Indian Patents. 231180:SUBSTITUTED LACTAMS AND A PROCESS FOR PREPARING THE SAME

Title of Invention	SUBSTITUTED LACTAMS AND A PROCESS FOR PREPARING THE SAME
Abstract	This invention relates to certain substituted lactam compounds of the formula (I), particularly caprolactam compounds, which are useful for the treatment of cancer This invention also relates to pharmaceutical compositions comprising said lactam compounds and a process for preparing said lactam compounds.

Full Text	Substituted lactams and their use as anti-cancer agents The present invention relates to the area of therapeutic agents for the treatment of cancer. More particularly, the present invention relates to certain substituted lactams, pharmaceutical compositions comprising said lactam compounds, a method of treating cancer with said lactam compounds, and a process for preparing said lactam compounds. BACKGROUND Cancer is a serious health problem throughout the world. As a result, an extensive number of research endeavors has been undertaken in an effort to develop therapies appropriate to the treatment and alleviation of cancer in humans. Research has been conducted to develop anti-cancer agents effective against various types of cancer. Oftentimes, anticancer agents which have been developed and found effective against cancer cells are, unfortunately, also toxic to normal cells. This toxicity manifests itself in weight loss, nausea, vomiting, hair loss, fatigue, itching, hallucinations, loss of appetite, and other undesirable effects. Additionally, conventionally used cancer treatment agent often do not have the effectiveness desired or are not as broadly effective against different types of cancers as desired. As a result, a great need exists for therapeutic agents which are not only more effective against multiple types of cancer, but which have a higher degree of selectivity for killing cancer cells with no or minimal effect on normal healthy cells. In addition, highly effective and selective anti-cancer agents, in particular, against cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva, small intestine, lymph glands, and blood cells are desired. Moreover, anti-cancer activity against colon, breast lung, pancreas, and prostate cancers as well as melanomas are particularly desired because of the lack of any particular effective therapy at the present time. SUMMARY The present invention provides new anti-cancer agents which are effective against a variety of cancer cells in particular, against all liquid and solid cancers that may arise in a subject, including cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva, small intestine, lymph glands, and blood cells. More particularly, the present invention relates to certain substituted lactams which exhibit a high degree of selectivity in killing cancer cells. DETAILED DESCRIPTION The invention relates to pharmaceutical compounds that are useful for the treatment of cancer of the formula I: wherein n is 0,1 or 2; R1 is H, Xr(C^) alky!-, (CM2)alkyl0(O)-, Xr(C2-4) alkenylene-, X2-(C2^) alkynylene-, XHC3-9)cycloalkyh X2-(C3.9)cycloa[kene-, Xraryh Xr(C3-7)cycloalkane-(C1^)alkylene-, XrCQj-rJcycloalkene-fCi-eJalkyiene-, or XraryKC^alkylene-; X, is H, (C-M4)alkyl, (C^cycloalkyl, (CL^alkyl substituted by (C^cycloalkyl, -ORa, -SRa, -N02, halo or (C^)alkylC(O)-; aryl, aryl-(C1.12)alkyl-J -ORai -SRa, -N02, halo, (C^alkyl-C(O)-, mono- or di-fC^alkylamino, amino(C1.i6)alkyl-) or mono- or di-(C1^)alkylamino(Ci_ ie)alkyl; X2 is H, (Chalky!, (C^cycloalkyl, (d.14)alkyl substituted by (C^cycloalkyl, -ORa -SRa, -N02, halo or (C-^alkyi-CfO)-; aryl, aryKd.^aikyl-, amino(Ci.16)alkyl- or mono- or di-(Ci. 4)aIkylamino(C1.16)alkyl; F2, R3, R4 and R5 independently are hydrogen or methyl; R6 is hydrogen; R7 is H or (C^alkyi; RB is H; and n is 2. In another embodiment, the invention provides pharmaceutical compositions, especially for the treatment of cancer in subjects, especially human, comprising a pharmaceutical^ acceptable carrier or diluent and an antitumorally effective dose of a compound of formula 1 above, or a pharmaceuticalfy acceptable salt thereof, where possible. In still another embodiment, the current invention provides a method for treating cancer comprising administering to a subject, especially human, in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutical^ acceptable salt thereof, where possible. The effective dosage of the compounds of the invention for such treatment may encompass a range of from about 0.01 milligrams per kilogram body weight per day to about 0.02 grams per kilogram of body weight per day. In another embodiment, the current invention relates to the use of a compound of formula I or of a pharmaceuticaliy acceptable salt of such a compound for the preparation of a pharmaceutical composition for use in the chemotherapy of cancer. Furthermore, the current invention relates to the use of a compound of formula I or of a pharmaceuticaliy acceptable salt of such a compound for the chemotherapy of cancer. In the above definitions: The alky! groups, including any alkyl portion of a substituent, such as alkoxy, are either straight or branched chain, of which examples of the latter include isopropyl, isobutyl, f-butyl, isopentyl, neopentyl, isohexyl, 3-methylpentyI, 2,2-dimethylbutyl, 2,3-dimethyIbutyI and 1,1,2,2-tetramethyIethyI unless otherwise noted. The term "alkyiene" as used herein refers to a straight or branched chain consisting solely of carbon and hydrogen. Examples of "alkylene" groups include methylene, ethylene, propylene, butylene, pentylene, and 3-methypentylene. The term "alkenylene" as used herein refers to a straight or branched chain consisting solely of carbon and hydrogen, containing at least one garbon-carbon double bond. Examples of "alkenylene" groups include ethenyiene, propenylene, butenylene, 3,3,-dimethylbut-l-enylene, 3-methylbut-1-enylene, pentenylene, 3-methylpentenylene, and butadiene. The term "alkynylene" as used herein refers to a straight or branched chain divalent group consisting solely of carbon and hydrogen containing at least one carbon-carbon triple bond. Examples of "alkynylene" groups include acetylene, propynylene, butynylene, pentynylene, 3-methylpentynylene. If R2 and R4 together or R3 and R5 together form an acetal group, R2 and R4 together or R3 and R5 together preferably form a group of the formula -C(R')(R"K wherein R' and Rn are selected independently of each other from Xr(Ci^) alkyl-, X2-(C2-4) alkenyl-, Xr(C3-7)cycloafkyh or Xr(C3.7)cycloaIkane-(Ci^)aIkyI- wherein X^ is as defined herein. The term "direct bond" as herein described refers to a single, double, or triple, covalent atomic bond which links together two moieties. Halo is chloro, bromo, iodo or fluoro, especially chloro, bromo or iodo. The substituent het is preferably a 3 to 9 membered aliphatic ring, such as a 4 to 7 membered aliphatic ring, containing from one to three heteroatoms selected from nitrogen, sulfur and oxygen, or het is a 5 to 7 member aromatic ring containing one or more heteroatoms, for example from 1 to 4 heteroatoms, selected from N, O and S, or het is a bicyclic and tricyclic fused ring system where each ring can independently be 5 or 6 membered and contain one or more heteroatoms, for example, 1, 2, 3, or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic. Examples of suitable het substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, and