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AU724216B2 - A method of treating cancer - Google Patents

A method of treating cancer Download PDF

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AU724216B2
AU724216B2 AU69532/98A AU6953298A AU724216B2 AU 724216 B2 AU724216 B2 AU 724216B2 AU 69532/98 A AU69532/98 A AU 69532/98A AU 6953298 A AU6953298 A AU 6953298A AU 724216 B2 AU724216 B2 AU 724216B2
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aryl
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cycloalkyl
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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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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 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 pm in diameter that resorb mineralized tissue, chiefly calcium carbonate and 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 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 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 osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or cav33, thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to avp3 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 effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
1- WO 98/44797 PCT/n rsoa/n;' A second integrin vitronectin receptor, avp5, has also been identified. A monoclonal antibody for oavp5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model. See M.C. Friedlander, et al., Science 270, 1500-1502, 1995, which is incorporated by reference herein in its entirety. Two collagen receptor integrins, acl 1 and a2pl, 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 entirety.
Additionally, avp3 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 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). avp3 antagonists, which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth and metastasis.
(See Brooks et al., Cell, 79:1157-1164 (1994)).
Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a class of post-translational modification (Glomset, J. Gelb, M. and Farnsworth, C. C.
(1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990).
FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins. Prenylated proteins share characteristic C-terminal sequences including CaaX (C, Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC. Three post-translational processing steps have been described for proteins having a C-terminal CaaX sequence: addition of either a 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 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 terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61, 355-386). For all of the prenylated proteins, addition of the isoprenoid 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), geranylgeranylprotein 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 famesyl diphosphate or geranylgeranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate. FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala. For FPTase, CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme. The enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. Schaber, M. Mosser, S. Rands, O'Hara, M. Garsky, V. M., Marshall, M. Pompliano, D. and Gibbs, J. J. Biol. Chem., 266:17438 (1991), U.S. Pat. No. 5,470,832).
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-
I
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.
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 induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R.
Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).
Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 271:810-812).
Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
The Ras protein is one of several proteins that are known to undergo post-translational modification. Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl 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)).
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-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)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. 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 than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Other farnesylated proteins include the Ras-related GTPbinding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol.
Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also 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 been described in two general classes. The first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates 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.
(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 Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
Mammalian cells express four types of Ras proteins 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 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 Kohl et al., Science, 260:1934- 1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993).
Recently, it has been shown that an inhibitor of famesyl-protein transferase blocks the growth of H-ras-dependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in H-ras transgenic mice 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 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 antagonist and a faresyl-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.
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 integrin antagonist and a selective farnesyl protein transferase inhibitor are used in such a combination.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of treating cancer 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 ocv33 integrin and 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.
Any compound which acts as an integrin antagonist and any compound which inhibits farnesyl 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 antagonist and the inhibitor of famesyl-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 would be required if such an integrin antagonist and a selective farnesylprotein 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 farnesylprotein transferase inhibitor sufficient to achieve the same therapeutic 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 compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the av33 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the avp3 integrin and the cav35 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 av133 integrin and a selective antagonist of the cav35 integrin. The term also refers to antagonists of the oa 131 and a2 31 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.
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 times greater activity against either an single integrin, a group of 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, avp3, alpl and a21p integrins. More preferably the selectivity is at least 100 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 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 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 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 adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small cell lung cancers and neurological tumors.
Other therapeutic effects provided by the instant composition include inhibiting: bone resorption mediated by osteoclast cells, restenosis, artherosclerosis, diabetic retinopathy, macular degeneration 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 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 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 the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the 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 Indolfi et al. Nature medicine, 1:541-545(1995).
The instant composition may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEBJournal, 2:A3160 (1988)).
The pharmaceutical composition of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
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 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 use, the active ingredients are combined with emulsifying and suspending 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 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 PCTIUS98/06823 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 described below and the other pharmaceutically active agent(s) within its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the combinations of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, 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 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 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 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 famesyl-protein transferase inhibitor.
Preferably, the dosage comprises from about 1 mg to about 100mg of an 11 WO 98/44797 PCT/US98/06823 integrin antagonist and from about 1mg to about 100mg of a farnesylprotein transferase inhibitor.
The integrin antagonist component of the instant invention may be selected from the following: 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 X is selected from
NR
2
NR
1
NR
2 II II II
-NR'R
2
-NR'-C-R
3
-C-NR
2
R
3 ,.NR1-C-NR3R4
NR
1
NR
2 -aryl-NR'R 2 -aryl-C-NR 2
R
3 -aryl-NR 1 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 N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with Rl, R 2
R
3 and R 4 or 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 or substituted with R 1
R
2
R
3 and R 4 Y is selected from CO-8 alkylene, C3-10 cycloalkyl, CO-8 alkylene-NR10-CO-CO-8 alkylene, 12 WO 98/44797 WO 9844797PCTIUS98/06823 CO-g alkylene-CONRi 0 -CO-8 alkylene, CO..8 alkylene-O-CO08 alkylene, C0-8 alkylene-NRIO-CO08 alkylene, CO-g alkylene-S()02-CO08 alkylene, CO-8 alkylene-S02-NRO-CO..8 alkylene, CO-8 alkylene-NR' 0 -S02-CO.8 alkylene, CO-8 alkylene-CO-C0-8 alkylene, (CH2)0-6 aryl(CH2)0-6, (CH2)O..6 aryl-CO-(CH2)O..6, (CH2)0-6 aryl-CO-NRIO-(CH2)0-6, (CH2)0-6 arylNRIOCO(CH2)0-6, or
OH
(CH
2 0 8 CH (CH 2 08 Z and A are each independently selected from 0
(CH
2 )m (CH 2 )mO(CH 2
(CH
2 )mNR' 1 (0H 2 )n (CH 2 )mNR 1
CNR
12
(CH
2 )n o 0 0 11 11 11
(CH
2 )mCNR" 1 (0H 2 )n,(0H 2 )mNR 1
C(CH
2 )n,(CH 2 )mC(CH 2 )n,
S
(CH
2 )mtb(H 2 (0H 2 )mSO 2
(CH
2 (0H 2 )m S(CH 2 )n, (0H 2 )mSO(0H 2 (0H 2 )mSO 2 N R 11
(CH
2
(CH
2 )mNR" S0 2
(CH
2
(CH
2 )mCR" =CR1 2
(CH
2 or (C where m and n are each independently an integer from 0 to 6; 13 WO 98/44797 WO 9844797PCT/US98/06823 B is 0 11 R6R 7 where p is an integer from 1 to 3; Rl, R 2
R
3
R
4
R
5
R
8
R
9 RIO, R 1 1 and R 12 are each independently selected from hydrogen, halogen, Cl-1b alkyl, aryl CO-8 alkyl, amino CO-g alkyl, Ci -3 acylamino CO-8 alkyl, C1-6 alkylamino CO-8 alkyl, Cl-6 dialkylamino CO-8 alkyl, aryl CO..6 alkylamino CO-6 alkyl, C 1-4 alkoxyamino CO- 8 alkyl, hydroxy Ci -6 alkylamino CO-8 alkyl, C 1-4 alkoxy CO-6 alkyl, hydroxycarbonyl CO-6 alkyl, Ci -4 alkoxycarbonyl CO-6 alkyl, hydroxycarbonyl CO-6 alkyloxy, hydroxy Ci -6 alkylamino CO-6 alkyl or hydroxy CO-6 alkyl;
R
6 is selected from hydrogen, fluorine, CI-8 alkyl, hydroxyl, 14 WO 98/44797 WO 9844797PCT/US98/06823 hydroxy CI -6 alkyl, carboxy CO-6 alkyl, Ci 1-6 alkyloxy, Ci -6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, aryl CO..6 alkylcarbonyloxy, C 1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl C0-6 alkyl, CO-6 alkylamino CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, Ci-g alkylsulfonylamino C0..6 alkyl, aryl C0..6 alkylsulfonylamino CO..6 alkyl, CI -8 alkyloxycarbonylamino alkyl, aryl CO..8 alkyloxycarbonylamino C0.8 alkyl, C 1-8 alkylcarbonylamino C0-6 alkyl, aryl C0-6 alkylcarbonylamnino C0.6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-8. alkylaminocarbonylamino CO-6 alkyl, CO-8 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino C0-6 alkyl, C 1-6 alkylsulfonyl C0..6 alkyl, aryl CO..6 alkylsulfonyl CO..6 alkyl, C1-6 alkylcarbonyl CO..6 alkyl, aryl C0-6 alkylcarbonyl CO..6 alkyl, C1-6 alkyithiocarbonylamnino C0.6 alkyl, or aryl CO..6 alkyithiocarbonylamnino CO-6 alkyl; wherein the alkyl or N atoms may be unsubstituted or substituted with R 5
R
7 is selected from hydrogen, CO-6 alkylamino CO..
6 alkyl, 15 WO 98/44797 WO 9844797PCT/US98/06823 C0-6 dialkylamino C0-6 alkyl, aryl C0.6 alkyloxycarbonylamino CO-6 alkyl, aryl CO06 alkylsulfonylamino CO..6 alkyl and aryl Crj-6 alkylcarbonylamnino 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; 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 1 4 R 15 R 1 6 and R 1 7 and wherein any of the alkyl groups may be unsubstituted or subsituted with R 14 and
R
13 is selected from hydroxy, C1-8 alkyloxy, aryl CO-6 alkyloxy, Ci1 8 alkylcarbonyloxy C 1-.4 alkyloxy, aryl CI -8 alkylcarbonyloxy Ci-.4 alkyloxy, C 1-6 dialkylaminocarbonylmethyloxy, aryl C 1-6 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 R 1 4 R 1 5 R 16 and R 17 are each independently selected from hydrogen, halogen, CI-1.0 alkyl, C3-..8 cycloalkyl, oxo, aryl, aryl C 1.-8 alkyl, amino, amino C 1-8 alkyl, CL1-3 acylamino, Ci -3 acylamnino C 1-8 alkyl, Ci -6 alkylamino, Ci -6 alkylamino- Clb8 alkyl, C1-6 dialkylamino, Cl..6 dialkylamino C1-8 alkyl, Ci1 -4 alkoxy, Ci1 -4 alkoxy C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci -6 alkyl, C 1-3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Ci1 -6 alkyl, hydroxycarbonyl- 16 WO 98/44797 WO 9844797PCTIUS98/06 823 C 1-6 alkyloxy, hydroxy, hydroxy C 1 -6 alkyl, C 1 -6 alkyloxy- C 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci -8 alkyl-S(O)q, Ci -8 alkylaminocarbonyl, C 1-8 dialkylaminocarbonyl, Ci -8 alkyloxycarbonylamino, Cl -8 alkylaminocarbonyloxy or Ci -8 alkylsulfonylamino; a compound of the formula I-b:
X-(CH
2 )IC-(CH) -N
NH
H R~ 8 R 9 1-b wherein X is selected from
NR
2 -+NRJ--C NR R~ I~A r~N1A Ar is a 4- to 1 0-membered mono- or polycyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or S and wherein the mono- or polycyclic aromatic or nonaromatic ring system is either unsubstituted or substituted with RI, R 2
R
3 and R 4 Rl, R 2
R
3 and R 4 are each independently selected from hydrogen, hydroxyl, C1-8 alkyl, halogen, aryl CO..8 alkyl, oxo, thio, amnino- CO..8 alkyl, C 1-3 acylamino CO..8 ailkyl, C1-6 alkylamino CO-8 alkyl, Cl -6 dialicylamino CO..8 alkyl, aryl CO..6 alkylamino CO-6 alkyl, C 1-4 alkoxyamino CO-8 alkyl, hydroxy C 1-6 alkylamino CO-8 alkyl, C 1-4 alkoxy CO-g alkyl, carboxy CO..8 alkyl, C 1-4 alkoxycarbonyl- CO-8 alkyl, carboxy CO..8 aikoxy, hydroxy CO...8 alkyl or C3-8g cycloalkyl CO..6 alkyl;
R
5 is selected from hydrogen, C 1 -6 alkyl, C0-6 alkylaryl, aryl or 17 WO 98/44797 WO 9844797PCTIUS98/06823 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 C 1-6 alkyl, carboxy- CO-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, Ci1-6 alkylcarbonyloxy, aryl CO..6 alkylcarbonyloxy, C 1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino- CO-6 alkyl, C0-6 dialkylamnino 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. C0-8 alkoxycarbonylamino CO..8 alkyl, aryl- CO...8 alkyl-S O2NR 3 -CO-8s alkyl, C1 -8 alkoxycarbonylamino CO-8 alkyl, Ci -8 alkylcarbonylamino CO..6 alkyl, aryl C0.6 alkylcarbonylamino- CO-6 alkyl, C0-8 alkylaminocarbonylamino CO..6 alkyl, aryl CO-8 alkylaminocarbonylamino CO-6 ailkyl, CO-8 alkylaminosulfonylamino CO-6 alkyl, aryl. CO08 alkylaminosulfonylamino- CO-.6 alk yl, Ci1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl- CO-6 alkyl, C 1-6 alkylcarbonyl CO..6 alkyl, aryl CO-6 alkylcarbonyl- CO-6 alkyl, Ci1-6 alkyithiocarbonylamino 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 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R 1 and R 2 R10 is selected from hydroxyl, CI-.8 alkoxy, aryl CO-6 alkoxy, C 1-8 alkylcarbonyloxy C 1-4 alcoxy, aryl C 1-8 alkylcarbonyloxy- C 1-4 alkoxy, Ci1 -6 dialkylaminocarbonylmethoxy, aryl C 1-6 dialkylaminocarbonylmethoxy or an L- or D-amino acid joined by an amnide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified by C 1-6 alkyl; and each n is independently an integer from 0 to three; 18 WO 98/44797 PCTUS98/06823 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 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 C1-6 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 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl CO-6 alkyl, CO-6 alkylamino- CO-6 alkyl, CO-6 dialkylamino CO-6 alkyl, aryl CO-8 alkoxycarbonylamino 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 alkylaminosulfonylamino CO-6 alkyl, aryl CO-8 alkylaminosulfonylamino CO-6 alkyl, Cl -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, CI-6 alkylthiocarbonylamino 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 alkylaminocarbonylamino; 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
0 N- I\or and R 6
R
7 and R 8 are each hydrogen, and R 1 0 is selected from hydroxyl and C1-8 alkoxy, then R 9 is selected from fluorine, C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, 19 WO 98/44797 WO 9844797PCT/US98/06823 C 1-6 alkoxy, C 1-6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, Ci1 -6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, C 1 -6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl C0-6 alkyl, CO-6 alkylamino- CO-6 ailkyl, C0-6 dialkylamino CO-6 alkyl, CI-8 alkylsulfonylamnino- CO-6 alkyl, CO-8 alkyl-SO2NR 3 -CO..8 alkyl, aryl CO-8 alkoxycarbonylamino CO-8 alkyl, CI-8 alkoxycarbonylamino CO..8 alkyl, CI-8 alkylcarbonylamino CO-6 alkyl, aryl CO-6 alkylcarbonylamino- CO-6 alkyl, CO-8 alkylaminocarbonylamino CO-6 alkyl, aryl CO-g alkylamninocarbonylamino CO-6 alkyl, C0.8 alkylamiino-sulfonylamino CO-6 alkyl, aryl CO..8 alkylaminosulfonylamino-CO.6 alkyl, C1-6 alkylsulfonyl CO-6 alkyl, aryl CO-6 alkylsulfonyl-CO06 alkyl, Ci -6 alkylcarbonyl CO-6 alkyl, aryl CO-6 alkylcarbonyl-CO.6 alkyl, Ci -6 alkyithiocarbonylamnino CO-6 alkyl, aryl CO-6 alkyl-thiocarbonylamino C0-6 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 orC3-g cycloalkyl CO-6 alkylamninocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R1 and R 2 a compound of the formnula I-c: 0Q 8 R R 9
X-Y-Z-(CH
2 C0 2
R'
H 10 R R 1
I-C
wherein X is selected from 1NR 2
-C-R
1 2
-NRI--C-NR'R
2 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatomns 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 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 Y is selected from
R
3 3 0 III
II
-N-(CH2) (CH2)N- -C-N-(CH2)
R
3 0
II
-N-C-(CH
2 )O -S(O)q-(CH 2
O-(CH
2 or -(CH2)-
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 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 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 R1, R 2
R
4
R
5
R
13 and R 14 are each independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl, 21 WO 98/44797 WO 9844797PCTIUS98/06823 aryl CI-8 alkyl, amino, amino C1-8 alkyl, CI-3 acylammno, Cl-3 acylamino Cl.8 alkyl, C1-6 alkylamino, C1-6 alkylamino- C1-8 alkyl, CI-6 dialkylamino, Cv.6 dialkylamino CI-g alkyl, Ci -4 alkoxy, Ci -4 alkoxy C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI-6 alkyl, C1-3 alkoxycarbonyl, Ci 3 alkoxycarbonyl Ci -6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy, hydroxy Ci1-6 alkyl, Ci -6 alkyloxy- C 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Cl-8 alkyl-S(O)q, CI-.8 aminocarbonyl, Ci 8 dialkylaminocarbonyl, Ci -8 alkyloxycarbonylamino, Ci -8 alkylaminocarbonyloxy or Ci -8 alkylsulfonylamino;
R
3 is selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, C 1-5 alkoxycarbonyl, aminocarbonyl, C3-8 cycloalkyl, amino Ci -6 alkyl, arylaminocarbonyl, aryl CI-5 alkylaminocarbonyl, hydroxycarbonyl Ci -6 alkyl, Cl-S alkyl, aryl C1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, aryl C1-6 alkylamino C1.6 alkyl, Ci -6 dialkylamino Ci -6 alkyl, C1-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C 1-8 alkoxycarbonyl, Cl-S alkylcarbonyl, 22 WO 98/44797 WO 9844797PCT/US98/06823 arylcarbonyl, aryl C 1-6 alkylcarbonyl, C 1-8 alkylaminocarbonyl, aminosulfonyl, Cl -8 alkylamninosulfonyl, arylaminosulfonylamino, aryl CI -8 alkylamninosulfonyl, Ci -6 alkylsulfonyl, arylsulfonyl, aryl CI-.6 alkylsulfonyl, aryl C1-6 alkylcarbonyl, Cl1 -6 alkyithiocarbonyl, aryithiocarbonyl, or aryl Ci -6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R1 4
R
6
R
7
R
8
R
9
R
10 and R I are each independently selected from hydrogen, aryl, -(CH2)p-aryl, halogen, hydroxyl, Ci -8 alkylcarbonylamino, aryl CI-5 alkoxy, alkoxycarbonyl, aminocarbonyl, Ci -8 alkylamninocarbonyl, Ci -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-6 alkylamino, amino Cl1-6 alkyl, 23 WO 98/44797 WO 9844797PCTIUS98/06823 arylaminocarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl CI -6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI -6 alkyl, CI-g alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Ci -5 alkylcarbonylamino, aryl C1-5 alkoxy, CI-5. alkoxycarbonyl, arninocarbonyl, Ci-5 alkylaminocarbonyl, CI-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C 1 3 alkylamino, amino C 1-3 alkyl, arylaminocarbonyl, aryl CI..5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci .4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Ci-5 alkyl, -(CH2)s C=-CH, -(CH2)s C=-C-C1-6 alkyl, -(CH2)s C C-C3-.7 cycloalkyl, -(CH2)s C=-C-ary1, -(CH2)s C=-C-CI-6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH C1-6 ailkyl, -(CH2)s CH=CH-C3-.7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH Cl-.6 alkylaryl, -(CH2)s S02CI-6 alkyl, -(CFI2)s S02CI-6 alkylaryl, Cl1-6 alkoxy, aryl CI -6 alkoxy, aryl C-6 alkyl, Cl-6 alkylamino CI-.6 alkyl, arylamino, arylamino C1-6 alkyl, aryl Cl-6 alkylamino, 24 WO 98/44797 WO 9844797PCT/US98/06823 aryl C1-6 alkylamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, Ci -6 dialkylamino, C1-6 dialkylamino C1..6 alkyl, Ci -6 alkylaminocarbonyloxy, Ci -8 alkylsulfonylamino, CI -8 alkylsulfonylamino Ci -6 ailkyl, arylsulfonylamino C1..6 alkyl, aryl Ci -6 alkylsulfonylamino, aryl C 1-6 alkylsulfonylamino C 1-6 alkyl, Ci -8 alkoxycarbonylamino, Ci -8 alkoxycarbonylamino Ci -8 alkyl, aryloxycarbonylamino Ci1-8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl Ci-8. alkoxycarbonylamino C1-8 alkyl, Ci -8 alkylcarbonylamino, C 1-8 alkylcarbonylamino CI -6 alkyl, arylcarbonylamino C 1-6 alkyl, aryl Ci -6 alkylcarbonylamino, aryl Ci -6 alkylcarbonylamino CI -6 alkyl, aminocarbonylamino Ci -6 alkyl, Ci -8 alkylaminocarbonylamino, C1-8 alkylaminocarbonylamino CI-.6 alkyl, arylaminocarbonylamino CI-6 alkyl, aryl C 1-8 alkylaminocarbonylamino, aryl Ci -8 alkylaminocarbonylamino C 1 -6 alkyl, aminosulfonylamino C 1-6 alkyl, Ci -8 alkylaminosulfonylanlino, C1-8 alkylaminosulfonylamino C1-6 alkyl, arylaminosulfonylamino C 1-6 alkyl, aryl C 1-8 alkylaminosulfonylamino, aryl Ci -8 alkylaminosulfonylamino Ci -6 alkyl, C 1-6 alkylsulfonyl, 25 WO 98/44797 WO 9844797PCTIUS98/06823 CI -6 alkylsulfonyl Ci -6 alkyl, arylsulfonyl CL-6 alkyl, aryl C 1-6 alkylsulfonyl, aryl Ci -6 alkylsulfonyl Ci -6 alkyl, Ci -6 alkylcarbonyl, Ci -6 alkylcarbonyl Ci -6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl Ci -6 alkylcarbonyl CI -6 alkyl, C1-6 alkyithiocarbonylamino, Ci 1-6 alkyithiocarbonylamino Ci 1-6 alkyl, aryithiocarbonylamino Ci -6 alkyl, aryl Ci -6 alkyithiocarbonylamnino, aryl Ci 1-6 alkyithiocarbonylamino C 1-6 alkyl, C1-8 alkylamninocarbonyl Cl-6 alkyl, arylaminocarbonyl CI -6 alkyl, aryl Ci -8 alkylaminocarbonyl, or aryl C1..8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and Ri1 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 I are attached is itself attached to no more than one heteroatom;
R
12 is selected from hydrogen, CI-8 alkyl, aryl, aryl Cl1-8 alkyl, hydroxy, C1- 8 alkoxy, aryloxy, aryl Ci-6 alkoxy, CI-g alkylcarbonyloxy Ci .4 aikoxy, 26 WO 98/44797 PCT/US98/06823 aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or C -8 dialkylaminocarbonylmethyleneoxy; 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 s is an integer from 0 to 3; a compound of the formula I-d: X-Y-Z-Ring-A-B I-d 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 2 7 and
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 -C-NR 3
R
4
NR
1
NR
2 II II -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 selected from N, O and S and either unsubstituted or substituted 27 WO 98/44797 WO 9844797PCT[US98/06823 with R 13
R
14
R
15 or R6 Y is selected from CO-8 aikylene, C3- 0 cycloalkyl, CO-8 alkylene-NR 5 -CO-C0-8 alkylene, CO-8 alkylene-CONR 5 -CO08 alkylene, CO-8 alkylene-O-C0-8 alkylene, CO-8 alkylene-NR 5 -C0-8 alkylene, CO-8 alkylene-S (O)0-2-CO..8 alkylene, CO- 8 alkylene-S02-NR 5 -CO-8 alkylene, CO-8 alkylene-NR 5 -S02-CO.8 alkylene, CO-8 alkylene-CO-C0-8 alkylene, (CH2)O..6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)O-6 aryl-CO-NR 5 -(CH2)0-6, (CH2)0-6 aryl-NR 5 -CO-(CH2)0-6, or
OH
(CH
2 0 8 0Hk%(OH 2 0 8 Z is selected from 28 v WO 98/44797 WO 9844797PCTIUS98/06823 0 (0H 2 )m (CH 2 )mO(CH 2
(CH
2
)MNR
6 (0H1)nR7 (CH)n,(0H 2 )mNR 6
CNR
7 (0H 2 )n 0 11
(CH
2 )mCNR
(CH
2 )n, 0 0 11 11 (0H 2 )mNR 6
C(CH
2
(CH
2
)MC(CH
2 )n,
S
(CH
2 )mt8(CH 2 )n,
(CH
2 )mSO(CH 2 )n, (0H 2 )mS0 2
(CH
2
(C
(0H 2 )mSO 2 NR R 6
(CH
2 0 11
H
2 )mS(C 2 )n, (0H 2 )MNR 6 S0 2 (0H 2 )n, (0H 2 )mCR 6 =CR 7
(H
2 )n, or (CH 2 )mC=C (CH 2 )n; where mn and n are each independently an integer from 0 to 6; A is selected from 0 (C(CH H)p (H)N R 29 (CH) (CH 2 )qNR 29 C 11 30
(CH
2 0 11 2
(CH
2 )qCNR 29
(CH
2 )p,
S
11
(CH
2 )qC(CHt 2 )p, 0 11
(CH
2 )qNR 29 C (CH 2 )p,
(CH
2 )qS0 2
(CH
2 )p, 0 11
(CH
2 )qC(CH 2 )p, 0 11
(CH
2 )qS(CH 2 )p,
(CH
2 )qS0(0H 2
(CH
2 )qS0 2 N R 29
(CH
2 (0H 2 )qNR 29 S0 2
(CH
2 )p.
(0H 2 )qCR 2 9=R 3
(CH
2 )p o(C 2 )qC=C-CH); where p and q are each independently an integer from 0 to 6; 29 WO 98/44797 PTU9/62 PCT/US98/06823 B is selected from o 12 9 or (CH 2 0 1
I
R 8R9 1 i R 1 R 1
R
2
R
3
R
4
R
5
R
6
R
7 R 1 7 R 1 8 R 1 9
R
2 0
R
2 1
R
2 2
R
2 3
R
24
R
2 5
R
26
R
2 7
R
2 8
R
2 9 and R 30 are each independently selected from hydrogen, halogen, C 1-10 alkyl, aryl CO..8 alkyl, amino CO-8 alkyl, Ci -3 acylamino C0-8 alkyl, C1-6 alkylamino CO-8 alkyl, CI-6 dialkylamino CO..8 alkyl, aryl CO-6 alkylamino CO-6 alkyl, C 1-4 alkoxyamino Co- 8 alkyl, hydroxy CI -6 alkylamino CO-8 alkyl, C1-4 alkoxy CO-6 alkyl, carboxy CO-6 alkyl, Ci -4 alkoxycarbonyl CO-6 alkyl, carboxy CO-6 alkyloxy, hydroxy Ci -6 alkylamino CO-6 alkyl, hydroxy CO-6 alkyl, NR 1 7 or
NR'
8
-NR
1 7 NR1 9
R
20
R
8
R
9 R 10 and R I are each independently selected from 30 I- WO 98/44797 WO 9844797PCTIUS98/06823 hydrogen, fluorine, C1-8 alkyl, hydroxyl, hydroxy C1-6 alkyl, carboxy CO-6 alkyl, C 1-6 alkyloxy, CI -6 alkylcarbonyl, aryl CO-6 alkylcarbonyl, CI-6 alkylcarbonyloxy, aryl CO-6 alkylcarbonyloxy, CI -6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl C0-6 alkyl, CO-6 alkylamino C0-6 alkyl, CO-6 dialkylamino CO-6 alkyl, C1-8 alkylsulfonylamino CO-6 alkyl, aryl C0-6 alkylsulfonylamino CO-6 alkyl, Ci -8 alkyloxycarbonylamino C0-8 alkyl, aryl CO-8 alkyloxycarbonylamino 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 alkylaminosulfonylamino CO..6 alkyl, aryl C0..8 alkylaminosulfonylamino C0-6 alkyl, Ci -6 alkylsulfonyl CO..6 alkyl, aryl CO..6 alkylsulfonyl CO..6 alkyl, Ci -6 alkylcarbonyl CO..6 alkyl, aryl CO-6 alkylcarbonyl C0..6 alkyl, C 1-6 alkyithiocarbonylamnino CO-6 alkyl, or aryl CO-6 alkyithiocarbonylamino 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 WO 9844797PCTJUS98/06823
R
2 2 any amino group such as -NH- can be substituted with R1to be -NR 2
R
12 is selected from hydroxy, Cl-s alkyloxy, aryl CO-6 alkyloxy, C 1-8 alkylcarbonyloxy C 1 -4 alkyloxy, aryl CO-8 alkylcarbonyloxy Ci1 -4 alkyloxy, CI -6 dialkylaminocarbonylmethyloxy, aryl Ci -6 dialkylaminocarbonylmnethyloxy 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 C 1-6 alkyl; and R 13 R 14 R 15 and R 16 are each independently selected from hydrogen, C 1-10 alkyl, aryl CO-8 alkyl, oxo, thio, amino CO-8 alkyl, C1-3 acylamnino CO-S alkyl, C1-6 alkylamnino Co-g alkyl, Cl.6 dialkylamino CO-8 alkyl, aryl CO-6 alkylamnino CO-6 alkyl, Ci -4 alkoxyamino CO-8 alkyl, hydroxy C1-6 alkylamino alkyl, C 1-4 alkoxy CO-6 alkyl, carboxy CO..6 alkyl, C 1-4 alkoxycarbonyl CO..6 alkyl, carboxy CO-6 alkyloxy, hydroxy C1-6 alkylamino C0-6 alkyl, hydroxy CO-6 alkyl, 32 I- WO 98/44797 WO 9844797PCT[US98/06823 NR 23 ~NR R 24
R
2 ,or NR 24
-NR
2
NR
25
R
2 provided that Ring is not a 6-membered monocyclic aromatic ring; provided further that when Ring is thiophene, then X is selected from
N
S' N3k
§NQN
H
N
N N
N
"N N Ri or N provided further that when Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, indole, benzothiazole, benzoxazole, -I 0 S S
S
then X is selected from 33 WO 98/44797 PCTIUS98/06823 13'
NN-
N N NN
N
H
H
N N
R
13 7 1' 3 r N N N orN and the pharmaceutically acceptable salts thereof.
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-CO08 atkylene, CO-8 alkylene-CONR 5 -CO08 alkylene, alkylene-O-CO08 alkylene, CO-.8 allcylene-NR 5 -CO08 alkylene, CO-8 alkylene-S (O)0-2-CO-8 alkylene, CO-8 alkylene-S02-NR 5 -CO-.8 alkylene, CO-8 allcylene-NR 5 -S02-CO08 alikylene, CO-8 alkylene-CO-CO..8 alkylene, (CH2)O..6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NH-(CH2)0-6, or
OH
(CH
2 0 8 0Ht (GHr 2 08 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; a compound of the formula I-e: 34 P WO 98/44797 WO 9844797PCTIUS98/0J6823 0 0V II I I X-Y-Z-C-CH
C-N
H
I-e wherein X is selected from N'R1 -C-NR R 3 NR 2
-NR
1
NR
3 R 4 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or S wherein the 5- or 6-meinbered ring system is either unsubstituted or substituted on a carbon atom with RI and R 2 or a 9- to lO-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, 0 or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R I and R 2 Y is selected from 0 0 0
-(CH
2 )F-S(0)q-(CH 2 )jm (C 2
(C
2 )m (CHAT~~- (CH 2 )fif- or (CH 2 )F N(CH 2
(CH
2 V. WO 98/44797 WO 9844797PCTIUS98/06823 Z is absent or is a 4- to 11 1-membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 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 R 15 R 16 and R 1 7 preferably, Z is not a 6-membered monocyclic aromatic ring system; Rl, R 2
R
3
R
4
R
5
R
1 I, R 12
R
13 R1 6 and R1 7 are each independently selected from hydrogen, halogen, CI-1O alkyl, C3-8 cycloalkyl, aryl, aryl CI-8 alkyl, amino, amino CI-g alkyl, Cl-3 acylamino, C 1 3 acylamino C1- 8 alkyl, Cl1-6 alkylamino, Cl.1-6 alkylamnino- Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamnino Cl-8 alkyl, CI -4 alkoxy, Cl -4 alkoxy Ci -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci -6 alkyl, C 1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl- Ci -6 alkyloxy, hydroxy or hydroxy Ci1-6 alkyl;
R
6
R
7
R
8
R
9 R 1 4 and R 15 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, C 1-8 alkylcarbonylamnino, aryl C1-5 alkoxy, alkoxycarbonyl, amninocarbonyl, C 1-8 alkylaminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C 1-6 alkylamnino, 36 0 WO 98/44797 WO 9844797PCT/US98/06823 amino C 1-6 alkyl, arylaminocarbonyl, aryl Ci -5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci -6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1-6 alkyl, Cl-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, CI-5 alkylcarbonylamino, aryl CI-5. alkoxy, alkoxycarbonyl, aminocarbonyl, C 1-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Ci 1 3 alkylamino, amino C 1-3 alkyl, arylaminocarbonyl, aryl alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C 1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C 1-5 alkyl, -(CH2)r C=-CH, -(CH2)r C=-C-C1..6 alkyl, -(CH2)r C=C-C3..7 cycloalkyl, -(CH2)r C=-C-aryl, -(CH2)r C=C-C1..6 alkylaryl, -(CH2)r CH=CH2, -(CH2)r CH=CH C 1-6 alkyl, -(CH2)r CH=CH-C3-7 cycloalkyl, -(CH2)r CH=CH aryl, -(CH2)r CH=CH C 1-6 alkylaryl, -(CH2)r SO2C1.6 alkyl, -(CH2)r S02C1-6 alkylaryl, C 1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, Cl-6 alkylamino C 1-6 ailkyl, arylamino, arylamino C1..6 alkyl, 37 I- WO 98/44797 WO 9844797PCT/US98/06823 aryl Ci -6 alkylamino, aryl C1-6 alkylamino C1-6 alkyl, arylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, C1-6 diallcylamino, CI-6 dialkylamino C 1-6 alkyl, Ci -6 alkylaminocarbonyloxy, Ci1 -8 alkylsulfonylamino, Ci -8 alkyisulfonylamino C 1-6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl Ci -6 alkylsulfonylamino, aryl Ci -6 alkylsulfonylamino CI -6 alkyl, C 1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino Cl-8 alkyl, aryloxycarbonylamino C 1-8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl C 1-8 alkoxycarbonylamino Ci -8 alkyl, Ci -8 alkylcarbonylamino, C 1-8 alkylcarbonylamino CI-.6 alkyl, arylcarbonylamino C1-6 alkyl, aryl Ci -6 alkyicarbonylamino, aryl Ci -6 alkylcarbonylamino Ci -6 alkyl, aminocarbonylamino C 1-6 alkyl, C 1-8 alkylaminocarbonylamino, Ci-g alkylaminocarbonylamino C1..6 alkyl, arylaminocarbonylamino Ci -6 alkyl, aryl C 1-8 alkylaminocarbonylamino, aryl C 1-8 alkylaminocarbonylamino CI -6 alkyl, aminosulfonylamino Ci -6 alkyl, Ci -8 alkylaminosulfonylamino, Ci -8 alkylaminosulfonylamino Ci -6 alkyl, arylaminosuifonylamino C 1-6 alkyl, aryl Ci -8 alkylaminosulfonylarnino, aryl CI-g alkylaminosulfonylamino C1..6 alkyl, 38 WO 98/44797 1Irf TU3ffU~h CI -6 alkylsulfonyl, C1-6 alkylsulfonyl C 1-6 alkyl, arylsulfonyl Ci1 -6 alkyl, aryl CI -6 alkylsulfonyl, aryl Ci -6 alkylsulfonyl Ci -6 alkyl, Ci -6 alkylcarbonyl, C 1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C 1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl CI-6 alkyl, Ci1 -6 alkyithiocarbonylamino, Ci -6 alkylthiocarbonylamnino Ci -6 alkyl, aryithiocarbonylamino C 1-6 alkyl, aryl CI -6 alkyithiocarbonylamino, aryl Ci -6 alkyithiocarbonylamino C 1-6 alkyl, C1-8 alkylaminocarbonyl C1..6 alkyl, arylaminocarbonyl C 1-6 alkyl, aryl Ci -8 alkylaminocarbonyl, or aryl Ci -8 alkylaminocarbonyl CI -6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R I and R 1 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; is selected from hydrogen, C1-8 alkyl, aryl, aryl Cl-8 alkyl, aryl Ci-6 alkoxy, C 1-8 alkylcarbonyloxy C 1-4 alkyl, aryl C 1 -8 aikylcarbonyloxy C 1-4 alkyl, C 1-8 alkylaminocarbonylmethylene, or 39 WO 98/44797 PCT/US98/06823 Ci -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; or a pharmaceutically acceptable salt thereof.
Specific examples of compounds that are integrin antagonists include the following: 4 2 -Guanidoethyloxy)phenylcarbonyl..2(S)-benzyloxycarbonylamino- f3 alanine, 4 2 -Guanidoethyloxy)phenylcarbonyl-2(S )-phenylsulfonylamino- falanine, 2(S)-Phenylsulfonylamino-3- 4 -(4-guanidobutyloxy)phenyl] -propionic acid, 2(S )-(N-Benzyloxycarbonylamino..3.[4-(5 -guanidopentyloxy)phenyl] propionic acid, 4 3 -Guanidinopropyloxy)benzoyl2-.(S )-phenylsulfonylamino-3alanine, 4 3 -Formamidinopropyloxy)benzoyl.2-(s )-phenylsulfonylamino-
I-
alanine, 3 -Methoxy- 4 3 -guanidinopropyloxy)benzoyl2(S)-phenylufonyl.
amino-fo-alanine, 3 -Methoxy-4-(3-aminopropyloxy)benzoyl..2(s )-phenylsulfonylamino-Palanine, 3 3 -Guanidinopropyloxy)benzoyl.2(S )-phenylsulfonylamino- f-alanine, 40 0 WO 98/44797 WO 9844797PCTIUS98/06823 4- 2 -(N-Phenylguanidino)ethyloxylbenzoyl-2(S)-phenylsulfonylamno-..
