituted haloaryl alcohol, such as 4 20 bromophenol, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the 25 instant compound. Compounds of the instant invention wherein the Al(CRla2)nA 2 (CRla2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 49. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a 30 suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 37) provides the instant compound XX. If other
R
1 substituent s are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. - 173 - WO 98/44797 PCT/US98/06823 Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the arylheteroaryl and the preferred W (imidazolyl) as shown in Scheme 50. Thus a halogenated arylheteroaryl, such as 4-(3-pyridyl)bromo 5 benzene, may undergo metal halogen exchange followed by reaction with a suitably substituted imidazolyl aldehyde and acteylation to form the alcohol. Then, similar substituent manipulation as shown in Scheme 49 may be performed on a fully functionalized compound which incorporates an R 2 hydroxyl moiety. 10 Scheme 51 illustrates the synthesis of a suitably substituted pyrimidinebromobenzene, which may be employed in the reaction illustrated in Scheme 49. This reaction and other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. 15 Sammes, Oxford (1979). Schemes 52 illustrates reactions wherein the moiety (R 8 )r V -A'(CR1a 2 )nA2(CRla 2 )n W -(CRb2)p-X. t incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group. 20 Thus, the intermediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in 25 Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid. Metalation chemistry may be utilized, as shown in Scheme 52, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl lithium reagent, prepared in situ, is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound 30 XXI can be deoxygenated by methods known in the art, such as a - 174 - WO 98/44797 PCT/US98/06823 catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The 5 product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures. 10 Incorporation of other moieties via the appropriate aldehyde starting material may be performed as illustrated in Scheme 52 and the intermediates manipulated as illustrated above in Schemes 4-9. SCHEME 37 15 R R6
(HO)
2 B N HO HO2 Pd(PPh 3
)
4 0 6 N LiAIH 4 HO 0 11e
R
2 N HO0 III - 175 - WO 98/44797 PCTIUS98/06823 SCHEME 37 (continued) Tr T NiCI 2 (PPh 3
)
2 N ZnBr /:\ R8 IV N- N (CF 3 S0 2
)
2 0, -780C HO NEtiPr 2 ~ 8C2o R 2 C~H 2 01 2 -8C20 N-N NN R 2 55-C, CH 3 0H
R
8 R N NN x V - 176- WO 98/44797 PCT/US98/06823 SCHEME 38 6R R6 /l I (HO)2B 'A -- Y 2 Pd(PPh 3
)
4
R
2 O O 0 N NaBH 4 N HO \
R
2 5 SCHEME 39 B(OH) 2 R MeO, Br
R
2 Pd(PPh 3
)
4 O N TR RLiAIH 4 MeO
HO
N - -- R HO
R
2 - 177 - WO 98/44797 PCT/US98/06823 SCHEME 40
B(OH)
2 R
R
3 Sio Br R 2 Pd(PPh 3
)
4 R3i
BU
4 NF
R
3 SR2 H O , R 2 Br R
R
3 SiO I
(HO)
2 B "I R2 Pd(PPh 3
)
4 N
BU
4 NF
R
3
SIO"
HO -178 - WO 98/44797 PCT/US98/06823 SCHEME 41
R
3 SiO IBrZn R 2 NiCI 2 (PPh 3
)
2 N
R
3 SiO BUN HO ZnI R 6 R 3 SB r I B R3SiO " R 2NiCI 2 (PPh 3
)
2 N6
R
3 SiO UN N6 HO, -179- WO 98/44797 PCT/US98/06823 SCHEME 42 N R 6 KMnO 4
H
3 C
R
2 N R LiAIH 4 HO O
R
2 N -r-R HO
R
2 180 - WO 98/44797 PCT/US98/06823 SCHEME 43 C0O2CH 3
NH
3
CONH
2
H
3 C-1 NH 2 EtOH H 3 C NH 2 '0 OH O, C 3 POCI, NaOH N OH H 2 SO4
CH
3 Nal/HI N
H
3 "CNN O Cl N:C1 6 H H 3 aC N
B(OH)
2 N NaBH 4 Pd(OAc) 2 H O
R
2 H3C HO
R
2 - 181 - WO 98/44797 PCT/US98/06823 SCHEME 44
R
2 Tr IX N Br N ii. MeOH reflux R 8 R 6 N
(HO)
2 B 2 Pd(PPh 3
)
4 R26
R
8 VIII N - \N N R 2 R8X - 182- WO 98/44797 PCT/US98/06823 SCHEME 45 H H
R
9 b \N Nal, NaHCO 3 , -I R 9 b \N Tr~l, NEt, 3 Ix x Tr Tr R <Nb NiC1 2 (PPh 3
)
2 N~ ZnBr f Nf N
R
9 b OTf i. -780'C-200C R8 ii. MeOH, reflu x X1 R 9 b f -183- WO 98/44797 PCT/US98/06823 SCHEME 46 O Si. R Br N I\ 55 0
C,CH
3 CN N N ii. EtOH,80 0 C, NH 2
NH
2 0 XII N N N H 2 XIII ×111 N acylation, sulfonylation < / 0 R2
---------
or alkylation RN. H ' R8- H N 0f fN R6 'S/ R 2
R
6 N N s R8- H f f N f\R6 N N Rka H R6 - 184 - WO 98/44797 PCT/US98/06823 SCHEME 47 \...OH i, Na, MeOH NC ii. 1200C XlV H 3 C 0 N N H Tr N TrCI, NEt 3 N NC O NC O XV XVI f R Tr 2 f N f i. -780C-200C N + ii. MeOH reflux NC O OTf XVI f
R
6
R
2 ff N
NC
O - 185 - WO 98/44797 PCT/US98/06823 SCHEME 48 H N B OH i, Na, MeOHN B ii. 120C /0\"
IIA
R
2
H
3 C- Br N /R 2 XVI N\
N
8 Tr TrCI, NEt 3 NN OTf i. -78OC-20°C B O ii. MeOH reflux B R2 R8 f B (O H )2 NR6 f Br /o DMF, Pd(PPh 3
)
4 -- K 3 P0O 4 , 800C
R
2 XVII
R
8 f-fo f.A\
R
6 f f
R
2 - 186
-
WO 98/44797 PCT/US98/06823 SCHEME 49 Tr, TrN EtMgBr N IN OH XVIII RR8 XIX Tr R6 NHO / ~ OAc (0F 3 S0 2
)
2 0,-7C R8 NEtiPr 2 ,0H 2 C1 2 N-:1 f LiOH N OHc N ,z 187 - O2 WO 98/44797 PCT/US98/06823 SCHEME 49 (continued) f f f
R
6 \
NH
3 , MeOH R2 Cl
R
8 -R6 N-f f N R2
NH
2 R8 + f ff R6 \ 2 S OMe R 8 - 188 - WO 98/44797 PCT/US98/06823 SCHEME 50
R
6 R2 f -f/f f BuLi f. -100°0 Br N N 0R6 R 6 O2f f R6 2 f f/f R 1 Rf RN R IX N Li OH
R
8 5 SCHEME 51
R
2
HCONH
2
CH
3 Br
R
2 N ICN Br - 189 - WO 98/44797 PCTIUS98/06823 SCHEME 52 R6 Boc NH R2 f II Boc NH'CHO Li' R2 f. f R6 1. catalytic f-~ hydrogenation
CH
2 C1 2 NHBoc XXI R2 f==fR 0H 2 01
NH
2 XXIv R2 fy R 6 CHO V;If BocNH ff_______ NaBH(OAC) 3
NH
2 Et 3 N , CICH 2
CH
2 CI XXIII - 190- WO 98/44797 PCT/US98/06823 SCHEME 52 (continued)
R
2 /=l=' f= f.,. R 6 BocNH // \ f BocNH- Rff CF 3
CO
2 H, CH 2
C
2 ; - NH NaHCO 3 / \/ XXIV
R
2 NH2f=f
R
6 \f-f - NH AgCN A
R
2 -I- f=f R 6 f-f R N9N lXXV The farnesyl transferase inhibitors of formula (II-f) can 5 be synthesized in accordance with Schemes 53-66, 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 3 , R 6 and R 8 , as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R 6 a, R6b, R 6 c, R6d, - 191 - WO 98/44797 PCT/US98/06823
R
6 e and R 8 ; although only one such R 3 , R 6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents. The compounds referred to 5 in the Synopsis of Schemes 53-66 by Roman numerals are numbered starting sequentially with I and ending with XXX. 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 10 reactions described in the Schemes. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. 15 Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995). Synopsis of Schemes 53-66: 20 The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 53-64 illustrate synthesis of the instant arylheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 53, for example, a 25 arylheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromonicotinic acid, to provide 30 the arylheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V. Schemes 54-55 illustrate other methods of synthesizing - 192 - WO 98/44797 PCT/US98/06823 the key alcohol intermediates, which can then be processed as described in Scheme 53. Thus, Scheme 54 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" phenyl moiety employed 5 in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 55. Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant 10 compounds, as shown in Scheme 56. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the arylheteroaryl VII. The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents. 15 Scheme 57 illustrates the preparation of a suitably substituted 3-hydroxymethyl-5-phenyl pyridine which could also be utilized in the reaction with the protected imidazole as described in Scheme 53. An Alternative preparation of a suitably substituted 5-hydroxymethyl-2-phenyl pyridine is also illustrated. 20 As illustrated in Scheme 58, the sequence of coupling reactions may be modified such that the aryl-heteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII. Intermediate VIII can then undergo Suzuki type coupling to a suitably 25 substituted phenyl boronic acid. Scheme 59 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then 30 be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove. Scheme 60 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the - 193 - WO 98/44797 PCT/US98/06823 biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well 5 known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown. Compounds of the instant invention wherein the
A
1 (CR12)nA 2 (CR12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 61. 10 The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV. After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove. 15 Scheme 62 illustrates an analogous series of reactions wherein the (CR 2 2)pX(CR 2 2)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as 3-chloro-2 pyridinol, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to 20 form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a aryl moiety by Suzuki chemistry to provide the instant compound. Compounds of the instant invention wherein the A 1
(CR
1 2)nA 2 (CR 12)n linker is a substituted methylene may be 25 synthesized by the methods shown in Scheme 63. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 53) provides the instant compound XX. If other 30 R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in - 194 - WO 98/44797 PCT/US98/06823 Scheme 64. Thus a sutiably substituted phenyl lithium can be reacted with pyridine to form the 2-substituted N-lithio-1,2-dihydropyridine XXa. Intermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation 5 as shown in Scheme 63 may be performed on the fully functionalized compound which incorporates an R 2 hydroxyl moiety. Scheme 65 illustrate reactions wherein the moiety
(R
8 )r V - A'(CR2)nA(CR2 n - (CR 1 2 )p-X t incorporated in the compounds of the instant invention is represented by 10 other than a substituted imidazole-containing group. Thus, the intermediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such 15 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. Lithioheteroaryl chemistry may be utilized, as shown in Scheme 65, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl N-lithio reagent is reacted with an aldehyde to provide 20 the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, 25 hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by 30 literature procedures. - 195 - WO 98/44797 PCT/US98/06823 If the arylheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 66, the protecting groups can be subsequently removed to unmask the hydroxyl group. The alcohol can be oxidized under 5 standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as alkyl lithium reagents, to obtain secondary alcohols such as XXX. Incorporation of other moieties via the appropriate aldehyde starting material may be performed as illustrated in Scheme 10 65-66 and the intermediates manipulated as illustrated above in Schemes 4-9. SCHEME 53 N I (HO) 2 B R6 HO 2 Pd(PPh 3
)
4 0 H O 0 NR6 N HO OII N..--' R 6 HO, " v
R
2 15 III - 196 - WO 98/44797 PCTIUS98/06823 SCHEME 53 (continued) Tr Tr NiCI 2 (PPh 3
)
2 N / ZnBr R 8 /~ R8 IV :N (CF 3
SO
2
)
2 0, -78-C HO2 NEtiPr 2 -780C-200C 0H 2 C1 2 TrR6 R 2 55 0 C, CH 3 0H NN ~ 4R6 V - 197- WO 98/44797 PCT/US98/06823 SCHEME 54 N B(OH) 2 R6 "'N, MeO ', 2Pd Br oR2 Pd(PPh 3
)
4 N MO R LiAIH 4 MeO L- R6 N R HO0 R2 - 198- WO 98/44797 PCT/US98/06823 SCHEME 55 N B(OH) 2 BrR
R
3 SiO IB R2 Pd(PPh 3
)
4
..R
6 N BU4NF
R
3 SiO
R
2 HO
R
3 SiO Br (HO) 2 B ~R R2 Pd(PPh 3
)
4 N BU 4 NF
R
3 SR2 HON - 199- WO 98/44797 PCTIUS98/06823 SCHEME 56 N 1 R
R
3 iOI BrZn R 2 NiCI 2 (PPh 3
)
2 N R
BU
4 NF
R
3 SiO" 1 NR HO0 R 2 N TZnI R
R
3 SiO Br R2 Ni01 2 (PPh 3
)
2 N I R - BU 4 NF
R
3 SiO R N R. -200 - WO 98/44797 PCT/US98/06823 SCHEME 57 6 R HR 6
H
3 1. KMnO 4 HO N 2 2. LiAIH 4 R R 2 N Br R6 (HO)2B KMnO 4
H
3 R 2 Pd(PPh 3
)
4 N R6 LiAIH 4
R
2 H0 2 R 6 HO-2
R
2 - 201 WO 98/44797 PCT/US98/06823 SCHEME 58
R
2 TN Br N ii. MeOH reflux
R
8
R
6
NIN(HO)
2 B Pd(PPh 3
)
4 Ra / VIII N R2 RR - 202 - WO 98/44797 PCT/US98/06823 SCHEME 59 H H ~9b N~Nal, NaHCO 3 , 1R 9 b <N rlN Nrl N ~ t ix x Tr N R 9 b ~i R 9b NiC1 2 (PPh 3
)
2 N I Zn Br R R 9 b N OTf i. -780'C-200C Ra;< ii. MeOH, reflux R R9b N~ R - 203 - WO 98/44797 PCT/US98/06823 SCHEME 60 0 O i. RBr O<\ 55 0
C,CH
3 CN N N ii. EtOH,80°C, NH 2
NH
2 0 O~ XII N N V NH 2
R
8
-<
-
\ XlII acylation, sulfonylation R 2 N N or alkylation RN. N NN R8 H N R 6 N N HX
R
6 - 204 - WO 98/44797 PCT/US98/06823 SCHEME 61 \OH i, Na, MeOH NC ii. 120 0 C XlV H3Co KN NN H Tr N \N N TrCI, NEt 3 N NC O NC( O XV XVI / R 6 Tr 2 1 RN Ni .-78°C-20C N N ii. MeOH reflux N OTf XVI /R6
R
2 N N
NC
O -205 - WO 98/44797 PCT/US98/06823 SCHEME 62 H N\OH INa, MeOH IN N Cl ii. 1200eO N
R
2
H
3
C
o CI J '
R
2 XVI NN N
R
8 Tr TrCI, NEt 3 , OTf N / i. -780C-200C / \ 0 ii. MeOH reflux
C
R
2 8 B(OH) 2 N N R6 R6 C O DMF, Pd(PPh 3
)
4
K
3
PO
4 , 80°C
R
2 XVII
R
8 /\ 0 -0 R OI
R
2 - 206 - WO 98/44797 PCT/US98/06823 SCHEME 63 Tr TrN S EtMgBr N OH XVIII R8 R xX XR6 Tr N R N HO AC20, py _N R2 Ac (0F 3
SO
2
)
2 0, -78°C R8 NEtiPr 2
,CH
2
CI
2 R'R N N LiOH R 2 OAc
R
8 XX L 6 N R N R2 SOCI 2 OH R2 207 - WO 98/44797 PCT/US98/06823 SCHEME 63 (continued)
--
6 N N R2 Cl
NH
3 , MeOH
R
8 N': NR NN R2
NH
2 N N R2 OMe
R
8 - 208 - WO 98/44797 PCT/US98/06823 SCHEME 64
R
6 H _ __Li N -/ N Li
R
6 N N RR R7 Na N N\ OH
R
8 - 209 - WO 98/44797 PCT/US98/06823 SCHEME 65 Boc NH H N Boc NH CHO II
R
6
R
6 1. catalytic -H hydrogenation N /2. CF3CO2H HO
CH
2
CI
2 Boc NH NHBoc XXI
R
6
NH
2 CH2C 2
NH
2 XXII
R
6 CHO .N BocNH NaBH(OAc) 3
NH
2 Et 3 N , CICH 2
CH
2 CI XXIII - 210 - WO 98/44797 PCT/US98/06823 SCHEME 65 (continued) -N -R 6 BocNHL
CF
3
CO
2 H, CH 2
CI
2 ; - NH NaHCO 3 \/ XXlV -N -R 6
NH
2 NC - NH AgCN & N . R 6 N N Ixxv - 211 - WO 98/44797 PCT/US98/06823 SCHEME 66 I H N Et 2 0 L~i 6 BnO BocNH CHO XXVI BnO HO -N - R6 20% Pd(OH) 2
H
2
\CH
3 0H NHBoc
CH
3 CO2H
R
2 HO -:N R6 CICOCOCI DMSO
CH
2 Cl 2 NHBoc
(C
2
H
5
)
3 N NHBoc XXVIl - 212 - WO 98/44797 PCT/US98/06823 SCHEME 66 (continued)
R
2 - N
-
R
6 0 / R'MgX H NHBoc XXIX
R
2 -IN R 6 HO R' R' NHBoc XXX The farnesyl transferase inhibitors of formula (II-g) can be synthesized in accordance with Schemes 67-78, in addition to other 5 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 3 , R 6 and R 8 , as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R 6 and R 8 ; although only one such R 3 , R 6 or R 8 is present in the intermediates and products 10 of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents. The compounds referred to in the Synopsis of Schemes 67-78 by Roman numerals are numbered starting sequentially with I and ending with XX. 15 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 Schemes. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other 20 reactions useful in the preparation of heteroaryl moieties are described - 213 - WO 98/44797 PCT/US98/06823 in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, 5 Pergamon Press (1995). Synopsis of Schemes 67-78: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the 10 most part. Schemes 67-78 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 67, for example, a biheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted pyridyl boronic acid I may be 15 reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromonicotinic acid, to provide the biheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted 20 benzylimidazolyl IV to provide, after deprotection, the instant compound V. Schemes 68-71 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 67. Thus, Scheme 68 illustrates the analogous series of 25 biheteroaryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" heteroaryl moiety employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 69. 30 Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 70. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the biheteroaryl VII. The heteroaryl - 214 - WO 98/44797 PCT/US98/06823 halide and the zinc bromide adduct may be selected based on the availability of the starting reagents. Scheme 71 illustrates the preparation of the pyridylmethanol intermediate starting with the 3-methyl pyridine. 5 As illustrated in Scheme 72, the sequence of coupling reactions may be modified such that the heteroaryl-heteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII. Intermediate VIII can then undergo Suzuki 10 type coupling to a suitably substituted pyridyl boronic acid. Scheme 73 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then 15 be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove. Scheme 74 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl 20 via an alkyl amino, sulfonamide or amide linker. Thus, the 4-amino alkylimidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well known in the art with various activated biheteroaryl moieties to 25 provide the instant compounds shown. Compounds of the instant invention wherein the
A
1
(CR
1 2)nA 2
(CR
1 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 75. The suitably substituted phenol XIV may be reacted with methyl 30 N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV. After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove. - 215 - WO 98/44797 PCT/US98/06823 Scheme 76 illustrates an analogous series of reactions wherein the (CR 2 2)pX(CR 2 2)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as 3-chloro-2 pyridinol, is reacted with methyl N-(cyano)methanimidate to provide 5 intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound. Compounds of the instant invention wherein the 10 A 1
(CR
1 2)nA 2
(CR
1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 77. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above 15 (in particular, Scheme 67) provides the instant compound XX. If other
R
1 substituent s are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Scheme 78 illustrates the use of halogenated 2 aminopyrimidine in the preapration of compounds of the instant 20 invention. - 216 - WO 98/44797 PCT/US98/06823 SCHEME 67 N Br (HO) 2 B N R I HO
R
2 Pd(PPh 3
)
4 0 NR6 N N LiAIH 4 HO
R
2 0 11 N HO R 2 III - 217 - WO 98/44797 PCT/US98/06823 SCHEME 67 (continued) Tr Tr N NiCI 2 (PPh 3
)
2 N N R a ZnBr N R / R8 IV .. LR 6 N N (CF 3
SO,)
2 0, -780C HO NEtiPr 2
R
2 2 -78C-20C CH2CI 2 Tr R 6 N R R2 550C, CHaOH 7D R'R RN R6 N N N / V R2 - 218 - WO 98/44797 PCT/US98/06823 SCHEME 68 N B(OH) 2
R
6 MeO .
Br ,
OR
2 Pd(PPh 3
)
4 N
R
6 N : MeR LiAIH 4 MeO 0R 2 NR6 N R HO
R
2 - 219 - WO 98/44797 PCTIUS98/06823 SCHEME 69 B(OH)2 R
R
3 SiO Br R2 Pd(PPh 3
)
4 N ") N -BU4NF
R
3 SiO,- I
R
2 N N
R
6 HO0 N Br +R6
R
3 SiO I (HO) 2 B" Nt R2 Pd(PPh 3
)
4 NNj BU 4 NF
R
3 SiO N HO
R
2 -220 - WO 98/44797 PCT/US98/06823 SCHEME 70 N I -R 6 RiBrZn
R
3 SiO R2 NiCI 2 (PPh3
)
2 N N 6 N Bu 4 NF
R
3 SiO" R
VIIR
2 N N HO
R
2 H o N.. 0 Zn NH
R
3 SiO II
R
2 NiCI 2 (PPh 3
)
2 H o N y 0 ON ON N T NH Bu 4 NF
R
3 SiO 0 .. N y 0
R
2 221 -N HO - 221 - WO 98/44797 PCT/US98/06823 SCHEME 71 I OTf , (HO) 2 B N KMnO 4 H3C
R
2 Pd(PPh 3
)
4 N 4 R6 LiAIH 4 N N H0 2 C
R
2 ."J...- R 6 HO
R
2 - 222 - WO 98/44797 PCT/US98/06823 SCHEME 72
R
2 Tr Br % i. I N B N N i. MeOH R/ reflux R8 R6 (HO)2 B N N a VIl R2 Pd(PPh 3
)
4 R - 223 - WO 98/44797 PCT[US98/06823 SCHEME 73 H H NN
R
9 b Nal, NaHCO 3 , 12 N TrCI, NEt,, INRb Ix x Tr T N N R 9 b
R
9 b N11(~ 3
)
2 N ZnBr/ s R81 R 8 / Tr ~ R~b N R2 OTf / \ i. -780'C-200C ii. MeOH, reflux Rx8 N-) N ~NR R9b N," -224 - WO 98/44797 PCT/US98/06823 SCHEME 74 0OR ( i. Br N \ 55 0
C,CH
3 CN N N ii. EtOH,80 0 C, NH 2
NH
2 O~ XII N N
NH
2
R
8 X11I N acylation, sulfonylation <' O R or alkylation NH N N ' S N O, 2NR / R 2 R6 N N HN N NN
R
6 - 225 H N N -225- WO 98/44797 PCT/US98/06823 SCHEME 75 \OH i, Na, MeOH NC ii. 1200C XlV H a
C
0 N H Tr N TrCI, NEt 3 ,N NC O NC O XV XVI / .R 6 Tr R 2 NN i. -780C-200C NN ii. MeOH reflux NC O OTf XVI /~ R 6
R
2 R N N NCO - 226 - WO 98/44797 PCT/US98/06823 SCHEME 76 H 1 -,.UN __\_N C OH i' NaMeOH N cI i 12000 N R2 H3CO % R 2 XVI N"N N R8 Tr TrCI, NEt 3 , N OTf N i. -780C-20°C SO ii. MeOH reflux
R
2
RB(OH)
2 R6 N N / R6 CI O DMF, Pd(PPh 3
)
4 <- K 3
PO
4 , 800C
R
2 XVII
R
8 N N
R
6
R
2 - 227 - WO 98/44797 PCT/US98/06823 SCHEME 77 Tr, Tr N S EtMgBr N OH XVIII R R xIx g . R6 Tr N 'T TN NHO Ac20, py N R2 /
(CF
3
SO
2
)
2 0, -780 R8 OAc NEtiPr 2
,CH
2 Cl 2 ,.g g R 6 N N N LiOH g R2 OAc
R
8 XX gg g m6 N N g N...: N\[ .. g--- R a N SOC1 2
R
2 OH
R
8 228 - WO 98/44797 PCT/US98/06823 SCHEME 77 (continued) 9 9 Ng- -N, " NH 3 , MeOH