pyrroloquinoline. Het is preferably pyridyl. In the instance where het is a nitrogen containing ring, N-substituted compounds are included- Suitable N-substituents include (Chalky!, such as N-methyl or N-ethyl, -C(0)Ci-12alkyl, such as methyiamido or ethyiamido, -C(OVO-(C1.u)alkyl, such as carbomethoxy or carboethoxy, or phenyl. het also includes the above rings with substitution on one or more carbons. Suitable C-substituents include (Chalky), such as methyl or ethyl, -ORa, such as methoxy and ethoxy, -SRa, halo, -N(RX)2 and the like. Aryl includes phenyl and naphthyl substituents. A "heteroaryT group is mono-, bi- or tri-cyclic, and comprises 3-24, preferably 4-16 ring atoms, and is most preferably mono-cyclic comprising 5-7 ring atoms, wherein at least one or more, preferably one to four ring carbons are replaced by a heteroatom selected from O, N or S such as azirinyl, imidazolyl, thienyl, furyl, indolyl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, 2f/-pyrrolyl, pyrrolyl, benzimidazolyl, pyrazofyl, pyrazinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3/-/-indolyI, benzimidazolyl, benzothiazolyl and benzo[1,2,5] thiadiazolyl, thiacumaryl, indazolyl, triazolyl, tetrazoiyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyi, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and chromanyl, each of these radicals being unsubstituted or substituted by one to two substituents. "Heterocyclic" refers to a heterocyclic radical containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. piperazinyl, lower alkyl-piperazinyl, azetidinyl, pyrrolidinyl, piperidino, morpholinyl, imidazolinyl). The heterocyclic radical is preferably unsaturated, saturated or partially saturated in the bonding ring; has 3-24, more preferably 4-16 ring atoms, wherein at least in the bonding ring one or more, preferably 1-4, especially one or two carbon ring atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the bonding ring preferably having 4-12, especially 4-7 ring atoms; the heterocyclic radical is unsubstituted or substituted by one or more, especially 1-4 substituents and is especially selected from the group consisting of indoly, tetrahydrofuranyl, benzofuranyl, thienyl, pyridyl, imidazolinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidino, piperidyl, pyrrolidinyl, oxiranyl, 1,2-oxathiolanyI, pyrrolinyl, imidazolidinyl, pyrazolidinyl and azetidinyl, with piperazinyl being especially preferred. In view of the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, hereinbefore and hereinafter any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient. Salts are especially the pharmaceutical^ acceptable salts of compounds of formula I. Salts of the compounds of formula I may be pharmaceutical^ acceptable acid or base addition salts with organic or inorganic acids or bases. Although the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, for example, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid may also be utilized. Preferably, R2, R R4 and R5 are in the relative stereochemical conformation to each other depicted in stereochemical formulae la and lb: The lactams of formula I may be prepared as depicted below: where each of R1, R5, R7 and R8 is as defined above. As to the individual steps, Step A involves the acylation of an aminolactam of formula VI with a lactone compound of formula VII to obtain a diamide compound of formula VIII. The acylation is conducted in a polar, organic solvent preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Alternatively, the acylation of an aminolactam of formula VI, or an acid addition salt thereof, with the lactone compound of formula VII in Step A may be earned out with in the presence of: 1) a weak base, preferably a carboxylate salt such as sodium 2-ethylhexanoate, and 2) a polar, organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between 0°C and 50°C, preferably at 25°C, for a period of between 1 hour and 7 days, preferably for 20 hours. Step B concerns the hydrolysis of the 1,3-dioxane group common to a diamide compound of formula VIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. Alternatively, the diamide compounds of formula Villa may be prepared according to the following 3-step reaction scheme: As to the individual steps, Step 1 involves the acylation of an aminolactam of formula IX with a lactone compound of formula VII to obtain a diamide compound of formula X. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Step 2 concerns the hydrolysis of the group P2 common to a diamide compound of formula X to obtain a hydroxylactam compound of formula XI. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutyf-ammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. Step 3 concerns the acylation of a hydroxylactam compound of formula XI by reacting it with an acid chloride of formula R12COCI where R12, is defined above, to obtain a diamide compound of formula Villa. The acylation is conducted in the presence of a base, preferably an alkylamine base such as triethylamine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours. Alternatively, the acylation of a hydroxylactam compound of formula XI in Step 3 may be carried out with a carboxylic acid of formula R12COCI where R12, is defined above, in the presence of a carboxylic acid coupling reagent, preferably a diimide such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, preferably a substituted pyridine such a 4-dimethylaminopyridine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours. The aminolactam compounds of formula la may be prepared as depicted below; As to the individual steps, Step 1a involves the cyclization of hydroxylysine (or any salt or hydrate preparation thereof) XII to obtain hydroxycyclolysine XIIL The cyclization is typically carried out in the presence of a coupling reagent, preferably a diimide such as 1-(3-dimethylaminopropyl)-3^thylcarbodiimide hydrochloride, and a suitable actuating agent common to diimide coupling reactions, preferably an AZ-hydroxy compound such as 1-hydroxybenztriazole hydrate, and a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 12 and 72 hours. Step 1b involves the A^acylation of hydroxycyclolysine XIII to obtain an N-acylhydroxycyclolysine compound of formula XIV. The acylating agent is typically an acid chloride or an anhydride. When Pi is f-butyloxycarbonyl, the acylating agent is di-ferf-butyldicarbonate. The reaction is carried out in the presence of a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours. Step 1c involves the Osilylation of an W-acylhydroxycyclolysine compound of formula XIV to obtain a silyl ether compound of formula XV, The silylating agent is typically a silyl chloride or trifluoromethanesutfonate. When P2 is ferf-butyldimethylsilyl, the silylating agent is ferf-butyldimethylsilylchloride. The reaction is carried out in the presence of a base, preferably a mild base such as imidazole, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours. Step 1d involves the /V-alkylation of a silyl ether compound of formula XV with an alkyl (defined as R7 above) halide or sulfonate to obtain an N-alkyl lactam compound of formula XVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsilyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 2 hours. Step 1e concerns the hydrolysis of the group P^ on an N-alkyl lactam compound of formula XVI. The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethyisifyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours-Step 1f involves the acylation of an aminolactam of formula XVII with a lactone compound of formula VII to obtain a diamide compound of formula X. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Step 1g concerns the hydrolysis of the group P2 common to an N-alkyl lactam compound of formula X, to obtain a hydroxylactam compound of formula XI. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutylammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 6 hours. Step 1h concerns the acylation of a hydroxylactam compound of formula XI by reacting it with an acid chloride of formula R12COCl where R12, is defined above, to obtain a diamide compound of formula VIII. The acylation is conducted in the presence of a base, preferably an alkylamine base such as triethylamine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours. Step 1i concerns the hydrolysis of the 1,3-dioxane group of compound formula VIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. Alternatively, the acylation of a hydroxylactam compound of formula XI in Step 1h may be carried out with a carboxyDc add of formula R12COOH where Ri2, is defined, in the presence of a carbolic acid coupling reagent, preferably a dfimide such as 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, preferably a substituted pyridine such a 4-dimethylaminopyridine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours. The aminolactam compounds of formula lib may be prepared as depicted below: R14 is a leaving group. where each R1, Rs» Rzand R12 is as defined above, and Pi is a carbonyl-containing group. Preferably, Pi is alkoxycarbonyl such as f-butyloxycarbonyl. P2 is an alcohol protective group. Preferably, P2 is a silyf group such as fert-butytdimethylsilyl. Step 2a concerns the hydrolysis of the group P2 common to an N-alkyl lactam compound of formula XVI, to obtain a hydroxylactam compound of formula XVII. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutylammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 6 hours. Step 2b involves the O-alkylation of a compound of formula XVII with an alkyl (defined as R12 above) halide or sulfonate to obtain an O-alkyl lactam compound of formula XVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsifyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 6 hours. Step 2c concerns the hydrolysis of the group P1 on an N-alkyl lactam compound of formula XVIII. The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethylsilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours. Step 2d involves the acylation of an aminoladam of formula XIX with a lactone compound of formula VII to obtain a diamide compound of formula XX. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Step 2e concerns the hydrolysis of the 1,3-dioxane group of compound formula XX, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. The aminolactam compounds of formula He may be prepared as depicted below: where each R1, R5, R7 is as defined above, R13 is an appropriate substituent based on the definition of Rs above and P% is a carbonyl-containing group. Preferably, P^ is alkoxycarbonyl such as f-butyloxycarbonyL Step 3a involves the substitution of the hydroxy group of the compound of formula XVI! for a heteroatom (defined as Y above) preferably with inversion of configuration and most preferably by a Mitsunobu type reaction (reference) involving a trialkyl or triaryi substituted phosphine, an azodicarboxylate diester and a nucleophile source such as diphenyiphosphoryl azide. Alternatively the hydroxy group can be converted to a sulfonate or haiide suitable for displacement. Step 3b concerns the hydrolysis of the group P^ on an N-alkyl lactam compound of formula XXI. The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethyisilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours. Step 3c involves the acylation of an aminoiactam of formula XXII with a lactone compound of formula VII to obtain a diamide compound of formula XXIII. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Step 3d concerns the hydrolysis of the 1,3-dioxane group of compound formula XXIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. The aminoiactam compounds of formula lid may be prepared as depicted below: where each R1, R5, and R7 is as defined above, and P-i is a carbonyl-containing group. Preferably. Pi is alkoxvcarbonvl such as f-butvloxvcarhonvl. Step 4a involves the A/-acyiation of cyclolysine XXIV to obtain an AJ-acylcycloIysine compound of formula XXV. The acylating agent is typically an acid chloride or an anhydride. When Pi is f-butyloxycarbonyl, the acylating agent is di-te/f-butyldicarbonate. The reaction is carried out in the presence of a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N7N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours. Step 4b involves the W-alkylation of an N-acylcyclolysine compound of formula XXV with an alkyl (defined as R7 above) halide or sulfonate to obtain an A/-alkyl lactam compound of formula XXVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsilyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 2 hours. Step 4c concerns the hydrolysis of the group Pi on an N-alkyl lactam compound of formula XXVI, The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethylsilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours. Step 4d involves the acylation of an aminolactam of formula XVII with a lactone compound of formula XXVII to obtain a diamide compound of formula XXIX. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropyiethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours. Step 4e concerns the hydrolysis of the 1,3-dioxane group of compound formula XXIX, to obtain a substituted lactam compound of formula Id. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours. The lactone compounds of formula VII may be prepared as depicted below. where R1 and R5 are as defined above. As to the individual steps, Step 5a involves the diketalization of polyhydroxylated lactone of formuia XXX with acetone io obtain bis(acetonide) XXXi. The diketalization is conducted in acetone as solvent using a catalyst such as iodine at a temperature of between 0 °C and the reflux temperature for a period of between 2 and 48 hours. Step 5b involves the alkylation of b/s(acetonide) XXXI with an alkylating agent such as an alkyl (defined as R5 above) halide, sulfonate or sulfate ester to obtain the ether XXXII. The alkylation is conducted in the presence of water and a base, preferably a metal oxide such as silver oxide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between 0 °C and the reflux temperature for a period of between 12 hours and 7 days. Step 5c involves the hydrolysis of alkyl ether XXXII to obtain the dihydroxy compound of formula XXXIII. The hydrolysis is conducted in the presence of water and a protic acid, preferably a carboxylic acid such as acetic acid, at a temperature of between 5 °C and 35 C for a period of between 1 and 24 hours. Step 5d involves the oxidative cleavage of dihydroxy compound XXXIII to obtain the aldehyde XXXIV. The reaction is conducted in the presence of an oxidant preferably a periodate salt such as sodium periodate, in a protic solvent, preferably an alkanol such as methanol, at a temperature of between 0 °C and 25 °C for a period of between 10 minutes and 4 hours. Step 5e involves the olefination of