1-alanine, 4- [2-(N,N-Dimethylguanidino)ethyloxy]benzoylp2(S )-phenylsulfonyl amino- f-alanine, 4 -(Guanidinophen-3-yloxy)benzoyl-2(S)-.phenylsulfonylamino 13alanine, 4- [2-(Guanidino)ethyloxymethyl]benzoyl.2(S )-phenylsulfonylamino- 1alanine, 2 -(Guanidino)ethylaminocarbonyl]benzoyl..2(S)-phenylsulfonylamino- 1-alanine, 4- 2 -Aminothiazol-4-yl)ethyloxy]benzoyl-2 (S)-phenylsulfonylamino- 1-alanine t-butyl ester, 4- [2-(2-Aminothiazol-4-yl)ethyloxy]benzoyl.2 (S)-phenylsulfonylamino- 1-alanine, 4- 2 -Imidazolin-2-yl)aminoethyloxy]benzoyl2(S)-phenylsulfonylammno- P-alanine, 2(S )-Phenylsulfonylamino-3 4 -(4-(N-imidazolin-2-yl)aminobutyloxy)phenylipropionic acid, 4- [Cis-3a,4 ,5 ,6,7,7a-Hexahydro- 1H-benzimidazol-2-yl] amino] ethyloxybenzoy1-2(S)-.phenylsulfonyaminopalanine, 4- 2 -(Pyrimidin- 2 -ylamino)ethyloxy]benzoyl-2(S)-phenylsulfonylaminof3-alanine, 41 WO 98/44797 PCTJUS98/06823 4- [2-(3,456Ttayrpriii- lmn~thlx~ezy-() phenylsulfonylamino-oJ-alanine, 4- [2-(2-Aminothiazol-4-yl)ethyl] benzoyl-2(S )-phenylsulfonylamino- falanine t-butyl ester, 4- [2-(2-Aminothiazol-4-yl)ethyl] benzoy1-2(S)-phenylsulfonylamino-jalanine, 4 2 2 -Jmidazolin-2-y)amino)propyloxylbenzoyl12(S)-phenysulfonylamino-f3-alanine, 4- 2 -(Imidazol-2-yl)ethyl]benzoyl.2(S )-phenylsulfonylamino- f-alanine, 4- 2 -(Thiazol-2-ylamino)ethyloxy]benzoyl.2(S )-phenylsulfonylamino- palanine, 4- (Pyrimidin-2-ylamino)ethyloxy]benzoyl12(S)-benzyloxycarbonyl amino-fo-alanine, 4- ,4,5 ,6-Tetrahydropyrimidin-2yamino)ethyloxy] benzoyl-2(S benzyloxycarbonylamino.. f-alanine, Methyl 2(S)-benzoylamino-3- 4 4 -pyrimridin-2-ylaminobutyloxy)phenyllpropionate, 2(S)-Benzoylamino-3..[ 4 4 -pyrimidin-2-ylamino)butyloxy)phenyl] propionic acid, 2(S )-Benzoylamino-3- ,4,5 6 -tetrahydropyrimidin-2-ylamino)butyloxy)phenyllpropionic acid, 4- 2 -(Pyrimidin- 2 -ylamino)ethyloxylbenzoyl..2(S)NmethylNphenylsulfonylamino-p-alanine t-butyl ester, 42 WO 98/44797 WO 9844797PCTIUS98/06823 4- 2 -(Pyrimidin-2-ylamino)ethyloxy]benzoyl.2(S )-N-methyl-N-phenylsulfonylamino-f3-alanine, 4- ,4,5 ,6-Tetrahydropyrimidin-2-ylamino)ethyloxy] benzoyl-2(S)-Nmethyl-N-phenylsulfonylamino- f-alanine, 4-[2-(N-(5,6-Dihydro-4-keto- 1 (H)-pyrimidin-2--yl)amino)ethyloxy].
benzoyl-2(S )-phenylsulfonylamino-fp-alanine, 4 2 -Aminopyridin-6-yethyny)benzoyl.2(S)-~phenylsulfonyl-amino. 13 alanine t-butyl ester, 4 -(2-Aminopyridin-6-ylethynyl)benzoyl-2(S )-phenylsulfonylamino- 1alanine, 4- [2-(2-Aminopyridin-6-yl)ethyl]benzoyl.2(S )-phenylsulfonylamino- 1alanine, 4- 2 -Aminopyridin-6-yl)ethyloxy]benzoyl..2(S)-phenylsulfonylamino-13-alanine t-butyl ester, 4- 2 2 -Aminopyridin-6-y)ethyloxybenzoyl-2(S)-phenysufonylamino- 1-alanine, 4- (Indol- 2 -yl)ethyloxy]benzoyl-2(S)-phenylsulfonylamino 1-alanine methyl ester, 4- 2 -(Indol- 2 -yl)ethyloxylbenzoyl-2(S)-phenysulfonylaminop...alanine, 4- 1H-Imidazo 4 ,5- 6 ]pyridin-2-yl)ethenyl]benzoyl.2(S )-phenylsulfonylamino-13-alanine t-butyl ester, 4- (1H-Imidazo[4,5-blpyridin-2.yl)ethenyl]benzoyl12(S)-phenyl..
sulfonylamino-13-alanine, 43 WO 98/44797 WO 9844797PCT/US98/06823 4- 1H-Imidazo [4,5 -b]pyridin-2-yl)ethyl]benzoyl-2(S)-phenyl.
sulfonylamino-pf-alanine, 4- 1, 8-Naphthyidin-7 -yl)ethenyl)benzoyl-2 (S )-phenylsulfonylaminof-alanine t-butylester, 4- 1,2,3 ,4-Tetrahydro- 1 ,8-naphthyridin-7-yl)ethy1]benzoyl12(S)phenylsulfonylamino-Jp-alanine t-butyl ester, 4- 1,2,3 ,4-Tetrahydro- 1, ,8-naphthyridin-7y1) ethyl] benzoyl2(S)phenylsulfonylamino- f-alanine, 4- (1 8 -Naphthyridin-7-y1)etheny1]benzoylb2(S)phenysufonyl.
amino-fp-alanine ethyl ester, 4- 1,2,3 ,4-Tetrahydro- 1 ,8-naphthyridin-7-yl)ethyl]benzoyl2(S)phenylsulfonylamino-J3-alanine ethyl ester, 4- (1,2,3 ,4-Tetrahydro- 1,8 naphthyridin-7-yl)ethyl]benzoyl.2(S [1I(S)1I 0-camphorsulfonylamido] fP-alanine ethyl ester, 4- (1,2,3 ,4-Tetrahydro- 1,8 naphthyridin-7-yl)ethyljbenzoyl-2(S [i(S)I1 -camphorsulfonylamido] IP-alanine, 4- [(3-Aminoisoquinolin- 1-yl)ethynyllbenzoyl-2(S)-phenylsulfonamido.
fP-alanine ethyl ester, 4- [(3-Aminoisoquinolin- 1 -yl)ethynyllbenzoyl-2(S)-phenylsulfonamido- P-alanine trifluoroacetate, 4- [2-(3-Aminoisoquinolin- 1 -yl)ethyllbenzoy-2(S)-phenysulfonamido-.
f 3 -alanine trifluoroacetate, 44 WO 98/44797 WO 9844797PCT/US98/06823 4- 1H-Benzimidazo-2-yl)aminolpropoxylbenzoyl2(S)phenylsulfonylamino-3-alanine t-butyl ester, and 4- 1H-B enzimidazol-2-yl)aminolpropoxylbenzoyl-2(S)phenylsulfonylamino-3-alanine.
0 r)
NHSO
2 -0 0 0 N' N C02 N N H N HH H
NHSO
2 N N
H
0 0
NI
CH
3
H
CN N
H
NHSO
2 45 WO 98/447Q7 o 0 N>(C02H N H H 'NHCO 2
CH-
2 o 0 N H
-N
H ~NHS0 2 2-Oxo-3- ,8-tetrahydro[ 1 ,8]-naphthyridin-2-yl)ethyl]piperidin- 1 -yl-acetyl-3 (S)-pyridin-3-yl- p-alanine ethyl ester; 2-Oxo-3- ,6,7 ,8-tetrahydro [1 8 ]-naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl- 3(S )-pyridin-3-yl- f- alanine trifluoroacetate; 2-Oxo-3 2 -(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin-1I-yl)acetyl-3 (S )-alkynyl- j-alanine ethyl ester; 2-Oxo-3 ,6,7,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl- f-alanine; 2-Oxo-3 ,6,7,8-tetrahydro [1 ,8]-naphthyridin-2-yl)ethyl] pyrrolidin- 1-yl)acetyl-3 (S )-pyridin-3 -yl- f-alanine ethyl ester; 2-Oxo-3(S)- 8-tetrahydro[ 1, 8]-naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S )-pyridin-3 -yl-p-alanine; 2-Oxo-3(R)- ,6,7,8-tetrahydro[ 1, 8]-naphthyridin-2yl)ethyljpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-fp-alanine ethyl ester; 2-Oxo-3(R)- ,6,7 ,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl- 3(8 )-alkynyl- f-alanine; 46 WO 98/44797 I-"r noU II u ayaluD3La 2 -Oxo-3 ,6,7 ,8-tetrahydro[ 1, 8 ]-naphthyridin-2 -yl) ethyl] pyrrolidin- 1-yl)acetyl-3 (S)-pyridin-3 -yl-fA-alanine ethyl ester; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1, 8]-naphthyridin-2yl)ethyl]pyrrolidin- 1-yl)acetyl-3 (S )-pyridin-3 -yl-f3-alanine; Ethyl 2-oxo- 3- (5,6,7,8 -tetrahydro 1, 8] naphthyridin-2-yl) ethyl] tetrahydropyrimidin-l-yl-acetyl- 3(S)-pyridin- 3-yl- p-alanine; 2-Oxo-3- ,6,7 ,8-tetrahydro[ 1, 8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin- 1-yl-acetyl-3 (S)-pyridin- 3-yl-f3-alanine; Ethyl 2-oxo-3- ,6,7 ,8-tetrahydro naphthyridin-2yl)ethyl]imidazolidin-1-yl-acetyl.3 (S )-pyridin- 3-yl- f-alanine; 2-Oxo-3- ,8-tetrahydro[ 1, 8]naphthyridin-2-ylI )ethyl]imidazolidin- 1-yl-acetyl-3 (S )-pyridin- 3-yl- 1-alanine; Ethyl 2-oxo-3(R)- ,6,7,8-tetrahydro[ 1,8]naphthyridin-2yl)ethyllpyrrolidin-l-yl)acetyl-3 (2-ethylindol-3-yl)-P3-alanine; 2-Oxo-3(R)- ,6,7,8-tetrahydro[ 1,8]naphthyridin-2yl)ethyl]pyrrolidin-1-yl)acetyl- 3(R)-(2-ethylindol-3 P-alanine; Ethyl {2-oxo-3- ,6,7,8-tetrahydro- [1 ,8]naphthyridin-2ylmethyl)-amino] -pyrrolidin- l-yl }-acetylamino)-3-(S )-pyridin- 3-ylpropionic acid; {2-Oxo-3- ,8-tetrahydro-[ 1, 8]naphthyridin-2-ylmethyl)aminolpyrrolidin- 1-yl I-acetylamino)- 3-(S)-pyridin-3 -yl-propionic acid;_ I2-oxo-3- 6 7 ,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)amino] -pyrrolidin- 1 -yl I -acetylamino)-3- (S )-quinolin- 3-yl-propionic acid; 47 WO 98/44797 PCTIUS98/06823 3- 2- [6-Oxo- 1 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3 aS, 6aS)pyrrolo 3 4 -blpyrrol-5-yl]-acetylamino pyridin-3-yl-propionic acid; 3- [6-Oxo-l1-(5,6,7 ,8-tetrahydro- 8]naphthyridin-2-ylmethyl)hexahydro-(3aR, 6aR)pyrrolo[3 4 -blpyrrol-5-yl]-acetylamino}-3 pyridin-3-yl-propionic acid; ,6,7,8-Tetrahydro- -naphthyridin-2-yl)naphthylen2yl] carbonyl-2(S)-phenylsulfonylamino- f-alanine ethyl ester; ,8-Tetrahydro- -naphthyridin-2-yl)naphthyle..2.yl] carbonyl-2(S)-phenysufonylamino-.falan 11 e; [N-Pyridin-2-yl)aminomethyl)naphthylen-2.yl)carbonyl.2(S phenylsulfonylamino-p-alanine ethyl ester; 6- ([N-Pyridin-2-yl)aminomethyl)naphthylen-2yly-carbonyl.2(S)phenylsulfonylamino-p3-alanine; 4- (5,6,7 ,8-Tetrahydro- [1 ,8]naphthyridin-2-yl)piperidin.1 -yl-carbonyl- 2(S )-phenylsulfonylamino- f-alanine t-butyl ester; 4-(5 ,6,7 ,8-Tetrahydro- [1 ,8]naphthyridin-2-yl)piperidin-1 -yl-carbonyl- 2 (S)-phenylsulfonylamino-f-alanine; 6- [(Pyrimidinyl- 2 -yl)aminomethyllnaphthylen-.2-.yl-carbonyl-2(S phenylsulfonyl-p-alanine ethyl ester; 6- [(Pyrimidinyl- 2 -yl)aminomethylnaphthylen2.ylcarbonyl-2(S)phenylsulfonyl-p-alanine; 48 WO 98/44797 WO 9844797PCTIUS98/06823 6- ,4,5 6 -Tetrahydropyrimidinyl-2-yl)aminomethyllnaphthylen2-y.
carbonyl-2(S )-phenylsulfonylamino-p-alanine; Ethyl 3 (S)-pyridin-3-yl-3- ,6,7,8-tetrahydro- [1 ,8]naphthyridin- 2 -yl)propylcarbamoyl]acetylamino propionate; 3 (S)-pyridin-3-yl-3- 12- ,6,7 ,8-tetrahydro- 1,8]naphthyridin-2yl)propylcarbamoyl] acetylamino Ipropionic acid; 3-(5 ,6,7 ,8-Tetrahydro-[ [1, 8 ]naphthyridin-2-ylmethyl)piperidinylb malonyl-3 (S)-pyridin-3 -yl- f-alanine ethyl ester; 3- 8-Tetrahydro- naphthyridin- 2-ylmethyl)piperidinylmalonyl-3(S)-pyridin-3-yl-fp-alanine; 4- 8-Tetrahydro- [1 ,8]naphthyridin- 2-ylmethyl)piperidinylmalonyl- 3(S )-pyridin-3-yl- f-alanine ethyl ester; 4- (5,6,7,8 -Tetrahydro- [1 naphthyridin- 2-ylmethyl)piperidinylmalonyl-3(S)-pyridin-3-yl-p-alanine; 4- 8-Tetrahydro- naphthyridin- 2-yl )piperidinyl-malonyl-3 (S pyridin-3-yl-fp-alanine ethyl ester; or 4-(5 ,6,7 ,8-Tetrahydro- [1 ,8]naphthyridin- 2-yl)piperidinyl-malonyl-3 (S pyridin-3-yl-of-alanine; or the pharmaceutically acceptable salts and optical isomers thereof.
Compounds which are described as antagonists of the axvP3 receptor and may therefore be useful in the present invention, and methods of synthesis thereof, can be found in the following pending applications and publications, which are herein incorporated by reference: 49 I- WO 98/44797 PCT/US98/06823 PCT Patent Pub. Nos. W096/00574; 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 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. W095/32710.
Examples of farnesyl protein transferase inhibiting compounds and in particular selective farnesyl protein transferase inhibiting compounds include the following: a compound represented by formula (II-a) through (II-c): 50 WO 98/44797 PTU9/62 PCTIUS98/06823 (R )r (R9R2 R3 V Al(CRla 2 )nA (CR On)W (CR b 2 x Y R 4
R
(Il-a)
(R
8 )r
RR
2
G
V Al(CRla 2 )nA (CRla 2 )n (CR b 2 )p N\ N-Z It X R 3 R 4 (11-b) (R )r
R
V -A A(CRla 2 )nA (CRl) OnAW (CRb 2
)NP\
wherein with respect to formula (11-a): (R )r (R9\R2 0 V A1(CR la 2 )nA 2 (CRla 2 On (CRb 2)p-,4N R 4 R (Il-a) or a pharmaceutically acceptable salt thereof, Ria and R Ib are independently selected from: 51 I. WO 98/44797PCJS8/62 PCT[US98/06823 a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 RI IS R I C(O)NR 10-, CN, N02, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3,
N(R
1 0 or RII0C(O)NRIO- C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-, RI IS(O)mn-, Rl 0 C(O)NRIO-,
CN,
(R
1 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, N(RlO)2, or R 1 1
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, 0 0 wherein the 1) 2) 3) 4) substituted group is substituted with one or more of: aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6
R
7 d) halogen, C3-6 cycloalkyl,
OR
6
SR
6
S(O)R
6 S02R 6 52 WO 98/44797 WO 9844797PCT/US98/06823 -NR 6 R 7 6) -N R 7 0 R 6 7) 7~ NR 7 a 0 8) -0O NR 6 R 7 0 9) -0o OR 6 0 NR 6 R 7 0 11) -S0 2 -NR R 7 12) -N-S 2
R
7 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 moiety selected from: 0, S -NC(O) and -N(COR 53 WO 98/44797 WO 9844797PCT/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 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
"YR
0 f) -S0 2
R
1 or g) N(RIO)2; or
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: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 0-,
R'
1 RIOC(O)NRIO-, CN, N02, R 1 0 2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, or R 1 1 0OC(O)NR 10-, and c) Ci1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RI I 1 S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, RIO0C(O)-, N3, -N(R 10)2, or R 1
OC(O)NH-;
54 P WO 98/44797 WO 9844797PCTIUS98/06823 R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R~IS(O)m-, RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C-(NRIO)-,
R
1 RIO0C(O)-, N3, N(R 10)2, or R I I0C(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by periluoroalkyl, F, Cl, Br, R 1 0 R1 1 R 1 C(O)NR 10-, CN,
(R
1 0 )2N-C(NR10)-, RlOC(O)-, RIO0C(O)-, N3, N(R'O)2, or RI IOC(O)NR 1 0-; RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C 1-C6 alkyl and aryl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(O)NR10-, -NRlOC(O)-, 0, -S(O)2N(Rlo)-, N(RlO)S(0)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom. selected from 0, S, and N, and e) C2-C20 alkenyl, 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 PTU9~62 PCTIUS98/06823 X is -CH2-, or Y is aryl, more of: heterocycle, unsubstituted or substituted with one or 1) Ci-.4 alkyl, unsubstituted or substituted with: a) C 1 4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6
R
7 2) aryl or heterocycle, 3) halogen, 4) OR 6
NR
6
R
7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6
-C(O)NR
6
R
7 or 11) C3-C6 cycloalkyl; 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 0 or 1; o or 1; and 4 or m is n is p is r is s is t is u is with respect to formula (11-b): 56 WO 98/44797 PCTIUS98/06823
(R
8 )r 7 R9 R 2
G
-Al(CRla 2 )nA (CRlaOn (CRlb 2 )P 7 N\ N-Z xj
R
3
R
(11-b) or a pharmaceutically acceptable salt thereof, Rla, Rlb, R 10
R
1 1, ma, R 2
R
3
R
6
R
7 p, R7a, u, R 8 Al, A 2 V, W, X, n, p, r, s, t and u are as defined above with respect to formula (11-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 carbon atom; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N-C-(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, N(R102,or R I I0C(O)NR 1 and c) C1I-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-,
CN,
(R
1 0 )2N-C(NRIO)-, RlOC(O)-, RIO0C(O)-, N3, N(R'0)2, or RI IOC(O)NRIO-;l G is H2 orO0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted. or substituted with one or more of the following: 1) Cl .4 alkyl, unsubstituted or substituted with: 57 WO 98/44797 PCTIUS98/06823 a) C 1-4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6
R
7 2) aryl or heterocycle, 3) halogen, 4) OR 6
NR
6
R
7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6
-C(O)NR
6
R
7 or 11) C3-C6 cycloalkyl; with respect to formula (11-c):
(R
8 )r (R9>R
R
3 V A(Cla 2 2 (CRla 2 )n
Z
(I l-c)rs
R
or a pharmaceutically acceptable salt thereof, Ria, Rib, RIO, RI 1, m, R 2
R
3
R
6
R
7 p, u, R.7a, R 8 Al, A 2 V, W, X, n, r and t are as defined above with respect to formula (Il-a);
R
4 is selected from H and CH3; and any two of R 2
R
3 and R 4 are optionally attached to the same carbon atom; 58 WO 98/44797 WO 9844797PCTIUS98/06823 G is 0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Ci -4 alkyl, unsubstituted or substituted with: a) Ci 1 4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6
R
7 2) aryl or heterocycle, 3) halogen, 4) OR 6
NR
6
R
7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6
-C(O)NR
6
R
7 or 11) C3-C6 cycloalkyl; and S is 1; a compound represented by formula (II-d): 59 WO 98/44797 WO 9844797PCT/US98/06823
(R
8 )r((R9) V-A' (CR a 2 )nA (CR O 2 n(W -(CRlb 2 )p X wherein: R 1a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 RI IS R 1 C(O)NR
R
1 1 (RIO)2NC(O)-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 or RI I0C(O)NRIO-, c) unsubstituted or substituted C 1 -C6 alkyl wherein the substituent on the substituted CI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-,
R
11 RIOC(O)NR (Ri (b2NC(O)-, R 10 2N- C(NR CN, R 1OC(O)-, N3, -N(R 10 and R 1 1 0OC(O)-
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-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl,
R
12 0-,
R
1 1 RIOC(O)NRIO-, (Rl 0
R
1 1 60 WO 98/44797
R
6 a, R 6 b a) b) c) d) PCTIUS98/06823 R1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R] 0 )2, or R 1 1 C(O)NR l0-, unsubstituted C1-C6 alkyl, substituted C I -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I 1
R
1 I C(O)NR 10-, (R I 0 )2NC(O)-,
R'
0 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 and R I I0C(O)-NR
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfinoroalkyl,
R
1 2 0-, R I 1 R 1 C(O)NR 10-, (R 1 R1 1 C(0)0-,
R
10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(R 1 O)2, or R I IOC(O)NR unsubstituted Ci -C6 alkyl, substituted C I -C6 alkyl wherein the sub stituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12
R
1
R
1 GC(O)NRIO-,
(R
1 0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 and R I I0C(O)-NR any two of R6a, 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-CH2-, -(CH2)4- and -(CH2)37; 61 WO 98/44797 WO 9844797PCT[US98/06823
R
7 is selected from: H; Cv..4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
YR
0 f) -S0 2
R
11 g) N(R 1 O)2 or h) CI-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R1 1 S(O)m-,
R
1 0
C(O)NR
1 (RI
R
1 0 2N-C(NRl
CN,
N02, R I N3, -N(R'1O)2, or R 1 1 OC(O)NR 10-, and c) ClI -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfinoroalkyl, F, Cl, Br, RIO0-, R 1 1
R
1 0 C(O)NHi-, (RIO)2NC(O)-,
R
10 2N-C(NRIO)-, CN, Rl 0 N3, -N(Rl 0 or RIO0C(O)NH-;
R
9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 peffluoroalkyl,
F,
Cl, Br, RIO0-, R11S(O)m-, RlOC(O)NRIO-, 62 WO 98/44797 WO 9844797PCT/US98/06823
(R
1 0
R'
0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, 1)2, or R I IOC(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, Br, R 1 0 R II 1 S(O)m-, RlOC(O)NRlO-,
(R
1 0
R
10 2N-C(NRI10>,
CN,
RIOC(O)-, N3, -N(RIO)2, or RI IOC(O)NRIO-; RIO is independently selected from hydrogen, CI -C6 aikyl, 2,2,2trifluoroethyl, benzyl and aryl; Ri 1 is independently selected from C Il-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I -C6 alkyl, C I -C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C1I-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, CI-C6 perfluoroalkyl, 2-aminoethyl and 2 ,2,2-trifluoroethyl;
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -CE-C-, -C(O)NR10-, -NRlOC(O)-, 0, S(0)2N(RIO)-, -N(RlO)S(0)2- or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 ailkenyl, provided that V is not hydrogen if 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-, 0,
-C(O)NR
7
-NR
7 -C(0)NR 7
-NR
7 N(RlO)S(O) 2 or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0,1, 2 or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Gori1; a compound represented by formula (II-e): f f" f\-,f (R 8 )r V A' (CRla 2 )nA 2 (CR~a, (CR 2)p X -(CRlb Ik-e wherein: Ria, Ri1b, R.
2
R
3
R
4
R.
5
R.
7
R
8
R
9 RIO, R1 1, Al, A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-d); from 1-3 of f(s) are independently N, and the remaining f s are independently
CR
6 and each R 6 is independently selected from: a) hydrogen, 64 V. WO 98/44797 WO 9844797PCTIUS98/06823 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI-C6 perfluoroalkyl,
R
1 2 0-, R1 1 R I C(O)NR 10-, (R 10 R I IC(0)0-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R' I IC(O)NR c) unsubstituted C1I-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CI10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 2 RI IS(O)m-, RIOC(O)NRIO-,
(R
1 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, and R 1 1 0OC(O)-NRl10-; 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-; a compound represented by formula (11-f): R 6 a-e
R
3 Il-f wherein: 65 I- WO 98/44797 WO 9844797PCT/US98/06823
R
3
R
4
R
5 R6a-e, R 7
R
8
R
9 RIO, RI I, Al, A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula (11-d); from 1-2 of f(s) are independently N, and the remaining f s are independently CH; and R 1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 RIIS(O)m-,
R
1 1 (Rl 0
R
1 0 2N-C(NR10)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or R 1
IOC(O)NRIO-,
c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 0 RI 1 RIOC(O)NRIO-, (Rl 0 )2NC(O)-,
R
10 2N-C(NRlO)-, CN, R 1 N3, -N(RIO)2, and R1 1 0C(O)-NR a compound represented by formula (11-g): 99 (R )r (R9 (I~c Ir'I f V A'(CR 1 2 )nA 2
C'
2 )n
C
2 W Xp I II-g wherein: 66 WO 98/44797 WO 9844797PCTIUS98/06823
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 (11-d); from 1-2 of f(s) are independently N, and the remaining f s are independently CH; from 1-3 of g(s) are independently N, and the remaining g's are independently
CR
6 RI and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10-, RI S R I C(O)NR 1-, RIIC(O)O-, (RIO)2NC(O)-, R102N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 O)2, or RI I0C(O)NRIO-, c) unsubstituted or substituted C 1 -C6 alkyl wherein the substituent on the substituted ClI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I 1 R 1 C(O)NR 10-, (R 10 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and RII0C(O)-NRIO-; and each R 6 is a) b) independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-.C6 perfluoroalkyl, R 1 2 0-, R1 1 R 1 C(O)NR 10-, (R 1 0 R' IIC(0)0-,
R
10 2N-C(NR10)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or Rl 1 0C(O)NRIO-,' unsubstituted C1I-C6 alkyl, 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
R
1 1 R10C(O)NR10-, (R10)2NC(O)-,
RI
0 2N-C(NR10)-, CN, RO1C(O)-, N3, -N(R10)2, and
R
1 1O
C(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-; a compound represented by formula (II-h):
R
2 0 RN H R 3
H
HS R R 4 II-h wherein Rc is selected from: OOR and
O
0 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 acyl groups comprise straight chain or branched chain 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 the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
R
4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
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 methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH20H or -CH2CH2CH20H;
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; T is O or S(O)m; m is 0, 1 or 2; n is 0, 1 or 2; 69 WO 98/44797 WO 9844797PCTIUS98/06823 a compound represented by formula (11-i): R 2 b wherein: RI a and R Ib 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-, 0 R 9
R
8
C(O)NR
8 CN, N02, (R 8 )2N-C(NR 8
R
8
R
8 N3, N(R 8 or R 9
OC(O)NR
8 c) CI-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8
R
9
R
8
C(O)NR
8 CN, (R 8 )2N-C(NR 8
R
8
R
8 N3, -N(R 8 )2, or R 9
OC(O)-NR
8 R2a, R2b and R 3 are independently selected from: Oa) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R
8
R
9
R
8
C(O)NR
8 CN, N3, (R 8 )2N-C(NR 8
R
8
-N(R
8 or R 9
OC(O)NR
8 c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 8 0-,
R
9
R
8
C(O)NR
8 CN, N02,
(R
8 )2N-C(NR 8
R
8
R
8 N3,
-N(R
8 halogen or R 9
OC(O)NR
8 and 70 WO 98/44797 WO 9844797PCTIUS98/06823 d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R4 and R 5 are independently selected from: a) hydrogen, and b)
(R
6 )r R7z V Al(CRlIa 2 )nA 2 (CRla) OnWl- (CR1b 2
A/
R6 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, ClI -C6 perfluoroalkyl, F, Cl, Br, R 8
R
9
R
8
C(O)NR
8 CN, N02, R 8 2N-C(NR 8
R
8
R
8 N3,
N(R
8 or R 9
OC(O)NR
8 and c) ClI-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, Cl-C6 perfluoroalkyl, F, Cl, Br,
R
8
R
9
R
8 C(O)NFI-, CN, H2N-C(NH)-, R 8
C(O)-
,R
8 N3, -N(R 8 or R 8
OC(O)NH-;
R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alikynyl, Cl-C6 perfluoroalkyl,
F,
Cl, Br, R 8
R
9
R
8
C(O)NR
8 CN, N02,
(R
8 )2N-C-(NR 8
R
8
R
8 N3, -N(R 8 or
R
9 0C(O)NR 8 and 71 I- WO 98/44797 PCT/US98/06823 c) C -C6 alkyl unsubstituted or substituted by C 1-C6 perfluoroalkyl, F, Cl, Br, R 8
R
9
R
8
C(O)NR
8 CN, (R 8 )2N-C(NR 8
R
8
R
8 N3, -N(R 8 )2, or R 9 0C(O)NR 8
R
8 is independently selected from hydrogen, Cl-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl;
R
9 is independently selected from C1-C6 alkyl and aryl;
R
10 is independently selected from hydrogen, Cl-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl; Al and A 2 are independently selected from: a bond, -CH=CH-,
-C(O)NR
8
-NR
8 O, -N(R 8 S(0)2N(R 8
-N(R
8 or S(0)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 72 k. WO 98/44797 WO 9844797PCT/US98/06823 Y is selected from: a bond, -C(RIO)=C(RIO)-,
-C(RIO)-
-C(R
1 0 2
-C(R
1 0 )2NRIO-, -C(O)NRIO-, -NRlOC(O)-, 0, NC(O)RIO-, -NC(O)0R 1 0 -S(O)2N(RI Oy, -N(R 1 0 or S(O)m; Z is H2 or 0; M is n is p is r is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; o to 5, provided that r is 0 when V is hydrogen; and 0 or 1; a compound represented by formula (11-mn): fl6a-e (R 8 )r(R V-A1(0R1 2 )lA 2 (CR 2 W) -(CR 2 2
X
Il-rn wherein: 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 0, and which also comprises a carbonyl, thiocarbonyl, -C(=NR 1 or sulfonyl moiety adjacent to the nitrogen atom attached to Y; 73 WO 98/44797 Y is PCTIUS98/06823 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 0, and wherein Y is attached to Q through a carbon atom; Ri and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-, Rl 1 RIOC(0)NRlO-, R 1 1C(0)0-, (R I 0 R I 0 2N-C(NR CN, N02,
R
1 N3, -N(RIO)2, or RI IOC(0)NR10-, c) unsubstituted or substituted Ci -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-, RI 1 IS(O)m-, RIOC(O)NR1O-,
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(R 1 0 and
R
1 1 0C(O)-NR10-;.
R
3
R
4 and a) b)
R
5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci -C6 perfluoroalkyl,
R
1 2 0-,
R
1 1 Rl 0 C(O)NRIO-,
(R
1 0
R
1 1 C(0)0-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I I0C(0)NRi10-, unsubstituted C I -C6 alkyl, substituted Ci -C6 alkyl wherein the sub stituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 ailkenyl, C2-C6 alkynyl, 74 WO 98/44797 R6a, R6b, a) b) c) d) PCT/US98/06823 R 1 2 R I S R I C(O)NR 10-, (R I 0 )2NC(O)-,
R
10 2N-C(NRlO)-, CN, RIOC(O)-, N3, -N(RlO)2, and
R
1 1 0C(O)-NRIO-;,
R
6 c, R6d and R6e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 1 R I S R 1 OC(O)NR 10-, (R I 02NC(0)-, RI 1 S(O)2NRIO-, (RIO)2NS(0)2-,
R
1 IC(0)O-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R 1 OC(0)NR 1 0-, unsubstituted C1-C6 alkyl, substituted C I -C6 alkyl wherein the sub stituent on the substituted C1I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-,
R
11 RIOC(0)NRIO-, (RI 0b2NC(O)-, RI 1 S(0)2NRIO-, (RlO)2NS(0)2-,
R
10 2N-C(NR10)-,
CN,
RlOC(0)-, N3, and R 1 1OC(0)-NRIO-; or any two of R6a, 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-;
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, b) aryl or heterocycle, 75 WO 98/44797 WO 9844797PCT/US98/06823 c)
"YR
0 d) -SO 2
R"
e) N(R 10 )2 or C 1-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 RI IS RI 0 C(O)NRIO-, (Rl 0 RIl S(O)2NRIO-, (RIO)2NS(O)2-,
R
10 2N-C(NRIO0>, CN, N02, RlOC(O)-, N3, -N(R 10 or R 1 1 0OC(O)NR 1 and C) CI -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(0)NRIO-, (RIO)2NC(O)-, RI IS(O)2NR10-, (R'O)2NS(O)2-,
R
10 2N-C(NRIO)-,
CN,
RIOC(O)-, N3, -N(RIO)2, or R 1 0 0C(0)NH-;
R
9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S R I C(O)NR 10-, (R 10 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R 1 10C(O)NR 10-, and C) C 1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 RI 1 (RIO)2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, RIOC(O)-, N3, N(R102,or R 11OC(O)NRl10-; 76 WO 98/44797 PCT/US98/06823
R
1 0 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R11 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, Ci-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R
13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -CEC-, -C(O)NRO1-, -NRlOC(O)-, O, -N(R 1 S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 77 WO 98/44797 WO 9844797PCT[US98/06823 X is a bond, -CH=CH-, 0, -C(O)NR 7
-NR
7 -C(0)NR 7
-NR
7 -S(O)2N(RIO)-,
N(R
1 0 or m is 0,l1or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Oorl1; a compound represented by formula (Il-n): (R 8 )r V A 1
(CR'
2 2
(CR'
11-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,
W, m, n, p, q, r and t are as previously defined with respect to formula (11-rn); 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 0, and which also comprises a carbonyl, thiocarbonyl, -C(=NR 1 3 or 78 WO 98/44797 WO 9844797PCT[US98/06823 sulfonyl moiety adjacent to the nitrogen atom attached to Y, provided that Q is not or
Q
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 0, and wherein Y is attached to Q through a carbon atom; or a pharmaceutically acceptable salt or disulfide thereof.
Examples of compounds which selectively inhibit farnesyl protein transferase include the following: 2(S)-Butyl-l1-(2,3-diaminoprop- 1-yl)-l1-(1 -naphthoyl)piperazine; 1- (3-Amino-2-(2-naphthylmethylamino)prop-1 -yl)-2(S )-butyl-4-( Inaphthoyl)piperazine; 2(S)-Butyl- 1- 2 -naphthylmethyl)]-4,5-dihydroimidazol Imethyl-4- (1 -naphthoyl)piperazine; 1- 1-B enzylimidazol)methyl]-2(S)-butyl-4 (1-naphthoyl)piperazine; 1-1{5- [1-(4-nitrobenzyl)] imidazolylmethyl )-butyl-4-( 1naphthoyl)piperazine; 79 WO 98/44797 PTU9/62 PCTIUS98/06823 1- (3-Acetamidomethylthio-2 aminoprop- 1 -yl)-2(S )-butyl-4- (1 naphthoyl)piperazine; 2(S)-Butyl- 1- [2-(l1 -imidazolyl)ethyl] sulfonyl-4-( 1 -naphthoyl)piperazine; 2(R)-B utyl- 1 -imidazolyl-4-methyl-4- (1 -naphthoyl)piperazine; 2(S )-Butyl-4- (1-naphthoyl)- 1 -(3-pyridylmethyl)piperazine; 1 2 (S)-butyl-(2(R)-(4-nitrobenzyl)amino- 3-hydroxypropyl)-4-( 1naphthoyl)piperazine; 1- (2(R)-Amino-3 -hydroxyheptadecyl)-2(S )-butyl-4-( 1 -naphthoyl)piperazine; 2(S)-B enzyl1-imidazolyl-4-methyl-4-( 1-naphthoyl)piperazine; 1 -(2(R)-Amino-3-(3-benzylthio)propyl)>2(S)..butyl-4-( 1naphthoyl)piperazine; 1- (2(R)-Amino-3 4 -nitrobenzylthio)propyl] )-butyl-4- (1naphthoyl)piperazine; 2(S)-Butyl- 1- [(4-imidazolyl)ethyl]-4- (1-naphthoyl)piperazine; 2(S)-Butyl-1- [(4-imidazolyl)methyl] 1 -naphthoyl)piperazine; 2(S)-Butyl-1- -naphth-2-ylmethyl)- 1 H-imidazol-5 -yl)acetyl]-4-( 1naphthoyl)piperazine; 2(S)-Butyl- 1- -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)ethyl]-4-( 1naphthoyl)piperazine; 80 WO 98/44797 WO 9844797PCTIUS98/06823 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; 1 2 -Amino-3-(2-benzyloxyphenyl)propyl)>2(S)-buty..4-( 1naphthoyl)piperazine; 1 -(2-Amino-3-(2-hydroxypheny)propy)-2(S )-butyl-4-( 1naphthoyl)piperazine; 1- (4-imidazolyl)propyl] -2(S )-butyl-4-( 1 -naphthoyl)-piperazine; 2(S )-n-Butyl-4-(2 ,3-dimethyiphenyl -1-(4-imidazolylmethyl)- 2(S)-n-Butyl- 1- [1 4 -cyanobenzyl)imidazo-5-ylmethyly4(2,3-.