\~R
2 Cl
R
8 N-N R2 I I N. --. .
NH
2
R
8 + R6 NN g
R
8 - 2OMe29 - 229 - WO 98/44797 PCT/US98/06823 SCHEME 78
R
6 N - Br (HO) 2 B_N.
H
2 N N N N CI
H
2 N NN R7, R 6 N <I H N N N R 8N R6 The farnesyl transferase inhibitors of formula (II-j) can be synthesized in accordance with Schemes 79-88, in addition 5 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 3 , R 6 and
R
8 , as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 ,
R
6 a, R6b, R6c, R6d, R 6 e and R 8 ; although only one such R 3 , R 6 or 10 R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heterocyclic moieties contain multiple substituents. - 230 - WO 98/44797 PCT/US98/06823 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 Schemes. The reactions described in the 5 Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. 10 Synopsis of Schemes 79-88: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures. Schemes 79-88 illustrate synthesis of the instant bicyclic 15 compounds which incorporate a preferred benzylimidazolyl side chain. Thus, in Scheme 79, for example, a bicyclic intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted pyridinone 1 may be reacted under coupling conditions with a suitably substituted iodobenzyl 20 alcohol to provide the intermediate alcohol 2. The intermediate alcohol 2 may converted to the corresponding bromide 3. The bromide 3 may be coupled to a suitably substituted benzylimidazolyl 4 to provide, after deprotection, the instant compound 5. Schemes 80-82 illustrate methods of synthesizing related 25 or analogous key alcohol intermediates, which can then be processed as described in Scheme 79. Thus, Scheme 80 illustrates pyridinonyl pyridyl alcohol forming reactions starting with the suitably substituted iodonicotinate 6. Scheme 81 illustrates preparation of the intermediate 30 alcohol 9 wherein the terminal lactam ring is saturated. Acylation of a suitably substituted 4-aminobenzyl alcohol 7 with a suitably substituted brominated acyl chloride provides the bisacylated intermediate 8. Closure of the lactam ring followed by saponifi - 231 - WO 98/44797 PCT/US98/06823 action of the remaining acyl group provides the intermediate alcohol. Preparation of the homologous saturated lactam 10 is illustrated in Scheme 82. Scheme 83 illustrates the synthesis of the alcohol 5 intermediate 13 which incorporates a terminal pyrazinone moiety. Thus, the amide of a suitably substituted amino acid 11 is formed and reacted with glyoxal to form the pyrazine 12, which then undergoes the Ullmann coupling to form intermediate 13. Scheme 84 illustrates synthesis of an instant compound 10 wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole 14 may be selectively iodinated to provide the 5-iodoimidazole 15. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 16. Intermediate 16 can then 15 undergo the alkylation reactions that were described hereinabove. Scheme 85 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the bicyclic moiety via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole 17, wherein the primary amine is protected 20 as the phthalimide, is selectively alkylated then deprotected to provide the amine 18. The amine 18 may then react under conditions well known in the art with various activated bicyclic moieties to provide the instant compounds shown. Compounds of the instant invention wherein the 25 AI(CR 1 2)nA 2
(CR
1 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 86. The suitably substituted phenol 19 may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole 20. After selective protection of one of the imidazolyl nitrogens, the 30 intermediate 21 can undergo alkylation reactions as described for the benzylimidazoles hereinabove. Compounds of the instant invention wherein the
A
1
(CR
1 2)nA 2 (CR12)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 87. Thus, the N - 232 - WO 98/44797 PCT/US98/06823 protected imidazolyl iodide 22 is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol 23. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 79) provides the instant 5 compound 24. If other R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Scheme 88 illustrates incorporation of an acetyl moiety as the (CR 2 2)pX(CR 2 2)p linker of the instant compounds. Thus the readily available methylphenone 25 undergoes the Ullmann reaction 10 and the acetyl is brominated to provide intermediate 26. Reaction with the imidazolyl reagent 4 provides, after deprotection, the instant compound 27. SCHEME 79 R LiAIH 4
H
3 CO o3 0 RR HN R H1 O HO
K
2
CO
3 /CuO/heat
R
6 N O NBS/DMS N 3 2 CH 2
CI
2 B R3 3 15 HO - 233 - WO 98/44797 PCT/US98/06823 SCHEME 79 (continued) Tr Tr / N CI 2 (PPh 3
)
2 N N ZnBr R8/ R8 R 6 N Br 0O CH 3 CN/reflux
R
3 Tr 4 R6 % ~ N R N N R 55oC, CH30H
R
8 R R 6 N", 0 5
R
8 - 234 - WO 98/44797 PCT/US98/06823 SCHEME 80 N I LiAIH 4 EtO O 6 N R 6 N I HN HO 1 O HO K2CO3/CuO/heat RR N Ne HO 0 R3 - 235 - WO 98/44797 PCT/US98/06823 SCHEME 81
R
6
/NH
2 Br/ 0 COCI HO\ Ho", R3
CH
2
CI
2 /Et3N 7
R
6 O Br O Cs 2 CO3/DMF
R
3 8 heat HN Br 0 O R Br OH 0 R3
R
3 NaOH O / MeOH O
R
6
R
6 9 - 236 - WO 98/44797 PCT/US98/06823 SCHEME 82
R
6
HNH
2 Br /- COCI HO
R
3
CH
2
CI
2 /Et 3 N
R
6 O'I Br 0 CS2CO3/DMF R3 heat
N
6 HN / Br 0 R6 OH
O
r ~ ~ OBr
R
3 R NaOH O MeOH O
R
6
R
6 10 - 237 - WO 98/44797 PCT/US98/06823 SCHEME 83 CO2CH 3
NH
3 (Liq.) CONH 2 O
R
6 NH2"HCI EtOH R NH2-HCI MeOH/NaOH 11 HCI NaHCO 3 N N R6 12 OH HO N
K
2 CO3/Cuo/heat HO 0
R
3 13 - 238 - WO 98/44797 PCT/US98/06823 SCHEME 84 H H N N
R
9 b Nal, NaHCO 3 , 12 R 9 b TrO, NEt, -- <\ ,N -- N N t 14 I 15. Tr tr
R
9 b R R
R
9 b NiC1 2 (PPh 3 ) -. R N N i. CH3CN/reflux R ii. MeOH, reflux ZnBr 16 R 9bBrB
R
9 b R i. CH 3 CN/reflux Ra/ ii. MeOH, reflux R - 239 - WO 98/44797 PCT/US98/06823 SCHEME 85 O0 0 O i. Br N 0 <\ 55 0 CCHzCN N N ii. EtOH,80°C, NH 2
NH
2 O 17 N N
NH
2 18 N N' 03 acylation, sulfonylation N N H or alkylation R N R0 0 N N R N N - 240 - WO 98/44797 PCT/US98/06823 SCHEME 86 \. OH i, Na, MeOH OHir, NC ii. 1200C 19
H
3 C-O /-N N H T( N TrCI, NEt3 N NC ONC o 20 21 Tr R 6 N N i. CH 3 CN/reflux N + 3 O ii. MeOH reflux NC C O Br 21 R 6 R N ~o NC 0 - 241 - WO 98/44797 PCT/US98/06823 SCHEME 87 T Tr N N- EtMgBr N O OH
R
8
R
8 22 23 Tr B - R N N Ac20O, py R3 / ODAc
CH
3 CN/reflux 2. MeOH
R
8 N N
R
3 LiOH OAc
R
8 24 rl - R6 NN N 0 R3
SOCI
2 OH
R
8 - 242 - WO 98/44797 PCT/US98/06823 SCHEME 87 (continued) R6 N Nr N 0 NH 3, MeOH
R
3 CI R8 N NH 2 RR+ N N OMe R 8 - 243 - WO 98/44797 PCT/US98/06823 SCHEME 88 R6 6 HN N R ,N
H
3 C 3 1 O H00 .I QR H3 C \R3 O R K 2
CO
3 /Cu /heat R 25 T Tr /1 N N - -R6 Br 2
/CHCI
3 N V O R 8 4 Br R 3 O 26 CH 3 CN/reflux
R
8 - R RR 6 0 +N R N+ R 55C, CH 3 0H N O I R8 Tr N o /N
R
3 N j 0 N O 27 5 The farnesyl transferase inhibitors of formula (II-k) can be synthesized in accordance with Schemes 89-97, in addition to other standard manipulations such as ester hydrolysis, cleavage - 244 - WO 98/44797 PCT/US98/06823 of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R 3 , R 6 and R8, as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R6a, R6b, R 6 c, R6d, R6e and R 8 ; although only one such R 3 , R 6 or 5 R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heterocyclic moieties contain multiple substituents. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to 10 synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: 15 Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. Synopsis of Schemes 89-97: The requisite intermediates are in some cases 20 commercially available, or can be prepared according to literature procedures. Schemes 89-96 illustrate synthesis of the instant bicyclic compounds which incorporate a preferred benzylimidazolyl side chain. Thus, in Scheme 89, for example, a bicyclic intermediate that is not commercially available may be synthesized by methods 25 known in the art. Thus, a suitably substituted pyridinonyl alcohol 29 may be synthesized starting from the corresponding isonicotinate 28 according to procedures described by Boekelhiede and Lehn (J. Org. Chem., 26:428-430 (1961)). The alcohol is then protected and reacted under Ullmann coupling conditions with a suitably 30 substituted phenyl iodide, to provide the intermediate bicyclic alcohol 30. The intermediate alcohol 30 may converted to the correspond ing bromide 31. The bromide 31 may be coupled to a suitably substituted benzylimidazolyl 32 to provide, after deprotection, the instant compound 33. - 245 - WO 98/44797 PCT/US98/06823 Schemes 90-92 illustrate methods of synthesizing related or alcohol intermediates, which can then be processed as described in Scheme 89. Thus, Scheme 90 illustrates preparation of a pyridyl pyridinonyl alcohol and thienylpyridinonyl alcohol starting with the 5 suitably substituted halogenated heterocycles. Scheme 91 illustrates preparation of the intermediate bromide 36 wherein the preferred pyridinone is replced by a saturated lactam. Acylation of a suitably substituted aniline 34 with a suitably substituted brominated acyl chloride provides the 10 acylated intermediate 35. Closure of the lactam ring provides the intermediate alcohol, which is converted to the bromide as described above. Scheme 92 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant 15 compound. Thus, a readily available 4-substituted imidazole 37 may be selectively iodinated to provide the 5-iodoimidazole 38. That imidazole 38 may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 39. Intermediate 39 can then undergo the alkylation reactions that were described 20 hereinabove. Scheme 93 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4 aminoalkylimidazole 40, wherein the primary amine is protected as 25 the phthalimide, is selectively alkylated then deprotected to provide the amine 41. The amine 41 may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown. Compounds of the instant invention wherein the 30 Al(CR12)nA 2 (CR12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 94. The suitably substituted phenol 42 may be reacted with methyl - 246 - WO 98/44797 PCT/US98/06823 N-(cyano)methanimidate to provide the 4-phenoxyimidazole 43. After selective protection of one of the imidazolyl nitrogens, the intermediate 44 can undergo alkylation reactions as described for the benzylimidazoles hereinabove. 5 Compounds of the instant invention wherein the A 1 (CR12)nA 2
(CR
1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 95. Thus, the N protected imidazolyl iodide 45 is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol 46. 10 Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 89) provides the instant compound 47. If other R1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Scheme 96 illustrates incorporation of an acetyl 15 moiety as the (CR 2 2)pX(CR 2 2)p linker of the instant compounds. Thus, the suitably substituted acetyl pyridine 48 is converted to the corresponding pyridinone and undergoes the Ullmann reaction with a suitably substituted phenyl iodide. The acetyl is then brominated to provide intermediate 49. Reaction with the imidazolyl reagent 32 20 provides, after deprotection, the instant compound 50. Scheme 97 illustrate reactions wherein the moiety
(R
8 )r
(R
9 )q V - A 1
(CR
1 2 )nA 2
(CR'
2
)
n W - (CR'1 2 )p-X. t incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group. 25 Thus, the intermediates whose synthesis are illustrated in the Schemes, and other pyridinonecarbocyclic and pyridinonehetero cyclic intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. 30 Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, - 247 - WO 98/44797 PCT/US98/06823 67, 69-75, from the appropriate amino acid. Knochel chemistry may be utilized, as shown in Scheme 97, to incorporate the aryl pyridinone moiety. Thus, a suitably substituted 4-(bromo)pyridine is converted to the corresponding pyridinone 51 as described above 5 and the pyridinone is coupled to a suitably substituted phenyl iodide as previously described above. The resulting bromide 52 is treated with zinc(0) and the resulting zinc bromide reagent 53 is reacted with an aldehyde to provide the C-alkylated instant compound 54. Compound 54 can be deoxygenated by methods known in the art, 10 such as a catalytic hydrogention, then deprotected with trifluoro acetic acid in methylene chloride to give the final compound 55. The compound 55 may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine 55 can further be selectively protected to 15 obtain 56, which can subsequently be reductively alkylated with a second aldehyde to obtain compound 57. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole 58 can be accomplished by literature procedures. - 248 - WO 98/44797 PCT/US98/06823 SCHEME 89 COOMe COOMe 30% H 2 0 2 AcO16 0 R3 30% H2O2 R3 Ac20 / 1600C N HOAc/A N+ I O" 28 COOMe OH LiBH 4 / THF TBDMSCI R - R 3 N O N O imidazole /DMF H H 29 OTBDMS I R N N R 3 L R 6 RN 0 H Cuo / K 2
CO
3 /1800C OTBDMS - 249 - WO 98/44797 PCT/US98/06823 SCHEME 89 (continued) TBAF R 3 - R 6 R - R 6 . -N CBr 4 /Ph 3 P THF 30O CH 2 CI2 O 30 31 OH Br TTr Tr ZnBr N R N N NiCI 2 (PPh 3
)
2
CH
3 CN/reflux
R
8 32 Tr R 3 6 N~N N 0 O 550C, CH 3 0H Ra R3 I6R R8 i _) NN O~ / 33
R
8 - 250 - WO 98/44797 PCT/US98/06823 SCHEME 90 Br OTBDMS NR RN N RNI 1 R 6R3-R N 0 Cuo K 2
CO
3 / 1800C 0O H OTBDMS N R 3 R 6 N 0 Br OTBDMS R1 6' R ST R R3 R3R N 0 Cuo / K 2
CO
3 / 1800C 0O H OTBDMS
R
3 S
-
R R N r~u 0 Br - 251 - WO 98/44797 PCT/US98/06823 SCHEME 91 R3 Br COCI
NH
2
CO
2
CH
3 R
CH
2
CI
2 /Et 3 N 34 R' 6 CS2CO3/DMF R
R
3 heat O N HN 2Br O CO2CH 3
R
3 CO2CH 3 35 :R 6 R6 LiAIH 4 CBr 4 /Ph 3 P THF O OHCH2C2 O B r OH Br 36 - 252 - WO 98/44797 PCT/US98/06823 SCHEME 92 H H N N 37I 38 Tr Tr R 9 b NiCI 2 PPh 3
.
2 R 9b\N N / ZnBr
R
8 1R8 Tr -N Nr
R
9 b -hB CHICN/reflux 8/ ii. MeOH, reflux 39 N 0
R
8 X -253 - WO 98/44797 PCT/US98/06823 SCHEME 93 0 R 8 -0 Oi. R I _ Br O 0 55°C,CHICN N N ii. EtOH,80 0 C, NH 2
NH
2 40 O0 N N
NH
2
R
8 -Q R 41 NO acylation, sulfonylation / I0 N N - O or alkylation
R
8 \-N - H NN N N 0 N R8 H
R
3
-R
6 N N O
R
3 " R 6 254 WO 98/44797 PCT/US98/06823 SCHEME 94 /\OH i, Na, MeOH NC ii. 120-C 42 H 3 C-O ,-N \--N H Tk N TrCI, NEt 3 N NC NC O 43 44 Tr R3 - R 6 N - N i. CH 3 CN/reflux IN + ii. MeOH reflux NC ~\O0 Br 31 NC 44R 3 [ -- R 6 NC - 255 - WO 98/44797 PCT/US98/06823 SCHEME 95 ,Tr Tr i,'"N N EtMgBr N N O OH 45 R8
R
8 46
R
3 R 6 Tr1 r N 1. Ac 2 0, py N Br 30 / O
CH
3 CN/reflux q./'/ OAc R 2. MeOH
R
8
R
3 R6 LiOH Y OAc 47
R
8
R
3
R
6 NN O
R
8 \ SOCI 2 OH - 256 - WO 98/44797 PCT/US98/06823 SCHEME 95 (continued)
R
3
-R
6 N N NH 3 , MeOH cl R8
R
3 - R 6 NN
NH
2
R
8 + R3
-R
6 NN O OMe
R
8 - 257 WO 98/44797 PCT/US98/06823 SCHEME 96 0 CH 3 0 CH 3 30%
H
2 0 2 N HOAc/A N O" 48 0 CH 3 7R6 Ac 2 O / 16000 AN
K
2 CO3/Cu+/heat H R -- R6 Br 2
/CHC
3
H
3 C 0 Tr 0 N N
R
-
R
8 32 Br 0 CH3CN/reflux O 49 - 258 - WO 98/44797 PCT/US98/06823 SCHEME 96 (continued) 86 R R 3 R6 + o 55oC, CH 3 0H N I Tr R
R
3 1 R 6 /N NJ o 50 - 259 - WO 98/44797 PCT/US98/06823 SCHEME 97 Br Br 30%
H
2 0 2 R3.-
R
3
K
N HOAcA N O" R 6 Br Ac 2 0 / 1600C 3 R3 QN 0 K 2
CO
3 /Cu'/heat H 51 R N - R6 Zn o Br~ O 52 - 260 - WO 98/44797 PCT/US98/06823 SCHEME 97 (continued) Boc NH 3 R Boc NH CHO N BrZn 0 53
R
3 1. catalytic 6HO \N R6 hydrogenation HO NR 2. CF 3
CO
2 H Boc NH
CH
2
CI
2 NHBoc 54
R
3 - N ' R 6 Boc20 NH2 O CH 2 Cl 2
NH
2 55 - 261 - WO 98/44797 PCT/US98/06823 SCHEME 97 (continued) R3 ~~CHO
R
6 BocNH 0 NaBH(OAc) 3
NH
2 56 Et 3 N , CICH 2
CH
2 CI R 3
NR
6 BocNH\ B0cNHo
CF
3
CO
2 H, CH 2
CI
2 ; - NH NaHCO 3 /\/ 57 R N R 6 R
NH
2 O NC - NH AgCN , R 3NR6 N- 0 N 58 5 - 262 - WO 98/44797 PCT/US98/06823 The farnesyl transferase inhibitors of formula (II-i) can be synthesized in accordance with Reaction Schemes, 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 5 experimental procedures. Some key reactions utilized to form the aminodiphenyl moiety of the instant compounds are shown. 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 10 reactions described in the Reaction Schemes. Reaction Schemes A-P describe the preparation of appropriately substituted aniline intermediates that may be further functionalized by the methods described in Reaction Schemes Q-Y to provide the compounds of the instant invention. 15 Reaction Schemes A-D illustrate use of Ullman reactions to provide diphenyl ethers, amines and sulfides from readily available fully substituted phenols/thiophenols/anilines and aryl halides. In such syntheses, the desired amine moiety is typically masked as a nitro group which is subsequently reduced by techniques well known in the art. An 20 alternative synthesis of the diphenyl ethers which employs para-nitro fluorobenzene is shown in Reaction Scheme E. Reaction Scheme F illustrates standard acid-amine coupling to provide the fully substituted N-phenylbenzamides. Reaction Scheme G illustrates formation of the aminomethyl spacer via a reductive 25 amination of a suitably substituted benzaldehyde. Reaction Scheme H illustrates coupling of suitably substituted anilines with readily available phenylsulfonyl chlorides. Access to aminobenzophenones is illustrated in Reaction Scheme I, which also illustrates the reduction of the carbonyl to provide the 30 unsubstituted methyl spacer. An alternative method of forming the benzophenone intermediates is illustrated in Reaction Scheme J. Also shown in Reaction Scheme J is reductive amination of the resulting carbonyl to provide the amine substituted methyl spacer. Another - 263 - WO 98/44797 PCT/US98/06823 method of forming the benzophenone intermediates, illustrated in Reaction Scheme K, is a Stille reaction with an aryl stannane. Reaction Schemes L and M illustrate palladium mediated formation of olefin and acetylene spacer units. Reaction Scheme N 5 illustrates formation of an appropriately substituted benzyl ether. Reaction Scheme P illustrates the use of the Claisen rearrangement to provide methyl spacers having substituents such as a vinyl group which can be further functionalized. 10 REACTION SCHEME A 0 2 N OH I R 2b Cu, K 2
CO
3 + ,
R
a
R
3 pyridine, reflux
R
2 b R 2 b O0 2 N 0 R2 H 2 , Pd/C
H
2 N 0 R2a R THF, MeOH 2a 3 - 264 - WO 98/44797 PCT/US98/06823 REACTION SCHEME B 0 2 N NH 2
R
2 b Cu, K 2
CO
3 +
R+
a R 3 pyridine, reflux H 2 b H R 2 b 0 2 N N R
H
2 ,Pd/C
H
2 N N O 2NN R T H F , M e O H R 3 R2a R3 R 5 REACTION SCHEME C 0 2 N SH I R2b CuBr * SMe 2 , NaH
R
a R pyridine, reflux 2 b R 2 b 0 2 N S y R 2b
H
2 , Pd/C
H
2 N S R 2b 2a 3 THF, MeOH 2a
R
3 - 265 - WO 98/44797 PCT/US98/06823 REACTION SCHEME D OHC HO ... #.. /2b OHC I HO R2b CuBr*SMe 2 , NaH +
R
2a R pyridine, reflux R2a R 4 R OHCO O R 2b NaBH(AcO) 3 R4HN O R 2b R 0CICH 2
CH
2 C"
R
2 a R3 H 2
NR
4 5 REACTION SCHEME E R2b 0 2 N R 2 b K2CO3, DMF
R
2 a F HO R3800 0 2 N
R
2 b
H
2 N
R
2 b O2N" / "O // Fe, AoOH I. /k. O I O MeOH, reflux O
R
2 a
R
3
R
2a R - 266 - WO 98/44797 PCT/US98/06823 REACTION SCHEME F H O EDC, HOBT H 7 HN R 2 b or HOOBT O OH Et 3 N, DMF
R
2 a
R
3 H 0O Na N
R
2 b HCI orTFA R O 00 H20 7 R 2b 7-N F , HO' R2 a / '~
R
3 5 REACTION SCHEME G O R2b 02 R7HN Na(OAc)3BH / +
R
2 a
R
3 02N7 b 2 zz b NR7/ Fe, HOAc NR
R
2 a 3 R 2 a 3 - 26"7 - WO 98/44797 PCT/US98/06823 REACTION SCHEME H 0 2 N S R 7 HN R 2 b base S0 2 CI
R
2a
R
3 0 2 N R7 R 2 b H 2 N R7 R 2 b S -SO 2 N R Fe, HOAc
-SO
2 N 7 I Fe,c 7>c R2a" R3,. R2"a3
R
a
R
3 5 REACTION SCHEME I O 0 2 N cI Bu 3 Sn
XR
2 b Pd(PPh 3
)
2
CI
2 +I
R
2 a
R
3 O R 2 b H 2 N R 2 b 0 2 R Pd/C, H 2 Hi R2a
R
3 R 2 a R REACTION SCHEME J 10 - 268 - WO 98/44797 PCT/US98/06823 BocHN OH BocHN 0NCH 3 R 2a 00H 3 MgBrPh(R 2 a) (R 3 ) or I LiPh(R 2 a)(R 3 ) BocHN 0 R 2 b HN(R 8
)
2 NaBH(OAc) 3
CICH
2
CH
2 CI BocHN Rb 1 H I or T A
H
2 N Rb -269- WO 98/44797 PCT/US98/06823 REACTION SCHEME K O 0 2 N Br or I R 2 b +
R
2a R 3 Pd O 0 2 N R2b R2a
R
3 Fe, HOAc O 0 2b H2N R2a R 3 1. MgBrR 8 2. R 8 1 aOR 8
R
8 OR R 2 b H2N 5
R
2a R3 - 270 - WO 98/44797 PCT/US98/06823 REACTION SCHEME L
H
2 N Br R 2 b Pd(OAc)2 + 2 R P(o-tol) 3 , Et 3 N
R
2a
R
3
R
2 b
H
2 N R3 R2a 5 REACTION SCHEME M
H
2 N I /R 2 b Pd(PPh 3
)
4 +
R
2a
R
3 Bu 3 Sn
R
2 b
H
2 N R R2a - 271 - WO 98/44797 PCT/US98/06823 REACTION SCHEME N
R
2 b
R
2 b H 2 N
O
2 N OH Br 1. NaH R Br 9 , 2. Fe, AcOH 2a
R
2 a
R
3
R
2a MeOH, reflux 5 REACTION SCHEME P CI O~ 2 0 2 N R 1 HO R 2 b N R R2b + IQIO
R
2a
R
3
R
2a
R
3 heat Rio Rio OH ON R 2 b 1. Tf 2 NPh, Et 3 N 0 2
R
2 b / 2. Pd(OAc) 2 3 R2a
R
3 Et 3
N/HO
2 CH R2a R DMF 10 Reaction Schemes Q- S illustrate reactions wherein the non-sulfhydryl-containing moiety(ies) of the compounds of the instant invention is attached to the aminodiphenyl subunit to provide the instant compounds. - 272 - WO 98/44797 PCT/US98/06823 Thus, the aminodiphenyl subunit can be reductively alkylated with aldehydes such as 1-trityl-4-carboxaldehyde or 1 trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme Q). The trityl protecting group can be removed 5 from VIII to give IX, or alternatively, VIII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the aminomethylbenzamide subunit can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XI can be converted to the 10 acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV. Hydrolysis and reaction with the aminodiphenyl subunit in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3 15 ethylcarbodiimide (EDC) leads to acylated products such as XV. Coupling reactions with other suitably substituted aldehydes may be performed as illustrated in Schemes 3 and 6-9 hereinabove. Reaction Scheme S illustrates a one pot synthesis of an instant compound wherein the N-terminus nitrogen is substituted 20 with two different non-sulfhydryl-containing moieties. Thus, the aminodiphenyl subunit is treated with one equivalent of an appropriate aldehyde and, after the reductive adduct has been formed, the in situ intermediate is treated with an equivalent of a different aldehyde. - 273 - WO 98/44797 PCT/US98/06823 REACTION SCHEME 0 . R~a R 2 b -'I
H
2 N-(CR b 2 )-.J -Y-j
(CH
2 )nCHO NaBH(OAC) 3 N- Ar Et 3 N, CICH 2
CH
2 CI ~ N
(CH
2 )nCHO Tr
N
(,N
(H
2 )n~l
R
2 a R 2 b N~ /b N-(CRb)~+ -Y H j3NaBH(OAc) 3 N
REI
3 N , CICH 2
CH
2 CI Tr Vill
CF
3 00 2 H, 0H 2 C1 2
(C
2
H
5
)
3 SiH 132
R
2 b N H (C N H Ix R~a
R
2 b (CH CR )DP '1 K> R3 N x - 274 - WO 98/44797 PCT/US98/06823 REACTION SCHEME R N CH 2
C
0 2 H N CH 2 CO2CH 3
CH
3 0H N HCI N H H HCI XI XII N CH 2 CO2CH 3 1) ArCH 2 X CH 3 CN
(C
6
H
5
)
3 CBr reflux
(C
2 Hs) 3 N N 2) CH 3 OH, reflux DMF Tr XIII Ar N- CH 2 CO2CH 3 2.5N HClaq 550C N XIV Ar N__CH 2
CO
2 H N - 275 - WO 98/44797 PCT/US98/06823 REACTION SCHEME R (continued)
R
2 a
R
2 b Ar- N-- CH2CO2H _l/
H
2 N-(CR b2)p-' + 3 N R EDC HCI HOBt Ar O R 2 a
R
2 b N N-(CR1b p XV - 276 -R 3 xv - 276- WO 98/44797 PCT/US98/06823 REACTION SCHEME S
R
2 a
R
2 b 1) RXCHO, NaBH(OAc) 3 , l Ib 2 CICH, 2
CH
2 CI
H
2 N-(cRlb 2 )p--..i 2) RYCHO, NaBH(OAc) 3 , R CICH 2
CH
2 CI
R
2 a
R
2 b NaOH RXA (R lb H 2 0, CH 3 OH; Rx" N-(CR 2) Ry
R
3
R
2a
R
2 b IbI RX N- (CRib 2 ) p RY P< R3 5 wherein, in the above Reaction Schemes, R' is Rla; R" is
(R
6 )r-V-Al-(CRla)n-; R'" is selected such that R"'CH2- is R 8 ; and Rx and RY are selected such that Rx CH2- and RYCH2- are either R 4 or R 5 . 10 EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention 15 and not limitative of the reasonable scope thereof. The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary 20 evaporator. - 277 - WO 98/44797 PCT/US98/06823 EXAMPLE 1
H
2 N C02H SOC 2
HCI*H
2 N C02Et NHCBZ EtOH NHCBZ 1-1 1-2 BOC20, NEt 3 , CH 3 CN BOCNH 0 2Et 10% Pd/C N C02Et HI H~fBOCN EtOAc HO H
N
2
H
2 NHCBZ 1-4 1-3 10(+) camphorsulfonyl chloride NMM, CH 2
CI
2 HCN)C02 E t - N C0 2 Et BOCN CO 2 Et HC*H 2 N C H H"EtOAc H-u r-2
NHSO
2
NHSO
2 1-5 1-6 OBOP, NMM N N
CH
3 CN H *HCI 1-7 C02H - 278 - WO 98/44797 PCT/US98/06823 H CO 2 Et NHS0 H"
-
o
NHSO
2 O O NaOH, C 2
H