aldehyde XXXIV to obtain a lactone compound of formula VII. The olefination is conducted in the presence of an organometaliic compound, preferably an organochromium compound such as the transient species generated from chromium(H)chloride and a diiodoalkane (defined as f^CH^ where Ri is as defined above), in the presence of a solvent mixture consisting of 1) a polar organic solvent, preferably an amide such as ty/V-dimethylformamide, and 2) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -80 °C and 25 °C for a period of between 5 minutes and 4 hours. Alternatively the lactone compounds of formula Vila may be prepared as depicted below: where R5 is defined above and R' is C^) alkyl Step 6a involves the conversion of XXXIII to an ortho ester XXXV by acid catalyzed transesterification with an alkyl orthoester, preferably triethylorthoformate and p-toluenesulfonic acid. The reaction can be run with excess alkyl orthoester as the solvent or an inert organic solvent may be used at a temperature of between 20 °C and 80 °C for a period between 1 and 24 hours. Step 6b involves the elimination of the orthoester XXXV to give alkene Vila. The reaction is conducted in an organic acid anhydride, preferably acetic anhydride at a temperature of 20 °C and 100 °C for a period between 1 and 24 hours. Alternatively the lactams of formula I may be prepared as depicted below: where each R1, R5, R7, R9* and X are defined above, R" is a C^9) branched alkyl or phenyl substituted C(1^j alkyl, preferably benzyl and Rm is a C(i-6) alkyl, preferably ethyl. P2 and P3 are alcohol protective groups, preferably silyl groups such as terf-butyldimethylsilyl and trimethylsilyl respectively. P4 is an alcohol protective group, preferably benzyl or 2-naphthlmethyl ethers. Step 7a involves an Evans type aldol condensation of oxyimide XXXVI with an aldehyde to give XXXVII. The reaction is conducted in the presence of a Lewis acid, preferably diethylborontriflate and an organic base, preferably diisopropylethylamine in an inert organic solvent such as CH2CI2at a temperature of between -100 °C and 0 °C for a period of 1-24 hours. Step 7b involves the O-siiylation of compound XXXVII to obtain a silyl ether compound of formula XXXVIIL The siiylating agent is typically a silyl chloride or trifluoromethanesulfonate. When P2 is fe/t-butyldimethylsilyl, the silylating agent is fert-butyldimethylsilylchloride. The reaction is carried out in the presence of a base, preferably a mild base such as imidazole, and a polar organic solvent, preferably an amide such as tyAWimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours. Step 7c involves the formation of thioester XXXIX from XXXVIII by reaction with an alkali metal salt of a thioether, preferably LiSEt, in an inert solvent, preferably THF, at a temperature of between -100 °C and 0 °C for a period of 1-24 hours. Step7d involves conversion of thioester XXXIX to the aldehyde XL by reduction with a metal hydride, preferably diisobutylaluminum hydride, in an inert solvent, preferably CH2CI2J at a temperature of between -100 °C and 0 °C for a period of 10 minutes to 1 hour. Step 7e involves a Gennari type coupling of aldehyde XL with a thiovinylether to give the thioester XLI. The reaction is conducted in the presence of a Lewis acid, preferably SnCU, in an inert solvent, preferably a mixture of CH2CI2 and heptane, at a temperature of between -100 °C and 0 °C for a period of 1-24 hours. Step 7f involves the acylation of thioester XLI with amine VI to give diamide XLII. The reaction is conducted in an inert solvent, preferably dioxane, at a temperature of between room temperature and 100 °C for a period of 1-48 hours. Step 7g involves the deprotection of diamide XLII to give compound I. The method employed is dependant on the P2 and P5 groups utilized, preferably when P2 is terf-butyldimethyisilyl and P4 is 2-naphthlmethyi ether a two step procedure is employed using DDQ in a mixture of wet CH3OH and CH2CI2 followed by treatment with tetrabutylammonium fluoride in THF to give compound I. The following specific examples are intended to further illustrate, but not limit, the invention. EXAMPLES EXAMPLE 1: Tetradecanoic acid (3R,6SHK)XI>1-pyridine 3,4,5-trihydroxy-2-methoxy-8,8^ ester a) Preparation of 3,5:6 J4)is-0-(1-iTiethylethylidene}-a-D-glucoheptonic y-Iactone. a-D-Glucoheptonic y-Iactone (500 g, 2.4 mol) is added into 9 L of acetone in a 5 gal plastic drum. The mixture is agitated mechanically until most of the solid dissolved (15-20 min). Iodine (60g, 0.236 mol) is added portion wise into the lactone solution over 5-10 min. The resulting mixture is stirred overnight. A saturated solution of Na2S203 (1.3 L) is added to the iodine solution to quench the reaction. The resulting solution is concentrated to about half of its original volume in vacuum, and brine solution (5 L) is added. The resulting mixture is extracted with 3 x 1.2 L EtOAc. AH organic layers are combined and evaporated to dryness. The solid is slurried with a mixture of ether and hexane (3:7), and filtered. The filter cake is washed with Et20 (50 mL) and air dried, giving 599 g of the desired compound as a white powder (86.5%): 1H NMR (CDCl3) 5 4.62 (m, 1H), 4.50 (m, 1H), 4.35 (m, 2H), 4.07 (m, 1H), 3.93 (m, 1H), 3.82 (dd, 1H), 3.08 (d, 1H), 1.51 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCI3) 5 174.4, 109.4, 98.6, 72.8, 71.4, 69.3, 68.4, 67.8, 66.7, 28.6, 26.7, 24.6, 19.3. Preparation of 2-Omethyl-3,5:6,7-bis-0-(1-methylethylidene)-a-D-glucoheptonic y-lactone. 3,5:6,7-bis-0(1-methylethylidene)-a-D-gIucoheptonicy-lactone (719 g, 2.49 mol) is added into 4.5 L of CH2CI2 in a 5 gal plastic drum. The mixture is stirred under N2. lodomethane (2500 g, 17.6 mol) is added immediately followed by addition of siiver(l) oxide (1750 g, 7.58 mol). Water (30 mL) is added to the reaction mixture. Ice bath is used to maintain the reaction temperature at 15-30 °C. The reaction is stirred in the absence of light for 18 h. After diluting the reaction mixture with 1.5 L of CH2CI2, the solid is filtered and washed with an additional 2.2 L of CH2CI2. The undesired solid is discarded and the filtrate is evaporated to dryness. The residue is slurried in Et20 (1.5 L), filtered, and dried to give 618 g product (82 %): 1H NMR (CDCI3) 5 4.75 (m, 1H), 4-33 (m, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 4.07 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.65 (s, 3H), 1.57 (s, 3H), 1.42 (s, 6H), 1.35 (s, 3H); 13C NMR (CDCI3) 8 172.5,109.6, 98.5, 79.0, 73.1, 69.5, 68.6, 67.5, 66.9, 59.1, 28.9, 26.9, 24.9, 19.4. Preparation of 2-0-Methyl-3,5-CK1-methylethyiidene)-a-D»glucoheptonic y-lactone. 2-(>methyl-3,5:6t7-bis-(>(1-m^ (618 g, 2.05 mol) is dissolved in 8 L of a mixture of acetic add and water (1:1) over 30 min. The solution is stirred at ambient temperature overnight The solution is evaporated to dryness in vacuum. The solid is slurried in 3-5 L of hot acetone and filtered. After oven drying at 20-30 °C, 363 g of the desired compound is obtained (67.6 %). 1H NMR(CDCU): 5 4.92 (d, 1H), 4.80 (m, 1H), 4.47 (d, 1H), 4.42 (t, 1H), 4.39 (m, 1H), 3.95 (dd, 1H), 3.75 (m, 2H), 3.4 (s, 3H), 2.5 (m, 1H), 1.42 (s,3H), 1.22 (s,3H). d) Preparation of 2,4-0-(1-methylethyiidene)-5-OmethyI-L-glucuronic y-lactone. 