-one; 1- [1-(4-Cyanobenzyl)imidazol-5 -ylmethyl] (2,3-dimethyiphenyl)- 2(S 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1 1-(1 ylmethyl] -piperazine; 2(S)-n-Butyl-4-( 1 -naplithoyl)- 1- [1-(2-naphthylmethyl)imidazol-5ylmethyl]-piperazine; 2(S)-n-Butyl- I1 4 -cyanobenzyl)imidazol-5-ylmethyl>4-( 1naphthoyl)piperazine; 2(S)-n-B utyl- 1-[l 4 -methoxybenzyl)imidazol-5-ylmethyl]4( 1naphthoyl)piperazine; 81 WO 98/44797 WO 9844797PCT/US98/06823 2(S)-n-Butyl- 1-[i1 -(3-methyl-2-butenyl)imidazol-5-yimethyl]-4-( 1naphthoyl)piperazine; 2(S)-n-Butyl- 1I-[1I -(4-fluorobenzyi)imidazol-5-ylmethyl]-4-( 1naphthoyl)piperazine; 2(S)-n-Butyl- 1- [I -(4-chlor obenzyl)imidazol-5-ylmethyl]-4-( 1naphthoyl)piperazine; 1- [1I 4 -Bromobenzyl)imidazol-5-yimethyi-2(S)nbuty-4-( 1naphthoyl)piperazine; 2(S )-n-Butyl-4-( 1 -naphthoyl)- 1 [1I -(4-trifluoromethylbenzyl)imidazol- -ylmethyl] -pip erazine; 2(S)-n-Butyl- 1-[rI -(4-methylbenzyl)imidazol-5-ylmethyl].4.( 1naphthoyl)-piperazine; 2(S)-n-Butyl- 1- (3-methylbenzyl)imidazol-5-ylmethyl] 1naphthoyl)-piperazine; 1I- (4-Phenylbenzyl)imidazol-5-ylmethyi] -2(S)-n-butyl-4-( 1naphthoyl)-piperazine; 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1 1 piperazine; 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1 1 ylmethyllpiperazine; 1- I -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] acetyl)} -2(S)-n-butyl-4-( 1naphthoyl)piperazine; I 3-Chlorophenyl)-4- [1 4 -cyanobenzyl)-5-imidazoiylmethyl]-5- [2- (methanesulfonyl)ethyl]-2-piperazinone; 82 WO 98/44797 PTU9/62 PCTIUS98/06823 (S 1 -Chiorophenyl 4 -cyanobenzy)-5-imidazoylmethyl]j-5- [2- (ethanesulfonyl)ethyl]-2-piperazinone; 2 5 -Chlorophenyl)-4- [1-(4-cyanobenzyl)-5 -imidazolylmethyl] [2- (ethanesulfonyl)methyl]-2-piperazinone; 1-(3 -Chlorophenyl)-4- (4-cyanobenzyl)- 5-imidazolylmethyl]
[N-
ethyl-2-acetamido] -2-piperazinone; (±)-5-(2-Butynyl)- 1 -(3-chlorophenyl)-4-[ 1 imidazolylmethyl] -2-piperazinone; 1- (3-Chlorophenyl)-4- [1-(4-cyanobenzyl)- 5-imidazolylmethyl]-2piperazinone; 5(S)-iButyl-4- 4 -cyanobenzyl-2-methyl)-5-imidazolylmethyly. 1 dimethylphenyl)-piperazin-2.one; 4- 2 -(4-Cyanophenyl)-2-propyl)-s -imidazolylmethyl] -1 (S 2 -methylsulfonylethyl)piperazin-2-one; (S)-n-Butyl-4- [1 4 -cyanobenzyl)-5-imidazolylmethyl] (2methylphenyl)piperazin-2-one; 4- 4 -Cyanobenzy1)-5-imidazolylmethyl]ys(Sy.(2-fluoroethyl)- 1 chlorophenyl)piperazin-2-one; 4- 3 4 -Cyanobenzyl)pyridin-4-yl]- 1 -(3-chlorophenyl)-5 (S methylsulfonylethyl)-piperazin2one; 4- [5-(4-Cyanobenzyl)- 1-imidazolylethyl]- -chlorophenyl)piperazin- 2 -one; [2(R)-Amino-3 -mercaptolpropylamino-3 (S)-methyl] pentyloxy- 3 -phenylpropionyl-homoserine lactone, 83 WO 98/44797 PCT/US98/l6823 [2(R)-Amino-3-mercapto] propylamino-3(S)methyl] pentyloxy-3-phenylpropionyl-homoserine, 2 (R)-Amino-3-mercaptolpropylamino-3 methyllpentyloxy-2-methy 1-3 -phenyipropionyl-homoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-.3 methyl]pentyloxy-2-methyl- 3-phenyipropionyl-homoserine, [2(R)-Amino-3 -mercapto)propylamino-3 (S methyllpentyloxy-4-pentenoyl-homoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-3 (8)-methyl] pentyloxy-4-pentenoyl-homoserine, [2(R)-Amino-3 -mercapto] propylamino-3 methyllpentyloxypentanoyl-homoserine lactone, 2 (R)-Amino-3-mercapto]propylaniino-3(S)methyl] pentyloxypentanoyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3(S).methyl]5-.
pentyloxy-4-methylpentanoyl-homoserine lactone, [2(R)-Amino-3-mercapto] propylamino- methyllpentyloxy-4-methylpentanoyl.homoserine, 2 (R)-Amino-3 -mercaptolpropylamino-3 methyllpentyloxy-3-methylbutanoyl-homoserine lactone, [2(R)-Amino-3-mercapto] propylamino-3 methyllpentyloxy-3-methylbutanoyl-homoserine, 84 WO 98/44797 WO 9844797PCT/US98/06823 [2(R)-Amino-3 -mercapto] propylamino-3 methyl] pentyloxy- 3-phenylbutanoyl-homoserine I actone, 2 (R)-Amino-3-mercaptoipropylamino-3 (S)-methyl]pentyloxy-3-phenylbutanoyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 methyllpentylthio- 2 -methyl-3-phenylpropionyl-homoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-3(S)methyl] pentylthio-2-methyl-3-phenylpropionyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 methyllpentylsulfonyl-2-methyl- 3-phenyipropionyl-homoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-.3(S)-methyl] pentylsulfonyl-2-methyl-3 -phenyipropionyl-homoserine, 2 (R)-Amino-3-mercapto]propylaniino-3(S)-methyl].
pentyloxy-3-phenylpropionyl-methionine methyl ester, [2(R)-Amino-3-mercapto] propylamino-3 methyllpentyloxy-3-phenylpropionyl.methionine, [2(R)-Amino-3-mercapto] propylamino- methyllpentyloxy-3-phenylpropionyl.methionine sulfone methyl ester (Compound 2 (R)-Amino-3-mercapto]propylamino-3(5)methyl]pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 6), [2(R)-Amino-3 -mercapto]propylamino-3 (S)-methylpentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, 85 WO 98/44797 PCT/US98/06823 2- 2 (R)-Amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy- 3 -naphth-2-yl-propionyt-rnethionine sulfone methyl ester, 2- (S [2(R)-Amino-3 -mercapto]propylamino-3 (S )-methyl] pentyloxy- 3 -naphth-2-yl-propionyl-methionine sulfone, 2 (R)-Amino-3-mercaptolpropylamino-3(5)methyl]pentyloxy-3-naphth. 1 -yl-propionyl-methionine sulfone methyl ester, 2 (R)-Amino-3-mercapto]propylamino-3(5)methyllpentyloxy-3-naphth- 1-yl-propionyl-methionine sulfone, 2 (R)-Amino-3-mercapto]propylamino-3(S)methyllpentyloxy-3-methybutanoyl-methionine methyl ester.
2 (R)-Amino-3-mercaptolpropylamino-3(S..
methyllpentyloxy-3-methybutanoyl.methionine, Disulphide of 2 (R)-Amino-3-mercaptolpropylamino-.
3 (S)methyllpentyloxy-3-phenylpropionyl.homoserine lactone, Disulphide of 2 (R)-Amino-3-mercaptolpropylamino. 3(S)methyl]pentyloxy-3-phenylpropionyl.homoserine, Disulphide of 2 (R)-Amino-3--mercapto] propylamino- 3 (S)methyl]pentyloxy-3-methylbutanoyl.methionine methyl ester l-( 4 -Biphenylmethyl)-5-(4-cyanobenzyl)imidazole l-( 4 -Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole 86 WO 98/44797 PTU9/62 PCTIUS98/06823 1- (2'-Trifluoromethyl-4-biphenylmethyl)-5- 4 -cyanobenzyl)imidazole 1 iphenylethyl)-5-(4-cyanobenzyl)imidazole 1- (2'-Bromo-4-biphenylmethyl)-5- 4 -cyanobenzyl)imidazole 1 2 -Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1- 2 -Trifluoromethoxy-4-biphenylmethyl)-5(4-.cyanobenzyl) imidazole 1 '-dichloro)-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole 1- (2'-Methoxy-4-biphenylmethyl)-s -(4-cyanobenzyl) imidazole 1- (2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 2 -Chloro-4-biphenylmethyl).-5-(4-cyanobenzyl) imidazole 1 3 -Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 1,5 is-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 87 WO 98/44797 WO 9844797PCT/US98/06823 1 -Trifluoromethyl-4-biphenylmethyl).5-(4-cyanobenzyl)-4methyl imidazole 1- 4 -Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole -(4-Cyanophenyloxy)- 1 2 '-methyl-4-biphenylmethyl)-imidazole 5- (4-Biphenyloxy)- 1-(4-cyanobenzyl)-imidazole 5-(2'-Methyl-4-biphenoxy)- 1-( 4 -cyanobenzyl)-imidazole '-dichloro)biphenylmethyl)-1- (4-cyanobenzyl)imidazole 1 -(4'-biphenylmethyl)-5-(1- S)-acetoxy-l1-(4cyanophenyl)methylimidazole 1 iphenylmethyl)-5-( 1-(R,S )-hydroxy-l1-(4-cyanophenyl) methylimidazole 1 -(4-Biphenylmethyl)-5-( 1 )-amino- 1 -(4-cyanophenyl) methylimidazole 1 -(4-biphenylmethyl)-5-( 1 -(R,S)-methoxy- 1 -(4-cyanophenyl)methylimidazole 1 -(4-Cyanobenzyl)-5-( 1-hydroxy-l1-(4-biphenyl)-methyl imidazole 88 WO 98/44797 PCT/US98/06823 1- (4-Cyanobenzyl)-5 -oxo-1- (4-biphenyl)-methyl imidazole 1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- 1 -(3-fluoro-4-biphenyl)-methyl)imidazole 1 -(4-Cyanobenzyl)-5- (1 -hydroxy- 1. -(3-biphenyl)methyl-imidazole 1,1 '-Biphenyl]vinylene)- 1 4 -cyanobenzyl)irnidazole 1- 4 -cyanobenzyl)-5-imidazolylmethyl)amino]-3.methoxy-4 phenylbenzene 1- (4-B iphenylmethyl)-5- 4 -bromophenyloxy)-imidazole 1 [Pyrid- 2 -yl]phenylmethy1)-5-(4-cyanobenzy1)imidazole 1 -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole 1- [Pyrid- 2 -yllpyrid-5-ylmethyl)>5-(4-.cyanobenzyl)imidazole N- I 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl -5-(pyrid-2-yl)-2amino-pyrimidine N, N-bis(4-Imidazolemethyl)amino-.3-[(3 -carboxyphenyl)oxy]benzene N,N-bis(4-Imidazolemethyl)amino-.4-[(3 -carboxyphenyl)oxy]benzene NN-bis(4-Imidazolemethyl)amino-3- -carbomethoxyphenyl)oxy]benzene NN-bis(4-Imidazolemethyl)amino-4. -carbomethoxyphenyl)oxy]benzene 89 WO 98/44797 WO 9844797PCTIUS98/06823 N- 4 -Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl.3- carboxyphenyl)oxy]benzene N- 4 -Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl.3- carbomethoxyphenyl)oxylbenzene
N-(
4 -Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene N- 4 -Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzene N- (4-Jrnidazolemethyl)-N- 4 -nitrobenzyl)amino-4-(phenylthio)benzene N-Butyl-N- I1 4 -cyanobenzyl)-5-imidazolemethyl] amino-4- (phenoxy)benzene N- [1 4 -Cyanobenzyl)-5-imidazolemethyl] amino-4- (phenoxy)benzene N-(4-Imidazolemethyl)amino-3- 3 -carboxyphenyl)oxy]benzene 4-1{3- 4 -(-2-Oxo-2-H-pyridin- 1 -yl)benzyl] -3-H-imidazol-4ylmethyl]benzonitrile 3- [4-3 -Methyl-2-oxo-2-H-pyridin- 1-yl)benzyl]-3-H-imidazol-4ylmethyllbenzonitrile (-2-Oxo-piperidin- 1 -yl)benzyl] -3 -H-imidazol-4ylmethyllbenzonitrile 4- [3-Methyl-4-(2-oxopiperidin- 1 -yl)-benzyl]-3-H-imidizol-4ylmethyl I -benzonitrile [4-(2-Oxo-pyrrolidin- 1 -yl)-benzyl] -3 H-imidizol-4-ylmethyl
I
benzonitrile 90 WO 98/44797 PCTIUS98/06823 4-13- -Methyl-2-oxo-2-H-pyrazin- 1 -yl)-benzyl- 3-H-imidizol-4ylmethyl -benzonitrile 4-13- [2-Methoxy-4- (2-oxo-2-H-pyridin- 1 -yl)-benzyl] -3-H-imidizol-4ylmethyl I -benzonitrile 4-11- (5-Chloro-2-oxo-2H-pyridin- 1 -yl)-benzyl]- 1 H-pyrrol-2ylmethyl I -benzonitrile 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)- 1 H-pyrrol-2ylmethyl] -benzonitrile 4 1 -phenyl- 1 ,2-dihydropyridin-4-ylmethyl)3H.imidazol.4ylmethyl]benzonitrile 4-1(3- -Chloro-phenyl)-2-oxo- 1 ,2-dihydropyridin-4-ylmethyl -3 Himidazol-4-ylmethyl Ibenzonitrile or a pharmaceutically acceptable salt, disulfide or optical isomer thereof.
Compounds which are described as inhibitors of farnesylprotein transferase and may therefore useful in the present invention, 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; European Pat. Publ. 0 618 221 European Pat. Publ. 0 675 112; WO 95/08542; WO 95/11917; WO 95/126 12; WO 95/1 2572; 91 WO 98/44797 PCT/US98/06823 WO 95/10514; WO 95/10515; WO 95/10516; WO 95/24612; WO 95/34535; WO 96/22278; WO 96/24611; WO 96/24612; WO 96/05168; WO 96/05169; WO 96/00736 and U.S. Pat. No. 5,571,792 granted on November 1996; WO 96/17861; WO 96/33159; WO 96/34850; WO 96/34851; WO 96/30017; WO 96/30018; WO 96/30362; WO 96/30363; WO 96/31111; WO 96/31477; WO 96/31478; WO 96/31501; and 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, 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; 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; U. S. Pat. No. 5,504,212 granted on April 2, 1996; U. S. Pat. No. 5,439,918 granted on August 8, 1995; 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; U. S. Pat. No. 5,576,293 granted on November 19, 1996 U. S. Pat. No. 5,468,733 granted on November 21, 1995 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 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, 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; 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 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 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; 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, 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; 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 January 21, 1997; 94 WO 98/44797 p USSN 60/010,860 filed on January 30, 1996; USSN 08/ January 21, 1997; 'CT/US98/06823 filed on USSN 60/011,081 January 21, 1997; USSN 60/010,798 January 21, 1997; USSN 60/014,587 USSN 60/014,589 USSN 60/014,592 USSN 60/014,593 USSN 60/014,594 USSN 60/014,668 USSN 60/014,775 USSN 60/014,776 USSN 60/014,777 USSN 60/014,791 USSN 60/014,792 USSN 60/014,793 filed on January 30, 1996; USSN 08/ filed on January 30, 1996; USSN 08/ filed on filed on filed filed filed filed filed filed filed filed filed filed filed filed on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, on April 3, 1996; 1996; 1996; 1996; 1996; 1996; 1996; 1996; 1996; 1996; 1996; 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; 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; USSN 60/022,341 filed on July 24, 1996; USSN 60/022,342 filed on July 24, 1996; 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; USSN 60/022,587 filed on July 24, 1996; USSN 60/022,647 filed on July 24, 1996; 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; 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.
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 methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, 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 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified alkoxy), or any number within this range methoxy, ethoxy, etc.).
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, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino Cl-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 Cl-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl or alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, Cl-6 alkylamino, C1-6 alkylamino Cl-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, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl or alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, 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.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent aryl CO-8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms shall refer independently to the number of carbon atoms in an alkyl or 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 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 aryl CO-8 alkyl), the group modified by CO is not present in 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 The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "oxy" means an oxygen atom. The term "thio" means a sulfur atom. The term "oxo" shall mean =0.
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 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 attachment. For example, a Cl-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to 0 I I alkyl-NH-C-C 1 5 alkyl.
With respect to the compounds of formulas II-a through II-n the following definitions apply: 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 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 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 carbon to carbon double bond is present, and up to four nonaromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2butenyl, 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 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 carboncarbon triple bonds may be present. Preferred alkynyl groups 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 phenyl, substituted phenyl and like groups as well as rings which are fused, 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 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 hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. The heteroaryl group is optionally substituted with up to three groups.
Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydrophthalidyl and saccharinyl, as defined below.
With regard to the farnesyl transferase inhibitors, the term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7membered 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, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, 101 WO 98/44797 PTU9/62 PCT/IJS98/06823 benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isocliromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2 -oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, 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, piperidyl, pyridyl and pyrrolidinyl.
With regard to the famnesyl 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 F, Cl, Br, CF3, N112, N(C1-C6 alkYl)2, N02, CN, (Cl-C6 alkyl)O-, OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Ci -C6 alkyl)C(O)-, (Ci -C6 alkyl)OC(O)-, N3,(Cl1-C6 alkyl)OC(O)NH- and CI -C20 alkyl.
In the present method, amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: Alanine Ala
A
Arginine Arg
R
Asparagine Asn
N
Aspartic acid Asp
D
Asparagine or Aspartic acid Asx
B
Cysteine Cys
C
Glutamine Gin
Q
102 WO 98/44797 PCT/US98/06823 Glutamic acid Glu
E
Glutamine or Glutamic acid Glx
Z
Glycine Gly
G
Histidine His
H
Isoleucine Ile
I
Leucine Leu
L
Lysine Lys
K
Methionine Met
M
Phenylalanine Phe
F
Proline Pro
P
Serine Ser
S
Threonine Thr
T
Tryptophan Trp
W
Tyrosine Tyr
Y
Valine Val
V
The compounds used in the present method may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless otherwise specified, named amino acids are understood to have the natural "L" stereoconfiguration With respect to the farnesyl-protein transferase inhibitors of the formulas II-d and II-f,the substituent illustrated by the structure R6a-e is a simplified representation of a phenyl ring having five substituents (hydrogens and/or non-hydrogens) and may also be represented by the structure 103 WO 98/44797 PCT/US98/06823
R
6
R
6 d With respect to the farnesyl-protein transferase inhibitors of the formulas II-d and II-f, the moiety described as
R
6a -e where 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-CH-, -(CH2)4- and -(CH2)4- includes the following structures: NN N1 "f N xCO IVOO It is understood that such fused ring moieties may be further substituted by the remaining R6a, 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 9.- '9 104- WO 98/44797 WO 9844797PCT/1US98/06823 represent an aromatic 6-membered heterocyclic ring and includes the following ring systems: R6 6
R
6 N R 6
R
6 N R 6
R
6 N N- N
R
6 4\ R 6 Y" NR 6
RA
6 R6
R
6 0 H N N H R 6
N,
A
6 0 HN NH wherein R 6 is as defined hereinabove.
With respect to the farnesyl-protein transferase inhibitors of the formulas 11-e and 11-g, the moieties designated by the following structures //f-f f /f f/ /g where any two of R 6 on adjacent carbon atoms are combined to form a diradical. selected from -CH=CH-CH=CH-, -CH=CFI-CH-, -(CH2)4- and -(CH2)4- include, but are not limited to the following structures: 105 WO 98/44797 PCT/US98/06823
N
Xi -Y 1^
N
NN N^
J~
N
Lv
N
I N) f N
^N^
NN
N
Nv~ 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 of the formulas II-f and II-g, the moiety designated by the following structure 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
A
N N N HN NH wherein it is understood that one of the ring carbon atoms is substituted with
R
6 ae g or 9 respectively.
With respect to the farnesyl-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 a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and 0, 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 PCTIUS98/06823 S1 SX 3- 0 >tN~ NH O
NH
O
O
0 0." \NyNH 0
O
0 0NN \N ~NH 0
O
O=S
0 O 'z 0 N ril 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 of the formula II-m, the moiety described as R6a-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: 108 WO 98/44797 PCT/US98/06823
O^N
o, N M, 0
N
°Vr 4 0 0N 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 hereinabove.
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 0, and wherein Y is attached to Q through a carbon atom and includes the following ring systems: 109 WO 98/44797 PTU9/62 PCT[US98/06823
N
\fN
N>
N
N
0 0
NH
S
H
N
'0
N
s rss'
S
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 a nitrogen atom through which Q is attached to Y and 0-2 additional heteroatoms selected from N, S and 0, 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: 0
O
N R1
H
-I
N
~~O 0
O
0 N- S
O
S
0O 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 6- or 7-membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and 0, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
N
0
'I
N'-
N
-,N
0C
N
N N
S
I
N~ N 0
N
112 WO 98/44797 PCT[US98/06823
IN
S
H N
NH
H
N
IN
N
?:NH
H
NN
N
0 ,iS"H
S
HN
With respect to the farnesyl-protein transferase inhibitors of the formula II-n, the moiety described as
R
6 a-e where any two of R 6 a, 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: I N N3
NC
113 WO 98/44797 PCT/US98/06823 Jw1
N,
N.\
ri s 1 N It is understood that such fused ring moieties may be further substituted by the remaining R6a, R6b, R 6 c, R6d and/or R 6 e as defined 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: In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such include, but are not limited to: heteroatom-containing cyclic moieties 0- S4 Oj
S
S
"I
0 's H 0
H^
COR
COR'
0 114 WO 98/44797 PCTIUS98/06823 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: The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is intended that the definition of any substituent or variable R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, N(RO1)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 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 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 av33 antagonist may be demonstrated by the methodology known in the art, such as the assays described in W095/32710, 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 works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie "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 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 (3acetylamino)alanine residue at the C-terminus, use of the commercially available Na-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: 116 WO 98/44797 PCT/US98/06823 Boc
DBU
DMAP
DME
DMF
EDC
HOBT
Et3N EtOAc
FAB
HOOBT
HPLC
MCPBA
MsCI NaHMDS Py
TFA
THF
Acetic anhydride; t-Butoxycarbonyl; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4-Dimethylaminopyridine; 1,2-Dimethoxyethane; Dimethylformamide; 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride; 1-Hydroxybenzotriazole hydrate; Triethylamine; Ethyl acetate; Fast atom bombardment; 3-Hydroxy- 1,2,2-benzotriazin-4(3H)-one; High-performance liquid chromatography; m-Chloroperoxybenzoic acid; Methanesulfonyl chloride; Sodium bis(trimethylsilyl)amide; Pyridine; Trifluoroacetic acid; 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 pharmaceutical chemist. 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 flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
Pharmaceutically acceptable salts include conventional non-toxic salts or quarternary ammonium salts formed, from 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, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods.
Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired saltforming inorganic or organic acid or base, in a suitable solvent or solvent combination.
The farnesyl transferase inhibitors of formula (II-a) 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 however their point of attachment to the ring is illustrative only and is not meant to be limiting.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
Synopsis of Schemes 1-22: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for 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 dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, 10% palladium on carbon at 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 deprotection as previously described gives the intermediate VIII (Scheme 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 the appropriate amino acid (Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride. The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to 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-4imidazolyl-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give 119 WO 98/44797 PCT/US98/06823 products such as XVI (Scheme 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 acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
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 to unmask the hydroxyl group (Schemes 6, 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 (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme or tertiary amines.
The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme Treating XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, 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 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 is the Boc-protected P-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII where n=l 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 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 hydrochloride (XLVI) in refluxing n -butanol to furnish compounds XLVII.
The resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
can be prepared as shown in Scheme 12. Reductive amination of Boc-protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L.
This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions; ring closure is effected with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give LI. The carbamate protecting group is removed under acidic conditions such as 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 2aminoglycinal 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 I 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 in Scheme 14. Following deprotection with trifluoroacetic acid, the Nbenzyl piperazine V can be acylated with an aryl carboxylic acid. The resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
Reaction Scheme 15 provides an 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 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 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 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 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 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 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 for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
123 WO 98/44797 PTU9/62 PCTIUS98/06823 SCHEME 1 0 0 yOH 0 R b PhCH 2
NHCHCO
2
C
2
H
DCC, CH 2
CI
2 o0 NTyN 0 0 2
C
2
H
H 0 R b 11 1) HOI, CH 2
CI
2 2) NaHCO 3 Ra0 -4
LAH
HN Nb THE, reflux 0 Rb/ HN N- Rb
BOC
2 0
CH
2 01 2 10% Pd/Co
H
2
CH
3 0H Rb N
VI-,\
124 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 2 BocN NH VI Rb BocN N Rb '0-HOI, HOBT
)MF
HOI, EtOAc R b Vill 125 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 3
R\/
HCI N N Boc NH 1 I Ix Boc NH CHO NaBH(OAc)3
EI
3 N CICH 2
CH
2
CI
Boc NH cN N- NHBoc R b
CF
3 00 2
H
CH
2 C1 2
NH
2 N N
N
NH
2 Rb
BOC
2 0
CH
2
CI
2 c~
CHO
NaBH (OAc)3 Et 3 N CICH 2
CH
2
CI
NH
2 Rb 126 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 3 (continued) BocNH N N- NH Rb
NH
2 N Nq NH Rb N N -b NfF Rb0 I
XV
CF
3 00 2 H, 0H 2 C1 2 NaHCO 3
NC
AgON L 127 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 4 HCI N N b Rb Vill NaBH(OAC) 3 Et 3 N ClCH 2
CH
2
CI
(CH
2 )nCHO
N
xvi 1) Ar CH 2 X, CH 3
CN
2) CF 3
CO
2 H, CH- 2
CI
2
(C
2
H
5 3 SiH
CF
3 00 2 H, CH- 2
CI
2
(C
2
H
5 3 SiH
N'
H
XVII
Ra
XVIII
128 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME N-
CH
2 00 2
H
H
(C
6
H
5 3 CBr
(C
2
H
5 3
N
DMF
CH
3 0H
HCI
-HOI
1) ArCH 2 X CH 3
CN
ref lux 2) CH 3 OH, reflux
XXI
Ar- -0HqC0qCH 3
N
XXII
2.5N HClaq 55 0
C
Ar' N-CH 2 00 2
H
N
N xl 129 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 5 (continued) Ar'\ CH 2 00 2
H
N
xxiII HCI-HN
N
Rb Vill EDC -HOI HOBt
DMF
HOI
Ra -N \N4- Rb
XXIV
Ar" rN 130 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 6
R\/
HOI -N
N-P
Rb NaBH(OAc) 3 Et 3 N CICH 2
CHC
BnOI BocNH
CHO
xxv BnO N N- NHBoc R b 20% Pd(OH) 2
H
2
CH
3 0H
CH
3 00 2
H
xxv'
R\/
H O NN NH~oc 'Rb xxvi"
CICOCOCI
DMSO
CH
2 01 2
(C
2
H
5 3
N
131 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 6 (CONTINUED) 0 N N- HF NHoc R 1. R'MgX (0 2
H
5 2 0 2. TEA,
CH
2 01 2 xxviII HO
N\_N
Rl NH 2
R
XXIX
132 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 7 HO N N- NHi oc Rb I XI HO N N4
NH
2 Rb
XXX
CF
3 00 2
H
CH
2
CI
2
ROCHO
NaBH(OAc) 3
CICH
2
CH
2
CI
0 NH R b
R'CH
2
XXXI
133 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 8 HO N N4- \K<o NHBoc Rb H H NaH, DMF 000 xxviI N N4 N Rb
H
XXXII
R'SH
(C
2
H
5 3
NA
CH
3 0HA R'S
ND
NH
2 Rb
XXXIII
134 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 9
HO
H
2 N C0 2
H
1) Boc 2 O, K 2 00 3
THF-H
2 0 2) CH 2
N
2 EtOAc oN BocNH 0 2
CH
3
XXXIV
XXXV
LIAIH
4
THE
0-200C
HO
BocNH CH 2 0H
R'CH
2
X
CS
2
CO
3
DMF
XXXVI
R-CH
2 0 BocNH CH 2 0H
XXXVII
pyridine
-SO
3
DMSO
(C
2
H
5 3 N BcH C 0
C
XXXVIII
135 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 9 (continued)
R'CH
2 0 BocNH CHO
XXXVIII
R'CH-
2 0Oq HCI -N N- Rb Vill NaBH(OAc) 3 C ICH 2
GH
2
CI
1) 20% Pd(OH) 2
CH
3 OH, CH 3
GO
2
H
2) HCt, EtOAc
HO
1 N N- XXXIX HCI ETOAc
NH
2 R b
XLI
-136 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME C0 2
R
HN N 0
XLII
1) LAH, Et 2
O
2) BOC 2 0
HO
R 6 1 0( NaH, DMF 0
XLIII
SCHEME 11
XLIV
ArNH 2
XLV
CI 2 NH .H
XLVI
n butanol ref lux Ra R b ArN NH -HCI a R b
XLVII
137 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 12 H 0 LAH, Et 2
O
0
CH
3
NHOCH
3
-HCI
EDC. HOI, HOBT DMF, Et 3 N, pH 7 0 Ra 0 ,yH H 0
XLIX
.0
N
H
XL VIII 'ir 0
N(CH
3 )00H 3 ArCH 2
NH
2 NaBH(OAc) 3
CICH
2
CH
2
CI
pH 6 0 0 N JNHCH 2 Ar 1) BrGH 2 COBr EtOAc, H 2 0, NaHCO 3 2) NaH, THE, DMF Ra 0 -N *0 \-4 0 1) TEA,
CH
2
CI
2 Ar HN
N-\
0 138 ,I WO098/44797 PCT[US98/06823 SCHEME 13 ArCHO
ULI
NH
2
CH
2 CH(00 2
H
5 2 NaBH
(OAC)
3 Ar CH 2
NHCH
2 OH(oO 2
H
5 2
LIV
0 Ra o N ,OH I H 0 EDO. HCt, HOBT DMF, Et 3 N, pH 7 ,0 R r Ar o IyN CH(OC 2
H
5 2 H 0
LV
6N HCI
THF
Ra 0 NN4 Ar
LVI
H
2 1 O%Pd/C
CH
3 0H Ra 0 N
N-
Ar
LVII
139 0 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 14 T-< 1) CF 3 C0 2 H, CH 2
CI
2 2) NaHCO 3 ArCO 2
H
EDO'-
HOI
HOBT, DMF
LVIII
Rb N N-< Ar
LIX
r-< R b 10% Pd/ C
H
2
CH
3 0H
HN
0 Ar 140 WO 98/44797 PCTIUS98/06823 SCHEME BocNH C0 2
H
PhCH 2
NHCH
2 00 2
C
2
H
DCC,
CH
2 C1 2 u BocNH N.-C 2
C
2
H
0 LXII a) TEA,
CH
2
CI
2 b) NaHCO 3
(CH
3 3
AI
CHCI
3
LXIII
Nb LiAIH 4
THF
LXIV
BOC
2 0
CH
2
CI
2 HN
N-
LXV
H
2 Pd/C
CH
3 0H BocN N
LXVI
141 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 15 (continued) Codi cO6 NaHCO 3 EtOAc BocN NH
LXVII
U
0 BooN N LX VIII a) TEA, 0H 2 C1 2 0
NN
N
CPh 3
LA
b) NaBH(OAc) 3 C(=0)H
N
N
CPh 3 TFA 0H 2 01 2 (0 2
H
5 3 SiH
LXX
142 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 16 BoNH CH ArNH 2 BoN N H BocNH CHO NaBH(OAc) 3 BoN r
CICH
2
CH
2
CI
XLIX
LXXI
0 C I
C
EtOAc
H
2 0 NaHC0 3
R
BocNH N-r
LXXII
NaH
DMF
R
BocN NAr
HCI
EtOAc
LXXIII
143 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 16 (continued)
R
HCI-HN N-Ar
LXXIV
C(Ph) 3
R
N N-Ar
N
(Ph) 3
C
NaBH(OAc) 3
CICH
2
CH
2
CI
pH 5-6
LXXV
ArCH 2
X
CH
3
CN
(Ph) 30
R
N N-Ar 0 xG LXX VI MeOH or
R
N \i
N
TFA, 0H 2 01
(C
2
H
5 3 SiH
LXXVII
144 WO 98/44797 WO 9844797PCT[US98/o6823 SCHEME 17 sub
H
2
N*
HCI 0 1. Boc 2 O, i-Pr 2 EtN sub Boc-N*0
OH
2. DIBAL LXXIX OH Ksub
H
ArNH 2 Bo I Nl Ar NaBH(OAc) 3 BoN
CICH
2
CH
2
CI
LXXX
0 ckI c EtOAc
H
2 0 NaHCO 3 HO sub BocNH N-Ar CI 0
LXXXI
CS
2
CO
3
DMF
HO sub BocN N-Ar
LXXXII
145 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 17continued) HO sub BocN N-Ar 0 1 (f 1. MsCI, iPr 2 NEt 2. NaSEt,/DMF EIS sub BocN N-Ar 0
LXXXII
001)2, Et.
3
N
Viso 2. NaCIO 2 t-BuOH 2-Me-2-butene NaH 2
PO
4 HO sub BocN N-Ar
LXXXIII
LXXXIV
146 i WO 98/44797 WO 9844797PCT/1JS98/06823 SCHEME 18 1. KOtBu, THE
R
2
X
2. 5% aqueous HCI
CO
2 Et Ph LXXX V
CO
2 Et
H
2
N
HCI
1. BOC 2 O, NaHCO 3 2. LiAIH 4 Et 2 0
CO
2
H
BocHN LXXX VI 147 WO 98/44797 WO 9844797PCT/US98/06823 REACTION SCHEME 19
OH
3
H
2
NNT
1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ C0 2
CH
3 Br"
N
MgCI ZnCI 2 ,NiCI 2 (Ph 3
P)
2 NaBH 4 (excess)
SO
3 'Py, Et 3
N
DMSO
R 6
-~CHO
CUN'
148 WO 98/44797 WO 9844797PCTIUS98/06823 REACTION SCHEME Br C 0 2
CH
3 1. EtO(CO)CI 2
R
6 Zn, CuON 3. S, xylene, heat C0 2
CH
3 NaBH 4 (excess) R 6 N SO 3 -Py, Et 3
N
CH
2 0H DMSO
N
.CHO
Brn 00 2 0H 3
U~
N ZnCI 2 NiCI 2 (Ph.
3 p) 2
.CO
2
CH
3 NaBH 4 (excess)
SO
3 'Py, Et 3
N
,CH
2 0H
,CHO
DMSO
149 WO 98/44797 WO 9844797PCTIUS98/06823 REACTION SCHEME 21 B~r
N
1. LDA, 002 2. MeOH, H+ C0 2
CH
3 Br
NI
MgCI ZnCI 2 NiC1 2 (Ph 3
P)
2 C.0 2
CH
3 NaBH 4 (excess)
CH
2 OH SOTPy, Et 3
N
DMSO
150 WO 98/44797 PCT/US98/06823 REACTION SCHEME 22 N Br 1. LDA, CO2 2. (CH 3 3 SiCHN,
CO
2
CH
3 Br
R
6 R 6 C0 2
CH
3 Zn, NiCI2(Ph 3
P)
2 excess NaBH 4 R6H N/ CH2OH N I
SO
3 aPy, Et 3
N
DMSO
R
6 h N CHO The farnesyl transferase inhibitors of formula (II-d) can 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, R6c, 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 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 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 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 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 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 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 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 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 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 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.
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 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 incorporate a preferred imidazolyl moiety connected to the 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 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 Al(CRla2)nA 2 (CRla2)n linker is oxygen may be synthesized by 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 for the benzylimidazoles hereinabove.
Scheme 33 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, 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 second aryl moiety by Suzuki chemistry to provide the 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 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 (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 (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)r(R9 I
I
V A(CRla 2 )nA 2 (CRla 2 n (CRlb 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 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 (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 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 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 and the intermediates manipulated as illustrated above in Schemes 4-9.
155 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 23 HO
X
0
II
Pd(PPh 3 4 R6 LiAIH- 4 0.
HO4 RI 2 156 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 23 (continued) Tr
HO
Tr NiC1 2 (PPh 3 2
N
cx\ ZnBr R 8 IV
(CF
3
SO
2 2 0, -78-C NEtiPr 2 0H 2 01 2 -78OC-200C R 6 5500, CH 3 0H 157 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 24
R~
(HO)2 B Pd(PPh 3 4 R 6 R 2 NaBH 4 HOP4
R
2 SCHEME
B(OH)
2 R +~6 Br R 2 Pd(PPh 3 4 LiAIH 4 R6
HO
158 WO 98/44797 WO 9844797PCT/U S98/0 6823 SCHEME 26
B(OH)
2
R
3
SIO
Br Pd(P Ph 3 4 R 6
BU
4
NF
R
3 Sil
HO.