5 OH N N NH 00 2 H H"' 1-o NHSO O O Stejl: Ethyl 2 (S)-N(c-Cbz-2,3-diaminopropionate hydrochloride 5 (1-21 1-1 (5 g, 21 mmol) was dissolved in 100 mL EtOH and cooled to 0OC. SOCl2 (9.2 mL, 126 mmol) was added followed by removal of the cooling bath. After 6 hours, the reaction was concentrated to provide 1-2 as a white solid. 10 1 H NMR (300 MHz, CD3OD) 6 7.35 (m, 5H), 5.14 (s, 2H), 4.44 (m, 1H), 4.22 (q, J=7Hz, 2H), 3.43 (m, 1H), 3.20 (m, 1H), 1.25 (t, J=7Hz, 3H). Step 2: Ethyl 2(S)-Ng-Cbz-Ng-Boc-2,3-diaminopropionate (1-3) 15 1-2 (2 g, 6.6 mmol) was dissolved in 60 mL CH3CN. NEt3 (1 mL, 7.2 mmol) was added followed by BOC20 (1.58 g, 7.3 mmol). After two hours, the reaction was concentrated, diluted with EtOAc, washed with sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4), filtered and concentrated to provide 1-3 as a clear oil. 20 TLC Rf 0.87 (silica, 80% EtOAc/hex). - 279 - WO 98/44797 PCT/US98/06823 1 H NMR (300 MHz, CDCl3) 5 7.35 (s, 5H), 5.75 (bs, 1H), 5.12 (s, 2H), 4.81 (bs, 1H), 4.39 (m, 1H), 4.19 (m, 2H), 3.56 (m, 2H), 1.42 (s, 9H), 1.29 (q, J=7Hz, 3H). 5 Step. 3: Ethyl 2 (S)-N.-Boc-2,3-diaminopropionate (1-4) 1-3 (2.4 g, 6.6 mmol) with 10% Pd/C (240 mg) in EtOAc (35 mL) was stirred under a H2 atmosphere for 20 hours. The reaction was filtered through a celite pad and concentrated to provide 1-4 as a clear oil. 10 TLC Rf 0.13 (silica, 80% EtOAc/hex). 1 H NMR (300 MHz, CDCl3) 8 5.00 (bs, 1H), 4.19 (m, 2H), 3.55 (m, 2H), 3.25 (m, 1H), 1.44 (s, 9H), 1.29 (q, J=7Hz, 3H). Step 4: Ethyl-2(S)-Nca-(l1(S)10-camphorsulfonylamino-Np-Boc 15 2,3-diamino-propionate (1-5) Amine 1-4A (760 mg, 3.27 mmol) was dissolved in 35 mL CH2C12 and cooled to 0oC. NMM (755 gL, 6.87 mmol) and 10(+) camphorsulfonyl chloride (1.23 g, 4.9 mmol) were added. After stirring at 0oC for one hour, the reaction was concentrated, then diluted 20 with EtOAc, washed with H20, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4), and concentrated to an oil. Flash chromatography (silica, 25-40% EtOAc/hexanes) provided 1-5 as a clear oil. TLC Rf 0.66 (silica, 50% EtOAc/hexanes). 1 H-NMR (300 MHz, CDCl3) 6 6.37 (d, J=8Hz, 1H), 4.99 (bt, 1H), 4.32 25 (m, 1H), 4.23 (q, J=8Hz, 2H), 3.56 (m, 3H), 3.0 (d, J=15 Hz, 1H), 2.4 (m, 1H), 2.05 (m, 4H), 1.43 (s, 9H), 1.30 (t, J=7 Hz, 3H), 1.00 (s, 3H), 0.91 (s, 3H). Step 5: Ethyl-2(S)-Nu-(1(S) 10-camphorsulfonylamino)-2,3 30 diaminopropionate hydrochloride (1-6) Ester 1-5 (900 mg, 2.18 mmol) was dissolved in 15 mL EtOAc and cooled to 0OC. HC1 (g) was bubbled through the reaction mixture for 15 minutes. The reaction was removed from the cooling - 280 - WO 98/44797 PCT/US98/06823 bath and purged with Ar (g) for 20 minutes followed by concentration to provide 1-6 as a foamly solid. TLC Rf 0.05 (silica, 20% MeOH/EtOAc). 1 H-NMR (300 MHz, CDCl3): 6 4.75 (m, 1H), 4.26 (q, J=7Hz, 2H), 3.50 5 (m, 4H), 2.40 (m, 3H), 1.98 (m, 4H), 1.30 (t, J=7Hz, 3H), 1.04 (s, 3H), 0.91 (s, 3H). 0 SC02Et 1-10 Step 6: Ethyl-4-(2-butanene)benzoate (1-10) 3-Buten-2-ol (2.15 mL, 25 mmol), ethyl 4-iodobenzoate 10 (5.52 q, 20 mmol) and NEt3 (3.5 mL, 25 mmol) were combined in 6 mL of CH3CN under Ar in a pressure tube. Pd(OAc)2 (19 mg, 0.08 mmol) was added and the reaction heated to 100 0 C for 3 hours. The reaction was cooled, then diluted with Et20, washed with H20, 10% KHSO4, sat. NaHCO3 and brine, dried (MgSO4) and concentrated to a 15 yellow oil. Flash chromatography (silica, 10% EtOAc/hex) provided 1-10 as a clear oil. TLC Rf 0.23 (silica, 30% EtOAc/hex). 1 H NMR (300 MHz, CDCl3): 8 7.95 (d, J=8Hz, 2H), 7.25 (d, J=8Hz, 2H), 4.36 (q, J=7Hz, 2H), 2.95 (t, J=7Hz, 2H), 2.78 (t, J=7Hz, 2H), 2.15 20 (s, 2H), 1.38 (t, J=7Hz, 3H). N N CO2Et 1-11 -281 - WO 98/44797 PCT/US98/06823 S : Ethyl 4-[2-(1,8-naphthyridin-7-yl)ethyllbenzoate (1-11) An ethanol solution of (70 mL) of 1-10 (3.15 g, 14.3 mmol), 2-amino-3-formylpyridine (Syn. Comm. 17(141, 1695(1987) (1.75 g, 14.3 mmol) and 20% KOH (2 mL) was refluxed for 18 hours. 5 The reaction was concentrated to dryness and the residue partitioned between EtOAc and H20. The organic layer was washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated to give a yellow oil. Flash chromatography (silica, 60%-80% EtOAc/hex) provided 1-11 as a yellow solid. 10 TLC Rf 0.31 (silica, 70% EtOAc/hex). 1 H NMR (300 MHz, CDCl3) 8 9.11 (m, 1H), 8.18 (d, J=8Hz, 1H), 8.08 (d, J=8Hz, 1H), 7.95 (d, J=8Hz, 2H), 7.47 (m, 1H), 7.30 (d, J=8Hz, 2H), 4.35 (q, J=7Hz, 2H), 3.35 (m, 4H), 1.38 (t, J=7Hz, 3H). N N HV CO2Et 1-12 15 Step 8: Ethyl 4-[2-(1,2,3,4-tetrahydro-1,8-naphthyridin-7 yl)ethyllbenzoate (1-12) A mixture of 1-11 (645 mg, 2.11 mmol), 10% Pd/C (65 mg), and ethanol (10 mL) was stirred under a hydrogen atmosphere 20 for 18 hr. Filtration through a celite pad followed by concentration provided by 1-12 as an off white solid. TLC Rf 0.75 (silica, 70% EtOAc/hex). 1 H NMR (300 MHz, CDC13) 8 7.94 (d, J=8Hz, 2H), 7.26 (d, J=8Hz, 2H), 7.03 (d, J=7Hz, 1H), 6.28 (d, J=7Hz, 1H), 4.81 (s, 1H), 4.35 (q, 25 J=7Hz, 2H), 3.40 (m, 2H), 3.03 (m, 2H), 2.84 (m, 2H), 2.69 (t, J=6Hz, 2H), 1.93 (t, J=6Hz, 2H), 1.38 (t, J=7Hz, 3H). - 282 - WO 98/44797 PCT/US98/06823 eHO2 N N HV HCI C 2H 1-7 Step 9: 4-[2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7 yl)ethyllbenzoic acid hydrochloride (1-7) 5 Ester 1-12 (680 mg, 2.11 mmol) in 10 mL 6N HCI was heated to 50oC for 18 hours. Concentration provided 1-7 as a yellow solid. 1 H NMR (300 MHz, CD3OD) 5 7.93 (d, J=8Hz, 2H), 7.52 (d, J=8Hz, 1H), 7.31 (d, J=8Hz, 2H), 6.54 (d, J=8Hz, 1H), 3.48 (t, J=5Hz, 2H), 3.03 10 (m, 4H), 2.79 (t, J=6Hz, 2H), 1.93 (t, J=6Hz, 2H). Step 10: 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7-yl)ethyl] benzoyl-2(S) [1(S)10-camphorsulfonylamino] 3-alanine ethyl ester (1-8) 15 1-7 (200 mg, 0.627 mmol), amine 1-6 (240 mg, 0.69 mmol), NMM (345 gL, 3.13 mmol) and BOP reagent (332 mg, 0.75 mmol) were combined in 5 mL CH3CN. After stirring overnight, the reaction was concentrated, then diluted with EtOAc, washed with H20, sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. 20 Flash chromatography (silica, EtOAc) provided 34-8 as an off-white foamy solid. TLC Rf 0.13 (silica, EtOAc). 1 H NMR (300 MHz, CDCl3) 5 7.70 (d, J=8Hz, 2H), 7.25 (d, J=8Hz, 2H), 7.03 (d, J=7Hz, 1H), 6.72 (t, J=5Hz, 1H), 6.5 (bm, 1H), 6.28 (d, 25 J=7Hz, 1H), 4.79 (s, 1H), 4.42 (bs, 1H), 4.25 (q, J=7Hz, 2H), 4.04 (m, 1H), 3.85 (m, 1H), 3.55 (d, J=15Hz, 1H), 3.41 (m, 2H), 3.00 (m, 3H), 2.82 (t, J=4Hz, 2H), 2.69 (t, J=6Hz, 2H), 2.04 (m, 8H), 1.58 (bs, 3H), 1.31 (t, J=7Hz, 3H), 1.00 (s, 3H), 0.90 (s, 3H). - 283 - WO 98/44797 PCT/US98/06823 Step 11: 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7-yl)ethyl] benzoyl-2(S)- [1(S)10-camphorsulfonylamino] P3-alanine (1-9) 1-8 (250 mg, 0.409 mmol) was dissolved in 4 mL EtOH, 5 IM NaOH (1.02 mL, 1.02 mmol) was added and the reaction mixture was stirred for two hours. The reaction mixture was neutralized with 1N HCI and then concentrated to a foamy solid. Flash chromatography (silica, 18:10:1:1 EtOAc/EtOHINH4OH/H20) provided 1-92 as a slightly yellow solid. 10 TLC Rf 0.49 (silica, 12:10:1:1 EtOAc/EtOH/NH4OH/H20). 1 H NMR (400 MHz, DMSO) 5 8.48 (bt, 1H), 7.72 (d, J=8Hz, 2H), 7.55 (bs, 1H), 7.28 (d, J=8Hz, 2H), 7.02 (d, J=7Hz, 1H), 6.37 (s, 1H), 6.26 (d, J=7Hz, 1H), 4.13 (s, 1H), 3.54 (m, 3H), 3.37 (m, 2H), 2.94 (m, 3H), 2.73 (t, J=7Hz, 2H), 2.6 (t, J=6Hz, 2H), 2.3 (m, 3H), 2.02 (m, 1H), 1.89 15 (m, 2H), 1.75 (m, 2H), 1.49 (m, 1H), 1.37 (m, 1H), 1.05 (m, 1H), 0.95 (s, 3H), 0.66 (s, 3H). EXAMPLE 2 O H,, NH BocHN N-- OCH3 0 2-1 HCI, EtOAc, 00C 0 HCI* H 2 N N 0 2-2 INaCNBH 4 N N CHO MeOH 2-3 - 284 - WO 98/44797 PCT/US98/06823 O N N N OCH 3 H 0 2-4 Boc20, THF O NN
OCH
3 "NBoo 0 - 2-5 0 N N N -N OCH 3 Boc O 10 % Pd/C EtOH O H H ,, .
N 2-6. R = CH 3 NaOH 2-6a, R =N _ N 2-7 EDC, HOBT, DMF HCI*H 2 N' N CO2Et - 285 - WO 98/44797 PCT/US98/06823 O CN H HH , NN N NCO2Et I H Boc O 2-8 6N HCI IQN H H/ H " N N N NCO2H H H 0 2-9 Step 1: (S )-(3-amino-2-oxo-pyrrolidin-1-vl)-acetic acid (2-2) A solution of 2-1 (0.50 g, 1.84 mmol) (prepared as 5 described by Freidinger, R. M.; Perlow, D. S.; Veber, D. F.; J. Org. Chem., 1982, 26, 104) in anhydrous ethyl acetate (50 mL) was cooled to 0OC and saturated with HCI gas, then stirred at 0OC for 2 h. The resulting colorless solution was concentrated at reduced pressure and the residue triturated with anhydrous diethyl ether giving 2-2 as a 10 hygroscopic white solid. IH NMR (300 MHz, CD 3 OD) 5 4.16 (d, 2H); 4.2 (m, 1H); 3.68 (s, 3H); 3.53 (m, 2H); 2.58 (m, 1H); 2.09 (m, 1H). Step 2: 2-oxo-3-(S)-[1,8]naphthyridin-2-ylmethyl)-amino] 15 pyrrolidin-1-yll-acetic acid (2-4) A solution of 2-2 (232 mg, 1.11 mmol) and [1,8]naphthyridin-2-ylcarboxaldehyde (176 mg, 1.11 mmol) (prepared as reported by Weissenfels, M.; Ulrici, B.; Z. Chem. 1978, 18, 20.) in anhydrous methanol (10 mL) was treated with NaOAc (91 mg, 1.11 20 mmol) , NaBH 3 CN (70 mg, 1.11 mmol) and powdered 4 A molecular sieves (450 mg). The resulting mixture was stirred at 0 for 3.5 h, then - 286 - WO 98/44797 PCT/US98/06823 concentrated and the residue subjected to flash chromatography on silica gel (95:4.5:0.5 CH 2 C12/MeOHINH 4 OH) to afford 2-4 as a colorless glass. FAB MS (315, M+I); 5 1H NMR (300 MHz, CD 3 OD) 5 9.04 (d, 1H); 8.41 (dd, 1H); 8.38(d, 1H); 7.72 (d, 1H); 7.62 (dd, 1H); 4.31 (d, 2H); 4.21 (m, 2H); 3.68 (s, 3H);3.63 (m, 1H); 3.53 (m, 2H); 2.52 (m, 1H); 1.95 (m, 1H). Step 3: Methyl-[3-(S)-[tert-butoxycarbonyl-[1,8]naphthyridin-2 10 ylmethyl)-amino]l-2-oxo-pyrrolidin- 1 -yl]l-acetic acid (2-5) A solution of amine 2-4 (69 mg, 0.22 mmol) in THF (5 mL) was treated with Boc 2 0 (83 mg, 0.24 mmol) and stirred at room temperature for 18 h. The solvent was removed in vacuo and the resulting residue isolated by chromatography on silica gel (5% 15 MeOH/CH2Cl2) to afford 2-5 as a yellow glass. FAB MS (415, M+1); 1H NMR (300 MHz, CD30D) 5 9.04 (d, 1H); 8.20 (m, 2H); 7.88 (d, 0.5H (rotamer a)); 7.82 (d, 0.5H (rotamer b)); 7.46(m, 1H); 5.1-4.3 (m, 5H); 3.81 (m, 2H); 3.72 (s, 3H); 3.41 (m, 2H); 2.36 (m, 2H); 1.47 20 (s, 4.5 H (rotamer a)); 1.30 (s, 4.5 H, (rotamer b)). Step 4: Methyl-3-(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-ylmethyl)-amino]-2-oxo-pyrrolidin 1-vl]-acetic acid (2-6) 25 A solution of 2-5 (40 mg, 0.097mmol) in EtOH (5 mL) was treated with 10% Pd on C (8 mg) and then stirred under a H2 filled balloon for 16 h. The catalyst was removed by filtration through celite and the filtrate concentrated to afford 2-6 as a colorless glass. 'H NMR (300 MHz, CD30D) 8 7.10 (d, 1H) 6.78 (d, 0.5H (rotamer a)); 30 6.62 (d, 0.5H (rotamer b)); 4.8-3.9 (m, 5H); 3.81 (m, 2H); 3.72 (s, 3H); 3.38 (m, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H (rotamer a)); 1.15 (s, 4.5 H, (rotamer b)). - 287 - WO 98/44797 PCT/US98/06823 Step 5: 3-(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-ylmethyl)-amino]-2-oxo-pyrrolidin 1-yll-acetic acid (2-6a) A solution of 2-6 (38 mg, 0.091 mmol) in 50 % aqueous 5 THF (2 mL) was treated with 1.0 N NaOH (95 mL, 0.095 mmol) and stirred at room temperature for 2 h. The reaction was nuetralized with 1N HC1, evaporated, and the residue dissolved in MeOH (2.5 mL), filtered and evaporated to afford 2-6a as a colorless glass. 1H NMR (300 MHz, CD 3 OD) 5 7.31 (d, 1H) 6.78 (br, d, 1H); 4.8-3.9 10 (m, 5H); 3.81 (m, 2H); 3.38 (m, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H (rotamer a)); 1.15 (s, 4.5 H , (rotamer b)). Step 6: Ethyl -3-(S)-(2- { 2 -oxo-3-[(5,6,7,8-tetrahydro [1, 8 ]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl } 15 acetylamino)-3-(R)-pyridin-3-vl-propionic acid (2-8) 2-6a (43 mg, 0.093 mmol), protected amino acid 2-7 (Zablocki et al., J. Med. Chem., 1995, 38, 2378), (25 mg, 0093 mmol), EDC (18 mg, 0.093 mmol), HOBT (13 mg, 0.093 mmol), and N methyl morpholine (31 mL, 0.28 mmol) in anhydrous DMF (5 mL) was 20 stirred at room temperature for 18 h, then concentrated in vacuuo and the residue chromatographed on silica gel using 5% MeOH/CH2Cl2 as eluent affording 2-8 as a colorless glass. 1 H NMR (300 MHz, CDCl 3 ) 8 8.61 (s, 1H); 8.45 (d, 1H); 8.00 (m, 1H); 7.68, (d, 1H); 7.21 (m, 1H); 7.17 (d, 1H); 5.56 (m, 1H); 4.75 (s, 2H); 25 4.45 (m, 2H); 4.05 (q, 2H); 3.95 (m, 1H); 3.5-3.3 (m, 4H); 2.92 (m, 1H); 2.87 (m, 1H); 2.74 (m, 2H); 2.35 (m, 2H); 1.92 (m, 2H); 1.36 (s, 9H); 1.21 (t, 3H). Step 7: 3-(S)-(2- { 2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2 30 ylmethyl)-amino]-pyrrolidin- 1-yl} I-acetylamino)-3-(R) pyridin-3-vl-propionic acid (2-9) 2-8 (25 mg, 0.043 mmol) was dissolved in 6 N HC1 (2 mL) and stirred at room temperature for 16 h, then evaporated to afford 2-9 as a pale yellow solid. - 288 - WO 98/44797 PCT/US98/06823 FAB MS (453, M+1); 1 H NMR (300 MHz, CD 3 OD) 8 9.00 (s, 1H); 8.81 (d, 1H); 8.79(m, 1H); 8.10 (m, 1H); 7.71 (d, 1H); 7.01 (m, 1H); 5.56 (m, 1H); 4.75 (s, 2H); 4.61 (m, 1H); 4.50 (m, 1H); 4.35 (m, 1H); 4.10 (s, 2H); 3.62 (m, 4H); 5 3.4 -3.0 (m, 2H); 2.8 (m, 2H); 2.70 (m, 1H); 2.45 (m 1H); 1.98 (m, 2H). EXAMPLE 2a 2a-1 I N malonic acid,
NH
4 OAc EtOH (800C) CHO N PhCH 2 COCI N NN Et 3 N, 0 Dioxane/H 2 0
C
2 H CO2H Ph CNH
H
2 N H 2a-3 2a-2 Penicillin Amidase (EC 3.5.1.11) pH = 7.8, H 2 0 - 289 - WO 98/44797 PCT/US98/06823 00 H,,,+ PhCOLN2CO2H H2NI H 2 N 2 H 2a-5 2a-4 6 N HCI 500 C H02 H CO2t HI*H CO2 2 HCI* H 2 N> CO2Et EtOH, HCI 2 HCI. H 2 N v COH 2a-7 95% 2a-6 3-quinolin-3-yl-propionic acid (2a-2). A solution containing quinoline-3-carboxaldehyde 2a-1 (5 5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 h. After cooling to room temperature, the resulting white solid was collected by filtration and washed with cold ethanol (150 mL) and then dried under vacuum to provide 2a-2 as a white solid. 10 1 H NMR (300 MHz, D20): 5 8.91 (d, J = 2 Hz 1H), 8.21 (d, J = 2 Hz, 1H), 8.12 (d, J = 8 Hz, 1H), 7.84 (d, J = 7 Hz, 1H), 7.72 (t, J = 7 Hz, 1H), 7.54 (t, J = 7 Hz, 1,H), 4.72 (m, 1H), 2.73 (m, 2H). 15 3-Phenvlacetylamino-3-quinolin-3-yl-propionic (2a-3) A 0o solution of 2a-2 (3.5 g, 16.2 mmol) and NaHCO3 (2.7 g, 32.4 mmol) in 50% aqueous dioxane (100 mL) was treated dropwise with a solution of phenylacetyl chloride (3.00 g, 19.4 mmol) in 25 mL of dioxane. The resulting solution was stirred at 00 for 2.5h - 290 - WO 98/44797 PCT/US98/06823 then warmed to room temperature, diluted with H20 (50 mL) and washed with ether (2 x 100 mL). The aqueous layer was adjusted to pH = 3 with 3N HC1 and then extracted with CH2C12 (3 x 150 mL). The pooled organic extracts were dried, filtered and concentrated to afford 5 2a-3 as an off white solid. 1H NMR (300 MHz, CD3OD): 8 8.85 (d, J = 2 Hz 1H), 8.20 (d, J = 2 Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 7.86 (d, J = 7 Hz, 1H), 7.76 (t, J = 7 Hz, 1H), 7.52 (t, J = 7 Hz, 1,H), 7.28 (m, 6H), 5.53 (t, J = 6.8 Hz, 1H), 3.57 (s, 2H), 2. 96 (m, 2H). 10 3-(S)-Ouinolin-3-vl-propionic acid dihvdrochloride (2a-6) Acid 2a-3 (5.0 g, 15 mmol) was suspended in water (3.5 L) then treated with IN NaOH (15 mL) to afford a clear solution. Penicillin amidase (Sigma, EC 3.5.1.11, 10,000 U) in 0.1 M phosphate 15 buffer was added. The pH of the mixture was adjusted to 7.8 with IN NaOH and the solution was stirred at room temperature for 4 days. The reaction was monitored periodically by hplc and the reaction stopped once the 50% conversion was reached. Next, the reaction solution was cooled to 0OC and adjusted to pH = 3 with 3N HC1. An oily yellow 20 precipitate formed and was collected by filtration then washed with water to afford crude 2a-5 (1.8 g, 5.3 mmol). The filtrate was extracted with CH2Cl2 (3 x 500 mL) to afford additional 2a-5 contaminated by phenylacetic acid. Both batches of crude 2a-5 were combined and stirred in 3 N HCI (200 mL) at 500 for 12 h then cooled, 25 washed with ether (2 x 100 mL) and evaporated to afford 2a-6. 3-(S)-Ouinolin-3-vl-propionic acid ethyl ester dihydrochloride (2a-7). The resolved acid 2a-6 was converted to 2a-7 by refluxing in ethanolic HC1. 30 1 H NMR (300 MHz, CD3OD): 8 9.25 (d, J = 2 Hz 1H), 8.31 (d, J = 2 Hz, 1H), 8.15 (d, J = 8 Hz, 1H), 7.84 (d, J =7 Hz, 1H), 7.72 (t, J = 7 Hz, 1H), 7.54 (t, J = 7 Hz, 1,H), 4.72 (m, 1H), 4.15 (q, J = 6 Hz, 2H), 2.73 (m, 2H) 1.18 (t, J= 6 Hz, 3H). - 291
-
WO 98/44797 PCT/US98/06823 EXAMPLE 2a (continued) o H H,,, NN OH N a'v r"-. Bo c 0 2-6a 2a-7 EDC, HOBT, DMF N 0 H H,, N CO2Et N N N IO H 6N HCI 0 N N H,,, H N-'A N C 0 2 H N CH7 H 0H 2a-9 - 292 - WO 98/44797 PCT/US98/06823 Ethyl -3-(S)-(2- { 2-oxo-3- [(5,6,7,8-tetrahydro- [1,81naphthyridin-2 vylmethyl)- tert-butoxvcarbonyl aminol-pyrrolidin-1-yll }-acetylamino)-3 (S)-quinolin-3-vl-propionic acid (2a-8) 2-6a (100 mg, 0.216 mmol) from Example 2, Step 5, 2a-7 5 (53 mg, 0.216 mmol), EDC (41 mg, 0.216 mmol), HOBT (30 mg, 0.216 mmol), and N-methyl morpholine (66 EtL, 0.48 mmol) in anhydrousous DMF (10 mL) was stirred at room temperature for 18 h, then concentrated in vacuo and the residue chromatographed on silica gel using 5% MeOH/CH2Cl2 as eluent affording 2a-8 as a colorless 10 glass. 1 H NMR (300 MHz, CDCl3) 8 8.82 (s, 1H); 8.13 (d, 1H); 8.08 (s, 1H); 7.91, (d, 1H); 7.63 (m, 1H); 7.58 (m, 1H); 7.53 (t, 1H); 7.05 (d, 1H); 6.45 (s, 1H); 5.63 (m, 1H); 5.05 (br, s, 1H); 4.75 (s, 2H); 4.45 (m, 2H); 15 4.05 (q, 2H); 3.95 (m, 1H); 3.5-3.3 (m, 4H); 2.92 (m, 1H); 2.87 (m, 1H); 2.74 (m, 2H); 2.35 (m, 2H); 1.92 (m, 2H); 1.34 (s, 9H); 1.20 (t, 3H). 3-(S)-(2- { 2-oxo-3- [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) 20 amino] -pyrrolidin- l-yl }-acetylamino)-3-(S)-quinolin-3-yl-propionic acid (2a-9). 2a-8 (125 mg, 0.24 mmol) was dissolved in 6 N HC1 (2 mL) and stirred at room temperature for 14 h, then evaporated to afford 2a-9 as a pale yellow solid which was purified by preparative 25 reverse phase hplc (C 18, 0.1% aqueous TFA/CH3CN). FAB MS (503, M+l); 1 H NMR (300 MHz, CD3OD) 8 9.01 (s, 1H); 8.93 (s, 1H); 8.09 (d, 1H); 8.0 5 (d, 1H); 7.91 (t, 1H); 7.81 (t, 1H); 7.38 (d, 1H); 6.82 (d, 2H); 5.58 (m, 1H); 4.45 (m, 1H); 4.3 (m, 1H); 4.20 (m, 1H); 4.35 (m, 1H); 30 4.10 (s, 2H); 3.62 (m, 4H); 3.4 -3.0 (m, 2H); 2.8 (m, 2H); 2.70 (m, 1H); 2.45 (m 1H); 2.05 (m, 1H); 1.98 (m, 2H). - 293 - WO 98/44797 PCT/US98/06823 EXAMPLE 3 0 0 1) CH 2 PPh 3
CH
2 0
CH
3 OEt CH 3 OH 3-1 2) NaOH 3-1 3-2 pivaloyl chloride CH 2 0 0 NaN(SiMe 3
)
2 3-2 0 ' CH 3 N' 0 then LiN , 03-3 Ph F 3
CSO
3 3 SPh 3-4 Ph
H
2 1) NaN 3
CH
2
OH
3 _- yO CH 3 NH S2) PPh 3 , H 2 0 3-6 Cl 3-5 Ph NaN(SiMe 3
)
2 CH3,N then CH 2 OtOs0 4 ' ,N 0 3-6 0
OH
3 OEt OEt 3-7 0 then NalO 4 5 Br 0 O 't OHN OlEt (N NH 2
CH
3 N O 1-4 3-8 0 proline - 294 - WO 98/44797 PCT/US98/06823 0 OEt N NN 3-9 0 Pd/C,
H
2 OEt N N N- QEI H 3-10 0 6N HCI OH N N NH *HCI 3-11 0 0 N.N OH H *HCI 3-11 EDC, HOBT NMM
H
2 N OEt 0 3-12 N *2HCI - 295 - WO 98/44797 PCT/US98/06823 0 H N N OEt 3-13 1N N SNaOH 0 H N N OH N NN H l 3-14 N Step 1l: 4-(Propyl-2-ene)butyric acid (3-2) To a stirred suspension of methyltriphenylphosphonium 5 bromide (67.7 g, 190 mmol) in 1 L THF at 00 C was added a solution of sodium bis(trimethylsilyl)amide (190 mL, 190 mmol, 1IM THF) . After an additional 30 minutes, ethyl 4-acetylbutyrate 3-1 (Aldrich Chemical Co.)(25.0 g, 158 mmol) was added, and the mixture stirred for 18 h. The mixture was filtered, and the filtrate concentrated. The residue 10 was triturated with hexanes, and then filtered. Following evaporative removal of the solvent, the residue was chromatographed on silica gel, eluting with 10% ethyl acetate/hexanes to give the olefin as a colorless oil. TLC Rf = 0.52 (10% ethyl acetate/hexanes). 1 H NMR (300 MHz, CHCl3) 6 4.71 (d, 2H, J=13 Hz), 4.13 (q, 2H, J=7 15 Hz), 2.29 (t, 2H, J=7 Hz), 2.05 (t, 2H, J= 8 Hz), 1.77 (m, 2H), 1.72 (s, 3H), 1.26 (t, 3H, J=7Hz). A solution of the above olefin (15.4 g, 98.6 mmol), 1 N NaOH (150 mL), and EtOH (300 mL) was stirred at ambient temperature for 2 h. Following acidification with 1 N HC1, the mixture 20 was extracted with ether. The ether layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-2 as a colorless oil. - 296 - WO 98/44797 PCT/US98/06823 1 H NMR (300 MHz, CHCl3) 8 4.70 (d, 2H, J=13 Hz), 2.27 (t, 2H, J=7 Hz), 2.06 (t, 2H, J= 7 Hz), 1.72 (m, 5H). Step 2: ( 4 -(Propyl- 2 -ene)butanoyl)-4(R)-benzyl-2-oxazolidinone 5 (3-3) To a solution of 3-2 (6.0 g , 46.8 mmol) in THF (200 ml) at -780 C was added triethylamine (7.19 mL, 51.5 mmol) followed by pivaloyl chloride (6.35 mL , 51.5 mmol). The mixture was warmed to 0 0 C for 1 h, then recooled to -780 C. In a separate flask, of (R)-(+) 10 4-benzyl-2-oxazolidinone (9.15 g, 51.5 mmol) was dissolved in THF (100 mL), cooled to -780 C, and n-BuLi (32.3 mL, 51.5 mmol; 1.6 M hexanes) was added dropwise. After 10 minutes, the lithium oxazolidinone was added to the pivalic anhydride. After 10 minutes, the mixture was warmed to 0 C for 1.5 h. The mixture was then poured 15 into ethyl acetate, washed with aqueous sodium bicarbonate, and dried over magnesium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, dichloromethane) to give 3-3 as a slightly yellow oil. TLC Rf = 0.8 (CH2Cl2). 20 1 H NMR (300 MHz, CHCl3) 8 7.40-7.18 (m, 5H), 4.80-4.60 (m, 3H), 4.18 (m, 2H), 3.30 (dd, 1H, J=3.2, 13.2 Hz), 2.95 (m, 2H), 2.76 (dd, 1H, J=9.5, 13.1 Hz), 2.11 (t, 2H, J=7.5 Hz), 1.87 (m, 2H), 1.74 (s, 3H). Step 3: 2-Chloroethyltriflate (3-4) 25 To a solution of 1.67 mL (24.8 mmol) of 2-chloroethanol and 3.47 mL (29.8 mmol) of 2,6-lutidine in 20 mL of dichloromethane at 00 C was added 4.59 mL (27.3 mmol) of triflic anhydride. After 1 h, the mixture was diluted with hexanes, washed with ice-cold 1N HC1, and dried over sodium sulfate. The solvents were evaporated to give 30 3-4 as a pink oil. 1 H NMR (300 MHz, CHC13) 8 4.69 (t, 2H, J=5.3 Hz), 3.78 (t, 2H, J=5.6 Hz). - 297 - WO 98/44797 PCT/US98/06823 StI 4: 2(S)-Chloroethyl-4-(propyl-2-ene)butanoyl-(4(R)-benzyl-2 oxazolidinone) (3-5) To a solution of 3-3 (11.0 g, 38.3 mmol) in THF (60 mL) at -78oC was added a solution of sodium bis(trimethylsilyl)amide (42.1 5 mL, 42.1 mmol; 1M/THF). After 20 min, 3-4 (16.2 ml, 115 mmol) was added over 5 min, and the resulting mixture stirred for 1.5 h at -78 0 C, then 2 h at -15'C. The mixture was diluted with hexanes, washed with sat. ammonium chloride, and dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed 10 (silica gel, 14% ethyl acetate/hexanes) to give 3-5 as a colorless oil. TLC Rf = 0.5 (20% ethyl acetate/hexanes). 1H NMR (300 MHz, CHCl3) 6 7.30-7.18 (m, 5H), 4.67 (m, 3H), 4.19 (m, 2H), 3.99 (m, 1H), 3.58 (m, 2H), 3.33 (dd, 1H, J=3.2, 12.0 Hz), 2.75 (dd, 1H, J=9.7, 13.5 Hz), 2.23 (m, 1H), 2.18-1.82 (m, 4H), 1.77 15 1.60 (m, 1H), 1.71 (s, 3H). Step 5: Ethyl 2 -oxo-3(S)-(3-methylenebutyl)pyrrolidine (3-6) A mixture of 3-5 (8.15 g, 23.3 mmol) and NaN3 (4.54 g, 69.8 mmol) in DMSO (120 mL) was heated at 750 C for 2 h. After 20 cooling, the mixture was diluted with ether and hexanes, washed with water, and dried over sodium sulfate. Evaporative removal of the solvent gave the azide as a colorless oil. TLC Rf = 0.5 (20% ethyl acetate/hexanes). 1 H NMR (300 MHz, CHC13) 8 7.30-7.22 (m, 5H), 4.69 (m, 3H), 4.17 25 (d, 2H, J=5.1 Hz), 3.89 (m, 1H), 3.38 (m, 3H), 2.74 (m, 1H), 2.13-1.63 (m, 6H), 1.71 (s, 3H). To a solution of of this azide (8.0 g , 22.4 mmol) in THF (250 mL) and water (40 mL) was added triphenylphosphine (8.24 g, 31.4 mmol) in 4 portions over 5 minutes. This mixture was heated 30 at reflux for 2 h, cooled, and evaporated. The residue was chromato graphed (silica gel, 10% chloroform/ethyl acetate) to give 3-6 as a colorless oil. - 298 - WO 98/44797 PCT/US98/06823 TLC Rf = 0.40 (20% chloroform/ethyl acetate). 1 H NMR (300 MHz, CHCl3) 8 6.47 (br s, 1H), 4.73 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.08 (m, 3H), 1.81 (m, 1H), 1.74 (s, 3H), 1.44 (s, 1H). 5 Step 6: Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidin- 1-yl)acetate (3-7) To a solution of 3-6 (2.50 g, 16.3 mmol) in THF (40 mL) at -780 C was added sodium bis(trimethylsilyl)amide (17.1 mL, 17.1 10 mmol; 1M/ THF) dropwise. After an additional 20 min, ethyl bromoacetate (2.17 mL, 19.6 mmol) was added dropwise over 3 min. After an additional 20 min, 20 mL sat. aqueous NH4Cl was added, and the cooling bath removed. The layers were separated, the aqueous layer washed with ether, and the combined organic extracts were dried over 15 sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes) to give 3-7 as a colorless oil. TLC Rf = 0.85 (50% chloroform/ethyl acetate). 1 H NMR (300 MHz, CHCl3) 8 4.73 (m, 2H), 4.18 (q, 2H, J=7.1Hz), 20 4.06 (dd, 2H, J=17.6, 20.8 Hz), 3.42 (m, 2H), 2.44 (m, 1H), 2.27 (m, 1H), 2.12 (m, 3H), 1.75 (m, 1H), 1.74 (s, 3H), 1.50 (m, 1H), 1.28 (t, 3H, J=7.3 Hz). Step 7: Ethyl 2-oxo-3(S)-(3-oxo-butyl)pyrrolidin-1-yl)acetate 25 (3-8) To a solution of 3-7 (3.35 g,14.0 mmol) and N methylmorpholine-N-oxide (3.27 g, 28.0 mmol) in THF (10 mL) and water (1 mL) was added OsO4 (5.7 mL, 0.56 mmol; 2.5 % t-butanol). After 1 h, NalO4 (5.99 g , 28 mmol) in warm water (30 mL) was added 30 over 2 min, and the resulting mixture stirred for 1 h. Water was then added, and the aqueous layer washed with ether and ethyl acetate, and the combined organic extracts were dried over sodium sulfate. Evaporative removal of the solvent gave 3-8 as a dark oil containing residual OsO4. - 299 - WO 98/44797 PCT/US98/06823 TLC Rf = 0.78 (70:20:10 chloroform/ethyl acetate/MeOH). 1H NMR (300 MHz, CHC13) 8 4.19 (m, 2H, J=7.2 Hz), 4.03 (s, 2H), 3.41 (m, 2H), 2.68 (t, 2H, J=9.4 Hz) 2.45 (m, 1H), 2.27 (m, 1H), 2.17 (s, 3H), 1.97 (m, 1H), 1.78 (m, 2H), 1.28 (t, 3H, J=7.2 Hz). 5 Ste 8: Ethyl 2-oxo-3(S)-[2-([1,8]-naphthyridin-2-yl)ethyl] pyrrolidin-1-yl)acetate (3-9) A mixture of 3-8 (3.25 g, 13.5 mmol), 2-amino-3-formyl pyridine (2.2 g, 18.2 mmol; for preparation see Synth. Commun. 1987, 10 17, 1695) and proline (0.62 g, 5.39 mmol) in absolute ethanol (45 mL) was heated at reflux for 15 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 3-9 as a colorless oil. TLC Rf = 0.24 (70:25:5 chloroform/ethyl acetate/MeOH). 15 1 H NMR (300 MHz, CHCl3) 8 9.08 (m, 1H), 8.16 (m, 2H), 7.47 (m, 2H), 4.17 (m, 4H), 3.42 (m, 2H), 3.21 (t, 2H, J=6.0 Hz), 2.56 (m, 1H), 2.39 (m, 2H), 2.08 (m, 1H), 1.87 (m, 1H), 1.27 (t, 3H, J=7.1 Hz). Step 9: Ethyl 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin 20 2-yl)ethyl]pyrrolidin- 1-yl)acetate (3-10) A mixture of 3-9 (3.33 g, 10.2 mmol) and 10% Pd/carbon (1.5 g) in EtOH (50 mL) was stirred under a balloon of hydrogen for 13 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl 25 acetate/MeOH to give 3-10 as a colorless oil. TLC Rf = 0.20 (70:20:10 chloroform/ethyl acetate/MeOH). 1H NMR (300 MHz, CHCl3) 5 7.05 (d, 1H, J=7.3 Hz), 6.38 (d, 1H, J=7.3 Hz), 4.88 (br s, 1H), 4.17 (dd, 2H, J=7.0, 14.4 Hz), 4.04 (dd, 2H, J=17.6, 27.3 Hz), 3.40 (m, 4H), 2.69 (m, 4H), 2.51 (m, 1H), 2.28 (m, 30 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.27 (t, 3H, J=6.9 Hz). - 300 - WO 98/44797 PCT/US98/06823 Step 10: 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2 yl)ethyl]pyrrolidin- 1-yl)acetic acid (3-11) A mixture of 3-10 (0.60 g, 1.81 mmol) and 6N HCI (25 mL) was heated at 600 C for 1 h. Evaporative removal of the solvent 5 gave 3-11 as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) 6 8.4 (br s, 1H), 7.60 (d, 1H, J=7.3 Hz), 6.63 (d, 1H, J=7.3 Hz), 3.92 (dd, 2H, J=17.6, 25.9 Hz), 3.43 (m, 2H), 3.35 (m, 2H), 2.74 (m, 4H), 2.28 (m, 2H), 2.03 (m, 1H), 1.82 (m, 2H), 1.67 (m, 2H). 10 Step 11: 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]-pyrrolidin- 1-yl)acetyl-3(S)-pyridin-3-yl-0-alanine ethyl ester (3-13) A mixture of 3-11 (0.30 g, 0.882 mmol), amino acid ester 15 3-12 (Rico et al., J. Org. Chem., 1993, 58, 7948), (0.354 g, 1.32 mmol), EDC (0.220 g (1.15 mmol), HOBT (0.143 g, 1.05 mmol) and NMM (0.680 mL (6.18 mmol) in CH3CN (5 mL) and DMF (3 mL) at 0 C was stirred for 10 min, then allowed to warm and stir for 20 h. The mixture was diluted with ethyl acetate, washed with water, brine, 20 and dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroformlethyl acetate/MeOH to give 3-13 as a colorless foam. TLC Rf = 0.31 (70:20:10 chloroform/ethyl acetate/MeOH). 