2-0-Methyl-3,5-0-(1-methylethylidene)-a-D-glucoheptonic y-lactone (200 g, 0.76 mol) is dissolved into a 1:1 mixture of methanol and water (3.6 L). The stirred mixture is cooled in an ice water bath to about 8 °C. Solid NaI04 (213 g, 0.98 mol) is added portion wise. Reaction is complete within 40 min as indicated by thin layer chromatography (TLC) (silica gel, 5% methanol, 15% EtOAc in CH2CI2). Solid NaCI is added into the reaction mixture to saturate the methanolic solution. The solid is filtered and washed with 2 L CH2CI2. The filtrate is extracted with 7x500 mL ChfeCfe. Combined organic layers are dried over Na2S04, filtered and concentrated to a syrup, which formed a precipitate upon addition of hexane. The solid is filtered and rinsed with Et20. A portion of the crude product (50 g) is dissolved in 3 L CHCI3 and heated to reflux. After rotary evaporation of 2.1 L of CHCI3at atmospheric pressure (methanol is driven out of the system by co-evaporation with CHCI3) the residue is evaporated to dryness. 44 g of the desired product is obtained as a solid after drying in vacuum overnight. 1H NMR (CDCI3): 59.60 (s, 1H),4.78(m, 1H), 4.42 (s, 2H), 4.15 (dd, 1H)f 3.65 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H); 13C NMR (CDCI3) 5 198.8, 171.9, 99.0, 78.4, 74.4, 72.9, 68.4, 67.4, 59.2, 28.7, 19.0. e) Preparation of (6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-0-methyl-3,5-0-(1-methylethylidene)-gu!o-non-6-enonic acid lactone. Into a 2 L round bottom flask, is added CrCI2 (50 g, 41 mmol), anhydrous THF (750 mL), and DMF (32 mL). The mixture is stirred under N2 for 1 h. A solution of 2,4-0-(U methylethy!idene)-5-0-methyl-L-gIucuronicY-lactone (12 g, 50 mmol), 1,1-diiodo-2,2-dimethylpropane (15 mL), and 500 mL of anhydrous THF is added slowly into the reaction mixture. After the addition, the reaction mixture is stirred at ambient temperature for 1.5 h. The reaction is quenched with saturated aqueous NhUCI. The residue is partitioned with EtOAc/water and chromatographed (5% EtOAc - CH2C!2) to give 9 g (63%) of the desired compound as a white crystalline solid: 1HNMR (CDCI3) 5 5.82 (d, 1H), 5.58 (q, 1H), 4.71 (m, 1H), 4.46 (m, 1H), 4.10 (dd, 1H), 4.0 (m, 1H), 3.66 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H), 1.07 (s, 9H); 13C NMR (CDCI3) 5 172.5, 147.0,120.2, 98.7, 79.1, 71.9, 70.3, 67.6, 59.2, 33.2, 29.3, 19.3. Preparation of (3S, 6/?)-3-(te/t-butoxycarbonyl)aminohexahydro-6-hydroxy-2W-azepin-2-one In a 1 L flask (5R)-5-hydroxy-L-lysine (10 g, 0.040 mol), 1-hydroxybenzotriazole hydrate (8.2 g, 0.060 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-HCI (11.6 g, 0.060 mol) are added to 500 mL DMF with stirring. After 0.5 h triethylamine (16.8 mL, 0.120 mol) is added. The reaction is stirred at room temperature for 48 h. Di-terf-butyl dicarbonate (17.6 g, 0.080 mol) and triethylamine (16.8 mL, 0.120 mol) are added. Stirring is continued for 16 h. The reaction mixture is filtered to remove triethylamine-HCI and the solvent is removed by rotary evaporation under high vacuum to give a thick oil. The oil is dissolved in 150 mL CH2CI2 and applied to a silica gel column (150 g, 40 x 250 mm). The column is eluted with 3% methanol in CH2CI2 to give the crude product as a solid. The crude solid is dissolved in 120 mL hot CH2CI2 and cooled to -20 °C for 1 h. The resulting solid is filtered and washed with 50 mL CH2CI2. The combined filtrates are evaporated to dryness. CH2CI2 (40 mL) is added to this residue and the resulting slurry is stirred for 0.5 h at room temperature. The slurry is filtered and the solid washed with 25 mL CH2CI2. The solids are combined to give 5.57 g of (3S, 6R)-3-(fert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one. 300 MHz 1H NMR (DMSO) 8 7.42 (1 H, t, J = 5.1 Hz), 6.38 (1 H, d, J = 6.6 Hz), 4.60 (1 H, d, J = 4.2 Hz), 4.07 (1 H, m), 3.74 (1 H, m), 3.32 (1 H, m), 3.03 (1 H, m), 1.8-1.5 (4 H, m), 1.39 (9 H,s). g) Preparation of (3S, 6ft)-3-(fe/^butoxycarbonyl)aminohexahydro-6+butyl-dimethylsilyloxy-2H-azepin-2-one. To a stirred solution of (3S, 6/?)«3-(tert-butoxycarbonyI)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol) in DMF (60 mL) is added te/f-butyldimethylsiiyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol). The reaction is stirred at room temperature for 18 h, diluted with 1 L of water and extracted with a 1:1 (2 x 200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine, dried with NaS04, and concentrated under vacuum. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S, 6/?)-3-(terf-butoxycarbonyI) aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin»2»one as a white solid, melting point: 65 - 66 °C; 1H NMR (CDCI3) 5 5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H)f 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H). h) Preparation of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2HDxo-1 -pyridin-3-yImethyI-azepan-3-yI]-carbamic acid tert-butyl ester To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (4.0 g, 11.1 mmol) in THF (30 mL) at -78 °C is added KN(Si(CH3)3)2 (45.0 mL 1M THF, 45.0 mmol) slowly. The mixture is stirred at room temperature for 20 min, cooled to -78 °C, and 3-chloromethyl-pyridine hydrochloride (2.75 g, 16.7 mmol) is added in portions. The reaction is warmed to room temperature and stirred for 16 h, H20 (20 mL) is added and the mixture is partitioned with H20/ether, the organic layer is separated, dried with Na2S04 and evaporated to give a white solid, 5.0 g (quantitative) of [(3S,6R)-6-(tert-butyl-dimethy^silanylox^^ acid tert-butyl ester. MS (ESI) 899.3 (2M+H)+ i) Preparation of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1 -pyridin-3-ylmethyI-azepan-2-one To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethy[-azepan-3-yI]-carbamic acid tert-butyl ester (5.0 g, 11.1 mmol) in CH2CI2 (50 mL) at-78 °C is added trimethylsilyl iodide (2.8 g, 14.0 mmol) neat After 30 min the reaction solution is warmed to 0 °C and stirred for 15 min. The reaction is quenched with a solution of CH3OH (25 mL) and NH4HC03 (10 mL, saturated in H20), and partitioned with H20/CH2CI2. The CH2CI2 fraction is dried over Na2S04 and evaporated to a gum and chromatographed on a) Preparation of [(3S,6R}-6-(tert-butyf-dimethyl-siianyloxy)-1 -methyl-2-oxo-azepan-3-yi]- carbamic acid tert-butyl ester Following the procedure of Example 1(f)-1(h), except CH3-I is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 is used in step 1(h) to give the product as an oil. 1H NMR (CDCI3) 5 0.05 (s( 3H), 0.07 (sf 3H), 0.87 (s, 9H), 1.44 (s, 9H), 1.8 (m, 4H), 3.06 (s, 3H), 3.2 (dd, 1H), 3.7 (d, 1H), 4.0 (m, 1H). 