R
3 SiO Br (HO)A2 B
R
R 2 Pd(PPh 3 4 +6
R
3 SiOBU 4
NF
159 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 27 I BrZn R2 NiCI 2 (PPh 3 2
-R
6 YIC
BU
4
NF
HO,
Znl
R
3 SiO 4R 6 Br.
Ni1C1 2 (P Ph 3 2
BU
4
NF
160 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 28 NBS, AMBN 0014 Br, SCHEME 29 ii. MeOH ref lux Pd(PPh 3 4 n -,R 6 161 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME
H
N"
ix Nal, NaHCO 3 12
N
R 9 b Tr~l, NEt.
R 9 b NiC1 2 (P Ph 3 2 Z nB r OTf i. -78OC-200C ii. MeOH, reflux n R 6 162 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 31 0, 0. R8Br
N
I 0 55-CCH 3
CN
Nl' N ii. EtOH,80 0 C, NH 2
NH
2 0 XII
N
N
NH
2 acylation, sulfonylation 0
N
or R-alkylation
H
N
N N R8-
H
163 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 32 NC aOH NCv i, Na, MeOH ii. 120"C N3
H
NCN
xv Tr ~Trl, N t3
I
NC xv' NC i. -780C-20QC ii. MeOH reflux OTf xv' NC -0 164 WO 98/44797 WO 9844797PCTIUS98/06823 Br 1
\OH
SCHEME 33 i, Na, MeOH ii. 1200C -'3C'Br
"N
H
-0 R 2
XVI
Tr~l,
<N
0
R-
OTf I.-780C-200C ii. MeOH reflux
B(OH)
2 R6~7 DMF, Pd(PPh 3 4
K
3 P0 4 8000 xviI 165 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 34 EtMgBr Tr
OH
R8
XIX
XVIII
AC
2 O, PY
(CF
3 S0 2 2 0, -78-C NEtiPr 2
,CH
2
CI
2 LiOH SOC1 2
OH
166 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 34 (continued)
NH
3 MeOH
NH
2 OMe 167 WO 98/44797 PCT/US98/06823 SCHEME R 2
N
BrMg
ND
0 R 8 168 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 36 BrMg Boc
NHI
Boc NH CHO Boc, NH xx'
NH
2 r NHBoc 1. catalytic hydrogenation 2. 0F 3 0C0 2
H
CH
2
CI
2
BOC
2 0 0H 2
CI
2
NCHO
NaBH(OAC) 3 Et 3 N CICH 2
CH
2
CI
NH
2
XXII
NH
2
XXII'
169 WO 98/44797 PCT/US98/06823 SCHEME 36 (continued) BocNH
CF
3
CO
2 H, CH 2
C
2 NaHCO 3
XXIV
R
2 NH2 R6
NC
AgCN NH SR6 N N
XXV
The farnesyl transferase inhibitors of formula (II-e) can 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 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 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 is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995).
Synopsis of Schemes 37-52: 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 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 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.
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 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 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 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 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 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 arylheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4aminoalkylimidazole 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 arylheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the Al(CRla2)nA 2 (CRla2)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 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 4bromophenol, 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 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 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 R1 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 Thus a halogenated arylheteroaryl, such as 4-(3-pyridyl)bromobenzene, 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.
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.
Sammes, Oxford (1979).
Schemes 52 illustrates reactions wherein the moiety
(R
8 )r V A(CRla 2 )nA 2 (CRa 2 )n W (CRlb 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 Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid.
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 XXI can be deoxygenated by methods known in the art, such as a 174 k, 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 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.
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 R6
(HO)
2 B
N
HO j R 2 Pd(PPh 3 4 0
R
6 N LiAIH 4 HO N
R
2 0 II
N
HO
R
2
III
175 k. WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 37 (continued) N'C1 2 (PPh 3 2 Nl x rZnBr
R
8 N/
R
8
IV
>R 6 N3
HO
(CF
3
SO
2 2 0, -78-C NEtiPr 2 0H 2 C1 2 -78OC-200C N N R 5500, CH 3 0H R8 176 V WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 38 (HO)2
B,
4
N
6R R 2 NaBH 4 R
HO
SCHEME 39 Br Pd(PPh 3 4 R 6 LiAIH 4 N6
HOR
177 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME B(OH)2 R6
R
3 SiO Br R 2 Pd(PPh 3 4
N
BU
4
NF
R
3 SiO"
HO
BrR6
R
3 Sio
(HO)
2
B
R 2 Pd(PPh 3 4
NR
BU
4
NF
R
3 SiO 178 WO 98/44797 PCT/US98/06823 SCHEME 41
R
3 SiO
R
R
3 SiO
N
HO
ZnI
R
3 SiO
R
3 Sio~
N
R
BrZn NiCI 2 (PPh 3 2
FR
6
BU
4
NF
R 6R Br N iCI 2 (PPh 3 2
BU
4
NF
179 WO 98/44797 WO 9844797PCT/1JS98/06823 SCHEME 42 N6 KMnO 4
H
3 C R2 N6
RLUAIH
4
HO
N6
-R
6 HO- n..
180 V WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 43 00 2
CH
3
H
3 C 'INH 2
NH
3 EtOH
CONH
2
H
3 0 NH 2 00 ~-NCH3 (N (OH PoCd 3
H
2 S0 4 NaOH
CH
3 0-
B(OH)
2 Pd(OAc) 2 Nal/HI ~N "CH 3 N I
H
3 C N 0 H
N
Hf 52 NaBH 4 181 I- WO 98/44797 WO 9844797PCT[US98/06823 SCHEME 44 Hi. MeOH ref lux Pd(PPh 3 4 Vill 182 X. WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME
H
N
R
9 b
ON
Nal, NaHCO 3
N
TrO, NEt 3 R9b
N
T
Tr
N
Zn r r I~ f Oi. 78OC-200C ii. MeOH, reflux f- f N I R 7 6 183 WO 98/44797 WO 9844797PCT[US98/06823 SCHEME 46 0- 0 R 8 0 55 0 C.CHnCN EtOH,80 0 0, NH 2
NH
2 x~l
N
N N H 2
R
8 -i acylation, sull or alkylation
N
~onylation
N
R
8 -j\
N
N
R
8
N
N
R
8 -j\ fZ1 f R 6 tz f
I
184 WO 98/44797 WO 9844797PCTIUJS98/06823 SCHEME 47 NC .aOH NCv i, Na, MeOH ii. 1200C KN
N
H
NCN
NC X0 Tr Tr~l, NEt 3 N
NC
XVI
Tr
NC
i. -780C-200C ii. MeOH ref lux OTf
XVI
f NC- 1- 185 k. WO 98/44797 WO 9844797PCTIUS98/06823 t. SCHEME 48 B /\OH Tr~l, Nt i, Na, MeOH ii. 1200 -130' Bi
"N
H
0 R 2
XVI
OTf i. -78 0 C-2 0
C
ii. MeOH reflux B(0
H)
2 f f- DMF, Pd(PPh 3 4
K
3 P0 4 8000
XVII
fI 0 186 k. WO 98/44797 W098/4797PCTIUS98/06823 SCHEME 49 EtMgBr
PIN
I
XVIII
XIX
AC
2 O, py (0F 3 S0 2 2 0, -780C NEtiPr 2
,CH
2
CI
2 f
R
UOcIH OAc
XX
OH
187 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 49 (continued)
NN
N N 3 MeOH 7- R2 c
NH
2 R6 f OMe 188 k, WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME BuLi -1 00 0
C
N
N
0 SCHEME 51 R2 0
OH
3 Br Br
HCONH
2 189 V WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 52 Li
N
Boc
NHI
Boo NH CHO Boo NH xx' f- R6 f 1 catalytic hydrogenation 2. CF 3 00 2
H
CH
2
CI
2 B0C20
CH
2
CI
2
CHO
NaBH(OAC) 3 Et 3 N CICH 2
CH
2
CI
NH
2
XXII
BocNH
NH
2
XXIII
190 k. WO 98/44797 PCT/US98/06823 SCHEME 52 (continued) f= f R6 BocNH f- f
NH
CF
3
CO
2 H, CH 2
CI
2 NaHCO 3
XXIV
NH,
NH
R
6 If
#--NC
AgCN A R2 N N Sxxv The farnesyl transferase inhibitors of formula (II-f) can 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 R, WO 98/44797 PCT/US98/06823
R
6 e and R8; 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 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 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.
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: 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 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 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 V* 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 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 Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant 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.
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.
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 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 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 0 411 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 known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the Al(CR12)nA 2 (CR12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 61.
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.
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-2pyridinol, 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 aryl moiety by Suzuki chemistry to provide the instant compound.
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 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
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 k' 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-l,2-dihydropyridine XXa. Intermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation 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 1 V A(CR' 2 )nA 2
(CR
2 )n W (CR 1 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 Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, as shown in Scheme to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl N-lithio 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 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 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.
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 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 65-66 and the intermediates manipulated as illustrated above in Schemes 4-9.
SCHEME 53 r-R6 N I
(HO)
2
B'
HO
SR
2 Pd(PPh 3 4 0
N
HO LiAIH 4 T R 2 0
II
HO R 6
III
196 V WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 53 (continued) NiCI 2 (pPh 3 2 N ZnBr i R8
IV
NR
HO
(CF
3
SO
2 2 0, -78C NEtiPr 2
CH
2 01 2 -780C-200C
CH
3 0H 197 V, WO 98/44797 WO 9844797PCTfUS98/06823 SCHEME 54
B(OH)
2 Br-" Pd(PPh 3 4 MeO.
NR
C,
LAIH
4 MeO
R
N
R.
HO T 198 WO 98/44797 WO 9844797PCTIUS98/06823 I SCHEME N -~B(OH) 2
R
3 SiO +R 6 Br Pd(PPh 3 4 R3"N
BU
4
NF
R 2I
R
6 HO R R3SO B (HO)2 BR6 R 2I Pd(PPh 3 4 NN
BU
4
NF.
1 3 SiO
T-
6
HO,
199 WO 98/44797 WO 9844797PCT[US98/06823 SCHEME 56
R
3 SiO y BrZn NiCI 2 (PPh 3 2
BU
4
NF
R
3 Si
R
3 SiO0 Br.
N iC1 2 (P Ph 3 2 N
BU
4
NF
R
3 SiO N ~N
TR
HO,
200 t, WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 57
H
3 C
R
1.KMnO 4
I
N\
2 2. LIAIH 4 KMnO 4
H
3
C-
Pd(PPh 3 4
,N
H0 2 C R 2 LiAIH 4 N
RN
HO l 201 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 58 Br,, Hi. MeOH ref lux I R 2
R
8 Vill (HO0) 2 B I Pd(PPh 3 4 202 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 59
H
N
R 9 b-~i Ix Nal, NaHCO 3
-I
9b
N
Rb Tr~l, NEt,,
NI
R
9 b NiC1 2 (PPh 3 2 ZnBr
R
9 b.
76
NR
OTf i. -78OC-200C ii. MeON, reflux R 9 b.
203 k, WO 98/44797 WO 9844797PCT/US98106823 I- SCHEME L Br 0 55 0 CCH3CN Nl N ii. EtOH,80-C,
NH
2
NH
2 0 XII
N
N 3 N H 2
N
acylation, sulfonylation 0 N l or alkylation R -H
R
8
N
N
NN
R 8 H
N
NN
R 8-
H
204 WO 98/44797 WO 9844797PCT/1US98/06823 SCHEME 61
NG\COH
NCv i, Na, MeCH ii. 120 0
C
H
3 C, 0
KNN
H
NC
XV
Tr Tr~l, NEt 3 N
NC
xvi Tr
N+
NC
L.-780C-2O0C ii. MeOH reflux OTf
XVI
NN
NCN
205 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 62
N
/\OH
ICI-- i, Na, MeOH ii. 1200C KN
~N
N
0
R
2
XVI
OTf i. -78 0 ii. MeOH ref lux
B(OH)
2
R
6
/X
DMF, Pd(PPh 3 4
K
3 P0 4 8000 Tr~l, NEt
CI-
N
N2 CI 0 I 1 2
XVII
206 L WO 98/44797 W09814797PCTIUS98/06823 SCHEME 63 Tr EtMgBr XVIII R
OH
R
XIX
N
HO
(CF
3
SO
2 2 0, -78 0
C
NEtiPr 2
,CH
2
CI
2 ja LIOH
AC
2 O, PY QAc
XX
SOC12 207 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 63 (continued)
NH
3 MeOH 208 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 64
N'
C/ 0 R 6
OH
209 V. WO 98/44797 WO 9844797PCT/US98/06823 SCHEME
H
N
R 6 Boc
NHI
Boo NH CHO Boc NH NHBoc: xxi
NH
2 BocNH 1 catalytic hydrogenation 2. CF 3 00 2
H
CH
2
CI
2
BOC
2 0
CH
2
CI
2
~~CHO
NaBH(OAC) 3 Et 3 N ClCH 2
CH
2
CI
NH
2
XXII
NH
2
XXIII
210 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 65 (continued) -N
R
BocNH\/
CF
3 00 2 H, CH 2
C
2 NaHCO 3
NH
xxiv
NH
2 NC__ NH A gON N R 6 NxxN 211 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 66 Et 2
O
BnO BocNH ICHO
XXVI
Pd(OH) 2
H
2
CH
3 0H
CH
3 00 2
H
NHBoc
HO
CICOCOCI
DMSO 0H 2 0 2
(C
2
H
5 3
N
NHBoc
XXVII
212 WO 98/44797 PCT/US98/06823 SCHEME 66 (continued)
R
2 N R 6 0 R'MgX H NHBoc
XXIX
R
2 N R 6
HO
NHBoc
XXX
The famesyl transferase inhibitors of formula (II-g) can be synthesized in accordance with Schemes 67-78, 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 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 in the Synopsis of Schemes 67-78 by Roman numerals are numbered starting sequentially with I and ending with XX.
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 reactions useful in the preparation of heteroaryl moieties are described 213 k- 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, 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 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 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 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 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.
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 k. 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.
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 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 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 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 known in the art with various activated biheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the
A
1
(CR
1 2)nA 2 (CR12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 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.
-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-2pyridinol, 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 instant compound.
Compounds of the instant invention wherein the A1(CR 1 2)nA 2 (CR12)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 (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 2aminopyrimidine in the preapration of compounds of the instant invention.
216 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 67 N Br
HO
0 (HO)B N Pd(PPh 3 4 N
R
N> LAIH 4 0
HO,
217 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME-67 (continued) Tr
N
HO
X
R 2 NiCI 2 (PPh 3 2 ZnBr (0F 3 S0 2 2 0, -7800 N Eti Pr 2
CH
2
C
2 R8 IV -780C-200C 5500, CH 3 0H 218 WO 98/44797 WO 9844797PCT[US98/06823 SCHEME 68 MeO N
ITB(OH)
2 MeO-X Br" Pd(PPh 3 4 LiAIH 4
NR
HO, y 219 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 69 N B(OH) 2
R
3 SiO N6 Br Pd(PPh 3 4
BU
4
NF
-R
6
(HO)
2 Nj-R Pd(PPh 3 4 N Br
R
3 SiO R6
N
1 N BU 4
NF
R
3 SiO-
R
2 220 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME N I
R
3 SiO
X
4.N ILR6 BrZn N i01 2 (PPh 3 2
FR
6
BU
4
NF
ZnI
R
3 SiO
R
NiC 2 (PPh 3 2
H
N y0
-NH
BU
4
NF
221 k. WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 71
(HO)A
2 B N N Pd(PPh 3 4 KMnO 4
N
N
HO
2
C
LiAIH 4 6 N 117R
N
HO,, J 222 k WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 72 ii. MeOH ref lux Br Pd(PPh 3 4 Vill 223 k. WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 73
H
R
9 b NTh Nal, NaHCO 3
-I
N
R 9 b TrC 1, NEta,
N
R9b_\
I
NiCI 2 (PPh 3 2 R81D ZnBr
N-)
NR
OTf i. -78 0 C-20 0
C
ii. MeOH, ref lux 224 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 74 0-
N
R 8 i. r Br 0 C,CHgCN ii. EtOH,8o-C,
NH
2
NH
2 All
N
N
NH
2
R
8
N
acylation, sulfonylation N or R 8 .alkylation H' R8, N
N
H
NN
N
N
R 8- H
N_
N
225 V WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME i, Na, MeOH ii. 120C NC
O
xIV
H
3 C, 0 N"
N
IN
NCo--
XV
Tr~l, NEt 3 N jNN
XVI
NC r
N
i. -780C-200C N ii. MeOH reflux OPf
XV'
N
N
NC-
226 k, WO 98/44797 WO 9844797PCTIUS98/06823
N
\OH
SCHEME 76 i, Na, MeOH ii. 1200C 3C
CI
H
R
2
XVI
Tr Tr~l,
NE
3
CI-
OTf i. -78OC-2O0C ii. MeOH reflux
B(OH)
2 R6
N
OME, Pd(PPh 3 4
K
3 P0 4 800C xvi' 227 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 77 EtMgBr
N
XVIII
xlx N g
HO,,
(0F 3 S0 2 2 0, -780C NEtiPr 2
,CH
2
CI
2
AC
2 O, py 1 g -19 LiOH QAc
XX
I*g -9 SOC1 2
OH
228 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 77 (continued) g
NH
3 MeOH g 9 R6 1 9
NH
2 g 229 V WO 98/44797 PCT/US98/06823 SCHEME 78
H
2 N'N N N CI
H
2 N N
R
6
N
H
N N 7
N
R
8
W
R
6 The farnesyl transferase inhibitors of formula (II-j) can be synthesized in accordance with Schemes 79-88, 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 R8, 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
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 k- 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 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.
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 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 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 Schemes 80-82 illustrate methods of synthesizing related or analogous key alcohol intermediates, which can then be processed as described in Scheme 79. Thus, Scheme 80 illustrates pyridinonylpyridyl alcohol forming reactions starting with the suitably substituted iodonicotinate 6.
Scheme 81 illustrates preparation of the intermediate alcohol 9 wherein the terminal lactam ring is saturated. Acylation of a suitably substituted 4-aminobenzyl alcohol 7 with a suitably substituted brominated acyl chloride provides the bisacylated intermediate 8. Closure of the lactam ring followed by saponifi- 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 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 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 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 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 AI(CR12)nA 2 (CR12)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 After selective protection of one of the imidazolyl nitrogens, the intermediate 21 can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
Compounds of the instant invention wherein the Al(CR12)nA 2
(CR
1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 87. Thus, the N- 232 V WO 98/44797 PCT/US98/06823 0 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 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 and the acetyl is brominated to provide intermediate 26. Reaction with the imidazolyl reagent 4 provides, after deprotection, the instant compound 27.
SCHEME 79
H
3
CO
Y R 3 0
HO
R
3 LiAIH 4
R
6 HNy 1 0
K
2
CO
3 /Cu /heat
NBS/DMS
2 CH2C1 2 tR 6 NBe B 0 R3
HO'
233 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 79 (continued) Tr NiC1 2 (PPh 3 2 ZnBr
N-
Br. 0 C H 3 C N/ref lux Tr r
N
N 0
R
3 55-C,
CH
3 0H N\ 0 R 8 234 WO 98/44797 WO 9844797PCTJS98/06823 SCHEME N I DtO 0 6
N
HO
R
LiAIH 4
HNI
K
2 CO3/CU /h eat r R 6 N
NV
A0 HO0
R
3 235 V WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 81
NH
2
HO
0H 2 01 2 /Et 3
N
r 0 IN R 6 0
CS
2
COJDMF
heat
OH
9 NaOH MeOH 236 v WO 98/44797 WO 9844797PCTIUS98/06823 19 SCHEME 82
NH
2
HO
R 6 0H 2 C1 2 /Et 3
N
"Br
CS
2
CO
3
IDMF
heat Br
R
6 0 NaOH Me0H 237 k WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 83 C0 2
CH
3
R
6
NH
2
HCI
NH
3 (Liq.) EtOH
CONH
2 Rr NH 2
-HCI
0 0 MeOH/NaOH HOI NaHCO 3 12 OH
HO"
R 3
K
2 CO3WCuo/heat 238 k, WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 84
H
R9b Nal, NaHCO 3 12
H
N-
R 9 b 1 TrO, NEt 9 NIb R 9N NiC 12(PP h 3 2 RI ZnBr Tr R9bN Ra
R
9 b.
NV
Br0
R
3 i. CH 3 CN/reflux ii. MeOH, reflux JjYR6 239 k, WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 0z 0 i. Br 0
.H
3
,CN
ii. EtOH,80 0 C, NH 2
NH
2
N
N
NH
2
N
acylation, sulfonylationN or alkylation
NN
N
N
H
7-N'
R
3 0~R 6 240 WO 98/44797 WO 9844797PCT/US98/06823
\OH
NC-c 19
H
NC-(
SCHEME 86 i, Na, MeOH ii. 120C
H
3 0-ON Tr~l, NEt 3 NC0 NC
-I
21
NR
L. CH 3 CN/reflux ii. MeOH reflux Br 0 NC 241 WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 87 ir EtMgBr
R
8
T
\OH
23
AC
2 O, PY Tr O Ac 1. NKR6 R 3 0
CH
3 CN/reflux 2. MeOH LiOH r. 1 R 6
SOC'
2
OH
242 WO 98/44797 WO 9844797PCT/US98/06823 0 SCHEME 87 -(continued)
NH
3 MeOH,
NH
2 243 9 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 88
HNV
K
2
CO:
3 /CU'/heat L6
N
00
H
3 0 ll 0 Br 2
/CH
C013
NV
Br Y
R
3 026 Ra 4 C H 3 0 N/ref lux 0 N+ R 3 5500, CH 3 0H 0
I
R8 ~Tr6
/NV
00 The farnesyl transferase inhibitors of formula (IL-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
R
8 as shown in the Schemes, represent the substituents
R
3
R
4
R
5 R6a, R6b, R6c, R6d, R6e 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 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 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: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Synopsis of Schemes 89-97: The requisite intermediates are in some cases 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 sidechain. Thus, in Scheme 89, for example, a bicyclic intermediate that is not commercially available may be synthesized by methods 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 Org. Chem., 26:428-430 (1961)). The alcohol is then protected and reacted under Ullmann coupling conditions with a suitably substituted phenyl iodide, to provide the intermediate bicyclic alcohol The intermediate alcohol 30 may converted to the corresponding bromide 31. The bromide 31 may be coupled to a suitably substituted benzylimidazolyl 32 to provide, after deprotection, the instant compound 33.
245 k' 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 pyridylpyridinonyl alcohol and thienylpyridinonyl alcohol starting with the 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 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 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 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 4aminoalkylimidazole 40, wherein the primary amine is protected as 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 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.
Compounds of the instant invention wherein the Al(CR12)nA 2 (CR12)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 95. Thus, the Nprotected imidazolyl iodide 45 is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol 46.
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 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 provides, after deprotection, the instant compound Scheme 97 illustrate reactions wherein the moiety
(R
8 V A(CR)nA(CR2) n (CR 1 )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 the Schemes, and other pyridinonecarbocyclic and pyridinoneheterocyclic 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, 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 arylpyridinone moiety. Thus, a suitably substituted 4-(bromo)pyridine is converted to the corresponding pyridinone 51 as described above 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, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound 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 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 v WO 98/44797 W098/4797PCTIUJS98/06823 SCHEME 89
COOM
N
H
2 0 2 HOAc/ A COOMe R 3 6-
AC
2 0O/ 16000 COOMe LiBH 4
/THF
TBDMSCI
.0 imidazole
/DMF
OTBDMS
N 0
H
Cu 0
K
2 00 3 1 80 0 C OTBDMS 249 Q WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 89 (continued)
TBAF
THF
CBr 4 /Ph 3
P
CH
2 01 2 r Br
OH
Tr Zn
N'CI
2 (PPh 3 2 Tr BrN R8 32
CH
3 CN/reflux
R
3 6 0 5500, CH 3 0H N NJ: x 33 R8 250 WO 98/44797 PTU9/62 PCTfUS98/06823 SCHEME
OTBDMS
R 3 N 001
H
Br
R
u 0
I/K
2 00 3 1800C
OTBDMS
R3 N 00C
H
R6 s u 0
K
2 C0 3 1
OTBDMS
251 V WO 98/44797 PCT/US98/06823 SCHEME 91 :_1C NH 2 34 C0 2
CH
3
CH
2 01 2 /Et 3
N
1) R 6 CS 2 00 3
DMF
R
3 heat HN Br 0 C0 2
CH
3 LiAIH 4
THE
o Br 4 /Ph 3
P
0H 2
CI
2 252 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 92
H
N
R
9 b
-CIN
Nal, NaHCO 3 I2
H
N
R
9 b_\I Tr~l, NEtg Tr N'l
R
9 b Nl
N
NiCI 2 (PPh 3 2 Z nB r Tr Nl
CH.
3 CN/reflux ii. MeOH, ref lux 253 V- WO 98/44797 PCTIUS98/06823 SCHEME 93 0 R8L- I Br N 0 550,CH 3
CN
N N ii. EtOH,80 0 C, NH 2
NH
2 0I
N
N 3
NH
2
R
8 41 acylation, sulfonylation 0 N N or alkylation
R
8 L.
H
NR 3 R 6
NN
N NS
R
8
H
R 3 254 V WO 98/44797 WO 9844797PCT[US98/06823 SCHEME 94 i, Na, MeOH ii. 1200C 1
OH
NC
H
3 C-O =N
NCI
43 Tr~l, NEt 3 IN NC-c-
NCN
44
R
3
R
N i. CH 3 CN/reflux o 1 ii. MeOH reflux Br 3
NC
255 k WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME Tr
\N
AC
2 O, py EtMgBr
N
OH
R
8 46 Br
CH
3 CN/reflux 2. MeOH LiOH SOC1 2 256 V, WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 95 (continued)
NH
3 MeOH R A 6 OMe 257 WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 96 0 OH 3
N
H
2 0 2 HOA A O OH 3 R3 .0H 3
AC
2 O 16000
K
2 CO3JCu'/heat Br 2
/CHCI
3
R
3
R
Br 0 0 49 7-- R8 32
CH
3 CN/reflux 258 k. WO 98/44797 WO 9844797PCTIUS98/06823 SCHEME 96 (continued)
CH
3 0H
N'
I
Tr 259 k, WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 97 Br
N
H
2 0 2 HOAc/
A
Br R 03 Ac 2 O 16000 Br N 0
H
K
2
CO
3 /CU+/heat R6 Zno 260 k WO 98/44797 WO 9844797PCT/US98/06823 SCHEME 97 (continued) Boc NH Boc NH ICHO 1. catalytic 6hydrogenation -R2.
CF
3 C0 2
H
CH
2
CI
2 Boc NH 0 NHBoc 54
\~R
6
BOC
2 0
CH
2
CI
2
NH-
2 261 11 WO98/44797 PTU9/62 PCTIUS98/06823 SCHEME 97 (continued)
~'I~IIC
0
HO
BocNH
NH
2 56 NaBH(OAc) 3 Et 3 N, CICH 2
CH
2
CI
N ~il
CF
3
CO
2 H, 0H 2 C1 2 NaHCO 3 I NC -NH AgON L 262 T 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 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 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.
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 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 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 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 anination 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 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.
REACTION SCHEME A R2b
O
2 N OH I R 2 b Cu, K 2
CO
3 RR pyridine, reflux R2a R 3 2b R 2 b
O
2 N 0 R 2 b H 2 Pd/C H 2 N O R 2b
R
2 a R3 THF,MeOH R2a
R
Sd 264 WO 98/44797 PCTIUS98/06823 REACTION SCHEME B
NH
2 Cu, K 2 C0 3 pyridine, reflux 0 2
N.
H
2 Pd/C THE, MeOH
H
2
N,
R
REACTION SCHEME C 0 2
N
F
0 2
N
CuBr SMe 2 NaH 3 pyridine, ref lux
H
2 Pd/C H 2 N S THE, MeOH fn2a/ 265 WO 98/44797 WO 9844797PCT/US98/06823 REACTION SCHEME D CuBr*SMe 2 NaH pyridine, reflux R 2 b R 2b NaBH(AcO) 3
CICH
2
OH
2
CI
R 2 a' R3
H
2 NR 4 REACTION SCHEME E
K
2 00 3
DMF
8000
HO'
0 2
N
tR 2 b
H
2
N.
Fe, AcOH 21 MeOH, reflux 266 WO 98/44797 WO 9844797PCT/tJS98/06823 REACTION SCHEME F 4 EDC, HOBT or HOOBT Et 3 N, OME HOI or TEA
H
2
N
REACTION SCHEME G 0 2
N
0 2
N.
R 7 HN R 2 b Na(QAc) 3
BH
Fe, HOAc 267 k. WO 98/44797 WO 9844797PCT/US98/06823 REACTION SCHEME H 0 2
N
0 2
N,~
R 7 HN R 2 b I-Cj base R 2 b Fe, HOAc REACTION SCHEME I Bu 3 S R~b Pd(PPh 3 2
CI
2 R 3 12b
H
2 N
X-R
2 b I PdIC, H 2 I 3 m2a R 3 0 2
N
REACTION SCHEME J 268 WO 98/44797 WO 9844797PCTJUS98/06823 BocHN
NCH
3
ICH
MgBrPh(R 2 a)(R 3) LiPh(R 2 a)(R 3 BocHN
HN(R
8 2 NaBH(OAc) 3
CICH
2
CH
2
CI
HCIlor
TEA
H
2
N
269 WO 98/44797 WO 9844797PCT/US98/06823 REACTION SCHEME K 0 0 2 N cI Br ori1r/
R
2 b
R
2 b 0 2
N
Fe, HOAc
H
2
N
1. MgBrR 8 2. R 8 1
H
2
N,
270 WO 98/44797 WO 9844797PCTJIJS98/06823 k.
REACTION SCHEME L
H
2 N N Br 7-2 Pd(OAc) 2 P(o-tol) 3 Et 3
N
REACTION SCHEME M
H
2 N -N 7-2 Pd(PPh 3 4
BU
3
SI
H
2
N.
271 WO 98/44797 WO 9844797PCTIUS98/06823 REACTION SCHEME N R 2 b 0 2 N ~OH
R
2 a
H
2
N..
1. NaH 2. Fe, AcOH MeOH, reflux REACTION SCHEME P 0 2 N R 2 b K2CO3 A i heat 02 IX 1 1. Tf2NPh, Et3N 0NNH R 2a~ R 3 Et 3
N/HO
2 CH R2
DMF
Reaction Schemes Q- S illustrate reactions wherein the non-suifflydryl-containing moiety(ies) of the compounds of the instant invention is attached to the aminodiphenyl subunit to provide the instant compounds.
272 k. WO 98/44797 PCT/US98/06823 Thus, the aminodiphenyl subunit can be reductively alkylated with aldehydes such as 1-trityl-4-carboxaldehyde or 1trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme The trityl protecting group can be removed 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 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)-3ethylcarbodiimide (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 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 I WO 98/44797 WO 9844797PCTIUS98/06823 REACTION SCHEME Q lb~ H2N-(C KA3 NaBH(OAC) 3 Et 3 N ,ClCH 2
GH
2
CI
(H
2 )n~l
N
Tr
CF
3
CO
2 H, CH 2 01 2 (0 2
H
5 3 SiH
(CH
2 )nCHO
N
N
NaBH(OAc) 3 Et 3 N CICH 2
CH
2
CI
Vill
N-(CR'
N
H
ix
R
2 b R2a R 2 b Hb4 274 WO 98/44797 WO 9844797PCTIUS98/06823 REACTION SCHEME R N- CH 2 00 2 H C3HCH 2 00 2
CH
3 N HOIN HH
HOI
X1 XII N CH 2 00 2
CH
3 1) ArCH 2 X CH 3
CN
(C
6
H
5 3 CBr \ref lux (0 2
H
5 3 N N 2) CH 3 OH, ref lux DMF Tr
XIII
Ar- \N-CH 2 00 2
CH
3
N
Ar' N-CH 2 00 2
H
N
2.5N HClaq 5500 275 WO 98/44797 WO 9844797PCT/US98/06823 REACTION SCHEME R (continued) N-CH2 00 2
H
N
1R b EDC -HOI HOBt Ar" Ni.
b~
N-(CR
1 H3
R
3 276 WO 98/44797 PCT/US98/06823 REACTION SCHEME S R2a R2b 1) RXCHO, NaBH(OAc) 3 lb I 1 CICH.,CHCI H N-(CR
H
2 N- (CR 2P 2) RYCHO, NaBH(OAc) 3
R
3
CICH
2
CH
2
CI
R
2a
R
2 b NaOH RX^N cRlb H20, CHaOH; RX N-(CR YK P. 21 H+ R2a
R
2 b RX--N-(CR 2)p Y i R
R
3 wherein, in the above Reaction Schemes, R' is Rla; R" is
(R
6 )r-V-Al-(CRla)n-; is selected such that R"'CH2- is R 8 and RX and RY are selected such that R x CH2- and RYCH2- are either R 4 or R 5
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 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 evaporator.
277 WO 98/44797 WO 9844797PCT/US98/06823 EXAMPLE 1
H
2 Nj C2H
NHCBZ
SOC1 2 EtOH HCI*H 2 N 2E
NHCBZ
1-1 B00 2 0, NEt 3
CH
3
CN
BOON f CO 2 Et 10% Pd/C H N 2 EtOAc NH2 u E3CN
O
2 Et
BOONNHCBZ
1 camphorsuffonyl chloride NMM, 0H 2 C1 2
BOON
H
BOP, NMM
CH
3
CN
*HCI 1-7 278 WO 98/44797 WO 9844797PCTIUS98/06823 H NH CO 2 Et 1-H" NHS0 2 0 NaOH, C 2
H
5
OH
H C0 2
H
19NH
H
(1-2) Li.l (5 g, 21 mmol) was dissolved in 100 mL EtOH and cooled to 0 0 C. SOC12 (9.2 mL, 126 minol) was added followed by removal of the cooling bath. After 6 hours, the reaction was concentrated to provide 1-2 as a white solid.
IH NMR (300 MHz, CD3OD) 8 7.35 (in, 5H), 5.14 2H), 4.44 (in, 4.22 J=7Hz, 2H), 3.43 (in, 1H), 3.20 (in, 1H), 1.25 J=7Hz, 3H).
Sto 2: Ethyl 2 (S)-Ni-Cbz-NI-Boc.2.3-diaminopropionate (1-3) 1-2 (2 g, 6.6 inmol) 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% KHS04 and brine, dried (MgSO4), filtered and concentrated to provide 1-3 as a clear oil.
TLC Rf 0.87 (silica, 80% EtOAc/hex).
-279 k' WO 98/44797 PCT/US98/06823 1H NMR (300 MHz, CDC13) 5 7.35 5H), 5.75 (bs, 1H), 5.12 2H), 4.81 (bs, 1H), 4.39 1H), 4.19 2H), 3.56 2H), 1.42 9H), 1.29 J=7Hz, 3H).
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 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.
TLC Rf 0.13 (silica, 80% EtOAc/hex).
1 H NMR (300 MHz, CDC13) 8 5.00 (bs, 1H), 4.19 2H), 3.55 (m, 2H), 3.25 1H), 1.44 9H), 1.29 J=7Hz, 3H).
Step 4: Ethyl-2(S)-Na-(1(S)10-camphorsulfonylamino-Np-Boc- 2 3 -diamino-propionate Amine 1-4 (760 mg, 3.27 mmol) was dissolved in 35 mL CH2C12 and cooled to 0°C. NMM (755 giL, 6.87 mmol) and camphorsulfonyl chloride (1.23 g, 4.9 mmol) were added. After stirring at 0°C for one hour, the reaction was concentrated, then diluted 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, CDC13) 5 6.37 J=8Hz, 1H), 4.99 (bt, 1H), 4.32 1H), 4.23 J=8Hz, 2H), 3.56 3H), 3.0 J=15 Hz, 1H), 2.4 1H), 2.05 4H), 1.43 9H), 1.30 J=7 Hz, 3H), 1.00 3H), 0.91 3H).
Step 5: Ethyl-2(S)-Na-(1(S)10-camphorsulfonylamino)-2,3diaminopropionate hydrochloride (1-6) Ester 1-5 (900 mg, 2.18 mmol) was dissolved in 15 mL EtOAc and cooled to 0°C. HCI 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 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, CDC13): 8 4.75 1H), 4.26 J=7Hz, 2H), 3.50 4H), 2.40 3H), 1.98 4H), 1.30 J=7Hz, 3H), 1.04 3H), 0.91 3H).
0 C02Et 1-10 Step 6: Ethvl-4-(2-butanene)benzoate (1-10) 3-Buten-2-ol (2.15 mL, 25 mmol), ethyl 4-iodobenzoate (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, KHSO4, sat. NaHCO3 and brine, dried (MgS04) and concentrated to a yellow oil. Flash chromatography (silica, 10% EtOAc/hex) provided 1-10 as a clear oil.
TLC Rf 0.23 (silica, 30% EtOAc/hex).
1H NMR (300 MHz, CDC13): 5 7.95 J=8Hz, 2H), 7.25 J=8Hz, 2H), 4.36 J=7Hz, 2H), 2.95 J=7Hz, 2H), 2.78 J=7Hz, 2H), 2.15 2H), 1.38 J=7Hz, 3H).
N N1-11 CO2Et 1-1 281 WO 98/44797 PCT/US98/06823 Ste 7: Ethyl 4-[2-(1.8-naphthyridin-7-vl)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.
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 (MgS04) and concentrated to give a yellow oil. Flash chromatography (silica, 60%-80% EtOAc/hex) provided 1-11 as a yellow solid.
TLC Rf 0.31 (silica, 70% EtOAc/hex).
1 H NMR (300 MHz, CDC13) 5 9.11 1H), 8.18 J=8Hz, 1H), 8.08 J=8Hz, 1H), 7.95 J=8Hz, 2H), 7.47 1H), 7.30 J=8Hz, 2H), 4.35 J=7Hz, 2H), 3.35 4H), 1.38 J=7Hz, 3H).