1 H NMR (300 MHz, CHCl3) 8 8.55 (d, 1H, J=2.2 Hz), 8.50 (dd, 1H, 25 J= 1.5, 4.6 Hz), 7.64 (m, 2H), 7.23 (m, 1H), 7.05 (d, 1H, J=7.3 Hz), 6.38 (d, 1H, J=7.3 Hz), 5.40 (m, 1H), 4.98 (br s, 1H), 4.01 (m, 4H), 3.39 (m, 4H), 2.85 (m, 2H), 2.68 (m, 4H), 2.49 (m, 1H), 2.25 (m, 2H), 1.83 (m, 4H), 1.16 (t, 3H, J=7.2 Hz). 30 Step 14: 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin 2-yl)ethyl]pyrrolidin- 1 -yl)acetyl-3 (S)-pyridin-3-yl-p alanine (3-14) To a solution of 3-13 (0.049 g, 0.102 mmol) in THF (1 mL) and water (0.3 mL) at 0 0 C was added 1M LiOH (0.112 ml, 0.112 - 301 - WO 98/44797 PCT/US98/06823 mmol). After warming to ambient temperature and stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 3-14 as a colorless foam. 5 TLC Rf = 0.15 (25:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1 H NMR (300 MHz, DMSO-d6) 8 8.74 (d, 1H, J=8.3 Hz), 8.51 (m, 1H), 8.42 (min, 2H), 7.70 (d, 1H, J=8.1 Hz), 7.33 (min, 1H), 7.21 (d, 1H, J=7.3 Hz), 6.36 (d, 1H, J=7.3 Hz), 5.14 (min, 1H), 4.00 (d, 1H, J=16.8 Hz), 3.70 (d, 1H, J=16.6 Hz), 3.30 (min, 4H), 2.68 (m, 7H), 2.20 (min, 3H), 1.71 (inm, 10 4H). EXAMPLE 4 (S)-l1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-imidazolylmethyl]-5-[2 (methanesulfonyl)ethyl]l-2-piperazinone dihydrochloride 15 Step A: 1-triphenylmethyl-4-(hydroxymethyl)-imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white 20 solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 immol) 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 25 which was sufficiently pure for use in the next step. Step B: 1-triphenylmethyl-4-(acetoxymethyl)-imidazole Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 30 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCI soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The acetate was - 302 - WO 98/44797 PCT/US98/06823 isolated as a white powder which was sufficiently pure for use in the next reaction. Step C: 1-(4-cyanobenzyl)-5-(acetoxymethyl)-imidazole 5 hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and oc-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 0 C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to 10 provide the solid imidazolium bromide salt. The filtrate was concen trated in vacuo to a volume 200 mL, reheated at 60 0 C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 0 C for another two hours, cooled to room temperature, and concentrated in vacuo to 15 provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 0 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 20 as a white solid which was used in the next step without further purification. Step D: 1-(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole To a solution of the acetate from Step C (50.4 g, 150 25 mmol) in 1.5 L of 3:1 THF/water at 0 0 C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude 30 product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification. - 303 - WO 98/44797 PCT/US98/06823 Step E: 1-( 4 -cyanobenzyl)-5-imidazolecarboxaldehvde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethyl amine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g, 254 5 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure for use in the next step without further purification. 10 Step F: {S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl 4-(methylthio)butanamide L-N-Boc-methionine (30.0 g, 0.120 mol), N,O-dimethyl hydroxylamine hydrochloride (14.1 g, 0.144 mol), EDC hydrochloride 15 (27.7 g, 0.144 mol) and HOBT (19.5 g, 0.144 mol) were stirred in dry DMF (300 mL) at 20 0 C under nitrogen. More N, O-dimethylhydroxyl amine hydrochloride (2.3 g, 23 mmol) was added to obtain pH 7-8. The reaction was stirred overnight, the DMF distilled to half the original volume under high vacuum, and the residue partitioned between ethyl 20 acetate and sat. NaHCO3 soln. The organic phase was washed with saturated sodium bicarbonate, water, 10% citric acid, and brine, and dried with sodium sulfate. The solvent was removed in vacuo to give the title compound. 25 Step G: (S)-2-(tert-butoxvcarbonylamino)-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 30 added over 30 min, maintaining the temperature below -40 0 C. When the addition was complete, the reaction was warmed to 5oC, then recooled to -45 0 C. Analysis by tlc revealed incomplete reaction. The solution was rewarmed to 5 oC, stirred for 30 minutes, then cooled to - 304 - WO 98/44797 PCT/US98/06823 -50 0 C. A solution of potassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly added, maintaining the temperature below -20 0 C. The mixture was wasmed to 5oC, filtered through Celite, and concentrated in vacuo to provide the title aldehyde. 5 Step H: (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl) 4-(methylthio)butanamine To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 10 mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The solution was diluted with CHCl3, and the organic phase was washed with water, 10% citric acid and brine. The solution was 15 dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound. Step I: (S)-4-(tert-butoxycarbonyl)- 1 -(3-chlorophenyl)-5-[2 20 (methylthio)ethyl]piperazin-2-one A solution of the product from Step H (22.0 g, 63.8 mmol) in ethyl acetate (150 mL) was vigorously stirred at 0OC with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwise, and the reaction stirred at 0OC for 2h. 25 The layers were separated, and the ethyl acetate phase was washed with 10% citric acid and saturated brine, and dried over sodium sulfate. After concentration in vacuo, the resulting crude product (27.6 g) was dissolved in DMF (300 mL) and cooled to 0OC under argon. Cesium carbonate (63.9 g, 196 mmol) was added, and the reaction was stirred 30 for two days, allowing it to warm to room temperature. Another portion of cesium carbonate (10 g, 30 mmol) was added, and the reaction was stirred for 16 hours. The DMF was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, and dried over sodium sulfate. - 305 - WO 98/44797 PCT/US98/06823 The crude product was chromatographed on silica gel with 20-25% ethyl acetate in hexane to obtain the title compound. Step J: (S)-4-(tert-butoxycarbonyl)- 1-(3-chlorophenyl)-5-[2 5 (methanesulfonyl)ethyl]piperazin-2-one A solution of the product from Step I (14.2 g, 37 mmol) in methanol (300 mL) was cooled to 0OC, and a solution of magnesium monoperoxyphthalate (54.9 g, 111 mmol) in 210 mL MeOH was added over 20 minutes. The ice bath was removed, and the solution was 10 allowed to warm to room temperature. After 45 minutes, the reaction was concentrated in vacuo to half the original volume, then quenched by the addition of 2N Na2S203 soln. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the 15 crude sulfone. This material was chromatographed on silica gel with 60-100% ethyl acetate in hexane to obtain the titled compound. Step K: (S)-1-(3-chlorophenyl)-5-[2-(methanesulfonyl)ethyl] piperazin-2-one 20 Through a solution of Boc-protected piperazinone from Step J (1.39 g, 3.33 mmol) in 30 mL of EtOAc at 0OC was bubbled anhydrous HC1 gas. The saturated solution was stirred for 35 minutes, then concentrated in vacuo to provide the hydrochloride salt as a white powder. This material was suspended in EtOAc and treated with dilute 25 aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc, and the combined organic mixture was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting amine was reconcentrated from toluene to provide the titled material suitable for use in the next step. 30 - 306 - WO 98/44797 PCT/US98/06823 Step L: (S)- 1-(3-chlorophenyl)-4- [1-(4-cyanobenzyl)imidazolyl methyl]-5-[2-(methanesulfonyl)-ethyl]-2-piperazinone dihydrochloride To a solution of the amine from Step K (898 mg, 2.83 5 mmol) and imidazole carboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mL of 1,2-dichloroethane was added sodium triacetoxyboro hydride (1.21 g, 5.7 mmol). The reaction was stirred for 23 hours, then quenched at 0 0 C with sat. NaHCO3 solution. The solution was poured into CHCl3, and the aqueous layer was back-extracted with 10 CHCl3. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (95:5:0.5-90:10:0 EtOAc:MeOH:NH4C1), and the resultant product was taken up in EtOAc/methanol and treated with 2.1 equivalents of 1 M HC1/ether 15 solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder. EXAMPLE 5 20 1-(3-chlorophenyl)-4- [1-(4-cyanobenzyl)imidazolyl-methyl]-2 piperazinone dihydrochloride Step A: N-(3-chlorophenyl)ethylenediamine hydrochloride To a solution of 3-chloroaniline (30.0 mL, 284 mmol) 25 in 500 mL of dichloromethane at 0 0 C was added dropwise a solution of 4 N HC1 in 1,4-dioxane (80 mL, 320 mmol HC1). 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 30 atmosphere at 160 0 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. - 307 - WO 98/44797 PCT/US98/06823 Step B: N-(tert-butoxycarbonyl)-N'-(3-chlorophenyl) ethylenediamine The amine hydrochloride from Step A (ca. 282 mmol, crude material prepared above) was taken up in 500 mL of THF 5 and 500 mL of sat. aq. NaHCO3 soln., cooled to 0OC, and di-tert butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without 10 further purification. Step C: N-[2-(tert-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)-2 chloroacetamide A solution of the product from Step B (77 g, ca. 282 mmol) 15 and triethylamine (67 mL, 480 mmol) in 500 mL of CH2Cl2 was cooled to 0OC. Chloroacetyl chloride (25.5 mL, 320 mmol) was added drop wise, and the reaction was maintained at 0 0 C with stirring. After 3 h, another portion of chloroacetyl chloride (3.0 mL) was added dropwise. After 30 min, the reaction was poured into EtOAc (2 L) and washed 20 with water, sat. aq. NH4C1 soln, sat. aq. NaHCO3 soln., and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the chloroacetamide as a brown oil which was used in the next step without further purification. 25 Step D: 4-(tert-butoxycarbonyl)- 1-(3-chlorophenyl)-2-piperazinone To a solution of the chloroacetamide from Step C (ca. 282 mmol) in 700 mL of dry DMF was added K2CO3 (88 g, 0.64 mol). The solution was heated in an oil bath at 70-75oC for 20 hours, cooled 30 to room temperature, and concentrated in vacuo to remove ca. 500 mL of DMF. The remaining material was poured into 33% EtOAc/hexane, washed with water and brine, dried (Na2SO4), filtered, and concen trated in vacuo to provide the product as a brown oil. This material was purified by silica gel chromatography (25-50% EtOAc/hexane) to yield - 308 - WO 98/44797 PCT/US98/06823 pure product, along with a sample of product (ca. 65% pure by HPLC) containing a less polar impurity. Step E: 1-(3-chlorophenyl)-2-piperazinone 5 Through a solution of Boc-protected piperazinone from Step D (17.19 g, 55.4 mmol) in 500 mL of EtOAc at -78 0 C was bubbled anhydrous HCI gas. The saturated solution was warmed to 0OC, and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HC1, and the mixture was warmed to room temperature. 10 The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2Cl2 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (8 x 300 mL) until tlc analysis indicated complete extraction. The combined organic mixture was dried 15 (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil. S te.: 1-(3-chlorophenyl)-4- [1-(4-cyanobenzyl)imidazolylmethyl] 2-piperazinone dihvdrochloride 20 To a solution of the amine from Step E (55.4 mmol, prepared above) in 200 mL of 1,2-dichloroethane at 0OC was added 4k powdered molecular sieves (10 g), followed by sodium triacetoxyboro hydride (17.7 g, 83.3 mmol). The imidazole carboxaldehyde from Step E of Example 4 (11.9 g, 56.4 mmol) was added, and the reaction was 25 stirred at 0OC. After 26 hours, the reaction was poured into EtOAc, washed with dilute aq. NaHCO3, and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 500 mL of 5:1 benzene:CH2Cl2, and propyl 30 amine (20 mL) was added. The mixture was stirred for 12 hours, then concentrated in vacuo to afford a pale yellow foam. This material was purified by silica gel chromatography (2-7% MeOH/CH2C12), and the resultant white foam was taken up in CH2C12 and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, - 309 - WO 98/44797 PCT/US98/06823 the product dihydrochloride was isolated as a white powder. EXAMPLE 6 5 Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl leucine methyl ester (Compound 6-1) Step A. Preparation of N-(2(R)-t-butoxycarbonyl-amino-3 triphenyl-methylmercaptopropyl)-valyl-isoleucyl-leucine 10 methyl ester The tripeptide ester valyl-isoleucyl-leucine methyl ester was synthesized using conventional solution phase peptide synthesis methods. The trifluoroacetate salt of this tripeptide (360 mg, 0.77 mmol) was dissolved in 5 mL of methanol with 147 mg (1.5 mmol) of potassium 15 acetate and 670 mg (1.5 mmol) of N-Boc-S-tritylcysteinal (prepared using the procedure of Goel, Krolls, Stier, and Kesten Org. Syn. 67: 69-74 (1988) for the preparation of N-Boc-leucinal) was added. Sodium cyanoborohydride (47 mg, 0.75 mmol) was added and the mixture was stirred overnight. The mixture was diluted with ether and washed with 20 water, 5% ammonium hydroxide and brine. The solution was dried (sodium sulfate) and evaporated to give a white foam which was purified by chromatography (1-15% acetone in methylene chloride). The title compound was obtained as an oily material. 25 Step B. Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl isoleucyl-leucine methyl ester A sample of the protected pseudopeptide prepared as described in Step A (728 mg, 0.92 mmol) was dissolved in 100 mL of methylene chloride, 50 mL of TFA was added and the resulting yellow 30 solution was treated immediately with 0.80 mL (5 mmol) of triethyl silane. After 45 min, the solvents were evaporated and the residue was partitioned between hexane and 0.1% aqueous TFA. The aqueous solution was lyophilized. This material was further purified by reverse phase HPLC (5-95% acetonitrile/0.1% TFA/water) to afford the title 35 compound. 1 H NMR (CD 3 OD) 8 8.65 (1H, d), 4.45 (1H, m), 4.3 (1H, -310 - WO 98/44797 PCT/US98/06823 d), 3.7 (3H, s), 3.4 (1H, m), 3.15 (1H, d), 2.75-2.95 (m), 0.8-1.05 (18 H, m). FAB mass spectrum, m/z = 447 (M + 1). Anal. Calcd for C21H42N404S* 1.8 TFA: C, 45.24; H, 6.75; N, 8.56. 5 Found: C, 45.26; H, 6.77; N. 8.50. EXAMPLE 7 N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine 10 (Compound 7-2) Step A. Preparation of N-(2(R)-t-butoxycarbonylamino-3 triphenylmethylmercaptopropyl)-valyl-isoleucvl-leucine The product of Example 6, Step A (60 mg, 0.076 mmol) 15 was dissolved in 1 mL of methanol and 150 pL of 1N NaOH was added. After stirring overnight, the solution was acidified with 150 pL of 10% citric acid and the product was extracted with ether. The ether solution was washed with water and brine and dried (sodium sulfate). Evaporation provided the title compound as a solid. 20 Step B. Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl isoleucyl-leucine Using the method of Example 6, Step B, the protecting groups were removed with TFA and triethylsilane to provide the title 25 compound. FAB mass spectrum, m/z = 433 (M+I). Anal. Called for C20H40N404S * 2 TFA: C, 43.63; H, 6.41; N, 8.48. Found: C, 43.26; H, 6.60; N. 8.49. -311 - WO 98/44797 PCT/US98/06823 EXAMPLE 8 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (Compound 5 8-1) and 2(S)-[ 2
(S)-[
2 (R)-Amino-3-mercapto]-propylamino-3(S) methyl]pentyloxy-3-phenyl-propionyl-homoserine (Compound 8-2) Step A: Preparation of N-(x-chloroacetyl)-L-isoleucinol To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and 10 triethylamine (28.56 ml, 0.204 mol) in CH2C12 (500 ml) at -78 0 C was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20 0 C. The mixture was diluted with EtOAc and washed sequentially with 1 M HC1, and brine and dried (Na2SO4). Evaporation in vacuo afforded the 15 amide title compound (35 g, 100%). Rf = 0.3 CH2Cl2: MeOH (95:5); 1H NMR (CDCl3) 5 6.80 (1H, brd, J = 5 Hz), 4.10 (2H, s), 3.84 (1H, m), 3.79 (2H, m), 2.65 (1H, brs), 1.72 (1H, m), 1.55 (1H, m), 1.17 (1H, m), 0.96 (3H, d, J = 6Hz) 0.90 (3H,t, J=6 Hz). 20 Step B: Preparation of 5(S)-[1l(S)-methyl]propyl-2,3,5,6-tetra hydro-4H- 1,4-oxazin-3-one To a stirred solution of N-(a-chloroacetyl)-L-isoleucinol (7.4 g, 0.038 mol) in THF (125 ml) under argon at 0OC was slowly 25 added sodium hydride (2.2 g of a 60% dispersion in mineral oil, 0.055 mol) with concomitant gas evolution. After completing the addition, the mixture was warmed to room temperature (R.T.) and stirred for 16 hr. Water (2.8 ml) was added and the solvents evaporated in vacuo. The residue was dissolved in CHC13 (70 ml) and washed with water saturated 30 NaC1 solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed using silica gel eluting with CH2Cl2:MeOH (96:4) to afford the lactam title compound (4.35 g, 72%) as a white solid. Rf = 0.35 CH2Cl2:MeOH (95:5); -312 - WO 98/44797 PCT/US98/06823 1H NMR 8 (CDCl3) 6.72 (1H, brs), 4.20 (1H, d, J = 14.5 Hz), 4.10 (1H, d, J = 14.5 Hz), 3.88 (1H, dd, J = 9 and 3.5 Hz), 3.58 (1H, dd, J = 9 and 6.5 Hz), 3.45 (1H, brqt, J = 3.5 Hz), 1.70-1.45 (2H, min), 1.34 - 1.15 (1H, min), 0.96 (3H, t, J = 6.5 Hz), 0.94 (3H, d, J = 6.5 Hz). 5 Step C: Preparation of N-(tert-butoxycarbonyl)-5(S)-[1(S) methyl]lpropyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one 5(S)- [1 (S)-Methyl]propyl-2,3,5,6-tetrahydro 4H-1,4 oxazin-3-one (12.2 g, 0.0776 mol) and DMAP (18.9 g, 0.155 mol) 10 were dissolved in methylene chloride (120 ml) under argon at R.T. Boc anhydride (33.9 g, 0.155 mol) was added to the stirred solution in one portion, with concomitant gas evolution and the mixture was stirred at R.T. for 16 hr. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with 10% citric 15 acid, 50% NaHCO3 and finally brine. The organic extract was dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue over silica gel eluting with 20% EtOAc in hexanes afforded the title compound (14.1 g, 71%) as a white solid. Rf = 0.75 EtOAc:hexanes (20:80); mp 59-60 0 C 20 Anal. Calc'd. for C13H2304N: C, 60.68; H,9.01; N, 5.44. Found: C, 60.75; H, 9.01; N, 5.58. 1H NMR (CDC13) 8 4.25 (1H, d, J = 15 Hz), 4.15 (1H, d, J = 15 Hz), 4.15 - 4.00 (2H, m), 3.73 (1H, dd, J = 10 and 2 Hz), 1.88 (1H, qt, J = 6 25 Hz), 1.55 (9H, s), 1.50 - 1.36 (1H, min), 1.35 - 1.19 (1H, m) 1.00 (3H, d, J = 6 Hz) 0.95 (3H, d, J = 6.5 Hz). Step D: Preparation of N-(tert-Butoxycarbonyl)-2(S)-benzyl-5(S) [1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3 30 one A solution of N-(tert-butoxycarbonyl)-5(S)-[1(S) methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (5.75 g, 22.34 mmol) in DME (100 ml) under argon was cooled to -60 0 C. The cold solution was transferred via canula to a second flask containing sodium - 313 - WO 98/44797 PCT/US98/06823 bis(trimethylsilyl)amide (24.58 ml of a IM solution in THF, 24.58 mmol) at -78 0 C under argon. After stirring for 10 minutes, benzyl bromide (2.25 ml, 18.99 mmol) was added over 5 minutes and the resulting mixture was stirred at -78 0 C for 3 hours. After this time, the 5 reaction mixture was transferred via cannula to another flask containing sodium bis(trimethylsilyl)amide (24.58 ml of a 1M solution in THF, 24.58 mmol) at -78 0 C, under argon. After stirring for a further 5 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (24.6 ml) and allowed to warm to room 10 temperature. This mixture was diluted with brine (50 ml) and water (20 ml) and then extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with brine (50 ml) and evaporated in vacuo to afford an oil. Chromatography of the residue over silica gel (230-400 mesh, 300 g) eluting with 10-20% ethyl acetate in hexanes afforded the 15 title compound (5.12 g, 67%) as a clear oil. Rf = 0.25 EtOAc:Hexanes (20:80); 1H NMR (CDC13) 8 7.35 - 7.15 (5H, m), 4.31 (1H, dd, J = 6 and 2 Hz), 4.03 (1H, d, J = 12 Hz), 3.88 (1H, dd, J = 6 and 1 Hz), 3.66 (1H, dd, J = 12 and 2 Hz), 3.29 (1H, dd, J = 12 and 3 Hz), 1.54 (9H, s), 3.12 20 (1H, dd, J = 12 and 7 Hz), 1.47 (1H, m), 1.25 (1H, m), 1.10 (1H, m), 0.83 (3H, d, J = 6 Hz), 0.80 (3H, t, J = 6 Hz). Step E: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino 3(S)-methyl]pentyloxy-3-phenyl-propionic acid 25 To a stirred solution of N-(tert-butoxycarbonyl)-2(S) benzyl-5(S)-[1(S)-methyl]-propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3 one (5.1 g, 14.7 mmol) in THF (150 ml) and water (50 ml) at 0OC was added hydrogen peroxide (15 ml of a 30% aqueous solution, 132 mmol) and lithium hydroxide (3.0 g, 63.9 mmol). After stirring for 30 30 minutes, the reaction was quenched with a solution of sodium sulfite (28.25 g, 0.224 mol) in water (70 ml). The THF was evaporated in vacuo and the aqueous phase was acidified to pH 3-4 by addition of -314 - WO 98/44797 PCT/US98/06823 10% citric acid solution and extracted with EtOAc. The organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by chromatography over silica gel eluting with 4% MeOH in CH2C12 to give the lactam 2(S)-benzyl-5(S)-[l(S)-methyl]propyl 5 2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (0.82 g 22%) and then with 20% MeOH in CH2Cl2 to afford the title compound (4.03 g, 75%) as a viscous oil. Rf = 0.4 MeOH:CH2Cl2 (5:95) + 0.3% AcOH; 1H NMR (d6 DMSO) 8 7.35 - 7.10 (5H, m), 6.68 (1H, br, s), 3.75 (1H, 10 dd, J = 7.5 and 2.5 Hz) 3.54 (1H, m), 3.5 - 3.2 (2H, m) 2.99 (1H, dd, J = 12.5 and 2.5 Hz), 2.75 (1H, dd, J = 12.5 and 7.5 Hz), 1.50 - 1.35 (11H, m), 0.98 (1H, sept, J = 6 Hz), 0.78 (3H, t, J = 6 Hz), 0.65 (3H, d, J = 6 Hz); FAB MS 366 (MH+) 266 (MH2+ - CO2tBu). 15 Step F: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino 3(S)-methyl]-pentyloxy-3-phenyl-propionyl-homoserine lactone To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-[2(S) 20 amino- 3 (S)-methyl]-pentyloxy-3-phenylpropionic acid (0.53 g, 1.45 mmol) and 3-hydroxy-1,2,3,-benzotriazin-4(3H)-one (HOOBT) (0.26 g, 1.6 mmol) in DMF (15 ml) at room temperature was added EDC (0.307 g, 1.6 mmol) and L-homoserine lactone hydrochloride (0.219 g, 6.0 mmol). The pH was adjusted to pH= 6.5 by addition of NEt3 (the pH 25 was monitored by application of an aliquot of the reaction mixture to a moist strip of pH paper). After stirring at room temperature for 16 hr, the reaction was diluted with EtOAc and washed with saturated NaHCO3 and then brine and dried (NaSO4). Evaporation in vacuo (sufficient to remove DMF) and chromatography over silica gel eluting with 5% 30 acetone in CH2Cl2 afforded the title compound (520 mg, 80%) as a white solid, mp 115-117 0 C. Rf = 0.3 Acetone: CH2C12 (5:95). 1H NMR (CDC13) 8 7.73 (1H, brd, J=5 Hz), 7.40-7.15 (5H, m), 4.68 (1H, dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, m), 4.33-4.18 (1H, m), 4.20 - 315 - WO 98/44797 PCT/US98/06823 (1H, dd, J=7 and 3 Hz), 3.78 (1H, m), 3.49 (1H, dd, J=7.5 and 4.0 Hz), 3.37 (1H, dd, J=7.5 and 6.5 Hz), 3.15 (1H, dd, J=1 1.5 and 2 Hz), 2.86 (1H, dd, J=11.5 and 7.5 Hz), 2.68 (1H, m) 2.11 (1H, q, J=9 Hz), 1.55 1.30 (11H, m), 1.07 (1H, m), 0.87 (3H, t, J=6.3 Hz), 0.79 (3H, d, J=6 5 Hz). Step G: Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy 3-phenylpropionyl-homoserine lactone hydrochloride Anhydrous HCl gas was bubbled through a cold (0 0 C) 10 solution of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl] pentyloxy-3-phenylpropionyl-homoserine lactone (3.0 g, 6.7 mmol) in ethyl acetate (120 ml) until a saturated solution was obtained. The resulting mixture was stirred at 0OC for 1 hr. The solution was purged with nitrogen and the mixture concentrated in vacuo to afford the title 15 compound as a sticky foam which was used without further purification. 1H NMR (d6 DMSO) 8 8.60 (1H, d, J=7 Hz), 8.08 (3H, brs), 7.35-7.15 (SH, m), 4.60 (1H, qt, J=8 Hz), 4.36 (1H, t J=7.5 Hz), 4.22 (1H, q, J=7.5 Hz), 4.15-3.95 (2H, m), 3.64 (1H, dd, J=9 and 2.5 Hz), 3.15-3.00 (2H, m), 2.92 (1H, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, m), 1.65 (1H, m), 20 1.43 (1H, m), 1.07 (1H, m), 0.82 (3H, t, J=6 Hz), 0.72 (3H, d, J=6.0 Hz). Step H: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl) amino-3-triphenylmethylmercap-to]propylamino-3 (S) 25 methyl]-pentyloxy-3-phenylpropionyl-homoserine lactone 2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenyl propionyl-homoserine hydrochloride (6.7 mmol) and N-(tert-butoxy carbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5 mmol) (prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine by 30 the procedure of Goel, O.P.; Krolls, U.; Stier, M.; Keston, S. O__Qrg. Syn. 1988, 67, 69.) and potassium acetate (3.66 g, 8.2 mmol) were dissolved in methanol (48 ml). Activated 4A molecular sieves (6g) and then Na(CN)BH3 (0.70 g, 10.7 mmol) were added and the resulting slurry was stirred under argon at room temperature for 16 hr. The solids -316 - WO 98/44797 PCT/US98/06823 were removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in EtOAc and washed sequentially with saturated aqueous NaHCO3 and brine and then dried (Na2SO4). Evaporation in vacuo afforded an oil which was purified by chromatography over silica 5 gel eluting with a gradient of 30-50% EtOAc in hexane to afford the title compound (2.34 g, 45%) contaminated with a small amount of the corresponding methyl ester. 1H NMR (CD3OD) 8 7.60-7.05(20H, m), 4.64 (1H, d, J=9.0Hz), 4.39 (1H, br t, J=9Hz), 4.25(1H, m), 3.93 (1H, m), 3.75-3.60(1H, m), 3.55 10 (1H, dd, J=9.0 and 2Hz), 3.20 (1H, dd, J=9.0 and 6.0 Hz), 3.04 (1H, dd, J=15.0 and 5.0 Hz), 2.85 (1H, dd, J=15.0 and 9.0 Hz), 2.60 (1H, dd, J=12.0 and 5.0 Hz), 2.50-2.15 (7H, m), 1.45 (9H, s), 1.40-1.20 (1H, m), 1.07 (1H, m), 0.87 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz). 15 Step I: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto] propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl homoserine lactone To a stirred solution of 2(S)-[2(S)-[2(R)-(tert-butoxy carbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S) 20 methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (2.72 g, 3.49 mmol) in CH2Cl2 (90 ml) was added HSiEt3 (2.16 ml, 13.5 mmol) and TFA (43.2 ml, 0.56 mol) and the solution was stirred at R.T. under argon for 2 hrs. The solvent was evaporated in vacuo and the residue partitioned between 0.1% aqueous TFA (200 ml) and hexanes (100 ml). 