4.28 (dd, 1H), 6.0 (d, 1H). b) Preparation of ((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-y[)-carbamic acid tert- butyl ester To a solution of [(3S,6R)-6-(tert-butyWimethyl-silany^ carbamic add tert-butyl ester (0.85 g, 2.27 mmol) in THF (40 mL) is added tetrabutylammonium fluoride (3 mL 1M THF, 3 mmol) at room temperature. The reaction solution is stirred for 4 h, then H20 (40 mL) is added and the solution concentrated under vacuum to 34 its volume and extracted 3x with CH2CI2 (40 mL). The combined CH2CI2 extracts are adsorbed on silica and chromatographed (5% CH3OH/ CH2CI2) to give 0.568 g (72%) of ((SS.eRJ-e-hydroxy-l-meth^-oxo-azepan-S-ylJ-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCI3) 5 1.44 (s, 9H)t 1.7-2.05 (m, 4H), 3.1 (s, 3H), 3.37 (dd, 1H), 3.73 (d, 1H), 4.07 (m, 1H), 4.31 (m, 1H), 6.0 (d, 1H). Preparation of [(3S,6R)-6-(6-azido-hexyloxy)-1«methyl-2-oxo-azepan-3-yll-carbamic acid tert-butyl ester To a stirred solution of ((3S,6R)-6-hydroxy-1-methyi-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester (0.70 g, 2.6 mmol) in THF (5 mL) cooled to -78 °C is added NaN(Si(CH3)3)2 (2.8 mL 1M THF, 2.8 mmol). After 10 min trifluoro-methanesulfonic acid 6-azido-hexyI ester (0.76 gf 3.1 mmol) is added neat and stirred for 10 min at -78 °C then warmed and stirred at room temperature for 1 h. NaHC03 (5 mL 1M H20) is added and the solution is partitioned with H20/EtOAc, the EtOAc extract is dried with Na2S04 and evaporated to an oil. The oil is adsorbed on silica and chromatographed (20% EtOAc/ CH2CI2) to give 0.32 g (32%) of [(3S,6R)^(6-azido-hexyloxy)-1-methyl-2K)Xo-azepan-3-yI]-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCI3) 5 1.34 (st 9H), 124-2.1 (m, 12H), 2.95 (s, 3H), 3.1-3.35 (rn, 6H), 3.44 (m, 1H), 3.55 (d, 1H), 4.2 (m, 1H). Preparation of (3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-a2epan-2-one To a stirred solution of [(3S,6R)-6-(6-azido-hexyioxy)-1-methyl-2-oxo-azepan-3-yl]-carbarnic acid tert-butyl ester (0.32 g, 0.83 mmol) in CH2CI2 (4 mL) is added TFA (1 mL) at room temperature. After 1 h, the reaction is evaporated under vacuum, toluene (20 mL) is added and evaporated under vacuum to remove remaining TFA. The residue is dissolved in CH2CI2 (20 mL) saturated with NH3 adsorbed on silica and chromatographed (50% EtOAc/CH2CI2/NH3 then 10% CH3OH/CH2CI2/NH3) to give 0.207 g (88%) of (3S,6R)-3-amino-6-(6-azido-hexyIoxy)-1-methyl-azepan-2-one as an oil. MS (ESI) 284.2 (M+H)+ Preparation of (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1 -methyI-2-oxo-azepan-3-yI]-2- [(4R,5R,6R)-6-((E)-3,3-dime^ methoxy-acetamide To a solution of (3S,6R)-3-amino-6-(6-aado-hexyloxy)-1-methyl-azepan-2-one (0.207 g, 0.73 mmol) in isopropanol (1 mL) is added (4R,4aR)-4-((E)-3,3-dimethyl-but-1-enyl)-7-methoxy- 2,2-dimethyl-tetrahydro-furo[3l2"d][1l3]dioxin-6-one (0.3 g, 1 mmol) and heated to reflux for 18 h. The solution is evaporated under vacuum adsorbed on silica and chromatographed (CH2CI2 to EtOAc gradient) to give 0.245 g (59%) of (R)-N-[(3S,6R)-6-(6-azido-hexyIoxy)-1- methyi-2-oxo-azepan-3-yl]-2~[^ dimethy!-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a solid. (ESi) 568.1 (M+H)+ f) Preparation of (EJ^R^R^S.SR^S^^-trihydroxy^-methoxy-S^-dimethyl-non-e-enoic acid [(3SI6R)-6-(6-azido-hexyloxy)-1 -methyl-2-oxo-azepan-3-yl]-amide Following the procedure of Example 1 m) except (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyi-2-oxo-azepan-3-yl]"2-[(4R,5R,6R)-6-((E)-3r3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-fl^Jdioxan^yll^-methoxy-acetamide is substituted for tetradecanoic acid (3R,6S)^(R)-2-[(4R,5R,6R)-6-((E)-3,3Ki'^ [1,3](Soxarv4-yl]-2-methoxy-acet^^ ester. MS (ESI) 528.0 (M+H)+ g) Preparation of title compound (E)-(2RI3Rl4S,5R)-3,4I5-trihydroxy-2-methoxy«8I8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-amino-hexyloxy)-1 -methyl-2-oxo-azepan-3-yl]-amide To a stirred solution of (EH2R3R,4Sf5R)-3,4)5-trihydroxy-2-methoxy-8,8KJimethyl-non-6-enoic acid [(3S,6R)-5-(6-a2ido-hexyloxy)-1-methyl-2HDxo-a2epan-3-yIl"amide (0.13 g, 0.25 mmol) in THF (2 mL) is added H2O and triphenylphosphine (0.120 g, 0.5 mmol). After 8 h the reaction solution is evaporated under vacuum to give a semisolid residue that is dissolved in CH2CI2 (10 mL), adsorbed on silica and chromatographed (CH2CI2/NH3 to 25% CH3OH/CH2CI2/NH3 gradient) to give 0.106 g (85%) of (EM2R,3R,4S,5R)-3,4,54rihydroxy-2-methoxy-8f8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-amino-hexyloxy)-1 -methyl-2-oxo-azepan-3-y!]-amide as a white solid. MS (ESI) 502.1 (M+H)+ EXAMPLE 3: (E)-(2R,3Rt4S,5R)-314I5-Trihydroxy-2-methoxy-8I8-dimethyl-non»6-enoic acid ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-amide Preparation of ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester To a stirred solution of ((3S,6R)-6-hydroxy-2-oxo-azepan-3-yl>-carbamic acid tert-butyl ester (3 g, 12.3 mmol example 1 f) and triphenylphosphine (3.75 g, 14.1 mmol) in THF (200 mL) at 0°C is added diethyl azodicarboxylate (2.2 mL, 13.5 mmol) at a rate to maintain a temperature gradient) to give 2.33 g (70%) of ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester as a solid. MS (ESI) 270 (M+H)+ Preparation of (3S,6S)-3-amino-6-azido~azepan-2-one Following the procedure of example 2 d) ((3Sf6S)-6-azido-2-oxo-a2epan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(6-a2ido-hexyloxy}-1-methyl-2-oxo-a2epan-3-yI]- carbamic acid tert-butyl ester to give (3S,6S)-3-amino-6-azido-azepan-2-one. MS (ESI) 170 (M+H)+ Preparation of (R)-hH(3S,6S)-6-aado-2^xo-^ but-1 -enyl)-5-hydroxy-2F2-dimethyl^1,3]dioxan-4-yQ-2-methoxy-acetamide Following the procedure of example 2 e) (3S,6S)-3-amino-6-azido-azepan-2-one is substituted for (3S,6R)-3-amino-6-(6-a2ido-hexyloxy)-1-methyl-azepan-2HDne to give (R)-N- ((3S,6S)-6-azido-2K>xo-azepan-3-yl>24(4R,5R^ hydroxy^^-dimethyl-Il^ldioxan-^yll^-methoxy-acetamide. MS (ESI) 454.2 (M+H)+ d) Preparation of title compound (E)-(2R,3RI4S,5R)-3)4l5-trihydroxy-2-methoxy-8f8- dimethyI-non-6-enoic acid ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-amide Following the procedure of example 1 m) (R)-N«((3S,6S)-6-azido-2-oxo-azeparH3-yl)-2- [(4R,5R,6R)-6-((E)-3>dimethyl-but-1^nyl^^ methoxy-acetamide is substituted for tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R)5RI6R)-6- ((E)-3,3 acetylamino}-7-oxo-1-pyridin-3"ylmethyl-azepan»3-yl ester to give the title compound. MS (ESI) 414.2 (M+H)+ EXAMPLE 4: [(S)-2-Oxo»3-((2R,3RJ4SJ5R)-(E)-3)4J5-trihydroxy-2-methoxy-8-methyl-non-6-enoylamino)-azepan-1-yl]-acetic acid benzyl ester Preparation of (4R,4aR)-7-methoxy-2,2 Following the procedure of example 1 a) - e) except 1,1-diiodo-2-methyl-propane is substituted for 1,1-dfiodo-2,2-dimethyl-propane to give (4R,4aR)-7-methoxy-2,2-dimethyl-4- ((E)-3-methyk>ut-1-enylMetrahydr^ as a white solid. 1HNMR (CDCl3).5 5.85 (dd, J=15.6, 6.22 Hz, 1H), 5.64 (ddd, J= 15.6, 7.5,1.27 Hz, 1H), 4.74 (dd, J= 3.79, 2.09 Hz, 1H), 4.48 (dd, J= 7.49,178 Hz, 1H), 4.12 (d, J= 3.86 Hx, 1H), 4.02 (t, J= 2.02 Hz, 1H), 3.68 (s, 3H), 2.36 (m, 1H), 1.56 (s, 3H), 1.51 (s, 3H), 1.04 (d, J= 1.9 Hz, 3H), 1.03 (d, J~ 1.9 Hz, 3H); 13C NMR (CDCfe) 8 172.8,143.2,122.0, 98.7,79.0, 71.7, 70.0, 67.6, 59.2, 30.7, 29.2, 21.9, 21.8,19.2. HRMS: calculated for (M+Na)+ (C^H^OsNa) 293.1365, found 293.1355. Preparation of ((S)-3-amino-2-oxo-azepan-1-yI)-aceticacid benzyl ester Following the procedure of example 1 h) except ((S)-2-oxoazepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(tert-butyi-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester and bromo-acetic acid benzyl ester is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 base to give ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. Removal of the Boc group by procedure 2 d) gives ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. c) Preparation of title compound [(S)-2-oxo-3-((2R,3R,4S,5RHE)-3,4l5-trihydroxy-2- methoxy-8-methyl-non-6-enoylamino)-azepan-1-yn"acetic acid benzyl ester The product of 4 b) is processed as in example 2 e) - f) to give the title compound as a white solid. Examples 5-59 The following compounds are prepared by similar methods utilizing analogous starting materials: The anti-tumor activity of the compounds of formula I may be demonstrated employing the Anchorage Dependent Growth Monolayer Assay (ADGMA) which measures the growth inhibitory effects of test compounds on proliferation of adherent