N N
H
V
CO2Et 1-12 Step 8: Ethyl 4-[2-(1,2,3,4-tetrahydro-1,8-naphthyridin-7vl)ethvllbenzoate (1-12) A mixture of 1-11 (645 mg, 2.11 mmol), 10% Pd/C mg), and ethanol (10 mL) was stirred under a hydrogen atmosphere 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) 5 7.94 J=8Hz, 2H), 7.26 J=8Hz, 2H), 7.03 J=7Hz, 1H), 6.28 J=7Hz, 1H), 4.81 1H), 4.35 (q, J=7Hz, 2H), 3.40 2H), 3.03 2H), 2.84 2H), 2.69 J=6Hz, 2H), 1.93 J=6Hz, 2H), 1.38 J=7Hz, 3H).
-282 WO 98/44797 WO 9844797PCTIUS98/06823 *HCI -C0 2
H
1-7 Step 9: 4- 1,2,3 ,4-Tetrahydro- 1, 8 -naphthyridin-7yl)ethyllbenzoic acid hydrochloride (1 -7) Ester 1-12 (680 mg, 2.11 mmol) in 10 mL 6N HCl was heated to 50'C for 18 hours. Concentration provided 1-7 as a yellow solid.
IH NMR (300 MHz, CD3OD) 5 7.93 J=8Hz, 2H), 7.52 J=8Hz, 1H), 7.31 J=8Hz, 2H), 6.54 J=8Hz, 1H), 3.48 J=5Hz, 2H), 3.03 (in, 4H), 2.79 J=6Hz, 2H), 1.93 J=-6Hz, 2H).
Step 10: 4- 1,2,3 ,4-Tetrahydro- 1 ,8-naphthyridin-7-yl)ethyl] benzoyl-2(S) [1(S)I1 -camphorsulfonylamino] P-alanine ethyl ester (1-8) 1-7 (200 mg, 0.627 inmol), amine 1-6 (240 mg, 0.69 mmol), NMM (345 gL, 3.13 inmol) and BOP reagent (332 mng, 0.75 mmol) were combined in 5 mnL CH3CN. After stirring overnight, the reaction was concentrated, then diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated.
Flash chromatography (silica, EtOAc) provided 34-8 as an off-white foamy solid.
TLC Rf 0.13 (silica, EtOAc).
1 H NMR (300 MHz, CDC13) 867.70 J=8Hz, 211), 7.25 J=8Hz, 2H), 7.03 (d J=7Hz, 1H), 6.72 J=5Hz, 111), 6.5 (bin, 1H), 6.28 (d, J=7Hz, 111), 4.79 1H1), 4.42 (bs, 4.25 J=7H-z, 2H), 4.04 (in, 111), 3.85 (mn, 1H), 3.55 J=15Hz, 1H), 3.41 (in, 2H), 3.00 (in, 3H), 2.82 J=4Hz, 2H), 2.69 J=6Hz, 2H), 2.04 (mn, 8H), 1.58 (bs, 3H), 1.31 J=7Hz, 311), 1.00 3H), 0.90 3H).
-283 WO 98/44797 WO 9844797PCTIUS98/06823 Stu 11: 4- 1,2,3 ,4-Tetrahydro- 1, 8-naphthyridin-7-yl)ethyl] benzoyl-2(S)- [1(S)I1 -camphorsulfonylamino] 1-alanine (1-9) (250 mg, 0.409 mniol) was dissolved in 4 mL EtOH, 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 HCl and then concentrated to a foamy solid. Flash chromatography (silica, 18: 10: 1: 1 EtOAcIEtOHINI-40HJH20) provided 1-9 as a slightly yellow solid.
TLC Rf 0.49 (silica, 12: 10: 1:1 EtOAcIEtOHNH4OI-1H 2 0).
1 H NMR (400 MHz, DMSO) 8 8.48 (bt, 1H), 7.72 J=8Hz, 2H), 7.55 (bs, 1H), 7.28 J=8Hz, 2H), 7.02 J=7Hz, 1H), 6.37 1H), 6.26 J=7Hz, 1H), 4.13 IH), 3.54 (in, 3H), 3.37 (in, 2H), 2.94 (in, 3H), 2.73 J=7Hz, 2H), 2.6 J=6Hz, 2H), 2.3 (mn, 3H), 2.02 (mn, 1H), 1.89 (mn, 2H), 1.75 (mn, 2H), 1.49 (in, 1H), 1.37 (in, lH), 1.05 (mn, 0.95 3H), 0.66 3H).
EXAMPLE 2 BocHN 00 OH 3 0 2-1 SHCI, EtOAc, 000 0 H 1 N-.'JOCH HCle H 2 N3 0 2-2 NaCNBH 4 N N CHO MeOH 2-3 -284 WO 98/44797 WO 9844797PCT[US98/06823 H,)7 0 C NN, N N OCH 3 0 2-4 Boc 2 O, THE
(N
N N
IN
H)T 0 N N-IIN OCH 3 Boc 0 Pd/C 2-7 HCMe2 NV C02Et 2-6.R
=CH
3 NaOH EDO, HOBT,
DMF
-285 WO 98/44797 WO 9844797PCTIUS98/06823 H N> N N N N> COE i H CX Boc 0 2-8 6N HOI 0IH..CN
HN
N N-A C02H H
HN
0 2-9 Step 1: (S )-(3-amino-2-oxo-p2yrrolidin- 1-ylB-acetic acid (2-2) A solution of 2-1 (0.50 g, 1.84 mnmol) (prepared as described by Freidinger, R. Perlow, D. Veber, D. J. Org.
Chem., 1982, 26, 104) in anhydrous ethyl acetate (50 mL) was cooled to 0 0 C and saturated with HCl gas, then stirred at 0 0 C 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 hygroscopic white solid.
I- NMR (300 MHz, CD 3 OD) 5 4.16 2H); 4.2 (in, 1H); 3.68 3H); 3.53 (in, 2H); 2.58 (in, 1H); 2.09 (in, LH).
Step 2: 2-oxo-3-(S)- naphthyridin-2-ylmethyl)-aminojpvrrolidin-1I-yll-acetic acid (2-4) A solution of 2-2 (232 mng, 1. 11 mmol) and [1 ,8]naphthyridin-2-ylcarboxaldehyde (176 mng, 1.11 minol) (prepared as reported by Weissenfels, Ulrici, Z Chem. 1978, 18, in anhydrous methanol (10 mL) was treated with NaQAc (91 ing, 1.111 mmol) NaBH 3 CN (70 ing, 1. 11 mmol) and powdered 4 A molecular sieves (450 ing). The resulting mixture was stirred at 0O for 3.5 h, then 286 1, WO 98/44797 PCTIUS98/06823 concentrated and the residue subjected to flash chromatography on silica gel (95:4.5:0.5 CH 2 C12/MeOHINH40H) to afford 2-4 as a colorless glass.
FAB MS (315, M+1); IH NMR (300 MHz, CD30D) 5 9.04 1H); 8.41 (dd, 1H); 8.38(d, 1H); 7.72 1H); 7.62 (dd, 1H); 4.31 2H); 4.21 2H); 3.68 (s, 3H);3.63 1H); 3.53 2H); 2.52 1H); 1.95 1H).
Step 3: Methyl-[3-(S)-[tert-butoxycarbonyl-[1,8]naphthyridin-2vlmethyl)-aminol-2-oxo-pyrrolidin-1-vll-acetic acid A solution of amine 2-4 (69 mg, 0.22 mmol) in THF 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 MeOH/CH2Cl2) to afford 2-5 as a yellow glass.
FAB MS (415, M+1); IH NMR (300 MHz, CD30D) 5 9.04 1H); 8.20 2H); 7.88 (d, (rotamer 7.82 0.5H (rotamer 7.46(m, 1H); 5.1-4.3 5H); 3.81 2H); 3.72 3H); 3.41 2H); 2.36 2H); 1.47 4.5 H (rotamer 1.30 4.5 H, (rotamer Step 4: Methyl-3-(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydro- [1,8]naphthyridin-2-ylmethyl)-amino]-2-oxo-pyrrolidinl-vll-acetic acid (2-6) 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.
IH NMR (300 MHz, CD30D) 6 7.10 1H) 6.78 0.5H (rotamer 6.62 0.5H (rotamer 4.8-3.9 5H); 3.81 2H); 3.72 3H); 3.38 2H); 2.36 2H); 1.21(s, 4.5 H (rotamer 1.15 4.5 H (rotamer 287 WO 98/44797 WO 9844797PCTIUS98/06823 St= 5: 3 -(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydronaphthyridin-2-ylmethyl)-amino] -2-oxo-pyrrolidin- 1-yll-acetic acid (2-6a) A solution of 2-6 (38 mg, 0.09 1 mmol) in 50 aqueous THF (2 m.L) 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 HCl, evaporated, and the residue dissolved in MeOH (2.5 mL), filtered and evaporated to afford 2-6a as a colorless glass.
IH NMR (300 MHz, CD 3 OD) 8 7.31 1H) 6.78 (br, d, 1H); 4.8-3.9 (in, 5H); 3.81 (in, 2H); 3.38 (in, 2H); 2.36 (mn, 2H); 1.21(s, 4.5 H (rotainer 1.15 4.5 H (rotamer Ste 6:Ethyl {2-oxo-3- ,8-tetrahydronaphthyridin-2-ylmethyl)-amino] -pyrrolidin- l-yl acetvlamino)-3-(R)-pvyridin-3-yl-propionic acid (2-8) 2-6a (43 mg, 0.093 ininol), protected amino acid 2-7 (Zablocki et al., J. Med. Chem., 1995, 38, 2378), (25 mg, 0093 inmol), EDC (18 ing, 0.093 iniol), HOBT (13 mng, 0.093 inmol), and Nmethyl inorpholine (31 mL, 0.28 mnmol) in anhydrous DMF (5 mL) was stirred at room temperature for 18 h, then concentrated in vacuuo and the residue chroinatographed on silica gel using 5% MeOHICH2Cl2 as eluent affording as a colorless glass.
IH NMR (300 MHz, CDCl 3 8 8.61 1H); 8.45 1H); 8.00 (in, 1H); 7.68, 1H); 7.21 (mn, 1H); 7.17 1H); 5.56 (mn, 1H); 4.75 2H); 4.45 (in, 2H); 4.05 2H); 3.95 (in, 1H); 3.5-3.3 (mn, 4H); 2.92 (in, 1H); 2.87 (mn, 1H); 2.74 (mn, 2H); 2.35 (mn, 2H); 1.92 (mn, 2H); 1.36 (s, 9H); 1.21 3H).
Ste (2-oxo-3-[(5 ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2ylinethyl)-ainino] -pyrrolidin- l-yl }-acetylainino)-3-(R)p2yridin-3-vl-propionic acid (2-9) 2- (25 mg, 0.043 mmol) was dissolved in 6 N HCl (2 mL) and stirred at room temperature for 16 hi, then evaporated to afford 2-9 as a pale yellow solid.
-288 WO 98/44797 WO 9844797PCTLJS98/06823 FAB MS (453, IH NMR (300 MHz, CD 3 OD) 8 9.00 1H); 8.81 1H); 8 .79(m, 1H); 8.10 (in, 1H); 7.71 1H); 7.01 (in, 1H); 5.56 (in, 1H); 4.75 2H); 4.61 (mn, 1H); 4.50 (mn, 1H); 4.35 (in, 1H); 4.10 2H); 3.62 (in, 4H); 3.4 -3.0 (in, 2H); 2.8 (mn, 2H); 2.70 (mn, 1H); 2.45 (in 1H); 1.98 (mn, 2H).
EXAM PLE 2a
N
malonic acid,I
NH
4 OAc EtOH (8000) CHO NPhCH 2 000I
N
NN
Et 3 N,a
H
2 N 0 2 14 Dioxane/H- 2 0 P h-- 1 .N C0 2
H
H2N H 2a-3 2a-2 Penicillin Amidase (EC 3.5. 1.11) pH 7.8, H 2 0 289 WO 98/44797 WO 9844797PCTIUS98/06823 N
N
C
2 H Ph,-JL1 C 2
H
H
2 N 2a4H 6 6NHCI 0
C
H N H HCI* H2N-, 0E EtCH, HCI2 I N2N 02 2a795% 2a-6 3-guinolin-3-vl-p2ropionic acid (2a-2).
A solution containing quinoline-3--carboxaldehyde 2a- g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate g, 63.6 mmol) in anhydrous ethanol (125 mnL) 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.
1 H NMR (300 MHz, D20): 8 8.91 J 2 Hz 1H), 8.21 J 2 Hz, 1H), 8.12 J 8 Hz, lH), 7.84 J 7 Hz, 1H), 7.72 J 7 Hz, 1H), 7.54 J 7 Hz, 4.72 (in, lH), 2.73 (in, 2H).
3 -Phenvlacetylamino-3-guinolin-3..v12ropionic (2a-3) A0' solution of 2a- (3.5 g,16.2 mmol) and NaHCO3 (2.7 g, 32.4 minol) in 50% aqueous dioxane (100 mL) was treated dropwise with a solution of phenylacetyl chloride (3.00 g, 19.4 minol) in 25 mL of dioxane. The resulting solution was stirred at 0' for -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 2a-3 as an off white solid.
1H NMR (300 MHz, CD30D): 8 8.85 J 2 Hz 1H), 8.20 J 2 Hz, 1H), 8.00 J 8 Hz, 1H), 7.86 J 7 Hz, 1H), 7.76 J 7 Hz, 1H), 7.52 J 7 Hz, 7.28 6H), 5.53 J 6.8 Hz, 1H), 3.57 2H), 2. 96 2H).
3-(S)-Ouinolin- 3 -vl-propionic acid dihydrochloride (2a-6) Acid 2a-3 (5.0 g, 15 mmol) was suspended in water 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 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 0°C and adjusted to pH 3 with 3N HC1. An oily yellow 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 CH2C12 (3 x 500 mL) to afford additional contaminated by phenylacetic acid. Both batches of crude 2a-5 were combined and stirred in 3 N HC1 (200 mL) at 50° for 12 h then cooled, 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.
1 H NMR (300 MHz, CD30D): 8 9.25 J 2 Hz 1H), 8.31 J 2 Hz, 1H), 8.15 J 8 Hz, 1H), 7.84 J =7 Hz, 1H), 7.72 J 7 Hz, 1H), 7.54 J 7 Hz, 4.72 1H), 4.15 J 6 Hz, 2H), 2.73 2H) 1.18 J= 6 Hz, 3H).
-291 WO 98/44797 WO 9844797PCT/US98/06823 EXAMPLE 2a (continued) 0 H
N
N ZN
OH
rBoc 2a-7 EDC, HOBT,
DMF
"N
HO
H
I 6N HCI H
S
N
H
2a-9 -292 WO 98/44797 WO 9844797PCTIUS98/06823 Ethyl I2-oxo-3-[(5 .6.7.8 -tetrahydro-[l. 1 I8naphthvridin-2vimethyl)- tert-butoxvcarbonyl aminol -pyrrolidin- 1 -vi -acetylamino)-3- (S-guinolin-3-vl-propionic acid (2a-8) 2-6 (100 mg, 0.216 mmol) from Example 2, Step 5, 2a-7 (53 mg, 0.216 mmol), EDC (41 mg, 0.216 mmol), HOBT (30 mg, 0.216 mmol), and N-methyl morpholine (66 IiL, 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- as a colorless glass.
1 H NMR (300 MHz, CDCl3) 8 8.82 1H); 8.13 1H); 8.08 1H); 7.91, 1H); 7.63 (in, 111); 7.58 (in, 1H); 7.53 1H); 7.05 1H); 6.45 1H); 5.63 (mn, 111); 5.05 (br, s, 1H); 4.75 2H); 4.45 (mn, 2H); 4.05 2H); 3.95 (in, 1H); 3.5-3.3 (in, 4H); 2.92 (in, 1H); 2.87 (mn, 1H); 2.74 (in, 2H); 2.35 (in, 2H); 1.92 (in, 2H); 1.34 9H); 1.20 (t, 3H).
3-(S-(2-2-oxo-3- (5 .6.7,8-tetrahydro-F[1.81naphthyridin-2-vlmethyl)amino] -pyffolidin- 1 -v I -acetvlamino)-3 -(S)-guinolin-3-yl-p2ropionic acid (2a-9).
2a- (125 mng, 0.24 inmol) was dissolved in 6 N HCl (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 reverse phase hplc (C 18, 0. 1% aqueous TFAICH3CN).
FAB MS (503, M+1); 1 H NMR (300 MHz, CD3OD) 5 9.01 1H); 8.93 1H); 8.09 (d, 1H); 8.0 5 1H); 7.91 1H); 7.81 1H); 7.38 1H); 6.82 2H); 5.58 (in, 1H); 4.45 (mn, 1H); 4.3 (in, 1H); 4.20 (mn, 1H); 4.35 (in, 1H); 4.10 2H); 3.62 (mn, 4H); 3.4 -3.0 (in, 2H); 2.8 (in, 2H); 2.70 (mn, 1H); 2.45 (in 1H); 2.05 (in, 1H); 1.98 (mn, 2H).
-293 WO 98/44797 WO 9844797PCTIUS98/06823 EXAMPLE 3 0 0
OH
3 Q OEt 3-1 1) OH 2 PPh 3
OH
2 0
OH
3
OH
3-2 2) NaOH 3-2 pivaloyl chloride LiN 0 Ph
CH
2 0 0 NaN(SiMe 3 2
OH
3 A N then 6 3-3 ~F 3 0S0 3
I
Ph 3-4
OH
2 0 0 CI 3-5 Ph 1) NaN 3
OH
2
OH
3
NH
2) PPh 3
H
2 0 2r NaN(SiMe 3 2 then 3-6 0
OH
3 QOEt Br OsO N 0 QOEt 3-7 0 then NatO 4 QlEt (N
NH
2 1-4 0 proline
OH
3 -294 WO 98/44797 WO 9844797PCTITJS98/06823 6N HCI NN N
OH
H HCI 3-11 0 0 CN N N O *HCI 3-110 EDC, HOBT
NMM
H
2 N QEt 0 3-12 *2HCI -295 WO 98/44797 PCT/US98/06823 O H N N N N
H
S 0 0 3-13 1
N
NaOH 0
H
H 0 II0 3-14 1
N
Step 1: 4-(Propyl-2-ene)butyric acid (3-2) To a stirred suspension of methyltriphenylphosphonium bromide (67.7 g, 190 mmol) in 1 L THF at 0° C was added a solution of sodium bis(trimethylsilyl)amide (190 mL, 190 mmol, 1M 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 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, CHC13) 8 4.71 2H, J=13 Hz), 4.13 2H, J=7 Hz), 2.29 2H, J=7 Hz), 2.05 2H, J= 8 Hz), 1.77 2H), 1.72 (s, 3H), 1.26 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 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/U TS9«/023 1H NMR (300 MHz, CHC13) 5 4.70 2H, J=13 Hz), 2.27 2H, J=7 Hz), 2.06 2H, J= 7 Hz), 1.72 Step 2: 4 -(Propyl- 2 -ene)butanoyl)-4(R)-benzyl-2-oxazolidinone (3-3) To a solution of 3-2 (6.0 g, 46.8 mmol) in THF (200 ml) at -78° 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°C for 1 h, then recooled to -78" C. In a separate flask, of 4-benzyl-2-oxazolidinone (9.15 g, 51.5 mmol) was dissolved in THF (100 mL), cooled to -78° 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 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).
1 H NMR (300 MHz, CHC13) 5 7.40-7.18 5H), 4.80-4.60 3H), 4.18 2H), 3.30 (dd, 1H, J=3.2, 13.2 Hz), 2.95 2H), 2.76 (dd, 1H, J=9.5, 13.1 Hz), 2.11 2H, J=7.5 Hz), 1.87 2H), 1.74 3H).
Step 3: 2-Chloroethyltriflate (3-4) 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 0° 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 3-4 as a pink oil.
1 H NMR (300 MHz, CHC13) 5 4.69 2H, J=5.3 Hz), 3.78 2H, J=5.6 Hz).
297 WO 98/44797 PCT/US98/06823 Ste 4: 2(S)-Chloroethyl-4-(propyl-2-ene)butanoyl-(4(R)-benzyl-2oxazolidinone) To a solution of 3-3 (11.0 g, 38.3 mmol) in THF (60 mL) at -78 0 C was added a solution of sodium bis(trimethylsilyl)amide (42.1 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 -15C. 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 (silica gel, 14% ethyl acetate/hexanes) to give 3-5 as a colorless oil. TLC Rf 0.5 (20% ethyl acetate/hexanes).
1 H NMR (300 MHz, CHC13) 8 7.30-7.18 5H), 4.67 3H), 4.19 2H), 3.99 1H), 3.58 2H), 3.33 (dd, 1H, J=3.2, 12.0 Hz), 2.75 (dd, 1H, J=9.7, 13.5 Hz), 2.23 1H), 2.18-1.82 4H), 1.77- 1.60 1H), 1.71 3H).
Step 5: Ethyl 2-oxo-3(S)-(3-methylenebutvl)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 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).
1H NMR (300 MHz, CHC13) 8 7.30-7.22 5H), 4.69 3H), 4.17 2H, J=5.1 Hz), 3.89 1H), 3.38 3H), 2.74 1H), 2.13-1.63 6H), 1.71 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 at reflux for 2 h, cooled, and evaporated. The residue was chromatographed (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, CHC13) 5 6.47 (br s, 1H), 4.73 2H), 3.31 (m, 2H), 2.33 2H), 2.08 3H), 1.81 1H), 1.74 3H), 1.44 (s, 1H).
Step 6: Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidin- l-yl)acetate (3-7) To a solution of 3-6 (2.50 g, 16.3 mmol) in THF (40 mL) at -78° C was added sodium bis(trimethylsilyl)amide (17.1 mL, 17.1 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 NH4C1 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 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, CHC13) 6 4.73 2H), 4.18 2H, J=7.1Hz), 4.06 (dd, 2H, J=17.6, 20.8 Hz), 3.42 2H), 2.44 1H), 2.27 (m, 1H), 2.12 3H), 1.75 1H), 1.74 3H), 1.50 1H), 1.28 (t, 3H, J=7.3 Hz).
Step 7: Ethyl 2 -oxo-3(S)-(3-oxo-butyl)pyrrolidin-1-yl)acetate (3-8) To a solution of 3-7 (3.35 g,14.0 mmol) and Nmethylmorpholine-N-oxide (3.27 g, 28.0 mmol) in THF (10 mL) and water (1 mL) was added Os04 (5.7 mL, 0.56 mmol; 2.5 t-butanol).
After 1 h, NaIO4 (5.99 g 28 mmol) in warm water (30 mL) was added 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 Os04.
-299 WO 98/44797 PCT/US98/06823 TLC Rf 0.78 (70:20:10 chloroform/ethyl acetate/MeOH).
1H NMR (300 MHz, CHC13) 4.19 2H, J=7.2 Hz), 4.03 2H), 3.41 2H), 2.68 2H, J=9.4 Hz) 2.45 1H), 2.27 1H), 2.17 3H), 1.97 1H), 1.78 2H), 1.28 3H, J=7.2 Hz).
Step 8: Ethyl 2-oxo-3(S)-[2-([1,8]-naphthyridin-2-yl)ethyl] pyrrolidin-1-vl)acetate (3-9) A mixture of 3-8 (3.25 g, 13.5 mmol), 2-amino-3-formylpyridine (2.2 g, 18.2 mmol; for preparation see Synth. Commun. 1987, 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).
1H NMR (300 MHz, CHC13) 5 9.08 1H), 8.16 2H), 7.47 (m, 2H), 4.17 4H), 3.42 2H), 3.21 2H, J=6.0 Hz), 2.56 1H), 2.39 2H), 2.08 1H), 1.87 1H), 1.27 3H, J=7.1 Hz).
Step 9: Ethyl 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin- 2-yl)ethyllpyrrolidin-1 -l)acetate (3-10) A mixture of 3-9 (3.33 g, 10.2 mmol) and 10% Pd/carbon 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 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, CHC13) 8 7.05 1H, J=7.3 Hz), 6.38 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 4H), 2.69 4H), 2.51 IH), 2.28 (m, 2H), 1.90 2H), 1.78 2H), 1.27 3H, J=6.9 Hz).
300 WO 98/44797 WO 9844797PCTIUS98/06823 Step 10: 2-Oxo-3 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2vl)ethylllpyrrolidin-.1-ylDacetic acid (3-11) A mixture of 3-10 (0.60 g, 1.81 mmnol) and 6N HCl mL) was heated at 60' C for 1 h. Evaporative removal of the solvent gave 3-11 as a yellow oil.
1H NMR (300 MHz, DMSO-d6) 6 8.4 (br s, 1H), 7.60 iN, J=7.3 Hz), 6.63 1 H, J=7.3 Hz), 3.92 (dd, 2H, J= 17.6, 25.9 Hz), 3.43 (in, 2H), 3.35 (in, 2H), 2.74 (in, 4H), 2.28 (in, 2H), 2.03 (mn, 1H), 1.82 (in, 2H), 1.67 (in, 2H).
Step 11: 2-Oxo-3 [2-(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyl]-pyrrolidin- 1 -yl)acetyl-3 (S)-pyridin-3 -yl- P-alanine ethyl este r (3-13)- A mixture of 3-1[ (0.30 g, 0.882 mmol), amino acid ester 3-12 (Rico et al., J. Org. Chem., 1993, 58, 7948), (0.354 g, 1.32 minol), EDC (0.220 g (1.15 minol), HOBT (0.143 g, 1.05 minol) and NMM (0.680 mL (6.18 mmol) in CH3CN (5 mL) and DMF (3 mL) at 00 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, and dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20: chloroform/ethyl acetate/MeOH to give 3-13 as a colorless foam.
TLC Rf 0.31 (70:20:10 chloroform/ethyl acetatefMeOH).
1H NMR (300 MHz, CHCl3) 5 8.55 1H, J=2.2 Hz), 8.50 (dd, 1H, J= 1.5, 4.6 Hz), 7.64 (in, 2H), 7.23 (in, 1H), 7.05 1H, J=7.3 Hz), 6.38 1H, J=7.3 Hz), 5.40 (in, 1H), 4.98 (br s, 1H), 4.01 (in, 4H), 3.39 (in, 4H), 2.85 (in, 2H), 2.68 (in, 4H), 2.49 (in, 1H), 2.25 (in, 2H), 1.83 (mn, 4H), 1.16 3H, J=7.2 Hz).
Step2 14: 2-Oxo-3 2 -(5,6,7,8-tetrahydro[ 1,8]-naphthyridin- 2-yl)ethyl]pyrrolidin- 1 -yl)acetyl-3(S )-pyridin-3-yl-P1alanine (3-14) To a solution of 3-13 (0.049 g, 0.102 minol) in THF (1 mL) and water 3 inL) at 0 0 C was added 1iM LiOH 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/NH40H to give 3-14 as a colorless foam.
TLC Rf 0.15 (25:10:1:1 ethyl 1 H NMR (300 MHz, DMSO-d6) 8 8.74 1H, J=8.3 Hz), 8.51 1H), 8.42 2H), 7.70 1H, J=8.1 Hz), 7.33 1H), 7.21 1H, J=7.3 Hz), 6.36 1H, J=7.3 Hz), 5.14 1H), 4.00 1H, J=16.8 Hz), 3.70 1H, J=16.6 Hz), 3.30 4H), 2.68 7H), 2.20 3H), 1.71 (m, 4H).
EXAMPLE 4 (S)-l-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-imidazolylmethyl]-5-[2- (methanesulfonyl)ethyl]-2-piperazinone dihydrochloride Step A: 1-triphenvlmethyl-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 solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step B: 1-triphenvlmethyl-4-(acetoxymethyl)-imidazole Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 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 5% aq. HC1 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 hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and a-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 provide the solid imidazolium bromide salt. The filtrate was concentrated 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 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 as a white solid which was used in the next step without further purification.
Step D: 1-( 4 To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of 3:1 THF/water at 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 and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude 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 To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then S03-pyridine complex (40.5 g, 254 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.
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-dimethylhydroxylamine hydrochloride (14.1 g, 0.144 mol), EDC hydrochloride (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-dimethylhydroxylamine 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 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.
Step G: (S)-2-(tert-butoxycarbonylamino)-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 -50C under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min, maintaining the temperature below -40 0 C. When the addition was complete, the reaction was warmed to 5 0 C, then recooled to -45 0 C. Analysis by tic revealed incomplete reaction. The solution was rewarmed to 5 stirred for 30 minutes, then cooled to -304 WO 98/44797 PCT/US98/06823 0 C. A solution of potassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly added, maintaining the temperature below 0 C. The mixture was wasmed to 5°C, filtered through Celite, and concentrated in vacuo to provide the title aldehyde.
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 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 CHC13, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with ethyl acetate in hexane to obtain the title compound.
Step I: (S)-4-(tert-butoxycarbonyl)- 1-(3-chlorophenyl)-5-[2- (methvlthio)ethvllpiperazin-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 0°C with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwise, and the reaction stirred at 0°C for 2h.
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 0°C under argon. Cesium carbonate (63.9 g, 196 mmol) was added, and the reaction was stirred 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.
Ste J: (S)-4-(tert-butoxycarbonyl)- 1-(3-chlorophenyl)-5-[2- (methanesulfonvl)ethyllpiperazin-2-one A solution of the product from Step I (14.2 g, 37 mmol) in methanol (300 mL) was cooled to 0°C, 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 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 crude sulfone. This material was chromatographed on silica gel with 60-100% ethyl acetate in hexane to obtain the titled compound.
Step K: 1-(3-chlorophenyl)-5-[2-(methanesulfonyl)ethyl] piperazin-2-one Through a solution of Boc-protected piperazinone from Step J (1.39 g, 3.33 mmol) in 30 mL of EtOAc at 0°C 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 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.
306 WO 98/44797 PCT/US98/06823 Step L: 1-(3-chlorophenyl)-4-[ 1- (4-cyanobenzyl)imidazolyl- 2 -(methanesulfonyl)-ethyl]-2-piperazinone dihydrochloride To a solution of the amine from Step K (898 mg, 2.83 mmol) and imidazole carboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (1.21 g, 5.7 mmol). The reaction was stirred for 23 hours, then quenched at 0°C with sat. NaHC03 solution. The solution was poured into CHC13, and the aqueous layer was back-extracted with 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 solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.
EXAMPLE 1-(3-chlorophenyl)-4-[ 4 -cyanobenzyl)imidazolyl-methyl]-2piperazinone dihydrochloride Step A: N-(3-chlorophenyl)ethvlenediamine hydrochloride To a solution of 3-chloroaniline (30.0 mL, 284 mmol) in 500 mL of dichloromethane at 0°C was added dropwise a solution of 4 N HCl in 1,4-dioxane (80 mL, 320 mmol 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 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 and 500 mL of sat. aq. NaHCO3 soln., cooled to 0°C, and di-tertbutylpyrocarbonate (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 further purification.
Step C: N-[2-(tert-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)-2chloroacetamide A solution of the product from Step B (77 g, ca. 282 mmol) and triethylamine (67 mL, 480 mmol) in 500 mL of CH2C12 was cooled to o0C. Chloroacetyl chloride (25.5 mL, 320 mmol) was added dropwise, and the reaction was maintained at 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 with water, sat. aq. NH4C1 soln, sat. aq. NaHCO3 soln., and brine. The solution was dried (Na2S04), filtered, and concentrated in vacuo to provide the chloroacetamide as a brown oil which was used in the next step without further purification.
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 K2C03 (88 g, 0.64 mol).
The solution was heated in an oil bath at 70-75 0 C for 20 hours, cooled 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 concentrated 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 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 HC1 gas. The saturated solution was warmed to 0°C, and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HC1, and the mixture was warmed to room temperature.
The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2C12 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2C12 (8 x 300 mL) until tic analysis indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.
Step F: 1-(3-chlorophenyl)-4-[1-( 4 -cyanobenzyl)imidazolylmethyl]- 2-piperazinone dihydrochloride To a solution of the amine from Step E (55.4 mmol, prepared above) in 200 mL of 1,2-dichloroethane at 0°C was added 4A powdered molecular sieves (10 followed by sodium triacetoxyborohydride (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 stirred at 0°C. After 26 hours, the reaction was poured into EtOAc, washed with dilute aq. NaHCO3, and the aqueous layer was backextracted 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 propylamine (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 MeOH/CH2Cl2), 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 Preparation of N-(2(R)-amino- 3 -mercaptopropyl)-valyl-isoleucylleucine methyl ester (Compound 6-1) Step A. Preparation of N-(2(R)-t-butoxycarbonyl-amino-3triphenyl-methylmercaptopropyl)-valyl-isoleucyl-leucine 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 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 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.
Step B. Preparation of N-(2(R)-amino-3-mercaptopropyl)-valylisoleucvl-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 solution was treated immediately with 0.80 mL (5 mmol) of triethylsilane. 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 compound. 1H NMR (CD30D) 8 8.65 (1H, 4.45 (1H, 4.3 (1H, -310 WO 98/44797 PCT/US98/06823 3.7 (3H, 3.4 (1H, 3.15 (1H, 2.75-2.95 0.8-1.05 (18 H, FAB mass spectrum, m/z 447 (M 1).
Anal. Calcd for C21H42N404S 1.8 TFA: C, 45.24; H, 6.75; N, 8.56.
Found: C, 45.26; H, 6.77; N. 8.50.
EXAMPLE 7
N-(
2 (R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine (Compound 7-2) Step A. Preparation of N-(2(R)-t-butoxycarbonylamino-3triphenylmethylmercaptopropyl)-valvl-isoleucvl-leucine The product of Example 6, Step A (60 mg, 0.076 mmol) was dissolved in 1 mL of methanol and 150 pL of IN NaOH was added.
After stirring overnight, the solution was acidified with 150 pL of 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.
Step B. Preparation of N-( 2 (R)-amino-3-mercaptopropyl)-valylisoleucyl-leucine Using the method of Example 6, Step B, the protecting groups were removed with TFA and triethylsilane to provide the title compound. FAB mass spectrum, m/z 433 Anal. Calcd for C20H40N404S 2 TFA: C, 43.63; H, 6.41; N, 8.48.
Found: C, 43.26; H, 6.60; N. 8.49.
311 ~C ~l.~nr WV uY/44/Y 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 8-1) and 2 2 (R)-Amino-3-mercapto]-propylamino-3(S)methyllpentvloxy-3-phenvl-propionvl-homoserine (Compound 8-2) Step A: Preparation of N-(ox-chloroacetyl)-L-isoleucinol To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and 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 amide title compound (35 g, 100%).
Rf 0.3 CH2C12: MeOH (95:5); 1H NMR (CDC13) 5 6.80 (1H, brd, J 5 Hz), 4.10 (2H, 3.84 (1H, 3.79 (2H, 2.65 (1H, brs), 1.72 (1H, 1.55 (1H, 1.17 (1H, 0.96 (3H, d, J 6Hz) 0.90 (3H,t, J=6 Hz).
Step B: Preparation of 5(S)-[l(S)-methyl]propyl-2,3,5,6-tetrahydro-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 0°C was slowly 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 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 NaCI 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 S (CDC13) 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 Hz), 3.45 (1H, brqt, J 3.5 Hz), 1.70-1.45 (2H, 1.34 1.15 (1H, 0.96 (3H, t, J 6.5 Hz), 0.94 (3H, d, J 6.5 Hz).
Step C: Preparation of N-(tert-butoxycarbonyl)-5(S)-[1(S)methyllpropyl-2.3.5.6-tetrahvdro-4H-1.4-oxazin-3-one 5(S)-[1(S)-Methyl]propyl-2,3,5,6-tetrahydro 4H-1,4oxazin-3-one (12.2 g, 0.0776 mol) and DMAP (18.9 g, 0.155 mol) 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 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°C Anal. Calc'd. for C13H2304N C, 60.68; H,9.01; N, 5.44.
Found: C, 60.75; H, 9.01; N, 5.58.
IH NMR (CDC13) 8 4.25 (1H, d, J 15 Hz), 4.15 (1H, d, J 15 Hz), 4.15 4.00 (2H, 3.73 (1H, dd, J 10 and 2 Hz), 1.88 (1H, qt, J 6 Hz), 1.55 (9H, 1.50 1.36 (1H, 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 [1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3one 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 1M solution in THF, 24.58 mmol) at -78 0 C under argon. After stirring for 10 minutes, benzyl bromide (2.25 ml, 18.99 rmmol) was added over 5 minutes and the resulting mixture was stirred at -78 0 C for 3 hours. After this time, the 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 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (24.6 ml) and allowed to warm to room temperature. This mixture was diluted with brine (50 ml) and water 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 title compound (5.12 g, 67%) as a clear oil.
Rf 0.25 EtOAc:Hexanes (20:80); 1H NMR (CDC13) 5 7.35 7.15 (5H, 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, 3.12 (1H, dd, J 12 and 7 Hz), 1.47 (1H, 1.25 (1H, 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)-methyllpentyloxv-3-phenyl-propionic acid To a stirred solution of N-(tert-butoxycarbonyl)-2(S)- 1(S)-methyl]-propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3one (5.1 g, 14.7 mmol) in THF (150 ml) and water (50 ml) at 0°C 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 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 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)-[1(S)-methyl]propyl- 2 3 ,5, 6 -tetrahydro-4H-1,4-oxazin-3-one (0.82 g 22%) and then with MeOH in CH2C12 to afford the title compound (4.03 g, as a viscous oil.
Rf 0.4 MeOH:CH2Cl2 (5:95) 0.3% AcOH; 1H NMR (d6 DMSO) 5 7.35 7.10 (5H, 6.68 (1H, br, 3.75 (1H, dd, J 7.5 and 2.5 Hz) 3.54 (1H, 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, 0.98 (1H, sept, J 6 Hz), 0.78 (3H, t, J 6 Hz), 0.65 (3H, d, J 6 Hz); FAB MS 366 266 (MH2+ CO2tBu).