25 The aqueous layer was separated and washed with hexanes (20 ml) and then lyophilised. The resulting white lyophilate was chromatographed in 5 equal portions over a Waters Prepak cartridge (C-18, 15-20 mM 100 A) eluting with a gradient of 95:5 to 5:95 0.1% TFA in H20 : 0.1% TFA in CH3CN at 100 ml/min over 60 min. The desired compound 30 eluted after 19 min. The CH3CN was evaporated in vacuo and the aqueous solution lyophilised to afford the title compound (1.95 g, 77%) as the TFA salt. The salt is hygroscopic and is prone to disulphide formation if left in solution and exposed to air. - 317 - WO 98/44797 PCT/US98/06823 1H NMR 8 (CD3OD) 7.40-7.15 (5H,m), 4.55-5.40 (2H, m), 4.33 (1H, m), 4.18 (1H, m), 3.90-3.62 (3H, m), 3.53 (1H, dd, J=10.5 and 4.0 Hz), 3.37 (1H, dd, J=10.5 and 6.0 Hz), 3.23 (1H, m), 3.15-2.95 (2H, m), 2.88 (1H, dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, m), 1.92 (1H, m), 1.49 5 (1H, m), 1.23 (1H, m), 0.94 (3H, t, J=6 Hz), 0.90 (3H, d, J=6Hz). FAB MS 873 (2M-H+) 438 (MH+) 361 (MHPh) Anal. calc'd for C22H3604N3S 2.6 TFA: C, 43.58; H, 5.25; N, 5,82. Found: C, 43.62; H, 5.07; N, 5.80. 10 Sitep : Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto] propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl homoserine 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propyl-amino-3(S) 15 methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (0.00326 mmol) was dissolved in methanol (0.0506 ml) and 1N sodium hydroxide (0.0134 ml) was added followed by methanol (0.262 ml). The conver sion of the lactone to the hydroxy-acid was confirmed by HPLC analysis and NMR. 20 EXAMPLE 9 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S) methyllpentyloxy-3-phenylpropionyl-methionine 25 Step A: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl) amino-3-triphenyl-methylmercapto]-propylamino-3(S) methyl]pentvloxy-3-phenyl-propionyl-methionine To a solution of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl) 30 amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-methionine methyl ester (120 mg, 0.143 mmol) in methanol (4 ml) was added sodium hydroxide (1N, 0.57 ml, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Another portion of sodium hydroxide (1N, 0.25 ml) was - 318 - WO 98/44797 PCT/US98/06823 added and stirring continued for 0.5 hours. The reaction mixture was concentrated and the residue was dissolved in a minimum amount of water and neutralized with hydrochloric acid (IN, 0.87 ml). The aqueous solution was extracted with ethyl acetate three times. The 5 combined extracts were dried (Na2SO4) and concentrated to yield the title compound (110 mg, 0.133 mmol, 93%). NMR (CD3OD) 8 0.70 (3H, d, J=6Hz), 0.80 (3H, t, J=6Hz), 1.05 (H, m), 1.34 (9H, s), 1.60 (H, m), 1.95 (3H, S), 2.7-2.9 (3H, m), 2.95-3.1 (2H, m), 3.95 (H, d of d, J=8, 4Hz), 4.27 (H, d of d, J=8.6Hz), 7.1-~7.4 (20H, m). 10 Step B: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto] propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl methionine The title compound was prepared in the same manner as 15 that described in Example 8, Step I, but using 2(S)-[2(S)-[2(R)-(tert butoxycarbonyl)-amino-3-triphenylmethylmercapto]-propylamino 3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine in place of 2(S) [2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto] propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserine 20 lactone. NMR (CD3OD) 5 0.82 (3H, d, J=6Hz), 0.95 (3H, t, J=6Hz), 1.20 (H, m), 1.40 (H, m), 1.85 (H, m), 2.10 (3H, s), 2.4-2.6 (2H, m), 3.1~3.2 (2H, m), 3.35 (H, d of d, J=14, 6Hz), 3.55 (H, d of d, J=14, 5Hz), 4.20 (H, d of d, J=10, 5Hz), 4.63 (H, d of d, J=10.6Hz), 7.27 (5H, m). 25 Anal. Calcd for C23H39N304S2*2CF3CO2H*2H20: C, 43.25; H, 6.05; N, 5.60. Found: C, 43.09; H, 6.01; N, 5.46. - 319 - WO 98/44797 PCT/US98/06823 EXAMPLE 10 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methylester 5 (Compound 10-1) Step A: Preparation of Methionine sulfone methyl ester Thionyl chloride (2.63 ml, 36 mmol) was added dropwise to a stirred solution of N-Boc-Met sulfone (5 g, 18 mmol) in methanol 10 (40 ml) cooled at 0 0 C. After the completion of the addition, the result ing mixture was warmed to room temperature and stirred overnight. The reaction mixture was recooled to 0OC and slowly treated with solid sodium bicarbonate to adjust the pH to 7. The mixture was concentrated in vacuo to remove methanol and the residue was dissolved in a 15 minimum amount of water (solution pH ca. 10) and extracted with ethyl acetate four times. The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.5 g). NMR (CD3OD) 6 2.04 (H, m), 2.21 (H, m), 2.98 (3H, s), 3.23 (2H, t, J=7Hz), 3.63 (H, d of d, J=8.6Hz), 3.77 (3H, s). 20 Step B: Preparation of N-(tert-Butoxycarbonyl)-2(S)-[2(S)-amino 3(S)-methyl]-pentyloxy-3-phenyl-propionyl-methionine sulfone methyl ester The title compound was prepared in the same fashion as 25 that described in Example 8, Step F, but using methionine sulfone methyl ester in place of homoserine lactone hydrochloride. NMR (CD3OD) 5 0.80 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1.12 (H, m), 1.47 (9H, s), 2.10 (H, m), 2.32 (H, m), 2.93 (3H, s), 3.5-3.7 (2H, m), 3.74 (3H, s), 4.01 (H, d of d, J=7.4Hz), 4.60 (H, d of d, J=9.5Hz), 6.60 (H, d, 30 J=8Hz), 7.25 (5H, m). - 320 - WO 98/44797 PCT/US98/06823 Step C: Preparation of 2(S)-[2(S)-Amino-3(S)-methyl]-pentyloxy 3-phenylpropionyl-methionine sulfone methyl ester hydrochloride The title compound was prepared in the same fashion as 5 that described in Example 8, Step G, but using N-(tert-butoxycarbonyl) 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester in place of N-(tert-butoxycarbonyl)-2(S)-[2(S) amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone. NMR (CD3OD) 8 0.85 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.20 (H, 10 m), 1.52 (H, m), 1.72 (H, m), 2.14 (H, m), 2.38 (H, m), 2.98 (3H, s), 3.57 (H, d of d, J=12, 6Hz), 3.73 (H, d of d, J=12, 9Hz), 3.78 (3H, s), 4.15 (H, d of d, J=8.6Hz), 4.63 (H, d of d, J=8.5Hz), 7.30 (5H, m). Step D: Preparation of 2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl) 15 amino-3-triphenylmethylmercapto]-propylamino-3(S) methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone methyl ester The title compound was prepared in a similar fashion as that described in Example 8, Step H, but using 2(S)-[2(S)-amino-3(S) 20 methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone methyl ester hydrochloride in place of 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3 phenylpropionyl-homoserine lactone hydrochloride. NMR (CD30D) 8 0.70 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1.10 (H, m), 1.47 (9H, s), 2.15 (H, m), 2.67 (H, m), 2.92 (3H, s), 3.67 (H, m), 4.68 (H, d of d, J=10, 25 6Hz), 7.15-~7.45 (20H, m). Step E: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto] propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl methionine sulfone methyl ester 30 The title compound was prepared in a similar fashion as that described in Example 8, Step I, but using 2(S)-[2(S)-[2(R)-(tert butoxycarbonyl)amino-3-triphenylmethylmercapto]propylamino-3(S) methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester in place of 2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-triphenyl - 321 - WO 98/44797 PCT/US98/06823 methylmercapto]propylamino-3(S)-methyl]pentyloxy-3-phenyl propionyl-homoserine lactone. NMR (CD3OD) 8 0.83 (3H, d, J=6Hz), 0.93 (3H, t, J=6Hz), 1.20 (H, m), 1.51 (H, m), 1.80 (H, m), 2.22 (H, m), 2.43 (H, m), 3.00 (3H, s), 3.78 (3H, s), 4.20 (H, d of d, J=8.4Hz), 4.72 5 (H, d of d, J=10, 6Hz), 7.30 (5H, m). FABMS m/z 532 (MH+). EXAMPLE 11 10 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S) methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 11-1) Step A: Preparation of 2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl) 15 amino-3-triphenylmethylmercapto]-propylamino-3(S) methyl]pentyloxy-3-phenvl-propionvl-methionine sulfone The title compound was prepared in a similar fashion as that described in Example 9, Step A, but using 2(S)-[2(S)-[2(R)-(tert butoxycarbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S) 20 methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester in place of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenyl methylmercapto]propylamino-3(S)-methyl]pentyloxy-methionine methyl ester. NMR (CD3OD) 6 0.79 (3H, d, J=6Hz), 0.90 (3H, t, J=6Hz), 1.47 (9H, s), 2.92 (3H, s), 4.08 (H, m), 4.32 (H, m), 7.15-7.35 (20H, m). 25 Step B: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto] propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl methionine sulfone The title compound was prepared in a similar fashion as 30 that described in Example 8, Step I, but using 2(S)-[2(S)-[2(R)-(tert butoxycarbonyl)amino-triphenylmethylmercapto]propylamino-3(S) methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone in place of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethyl mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl - 322 - WO 98/44797 PCT/US98/06823 3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone. NMR (CD3OD) 5 0.84 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.21 (H, m), 1.50 (H, m), 1.82 (H, m), 2.24 (H, m), 2.47 (H, m), 2.98 (3H, s), 3.6-3.75 (3H, m), 4.20 (H, d of d, J=9.5Hz), 4.64 (H, d of d, J=9.6Hz), 7.30 (5H, 5 m). Anal. Called for C23H39N306S2*3CF3CO2H: C, 40.51; H, 4.92; N, 4.89. Found: C, 40.47; H, 5.11; N, 4.56. 10 EXAMPLE 12 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino 3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone isopropvl ester HS H H 0
H
2 N O N O 0 ). (O° 0 2 S\ 15 CH 3 The title compound was prepared using methods A-E from Example 10, except for Method A. Methionine sulfone isopropyl ester was prepared by coupling t-butyloxycarbonyl-methionine sulfone with isopropyl alcohol using dicyclohexylcarbodiimide (DCC) and 4 20 dimethylaminopyridine (DMAP) followed by deprotection with HCI in EtOAc. NMR (CD3OD) 6 0.83 (3H, d, J = 6 Hz), 0.94 (3H, t, J = 6 Hz), 1.11-1.56 (2H, m), 1.28 (6H, d, J = 6 Hz), 1.8-1.96 (1H, m), 2.12 2.27 (1H, m), 2.89-3.0 (2H, m), 3.01 (3H, s), 3.06-3.3 (4H, m), 3.42 (1H, dd, J = 6, 13 Hz), 3.65 (1H, dd, J = 6,13 Hz), 3.68-3.91 (3H, m), 25 4.2-4.27 (1H, m), 4.61-4.7 (1H, m), 4.96-5.12 (2H, m), 7.19-7.44 (5H, m). - 323 - WO 98/44797 PCT/US98/06823 Anal. Calc'd. for C26H45N306S2 * 2 CF3CO2H: C, 44.07; H, 5.67; N, 4.97; Found C, 44.35; H, 5.68; N, 5.23 5 EXAMPLE 13 4- [1 -(5-Chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)- 1H-pyrrol-2 ylmethyll-benzonitrile 10 Step 1: 5-Chloro-5'-methyl- [1,2'lbipyridinyl-2-one 5-Chloro-2-pyridinol (2.26g, 17.4 mmol), 2-bromo-5 methylpyridine (3.00g, 17.4 mmol), copper (0.022g, 0.35 mmol) and
K
2 CO3 (2.66g, 19.2 mmol) were heated at 180 0 C for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with 15 saturated NaHCO 3 . The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried (Na 2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH 2
C
2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 20 'H NMR (400 MHz, CDC1 3 ) 8 8.37 (s, 1H), 7.96(d, J=3.0Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.65(dd, J=2.4 and 8.2Hz, 1H), 7.32(dd, J=2.9 and 9.7 Hz, 1H), 6.61(d, J=9.7Hz, 1H) and 2.39(s,3H)ppm. Ste 2: 5'-Bromomethyl-5-chloro-[ r1,2'lbipyridinyl-2-one 25 A solution of the pyridine from Step 1(1.00g, 4.53 mmol), N-bromosuccinimide (0.81g, 4.53 mmol) and AIBN (0.030g, 0.18 mmol) in CC1 4 (40mL) was heated at reflux for 2 hrs. The solids were filtered and the filtrate collected. The solvent was evaporated in vacuo and the residue chromatographed (silica gel, EtOAc: CH 2
C
2 25:75 to 30 50:50 gradient elution) to afford the title bromide. 'H NMR (400 MHz, CDC1 3 ) 8 8.55 (s, 1H), 8.04( d, J= 2.9 Hz, 1H), 8.01 (d, J=8.4Hz, 1H), 7.88 (dd, J=2.4 and 8.6Hz, 1H), 7.34(dd, J= 2.9 and 9.8Hz, 1H), 6.61(d, J=9.9Hz, 1H) and 4.51 (s,2H) ppm. - 324 - WO 98/44797 PCT/US98/06823 Step 3: 4- [1-(5-Chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl) 1H-pyrrol-2-vlmethyl]l-benzonitrile hydrochloride The bromide from Step 2 (0.750g, 2.50 mmol) and the 4-(1-trityl- 1H-imidazol-4-ylmethyl)-benzonitrile (1.06g, 2.50 mmol) 5 in CH 3 CN (10 mL) were heated at 60oC. The reaction was cooled to room temperature and the solids collected by filtration and washed with EtOAc (10mL). The solid was suspended in methanol (50 mL) and heated at reflux for 1 hr, cooled and the solvent evaporated in vacuo. The sticky residue was stirred in EtOAc (40mL) for 4 hrs and 10 the resulting solid hydrobromide salt collected by filtration and washed with EtOAc (40mL) and dried in vacuo. The hydrobromide salt was partitioned between sat. NaHCO 3 and CH 2
C
2 and extracted with CH 2 C1 2 . The organic extracts were dried (Na 2
SO
4 ) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH 2
C
2 4:96 to 5:95 15 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid. 'H NMR (400 MHz, CD 3 OD) 6 9.11 (s, 1H), 8.35 (s, 1H), 8.03(d, J=2.9Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.76 (dd, J=2.4 and 9.6Hz, 1H), 7.68-7.58 (m, 3H), 7.48 (s, 1H), 7.31(d, J=8.6Hz, 2H), 6.68 (d, J=9.3Hz, 20 1H), 5.53 (s, 2H) and 4.24 (s, 2H) ppm. Analysis: Calc for C 22
H
16
N
5 0C1: 1.75 HC1, 0.15 EtOAc C 56.69, H 3.99, N 14.62 Found: C 56.72, H 4.05, N 14.54 25 BIOLOGICAL ASSAYS. The ability of compounds of the present invention to inhibit cancer can be demonstrated using the following assays. 30 SPA Assay - oav33 Receptor Binding The test procedures employed to measure av33 binding activity of the antagonist compounds of the av33 receptor of the present invention is described below. - 325 - WO 98/44797 PCT/US98/06823
N-(
4 -Iodo-phenylsulfonylamino)-L-asparagine (AR-2) To a stirred solution of acid L-asparagine (4.39 g, 33.2 mmol), NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H20 (30 ml) at 0 0 C was added pipsyl chloride (10.34 g, 34.2 mmol). After -5 minutes, 5 NaOH (1.49, 37.2 mmol) dissolved in 15 ml H20, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved in H20 (300 ml) and then washed with EtOAc. The aqueous portion was cooled to 0OC and then acidified with concentrated HC1. The solid was collected and then 10 washed with Et20 to provide acid AR-2 as a white solid. 1H NMR (300 MHz, D20) 8 7.86 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz) 3.70 (m, 1H), 2.39 (m, 2H). 2(S)-(4-Iodo-phenvlsulfonvlamino)-5-alanine (AR-3) 15 To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H20 (40 ml) at 0 0 C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten minute period. After -5 minutes, acid AR-2 (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H20 (35 ml) were combined, cooled to 0OC and then added in a single portion to the reaction. After stirring 20 for 20 minutes at 0OC, the reaction was heated to 90 0 C for 30 minutes and then recooled to 0oC. The pH was adjusted to -7 by dropwise addition of concentrated HC1. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid AR-3 as a white solid. 1 H NMR (300 MHz, D20) 8 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 25 4.36 (m, 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 (m, 1H). Ethyl 2 (S)-(4-iodo-phenylsulfonylamino)-3-alanine hydrochloride (AR-4) HCI gas was rapidly bubbled through a suspension of acid 30 AR-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0 0 C for 10 minutes. The cooling bath was removed and the reaction was heated to 60'C. After 18 h, the reaction was concentrated to provide ester AR-4 as a white solid. - 326 - WO 98/44797 PCT/US98/06823 1 H NMR (300 MHz, CD3OD) 8 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t, 3H, J=7Hz). 5 Ethyl 4-[2-(2-Aminopyridin-6-vl)ethyl]lbenzoate (AR-5) A mixture of ester AR-5a (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publica tion No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction 10 was filtered through a celite pad and then concentrated to provide ester AR-5 as a brown oil. TLC Rf = 0.23 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDCl3) 8 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, 1H, J=7Hz), 6.35 (d, 1H, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 15 (m, 2H), 1.39 (t, 3H, J=7Hz). 4-[2-(2-Aminopyridin-6-vl)ethyllbenzoic acid hydrochloride (AR-6) A suspension of ester AR-5 (625 mg, 2.31 mmol) in 6N HC1 (12 ml) was heated to 60oC. After -20 h, the reaction was 20 concentrated to give acid AR-6 as a tan solid. 1 H NMR (300 MHz, CD3OD) 8 7.96 (d, 2H, J=8Hz), 7.80 (m, 1H), 7.33 (d, 2H, J=8Hz), 6.84 (d, 1H, J=9Hz), 6.69 (d, 1H, J=7Hz), 3.09 (m, 4H). Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo 25 phenylsulfonylamino)-[-alanine (AR-7) A solution of acid AR-6 (400 mg, 1.43 mmol), amine AR-4 (686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 gl, 5.72 mmol) and DMF (10 ml) was stirred for -20 h. The reaction was diluted with EtOAc and then washed with 30 sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chroma tography (silica, EtOAC -- 5% isopropanol/EtOAc) provided amide AR-7 as a white solid. TLC Rf = 0.4 (silica, 10% isopropanol/EtOAc) - 327 - WO 98/44797 PCT/US98/06823 1 H NMR (300 MHz, CD3OD) 8 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 (d, 2H, J=9Hz), 7.29 (m, 1H), 7.27 (d, 2H, J=8Hz), 4.20 (m, 1H), 3.95 (q, 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz). 5 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl sulfonylamino)-5-alanine (AR-8) A solution of ester AR-7 (200 mg, 0.3213 mmol) and 6N HC1 (30 ml) was heated to 60 0 C. After -20 h, the reaction mixture was 10 concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/ NH4OH/H20) provided acid AR-8 as a white solid. TLC Rf = 0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH4OH/H20) 1 H NMR (400 MHz, DMSO) 8 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 15 (d, 1H, J=7Hz), 6.25 (d, 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H), 2.97 (m, 2H), 2.79 (m, 2H). 4-[ 2
-(
2 -Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl phenylsulfonylamino-o-alanine (AR-9) 20 A solution of iodide AR-8 (70 mg, 0.1178 mmol), (CH3Sn)2 (49 pl, 0.2356 mmol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) was heated to 90 0 C. After 2 h, the reaction was concentrated and then purified by prep HPLC (Delta-Pak C18 15 pM 100Ao , 40 x 100 mm; 95:5 --- 5:95 H20/CH3CN) provided the trifluoroacetate salt. The salt 25 was suspended in H20 (10 ml), treated with NH4OH (5 drops) and then lyophilized to provide amide AR-9 as a white solid. 1H NMR (400 MHz, DMSO) 8 8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), 7.67 (m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 30 2.86 (m, 2H). - 328 - WO 98/44797 PCT/US98/06823 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-1 2 5 iodo phenylsulfonylamino-b3-alanine (AR-10) An iodobead (Pierce) was added to a shipping vial of 5 mCi of Nal 2 5 I (Amersham, IMS30) and stirred for five minutes at room 5 temperature. A solution of 0.1 mg of AR-9 in 0.05 mL of 10% H2SO4/ MeOH was made and immediately added to the Na 12 5 I/iodobead vial. After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH4OH was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for 10 purification [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H20 (0.1% TFA) to 90% acetonitrile (0.1% TFA):H20 (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of AR-10 is 17 minutes under these conditions. Fractions containing the majority of the radioactivity were pooled, 15 lyophilized and diluted with ethanol to give approximately 1 mCi of AR-10, which coeluted on HPLC analysis with an authentic sample of AR-8. Instrumentation: Analytical and preparative HPLC was carried out 20 using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular 25 guard column. The acetonitrile used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman 170 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x 250 mm was used for analytical and preparative HPLC. Solutions of radioactivity were concentrated using a Speedvac vacuum centrifuge. 30 Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV/Vis Diode Array Spectrophotometer. Sample radioactivities were determined in a Packard A5530 gamma counter. - 329 - WO 98/44797 PCT/US98/06823 MATERIALS: 1. Wheatgerm agglutinin Scintillation Proximity Beads (SPA): Amersham 5 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem 4. NaCl: Fisher 5. CaCl2: Fisher 6. MgC12: SIGMA 10 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. AR-10 (specific activity 500-1000 Cilmmole) 10. test compound 11. Purified integrin receptor: avP3 was purified from 293 cells 15 overexpressing exvi3(Duong et al., J. Bone Min. Res., 8:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaC1, 1 mM Ca 2 +/Mg 2 +, 0.5 mM PMSF 20 13. 50 mM octylglucoside in binding buffer: 50-OG buffer PROCEDURE: 1. Pretreatment of SPA beads: 25 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer. 2. Preparation of SPA beads and receptor mixture 30 In each assay tube, 2.5 ptl (40 mg/ml) of pretreated beads were suspended in 97.5 p l of binding buffer and 20 p1 of 50-OG buffer. 5 p l (-30 ng/p l) of purified receptor was added to the beads in suspension with stirring at room temperature for 30 minutes. The mixture was then centrifuged at 2,500 rpm in a - 330 - WO 98/44797 PCT/US98/06823 Beckman GPR Benchtop centrifuge for 10 minutes at 4oC. The pellets were then resuspended in 50 tl of binding buffer and 25 pl of 50-OG buffer. 5 3. Reaction The following were sequentially added into Optiplate in corresponding wells: (i) Receptor/beads mixture (75 pl) (ii) 25 pl of each of the following: compound to be tested, binding 10 buffer for total binding or 8-8 for non-specific binding (final concentration 1 RM) (iii) 8-10 in binding buffer (25 ptl, final concentration 40 pM) (iv) Binding buffer (125 pl) (v) Each plate was sealed with plate sealer from PACKARD and 15 incubated overnight with rocking at 4 0 C 4. Plates were counted using PACKARD TOPCOUNT 5. % inhibition was calculated as follows: 20 A = total counts B = nonspecific counts C = sample counts % inhibition = [{(A-B)-(C-B)}/(A-B)]/(A-B) x 100 25 cvD5 ATTACHMENT ASSAY Duong et al., J. Bone Miner. Res., 11:S 290, which is incorporated by reference herein in its entirety describe a system for expressing the human avb5. 30 Materials: 1. Media and solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma. 2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid free BSA and 2 mM CaCl2. - 331 - WO 98/44797 PCT/US98/06823 3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl-N acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH 5.0. 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM 5 EDTA, pH 10.5. Methods: 1. Plates (96 well, Nunc Maxi Sorp) are coated overnight at 4 oC with human vitronectin (3 ug/ml) in 50 mM carbonate buffer 10 (pH 9/.6), using 100 gl/well. Plates are then washed 2X with DPBS and blocked with 2% BSA in DPBS for 2h at room temperature. After additional washes (2X) with DPBS, plates are used for cell attachment assay. 2. 293 (alpha v beta 5) cells are grown in MEM media in 15 presence of 10% fetal calf serum to 90% confluence. Cells are then lifted from dishes with 1X Trypsin/EDTA and washed 3X with serum free MEM. Cells are resuspended in attachment medium (3 X 10 5 cells/ml). 3. Test compounds are prepared as a series of dilutions at 2X 20 concentrations and added as 50 gl/well. Cell suspension is then added as 50 ml/well. Plates are incubated at 37 oC with 55 CO2 for 1 hour to allow attachment. 4. Non-adherent cells are removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase 25 substrate solution (100 gl/well), overnight at room temperature in the dark. To quantitate cell numbers, a standard curve of glucosaminidase activity is determined for each experiment by adding samples of cell suspension directly to wells containing the enzyme substrate solution. 30 5. The next day, the reaction is developed by addition of 185 gl/well of gylcine/EDTA solution and reading absorbance at 405 nm using a Molecular Devices V-Max plate reader. Average test absorbance values (4 wells per test samples) are calculated. Then, the number of attached cells at each drug - 332 - WO 98/44797 PCT/US98/06823 concentration is quantitated versus the standard curve of cells using the Softmax program. In vitro inhibition of farnesyl-protein transferase 5 Transferase Assays. Isoprenyl-protein transferase activity assays were carried out at 30 oC unless noted otherwise. A typical reaction contained (in a final volume of 50 pL): [ 3 H]farnesyl diphosphate or [ 3 H]geranylgeranyl diphosphate, Ras protein , 50 mM HEPES, pH 7.5, 5 mM MgCl 2 , 5 mM dithiothreitol and isoprenyl 10 protein transferase. The FPTase employed in the assay was prepared by recombinant expression as described in Omer, C.A., Kral, A.M., Diehl, R.E., Prendergast, G.C., Powers, S., Allen, C.M., Gibbs, J.B. and Kohl, N.E. (1993) Biochemistry 32:5167-5176. The geranylgeranyl-protein transferase-type I employed in the assay was prepared as described in 15 U.S. Pat. No. 5,470,832, incorporated by reference. After thermally pre-equilibrating the assay mixture in the absence of enzyme, reactions were initiated by the addition of isoprenyl-protein transferase and stopped at timed intervals (typically 15 min) by the addition of 1 M HC1 in ethanol (1 mL). The quenched reactions were allowed to stand for 15 20 m (to complete the precipitation process). After adding 2 mL of 100% ethanol, the reactions were vacuum-filtered through Whatman GF/C filters. Filters were washed four times with 2 mL aliquots of 100% ethanol, mixed with scintillation fluid (10 mL) and then counted in a Beckman LS3801scintillation counter. 