cell monolayers. This assay was adapted from the 60 cell line assay used by the National Cancer Institute (NCI) with the following modifications: 1) cell lines representative for the important tumor types, for example, MDA-MB-435 breast and A549 non-small cell lung, are utilized; and 2) a tetrazolium derivative, wz, MTS, is utilized to determine cell density. The ADGMA compares the number of viable cells following a 3-day exposure to a test compound relative to a number of cells present at the time the test compound is added. Cell viability is measured using a tetrazolium derivative, wz, 3-(4,5-dimettiyIthiazol-2»yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazoliumI inner salt (MTS) that is metabolically reduced in the presence of an electron coupling agent (PMS; phenazine methosulfate) by viable cells to a water-soluble formazan derivative. The absorbance at 490 nm (A490) of the formazan derivative is proportional to the number of viable cells. The IC50 for a test compound is the concentration of compound required to reduce the final cell number to 50% of the final control cell number. The MDA-MB-435 breast carcinoma line is obtained from the American Type Culture Collection (ATCC) and used between passages 4-20 following thawing. MDA-MB-435 breast carcinoma is maintained and plated in DME/F12 medium containing 10% fetal bovine serum, 15 mM HEPES (pH=7.4), penicillin 100 units/mL, and streptomycin 100 micrograms/mL The A549 non-small cell lung lines are obtained from the American Type Culture Collection (ATCC) and used between passages 4-20 following thawing. A549 cells are maintained in RPMI 1640 containing 5% FBS, 5 mg/mL insulin, 5 mg/mL transferring, 5 mg/mL selenous acid, 1 nM [3- estradiol, 1 nM testosterone, 100 units/mL penicillin and 100 ug/mL streptomycin. Cell lines are trypsinized and counted using a Coulter counter to determine plating densities. Cells are then plated in their respective maintenance media (100 pL/well) in 96 well plates at the following densities: MDA-MB-435, 3,000 cells/well; A549, 700 cells/well. The number of cells plates as determined in preliminary experiments, results in cell densities of 75-90% of confluency by 4 days after plating. Initial cell densities, assayed one day after plating, are roughly 0.15-0.20 absorbance units greater than the media blank. Ninety-six well plates are seeded on day 0 and the test compounds are added on day 1. A control plate is created for each cell Fine that receives media only in row A and cells in row B. One day following plating, test compounds are added (in a final volume of 100 pL) to the test plates. Control plates receive 10 pL MTS mixture (prepared fresh on day of addition to cell plates at a ratio of 10 pL of a 0.92 mg/mL solution of PMS to a 190 pL of a 2 mg/mL solution of MTS) and 100 pL media. A490 of control plates is read 4 h after MTS addition to determine initial cell density values for each cell line. Three days after addition of the test compound, 10 pL/wel! of MTS mixture is added to the test plates and A490 is read 4 h later. A490 values for wells containing cells are corrected for media absorbance, then normalized to initial density readings to determine percent net growth. IC50 values are determined from graphs of percent net growth as a function of compound concentration. Percent net growth is calculated as (Cell + Drug A490 - Initial A49o/Cell + Drug Vehicle A490 - Initial A490). Each of the compounds of Examples 1-59 shows an IC50 value in the range from 0.001 pM to 100 pM in the ADGMA with at least one carcinoma cell line. What is claimed is: 1. A compound of the formula I: or a salt thereof, wherein n is 0,1 or 2; R1 is H, Xr(d-e) alkyl-, (Ci.12)aIkylC(0)-, XHCM) alkenylene-, X^CM) alkynylene-, Xr(Cs. 9)cycloaIkyh X^C^cycloalkene-, X-i-aryl-, XHQw)cycloalkane-(d-6)alkytene-, X2- (C3-7)cycloalkene-(C1^)alkylene-, or Xraryl-(d-e)alkytenes Xi is H, (Ci-i4)alkyl, (d-7)cycloalkyI, (d.14)alkyl substituted by (C^cycloalkyl, -ORa, -SRa, -N02, halo or (C^)alkylC(O)-; aryl, aryi~(d-i2)alkyh -ORa, -SRa, -N02, halo, (d- iiOatkyl-CfO)-, mono- or di-(C1^)a!kyiamino, amino(d-i6)aIkyh or mono- or di-(Ci. 4)alkylamino(C1.16)alkyl; X2 is H, (Ci.i4)alkyl> (C^cycloalkyl, (d-i4)alkyl substituted by (C^cycloalkyl, -ORa -SRa, -N02, halo or (d-6)alkyl-C(0)-; aryl, aryl-(d-i2)alkyh amino(d-i6)a!kyl- or mono- or di- (CM)alkylamino(Ci-i6)alkyl; Ra is H, (d-is)aikyl, aryl, or (Ci.i8)alkyl substituted by (C^cycloalkyl, aryl, -OH, -0-(d-6)alkyl or halo; R2, R3» R4 and R5 are independently hydrogen or (Ci.i8)alkyl, R5 is also phenyl or (d-ie)alkyl which is substituted by phenyl, wherein there is no more than a total of 18 carbon atoms in the combined R2, R3, R4 and R5 alkyl substituents, or R2 and R together or R3 and R5 together form an acetal group; R6 is hydrogen or (d.6) alkyl; R7 is H, (d-i8)alkyl, phenyl, pyridyl, (Ci.i8)alkyl substituted by (C^cycloalkyl, -ORx, N3l halo, -N(RX)2, Rx, -0-(d-6)alkyl, -OC(OHd-i6)alky! or pyridyl; -Y-Rb or a substituent of formula lla or Ilia wherein R7 and Re are defined above, with the compound of formula VII wherein Ri and R5 are defined above, to form a compound of formula VIII (b) hydrolyzing the compound of formula VIII. 11. The process as claimed in claim 10, wherein step (a) is conducted in a polar organic solvent or in the presence of a weak base and a polar organic solvent. 12. The process as claimed in claim 10, wherein the compound of VIII is prepared by reacting the compound of XI wherein Ru R5 and R7 are defined in claim 10, with an acid chloride in the presence of a base and a solvent. 13. The process as claimed in claim 12, wherein the acid chloride is of the formula R12COCt, wherein R12 is an appropriate substituent based on the definition of Re; the base is triethylanime and the solvent is dichloromethane. 14. The process as claimed in claim 10, wherein the compound of VIII is prepared by reacting the compound of XI wherein Ri, R5 and R7 are defined in claim 11, with a carboxyiic acid in the presence of a carboxylic acid coupling agent and an activating agent. 15. The process as claimed in claim 14, wherein the carboxylic acid is of the formula R12COOH wherein R12 is an appropriate substituent based on the definition of R%, the carboxylic acid coupling reagent is 1-{3-dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride and the activating agent is 4-dimethyaminopyridine. 16. The process as claimed in claim 10 wherein the compound of formula VII is prepared by cleaving the compound of formula XXXIII wherein R5 is defined in claim 10, to obtain the compound XXXIV reacting the compound of XXXIV with an organometallic compound in the presence of a solvent mixture. 17. The process as claimed in claim 16, wherein cleaving the compound of formula XXXlll is carried out in the presence of a periodate salt in a solvent. 18. The process as claimed in claim 17, wherein the periodate salt is sodium periodate and the solvent is methanol. 19. The process as claimed in claim 16, wherein the organometallic compound is an organochromium compound, and the solvent mixture comprises of a polar organic solvent and an inert organic solvent 20. The process as claimed in claim 19, wherein the polar organic solvent is N,N-dimethytformamide and the inert organic solvent is tetrahydrofuran. 