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)amino- 3 (S)-methyl]-pentyloxy-3-phenylpropionic acid (0.53 g, 1.45 mmol) and 3-hydroxy-l, 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, mmol). The pH was adjusted to pH= 6.5 by addition of NEt3 (the pH 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 (NaS04). Evaporation in vacuo (sufficient to remove DMF) and chromatography over silica gel eluting with acetone in CH2C12 afforded the title compound (520 mg, 80%) as a white solid, mp 115-117°C.
Rf 0.3 Acetone: CH2C12 (5:95).
1H NMR (CDC13) 8 7.73 (1H, brd, J=5 Hz), 7.40-7.15 (5H, 4.68 (1H, dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, 4.33-4.18 (1H, 4.20 -315 WO 98/44797 PCT/US98/06823 (1H, dd, J=7 and 3 Hz), 3.78 (1H, 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=l 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, 1.07 (1H, 0.87 (3H, t, J=6.3 Hz), 0.79 (3H, d, J=6 Hz).
Step G: Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy- 3-phenylpropionvl-homoserine lactone hydrochloride Anhydrous HC1 gas was bubbled through a cold (0°C) 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 0°C for 1 hr. The solution was purged with nitrogen and the mixture concentrated in vacuo to afford the title compound as a sticky foam which was used without further purification.
1H NMR (d6 DMSO) 5 8.60 (1H, d, J=7 Hz), 8.08 (3H, brs), 7.35-7.15 4.60 (1H, qt, J=8 Hz), 4.36 (1H, t J=7.5 Hz), 4.22 (1H, q, Hz), 4.15-3.95 (2H, 3.64 (1H, dd, J=9 and 2.5 Hz), 3.15-3.00 (2H, 2.92 (1H, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, 1.65 (1H, m), 1.43 (1H, 1.07 (1H, 0.82 (3H, t, J=6 Hz), 0.72 (3H, d, Hz).
Step H: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercap-to]propylamino-3(S)methyll-pentvloxv-3-phenylpropionyl-homoserine lactone 2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine hydrochloride (6.7 mmol) and N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5 mmol) (prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine by the procedure of Goel, Krolls, Stier, Keston, S. Org. 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 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 (CD30D) 8 7.60-7.05(20H, 4.64 (1H, d, J=9.0Hz), 4.39 (1H, br t, J=9Hz), 4.25(1H, 3.93 (1H, 3.75-3.60(1H, 3.55 (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, 1.45 (9H, 1.40-1.20 (1H, m), 1.07 (1H, 0.87 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz).
Step I: Preparation of 2 (S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionylhomoserine lactone To a stirred solution of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (2.72 g, 3.49 mmol) in CH2C12 (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).
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 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 WO 9844797PCT[US98/06823 1H NMR 8 (CD3OD) 7.40-7.15 4.55-5.40 (2H, in), 4.33 (1H, in), 4.18 (OH, in), 3.90-3.62 (3H, in), 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, in), 3.15-2.95 (2H, in), 2.88 (1H, dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, mn), 1.92 (1H, in), 1.49 (1H, in), 1.23 (1H, in), 0.94 (3H, t, J=6 Hz), 0.90 (3H, d, J=6Hz).
FAB MS 873 438 361 (MH±+Ph) 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.
Step J: Preparation of [2(R)-Amino-3-inercapto]propylamino-3 (S )-methyllpentyloxy-3 -phenyipropionylhomoserine 2 2 (R)-Amino-3-mercapto]propyl-amino-3(S)methyllpentyloxy-3-phenylpropionyl-homoserine lactone (0.00326 mmol) was dissolved in methanol (0.0506 ml) and iN sodium hydroxide (0.0134 ml) was added followed by methanol (0.262 ml). The conversion of the lactone to the hydroxy-acid was confirmed by HPLC analysis and NMR.
EXAMPLE 9 Preparation of [2(R)-Ainino-3 -mercapto]-propylainino-3 Methyllpentyloxy-3-phenylpropionyl-methionine Step A: Preparation of [2(S)-[2(R)-(tert-butoxy-carbonyl)amino-3-triphenyl-methylmercapto] -propylainino-3 inethyl1 entyloxy-3-12henyl1 ro ~iony1-methionine To a solution of [2(S )-[2(R)-(tert-butoxycarbonyl)amino- 3 -triphenylinethylinercapto]-propylamino-3(Sy..methylypentyloxy-3-phenylpropionyl-methionine methyl ester (120 mng, 0.143 mmnol) in methanol (4 ml) was added sodium hydroxide (IN, 0.57 ml, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Another portion of sodium hydroxide (iN, 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 (1N, 0.87 ml). The aqueous solution was extracted with ethyl acetate three times. The combined extracts were dried (Na2S 04) and concentrated to yield the title compound (110 mg, 0.133 mnmol, NMR (CD3OD) 8 0.70 (3H, d, J=6Hz), 0.80 (3H, t, J=6Hz), 1.05 in), 1.34 (9H, 1.60 (H, in), 1.95 (3H, 2.7-2.9 (3H, 2.95-3.1 (2H, mn), 3.95 d of d, J=8, 4Hz), 4.27 d of d, J=8.6Hz), 7.1-7.4 (20H, in).
Step B: Preparation of [2(R)-Amino-3-mercapto]propylamino-3 (S )-methyllpentyloxy-3-phenylpropionyl.
inethionine The title compound was prepared in the same manner as that described in Example 8, Step 1, but using butoxycarbonyl)-amino-3 -triphenylmethylmercaptol-propylamino- 3 (S)-methyl]-pentyloxy-3-phenylpropiony-methionine in place of 2(S)- [2 [2 (tert-butoxycarbonyl)- amino- 3 -triphenylmethylmercapto] propylamino-3 (S )-methyl] -pentyloxy-3-phenylpropionyl-homoserine lactone. NMR (CD3OD) 8 0.82 (3H, d, J=6Hz), 0.95 (3H, t, J=6Hz), 1.20 in), 1.40 in), 1.85 in), 2.10 (3H, 2.4-2.6 (2H, in), 3.1-3.2 (2H, in), 3.35 d of d, J=14, 6Hz), 3.55 d of d, J=14, 4.20 d of d, J=10, 5Hz), 4.63 d of d, J=10.6Hz), 7.27 in).
Anal. Calcd for C23H39N304S202CF3C02H02H20: 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 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl_ester (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 (40 ml) cooled at 0°C. After the completion of the addition, the resulting mixture was warmed to room temperature and stirred overnight.
The reaction mixture was recooled to 0°C 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 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 NMR (CD30D) 5 2.04 2.21 2.98 (3H, 3.23 (2H, t, J=7Hz), 3.63 d of d, J=8.6Hz), 3.77 (3H, s).
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 that described in Example 8, Step F, but using methionine sulfone methyl ester in place of homoserine lactone hydrochloride. NMR 5 0.80 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1.12 1.47 (9H, 2.10 2.32 2.93 (3H, 3.5-3.7 (2H, 3.74 (3H, 4.01 d of d, J=7.4Hz), 4.60 d of d, J=9.5Hz), 6.60 d, J=8Hz), 7.25 (5H, m).
-320 WO 98/44797 WO 9844797PCTIUS98/06823 Ste C: Preparation of [2(S)-Amino-3 (S)-methyl]-pentyloxy- 3-phenyipropionyl-methionine sulfone methyl ester hydrochloride The title compound was prepared in the same fashion as that described in Example 8, Step G, but using N-(tert-butoxycarbonyl)- [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-phenyipropionyl-homoserine lactone.
NMR (CD3OD) 8 0.85 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.20 (H, in), 1.52 in), 1.72 in), 2.14 in), 2.38 in), 2.98 (3H, s), 3.57 d of d, J=12, 6Hz), 3.73 d of d, J=12, 9Hz), 3.78 (3H, s), 4.15 d of d, J=8.6Hz), 4.63 d of d, J=8.5Hz), 7.30 (5H, in).
Step D: Preparation of 2 2 (S)-12(R)-(tert-Butoxy-carbonyl)amino- 3-triphenylmethylmercapto] -propylamino-3 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)-12(S)-amino-3(S)methyl]pentyloxy-3-phenyl-propiony-methionine sulfone methyl ester hydrochloride in place of [2(S)-amino- 3(S)-inethyl]pentyloxy-3phenyipropionyl-hoinoserine lactone hydrochloride. NMR (CD3OD) 8 0.70 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1. 10 in), 1.47 (9H, 2.15 in), 2.67 in), 2.92 (3H, 3.67 in), 4.68 d of d, 6Hz), 7.15-7.45 (20H, in).
Ste E: Preparation of [2(R)-Amino-3-mercapto]propylamino-3 (S )-methyljpentyloxy-3-phenylpropionylinethionine sulfone methyl ester The title compound was prepared in a similar fashion as that described in Example 8, Step 1, but using butoxycarbonyl)amino-3 -triphenylmethylmercaptolpropylainino- inethyl]-pentyloxy-3-phenylpropiony..methionine sulfone methyl ester in place of 2 (R)-(tert-butoxy-carbonyl)-anuno-3-triphenyl.
321 WO 98/44797 WO 9844797PCTIUS98/06823 methylmercaptolpropylamino- 3(S)-methyl]pentyloxy-3 -phenylpropionyl-homoserine lactone. NMR (CD3OD) 8 0.83 (3H, d, J=6Hz), 0.93 (3H, t, J=6Hz), 1.20 mn), 1.51 in), 1.80 mn), 2.22 in), 2.43 in), 3.00 (3H, 3.78 (3H, 4.20 d of d, J=8.4Hz), 4.72 d of d, J=10, 6Hz), 7.30 (5H, in).
FABMS m/z 532 EXAMPLE 11I Preparation of 2 2 2 (R)-Amino-3-mercapto]-propylamino-3 methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 11-1) Step A: Preparation of 2 2 (S)-[2(R)-(tert-Butoxy-carbonyl)amino- 3 -triphenylmethylmercapto]-propylamino-3 methvllpentyloxy-3-phenyl-propionyl.methionine sulfone The title compound was prepared in a similar fashion as that described in Example 9, Step A, but using butoxycarbonyl)amino- 3-triphenylmethylmercapto] -propylainino-3 methyl]-pentyloxy-3-phenylpropionyl.methionine sulfone methyl ester in place of 2 (R)-(tert-butoxycarbonyl)amino-3-triphenylmethylinercaptolpropylamino-3(S)-methyllpentyloxy-methionine methyl ester. NMR (CD3OD) 8 0.79 (3H, d, J=6Hz), 0.90 (3H, t, J=6Hz), 1.47 (9H, 2.92 (3H, 4.08 in), 4.32 in), 7.15-7.35 (20H, in).
Step B: Preparation of [2(R)-Amino- 3-mercapto]propylamino-3(S )-methyl] -pentyloxy-3-phenylpropionylmethionine sulfone The title compound was prepared in a similar fashion as that described in Example 8, Step 1, but using inethyl]-pentyloxy- 3 -phenylpropionyl-methionine sulfone in place of 2 (R)-(tert-butoxycarbonyl)anino-.3-.triphenylinethylinercapto]propylainino-3 (S)-methyl]-pentyloxy-3-phenylpropionyl- 322 WO 98/44797 WO 9844797PCTJUS98/06823 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 in), 1.50 in), 1.82 mn), 2.24 in), 2.47 in), 2.98 (3H, 3.6-3.75 (3H, in), 4.20 d of d, J=9.5Hz), 4.64 d of d, J=9.6Hz), 7.30 in).
Anal. Calcd for C23H39N306S2-3CF3C02H: C, 40.51; H, 4.92; N, 4.89.
Found: C, 40.47; H, 5.11; N, 4.56.
EXAMPLE -12 Preparation of 2 2 (S)-[2(R)-Amino-3-mercapto-propylamino- 3(S)-methyl] -pentyloxy-3 -phenyipropionyl-methionine sulfone isop~ropyl ester
HS
H H 0
H
2 N :0 0 0- 0 0 2
S\
GH
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-inethionine sulfone with isopropyl alcohol using dicyclohexylcarbodiimide (DCC) and 4diinethylaminopyridine (DMAP) followed by deprotection with HCl in EtOAc. NMR (CD3OD) 8 0.83 (3H, d, J 6 Hz), 0.94 (3H, t, J 6 Hz), 1. 11-1.56 (2H, in), 1.28 (6H, d, J 6 Hz), 1.8-1.96 (1H, in), 2.12- 2.27 (1H, in), 2.89-3.0 (2H, in), 3.01 (3H, 3.06-3.3 (4H, in), 3.42 (1H, dd, J 6, 13 Hz), 3.65 (1H, dd, J 6,13 Hz), 3.68-3.91 in), 4.2-4.27 (1H, in), 4.61-4.7 (1H, in), 4.96-5.12 (2H, in), 7.19-7.44 mn).
323 WO 98/44797 WO 9844797PCTIUS98/06823 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 EXAMPLE 13 4- [1-(5-Chloro-2-oxo-2H- [1 ,2']bipyridinyl-5 '-ylmethyl)-l1H-pyrrol-2yl-methyll-benzonitrile Step 1: 5 -Chloro-5 '-methvl-[ 1.2'lbipvyridinvl-2-one 5-Chloro-2-pyridinol (2.26g, 17.4 mmol), methylpyridine (3.00g, 17.4 mmol), copper (0.022g, 0.35 mmol) and
K
2 C0 3 (2.66g, 19.2 mmol) were heated at 180'C for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO 3 The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried (Na 2 S 04) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH 2 1 2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid.
'H NMR (400 MHz, CDC1 3 5 8.37 1H), 7.96(d, J=3.OHz, 1H), 7.83 3=8.4Hz, 1H), 7.65(dd, J=2.4 and 8.Hz, 1H), 7.32(dd, J=2.9 and 9.7 Hz, 1H), 6.6 1(d, J=9.7Hz, 1H) and 2.39(s,3H)ppm.
SU 2: 5'-Bromomethyl-5-chloro- 1 .2'lbipyridinvl-2-one A solution of the pyridine from Step 1(1.O0g, 4.53 mmol), N-bromosucciniinide (0.81ig, 4.53 mmol) and ALBN (0.030g, 0.18 mmol) inCC1 4 (4OmL) 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 Cl 2 25:75 to 50:50 gradient elution) to afford the title bromide.
'H NMR (400 MHz, CDC1 3 5 8.55 1lH), 8.04( d, 1= 2.9 Hz, 1 8.01 J=8.4Hz, 1H), 7.88 (dd, J=2.4 and 8.6Hz, 1H), 7.34(dd, J= 2.9 and M.Hz, I1H), 6.61(d, 1=9.9Hz, 1H) and 4.51 (s,2H) ppm.
324 WO 98/44797 PCTIUS98/06823 Step 3: 4- [1-(5-Chloro-2-oxo-2H- [1, 2 1H-pyrrol-2-vlmethyll-benzonitrile hydrochloride The bromide from Step 2 (0.750g, 2.50 mmol) and the 4-(l-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (1.06g, 2.50 mmol) in CH 3 CN (10 mL) were heated at 60 0 C. 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 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 C1 2 and extracted with CH2C1 2 The organic extracts were dried (Na 2
SO
4 and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH 2 C2 4:96 to 5:95 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) 8 9.11 1H), 8.35 1H), 8.03(d, J=2.9Hz, 1H), 7.83 J=8.4 Hz, 1H), 7.76 (dd, J=2.4 and 9.6Hz, 1H), 7.68-7.58 3H), 7.48 1H), 7.31(d, J=8.6Hz, 2H), 6.68 J=9.3Hz, 1H), 5.53 2H) and 4.24 2H) ppm.
Analysis: Calc for C22HI 6 NsOC1: 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 BIOLOGICAL
ASSAYS.
The ability of compounds of the present invention to inhibit cancer can be demonstrated using the following assays.
SPA Assay avp3 Receptor Binding The test procedures employed to measure avp3 binding activity of the antagonist compounds of the oavp3 receptor of the present invention is described below.
-325 ll/" no I A An V. y oJ PCT/US98/06823
N-(
4 -Iodo-phenvlsulfonvlamino)-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°C was added pipsyl chloride (10.34 g, 34.2 mmol). After -5 minutes, 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 0°C and then acidified with concentrated HC1. The solid was collected and then washed with Et20 to provide acid AR-2 as a white solid.
1H NMR (300 MHz, D20) 6 7.86 2H, J=8Hz), 7.48 2H, J=8Hz) 3.70 1H), 2.39 2H).
4 -Iodo-phenvlsulfonvlamino)-3-alanine (AR-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and (40 ml) at 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 0°C and then added in a single portion to the reaction. After stirring for 20 minutes at 0°C, the reaction was heated to 90 0 C for 30 minutes and then recooled to 0°C. 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) 6 8.02 2H, J=8Hz), 7.63 2H, J=8Hz), 4.36 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 1H).
Ethyl 2 4 -iodo-phenylsulfonylamino)-3-alaninehydrochloride (AR-4) HCI gas was rapidly bubbled through a suspension of acid AR- (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0°C for 10 minutes. The cooling bath was removed and the reaction was heated to 60 0 C. After 18 h, the reaction was concentrated to provide ester AR-4 as a white solid.
-326 WO 98/44797 PCT/US98/06823 1H NMR (300 MHz, CD30D) 8 7.98 2H, J=8Hz), 7.63 2H, J=8Hz), 4.25 1H, J=5Hz), 3.92 2H), 3.33 1H), 3.06 1H), 1.01 3H, J=7Hz).
Ethyl 4-r 2 2 -Aminopvridin-6-vl)ethyllbenzoate A mixture of ester AR-5a (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication 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 was filtered through a celite pad and then concentrated to provide ester as a brown oil.
TLC Rf 0.23 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 7.95 2H, J=8Hz), 7.26 3H), 6.43 1H, J=7Hz), 6.35 1H, J=8Hz), 4.37 4H), 3.05 2H), 2.91 2H), 1.39 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 60°C. After -20 h, the reaction was concentrated to give acid AR-6 as a tan solid.
1 H NMR (300 MHz, CD30D) 8 7.96 2H, J=8Hz), 7.80 1H), 7.33 2H, J=8Hz), 6.84 1H, J=9Hz), 6.69 1H, J=7Hz), 3.09 4H).
Ethyl 4-[ 2 -(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenylsulfonvlamino)-13-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 pl, 5.72 mmol) and DMF (10 ml) was stirred for -20 h. The reaction was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (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 WO 9844797PCT[US98/06823 1 H NMR (300 MHz, CD3OD) 8 7.79 2H, J=9Hz) 7.61 2H, J=8Hz), 7.52 2H, J=9Hz), 7.29 (in, 1H), 7.27 2H, J=8H-z), 4.20 (in, 1H), 3.95 2H, J=:7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (in, 2H), 2.86 (in, 2H), 1.08 3H, J=7Hz).
4 2 2 -Aminopyridin6-y)ethy]benzoy..2(S).(4.iodophenyl sulfonylaminol--a~n (A-8) A solution of ester AR-7 (200 mng, 0.3213 minol) and 6N HC1 (30 ml) was heated to 60'C. After 20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20: 1: 1 EtOAc/EtOI-I NH4OHJH2O) provided acid AR-8 as a white solid.
TLC Rf 0.45 (silica, 20:20: 1:1 EtOAc/EtOHJNH4OI-LH 2
O)
1H NMR (400 MHz, DMSO) 8 8.40 (mn, 1H), 8.14 (Bs, 1H), 7.81 2H, J=8Hz), 7.62 2H, J=8Hz), 7.48 2H, J=8Hz), 7.27 (in, 3H), 6.34 1H, J=7Hz), 6.25 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (in, 2H), 2.97 (mn, 2H), 2.79 (in, 2H).
4- 2 2 -Aminopyridin-6-yl)ethyl)benzoyl..2(S)..(4-trimethylstannyl p2henylsulfonylamino-fD-alanine (AR-9) A solution of iodide AR-8 (70 mg, 0. 1178 minol), (CH3Sn)2 (49 WA, 0.2356 inmol), Pd(PPh3)4 (5 ing) and dioxane (7 ml) was heated to 90*C. After 2 h, the reaction was concentrated and then purified by prep HPLC (Delta-Pak C 18 15 pM I100A*, 40 x 100 mm; 95:5 5:95 H20/CH3CN) provided the trifluoroacetate salt. The salt was suspended in H20 (10 treated with NH40H (5 drops) and then lyophilized to provide amnide AR-9 as a white solid.
1 H NMR (400 MHz, DMSO) 8 8.40 (mn, 1H), 8.18 1H, J=8Hz), 7.67 (mn, 5H), 7.56 2H, J=8Hz), 7.29 2H, J=8Hz), 6.95-7.52 (in, 2H), 6.45 (bs, 2H), 4.00 (in, 1H), 3.50 (in, 1H), 3.33 (mn, 1H), 2.97 (in, 2H), 2.86 (in, 2H).
328 WO 98/44797 PCT/US98/06823 4 2 2 -Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4- 12 5 iodophenylsulfonylamino- -alanine An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na 1 2 5 I (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of AR-9 in 0.05 mL of 10% H2S04/ MeOH was made and immediately added to the Nal 2 5 I/iodobead vial.
After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH40H was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitrile (TFA):H20 TFA) to acetonitrile TFA):H20 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, lyophilized and diluted with ethanol to give approximately 1 mCi of which coeluted on HPLC analysis with an authentic sample of AR-8.
Instrumentation: Analytical and preparative HPLC was carried out 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 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.
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 P, WO 98/44797 PCT/US98/06823
MATERIALS:
1. Wheatgerm agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem 4. NaCI: Fisher CaCl2: Fisher 6. MgC12: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. AR-10 (specific activity 500-1000 Ci/mmole) test compound 11. Purified integrin receptor: avp3 was purified from 293 cells overexpressing avi3(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 13. 50 mM octylglucoside in binding buffer: 50-OG buffer
PROCEDURE:
1. Pretreatment of SPA beads: 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 In each assay tube, 2.5 il (40 mg/ml) of pretreated beads were suspended in 97.5 pll of binding buffer and 20 pl of buffer. 5 pll (-30 ng/tl) of purified receptor was added to the beads in suspension with stirring at room temperature for 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 4°C. The pellets were then resuspended in 50 pl of binding buffer and ll of 50-OG buffer.
3. Reaction The following were sequentially added into Optiplate in corresponding wells: Receptor/beads mixture (75 .1) (ii) 25 p.1 of each of the following: compound to be tested, binding buffer for total binding or 8-8 for non-specific binding (final concentration 1 gM) (iii) 8-10 in binding buffer (25 l1, final concentration 40 pM) (iv) Binding buffer (125 p1) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4 0
C
4. Plates were counted using PACKARD TOPCOUNT inhibition was calculated as follows: A total counts B nonspecific counts C sample counts inhibition x 100 av35 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 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 CaC12.
-331 t. I WO 98/44797 PCT/US98/06823 3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl-Nacetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.
Methods: 1. Plates (96 well, Nunc Maxi Sorp) are coated overnight at 4 °C with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 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 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 105 cells/ml).
3. Test compounds are prepared as a series of dilutions at 2X concentrations and added as 50 gl/well. Cell suspension is then added as 50 ml/well. Plates are incubated at 37 °C with 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 substrate solution (100 pl/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.
The next day, the reaction is developed by addition of 185 Il/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 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 iL): 3 H]farnesyl diphosphate or 3 H]geranylgeranyl diphosphate, Ras protein 50 mM HEPES, pH 7.5, 5 mM MgC12, 5 mM dithiothreitol and isoprenylprotein transferase. The FPTase employed in the assay was prepared by recombinant expression as described in Omer, Kral, Diehl, Prendergast, Powers, Allen, 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 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 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 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. IC5o values were determined with both transferase substrates near KM concentrations. Nonsaturating substrate conditions for inhibitor IC50 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 Rati 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 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., 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 After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetal bovine serum, 400 gCi[ 3 5 S]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., 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 NP40/20 mM HEPES, pH 7.5/5 mM MgC12/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 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 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 4 0 C, 200 pg of a 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 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 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 transformed with human Ha-ras, N-ras or Ki4B-ras can also be utilized.
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 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 Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound.
Photomicrographs are taken approximately 16 days after the cultures are seeded and comparisons are made.
In addition, the activity of the compounds of the present 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/Io9/n8t In vivo tumor growth inhibition assay (nude mouse) Rodent fibroblasts transformed with oncogenically mutated human Ha-ras or Ki-ras (10 6 cells/animal in 1 ml of DMEM salts) are injected subcutaneously into the left flank of 8-12 week old 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 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 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 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): 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 Group E: A+C Group F: A+D Group G: B C Group H: B D Additional doses of FTI and antagonist can be selected as needed.
-336

Claims (15)

1. A method for achieving a therapeutic effect in a mammal in need thereof which comprises administering to said mammal amounts of at least two therapeutic agents selected from a group consisting of: a) a famesyl-protein transferase inhibitor and b) an integrin antagonist; wherein the amount of a) alone or the amount of b) alone is insufficient to achieve said therapeutic effect.
2. 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 to achieve a therapeutic effect when used in achieving said therapeutic effect.
3. A 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 to achieve a therapeutic effect for use in achieving said therapeutic effect.
4. The use 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 to achieve a therapeutic effect for the manufacture of a medicament for achieving said therapeutic effect. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein an amount of a famesyl-protein transferase inhibitor and an amount of an integrin antagonist are administered simultaneously. 20 6. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein the integrin antagonist is a selective antagonist of the avp3 integrin.
7. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein i: the integrin antagonist is a selective antagonist of the avp5 integrin.
8. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein 25 the integrin antagonist is an antagonist of both the avp3 integrin and the av35 integrin.
9. 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 famesyl-protein transferase inhibitor; b) a selective antagonist of the avp3 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.
10. three therapeutic agents which are: a) a farnesyl-protein transferase inhibitor; b) a selective antagonist of the avp3 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 a therapeutic effect when used in achieving said therapeutic effect.
11. three therapeutic agents which are: a) a farnesyl-protein transferase inhibitor; b) a selective antagonist of the cav3 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 a herapeutic effect for use in achieving said therapeutic effect.
12. The use of three therapeutic agents which are: a) a farnesyl-protein transferase inhibitor; a selective antagonist of the avp3 integrin; and c) a selective antagonist of the avp5 integrin; c07897 338 wherein the amount of a) alone, the amount of b) alone or the amount of c) alone is insufficient to achieve a therapeutic effect for the manufacture of a medicament for achieving said therapeutic effect.
13. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein the therapeutic effect is treatment of cancer.