25 For inhibition studies, assays were run as described above, except inhibitors were prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 20-fold into the enzyme assay mixture. IC 50 values were determined with both transferase substrates near KM concentrations. Nonsaturating substrate conditions for 30 inhibitor ICs0 determinations were as follows: FTase, 650 nM Ras CVLS, 100 nM farnesyl diphosphate; GGPTase-I, 500 nM Ras-CAIL, 100 nM geranylgeranyl diphosphate. In vivo ras prenylation assay - 333 - WO 98/44797 PCT/US98/06823 The cell lines used in this assay consist of either Rat1 or NIH3T3 cells transformed by either viral Ha-ras; an N-ras chimeric gene in which the C-terminal hypervariable region of v-Ha-ras was substituted with the corresponding region from the N-ras gene; or 5 ras-CVLL, a v-Ha-ras mutant in which the C-terminal exon encodes leucine instead of serine, making the encoded protein a substrate for geranylgeranylation by GGPTase I. The assay can also be performed using cell lines transformed with human Ha-ras, N-ras or Ki4B-ras. The assay is performed essentially as described in DeClue, J.E. et al., 10 Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound(s) (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37oC, the cells are labelled in 3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetal bovine serum, 15 400 gCi[35S]methionine (1000 Ci/mmol) and test compound(s). Cells treated with lovastatin, a compound that blocks Ras processing in cells by inhibiting the rate-limiting step in the isoprenoid biosynthetic pathway (Hancock, J.F. et al. Cell, 57:1167 (1989); DeClue, J.E. et al. Cancer Res., 51:712 (1991); Sinensky, M. et al. J. Biol. Chem., 20 265:19937 (1990)), serve as a positive control in this assay. After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Alternatively, four 25 hours after the additon of the labelling media, the media is removed, the cells washed, and 3 ml of media containing the same or a different test compound added. Following an additional 16 hour incubation, the lysis is carried out as above. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer 30 lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4oC, 200 gl of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with - 334 - WO 98/44797 PCT/US98/06823 IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0. 1 %/SDS/0.1 M NaC1) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried 5 and autoradiographed. The intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein. In vivo growth inhibition of Ras transformed cells assay 10 To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cell lines trans formed with human Ha-ras, N-ras or Ki4B-ras can also be utilized. 15 Cells transformed by v-Raf and v-Mos may be included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in 20 a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). 25 The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken approximately 16 days after the cultures are seeded and comparisons are made. In addition, the activity of the compounds of the present 30 invention for treating cancer and/or inhibiting tumor growth is confirmed utilizing the nude mouse tumor xenograft assay described in Kohl et al., PNAS 91 (1994) 9141-45. - 335 - WO 98/44797 PCT/US98/06823 In vivo tumor growth inhibition assay (nude mouse) Rodent fibroblasts transformed with oncogenically mutated human Ha-ras or Ki-ras (106 cells/animal in 1 ml of DMEM salts) are injected subcutaneously into the left flank of 8-12 week old 5 female nude mice (Harlan) on day 0. The mice in each oncogene group are randomly assigned to a vehicle, compound or combination treatment group. Animals are dosed subcutaneously starting on day 1 and daily for the duration of the experiment. Compound, compound combination or vehicle is delivered in a total volume of 0.1 ml. Alternatively, the 10 farnesyl-protein transferase inhibitor and/or the integrin antagonist may be administered by a continuous infusion pump. Tumors are excised and weighed when all of the vehicle-treated animals exhibited lesions of 0.5 - 1.0 cm in diameter, typically 8-15 days after the cells were injected. The average weight of the tumors in each treatment group for each cell 15 line is calculated. The following dosage groups are utilized to determine the efficacy of the combination of the farnesyl-protein transferase inhibitor (FTI) and integrin antagonist (antagonist): 20 Group O Vehicle controls Group A: FTI at maximum no effect dose Group B: FTI at minimal efficacy dose Group C: antagonist at maximal no effect dose Group D: antagonist at minimal efficacy dose 25 Group E: A + C Group F: A + D Group G: B + C Group H: B + D 30 Additional doses of FTI and antagonist can be selected as needed. - 336 -

Claims (22)

1. A method for achieving a therapeutic effect in a mammal in need thereof which comprises administering to said 5 mammal amounts of at least two therapeutic agents selected from a group consisting of: a) a farnesyl-protein transferase inhibitor and b) an integrin antagonist; wherein the amount of a) alone or the amount of b) alone is insufficient 10 to achieve said therapeutic effect.
2. The method according to Claim 1 wherein an amount of a farnesyl-protein transferase inhibitor and an amount of an integrin antagonist are administered simultaneously. 15
3. The method according to Claim 1 wherein the integrin antagonist is a selective antagonist of the cvP3 integrin.
4. The method according to Claim 1 wherein the integrin 20 antagonist is a selective antagonist of the exvP5 integrin.
5. The method according to Claim 1 wherein the integrin antagonist is an antagonist of both the cxvP3 integrin and the xvP5 integrin. 25
6. A method for achieving a therapeutic effect in a mammal in need thereof which comprises administering to said mammal amounts of three therapeutic agents which are: a) a farnesyl-protein transferase inhibitor; 30 b) a selective antagonist of the cavP3 integrin; and c) a selective antagonist of the avP5 integrin; wherein the amount of a) alone, the amount of b) alone or the amount of c) alone is insufficient to achieve said therapeutic effect. - 337 - WO 98/44797 PCT/US98/06823
7. The method according to Claim 1 wherein the therapeutic effect is treatment of cancer.
8. The method according to Claim 7 wherein the 5 therapeutic effect is selected from inhibition of cancerous tumor growth and regression of cancerous tumors.
9. The method according to Claim 1 wherein the farnesyl protein transferase inhibitor is selected from: 10 (a) a compound represented by formula (II-a) through (II-c): (R )r R9 R2 R V - A'(CRla 2 )nA 2 (CR la 2 ) n - W t- (CR 1 b 2 )pX /N\ YN R 4 R 5 (Il-a) ( )r R9 R 2 G V - A'(CRla 2 )nA 2 (CRla 2 ) n -W - (CR 1 b 2 )p> N\ N-Z t X V ~ R 3 R 4 (Il-b) (R 8 )r R9 R2 R 3 V - Al(CRla 2 )nA 2 (CRla 2 ) n W - (CRlb 2 )p\ ,N 'N-Z (It X / G 15 R 4 15 (II-c) wherein with respect to formula (II-a): - 338 - WO 98/44797 PCT/US98/06823 (R )r R9 R 2 R 3 V - A'(CRla 2 )nA 2 (CRla 2 )n - W - (CR0b2)p \ / t x Y R 4 R 5 (ll-a) or a pharmaceutically acceptable salt thereof, Rla and Rlb are independently selected from: 5 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(0)m-, R10C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 1 0)-, R 10 C(0)-, R10OC(0)-, N3, -N(R10)2, or R 1 1OC(0)NR10-, 10 c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(0)m-, R 10 C(O)NR1 0 -, CN, (R 10 )2N-C(NRO10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 0C(O)-NR10-; 15 R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 20 R 6 R 7 or R6 0 O wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: 25 a) C1-4 alkyl, b) (CH2)pOR 6 , - 339 - WO 98/44797 PCT/US98/06823 c) (CH2)pNR 6 R 7 , d) halogen, 2) C3-6 cycloalkyl, 3) OR 6 , 5 4) SR 6 , S(O)R 6 , SO2R 6 , 5) -NR 6 R 7 R6 6) -N R 7 O 0 R 6 7) I6 -N , NR7R 7 a 0 8)0 9) - ,OR 6 10) NR 6 R 7 0 O 11) -SO 2 -NR 6 R 7 R 6 I 10 12) -N-SO 2 - R 7 - 340 - WO 98/44797 PCT/US98/06823 13) R , or 0 14) .rOR 6 or 0 R 2 and R 3 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 5 moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-; R 4 and R 5 are independently selected from H and CH3; 10 and any two of R 2 , R 3 , R 4 and R 5 are optionally attached to the same carbon atom; R 6 , R 7 and R7a are independently selected from: H; C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, 15 heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) rRl 0 20 f) -SO 2 R11 , or g) N(R 10 )2; or R 6 and R 7 may be joined in a ring; 25 R 7 and R7a may be joined in a ring; - 341 - WO 98/44797 PCT/US98/06823 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, 5 R 1 1 S(O)m-, R 10 C(O)NR1 0 -, CN, NO2, R 10 2N-C(NR10)-, RlOC(O)-, R10OC(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 10 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-, R 1 0C(O)NH-, CN, H2N-C(NH)-, RO10C(O)-, R 10 0C(O)-, N3, -N(R 10 )2, or R10OC(O)NH-; R9 is selected from: 15 a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 1 0-, CN, NO2, (R 10 )2N-C-(NR 10 )-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 -, and 20 c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, CN, (R 10 )2N-C(NR 1 0)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NRO- 10 ; 25 R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; 30 A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, -NR10OC(O)-, O, -N(R10)-, -S(0)2N(R 10 )-, -N(R10)S(0)2-, or S(O)m; - 342 - WO 98/44797 PCT/US98/06823 V is selected from: a) hydrogen, b) heterocycle, c) aryl, 5 d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen 10 if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, -C(=O)-, or -S(=O)m-; 15 Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, 20 b) NR 6 R 7 , c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 , or 25 g) -C(O)NR 6 R 7 , 2) aryl or heterocycle, 3) halogen, 4) OR 6 , 5) NR 6 R 7 , 30 6) CN, 7) NO2, 8) CF3; 9) -S(O)mR 6 , 10) -C(O)NR 6 R 7 , or - 343 - WO 98/44797 PCT/US98/06823 11) C3-C6 cycloalkyl; m is 0, 1 or 2; nis 0, 1,2,3 or4; 5 p is 0, 1,2, 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; 10 with respect to formula (II-b): (R)r R9' R2 G V -A'(CRla2)nA2(CRla2) n - W - (CRlb2)PN\ ' N-Z t X " -~ R 3 R 4 (II-b) or a pharmaceutically acceptable salt thereof, 15 Ria, Rlb, R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, R7a, u, R 8 , A 1 , A 2 , V, W, X, n, p, r, s, t and u are as defined above with respect to formula (II-a); R 4 is selected from H and CH3; 20 and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom; R 9 is selected from: a) hydrogen, 25 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1S(O)m-, R 10 C(O)NR1 0 -, CN, NO2, (R 10 )2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 -, and - 344 - WO 98/44797 PCT/US98/06823 c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, CN, (R 10 )2N-C(NR 1 0)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11 OC(O)NR10-; 5 G is H2 or O; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or 10 substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, 15 d) aryl or heterocycle, e) HO, f) -S(O)mR 6 , or g) -C(O)NR 6 R 7 , 2) aryl or heterocycle, 20 3) halogen, 4) OR 6 , 5) NR 6 R 7 , 6) CN, 7) NO2, 25 8) CF3; 9) -S(O)mR 6 , 10) -C(O)NR 6 R 7 , or 11) C3-C6 cycloalkyl; 30 with respect to formula (II-c): - 345 - WO 98/44797 PCT/US98/06823 (R")r R9 R2 R 3 V- A'(CRa 2 )nA 2 (CRa 2 )n W - (CR lb 2 )p, N N-Z t X '/ sG (Il-c) R or a pharmaceutically acceptable salt thereof, Rla, Rib, R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, u, R 7 a, R 8 , A 1 , A 2 , V, W, X, 5 n, r and t are as defined above with respect to formula (II-a); R 4 is selected from H and CH3; and any two of R 2 , R 3 and R 4 are optionally attached to the same 10 carbon atom; G is O; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, 15 arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 , 20 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 , or g) -C(O)NR 6 R 7 , 25 2) aryl or heterocycle, 3) halogen, 4) OR 6 , 5) NR 6 R7, - 346 - WO 98/44797 PCT/US98/06823 6) CN, 7) NO2, 8) CF3; 9) -S(O)mR 6 , 5 10) -C(O)NR 6 R 7 , or 11) C3-C6 cycloalkyl; and sis 1; 10 (b) a compound represented by formula (II-d): R 6 a-e R 3 2 a 8 )r (R 9 )q 2 I V - A'(CRla 2 )nA 2 (CRla 2 )n W - (CR 1 b2)p- X -(CR 1 b2)p R4 t II-d wherein: Rla and Rlb are independently selected from: 15 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, R 1 1 C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR 1 0)-, CN, NO2, R 10 C(O)-, N3,-N(R 10 )2, or RllOC(O)NR 10 -, 20 c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -347 - WO 98/44797 PCT/US98/06823 R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, R 10 C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR10-; 5 R 2 , R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, 10 R 1 1 S(O)m-, R 10 C(O)NR1 0 -, (R 10 )2NC(O)-, R 1 1 C(0)O-, R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted Cl1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the 15 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, and 20 R 1 1O C(O)-NR 10 -; R6a, R6b, R 6 C, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 25 substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R 1 1 C(O)O-, R 10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR10-, 30 c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or - 348 - WO 98/44797 PCT/US98/06823 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-, R 10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and 5 R 1 1OC(O)-NR10-; any two of R 6 a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; 10 R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, 15 b) aryl or heterocycle, c) halogen, d) HO, e) ' R 0 f) S02R , g) N(R 10 )2 or 20 h) C1-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, 25 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-, RlOC(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 -, and c) C 1-C6 alkyl unsubstituted or substituted by aryl, 30 cyanophenyl, heterocycle, C3-C 10 cycloalkyl, - 349 - WO 98/44797 PCT/US98/06823 C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NH-, (R 1 0)2NC(O)-, R 10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, or R10OC(O)NH-; 5 R 9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, 10 (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1 -C6 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10OC(O)NR10-, (R 10 )2NC(O)-, R102N-C(NR 10 )-, CN, 15 R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -; R 10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2 trifluoroethyl, benzyl and aryl; 20 R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, 25 heteroaryl, substituted heteraryl, C 1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -CC-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, 30 -S(O)2N(R 10 )-, -N(R 10 )S(O)2- or S(O)m; V is selected from: a) hydrogen, - 350 - WO 98/44797 PCT/US98/06823 b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, 5 and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 10 W is a heterocycle; X is a bond, -CH=CH-, O, -C(=0)-, -C(0)NR 7 -, -NR 7 C(0)-, -C(0)O-, -OC(0)-, -C(O)NR 7 C(0)-, -NR 7 -, -S(O)2N(R 10 )-, -N(R 10 )S(O)2- or -S(=O)m 15 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; 20 r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 0 or 1; (c) a compound represented by formula (II-e): 2 3 f \ ' f+ (RR), R ( R r ( R 9 1 V - A'(CRla 2 )nA 2 (CRla 2 )n - (CRb 2 )p X -. (CRlb 2 )p R4 II-e 25 wherein: - 351 - WO 98/44797 PCT/US98/06823 Rla, Rlb, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-d); 5 from 1-3 of f(s) are independently N, and the remaining fs are independently CR 6 ; and each R 6 is independently selected from: a) hydrogen, 10 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 11S(O)m-, R 10 C(O)NR 10 -, (R10)2NC(O)-, R 11 C(0)O-, R 10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, 15 or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 20 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-; or 25 any two of R 6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; (d) a compound represented by formula (II-f): - 352 - WO 98/44797 PCT/US98/06823 R 6 a-e Q R3 (R)r (R) V - A 1 '(CR 1 ' 2 )nA 2 (CR 1 2 ) n W - (CR 2 2 )p - X -(CR2 )p 4 R 5 II-f wherein: R 3 , R 4 , R 5 , R6a-e, R 7 , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p, q, r and 5 t are as previously defined with respect to formula (II-d); from 1-2 of f(s) are independently N, and the remaining fs are independently CH; and 10 R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R10C(O)NR 10 _, R 1 1 C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, 15 R10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 20 R100-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R10)2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 0C(O)-NR 10 -; (f) a compound represented by formula (II-g): - 353 - WO 98/44797 PCT/US98/06823 99 g-g R 3 _ ,g 8 R (R 8 )r 9 - A(CR')A 2 (CR 2 ) - (CR 2 2 ) - X -(CR 2 2 R R 4 II-g wherein: R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p, q, r and t are 5 as previously defined with respect to formula (II-d); from 1-2 of f(s) are independently N, and the remaining fs are independently CH; 10 from 1-3 of g(s) are independently N, and the remaining g's are independently CR 6 ; R1 and R 2 are independently selected from: a) hydrogen, 15 b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, R1 1 C(0)O-, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R10OC(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted or substituted C1-C6 alkyl wherein the 20 substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R10)2NC(O)-, R 10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and 25 R11OC(O)-NR10-; and - 354 - WO 98/44797 PCT/US98/06823 each R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, 5 C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 1 1 C(O)O-, R 10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, 10 d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, (R 10 )2NC(O)-, 15 R 10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-; or any two of R 6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, 20 -(CH2)4- and -(CH2)3-; (g) a compound represented by formula (II-h): R O RNH N NRc S H 3 I H /• R4 HS R 4 II-h wherein 25 Rc is selected from: - 355 - WO 98/44797 PCT/US98/06823 R s OR 6 and n C O R1 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 5 acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R 2 and R 3 are the side chains of naturally occurring amino acids, including their 10 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 15 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 20 atoms; - 356 - WO 98/44797 PCT/US98/06823 R 5 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 5 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 10 aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH2OH or -CH2CH2CH2OH; R6 is a substituted or unsubstituted aliphatic, aromatic or 15 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; 20 Tis O or S(O)m; m is 0, 1 or 2; n is 0, 1 or 2; (h) a compound represented by formula (II-i): R 2 a R 2 b R lb 'N-(CR 2)-) clb I "" K>I" R 5 R 25 II-i wherein: Rla and Rlb are independently selected from: a) hydrogen, - 357 - WO 98/44797 PCT/US98/06823 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 0-, R 9 S(O)m-, 5 R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 10 alkenyl, C2-C6 alkynyl, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)-NR 8 -; R2a, R2b and R 3 are independently selected from: 15 a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, N3, (R 8 )2N-C(NR 8 ) , R 8 C(O)-, R 8 OC(O)-, -N(R 8 )2, or R 9 OC(O)NR 8 -, c) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, halogen or R 9 OC(O)NR 8 -, and 25 d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R 4 and R 5 are independently selected from: 30 a) hydrogen, and b) - 358 - WO 98/44797 PCT/US98/06823 (R 6 )r R7 z V - Al(CRa 2 )A 2 (CRla 2 ) n W - (CR1b 2 ) ( U R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 5 substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or 10 R 9 OC(O)NR 8 -, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, 15 R 8 0-, R 9 S(O)m-, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O), R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R 7 is selected from: a) hydrogen, 20 b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(RS)2, or R 9 OC(O)NR 8 -, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 25 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -; R 8 is independently selected from hydrogen, C1-C6 alkyl, substituted or 30 unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; - 359 - WO 98/44797 PCT/US98/06823 R 9 is independently selected from C1-C6 alkyl and aryl; R 10 is independently selected from hydrogen, C1-C6 alkyl, substituted 5 or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 8 -, -NR 8 C(O)-, O, -N(R 8 )-, 10 -S(O)2N(R 8 )-, -N(R 8 )S(O)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, 15 c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 20 provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 25 Y is selected from: a bond, -C(R10)=C(R10)-, -C-C-, -C(0)-, -C(R10) 2-, -C(OR10)R10-, -CN(R10)2 R 10 - , -OC(R10)2-, -NR10C(R10)2- ' -C(R 10 ) 2 0-, -C(R 10 )2NR 10 -, -C(0)NR10-, -NR10C(0)-, O, NC(0)R10-, -NC(0)OR10-, -S(O)2N(R 10 )-, -N(R 10 )S(0)2-, or 30 S(O)m; Z is H2 or O; mis 0, 1 or 2; - 360 - WO 98/44797 PCT/US98/06823 nis 0, 1,2,3 or4; pis 0,1,2, 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; and u is 0 or 1; 5 (e) a compound represented by formula (II-m): R 6 a-e Q R 3 (R 8 )r (R) Y V - A'(CR 1 2 )nA 2 (CR' 2 )n - (CR 2 2 )p - X -(CR22)p R II-m wherein: 10 Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom attached to Y; 15 Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom; 20 R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, - 361 - WO 98/44797 PCT/US98/06823 C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, R 1 1 C(0)O-, (R10)2NC(O)-, R 10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 lOC(O)NR 1 0-, c) unsubstituted or substituted C1-C6 alkyl wherein the 5 substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R11S(O)m-, R 10 C(O)NR 10 - , (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and 10 R11OC(O)-NR 10 -; R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 15 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 - , (R10)2NC(O)-, R 1 1C(O)O - , R102N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11OC(O)NR10-, 20 c) unsubstituted C 1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 25 R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R102N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1OC(O)-NR10-; R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 30 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, - 362 - WO 98/44797 PCT/US98/06823 R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 1 0)2NC(O)- , R1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R11C(O)O-, R 10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, 5 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, 10 R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, Rl 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR 10 )-, CN, RlOC(O)-, N3, -N(R 10 )2, and R 1 1OC(O)-NR 10 -; or any two of R 6 a, R6b, R 6 C, R6d and R6e on adjacent carbon atoms are 15 combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or 20 substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) "' R 0 d) -SO 2 R', 25 e) N(R 10 )2 or f) C1-4 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, 30 b) aryl, substituted aryl, heterocycle, substituted heterocycle, - 363 - WO 98/44797 PCT/US98/06823 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-, RlOC(O)NR 10 -, (R 10 )2NC(O)-, R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, 5 N3, -N(R 10 )2, or R 1 lOC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R1 1 S(O)m-, R10C(O)NR 10 -, (R 1 0 )2NC(O)-, 10 R11S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR10)-, CN, RlOC(O)-, N3, -N(R 10 )2, or R10OC(O)NH-; R 9 is independently selected from: a) hydrogen, 15 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR10-, and c) Cl1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, 20 F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 -; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 25 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 30 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; - 364 - WO 98/44797 PCT/US98/06823 R 13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl; 5 A 1 and A 2 are independently selected from: a bond, -CH=CH-, -CE-C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R 10 )S(O)2-, or S(O)m; V is selected from: 10 a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and 15 e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 20 X is a bond, -CH=CH-, O, -C(=0)-, -C(0)NR 7 -, -NR 7 C(O)-, -C(0)O-, -OC(O)-, -C(0)NR 7 C(O)-, -NR 7 -, -S(O)2N(R 10 )-, -N(R 10 )S(O)2- or -S(=O)m-; 25 mis 0, 1 or2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and 30 t is 0 or 1; (f) a compound represented by formula (II-n): - 365 - WO 98/44797 PCT/US98/06823 R 6 a-e Y R 3 (R 8 )r (R 9 )q Q V - A'(CR'2)nA2(CR2) n - W - (CR 2 2 )p - X -(R22)p R t R 4 II-n wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R6a-e, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , A 1 , A 2 , V, 5 W, m, n, p, q, r and t are as previously defined with respect to formula (II-m); Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom through which Q is attached to Y and 0-2 10 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom attached to Y, provided that Q is not o 0 0 0-1 0-1 0 or 0-1 O 0 0 15 - 366 - WO 98/44797 PCT/US98/06823 Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom; 5 or a pharmaceutically acceptable salt or disulfide thereof.