14. The method, therapeutic agents or use according to any one of claims 9 to 12, wherein the therapeutic effect is selected from inhibition of cancerous tumour growth and regression of cancerous tumours. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein the farnesyl-protein transferase inhibitor is selected from: a compound represented by formula (II- a) through (Il-c): (R 8 2) 1 R V-A1(CRa2)A(CR1a )n w (CR 2 )p R 4 R (I-a) (118)r 1R\2 V- A'(CR'a 2 )A 2 (CRan) (CR lb 2)N KN NJ R 3 R 4 (Il-b) (Rr R 3 .0 V A'(CRlaA 2 CRla 2 )n (W (CR N -b S.G R4 wherein with respect to formula (Il-a): (R 8 )r R 9 R 2 R 3 V Al(CR1a 2 ),A 2 (CR1a) W (CR2)p\ R 4 R (I-a) or a pharmaceutically acceptable salt thereof, Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C 3 -C 1 0 cycloalkyl, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, R 1 0 0oO-, R 11 S(O)m-, R'oC(O)NRO-, CN, N02, (R1o) 2 N-C(NRo10)-, R 1 Ro10OC(O)-, N 3 -N(R 1 0 or R11OC(O)NRO-, c) S C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 1 0 0oO-, R 1 IS(O)m-, R1oC(O)NRo-, CN, (R 10 2 N-C(NRo 0 RiOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R11OC(O)-NRio-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted C 1 4 alkyl, unsubstituted or substituted C28 alkenyl, unsubstituted or substituted C 2 _8 alkynyl, unsubstituted 'Il R6R 7 ~or R 6 RR or R6 or substituted aryl, unsubstituted or substituted heterocycle, 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or i r'Aubstituted with: a) C14 alkyl, b) (CH2)pOR 6 c) (CH2)pNR6R7, d) halogen, 2) C36 cycloalkyl, 3) OR 6 4) 6, S(O)R 6 S0 2 R 6 c07897 -NR 6 R 7 R 6 6) -NyR 0 R 6 7) 7I 7 0 8) -O..NRR 7 0 9) _Y 0 0 -,NR 6 R 7 11) -S0 2 -NRR 7 R 6 12) -N JS0 2 -R 7 13) rR 6 or 0 14) YOR 6 or 0 R 2 and R 3 are attached to the same C atom and are combined to form (CH2). wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)- R 4 and R 5 are independently selected from H and CH 3 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; C1-4 alkyl, C 3 -6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C14 alkoxy, b) aryl or heterocycle, C) halogen, d) HO, 0 f) S0 2 R 11 or g) N(R 10 or R 6 and R 7 may be joined in a ring; R 7 and Ria may be joined in a ring; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 R 1 0 C(O)NR 1 0 CN, N02, R 1 0 2 N-C(NRIO)-, R 10 C(O)- ,R 10 N 3 -N(RlO) 2 or Rl 1 OC(O)NRO-, and c) Cl-C 6 alkyl unsubstituted or substituted by aryl, heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S(O)m- ,R 1 0 0(O)NH-, CN, H 2 RlOC(0)-, RIO00(O)-, N3, -N(R 10 or R'OOC(O)NH-; R 9 is selected from: a) hydrogen, b) 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R 1 1 S(O)m-, R 10 0(0)NRO-, CN, NO 2 (R10) 2 Rl 0 R 1 0 N 3 -N(R 10 or R11OC(O)NRIO-, and C) 01-06 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S(O)m-, R'OC(0)NRO-, ON, (Rlo) 2 N-C(NR1 0 RlOC(0)-, R10OC(O)-, N3, -N(Rlo) 2 or R11OC(O)NRO-; R 1 0 is independently selected from hydrogen, 01-06 alkyl, benzyl and aryl; R 1 1 is independently selected from 01-06 alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, RAZ/ -C()NRlO-, -NRIOC(O)-, 0, -S(O) 2 -N(RO)S(O) 2 or S(O)m; V is selected from: a) ydrogen, b) heterocycle, c) aryl, d) 01-020 alkyl wherein from 0 to 4 carbon atoms are replaced with c07897 a a heteroatomn selected from 0, S, and N, and e) C 2 -C 2 o alkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is CH 2 or Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C 1 -4 alkyl, unsubstituted or substituted with: a) Cg- alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 6) CN, 7) NO 2 8) CE 3 9) -S(O)mR 6 10) -C(O)NR 6 R 7 or 11) C 3 -C 6 cycloalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; 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 4or with respect to formula (1l-b): VI A(CRla 2 ).A 2 (CRla2)n f) R3 R4 (lb or a pharmaceutically acceptable salt thereof, Ria, Rib, R 1 0 R 1 1 m, R 2 R 3 R 6 R 7 p, R7a, u, R 8 A', A 2 V, W, X, n, p, r, s, t and u are as defined above with respect to formula 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; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R' 1 S(O)m-, R'OC(O)NR' 0 CN, N02, (Rlo) 2 N-C-(NR 1 0 RlOC(O)-, R' 0 N3, -N(R' 0 or R11OC(O)NRIO-, and C) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 R' 1 S(O)m-, R'OC(O)NR' 0 CN, (R10) 2 N-C(NRO)-, RlOC(O)-, R10OC(O)-, N 3 -N(R1 0 or R11OC(O)NRO-; G is H2 or 0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C 1 4 alkyl, unsubstituted or substituted with: a) C14 20 alkoxy, b) NR 6 R 7 c) Cm cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6 R 7 6) CN, 7) N02, 8) CE 3 9) -S(O)mR 6 10) C(O)NR 6 R 7 or 11) C 3 -C 6 cycloalkyl; with respect to formula (Il-c): R 2 3~ V Al(CRla 2 2 (CRla 2 W-(CR'I 2)p' 25 or a pharmaceutically acceptable salt thereof, R18, Rib, R1 0 m, R 2 ,I R 3 ,I R 6 1 R 7 p, U, Rla, R 8 A', A 2 V, W, X, n, r and t are as defined above with respect to formula R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; G is 0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C14 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C 3 -6 cycloalkyl, d) aryl or heterocycle, e) HO, I) -S(O)mR 6 or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6 R7, 6) ON, 7) N02, 8) CE 3 9) -S(O)mR 6 10) -C(O)NR 6 R 7 or 11) 03-06 cycloalkyl; and s is 1; a compound represented by formula (11-d): c07897 341 R V Al(CRla,)nA(CRla)n X R 4 II-d wherein: Ri8 and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, 03-Cia cycloalkyl, C2-06 alkenyl, 02-06 alkynyl, R 10 R 11 R 1 0 0(O)NR 10 (R 1 0 Rlo 2 N-C(NRO)-, CN, N02, RlOC(O)-, N3, -N(RO) 2 or RilOC(O)NRO-, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted 01-06 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, RI'O-, R 11 S(O)m-, RIOC(O)NRO-, (R10)2NC(O)-, R1O 2 N-C(NRIO)-, ON, RlOO(O)-, N3, -N(R 10 and RliOC(O)-NRO-; R 2 R 3 R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, halogen, Ci- 06 perfluoroalkyl, R 1 2 R 1 1 RI 0 O(O)NRlO-, (R 1 0 2 R 1 1I0)O-, R1 0 2 NC(NRlO)-, ON, N02, RlOO(O)-, N3, -N(R 10 or R'iOO(O)NRO-, c) unsubstituted 01-06 alkyl, d) substituted 01-06 alkyl wherein the substituent on the substituted 01-06 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 03-Cia cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, R 1 2 R 11 S(O)m-r, R100(O)NRlo-, (RiO) 2 R1 0 2 N-C(NR 1 0 ON, Rl 0 N 3 -N(R 10 )2, and R'iOC(O)-NRO-; R 6 a, R6b, R~c, R6d and We~ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, halogen, 01-06prloolyR 2 R 1 1 R'OC(O)NR 1 0 (Rlo)2NC(O)-, RliC(O)O-, R1O 2 N-C(NRIO)-, ON, N02, RlQC(O)-, N 3 -N(R 10 or R11OC(O)NRO-, c) unsubstituted Ci- 6 alkyl, d) substituted 01-06 alkyl wherein the substituent on the substituted 01-06 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 03-010 cycloalkyl, 02- 06 alkenyl, 02-06 alkynyl, R 1 2 R 11 Ri 0 C(O)NR 1 0 (Rlo) 2 R1 0 2 N-C(NRlO);, ON, R1OO(O)-, N3, -N(R 10 and RiiOC(O)-NR 0 any two of R 6 a, R6b, R 6 c, R6d and RWe on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, 25 arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci4 alkoxy, b) aryl or heterocycle, halogen, d) HO, f) -S 2 R 1 g) N(R 10 )2 or h) C14 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 11 R100(O)NR10O, (R1)2N0(O)-, R1 0 2 N- C(NR10)-, ON, N02, RlOC(O)-, N 3 -N(R 10 or R'iOC(O)NR 10 and c) 01-06 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, rfurakl F, Cl, Br, R1 0 R 11 R 10 0(O)NH-, (R 10 R10 2 N0C(NRiO)-, ON, R 10 -N( 10 r RiOOCO)NH-;R 9 is independently selected from: a) hydrogen, b) 02-06akey,0 c07897 06 alkynyl, C1-06 perfluoroalkyl, F, Cl, Br, R1 0 R 1 1 R'OC(O)NR 10 (R' 0 R 1 0 2 N- ON, N0 2 R 10 N 3 -N(R' 0 or RllOC(O)NR'O-, and c) 01-06 alkyl unsubstituted or substituted by 01-06 perfluoroalkyl, F, CI, Br, R 1 0 R 11 R 1 0 C(O)NR 1 0 (R' 0 2 R 1 0 2 N- ON, R10C(0)-, N3, -N(R 1 0 or R1lOC(O)NRIO-; RIO is independently selected from hydrogen, 01-06 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R' 1 is independently selected from 01-06 alkyl and aryl; R12 is independently selected from hydrogen, 01-06 alkyl, 01-06 aralkyl, 01-06 substituted aralkyl, 01-06 heteroaralkyl, 01-06 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, 01-06 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A' and A 2 are independently selected from: a bond, -CH=CH-, -NRlOC(O)-, 0, -S(O) 2 -N(RI 0 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) 01-020 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) 02-020 alkenyl, provided that V is not hydrogen if A' is S(0)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; X is a bond, -OH=CH-, 0, -C(O)NR7-, -NR 7 -C(O)NR7C(0)-, -NR7-, -S(O) 2 N(RlO)-, N(R' 0 or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q isO0, 1, 2 or 3; r is 0to 5, provided that ris 0when V is hydrogen; and t is 0ori1; a compound represented by formula (11-e): 3 f/ (R 8 )r(9 2 :VA(Ia,( C RCR .c 2 )p X-(CR 2)p R 4 wherein: Ria, Rib, R 2 R 3 R 4 R 5 R 7 R 8 R 9 RIO, R 1 1 A 1 A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula from 1-3 of f(s) are independently N, and the ::remaining f s are independently CR 6 and each R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, halogen, 01-06 perfiuoroalkyl, R 1 2 R 11 R 10 0(0)NR1 0 (R' 0 2 25 RlIC(0)O-, R1O 2 N-C(NRIO)-, ON, N02, R1OC(O)-, N3, -N(R' 0 or Rl'0C(0)NR'O-, c) unsubstituted Ci- 6 alkyl, d) substituted 01-06 alkyl wherein the substituent on the substituted 01-06 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 03-010 cycloalkyl, 02- 06 alkenyl, 02-06 alkynyl, R 12 R 11 R'O0(0)NR' 0 (R 1 O)2N0(0)-, R1o 2 N-C(NR10)., ON, R1OC(0)-, N 3 -N(R 10 and Ri'0C(0)-NRO-; 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-, -(0H2)4- and -(OH 2 3 a compound represented by formula (R 9 A'CR V (CR 2 2 )p -(cR2 2 R 2 19) 2I2-f c07897 wherein: R 3 R 4 R 5 R6a-e, R 7 R 8 R 9 R 1 0 R 1 1 A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula from 1-2 of f(s) are independently N, and the remaining f's are independently CH; and RI and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C 3 -C1O cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R1 0 R 11 RlOC(O)NRO-, R' 1 C(O)O-, (Rl0) 2 R1O 2 N-C(NR10)-, CN, N0 2 RlOC(O)-, N 3 -N(R 10 or Ri 1 OC(O)NR 1 0 c) unsubstituted or substituted CI-C6 alkyl wherein the substituent on the substituted Cl-C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -CIO cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 1 0 0-, R 11 R 10 0(O)N R 1 0 (Rlo) 2 R 1 0 2 N-C(N R 1 0 CN, Rl 0 N 3 -N(R 1 0 and R' 10(0). NR' 0 a compound represented by formula (11-g): g-9' (R 8 fR9 V A' (CR1 2 2c1)\w (CR 2 2 X _(CR2 2 II-g wherein: R 3 R 4 R 5 R 7 R 8 R 9 R 1 0 R 1 1 A 1 A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula from 1-2 of f(s) are independently N, and the remaining f's are independently CH; from 1-3 of g(s) are independently N, and the remaining g's are independently CR 5 R, and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, 03-010 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, R1 0 R 11 R 10 C(O)NR 10 R 11 (R 10 2 R 1 0 2 N-C(NR 1 0 CN, N02, RIOC(O)-, N 3 -N(R 10 or R 1 IOC(0)NRO-, c) unsubstituted or substituted 01-06 alkyl wherein the substituent on the substituted Cl-C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, 03-010 cycloalkyl, 02-06 alkenyl, C 2 -C 6 alkynyl, R 10 R' 1 Rl 0 C(0)NR' 0 20 (R 1 0 R1O 2 N-C(NR10)-, CN, RIOC(O)-, N3, -N(RlO) 2 and R"lOC(O)-NRO..; and each R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -CIO cycloalkyl, C 2 -C 6 alkenyl, 02-06 alkynyl, halogen, CI-C6 perfluoroalkyl, R 1 2 RlIS(O)m-, R'OC(O)NR 10 (R 10 2 R' 1 R 1 0 2 N-C(NR 1 0 CN, N02, R 10 N3, N(RlO) 2 or R 11 0C(O)NRO-, c) unsubstituted 01-06 alkyl, d) substituted Cl-C 6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 0 3 -CIO cycloalkyl, C2-C6 alkenyl, 02-C6 alkynyl, R 12 0-, R 11 RIOC(O)NR10-, (Rlo) 2 R1O 2 N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 10 and RllOC(O)- NR' 0 or any two of R 6 on adjacent carbon atoms are combined to form a diradical selected from CH=CH-CH=CH-, -CH=CH-0H 2 -(CH2)4- and -(CH 2 3 a compound represented by formula (1l-h): R T I NRC HHH 11-h c07897 R O R 6 and O wherein Rc is selected from: o R 1 is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R 2 and R 3 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; R 4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; 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 methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH 2 CH 2 0H or CH 2 CH 2 CH 2 0H; 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; T is O or S(O)m; m is O, 1 or 2; n is O,1 or 2; 20 a compound represented by formula (ll-i): R R2a R 2b N-(CR b 2 II-i wherein: R la and R 1 b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 6 cycloalkyl, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, R 8 R 9 RBC(O)NRS-, CN, N02, (R8) 2 N-C(NR 8 R 8 25 N3, -N(R 8 2 or R9OC(O)NR 8 c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C 3 -C6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, RO 8 R 9 R 8 C(O)NR 8 CN, (R8) 2 N-C(NRB)-, R 8 R 8 N 3 -N(R 8 or RSOC(0)-NR 8 R 2a R2b and R 3 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C 2 -C6 alkenyl, R 8 R 9 R8C(0)NR 8 S 30 CN, N3, (R 8 2 R 8 RBOC(O)-, -N(R 8 2 or R90C(O)NR 8 c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 8 0-, R 9 R8C(O)NR 8 CN, NO 2 (R8) 2 N-C(NR8)-, R8C(0)-, R 8 N3, -N(R 8 halogen or R 9 OC(O)NR 8 and d) Ci-C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C 3 -C10 cycloalkyl; R 4 and R 5 are independently selected from: a) hydrogen, and 35 V (CRa 2 )A 2 (CR 2 2)p R 6 is independently selected from: a) hydrogen, b) c07897 unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-06 cycloalkyl, C2-C6 alkenyl, 02-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 R8C(O)NRS-, CN, NO 2 R8 2 N-C(NR8)-, R8C(O)-, R 8 N3, -N(R 8 or R 9 0C(O)NR 8 and c) Cl-C 6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C6 cycloalkyl, C 2 -C 6 alkenyl, C 2 C 6 alkynyl, Cl-C6 perfiuoroalkyl, F, Cl, Br, R 8 R9S(O)m,-, R8C(O)NH-, CN, H 2 R 8 R 8 N 3 N(R8) 2 or R800(O)NH-; R 7 is selected from: a) hydrogen, b) 02-06 alkenyl, C 2 -C 6 alkynyl, Cl-C 6 perfluoroalkyl, F, Cl, Br, R 8 R 9 R8C(O)NR-, CN, N02, (R8) 2 N-C-(NR 8 R 8 R 8 00(O)-, N 3 -N(RB)2, or R 9 0C(O)NR 8 and C) 0,-C 6 alkyl unsubstituted or substituted by CI-C 6 perfluoroalkyl, F, Cl, Br, R80O, R 9 R8C(O)NR 8 CN, (R 8 2 N-C(NR 8 R 8 R 8 N 3 -N(R 8 or R900(O)NR 8 R 8 is independently selected from hydrogen, Cl-C 6 alkyl, substituted or unsubstituted Cl-C6 aralkyl and substituted or unsubstituted aryl; R 9 is independently selected from Cl-C6 alkyl and aryl; R 1 0 is independently selected from hydrogen, CI-C6 alkyl, substituted or unsubstituted CI-C6 aralkyl and substituted or unsubstituted aryl; A' and A 2 are independently selected from: a bond, CH=CH-, -C(O)NR 8 -NR 8 0, -N(R 8 -S(O) 2 N(R 8 -N(R 8 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl-C 2 o alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C2o alkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is W is a heterocycle; Y is selected from: a bond, -C(R 10 )=C(R 10 -C(R 10 -C(OR'G)R' 0 CN(R 1 O) 2 R 10 -OC(Rlo)2-, -NRIOC(Rl 0 -C(R 1 0 -C(Rlo)2NR 1 0 -C(O)NR 1 0 -NRlOC(O)-, 0, NC(O)RIO-, -NC(O)0R 10 -S(O) 2 N(RlO)-, -N(R 1 0 or S(O)m; Z is H2 or 0; m is 0, 1 or 2; n is 0, 1, 3or 4; p isO0, 1, 2, 3or4; ris to 5,provided that riso0when Vis hydrogenand uisorl1 a compound represented by formula (1l-rn): 3 V A(CR'2,WC' C;2,X-C;2 R 25 wherein: 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 0, and which also comprises a carbonyl, thiocarbonyl, -C(=NR 1 3 or sulfonyl moiety adjacent to the nitrogen atom :attached to Y; 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 0, and wherein Y is attached to Q through a carbon atom; R 1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, 03-CIO cycloalkyl, 02-06 alkenyl, 02-CS alkynyl, R' 0 R 1 1 R100(O)NRlO-, R' 1 (R10)2NC(O)-, R' 0 2N- ON, NO 2 N3, -N(RO) 2 or R'lOC(0)NR 10 c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or T~ysubstituted aryl, heterocyclic, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, R 10 RI 1 S(O)m-, *35< 0 C(O)NR 10 (R 10 2 RlO 2 N-C(NRl0)-, CN, R1OC(O)-, N3, -N(R 10 and R11OC(O)-NR'o-; R 3 c07897 346 R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -Cio cycloalkyl, 02-06 alkenyl, C 2 C6 alkynyl, halogen, C 1 06 perfluoroalkyl, R 1 2 R 1 R 1 OC(O)NR' 0 (RI) 2 R 1 1 R1O2N-C(NR10)-, ON, NO 2 RIOC(O)-, N3, -N(R' 0 or R11OC(O)NRO-, c) unsubstituted 01-06 alkyl, d) substituted 01-06 alkyl wherein the substituent on the substituted 01-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 03-Cia cycloalkyl, 02-C6 alkenyl, 02-06 alkynyl, R 1 2 R 11 R'OC(O)NR1 0 (R' 0 2 R1 2 NC(NR1o)-, ON, R 1 0 N 3 -N(R 1 0 2 and R 1 1 00(O)-NR 10 R6a, R6b, R6c, R6d and RWe are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 03-Cia cycloalkyl, 02-06 alkenyl, 02-C6 alkynyl, halogen, Ci-Ce perfluoroalkyl, R' 2 R' 1 R100(O)NRlO-, (R' 0 2 NC(O)-, R 11 S(O)2NR1 0 (RlO)2NS(O)2-, RllC(O)O-, R10 2 N-C(NRO)-, CN, N02, R1OC(O)-, N 3 -N(R' 0 or RIlOC(O)NRO-, c) unsubstituted01-C6 alkyl, d) substituted01-06 alkyl wherein the substituent on the substituted01-06 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 03-010 cycloalkyl, C2-06 alkenyl, 02-06 alkynyl, R 1 2 R 11 R100(O)NRIO-, (R10) 2 RlS(O)2NRO-, (R 10 2 NS(O) 2 R1O 2 N-C(NRIO)-, ON, R1OC(O)-, N 3 -N(R 10 and R'lOC(O)-NR 0 or any two of R6a, R6b, RWdand R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) CiA alkoxy, b) aryl or heterocycle, of 0* 20 d) -SO 2 R1 e) N(R 10 )2 or f) C1-4 perfluoroalkyl; R 8 is independently selected from: a) o:. hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R 1 1 R100(O)NRIO;, (R 1 0 )2NC(O)-, R11S(O) 2 NR10-, (RlO) 2 NS(O)2-, R 1 0 2 N-C(NR 1 0 ON, N02, R1OC(O)-, N 3 -N(R 10 or R11OC(O)NRO-, and C) 01-06 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, 03-010 cycloalkyl, 02-06 alkenyl, 02-06 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R' 1 RI 0 C(O)NR' 0 (R' 0 2 NC(O)-, Ri1S(O) 2 NRO-, (RIO) 2 NS(O) 2 R 1 0 2 N-C(NR 1 0 ON, RIOC(O)-, N3, -N(R 10 or R10OC(O)NH-; R 9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, CI, Br, R' 0 0-, R' 1 R100(O)NRO-, (R 1 0 R1O 2 N-C(NR10)-, ON, N02, N3, -N(R' 0 or R11O0(O)NRO-, and C) 01-06 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, 30 R 11 R 10 C(O)NR 10 (R10) 2 NC0)-, R1O 2 N-C(NR10)-, ON, R1OC(O)-, N3, -N(R 10 or oe o ;R11O0(O)NRO-; RIO is independently selected from hydrogen, CI-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R' 1 is independently selected from 01-06 alkyl and aryl; R 12 is independently selected from hydrogen, 01-06 alkyl, 01-06 aralkyl, 01-06 Substituted aralkyl, 01-06 heteroaralkyl, 01-06 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, 01-06 perfluoroalkyl, 2- aminoethyl and 2,2,2-trifluoroethyl; R 1 3 is selected from hydrogen, 01-06 alkyl, cyano, 01-06 alkylsulfonyl and 01-06 acyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, 0(),-C(O)NR 1 0 -NRIOC(O)-, 0, -N(R 1 0 -S(O) 2 N(Rl 0 or S(O)m; V is selected rom: a) hydrogen, b) heterocycle, c) aryl, d) 01-02o alkyl wherein from 0 to 4 carbon atoms are c07897 replaced with a heteroatomn selected from 0, S, and N, and e) C 2 -C2 0 alkenyl, provided that V is not hydrogen if A' is S(0)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(0)m; W is a heterocycle; X is a bond, -CH=CH-, 0, -C(0)NR 7 -NR 7 C(0)NR 7 -NR 7 -S(0) 2 N(Rl 0 or m is 0, 1 or 2; n is independently 0, 1, 2, 3or 4; pisindependently 0, 1, 2, 3or4; qis0, 1, 2or 3; ris to 5,provided that ris 0when Vis hydrogen; and t is 0 or 1; a compound represented by formula (1l-n): Rea-e P 3 (R 8 )r QR 9 V-A 1 (CR 1 2 ),.A(CR 1 2 W (C 2 (R4 wherein: R 1 R 2 R 3 R 4 R 5 R6a-e, R7, R 8 W 9 R 1 0 R 1 1 R 1 2 R 1 3 A 2 V, W, m, n, p, q, r and t are as previously defined with respect to formula (1l-rn); 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 0, 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 0 0 0 0 os~ or 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 0, and wherein Y is attached to Q through a carbon atom; or a pharmaceutically acceptable salt or disulfide thereof.
16. The method, therapeutic agents or use according to any one of claims 9 to 12, wherein *the protein substrate competitive inhibitor is selected from: 2(S)-butyl-1 -(2,3-diaminoprop-1 -yl)-1 -naphthoyl)piperazine; 1 -(3-amino-2-(2-naphthylmethylamino)prop-1 -yI)-2(S)-butyl-4-(1 -naphthoyl)piperazine; 2(S)-butyl-1 -{5-11 -(2-naphthylmethyl)J-4,5-dihydroimidazol)methyl-4-(1 -naphthoyl)piperazine; 1 .[5-(1-benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine; 14-5-[1 -(4-nitrobenzyl)]imidazolylmethy}-2(S)-butyl-4-(1 -naphthoyl)piperazine; 1 -(3-acetamidomethylthio-2(R)-aminoprop-1 -yl)-2(S)-butyl-4-(l -naphthoyl)piperazine; 2(S)-butyl-1 -imidazolyl)ethyllsulfony-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; 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)-piperazine; /s~9~~)-benzyl1 -imidazolyl-4-methyl-4-(1 -naphthoyl)piperazine; c07897 I -(2(R)-amino-3-(3-benzylthio)propy)-2(S)-butyI-4-(1 -naphthoyl)piperazine; 1 -(2(R)-amino-3-[3-(4-nitrobelzylthio)propyI)-2(S)-butyI-4-(I -naphthoyl)piperazine; 2(S)-butyl-1 -[(4-imidazolyl)ethyl]-4-(1 -naphthoyl)piperazine; 2(S)-butyl-1 -[(4-imidazoy)methyI-4-(l -naphthoyi)piperazifle; 2(S)-butyl-1 -naphth-2-ylmethyl)-1 H-imidazol-5-yI)acetyll-4-(1 -naphthoyl)piperazine; 2(S)-butyl-1 -naphth-2-ylmethyl)-1 H-imidazol-5-yI)ethyl]-4-(1 -naphthoylpiperazine; 1 -(2(R)-amino-3-hydroypropyl)-2(S)-butyI-4-(1 -naphthoyl)piperazine; 1 -(2(R)-amino-4-hydroxybutyl)-2(S)-buty-4-(I -naphthoyl)piperazine; 1 -(2-amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyI-4-(l -naphthoyl)piperazine; 1 -(2-amino-3-(2-hydroxyphenyl)propyl)-2(S)-buty-4-(1 -naphthoyl)piperazine; I -[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1 -naphthoyl)-piperazine; 2(S)-n-butyl-4-(2,3-dimethylphenyl)-1 2(S)-n-butyl-1 -(4-cyanobenzyI)imidazo-5-ylmethy]-4-(2,3-dimethyIphel)piperazil-5-ole; one; 2(S)-n-butyl-4-(1 -naphthoyl)-1 2(S)-n-butyl-4-(1 -naphthoyl)-1 2(S)-n-buyl-1 -(4-cyanobenzyl)imidazol-5-ylmethyll-4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 -(4-methoxybenzyl)imidazol-5-ylmethy]-4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 -(3-methyl-2-buteny)imidazol-5-ylmethyl]4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 -(4-fluorobenzyl)imidazol-5-ylmethyli-4-( 1 -naphthoyl)piperazine; :0::2(S)-n-butyl-1 -(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1 -naphthoyl)piperazine; 1 -(4-bromobenzy)imidazol-5-ylmethyl]-2(S)-l-butyl-4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-4-(1 -naphthoyl)-1 -[1-(4-t~dfuoromethylbenzyI)imidazo-5-ylmethyII-piperazile; 25 2(S)-n-butyl-1 -(4-methylbenzyl)imidazoi-5-ylmethyl]-4-(1 -naphthoyl)-piperazine; 2(S)-n-butyl-1 -(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1 -naphthoyl)-piperazine; 1 -(4-phenylbenzyl)imidazol5-ylmethyl]-2(S)-l-butyl-4-(1 -naphthoyl)-piperazile; *2(S)-n-butyl-4-(1 -naphthoyl)-1 2(S)-n-butyl-4-(1 -naphthoyl)-i-[1 1-[l -(4-cyanobenzyl)-1 H-imidazol-5-yllacetyl}-2(S)-n-butyl-4-(1 -naphthoyl)piperazine; 00: -(3-chlorophenyl)-4-[1 -(4-cyanobenzyI)-5-imidazolylmethy]-5-2-(methalfofl)ethyI]- 2 piperazinone -(3-chlorophenyl)-4-[1 -(4-cyanobenzyl)-5-imidazoylmethy1-5-2-(ethasltflnyI)ethyI]- 2 piperazinone -(3-chlorophenyl)-4-[1 -(4-cyanobenzy)-5-imidazolylmethy]-5-[2-(etha lfoflyI)methyI- 2 piperazinone -(3-chlorophenyl)-4A1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetaidol- 2 Spiperazinone T 4 +)-5-(2-butynyl)-1 -(3-chlorophenyl)-4-[l-(4-cyanobenzyI)-5-imidazolylmethyII-2-piperaziflofe -0 40 A 3-chlorophenyl)-4-[l -(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazi none c07897 5(S)-butyl-4-[1 -(4-cyanobenzyl-2-methyl)-5-imidazolylmethy]-1 -(2,3-dimethylphenyl)-piperazin-2-one 4-[1 -(2-(4-cyanophenyl)-2-propyl)-5-inidazoYllethyI]-l -(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 4-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyI)-1 -(3-chlorophenyl)piperazin-2-one 4-[3-(4-cyanobenzyl)pyidin-4-y]-1 -(3-chlorophenyl)-5(S)-(2-methylsulfoflylethyl)-piperazin-2-one 4-[5-(4-cyanobenzyl)-1 -imidazolylethyl]-1 -(3-chlorophenyl)piperazin-2-one; 2()[()[()aio3mrat~rplmn-()mty]pnyoy3peypoinl homoserine lactone, 2(S)-[2(S)-[2(R)-amino-3-mercaptopropylamino-3(S)-methypeloxy- 3 -phelpropiofl- homoserine, 2(S)-[2(S)-[2(R)-amino-3-merapto]propyamino-3(S)-ethytIpetyIoxy-2-methyl -3-phenyipropionyl- homoserine lactone, 2()[()[()aio3mrat~rplmn-()mty~etlx--ehl3peypoinl homoserine, 2()[()[()aio3mrat~rplmn-3S-ehlpnyoy4pneolhmsrn lactone, 2()[()[()aio3mrat~rplmn-()mtyjetlxpnaolhmsrn lactone, homoserine lactone, homoserine, lactone, lactone, 00 homoserine, homoserine lactone, 2()[()[()aio3mrat~rplmn-(S-ehlpnyti--ehl3peypoinl homoserine,. 2()[()[()aio3mrat~rplmio3S-ehlpnysloy--ehl3 phenyipropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-amino-3-mercapto]propyamino-3(S)-ethy-petylsufoyl-2-methyI- 3 c07897 350 2(S)-[2(S)-[2(R)-amino-3-mercaptopropylaniino-3(S)-ethyl-pefltyloxy-3-phelpropiofl-methioflie methyl ester, sulfone methyl ester (Compound 2()[()[()aio3mrat~rplmn-(S-ehlpnyoy3peypoinlmtinn sulfone (Compound 6), 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-ethyl]-peloxy-3-phelpropioflyl-methioflie sulfone isopropyl ester, 2-S-2S-2R-mn--ecpopoyaio3()mty]pnyoy3npt--lpoint methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-amino-3-mercaptopropylamino-3(S)-methyl]-petyoxy-3-laphth-2-yi-propioflyl- methionine sulfone, 2-(S)-[2(S)-[2(R)-amino-3-mercapto]propyamin-3(S)-methy]petyloxy-3-flaphth-1 -yl-propionyl- methionine sulfone methyl ester, 2-S-2S-2R-mn--ecpopoyaio3S-ehlpnyoy3npt- -yI-propionyl- methionine sulfone, 2-S-2S-2R-mn--ecpopoyaio3S-ehlpnyoy3mtyuaolmtinn methyl ester. lactone disulfide, :disulfide, methyl ester disulfide, I -(4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(4-cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole I -(2'-triuoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(4-biphenylethyl)-5-(4-cyanobenzyl)imidazole 1*2-rm--bpeymty) -4caoenySmdzl 1 -(2'-bromol-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole *1 -(2'-trfrmeth y-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazo 1C.('5-ihor)bpeymty)--4caoezi *mdzl 1-(2'-tilrmethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole I -(4-,'-dchloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole s 1 -(2'-mhox-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole I -(2'-chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole Rei 4-(3',5'.Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobelzyl) imidazole (2'-trifluoromethyl-4-biphenylmethyl)-5-(4-cyalobelzyl)-4-nlethylimidazole C07897 351 1 -(4-Biphenylmethyl)-5-(4-cyanopheloxy)-imidazole 5-(4-cyanophenyloxy)-1 -(2'-methyl-4-biphenylmethyl)-imidazole 5-(4-Biphenyloxy)-1 -(4-cyanobenzyl)-imidazole 5-(2'-methyl-4-biphenoxy)-l -(4-cyanobenzyl)-imidazole 5-(4-(3',5'-dichloro)biphenylmethyl)-1 -(4-cyanobenzyl)imidazole 1 -(4-biphenylmethyl)-5-(1 -(R,S)-acetoxy-1 -(4-cyanophenyl)methylimidazole 1 -(4-Biphenylmethyl)-5-(1 -(RS)-hydroxy-1 -(4-cyanophenyl) methylimidazole 1 -(4-Biphenylmethyl)-5-(l1-(R,S)-amino-1 -(4-cyanophenyl) methylimidazole 1 -(4-biphenylmethyl)-5-(1 -(R,S)-methoxy-1 -(4-cyanophenyl)-methylimidazole 1 -(4-cyanobenzyl)-5-(1 -hydroxy-1 -(4-biphenyl)-methyl imidazole 1 -(4-cyanobenzyl)-5-(1 -oxo-1 -(4-biphenyl)-methyl imidazole 1 -(4-cyanobenzyl)-5-(1 -hydroxy-1 -(3-fluoro-4-biphenyl)-methyl)- imidazole I -(4-cyanobenzyl)-5-(1 -hydroxy-1 -(3-biphenyl)methyl-imidazole I '-Biphenyllvinylene)-1 -(4-cyanobelzyl)imidazole 1 1 -(4-Biphenylmethy)-5-(4-bromopheloxy)-imlidazole 1 -(4-[pyrid-2-yI]phenylmethy)-5-(4-cyalobel)imidazole 1 -(2-phenylpyrid-5-ylmethy)-5-(4-cyalobel)i'fidazole 1 yd--lpdd5ymehl--(4-cyanobenzyl)-1 dzol N, N-bis(4-imidazolemethylamino-3[(3-carboxyphel)oxy~belzefle ~NN-bis(4-imidazolemethy)amino-4-(3-carboxyphel)oxylbelzefle NN-bis(4-imidazoemethy)amio3[(3-carbomlethoxypheyl)-oxylbelzefle NN-bis(4-imidazolemethy)amino-4-[(3-carbomethoxyphel)-oxylbelzefle N-(4-imidazolemethy)-N-(4-nitrobenzy)amilo-3-(pheloxy)belzefle N-(4-imidazolemethy)-N-(4-nitrobel)ailo-4-(pheloxy)belzefle N-butyl-N-[l (4-cyanobenzyl)-5-imidazolemethyailo-4-(pheloxy)belzefle N-fl -(4-cyanobenzyI)-5-imidazolemethyamino-4-(pheloxy)belzefle N-(4-imidazolemethy)amino-3-(3-carboxyphel)oxy~beflzefe 1 -(-ynbny)5iiaoymty)N(-ynbny~mnl4(hnx~ezn (±)-4-[(4-imidazolylmethyl)amino]pel-1 -(phenoxy)benzene 1 -(-ynbny)5iiaoymty)N(nbtlaiomty]4(hnx~ezn -(4-cyanobenzy)-5-imidazoylmethyl-N-(l-butyI)amil-l -(phenylthio)benzene -(4-cyanobenzyI)-4-imidazolylmethyl-N-(l-butyI)amifl-l -(phenylsulfinyl)benzefle \j R-44/ 1 -(4-cyanobenzy)-5-imidazolylmethy)amifloI-3-methoxy-4phelbelzele 040 -3-[4-(2-oxo-2-H-pyridin-1 -yI)benzyl]-3-H-imidazol-4-ylmethy]belzofitrile c07897 I 352 4-{3-[4-3-methyl-2-oxo-2-H-pyridin-1 -yl)benzylI-3-H-imidazol-4-ylmethylbelzofitdile 4-{3-[4-(2-oxo-piperidin-1 -yl)benzyl]-3-H-imidazol-4-ylmethyl~benzoflitrile 4-{3-13-methyl-4-(2-oxopiperidin-1 -y)-benzyl]-3-H-imidizol-4-ylmethyl1-benzoflitrile (443-[4-(2-oxo-pyrrolidin-1 -yI)-benzyl]-3H-imidizol-4-ylmethyl}-benzonitflle 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-pyidin-1 -yl)-benzyIJ-3-H-imidizol-4-ylmethyl-benzoflitle
41-[4-(5-chloro-2-oxo-2H-pyidin-1 -yl)-benzyl]-1 H-pyrrol-2-ylmethyl)-benzoflitrile 4-[l-(2-oxo-2H-[1 ,2']bipyridinyl-5'-ylmethyl)-1 H-pyrrol-2-ylmethyl]-benzonitrile 4-[1 -(5-chloro-2-oxo-2H-I1 ,2']bipyridinyl-5'-ylmethyl)-1 H-pyrrol-2-ylmethyl]-belzonitrile 4-[3-(2-oxo-1 -phenyl-1 ,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]belzonitflle -(3-chloro-phenyl)-2-oxo-1 ,2-dihydropyridin4-ylmethyl]-3H-imidazol4-ylmethyIlbelzonitle or a pharmaceutically acceptable salt, disulfide or optical isomer thereof. 17. The method, therapeutic agents or use according to any one of claims 1 to 4, wherein the integrin antagonist is selected from: 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 X is selected from NR' NR' NR 2 *NR 1 R 2 -NR'1iR3, .I-NRR3, c R4 -NR 1 NRR 4 ~NR' NR 2 -aryI-NR 1 Fe, -aryl-C-NR 2 R, -aryI-NR 1 -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 N, 0 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 l1-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, 0 or S, and wherein the polycyclic ring 25 system is either unsubstituted or substituted with R 2 R 3 and R 4 Y is selected from Co-8 alkylene, C:3io cycloalkyl, Co-a alkylene-NR 10 -CO-Co-8 alkylene, Co- alkylene-CONR 0 -Cm- alkylene, Co-a alkylene-O-Co-8 alkylene, CO-a alkylene-NRI 0 -Co- alkylene, alkylene-S()o-2-Co-8 alkylene, CO-a alyeeS2-ROC- alKylene, CO-a alkylene-NRI 0 -S02-Co-8 alkylene, Co-a alkylene-CO-Co-8 6.alkylene, (CH2)o-6 Orl( H6 (CH2)o-6 aryl-CO-(CH2)o-6, (CH2)o-6 aryl-CO-NR 1 (CH2)0-6 ee 30 aryINRlOCO(CH2)o-, or (H).CCH)o;Z and A are each independently selected from c07 897 0 11 (CH2)m (CH 2 )mO(CH 2 (CH 2 )mNR1I(CH 2 )n,(CH 2 )mNRllCNR 2 (CH 2 )n 0 0 0 11 1111 (CH 2 )mCNR 1 (CH 2 2 )mNR 1 C(CH 2 )n.(CH 2 )mL(0H 2 )n, S (CH 2 )mACH)n. (CH 2 )mSOz(CH 2 )ji (CH 2 )mS(CH 2 )n, (CH 2 )mSO(CH 2 (CH 2 )mSO 2 NR 1 1 (CH 2 )n, (CH 2 SO 2 (CH 2 (CH 2 )mCR 1 =CR 2 (CH 2 or (CH 2 )mrC-C1CH 2)n' C 1 1 where m and n are each independently an integer from 0 to 6; B is where pis an integer from 1 to 3; R 1 R 2 R 3 R 4 R 5 R 8 R 9 R1 0 R 1 1 and R 1 2 are each independently selected from hydrogen, halogen, Ci-io alkyl, aryl Co-a alkyl, amino Co-8 alkyl, 01-3 acylamino Co-8 alkyl, 01.0 alkylamino 004 alkyl, 01.0 dialkylamino Co-8 alkyl, aryl 00.0 alkylamino Co.0 alkyl, 01.4 alkoxyamino CH- alkyl, hydroxy 0146 alkylamino 00.0 alkyl, 01.4 alkoxy 00.0 alkyl, hydroxycarbonyl 00.0 alkyl, C14 alkoxycarbonyl alkyl, hydroxycarbonyl Co-6alkyloxy, hydroxy 014 alkylamino Co-a alkyl or hydroxy Co-e alkyl; R 6 is selected from hydrogen, fluorine, Ci-8aalkyl, hydroxy, hydroxy 01.0 alkyl, carboxy Co-a alkyl, Ci-6 alkyloxy, CI-6 alkylcarbonyl, aryl Cm. alkylcarbonyl, C,-6 alkylcarbonyloxy, aryl Co-6 0:10 alkylcarbonyloxy, Cl.0 alkylaminocarbonyloxy, C3-8cycloalkyl, aryl Co-a alkyl, 00.6 alkylamino 00.0 alkyl, Co-e dialkylamino 00.0 alkyl, 01.0 alkylsulfonylamino Co-6alkyl, aryl Co-a alkylsulfonylamino 00.0 alkyl, Ci- 8 alkyloxycarbonylamino Co-a alkyl, aryl Co-a alkyloxycarbonylamino Co- alkyl, 01.0 alkylcarbonylamino Co.0 alkyl, aryl 004 alkylcarbonylamino 00.0 alkyl, 0048 alkylaminocarbonylamino Co-6 alkyl, aryl Co.a 15 alkylaminocarbonylamino 00.0 alkyl, Co-8 alkylaminosulfonylamino 0046 alkyl, aryl Cu- alkylaminosulfonylamino 00.0 alkyl, 01.0 alkylsulfonyl Co-6 alkyl, aryl Co.0 alkylsulfonyl Co-6alkyl, Ci-e alkylcarbonyl Co-a alkyl, aryl 00.0 alkylcarbonyl 00.0 alkyl, 01.0 alkylthiocarbonylamino 00.0 alkyl, or aryl 00.0 alkylthiocarbonylamino Co.6 alkyl; wherein the alkyl or N atoms may be unsubstituted or substituted with R 5 R 7 is selected from hydrogen, 00.0 alkylamino Co-6 alkyl, Co-a dialkylamino 00.0 alkyl, aryl Cm- alkyloxycarbonylamino Com alkyl, aryl 00.0 alkylsulfonylamino 00.0 alkyl and aryl Com alkylcarbonylamino 00.0 alkyl; 07-20 polycyclyl Cm- alkylsulfonylamino 00.0 alkyl; 07-20 polycyclyl Co- alkylcarbonylamino 00.0 alkyl; C7-20 POlycyclyl Co-a alkylaminosulfonylamino 00.0 alkyl; C7-20 polycycyl Co-a alkylaminocarbonylamino Co-6 alkyl or C7-o polycyclyl Co- alkyloxycarbonylamino Cm- alkyl; *wherein the polycyclyl may be unsubstituted or substituted with R 1 4 R 1 5 R 1 6 and R 17 and wherein any of the alkyl groups may be unsubstituted or subsituted with R 1 4 and R 1 5 R 1 3 is selected fromhydroxy, 01-8 alkyloxy, aryl Co-a alkyloxy, 01.8 alkylcarbonyloxy Ci-4 alkyloxy, aryl Ci-8 alkylcarbonyloxy C1-4 alkyloxy, 01.0 dialkylaminocarbonylmethylOXy, aryl 01.0 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and wherein the FRZ carboxylic acid moiety of said amino acid is as the free acid or is esterified by 01.0 alkyl; and R 1 4 R' 5 44 R< 1 6and R17are each independently selected from hydrogen, halogen, Ci-io alkyl, 03-a cycloalkyl, oxo, c07897 aryl, aryl 0148 alkyl, amino, amino 01_8 alkyl, Ci_3 acylamino, C1_3 acylamino C018 alkyl, 01.6 alkylamino, C 1 alkylamino-Cia8 alkyl, C1_ dialkylamino, C1_6 dialkylamino C1_8 alkyl, Opt4 alkoxy, 01-4 alkoxy 01_6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01_6 alkyl, C1-3 alkoxycarbonyl, 01-3 alkoxycarbonyl C1_6 alkyl, hydroxycarbonyl-Oia6 alkyloxy, hydroxy, hydroxy 0146 alkyl, C1_6 alkyloxy-COjo alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, 01_8 alkyl-S(O)q, C1-8 alkylaminocarbonyl,C1.8 dialkylaminocarbonyl, Ci_8 alkyloxycarbonylamino, C1_8 alkylaminocarbonyloxy or 01. 8alkylsulfonylamino; a compound of the formula I-b: -H I-b NF1 2 11 wherein X is selected from -RCRR I or,~ Ar is a 4- to 1 -Membe red mono- or polycyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or S and wherein the mono- or polycyclic aromatic or non-aromatic ring system is either unsubstituted or substituted with R 2 R 3 and R 4 R 1 R 2 R 3 and R 4 are each independently selected from hydrogen, hydroxy, 01_8 alkyl, halogen, aryl Cu 4 alkyl, oxo, thio, amino-CH. alkyl, 01.3 acylamino Cua alkyl, 01.6 alkylamino 004 alkyl, C 1 _6 dialkylamino 00H alkyl, aryl Co-6 alkylamino Co-6 alkyl, 014 alkoxyamino Co 4 8 alkyl, hydroxy Ci_6 alkylamino Co-8 alkyl, C14 alkoxy Co-8 alkyl, carboxy Co- 8 alkyl, C 14 alkoxycarbonyl-Co-8 alkyl, carboxy Co- alkoxy, hydroxy 00.8 alkyl or 03.8 cycloalkyl Co-6 alkyl; R 5 is selected from hydrogen, C1.6 alkyl, Coo6 alkylaryl, ary or 0348 cycloalkyl 00.6 alkyl; R6, R 7 R 8 and R 9 are each independently selected from hydrogen, fluorine, Ci_8 alkyl, hydroxy, hydroxy C1_6 alkyl, carboxy-Co-s alkyl, Ci_6 alkoxy, C1_6 alkylcarbonyl, aryl Co-6 alkylcarbonyl, C1.o alkylcarbonyloxy, aryl Cm.. alkylcarbonyloxy, C1_6 alkylamino-carbonyloxy, C3-8 cycloalkyl, aryl Co-6 alkyl, Co-s alkylamino- Co-6 alkyl, Cu- dialkylamino Co-6 alkyl, 01_8 alkylsulfonylamino-Co-s alkyl, aryl Co-6 alkylsulfonylamino Co-6 alkyl, 0048 alkyl-SO2NR 3 -Co-8 alkyl, aryl Cu alkoxycarbonylamino 004 alkyl, aryl-0o48 alkyl- 25 SO 2 NR 3 -Co_8 alkyl, C1_8 alkoxycarbonylamino 00u alkyl, 01.8 alkylcarbonylamino Co-6 alkyl, aryl 0Cm alkylcarbonylamino-Co-6 alkyl, 0048 alkylaminocarbonylamino 00.6 alkyl, aryl 0048 alkylaminocarbonylamino 00.6 alkyl, 0048 alkylamino-sulfonylamino Co-s alkyl, aryl Cm4 alkylaminosulfonylamino-Co-6 alkyl, C1_6 alkylsulfonyl 0046 alkyl, aryl Co-6 alkylsulfonyl-Co-6 alkyl, 01.6 alkylcarbonyl 0046 alkyl, aryl 0046 alkylcarbonyl-Com alkyl, 0i_ alkylthiocarbonylamino Co-s alkyl, aryl Cm- alkyl-thiocarbonylamino Cm- alkyl, 0348 cycloalkyl 0046 alkyl, 0348 cycloalkyl Co-s alkylsulfonylamino Co- akyl, C3_ cvcloalkvl-Co-6 alkvlcarbonl, 0348 cvcloalkyl 0046 alkylaminocarbonyloxy or 0348 0. cycloalkyl 0046 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or .0 substituted with R 1 and R 2 R 1 0 is selected from hydroxy, 01-8 alkoxy, aryl CH- alkoxy, 0148 *alkylcarbonyloxy 014 alkoxy, aryl 0148 alkylcarbonyloxy-Opt4 alkoxy, 01.6 dialkylaminocarbonylmethoxy, aryl Ci-s 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 01_6 alkyl; and each n is independently an integer from 0 to three; provided that when R -Vhydrogen and X is Ar and Ar is a 6-membered monocyclic non-aromatic ring system containing one C07897 nitrogen atom and R 6 and R 7 are each hydrogen, and R 8 is selected from hydrogen or C1-6 alkyl, and RIO is selected from hydroxy, C018 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 C1-6 alkyl, then R 9 is selected from fluorine, hydroxy, hydroxy CI-6 alkyl, carboxy-Co-6 alkyl, CI-6 alkoxy, C1-6 alkylcarbonyl, aryl 0Cm alkylcarbonyl, 0146 alkylcarbonyloxy, aryl Co-6 alkylcarbonyloxy, Ci-6 alkylamino-carbonyloxy, Cm- cycloalkyl, aryl Co-6 alkyl, 00-6 alkylamino-Co-s alkyl, 0046 dialkylamino 0046 alkyl, aryl 0048 alkoxycarbonyl-amino Co-a alkyl, C,-8 alkoxycarbonyl amino Cm~ alkyl, Cl-a alkyl-carbonylamino Co-6 alkyl, aryl 0046 alkylcarbonylamino Cm 4 alkyl, CH. alkylaminocarbonylamino Co-6 alkyl, aryl Cu- alkylamino-carbonylamino Co. 6 alkyl, CO.8 alkylaminosulfonylamino Co- alkyl, aryl Cm- alkylaminosulfonylamino Cm- alkyl, Ci.6 alkylsulfonyl-Co-6 alkyl, aryl 0046 alkylsulfonyl Co.6 alkyl, 01.6 alkylcarbonyl-Co-6 alkyl, aryl Co-6 alkylcarbonyl Co 4 6 alkyl, Ci- 6 alkylthiocarbonyl-amino 004 alkyl, aryl Co-6 alkyithiocarbonylamino Co-6 alkyl, C3-8 cycloalkyl Co-6 alkyl, Cma cycloalkyl Co-6 alkylsulfonylamino-Co-6 akyl, 03-8 cycloalkyl Cm- alkylcarbonyl, C3-8 cycloalkyl-Co-6 alkylaminocarbonyloxy or C3-8 cycloalkyl 00m alkylamino-carbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with R' and R 2 and provided further that when R 5 is hydrogen and X is Ar and Ar is N- or and R 6 R 7 and R 8 are each hydrogen, and RIO is selected from hydroxy and 0148 alkoxy, then R 9 is selected from fluorine, 0148 alkyl, hydroxy, hydroxy 01-6 alkyl, carboxy 0046 alkyl, 0146 alkoxy, C1.6- alkylcarbonyl, aryl 004 alkylcarbonyl, 01-6 alkylcarbonyloxy, aryl 00-6 alkylcarbonyloxy, 01-6 alkylamino-carbonyloxy, Cma cycloalkyl, aryl Co-6 alkyl, 0046 alkylamino-C04 alkyl, 00-6 dialkylamino Co- 6 alkyl, 01.8 alkylsulfonylamino-Co-6 alkyl, 0048 alkyl-SO2NR 3 -Co-8 alkyl, aryl Co- alkoxycarbonyl-amino Co- alkyl, CI- alkoxycarbonylamino Co-a alkyl, C1.8 alkylcarbonylamino 0046 alkyl, aryl 0046 alkylcarbonylamino-0046 alkyl, Co-a alkylaminocarbonylamino 0046 alkyl, aryl Co- alkylaminocarbonylamino 0046 alkyl, Co-a alkylamino-sulfonylamino 0046 alkyl, aryl Co-a alkylaminosulfonylamino-Co-6 alkyl, 0146 alkylsulfonyl 0046 alkyl, aryl 0046 alkylsulfonyl-0o-6 alkyl, 0146 *alkylcarbonyl 0046 alkyl, aryl 004 alkylcarbonyl-Co.s alkyl, 0146 alkylthiocarbonylamino 0046 alkyl, aryl 0046 alkyl-thiocarbonylamino Co-6 alkyl, 03-8 cycloalkyl 0046 alkyl, 03-a cycloalkyl Co-6 alkylsulfonylamino Co-s akyl, C3- cycloalkyl-0046 alkylcarbonyl, 03-8 cycloalkyl 0046 alkylaminocarbonyloxy or Cma cycloalkyl 004 alkylaminocarbonylamino; wherein any of the alkyl groups may be unsubstituted or substituted with RI and R 2 a compound of the formula 1-c: 0 8 R R 9 X.Y.Z(CH 2 )r4"-N )C02R2 'OR R 11 wherein X is selected from A-NRIR I -NRLtC-NRR' a 5- or 6-membered monocyclic aromatic or ,,nnroai ring system containing 0, 1, 2, 3 or 4 heteroatomns selected from N, 0 or S wherein the 4 r6-membered ring system is either unsubstituted or substituted on a carbon atom with RI and R 2 c07897 or a 9- to lO-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, 0 or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 and R 2 y is selected from -N(C2m-, N -C-(CH 2 ym CN-C2i R 3 0 11 4JC-CH 2 -S(0)q-(CH 2 )F (CHA)n 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, 0 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 membered nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 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 R 1 R 2 R 4 R 5 R 1 3 and R 14 are each independently selected from hydrogen, halogen, Ci-io alkyl, Cm cycloalkyl, aryl, aryl Ci- 8 alkyl, amino, amino C1.6 alkyl, 01.3 acylamino, 01-3 acylamino C1-8 alkyl, Cl.6 alkylamino, 01.6 alkylamino-01-8 alkyl, Ci-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl,hydroxycarbonyl Ci-6 alkyl, 01-3 alkoxycarbonyl, 01-3 alkoxycarbonyl 01.6 alkyl, hydroxycarbonyl-C1.6 alkyloxy, hydroxy, hydroxy 01-6 alkyl, 01-6 alkyloxy-Ci-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C0l alkyl-S(0)q, C 1 8 aminocarbonyl, C1-8 dialkylaminocarbonyl, 01.8 alkyloxycarbonylamino, 01.6 alkylaminocarbonyloxy or C1-8 alkylsulfonylamino; R 3 is selected from hydrogen, aryl,-(CH2)p-aryl, hydroxy, C1-5 alkoxycarbonyl, aminocarbonyl, C3-8 cycloalkyl, amino 01.6 alkyl, arylaminocarbonyl, aryl 01.5 alkylaminocarbonyl, hydroxycarbonyl C1-6 alkyl, 01.6 alkyl, aryl 01. alkyl, 01-6 alkylamino 01-6 alkyl, aryl C1-6 alkylamino 01-6 01-6 dialkylamino C1- alkyl, 01.6 alkylsulfonyl, CO-8 alkoxycarbonyl,aryloxycarbonyl, aryl C- alkoxycarbonyl, 01.8 alkylcarbonyl, arylcarbonyl, aryl C1- alkylcarbonyl, C1-8 alkylaminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, arylaminosulfonylamino, aryl 01-8 alkylaminosulfonyl, 01.6 alkylsulfonyl, arylsulfonyl, aryl 01-6 alkylsulfonyl, aryl 01.8 alkylcarbonyl, 01-6 alkylthiocarbonyl, arylthiocarbonyl, or aryl 01.6 alkylthiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 13 and R 1 4 R 6 R 7 R 8 R 9 R 1 0 and R 1 1 are each independently selected from 30 hydrogen, aryl, -(0H2)p-aryl, halogen, hydroxy, 01-8 alkylcarbonylamino, aryl Ci-5 alkoxy, U alkoxycarbonyl, aminocarbonyl, 01.6 alkylaminocarbonyl, 01.6 alkylcarbonyloxy, Cm cycloalkyl, oxo, .1 amino, 01.6 alkylamino, amino 01-6 alkyl, arylaminocarbonyl, aryl 01.5 alkylaminocarbonyl, o: aminocarbonyl, aminocarbonyl 01-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01-6 alkyl, 01-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxy, 01-5 alkylcarbonylamino, aryl C1-5 alkoxy, 0 -5 alkoxycarbonyl, aminocarbonyl, 01-5 alkylamino-carbonyl, R 1 ,4 COi alkylcarbonyloxy, 03-8 cycloalkyl, oxo, amino, 01-3 alkylamino, amino 01-3 alkyl, arylamino- Sarbonyl, aryl 01-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C14 alkyl, hydroxycarbonyl, or c0789 7 hydroxycarbonyl C 1 5 alkyl, -(0H2)s C=-CH, -(0H2)s C=_C-C1_6 alkyl, -(0H2)s C=C-C3-7 cycloalkyl, -(CH- 2 C=-C-aryI, -(CH2)s C=_C-Cj_6 alkylaryl, -(CH2)s CH=CH 2 -(CH2)S CH=CH Ci_6 alkyl, -(CH2)s CH=CH-C3-7 cycloalkyl, -(OH- 25 CH=CH aryl, -(0H2)s CH=CH C1_6 alkylaryl, -(OH 25 SO 2 C 16 alkyl, -(CH2)s SO2C1.6 alkylaryl, Ci_6 alkoxy, aryl 01_6 alkoxy, aryl 01_6 alkyl, Cl.6 alkylamino C1_6 alkyl, arylamino, arylamino C1_6 alkyl, aryl 01_6 alkylamino, aryl C,_6 alkylamino C1_6 alkyl, arylcarbonyloxy, aryl C1_6 alkylcarbonyloxy, C1_6 dialkylamino, 01.6 dialkylamino Ci-6 alkyl, C1_6 alkylamninocarbonyloxy, C1_8 alkylsulfonylamino, C1_8 alkylsulfonylamino C1_6 alkyl, arylsulfonylamino C1_ alkyl, aryl Ci_6 alkylsulfonylamino, aryl Ci_6 alkylsulfonylamino Ci_6 alkyl, C 1 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1_8 alkyl, aryloxycarbonylamino C1_8 alkyl, aryl C1_8 alkoxycarbonylamino, aryl 01.8 alkoxycarbonylamino C1_8 alkyl, C1.8 alkylcarbonylamino, C1.8 alkylcarbonylamino 01.6 alkyl, arylcarbonylamino Ci_6 alkyl, aryl 01_6 alkylcarbonylamino, aryl C1_6 alkylcarbonylamino Ci_6 alkyl, aminocarbonylamino CI-6 alkyl, 01.8 alkylaminocarbonylamino, CI-8 alkylaminocarbonylamino C1_6 alkyl, arylaminocarbonylamino Ci_6 alkyl, aryl C1_8 alkylaminocarbonylamino, aryl 01.8 alkylamninocarbonylamino C,.6 alkyl, aminosulfonylamino 01.6 alkyl, C1_ alkylaminosulfonylamino, Cia alkylaminosulfonylamino C1_6 alkyl, arylaminosulfonylamino C1.6 alkyl, aryl C1_8 alkylaminosulfonylamino, aryl C1_8 alkylaminosulfonylamnino 01.6 alkyl, C1_6 alkylsulfonyl, Ci_6 alkylsulfonyl C1.6 alkyl, arylsulfonyl 01_6 alkyl, aryl 0i. alkylsulfonyl, aryl 01_6 alkylsulfonyl C1_6 alkyl, C1_ 6 alkylcarbonyl, Ci. alkylcarbonyl Ci_6 alkyl, arylcarbonyl C1.6 alkyl, aryl C1_6 alkylcarbonyl, aryl 01_6 alkylcarbonyl C1_6 alkyl, C1_6 alkylthiocarbonylamino, C1_6 alkylthiocarbonylamino 01.6 alkyl, arylthiocarbonylamino 01_6 alkyl, aryl 01_6 alkylthiocarbonylamino, aryl Cis, alkylthiocarbonyl amino 01_6 alkyl, C1_8 alkylaminocarbonyl alkyl, arylaminocarbonyl 01_6 alkyl, aryl C 18 alkylaminocarbonyl, or aryl C 1 .8 alkylaminocarbonyl 01.6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and R 1 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 1 0 and R 1 1 are attached is itself attached to no more than one heteroatom; R 1 2 is selected from hydrogen, 01.8 alkyl, aryl, aryl 01.8 alkyl, hydroxy, 01_8 alkoxy, aryloxy, aryl 01_6 alkoxy, C1_8 :alkylcarbonyloxy C1_4 alkoxy, aryl C1_8 alkylcarbonyloxy 014 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or 01.8 dialkylaminocarbonylmethyleneoxy; m is an integer from 0 3; n is an integer from i to 3; p is an integer from i 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; a compound of the formula 1-d X-Y-Z-Ring-A-B 1-d Swherein: Ring is a 4 to lO-membered mono-or polycyclic aromatic or nonaromatic ring system 35 containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, and either unsubstituted or substituted with R 27 and R 2 8 X is selected from NR 2 NR 2 NR 2 11 11 11 -NR 1 R 2 *NR 1 -C-R 3 -C-NHR 4 -NR 1 -C-NR 3 R 4 NR' R -aryl-NR 1 R 2 -aryI-C-NR 2 R 3 P, -aryl-NR 1 -C-NR 3 RI. c07897 358 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, 0 and S and either unsubstituted or substituted with R 13 R1 4 R' 5 or R 1 6 Y is selected from 0048 alkylene, 03-10 cycloalkyl, C048 alkylene-NR 5 -C0O- alkylene, 0048 alkylene-CONR 5 -0o-8 alkylene, 0048 alkylene-0-Co-8 alkylene, Co-8 alkylene-NR 5 -Co-8 alkylene, Co48 alkylene-S(0)o-2-Co-8 alkylene, Co-8 alkylene-S02-NR 5 -Co-8 alkylene, 0048 alkylene-NR 5 -S02-CO-8 alkylene, 0048 alkylene-C0-0o-8 alkylene, (CH 2 )o04 aryl(0H2)o-6, (CH 2 )o4 aryl-CO-(CH2)-6, (CH2)o-s aryl- OH CO-NR 5 -(CH2)046, (CH 2 )o4 aryl-NR 5 -C0-(CH2)046, or (CH 2 )o"eC(CH 2 o-8; Z is selected from 0 (C-H 2 (CH 2 )mO(CH 2 (CH 2 )miNR 6 (CH 2 (CH 2 ),NR 6 1C NR(CHA 0 0 0 (CH 2 )mCNR 6 (0H 2 (0H 2 )mNR 6 C(CH 2 )n (CH 2 )mUCH 2 )n s 0 (CHO)A~CHA), (0H 2 )mSO 2 (CHA, (CH 2 )mICH 2 )n (CH 2 )mSO(CH 2 n. (C1 )mSO 2 NR 6 (CH 2 (0H 2 )mNR 6 SO 2 (CH 2 )n, (CH 2 )mCR 6 =CR 7 (CH 2 )n or (CH 2 )mC= 0 -(CH 2 )n; where m and n are each independently an integer from 0 to 6; A is selected from 0 (CH 2 )qO(CH2)p, (CH 2 )qNR2 (CH 2 (CHi 2 ),NR 2 CNR 30 (CH 2 )p 0 0 0 (CH 2 9 CNR g(CH 2 (CH' 2 )qNR A(H 2 (CH 2 9 C(CH 2 )p, S 0 (CH 2 )qC(CH2)p. (CH 2 )qSO 2 (CH2)p, (CH2)qS(CH2)p, (CH 2 )qSO(CH 2 (CH 2 )qSO 2 NR 29 (CH 2 (CH 2 9 NR 29 SO 2 (CH 2 )p .(CH 2 )qCjR 29 =CR 30 (CF 2 P or (CH 2 )CECi(CH 2)p; where pand qare each independently an integer from 0to 6; Bisselected from .90 8 12 or IL 12 o (CH 2 )o-C-R' F 8 R9 R :R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 1 7 R 1 8 R 1 9 R 20 R 21 R 2 2 R 23 R 24 R 25 R 26 R 2 7 W 28 R 2 9 and R 30 are each S 15 independently selected from hydrogen, halogen, Ci-jo alkyl, aryl 0048 alkyl, amino 0048 alkyl, 01-3 acylamino 0048 alkyl, 014 alkylamino 0048 alkyl, 01-6 dialkylamino 0048 alkyl, aryl 004 alkylamino 0046 *alkyl, Ci-4alkoxyamino 0048 alkyl, hydroxy 014 alkylamino 0048 alkyl, CiA alkoxy 004 alkyl, carboxy Co- 6 alkyl, C,4 alkoxycarbonyl 0046 alkyl, carboxy 0046 alkyloxy, hydroxy 0146 alkylamino Co-6 alkyl, 5 hydroxy Co-s alkyl, NR 17 )NR18R19 o NR 18 -NR1'ANR9R2O R 8 R 9 R 1 0 and R' 1 are each independently selected from hydrogen, fluorine, Ci-s yhydroxy, hydroxy alkyl, carboxy 0046 alkyl, 0146 alkyloxy, 01-6 alkylcarbonyay 0 C07897 359 alkylcarbonyl, alkylcarbonyloxy, aryl Co-6 alkylcarbonyloxy, C1-6 alkylaminocarbonyloxy, C3-8 cycloalkyl, aryl Co-6 alkyl, Co-6 alkylamino Co-6 alkyl, Co-a dialkylamino Co-a alkyl, C1-8 alkylsulfonylamino Co-6 alkyl, aryl Co-6 alkylsulfonylamino Co-a alkyl, Ci-8 alkyloxycarbonylamino Co-8 alkyl, aryl Co-8 alkyloxycarbonylamino Co-a alkyl, C1.8a alkylcarbonylamino Co-6 alkyl,aryl Co-a alkylcarbonylamino Co-6 alkyl, Co-8 alkylaminocarbonylamino Co-6 alkyl, aryl Co-8 alkylaminocarbonylamilO Co- alkyl, Co-a alkylaminosulfonylamino Co-6 alkyl, aryl Cm.. alkylaminosulfonylamino Co-6 alkyl, C1-6 alkylsulfonyl Co-6 alkyl, aryl Co-6 alkylsulfonyl Co-a alkyl, C1-6 alkylcarbonyl Co-a alkyl,aryl Co-a alkylcarbonyl Cou alkyl, C1-6 alkylthiocarbonylamino Co-a alkyl, or aryl Co-a alkyithiocarbonylamino Co-a alkyl wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R 21 and R 22 any amino group such as -NH- can be substituted with R 2 1 to be -NR 21 R 1 2 is selected from hydroxy, CI-8 alkyloxy, aryl Co-a alkyloxy, C,-8 alkylcarbonyloxy C14 alkyloxy, aryl Co-a alkylcarbonyloxy C14 alkyloxy, Cla6 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 Ci-6 alkyl; and R 1 3 R 1 4 R 15 and R 16 are each independently selected from hydrogen, Ci-io alkyl, aryl Co-a alkyl, oxo, thio, amino Co-a alkyl, C1-3 acylamino Cu- alkyl, C1-6 alkylamino Co-a alkyl, C1.6 dialkylamino Co-a alkyl, aryl Cm- alkylamino Co-a alkyl,C14 alkoxyamino Co-a alkyl, hydroxy Ci.6 alkylamino Co-a alkyl, C1-4t alkoxy Co" alkyl, carboxy Co- alkyl, Ci- 4 alkoxycarbonyl Co-a alkyl, carboxy Co-a alkyloxy, hydroxy C,-6 alkylamino Co-a alkyl, hydroxy Com alkyl, NR 23 NR 24 R 25 ,o NR 24 W N k 25 R 26 provided that Ring is not a 6-membered monocyclic aromatic ring; provided further that when Ring is thiophene, then X is selected from CN N *H H provided further that when Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, indole, benzothiazole, benzoxazole, or then X is selected from R1 1 1 rR 1 3 R 1 RR3' 3 N N ,N N~N H H or R~1 R" c07897 360 and the pharmaceutically acceptable salts thereof; a compound of the formula l-e: 6D D 6 R 7 X 4 N23-NR-C-iNR 4 ,R" wherein X is selected from -tR2R31-R "NR4,a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or S wherein the or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R' and R 2 or a 9- to 1O-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, 0 or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with RI and R 2 Y is selected from R 5 0 0 0 -(HY-IIN-C 2Y I -CH 2 )FS(0)q-(CH 2 -(CHATj 0-{CH 2 R13 -(CHM--CH2iT-or -(CH 2 )r-N-(CH2)FiiN-CH2)ii Z is absent or is a 4-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one 15 or more groups independently selected from R 1 4 R1 5 R1 6 and R 1 7 preferably, Z is not a 6-membered 0 monocyclic aromatic ring system; R 1 R 2 R 3 R 4 R 5 R 1 1 R 1 2 R 1 3 R1 6 and R1 7 are each independently selected from hydrogen, halogen, C1io alkyl, C 3 -8 cycloalkyl, aryl, aryl C1.8 alkyl, amino, amino Ci-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, Ci-6 alkylamino-CI-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C 1 -8 alkyl, C1-4 alkoxy, C14 alkoxy C1.6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1 -6 alkyl, C 13 alkoxycarbonyl, C 1 -3 alkoxycarbonyl Cl.8 alkyl, hydroxycarbonyl-C1.6 alkyloxy, hydroxy or hydroxy C 1 .6 alkyl; R6, R 7 R 8 R 9 R 14 and R1 5 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, hydroxy, Ci.8 alkylcarbonylamino, aryl C1.5 alkoxy, C 1 alkoxycarbonyl, aminocarbonyl, Cl.8 alkylaminocarbonyl, C,-6 alkylcarbonyloxy, C 3 8 cycloalkyl, oxo, amino,Ci-6 alkylamino, amino C1.6 alkyl, arylaminocarbonyl, aryl CI- 5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI-6 alkyl, C1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxy, alkylcarbonylamino, aryl C1-5 alkoxy, C 15 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino-carbonyl, alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Ci- 3 alkylamino, amino C1-3 alkyl, arylamino- carbonyl, aryl 01-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci-4 alkyl, hydroxycarbonyl, or o hydroxycarbonyl C1. 5 alkyl, -(CH2)r C=-CH, -(CH2)r C=aC-Cj-6 alkyl, -(CH2)r C=-C-C 3 7 cycloalkyl, -(CH2)r F;W C=-C-aryl, -(CH 2 )r alkylaryl, -(CH2)r CH=CH2, -(CH2)r CH=CH C1-6 alkyl, -(CH2)r CH=CH-C3-7 Sycloalkyl,-(CH2)r CH=CH aryl, -(CH2)r CH=CH C1-6 alkylaryl,-(CH2)r S0 2 C1-6 alkyl, -(CH2)r S02CI-6 c07897 alkylaryl, C 1 -6 alkoxy, aryl 01-6 alkoxy,aryl C1-6 alkyl, C 1 -6 alkylamino C1-6 alkyl, arylamino, arylamino C1.6 alkyl, aryl C1-6 alkylamino,aryl C1-6 alkylamino C1-6 alkyl,arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, C 0 1s dialkylamino,Ci-6, dialkylamino C1-6 alkyl,Oi-s alkylaminocarbonyloxy, C1-8 alkylsulfonylamino, C1' 8 alkylsulfonylamino 01.6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl CI-6 alkylsulfonylamino C1-6 alkyl,C1-8 alkoxycarbonylamino, C 1 -8 alkoxycarbonylamino 01.6 alkyl, aryloxycarbonyl amino C1-8 alkyl, aryl 01.6 alkoxycarbonylamino, aryl 01.6 alkoxycarbonylamino 01-8 alkyl, 01-8 alkylcarbonylamino, 0148 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino CI-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C,-6 alkylcarbonylamino CI-6 alkyl, aminocarbonylamino C1-6 alkyl, CI-8 alkylaminocarbonylamino, 01.6 alkylaminocarbonylamino CI-6 alkyl, arylaminocarbonylamino C1-6 alkyl, aryl C 1 -8 alkylaminocarbonylamino, aryl 0148 alkylaminocarbonylamino Cir, alkyl, aminosulfonylamino Ci-6 alkyl, 01-8 alkylaminosulfonylamino, 01-8 alkylaminosulfonylamino Cl16 alkyl, arylaminosulfonylamiflo Ci-6 alkyl, aryl C1-8 alkylaminosulfonylamiflo, aryl CI-8 alkylaminosulfonylamilO 01-6 alkyl, C1-6 alkylsulfonyl, 01-6 alkylsulfonyl Ci-6 alkyl, arylsulfonyl 0146 alkyl, aryl CI-6 alkylsulfonyl, aryl 01-6 alkylsulfonyl C1-6 alkyl, Ci- 6 alkylcarbonyl, C1-6 alkylcarbonyl 01-6 alkyl, arylcarbonyl CI-6 alkyl, aryl Ci-6 alkylcarbonyl, aryl 0146 alkylcarbonyl Ci-6 alkyl, Ci-6 alkylthiocarbonylamino, 0146 alkylthiocarbonylamino 01.6 alkyl, aryithiocarbonylamino C1-6 alkyl, aryl C 1 -6 alkylthiocarbonylamino, aryl 01-6 alkylthiocarbonylamiio C1-6 alkyl, 0148 alkylaminocarbonyl Ci-6 alkyl, arylaminocarbonyl Ci-6 alkyl, aryl 0148 alkylaminocarbonyl, or aryl 0148 alkylaminocarbonyl 01-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 1 and R 1 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; R' 0 is selected from hydrogen, 0148 alkyl, aryl, aryl 0148 alkyl, aryl 0146 alkoxy, 01-8 alkylcarbonyloxy C,-4 alkyl, aryl 0148 25 alkylcarbonyloxy C14 alkyl, C1-8 alkylaminocarbonylmethylene, or 0148 dialkylaminocarbonylmethylene; m, n and r are each independently an integer from 0 to 3; p is an integer from i to 4; and q is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof. :18. The method, therapeutic agents or use according to claim 17, wherein the integrin antagonist is selected from: 4-2gaiotyoypeycroy-(S-ezlxcroyaioPaaie 3o 4-(2-guanidoethyloxy)phenylcarbonyl-2(S)-phenylsulfonylamino-oalanine, 2()peysloyaio3[-4-undbyx~hnl-rpoi acid, 2()(-ezlxcabnlmn)3[-(-undpnyoy~hnl-rpoi acid, 35 3-methoxy4-(3guanidinopropyloxy)benzoy2(S)phenylsulfonylaminoPalanine I1~ ,N-Dimethylguanidino)ethyloxybenzoyl2(S)phenyIulfonylaminopalanine, (guanidinophen-3-yloxy)benzoyl2(S)phenyIsulfonylaminoi-alanine, c07897 4-[2-(guanidino)ethyloxymethybenolZ-2(S)-phenylYUfoflYamiolQ-alanine, 3-[2-(guanidino)ethylamilocarboflyl]benzlZOI2(S)pheflyisulfofyl-aminoPalanine 4-2(-mntizl4y~tyoybnol2S-hnlufnlmn--lnn t-butyl ester, 2()peysloyaio3[-4(-mdzln2y~mnbtlx)peylrpoi acid, 4-[2-[N-[cis-3a,4,5,6,7,7a-Hexahydro-1 H-benzimidazo-2-y~amino]-ethyIoxybeflzQyl- 2 phenylsulfonylamino-f3-alaflife, 4-2(-mntizl4y~ty~ezyl2S-hniufnlmn--lnn t-butyl ester, 4-2(-mntizl4y~ty~ezy-()peysloyaioPaaie methyl 2()bnolmn--4(-yiii--lmnbtlx)pey~rpoae 2()bnolmn--4(-yi ii-2ya iobtlx~hnl-rpoi acid, 2()bnolmn--4(-3456ttayrp~mdn2yaio-uyoypeylrpoi acid, 4-2(yi ii--lmn~tyoybnol2S--ehlNpey-ufnlmn--lnn t-butyl ester, alanine, 4-[2-(N-(5,6-dihydro-4-keto-1 (H-ymdn2y~mn~tyoy-ezy-()peysloyaioo alanine, 4-2a ioyii--ltyy~ezy-()peysloy-mn--lnn t-butyl ester, :4-(2-aminopyridin-6yethynyl)benzoylI2(S)-phenylsulfonylamino-Dalanine, 4-2(-mnpfdn6y~tyoybnoy-()pey-ufnlmn--lnn t-butyl ester, 4-[2-(indol-2-yl)ethyloxy~beflzoyl-2(S)-pheflylsulfoflylamiflo-palanine methyl ester, 35 iiao456p~dn2y~tey~ezol2S-hnislfnlmn--lnn t-butyl ester, H-mdz[,-lyii--lehnlbnol2S-hnisloya iopaaie H-mdz[,-~yii--lehlbnol2S-hnisloya iopaaie 18- hii--y~tey~enol2S-heysloyamn--ln t-butylester, 42(1 ,2,3,4-tetrahydro-1,8nptyii- lehylezy-()peysufnlmn--lnn t (I 4 uy ester, c07897 363 ,2,3,4-tetrahydro-1 ,8-naphthyridin-7y)ethyllbelzoyl-2(S)-phelsulfoflylamiflo-ialaflife, 4-[2-(1,8npty i--lehnlbnol-()peysloy-mn--lnn ethyl ester, ,2,3,4-tetrahydro-1 ,8-naphthyidin-7-yI)ethyl~belzoyi-2(S)-pheflslUfoflylamiflo-oalaflife ethyl ester, ,2,3,4-tetrahydro-1 ,8naphthyidin-7-yl)ethyl]belzoyl-2(S)-[l (S)1 0-camphorsulfonylamido] P3- alanine ethyl ester, ,2,3,4-tetrahydro-1 ,8naphthyddin-7-yl)ethylbenzoyl-2(S)-[1 (S)1 0-camphorsulfonylamido] alanine, 4-[(3-aminoisoquinolin-1 -yl)ethynyl]benzoyl-2(S)-phenyIsulfoflamido-p-alaflife ethyl ester, 4-[(3-aminoisoquinolin-1 -yl)ethynyl]benzoyl-2(S)-phenylSUfoflamido-I3-alaflife trifluoroacetate, 4-[2-(3-aminoisoquinolin-1 -yl)ethyIlbenzoyl-2(S)-phenyIsulfoflamido-p-alaflife trifluoroacetate, 4-13-[N-(1 H-ezmdz--laiopooybnol2S-hniufnlmn--lnn t-butyl ester, H-benzimidazoI-2-yl)amiflpropoxybeflzoyl2(S)-phefyl5ulfofylamifopalanine, 0 0 NH N C2 H 2 Njt- JH H~x F H NH0 2 0 NH 0 0 H2~ 0 0 H O H H- H NHS i~ .0 0 H* X*HHNH0- H* oC00 HH NHSO 2 -2- *0 0 HH NHC0CH-( *0 0 H NHSO 2 2-oxo-3-[2-(5,6,7,8-tetrahydro[1 ,8]-flaphthyridifl-2-yl)ethyllpiperidifl-1 -yl-acetyl-3(S)-pyridin-3-y- 3 20 alanine ethyl ester; C 2-oxo-3-[2-(5,6,7,8-tetrahydro[1 ,8]-naphthyridin-2-y)ethyl]pipeif-1 -yl-acetyl-3(S)-pyridin-3-yl-I 3 alanine trifluoroacetate; 2-oxo-3(S)-I2-(5,6,7,8-tetrahydroI1 ,8]-naphthyfidin-2-yl)ethyllpyrrolidifl-i-yl)acetyl-3(S)-alkyny-3- .~~77N~alanine ethyl ester; cO78 97 364 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1 ,8]-naphthyridin-2-yl)ethyllpyrrolidifl-1 -yI)acetyl-3(S)-alkynyl-3- alanine; 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1 ,8]-naphthyridin-2-y)ethyl-pyrroidil-1 -yl)acetyI-3(S)-pyridin-3-yl-P- alanine ethyl ester; 2-oxo-3(S)-[2-(5,6,7,8-tetrahydroll ,8]-naphthyidin-2-yl)ethylpyFolidifl-1 -yl)acetyl-3(S)-pyidin-3-y-3- alanine; 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1 ,81-naphthyridin-2-ylethylpyrrolidifl-1 -yl)acetyl-3(S)-alkynyl-p- alanine ethyl ester; 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1 ,8]-naphthyddin-2-yl)ethyllpyrroidil-1 -yI)acetyI-3(S)-alkynyl-p- alanine; 2-oxo-3(R)-[2-(5,6,7,8-tetrahydroll ,81-naphthyidin-2-y)ethyl-pyrrolidifl-l -yI)acetyI-3(S)-pyidin-3-y-P- alanine ethyl ester; 2-oxo-3(R)-t2-(5,6,7,8-tetrahydro[i ,8]-naphthyddin-2-yl)ethypyrroidifl-1 -yl)acetyl-3(S)-pyidin-3-yl-p- alanine; ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydo[1,8nptyii- letylttayrprmii--laey-() pyridin-3-yi-Io-alanine; 2-oxo-3-[2-(5,6,7,8-tetrahydro[1 ,8]naphthyridin-2-y~ethyl]-tetrahydropyrimlidifl-l -yI-acetyl-3(S)-pyridin- 3-yi-p3-alanine; ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro[18nptydil lehllmdzldn--laey-3S-ydn3 yl-p-alanine; 2-oxo-3-[2-(5,6,7,8-tetrahydro[1 ,8]naphthyidin-2-yllethyl-imfidazolidifl-l yl-acetyl-3(S)-pyridin-3-yl-3- alanine; ethyl 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8nptydn2y ehlproii--y~ctl3R-2 2-oxo-3(R)-t2-(5,6,7,8-tetrahydro[18nptyidnly tylproii--l~ctl3R-2-tyidl3 yl)-1-alanine; ethyl 3-(S)-(2-{2-oxo-3-[(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethyl)-amifloI-pyrrolidifll -yl}- acetylamino)-3-(S)-pyidin-3-yl-propioflic acid; 3-(S)-(2-{2-oxo-3-[(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethy)-amliflo]pyrrolidifl-l -yI}- acetylamino)-3-(S)-pyidin-3-yl-propioflic acid; 3-S-22oo3[5,,,-erhdo[,8]naphthyridin-2-ylmethyl)-amiflo]-pyrrolidifll -yl}- acetylamino)-3-(S)-quinolin-3-yl-propioflic acid; 3-{2-[6-oxo-l -(5,6,7,8-tetrahydro-il ,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrrolo[3,4- 35 blyrl5ylaeyaio3()prdn3y-rpoi acid; 3-{2-16-oxo-1 -(5,6,7,8-tetrahydro-Il ,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrrolo[3,4- blyrl5ylaeyaio3-S-ydn3y-rpoi acid; t6-(5,6,7,8-tetrahydro-[1,8-ahh i--lnptye--l-croy-()peysloyaiop RA4-'-alanile ethyl ester; C07897 [6-(5,6,7,8-tetrahydro-11-nptyii -inptye--l-croy-()peysloyaiop alanine; 6 -([N-pyridin2yl)aminomethy)naphthylen2y)carbonyl2(S)phenylsulfonylaminopalanine ethyl ester; 6-[-ydn2y~mnmty~ahhln2y)croy-()peysioyaiooaaie 4-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)piperidin-1 -yI-carbonyl-2(S)-phenylsulfonylamino-p- alanine t-butyl ester; 4-(5,6,7,8-tetrahydro-1,8lnaphthyddin-2-y)piperidin-1 -yI-carbonyl-2(S)-phenylsulfonylamino-IV alanine; 6-(ymdnl2y~mnmty~ahhln2-lcroy-()peysloy--lnn ethyl ester; 6 -[(pyrimidinyl2yl)aminomethylnaphthylen2ylCrbonyl2(S)phenylsulfonylpalanine; 6-1(1 ,4,5,6-tetrahydropyrimidinyl-2-yl)aminomethylnaphthylen2-ylcarbonyl- 2 phenylsulfonylamino-p-alaflife; ethyl 3(S)-pyridin-3-yl-34{2-[3-(5,6,7,8-tetrahydro[1 ,8]naphthyidin-2-yl)propylearbamoyllacetylaminoI propionate; 3()pdi--l32[-(,,,-erhdo[,8lnaphthyddin-2- yI)propylcarbamoylacetylamino}propioflic acid; 3-(5,6,7,8-tetrahydro-1,8lnaphthyridin-2-ylmethyl)pipefldinylmaIofyl-3(S)pyfdin 3 -yl-palanine ethyl ester; 3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethyl)pipefldinyl-malonyl-3(S)pyridin 3 ylpalanine; 4-(5,6,7,8-tetrahydro-1,8lnaphthyridin-2-ymethyl)pipeidifylYImalonyl-3(S)pyfdin 3 yl-alanine ethyl ester; 4-(5,6,7,8-tetrahydro-[1,8npty i--lehlpp~dnl-aoy-()pdi--lpaaie 4-(5,6,7,8-tetrahydro-[1,8nptydn2y iednimloy-()pfdn3y--lnn ethyl ester; or 4-(5,6,7,8-tetrahydro-1,8 1 flaphthyridin-2yl)piperidinylmaloyl3(S)pyidin 3 yI-valanine; or the pharmaceutically acceptable salts and optical isomers thereof. 19. A pharmaceutical composition for achieving a 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 famesyl-protein transferase inhibitor and b) an integrin antagonist; wherein the amount of a) alone or the amount of b) alone is insufficient to achieve said therapeutic effect.
920. The pharmaceutical composition according to claim 19, comprising amounts of two therapeutic agents which are a farnesyl-protein transferase inhibitor and a compound that is an integrin antagonist. 35 21. The pharmaceutical composition according to claim 20, wherein the integrin antagonist is a selective antagonist of the axvP3 integrin. 22. The pharmaceutical composition according to claim 20, wherein the integrin antagonist is a selective antagonist of the av135 integrin. 23. The pharmaceutical composition according to claim 20, wherein the integrin antagonist i an- antagonist of both the uxv13 integrin and the ccvP5 integrin. c07897 366 24. A pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof which comprises amounts of three therapeutic agents which are: a) a farnesyl-protein transferase inhibitor; b) a selective antagonist of the avp3 integrin; and c) a selective antagonist of the av35 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. The pharmaceutical composition according to claim 19, wherein the therapeutic effect is treatment of cancer. 26. The pharmaceutical composition according to claim 19, wherein the therapeutic effect is selected from inhibition of cancerous tumour growth and the regression of cancerous tumours. 27. 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 famesyl-protein transferase inhibitor and b) an integrin antagonist; wherein the amount of a) alone or the amount of b) alone is insufficient to achieve said therapeutic effect. 28. The method of preparing a pharmaceutical composition according to claim 27, comprising mixing an amount of a famesyl-protein transferase inhibitor and an amount of an integrin antagonist. Dated 24 November 1999 MERCK CO., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0: S 4 t S@ c07897
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