10. The method according to Claim 7 wherein the protein substrate competitive inhibitor is selected from: 10 2(S)-Butyl- 1 -(2,3-diaminoprop- 1 -yl)- 1 -(1 -naphthoyl)piperazine; 1-(3-Amino-2-(2-naphthylmethylamino)prop- 1-yl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 15 2(S)-Butyl-1- { 5- [1 -(2-naphthylmethyl)]-4,5-dihydroimidazol } methyl-4 (1-naphthoyl)piperazine; 1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine; 20 1- { 5-[1-(4-nitrobenzyl)]imidazolylmethyl } -2(S)-butyl-4-(1 naphthoyl)piperazine; 1-(3-Acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1 25 naphthoyl)piperazine; 2(S)-Butyl- 1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine; 2(R)-Butyl-l1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine; 30 2(S)-Butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl)piperazine; 1- 2 (S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1 naphthoyl)piperazine; - 367 - WO 98/44797 PCT/US98/06823 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl) piperazine; 5 2(S)-Benzyl- 1 -imidazolyl-4-methyl-4-(1-naphthoyl)piperazine; 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 10 1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1 naphthoyl)piperazine; 2(S)-Butyl- 1- [(4-imidazolyl)ethyl]-4-( 1 -naphthoyl)piperazine; 15 2(S)-Butyl- 1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine; 2(S)-Butyl- 1- [(1 -naphth-2-ylmethyl)- 1H-imidazol-5-yl)acetyl]-4-( 1 naphthoyl)piperazine; 20 2(S)-Butyl- 1- [(1-naphth-2-ylmethyl)- 1H-imidazol-5-yl)ethyl]-4-(1 naphthoyl)piperazine; 1-(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine; 25 1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine; 1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 30 1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1 naphthoyl)piperazine; 1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1 -naphthoyl)-piperazine; - 368 - WO 98/44797 PCT/US98/06823 2(S)-n-Butyl-4-(2,3-dimethylphenyl)- 1-(4-imidazolylmethyl) piperazin-5-one; 2(S)-n-Butyl- 1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3 5 dimethylphenyl)piperazin-5-one; 1-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl) 2(S)-(2-methoxyethyl)piperazin-5-one; 10 2(S)-n-Butyl-4-(1-naphthoyl)- 1- [ 1-(1-naphthylmethyl)imidazol-5 ylmethyl]-piperazine; 2(S)-n-Butyl-4-(1-naphthoyl)- 1-[1-(2-naphthylmethyl)imidazol-5 ylmethyl]-piperazine; 15 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 2(S)-n-Butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1 20 naphthoyl)piperazine; 2(S)-n-Butyl- 1-[1 -(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 25 2(S)-n-Butyl- 1- [ 1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 2(S)-n-Butyl- 1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)piperazine; 30 1-[1-(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1 naphthoyl)piperazine; - 369 - WO 98/44797 PCT[US98/06823 2(S)-n-B utyl-4- (1 -naphthoyl)- 1-[ [1 -(4-trifluoromethylbenzyl)imidazol-5 ylmethyl] -piperazine; 2(S)-n-Butyl-1- [1- (4-methylbenzyl)imidazol- 5-ylmethyl] -4-( 1 5 naphthoyl)-piperazine; 2(S)-n-Butyl- 1-[ [1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-( 1 naphthoyl)-piperazine; 10 1 -[1 -(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-( 1 naphthoyl)-piperazine; 2(S)-n-B utyl-4- (1-naphthoyl)- 1-[ 1- (2-phenylethyl)imidazol-5-ylmethyl] pip erazine; 15 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1- [i -(4-trifluoromethoxy)imidazol-5 ylmethyllpiperazine; 1- { [1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetyl I-2(S)-n-butyl-4-( 1 20 naphthoyl)piperazine; (S)-l1-(3 -Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl] -5- [2 (methanesulfonyl)ethyl]-2-piperazinone 25 (S)-i -(3-Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl] -5- [2 (ethanesulfonyl)ethyl] -2-piperazinone (S)-i -(3 -Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl] -5- [2 (ethanesulfonyl)methyl] -2-piperazinone 30 (S)- 1- (3 -Chlorophenyl)-4- [1-(4-cyanobenzyl)-5 -imidazolylmethyl] -5- [N ethyl-2-acetamido] -2-piperazinone (±)-5- (2-B utynyl)- 1 -(3 -chlorophenyl)-4- [1-(4-cyanobenzyl)-5 35 imidazolylmethyl]-2-piperazinone _ 370 - WO 98/44797 PCT/US98/06823 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2 piperazinone 5(S)-Butyl-4- [1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-1-(2,3 5 dimethylphenyl)-piperazin-2-one 4-[1- (2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]-1 -(3 chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one 10 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2 methylphenyl)piperazin-2-one 4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)- 1-(3 chlorophenyl)piperazin-2-one 15 4-[3-(4-Cyanobenzyl)pyridin-4-yl]- 1-(3-chlorophenyl)-5(S)-(2 methylsulfonylethyl)-piperazin-2-one 4-[5-(4-Cyanobenzyl)-1-imidazolylethyl]-1 -(3-chlorophenyl)piperazin 20 2-one; 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-homoserine lactone, 25 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-2-methy 1l-3-phenylpropionyl-homoserine lactone, 30 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto)propylamino-3(S) 35 methyl]pentyloxy-4-pentenoyl-homoserine lactone, - 371 - WO 98/44797 PCT/US98/06823 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-4-pentenoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) 5 methyl]pentyloxypentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S) methyl]pentyloxypentanoyl-homoserine, 10 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]5 pentyloxy-4-methylpentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-4-methylpentanoyl-homoserine, 15 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S) methyllpentyloxy-3-methylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) 20 methyl]pentyloxy-3-methylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylbutanoyl-homoserine lactone, 25 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, 30 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine, - 372 - WO 98/44797 PCT/US98/06823 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] 5 pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S)-methyl] pentyloxy-3-phenylpropionyl-methionine methyl ester, 10 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester 15 (Compound 5), 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 6), 20 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, 2-(S)-[ 2 (S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-naphth-2-yl-propionyt-methionine sulfone methyl ester, 25 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) 30 methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[ 2 (R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone, - 373 - WO 98/44797 PCT/US98/06823 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyllpentyloxy-3-methybutanoyl-methionine methyl ester. 5 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-methybutanoyl-methionine, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino 3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone, 10 Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S) methyl]pentyloxy-3-phenylpropionyl-homoserine, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino 15 3(S)methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole 20 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 25 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 30 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole - 374 - WO 98/44797 PCT/US98/06823 1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 5 1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 10 1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 15 1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 20 1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4 25 methylimidazole 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole 30 5-(4-Cyanophenyloxy)-1-(2'-methyl-4-biphenylmethyl)-imidazole 5-(4-Biphenyloxy)- 1-(4-cyanobenzyl)-imidazole - 375 - WO 98/44797 PCT/US98/06823 5-(2'-Methyl-4-biphenoxy)- 1-(4-cyanobenzyl)-imidazole 5 5-(4-(3',5'-dichloro)biphenylmethyl)- 1-(4-cyanobenzyl)imidazole 1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy- 1 -(4 cyanophenyl)methylimidazole 10 1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy- 1-(4-cyanophenyl) methylimidazole 15 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino- 1-(4-cyanophenyl) methylimidazole 20 1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy- 1-(4-cyanophenyl) methylimidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy- 1-(4-biphenyl)-methyl imidazole 25 1-(4-Cyanobenzyl)-5-(1-oxo- 1-(4-biphenyl)-methyl imidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy- 1-(3-fluoro-4-biphenyl)-methyl) 30 imidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy-l1-(3-biphenyl)methyl-imidazole 35 - 376 - WO 98/44797 PCT/US98/06823 5-(2-[ 1,1 '-Biphenyl]vinylene)- 1-(4-cyanobenzyl)imidazole 1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4 phenylbenzene 5 1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole 1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole 10 1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 15 N- { 1-(4-Cyanobenzyl)- 1H-imidazol-5-yl)methyl } -5-(pyrid-2-yl)-2 amino-pyrimidine N,N-bis(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene 20 N,N-bis(4-Imidazolemethyl)amino-4-[(3-carboxyphenyl)oxy]benzene N,N-bis(4-Imidazolemethyl)amino-3-[(3-carbomethoxyphenyl) oxy]benzene 25 N,N-bis(4-Imidazolemethyl)amino-4-[(3-carbomethoxyphenyl) oxy]benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3 30 carboxyphenyl)oxy]benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3 carbomethoxyphenyl)oxy]benzene 35 N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene - 377 - WO 98/44797 PCT/US98/06823 N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzene N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenylthio)benzene 5 N-Butyl-N- [1 -(4-cyanobenzyl)-5-imidazolemethyl]amino-4 (phenoxy)benzene N- [1 -(4-Cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzene 10 N-(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene 1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4 cyanobenzyl)amino]-4-(phenoxy)benzene 15 (±)-4-[(4-imidazolylmethyl)amino]pentyl- 1 -(phenoxy)benzene 1-[(N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n butyl)amino)methyl]-4-(phenoxy)benzene 20 4-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino]-1 (phenylthio)benzene (±)-4-[N-(1-(4-cyanobenzyl)-4-imidazolylmethyl)-N-(n-butyl)amino]-1 25 (phenylsulfinyl)benzene 3-[N-(4-imidazolylmethyl)-N-(n-butyl)amino]-N (phenyl)benzenesulfonamide and 30 1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4 phenylbenzene 4- { 3-[4-(-2-Oxo-2-H-pyridin-1-yl)benzyl]-3-H-imidazol-4 ylmethyl]benzonitrile 35 - 378 - WO 98/44797 PCT/US98/06823 4- { 3-[4-3-Methyl-2-oxo-2-H-pyridin- 1-yl)benzyl]-3-H-imidazol-4 ylmethyl]benzonitrile 4- { 3-[4-(-2-Oxo-piperidin- 1 -yl)benzyl]-3-H-imidazol-4 5 ylmethyl]benzonitrile 4- { 3-[3-Methyl-4-(2-oxopiperidin- 1 -yl)-benzyl]-3-H-imidizol-4 ylmethyl } -benzonitrile 10 (4- { 3- [4-(2-Oxo-pyrrolidin- 1-yl)-benzyl]-3H-imidizol-4-ylmethyl } benzonitrile 4- { 3- [4-(3-Methyl-2-oxo-2-H-pyrazin- 1 -yl)-benzyl-3-H-imidizol-4 ylmethyl I -benzonitrile 15 4- { 3-[2-Methoxy-4-(2-oxo-2-H-pyridin- 1-yl)-benzyl]-3-H-imidizol-4 ylmethyl } -benzonitrile 4- { 1- [4-(5-Chloro-2-oxo-2H-pyridin- 1-yl)-benzyl]- 1H-pyrrol-2 20 ylmethyl } -benzonitrile 4-[1-(2-Oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)- 1 H-pyrrol-2-ylmethyl] benzonitrile 25 4- [1-(5-Chloro-2-oxo-2H- [ 1,2']bipyridinyl-5'-ylmethyl)- 1H-pyrrol-2 ylmethyl]-benzonitrile 4- [3- (2-Oxo- 1-phenyl- 1,2-dihydropyridin-4-ylmethyl)-3 H-imidazol-4 ylmethyl]benzonitrile 30 4- { 3- [1-(3-Chloro-phenyl)-2-oxo- 1,2-dihydropyridin-4-ylmethyl]-3H imidazol-4-ylmethyl } benzonitrile or a pharmaceutically acceptable salt, disulfide or optical isomer 35 thereof. - 379 - WO 98/44797 PCT/US98/06823
11. The method according to Claim 1 wherein the integrin antagonist is selected from: 5 (a) a compound of the formula I-a: X-Y-Z-Aryl-A-B wherein: 10 Aryl is a 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R 8 and R 9 ; X is selected from NR 2 NR 1 NR 2 2 I_ II -1 II -NR'R, -NR'-C-R 3 , -C-NR 2 R 3 ,-NR'-C-NR 3 R 4 , NR 1 NR 2 II 2 3 1II 3 -aryl-NR 1 R 2 , -aryl-C-NR 2 R 3 , -aryl-NR'-C-NR R 15 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 , R 2 , R 3 and R 4 , or 20 a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted 25 or substituted with R 1 , R 2 , R 3 and R 4 ; Y is selected from CO-8 alkylene, - 380 - WO 98/44797 PCT/US98/06823 C3-10 cycloalkyl, CO-8 alkylene-NR 10-CO-CO- 8 alkylene, CO-8 alkylene-CONR 10 -CO-8 alkylene, CO-8 alkylene-O-CO-8 alkylene, 5 CO-8 alkylene-NR10-CO-8 alkylene, CO-8 alkylene-S(0)0-2-CO-8 alkylene, CO-8 alkylene-SO2-NR 10 -CO-8 alkylene, CO-8 alkylene-NR10-SO2-CO-8 alkylene, CO-8 alkylene-CO-CO-8 alkylene, 10 (CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NR 10 -(CH2)0-6, (CH2)0-6 arylNR 10 CO(CH2)0-6, or OH I (CH 2 ) 0 -8CH (CH 2 )0-8 . 15 Z and A are each independently selected from O 1II 12 (CH 2 )m, (CH 2 )mO(CH 2 )n, (CH 2 )mNR"(CH 2 )n,(CH 2 )mNR" 1 CNR 2 (CH 2 ) n 0 0 0 I 11 II (CH 2 )mCNR 1 (CH 2 ) n, (CH 2 )mNR 1 " (CH 2 )n,(CH 2 )mC(CH 2 )n, S (CH 2 )m(CH 2 )n, (CH 2 )mSO 2 (CH 2 )n, (CH 2 )mS(CH 2 )n, (CH 2 )mSO(CH 2 )n, (CH 2 )mSO 2 NR 11 "(CH 2 )n, (CH 2 )mNR 11 "SO 2 (CH 2 )n, (CH 2 )mCR 1 1=CR 12 (CH 2 )n, or (CH 2 )mCC- (CH 2 )n, - 381 - WO 98/44797 PCT/US98/06823 where m and n are each independently an integer from 0 to 6; B is O II C-R 1 R6R 7 5 where p is an integer from 1 to 3; R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 1 1 and R 12 are each independently selected from hydrogen, 10 halogen, C1-10 alkyl, aryl CO-8 alkyl, amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, 15 C1-6 alkylamino CO-8 alkyl, C1-6 dialkylamino CO-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, 20 C1-4 alkoxy CO-6 alkyl, hydroxycarbonyl CO-6 alkyl, C1-4 alkoxycarbonyl CO-6 alkyl, hydroxycarbonyl CO-6 alkyloxy, hydroxy C1-6 alkylamino CO-6 alkyl or 25 hydroxy CO-6 alkyl; R 6 is selected from hydrogen, fluorine, - 382 - WO 98/44797 PCT/US98/06823 C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, 5 C1-6 alkyloxy, C1-6 alkylcarbonyl, aryl C0-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl C0-6 alkylcarbonyloxy, 10 C1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino C0-6 alkyl, CO-6 dialkylamino CO-6 alkyl, 15 C1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, C1-8 alkyloxycarbonylamino CO-8 alkyl, aryl C0-8 alkyloxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, 20 aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylaminocarbonylamino C0-6 alkyl, C0-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino C0-6 alkyl, 25 C1-6 alkylsulfonyl C0-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, or 30 aryl CO-6 alkylthiocarbonylamino CO-6 alkyl; wherein the alkyl or N atoms may be unsubstituted or substituted with R 5 ; R 7 is selected from - 383 - WO 98/44797 PCT/US98/06823 hydrogen, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, aryl CO-6 alkyloxycarbonylamino CO-6 alkyl, 5 aryl CO-6 alkylsulfonylamino CO-6 alkyl and aryl CO-6 alkylcarbonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylsulfonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylcarbonylamino CO-6 alkyl; C7-20 polycyclyl CO-8 alkylaminosulfonylamino CO-6 alkyl; 10 C7-20 polycyclyl CO-8 alkylaminocarbonylamino CO-6 alkyl or C7-20 polycyclyl CO-8 alkyloxycarbonylamino CO-6 alkyl; wherein the polycyclyl may be unsubstituted or substituted with R 14 , R 15 , R 16 and R 17 ; and wherein any of the alkyl groups may be unsubstituted or subsituted with R 14 and 15 R15; R 13 is selected from hydroxy, C1-8 alkyloxy, 20 aryl CO-6 alkyloxy, Ci1-8 alkylcarbonyloxy C 1-4 alkyloxy, aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy, C1-6 dialkylaminocarbonylmethyloxy, aryl C1-6 dialkylaminocarbonylmethyloxy or 25 an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1-6 alkyl; and R 14 , R 15 , R 16 and R 17 are each independently selected from 30 hydrogen, halogen, C-10 alkyl, C3-8 cycloalkyl, oxo, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, - 384 - WO 98/44797 PCT/US98/06823 hydroxycarbonyl C1-6 alkyl, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl, C1-6 alkyloxy C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, 5 trifluoroethoxy, C1-8 alkyl-S(O)q, CI1-8 alkylaminocarbonyl, C1-8 dialkylaminocarbonyl, C1-8 alkyloxycarbonylamino, CI1-8 alkylaminocarbonyloxy or C 1-8alkylsulfonylamino; (b) a compound of the formula I-b: 0 O 6 R 7 0 Rs C-Rio X-(CH 2 )-C-(CH 2 )-N NH H R8 R 9 10 I-b wherein X is selected from NR 2 - 1 -NR 3 R -NR4 -- Ar or -- NR -Ar Ar is a 4- to 10-membered mono- or polycyclic aromatic or non aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected 15 from N, O or S and wherein the mono- or polycyclic aromatic or non aromatic ring system is either unsubstituted or substituted with R 1 , R 2 , R 3 and R 4 ; R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, 20 hydroxyl, C1-8 alkyl, halogen, aryl CO-8 alkyl, oxo, thio, amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, C1-6 dialkylamino CO-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C1-4 alkoxy CO-8 alkyl, carboxy CO-8 alkyl, C1-4 alkoxycarbonyl 25 CO-8 alkyl, carboxy CO-8 alkoxy, hydroxy CO-8 alkyl or C3-8 cycloalkyl CO-6 alkyl; - 385 - WO 98/44797 PCT/US98/06823 R 5 is selected from hydrogen, C 1-6 alkyl, CO-6 alkylaryl, aryl or C3-8 cycloalkyl CO-6 alkyl; 5 R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, fluorine, C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino 10 C0-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, CO-8 alkyl SO2NR 3 -CO-8 alkyl, aryl CO-8 alkoxycarbonylamino CO-8 alkyl, aryl CO-8 alkyl-SO2NR 3 -CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino C0-6 alkyl, aryl CO-6 alkylcarbonylamino 15 CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylamino sulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl 20 CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, aryl C0-6 alkyl thiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl C0-6 alkyl, C3-8 cycloalkyl CO-6 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy or C3-8 cycloalkyl C0-6 alkylaminocarbonylamino; wherein any of the 25 alkyl groups may be unsubstituted or substituted with R 1 and R 2 ; R 10 is selected from hydroxyl, C1-8 alkoxy, aryl CO-6 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-6 dialkylaminocarbonylmethoxy, 30 aryl C1-6 dialkylaminocarbonylmethoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified by C1-6 alkyl; and each n is independently an integer from 0 to three; - 386 - WO 98/44797 PCT/US98/06823 provided that when R 5 is hydrogen and X is Ar and Ar is a 6-membered monocyclic non-aromatic ring system containing one nitrogen atom and R 6 and R 7 are each hydrogen, and R 8 is selected from hydrogen or 5 C1-6 alkyl, and R 10 is selected from hydroxyl, C1-8 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified with C 1-6 alkyl, then R 9 is selected from fluorine, hydroxyl, hydroxy C1-6 alkyl, carboxy 10 CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, aryl CO-8 alkoxycarbonyl amino CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkyl 15 carbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylamino carbonylamino CO-6 alkyl, CO-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl 20 CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonyl amino CO-6 alkyl, aryl CO-6 alkylthiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl CO-6 alkyl, C3-8 cycloalkyl CO-6 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy or C3-8 cycloalkyl CO-6 alkylamino 25 carbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R 1 and R 2 ; and provided further that when R 5 is hydrogen and X is Ar and Ar is H 2 N N- N 0 N IN- or 30 and R 6 , R 7 and R 8 are each hydrogen, and RO10 is selected from hydroxyl and C1-8 alkoxy, then R 9 is selected from fluorine, - 387 - WO 98/44797 PCT/US98/06823 C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylamino carbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino 5 CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino CO-6 alkyl, CO-8 alkyl-SO2NR 3 -CO-8 alkyl, aryl CO-8 alkoxycarbonyl amino CO-8 alkyl, C1-8 alkoxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, 10 aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylamino sulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl CO-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, aryl CO-6 alkyl 15 thiocarbonylamino CO-6 alkyl, C3-8 cycloalkyl CO-6 alkyl, C3-8 cycloalkyl CO-6 alkylsulfonylamino CO-6 akyl, C3-8 cycloalkyl CO-6 alkylcarbonyl, C3-8 cycloalkyl CO-6 alkylaminocarbonyloxy or C3-8 cycloalkyl CO-6 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R 1 and R 2 ; 20 (c) a compound of the formula I-c: O 8 R R 9 X-Y-Z-(CH 2 )-C- N CO 2 R 12 H 1 0 R 1 lR RI I-c wherein X is selected from N ' R 1 NR 2 -C-NR'R 2 -NRl-C-NR'R 2 25 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O - 388 - WO 98/44797 PCT/US98/06823 or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 , or a 9- to 10-membered polycyclic ring system, wherein one or 5 more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 and R 2 ; 10 Y is selected from R 3 R3 0 , I I II 00 -N-(CH 2 )m- , -(CH2)i;-N- -C-(CH 2 )'- -C-N-(CH 2 ) - m R 3 O II -N-C-(CH2);- -S(O)q-(CH2) , - O-(CH2)- or - (CH2)r' R 3 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring 15 system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R 5 , R 6 and R 7 ; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is a 5-11 membered nonaromatic mono- or polycyclic ring system 20 containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R 5 , R 6 and R 7 ; 25 R 1 , R 2 , R 4 , R 5 , R 13 and R 14 are each independently selected from hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, - 389 - WO 98/44797 PCT/US98/06823 C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy Ci1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI -6 alkyl, Ci1-3 alkoxycarbonyl, 5 C1-3 alkoxycarbonyl CI1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)q, C1-8 aminocarbonyl, C1-8 dialkylaminocarbonyl, C1-8 alkyloxycarbonylamino, 10 C1-8 alkylaminocarbonyloxy or C1-8 alkylsulfonylamino; R 3 is selected from hydrogen, aryl, 15 -(CH2)p-aryl, hydroxyl, C1-5 alkoxycarbonyl, aminocarbonyl, C3-8 cycloalkyl, 20 amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, 25 aryl C1-6 alkyl, C1-6 alkylamino C1-6 alkyl, aryl C1-6 alkylamino C1-6 alkyl, C1-6 dialkylamino C1-6 alkyl, C1-8 alkylsulfonyl, 30 C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, - 390 - WO 98/44797 PCT/US98/06823 aryl C1-6 alkylcarbonyl, C1-8 alkylaminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, 5 arylaminosulfonylamino, aryl C1-8 alkylaminosulfonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl C1-6 alkylsulfonyl, 10 aryl C1-6 alkylcarbonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, or aryl C1-6 alkylthiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with 15 R 13 and R14; R 6 , R 7 , R 8 , R 9 , R 10 and R 1 1 are each independently selected from hydrogen, aryl, 20 -(CH2)p-aryl, halogen, hydroxyl, C 1-8 alkylcarbonylamino, aryl C1-5 alkoxy, 25 C1-5 alkoxycarbonyl, aminocarbonyl, C1-8 alkylaminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, 30 oxo, amino, C1-6 alkylamino, amino C1-6 alkyl, arylaminocarbonyl, - 391 - WO 98/44797 PCT/US98/06823 aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, 5 hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, C1-5 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino 10 carbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, amino C1-3 alkyl, arylamino carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C1-5 alkyl, 15 -(CH2)s C-CH, -(CH2)s C-C-C1-6 alkyl, -(CH2)s CEC-C3-7 cycloalkyl, -(CH2)s CEC-aryl, -(CH2)s C-C-C1-6 alkylaryl, 20 -(CH2)s CH=CH2, -(CH2)s CH=CH C1-6 alkyl, -(CH2)s CH=CH-C3-7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH C1-6 alkylaryl, 25 -(CH2)s SO2C1-6 alkyl, -(CH2)s SO2C1-6 alkylaryl, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, 30 C1-6 alkylamino C1-6 alkyl, arylamino, arylamino C1-6 alkyl, aryl C1-6 alkylamino, aryl C1-6 alkylamino C1-6 alkyl, - 392 - WO 98/44797 PCT/US98/06823 arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, C 1-6 dialkylamino, C1-6 dialkylamino C1-6 alkyl, 5 C1-6 alkylaminocarbonyloxy, C1-8 alkylsulfonylamino, C 1-8 alkylsulfonylamino C 1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, 10 aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C 1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, 15 aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, 20 aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, C1-8 alkylaminocarbonylamino, C1-8 alkylaminocarbonylamino C1-6 alkyl, arylaminocarbonylamino C1-6 alkyl, 25 aryl C1-8 alkylaminocarbonylamino, aryl C1-8 alkylaminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, C1-8 alkylaminosulfonylamino, C1-8 alkylaminosulfonylamino C1-6 alkyl, 30 arylaminosulfonylamino C1-6 alkyl, aryl C1-8 alkylaminosulfonylamino, aryl C 1-8 alkylaminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, - 393 - WO 98/44797 PCT/US98/06823 arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, 5 C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, 10 C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C 1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, C1-8 alkylaminocarbonyl C1-6 alkyl, 15 arylaminocarbonyl Ci1-6 alkyl, aryl C1-8 alkylaminocarbonyl, or aryl C1-8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 13 and R1 4 ; and provided that the carbon atom to which R 8 and R 9 20 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R 1 1 are attached is itself attached to no more than one heteroatom; R 12 is selected from 25 hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, hydroxy, 30 C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, - 394 - WO 98/44797 PCT/US98/06823 C1-8 alkylaminocarbonylmethyleneoxy, or C1-8 dialkylaminocarbonylmethyleneoxy; m is an integer from 0 to 3; 5 n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and s is an integer from 0 to 3; 10 (d) a compound of the formula I-d: X-Y-Z-Ring-A-B I-d 15 wherein: Ring is a 4 to 10-membered mono-or polycyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, and either unsubstituted or substituted with R 27 and 20 R 2 8 ; X is selected from NR 2 NR 2 NR 2 II II II -NR' 1 R 2 , -NR'-C-R 3 , -C-NHR 4 , -NR 1 -C-NR 3 R 4 NR 1 NR 2 II 3 1I 4 -aryl-NR 1 R 2 , -aryl-C-NR 2 R 3 , -aryl-NR'-C-NR R 25 or a 4- to 10- membered mono- or polycyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S and either unsubstituted or substituted with R 13 , R1 4 , R 15 or R16; 30 Y is selected from - 395 - WO 98/44797 PCT/US98/06823 CO-g alkylene, C3-10 cycloalkyl, CO-g alkylene-NR 5 -CO-CO.8 alkylene, CO-8 alkylene-CONR 5 -COyg alkylene, 5 CO-g alkylene-O-CO.8 alkylene, CO-8 alkylene-NR 5 -CO.8 alkylene, CO-8 alkylene-S()02-CO08 alkylene, CO-8 alkylene-S02-NR 5 -CO08 alkylene, CO-8 allcylene-NR 5 -S02-CO08 alkylene, 10 CO-8 alkylene-CO-CO08 alkylene, (CH2)0-6 aryl(CH2)o..6, (CH2)0-6 aryl-CO-(CH2)O.6, (CH2)0.6 aryl-CO-NR 5 -(CH2)0-6, (CH2)0-6 aryl-NR 5 -CO-(CH2)0..6, or 15 OH (0H 2 ) 0 .. 8 0Hk(OH 2 ) 0 . 8 Z is selected from 0 (0H 2 )m (0H 2 )mO(0H 2 )n, (C0H 2 )mNR 6 (0 2 )n, (C2mN N (H) 00 0 11 6 11 1 (0H 2 )mCNR 6 (H 2 )n, (0H 2 )mNR C(CH 2 )n, (CH 2 )mC(0H 2 )n, s 0 (CH 2 )m8(OH 2 )n, C2mO(H), (H)SC2n (0H 2 )mSO(0H 2 )n, (0H 2 )mSO 2 NR R 6 (CH 2 )n, (0H 2 )m N R 6 SO 2 (CH 2 )n, (0H 2 )mCR =CR (CH 2 )n, or (CH 2 ) mC C -(CH 2 )n; - 396 - WO 98/44797 PCT/US98/06823 where m and n are each independently an integer from 0 to 6; A is selected from O SII (CH2)qO(CH2)p, (CH 2 )qNR 2 9 (CH 2 )p, (CH 2 )qNR 29 CNRa(CH 2 )p OO O 0 0 0 II II (CH 2 )qCNR 29 (CH 2 )p, (CH 2 )qNR 2 9 C(CH 2 )p, (CH 2 )qC(CH 2 )p, S O II II (CH2)qC(CH2)p, (CH 2 )qSO 2 (CH 2 )p, (CH 2 )qS(CH2)p, (CH 2 )qSO(CH 2 )p, (CH 2 )qSO 2 NR 2 9 (CH 2 )p, (CH 2 )qNR 2 9 SO 2 (CH 2 )p, 5 (CH 2 )qCR 29 =CR 30 (CH 2 )p or (CH2)qC-C-(CH 2 )p; where p and q are each independently an integer from 0 to 6; B is selected from 0 R 8 II R 9 O C-R 12 0 or II or 9(CH 2 )0- 1 -C- R 2 R8 R9 R 1 0 R 10 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 17 , R 18 , R 19 , R 2 0, R 2 1 , R 2 2 , R 2 3 , R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 , R 2 9 and R 3 0 are each independently selected from hydrogen, halogen, C1-10 alkyl, 15 aryl CO-8 alkyl, - 397 - WO 98/44797 PCT/US98/06823 amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, C 1-6 dialkylamino CO-8 alkyl, 5 aryl CO-6 alkylamino CO-6 alkyl, C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C1-4 alkoxy CO-6 alkyl, carboxy CO-6 alkyl, 10 C1-4 alkoxycarbonyl CO-6 alkyl, carboxy C0-6 alkyloxy, hydroxy C1-6 alkylamino CO-6 alkyl, hydroxy CO-6 alkyl, NR 17 NR 18 R 19 , or NR 18 -NR1 7 " NR1 9 R 2 0 15 R 8 , R 9 , R 10 , and R 1 1 are each independently selected from hydrogen, fluorine, 20 C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C1-6 alkyloxy, 25 C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C1-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylaminocarbonyloxy, - 398 - WO 98/44797 PCT/US98/06823 C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, 5 C1-8 alkylsulfonylamino CO-6 alkyl, aryl CO-6 alkylsulfonylamino CO-6 alkyl, C1-8 alkyloxycarbonylamino CO-8 alkyl, aryl CO-8 alkyloxycarbonylamino CO-8 alkyl, C1-8 alkylcarbonylamino CO-6 alkyl, 10 aryl CO-6 alkylcarbonylamino CO-6 alkyl, C0-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 alkyl, C0-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, 15 C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl CO-6 alkyl, C1-6 alkylcarbonyl CO-6 alkyl, aryl C0-6 alkylcarbonyl C0-6 alkyl, C1-6 alkylthiocarbonylamino CO-6 alkyl, or 20 aryl CO-6 alkylthiocarbonylamino CO-6 alkyl wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R 2 1 and R 2 2 (e.g., any amino group such as -NH- can be substituted with R21 to be -NR 2 1-); 25 R 12 is selected from hydroxy, Cl-8 alkyloxy, aryl CO-6 alkyloxy, 30 C1-8 alkylcarbonyloxy C1-4 alkyloxy, aryl CO-8 alkylcarbonyloxy C1-4 alkyloxy, C1-6 dialkylaminocarbonylmethyloxy, aryl C1-6 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and - 399 - WO 98/44797 PCT/US98/06823 wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1-6 alkyl; and R 13 , R 14 , R 15 and R 16 are each independently selected from 5 hydrogen, C1-10 alkyl, aryl CO-8 alkyl, oxo, thio, 10 amino CO-8 alkyl, C1-3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, C1-6 dialkylamino C0-8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, 15 C1-4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino CO-8 alkyl, C1-4 alkoxy CO-6 alkyl, carboxy CO-6 alkyl, C1-4 alkoxycarbonyl CO-6 alkyl, 20 carboxy CO-6 alkyloxy, hydroxy C1-6 alkylamino CO-6 alkyl, hydroxy CO-6 alkyl, NR 23 NR 2 4 R 2 5 , or NR 24 -NR 23 NR 25 R 26 . 25 provided that Ring is not a 6-membered monocyclic aromatic ring; provided further that when Ring is thiophene, then X is selected from - 400 - WO 98/44797 PCT/US98/06823 RR13 R13 NH N N H H N N RR R13OR L N N CN or N' provided further that when Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, 5 indole, benzothiazole, benzoxazole, ,S or " then X is selected from R13 R 13 R13 S , N H H NI N R 13 R 13_ RN RN or N: R 1 R 1 R 1 and the pharmaceutically acceptable salts thereof. 10 In one embodiment of the invention is the compound wherein Y is selected from CO-8 alkylene, C3-10 cycloalkyl, CO-8 alkylene-NR 5 -CO-CO-8 alkylene, 15 CO-8 alkylene-CONR 5 -CO-8 alkylene, - 401 - WO 98/44797 PCT/US98/06823 CO-8 alkylene-O-CO-8 alkylene, CO-8 alkylene-NR 5 -CO-8 alkylene, CO-8 alkylene-S(0)0-2-CO-8 alkylene, CO-8 alkylene-SO2-NR 5 -CO-C08 alkylene, 5 CO-8 alkylene-NR 5 -SO2-CO-8 alkylene, CO-8 alkylene-CO-CO-8 alkylene, (CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NH-(CH2)0-6, or OH I 10 (CH 2 )0-8CH(CH 2 )o-a 8 Z is (CH2)m where m is an integer from 0 to 3; preferably, m is zero; and all other variables are as defined above; 15 (e) a compound of the formula I-e: 0 0 6 R R 7 X-Y-Z-C-CH2- C NR 0 H 8 RR 9 I-e wherein X is selected from N , R NR 2 -C-NR 2 R 3 -NR-C-NRR 4 a 5- or 6-membered monocyclic aromatic or nonaromatic ring 20 system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R1 and R 2 , or - 402 - WO 98/44797 PCT/US98/06823 a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted 5 or substituted on a carbon atom with R1 and R 2 ; Y is selected from R 5 0 R s O I II -(CH2)inN-(CH2)- 2)-C-(CH2) , 0 0 II II -(CH2 2)- -(CH2)K-N-C-(CH2) m R 5 R 5 -(CH2),S(0)q-(CH2)-, -(CH2)'- 0-(CH2) m R13 Rs -(CH2)-(CH2)m- or -(CH2)-N-(CH2)-N-(CH2)E Z is absent or is a 4-11 membered aromatic or nonaromatic 10 mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 14 , R15, R16 and R17; preferably, Z is not a 15 6-membered monocyclic aromatic ring system; R1, R 2 , R3, R 4 , R5, R11, R12, R13, R16 and R17 are each independently selected from hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, aryl, 20 aryl Cl-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, - 403 - WO 98/44797 PCT/US98/06823 hydroxycarbonyl Ci1-6 alkyl, Ci1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy or hydroxy C1-6 alkyl; 5 R 6 , R 7 , R 8 , R 9 , R 14 and R 15 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, 10 C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-8 alkylaminocarbonyl, 15 C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-6 alkylamino, 20 amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, 25 hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, C1-5 alkylcarbonylamino, aryl C1-5 alkoxy, 30 C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino carbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, amino C1-3 alkyl, arylamino carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-4 alkyl, hydroxycarbonyl, or - 404 - WO 98/44797 PCT/US98/06823 hydroxycarbonyl C1-5 alkyl, -(CH2)r C-CH, -(CH2)r C-C-C1-6 alkyl, -(CH2)r C-C-C3-7 cycloalkyl, 5 -(CH2)r C-C-aryl, -(CH2)r C-C-C1-6 alkylaryl, -(CH2)r CH=CH2, -(CH2)r CH=CH C1-6 alkyl, -(CH2)r CH=CH-C3-7 cycloalkyl, 10 -(CH2)r CH=CH aryl, -(CH2)r CH=CH C1-6 alkylaryl, -(CH2)r SO2C1-6 alkyl, -(CH2)r SO2C1-6 alkylaryl, C1-6 alkoxy, 15 aryl C1-6 alkoxy, aryl C1-6 alkyl, C1-6 alkylamino C1-6 alkyl, arylamino, arylamino C1-6 alkyl, 20 aryl C1-6 alkylamino, aryl C1-6 alkylamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, C1-6 dialkylamino, 25 C1-6 dialkylamino C1-6 alkyl, C1-6 alkylaminocarbonyloxy, Ci1-8 alkylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, 30 aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, - 405 - WO 98/44797 PCT/US98/06823 aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, 5 arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino Ci1-6 alkyl, C1-8 alkylaminocarbonylamino, 10 C1-8 alkylaminocarbonylamino C1-6 alkyl, arylaminocarbonylamino C1-6 alkyl, aryl C1-8 alkylaminocarbonylamino, aryl C1-8 alkylaminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, 15 C1-8 alkylaminosulfonylamino, Cl-8 alkylaminosulfonylamino C 1-6 alkyl, arylaminosulfonylamino C 1-6 alkyl, aryl C1-8 alkylaminosulfonylamino, aryl C1-8 alkylaminosulfonylamino C1-6 alkyl, 20 C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, 25 C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, 30 C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C 1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, - 406 - WO 98/44797 PCT/US98/06823 C1-8 alkylaminocarbonyl C1-6 alkyl, arylaminocarbonyl C1-6 alkyl, aryl C1-8 alkylaminocarbonyl, or aryl C1-8 alkylaminocarbonyl C1-6 alkyl, 5 wherein any of the alkyl groups may be unsubstituted or substituted with R 1 1 and R1 2 ; and provided that the carbon atom to which R 6 and R 7 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; 10 R 10 is selected from hydrogen, C1-8 alkyl, aryl, 15 aryl C1-8 alkyl, aryl C1-6 alkoxy, C1-8 alkylcarbonyloxy Cl1-4 alkyl, aryl C1-8 alkylcarbonyloxy C 1-4 alkyl, C1-8 alkylaminocarbonylmethylene, or 20 C1-8 dialkylaminocarbonylmethylene; m, n and r are each independently an integer from 0 to 3; p is an integer from 1 to 4; and q is an integer from 0 to 2; 25 or a pharmaceutically acceptable salt thereof.
12. The method according to Claim 11 wherein the integrin antagonist is selected from: 30 4-(2-Guanidoethyloxy)phenylcarbonyl-2(S)-benzyloxycarbonylamino- alanine, 4 -(2-Guanidoethyloxy)phenylcarbonyl-2(S)-phenylsulfonylamino-3 alanine, - 407 - WO 98/44797 PCT/US98/06823 2(S)-Phenylsulfonylamino-3-[4-(4-guanidobutyloxy)phenyl]-propionic acid, 5 2(S)-(N-Benzyloxycarbonylamino)-3-[4-(5-guanidopentyloxy)phenyl] propionic acid, 4-(3-Guanidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-P alanine, 10 4-(3-Formamidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-3 alanine, 3-Methoxy-4-(3-guanidinopropyloxy)benzoyl-2(S)-phenylsulfonyl 15 amino- P-alanine, 3-Methoxy-4-(3-aminopropyloxy)benzoyl-2(S)-phenylsulfonylamino-0 alanine, 20 3-(3-Guanidinopropyloxy)benzoyl-2(S)-phenylsulfonylamino-0-alanine, 4-[2-(N-Phenylguanidino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino P-alanine, 25 4-[2-(N,N-Dimethylguanidino)ethyloxy]benzoyl-2(S)-phenylsulfonyl amino-0-alanine, 4-(Guanidinophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-1 alanine, 30 4-[2-(Guanidino)ethyloxymethyl]benzoyl-2(S)-phenylsulfonylamino-1 alanine, - 408 - WO 98/44797 PCT/US98/06823 3-[2-(Guanidino)ethylaminocarbonyl]benzoyl-2(S)-phenylsulfonyl amino-0-alanine, 4-[2-(2-Aminothiazol-4-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 5 P-alanine t-butyl ester, 4-[ 2 -( 2 -Aminothiazol-4-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 3-alanine, 10 4-[2-(N-(2-Imidazolin-2-yl)aminoethyloxy]benzoyl-2(S)-phenylsulfonyl amino-3-alanine, 2(S)-Phenylsulfonylamino-3-[4-(4-(N-imidazolin-2-yl)aminobutyloxy) phenyl]propionic acid, 15 4- [2- [N- [Cis-3 a,4,5,6,7,7a-Hexahydro- 1H-benzimidazol-2-yl] amino] ethyloxybenzoyl-2(S)-phenylsulfonylamino-p-alanine, 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 20 P-alanine, 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S) phenylsulfonylamino-1-alanine, 25 4-[2-( 2 -Aminothiazol-4-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino- alanine t-butyl ester, 4-[2-(2-Aminothiazol-4-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino-13 alanine, 30 4-[2(S)-(N-( 2 -Imidazolin-2-yl)amino)propyloxy]benzoyl-2(S)-phenyl sulfonylamino-1-alanine, 4-[2-(Imidazol-2-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino-p3-alanine, - 409 - WO 98/44797 PCT/US98/06823 4-[2-(Thiazol-2-ylamino)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-P3 alanine, 5 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-benzyloxycarbonyl amino-P-alanine, 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S) benzyloxycarbonylamino-p-alanine, 10 Methyl 2(S)-benzoylamino-3-[4-(4-pyrimidin-2-ylaminobutyloxy) phenyl]propionate, 2(S)-Benzoylamino-3-[4-(4-pyrimidin-2-ylamino)butyloxy)phenyl] 15 propionic acid, 2(S)-Benzoylamino-3-[4-(4-(3,4,5,6-tetrahydropyrimidin-2-ylamino) butyloxy)phenyl]propionic acid, 20 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N-methyl-N-phenyl sulfonylamino--alanine t-butyl ester, 4-[2-(Pyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N-methyl-N-phenyl sulfonylamino-3-alanine, 25 4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2(S)-N methyl-N-phenylsulfonylamino- p-alanine, 4-[2-(N-(5,6-Dihydro-4-keto- 1 (H)-pyrimidin-2-yl)amino)ethyloxy] 30 benzoyl-2(S)-phenylsulfonylamino--alanine, 4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-3 alanine t-butyl ester, - 410 - WO 98/44797 PCT/US98/06823 4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-3 alanine, 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-phenylsulfonylamino-3 5 alanine, 4-[2-(2-Aminopyridin-6-yl)ethyloxy]benzoyl-2(S)-phenyl sulfonylamino-p-alanine t-butyl ester, 10 4-[2-(2-Aminopyridin-6-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino P-alanine, 4-[2-(Indol-2-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-3- alanine methyl ester, 15 4-[2-(Indol-2-yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino-f-alanine, 4-[2-( 1H-Imidazo[4,5-6]pyridin-2-yl)ethenyl]benzoyl-2(S)-phenyl sulfonylamino-p-alanine t-butyl ester, 20 4-[2-( 1H-Imidazo[4,5-b]pyridin-2-yl)ethenyl]benzoyl-2(S)-phenyl sulfonylamino- -alanine, 4-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)ethyl]benzoyl-2(S)-phenyl 25 sulfonylamino- -alanine, 4-[2-(1,8-Naphthyidin-7-yl)ethenyl)benzoyl-2(S)-phenylsulfonylamino P-alanine t-butylester, 30 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7-yl)ethyl]benzoyl-2(S) phenylsulfonylamino-3-alanine t-butyl ester, 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7yl)ethyl]benzoyl-2(S) phenylsulfonylamino-p-alanine, 35 - 411 - WO 98/44797 PCT/US98/06823 4-[2-(1,8-Naphthyridin-7-yl)ethenyl]benzoyl-2(S)-phenylsulfonyl amino-p-alanine ethyl ester, 4-[2-(1,2,3,4-Tetrahydro- 1,8-naphthyridin-7-yl)ethyl]benzoyl-2(S) 5 phenylsulfonylamino-3-alanine ethyl ester, 4-[2-(1,2,3,4-Tetrahydro- 1,8 naphthyridin-7-yl)ethyl]benzoyl-2(S) [1(S)10-camphorsulfonylamido] 3-alanine ethyl ester, 10 4-[2-(1,2,3,4-Tetrahydro-l1,8 naphthyridin-7-yl)ethyl]benzoyl-2(S) [1(S)10-camphorsulfonylamido] P-alanine, 4-[(3-Aminoisoquinolin-1-yl)ethynyl]benzoyl-2(S)-phenylsulfonamido P-alanine ethyl ester, 15 4-[(3-Aminoisoquinolin-1-yl)ethynyl]benzoyl-2(S)-phenylsulfonamido P-alanine trifluoroacetate, 4-[2-(3-Aminoisoquinolin-1-yl)ethyl]benzoyl-2(S)-phenylsulfonamido 20 f-alanine trifluoroacetate, 4-[3-[N-(1H-Benzimidazo-2-yl)amino]propoxy]benzoyl-2(S) phenylsulfonylamino-p-alanine t-butyl ester, and 25 4-[3-[N-(1H-Benzimidazol-2-yl)amino]propoxy]benzoyl-2(S) phenylsulfonylamino- -alanine. - 412 - WO 98/44797 PCT/US98/06823 0 0 NH H2N N N CCO2H H 2 N H H" NHSO_ O O HN N N , ,N,,, CO2H . NH N N N NH N HO H H H \ NCO2H H \ CiN,. , HI H"H0__ 0 0 ~N N ' "C02H "-/ i00H N N 0HH" H NHSO 2 / - 413 -413 - WO 98/44797 PCT/US98/06823 o 0 C0 2 H N NN N H H NHCO 2 CH- 2 o 0 IHCO 2 H N N N_ H -N H HH NHSO 2-Oxo-3- [2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2-yl)ethyl]piperidin 1-yl-acetyl-3(S)-pyridin-3-yl-3-alanine ethyl ester; 5 2-Oxo-3-[2-(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2-yl)ethyl]piperin 1-yl-acetyl-3(S)-pyridin-3-yl-0-alanine trifluoroacetate; 2-Oxo-3 (S)-[2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2 yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-0-alanine ethyl ester; 10 2-Oxo-3(S)- [2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2 yl)ethyl]pyrrolidin-1-yl)acetyl- 3 (S)-alkynyl- -alanine; 2-Oxo-3 (S)-[2-(5,6,7,8-tetrahydro [1,8]-naphthyridin-2-yl)ethyl] 15 pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-0-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-3-alanine; 20 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 yl)ethyl]pyrrolidin- 1 -yl)acetyl-3(S)-alkynyl- 3-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2 yl)ethyl] pyrrolidin-1-yl)acetyl-3(S)-alkynyl- -alanine; 25 - 414 - WO 98/44797 PCT/US98/06823 2-Oxo-3 (R)- [2-(5,6,7,8-tetrahydro [ 1,8]-naphthyridin-2-yl)ethyl] pyrrolidin-1l-yl)acetyl-3(S)-pyridin-3-yl--alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2 5 yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-3-alanine; Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yl)ethyl] tetrahydropyrimidin-l-yl-acetyl-3(S)-pyridin-3-yl-p-alanine; 10 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl }ethyl] tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-0-alanine; Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2 yl)ethyl]imidazolidin-l-yl-acetyl-3(S)-pyridin-3-yl--alanine; 15 2-Oxo-3-[2-(5,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yl I ethyl] imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-3-alanine; Ethyl 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2 20 yl)ethyl]pyrrolidin-l-yl)acetyl-3(R)-(2-ethylindol-3-yl)-0-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[ 1,8]naphthyridin-2 yl)ethyl]pyrrolidin-l-yl)acetyl-3(R)-(2-ethylindol-3-yl)-0-alanine; 25 Ethyl 3-(S)-(2- { 2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2 ylmethyl)-amino]-pyrrolidin-1-yl } -acetylamino)-3-(S)-pyridin-3-yl propionic acid; 3-(S)-(2- { 2-Oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl) 30 amino]pyrrolidin- 1-yl I -acetylamino)-3 - (S)-pyridin-3-yl-propionic acid; 3-(S)-(2- { 2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl) amino]-pyrrolidin- 1-yl } -acetylamino)-3-(S)-quinolin-3-yl-propionic acid; - 415 - WO 98/44797 PCT/US98/06823 3- { 2-[6-Oxo- 1 -(5,6,7,8-tetrahydro- [ 1,8]naphthyridin-2-ylmethyl) hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino } -3-(S) pyridin-3-yl-propionic acid; 5 3- { 2-[6-Oxo- 1 -(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl) hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino }-3-(S) pyridin-3-yl-propionic acid; 10 [6-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)naphthylen-2-yl] carbonyl-2(S)-phenylsulfonylamino-3-alanine ethyl ester; [6-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)naphthylen-2-yl] carbonyl-2(S)-phenylsulfonylamino-p-alanine; 15 6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S) phenylsulfonylamino-p-alanine ethyl ester; 6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)-carbonyl-2(S) 20 phenylsulfonylamino- -alanine; 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidin- 1 -yl-carbonyl 2(S)-phenylsulfonylamino-0-alanine t-butyl ester; 25 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidin- 1 -yl-carbonyl 2(S)-phenylsulfonylamino-p-alanine; 6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S) phenylsulfonyl-p-alanine ethyl ester; 30 6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S) phenylsulfonyl- -alanine; - 416 - WO 98/44797 PCT/US98/06823 6-[(1,4,5,6-Tetrahydropyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl carbonyl-2(S)-phenylsulfonylamino-0-alanine; Ethyl 3(S)-pyridin-3-yl-3- { 2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)propylcarbamoyl] acetylamino } propionate; 5 3(S)-pyridin-3-yl-3- { 2-[3-(5,6,7,8-tetrahydro- [1,8]naphthyridin-2 yl)propylcarbamoyl]acetylamino } propionic acid; 3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl 10 malonyl-3(S)-pyridin-3-yl-3-alanine ethyl ester; 3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl- p-alanine; 15 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl-0-alanine ethyl ester; 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)piperidinyl malonyl-3(S)-pyridin-3-yl-0-alanine; 20 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidinyl-malonyl-3(S) pyridin-3-yl-p-alanine ethyl ester; or 4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)piperidinyl-malonyl-3(S) 25 pyridin-3-yl-p-alanine; or the pharmaceutically acceptable salts and optical isomers thereof.
13. A pharmaceutical composition for achieving a 30 therapeutic effect in a mammal in need thereof which comprises amounts of at least two therapeutic agents selected from a group consisting of: a) a farnesyl-protein transferase inhibitor and b) an integrin antagonist; - 417 - WO 98/44797 PCT/US98/06823 wherein the amount of a) alone or the amount of b) alone is insufficient to achieve said therapeutic effect. 5
14. The pharmaceutical composition according to Claim 13 comprising amounts of two therapeutic agents which are a farnesyl protein transferase inhibitor and a compound that is an integrin antagonist. 10
15. The pharmaceutical composition according to Claim 14 wherein the integrin antagonist is a selective antagonist of the cvP3 integrin.
16. The pharmaceutical composition according to Claim 14 15 wherein the integrin antagonist is a selective antagonist of the avP5 integrin.
17. The pharmaceutical composition according to Claim 14 wherein the integrin antagonist is an antagonist of both the cvP3 20 integrin and the avP5 integrin.
18. A pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof which comprises amounts of three therapeutic agents which are: 25 a) a farnesyl-protein transferase inhibitor; b) a selective antagonist of the axvP3 integrin; and c) a selective antagonist of the xvP5 integrin; wherein the amount of a) alone, the amount of b) alone or the amount of 30 c) alone is insufficient to achieve said therapeutic effect.
19. The pharmaceutical composition according to Claim 13 wherein the therapeutic effect is treatment of cancer. - 418 - WO 98/44797 PCT/US98/06823
20. The pharmaceutical composition according to Claim 13 wherein the therapeutic effect is selected from inhibition of cancerous tumor growth and the regression of cancerous tumors. 5
21. A method of preparing a pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof which comprises mixing amounts of at least two therapeutic agents selected from a group consisting of: a) a farnesyl-protein transferase inhibitor and 10 b) an integrin antagonist; wherein the amount of a) alone or the amount of b) alone is insufficient to achieve said therapeutic effect. 15
22. The method of preparing a pharmaceutical composition according to Claim 21 comprising mixing an amount of a farnesyl protein transferase inhibitor and an amount of an integrin antagonist. - 419 -
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