21. A process to prepare the compound of the formula I: or a salt thereof, wherein n is 0,1 or 2; R1 is H, XHd-e) alkyh (Ci.t2)alkylC(Oh XHC2-4) aikenyiene-, X^QM) alkynyiene-, XHd- 9)cycloalkyh X^C^cycloalkene-, Xraryt-, X^KCwJcycloalkane-^^Jalkylene-, X2- (d-7)cycloalkene-(d-6)alkytene-, or X-t-aryHC^alkylene-; X1 is H, (d-i4)alkyl, (C^cydoalkyl, (C1.14)alkyl substituted by (d-rjcycloalkyl, -ORa, -SRa, -N02l halo or (d-e)aikylC(O)-; aryl, aryl-(d-i2)alkyl-, -ORa, -SRat -N02, halo, (d- i2)alky!-C(0)-, mono- or di-(Ci-4)alkylamino, amino(Ci.16)alkyh or mono- or di-(d- 4)alkylamino(C1.16)alkyl; X2 is H, (Ci-i4)atkyl, (C^cycloalkyl, (d-i4>alkyl substituted by (Cs^cycioalkyl, -OR3 -SRa, -N02) halo or (d-6)alkyl-C(0)-; aryl, aryl-(d-i2)alkyh amino(d-i6)alkyl- or mono- or di- (d^)alkylamino(Ci.i6)alkyl; Ra is H, (d-is)alkyl, aryl, or (d-is)alkyl substituted by (C^cycloalkyl, aryl, -OH, -0-(d-e)aIkyl or halo; R* R3. R4 and R5 are independently hydrogen or (Ci.i8)alkylv R5 is also phenyl or (Cv16)alkyI which is substituted by phenyl, wherein there is no more than a total of 18 carbon atoms in the combined R2, R3, R4 and R5 alkyl substituents, or R2 and R4 together or R3 and R5 together form an acetal group; R6 is hydrogen or (d-e) alkyl; R7 is H, (CvisJaikyI, phenyl, pyridyi, (d-ia)a!kyi substituted by (C^cydoalkyl, -0RX, N3, halo, -N(RX)2, Rx, -0-(d.6)alkyi, -OC(OHCi.i6)alkyl or pyridyi; -Y-Rt> or a substituent of formula Ha or Ilia wherein R9 is from 0 to 3 substituents selected from (d-e)alkyl, -ORa, -SRa, -NO;, halo, -N3, (d-i2)alkylC(0)-, mono- or di«(d^)alkylamino, amino(d-i6)alkyi-, mono- or di-(d-4)alkylamino(d.i6)alkyl. (CH2)o.2-C&.7cycloalkylI (CH2)o-2-heterocyclic1 (CH^-C^aryl, or (CH2)o.rheteroaryl; Y is a linking group selected from -(d.10)alkyl-, KCo-io)aIkyiene-CO-N(RxHCo-io)alkyIene-, -(CCMo)alkylene-N(Rx)-CO-(Co-1o)alkylene-, -(d-ioJalkylene-CO-O-Cd-toJalkylene-, -(Cv io)alkylene-0-C(0>(C1.io)aIkylene^-(Co-io)alkyiene-CO-(C0.io)alkyJene-l-(Co. 10)alkylene-(Rx)N-CO-0-(Co.10)alkylene-, -(Co.io)alkylene-0-CO-(Rx)N-(Co.io)alkylene-or -(Co.i8)alkylene-arylene-(Co-i8)alkylene-; Rx is H, (C-^alkyl or phenyl; Rh is (d.16)alkyi or (Ci.ie)alkyl which is substituted by (C^cycloalkyl, -ORx, N3, halo, -N(RX)2, -0-(C^)alkyl, -OC(OHd.16)aIkyl or pyridyi; R8 is H, halo, -N3, (CM6)alkyI> -Z-(d-i6)alkyl, (Ci.16)alkyl substituted by (C^cycloalkyi, -N3l -N(RX)2( -Z-het, -ORa or -SRa, -Z-(Ci.16)alkyl substituted by (d^cycloalkyl, -N3) -N(RX)2, -Z-het, -ORa or -SRa, -0(d-ie)alkylene-N3, -0(d_16)alky)ene-N(Rx)2l -(C0.6)a)kylene-OCCOHd-ieJalkyl, -(Cw)alkylene-(0)C-0-(Ci.16)alkyl1 ~(Co.6)alkytene-OC(OHd. 7)cycloalkyl, -(Co^alkyleneKOJC-O-CC^cycloalkyl, pyridyi, -OC(0)0(d.i2)aikyIt -O-C0-X-R2, or -0-CO-(CH2)m-0-(CH2)m-X-Rz wherein X is a direct bond, (d.i2)alkylene, (Ci.12)alkenylene or (d.12)alkynylene and R2 is H, (C^cycloatkyi, phenyl, phenyl substituted by one or more of chloro, methoxy, (Ci.18)alkyl or (Ci-i8)alkoxy, pyrroiyl, furanyl, thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13, -Z-het, -ORa, -SRa, mono- or dHC-u 4)a!kylamino, amino(Ci.i6)alkyl-, mono- or di-(C1J()alkylamino(Ci.i6)alkylI -Z-Si((Ci. 6)alkyF)3 or a substituent selected from the following two formulae: Z is a direct bond, -(C^alkylene-, -(d.^alkylene-O-, -0-(Ci.12)alkylene-, -(Cj.12)alkylene-N(RX)-, -N(Rxh -WxHCi-^alkytene-, -N(Rx>C(0)-, -NfRxJ-CfOHCL^alkylene-, -(C1.12)alkylene-N(Rx)-C(0)-,-(C1-6)aIkylene-N(Rx)-C(OHC14)a!kylene-,-(C1.12)alkylene-CO-N(Rx)-, -CO-N(Rx)-(C1.12)alkylene-, -(d^alkylene-CO-NfRxHC^Jalkylene-, -CO-N(RX)-, -(d.^alkylene-CO-O-, -(d.^alkylene-O-CKO)-, -OC(0.)-(Ci-i2)alkylene-, -CKOJ-O-fCviaJalkylene-, -(d-u^alkylene-CO-, -{C^Jalkylene-CO-tC^^alkylene-, -CO-(d-i2)alkylene-, -C(O)-, -N(Rx)-C(0)-0-, -N(Rx)-C(0)-0-(C1.12)alkylene-1 -(d. 12)alkylene-N(Rx)-C(0)-O-)-(C1^)alkylene-N(Rx)-C(0)-0-(C^)alkylene-,-(C1. 12)alkylene-0-CO-N(Rx)-,-O-CO-NtRO-CCvizialkytene-, -(d-e)alkylene-0-CO-N(Rx)-(C^)alkylene-, -0-CO-N(Rx)-, -O-CO-O-, -(d-i2)alkylene-0-CO-0-, -0-CO-O-(d-12)a!kylene- or -(d^)a(kylene-O-C(0)-0-(d-8)alkylene-; Zt is a direct bond, -(d-i2)alkytene-, -0-(d-i2)alkylene-, -N(RxMd-i2)alkylene-, -N(Rx)-C(0)-(Cvizialkytene-.^C^Jal^eTO-NCRxKltOKC^ialkylene-.-CO-NtRxHCi.-isJalkylene-, ~(C1^)alkylene-CO-N(Rx)-(C1^)alkylene-, -OC(OHd.i2)alkylene-, -C(0)-O-(Ci-12)alkylene-, -(d-8>alkytene-CO-(d-8))alkytene-. -CO-(Ci-i2)alkylene-, -C(OK -N(RX>-C(0)-0-(Ci.12)alkylene-, -(Ci^)alkylene-N(Rx)-C(0}-0-(C1^)alkylene-, -0-CO-N(Rx>-(d-i2)alkyiene-, -(C1^)alkylene-0-CO-N(Rx)-(C1^)alkylene-I-O-CO-O^Ci.^Jalkylene-or-(d)alkylene-0-C(0)-0-(d-8)alkylene-; R10 is from 0 to 3 substituents selected from hydroxy, halo, -(C1.17)alkyl, -0-(d-i7)alkyl, -(CHz)m-C3.7 -cycloalkyl, -(CH2)o-io-aryl or -(CH2)o-io -het; het is a heterocyclic or heteroaromatic ring; pis 1-18; with the proviso that when n is 2 and Rn is (d-6)a!kyI-CH=CH- or (C3.6)cycloalkyl-CH=CH-then R7 is not H or (Chalky! or R8 is not -0-CO-X-R2 or -0-CO-(CH2)m-0-(CH2)m-X- R2 where X is a direct bond, (C^alkylene, (C^alkenylene or (C1.12)alkynyiene and R2 is H, (C^cycloalkyi, phenyl, phenyl substituted by one or more of chloro, methoxy (Ci.i8)alkyl or (Ci.18)aIkoxyJ pyrrolyl, furanyl, thbfuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13^ and with the further proviso that Re is not -OH when n is 2, R7 is H or methyl and R, is 3-methyIbut-1 -enylene; comprising the following steps: (a) reacting a compound of formula XLI wherein R^ and R5 are defined above, P2 and P4 are protective groups, and Rm is a (Chalky], with the compound of formula VI wherein R7 and Re are defined above, to form the compound of formula XLI I (b) deprotecting the compound of formula XLII. 22. The process as claimed in claim 21, wherein R'" is ethyl, P2 is fert-butyldimethylsilyl, and P4 is selected from benzyl or naphthlmethy! ethers.

Full Text

Substituted lactams and their use as anti-cancer agents
The present invention relates to the area of therapeutic agents for the treatment of cancer. More particularly, the present invention relates to certain substituted lactams, pharmaceutical compositions comprising said lactam compounds, a method of treating cancer with said lactam compounds, and a process for preparing said lactam compounds.
BACKGROUND
Cancer is a serious health problem throughout the world. As a result, an extensive number of research endeavors has been undertaken in an effort to develop therapies appropriate to the treatment and alleviation of cancer in humans. Research has been conducted to develop anti-cancer agents effective against various types of cancer. Oftentimes, anticancer agents which have been developed and found effective against cancer cells are, unfortunately, also toxic to normal cells. This toxicity manifests itself in weight loss, nausea, vomiting, hair loss, fatigue, itching, hallucinations, loss of appetite, and other undesirable effects.
Additionally, conventionally used cancer treatment agent often do not have the effectiveness desired or are not as broadly effective against different types of cancers as desired. As a result, a great need exists for therapeutic agents which are not only more effective against multiple types of cancer, but which have a higher degree of selectivity for killing cancer cells with no or minimal effect on normal healthy cells. In addition, highly effective and selective anti-cancer agents, in particular, against cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva, small intestine, lymph glands, and blood cells are desired. Moreover, anti-cancer activity against colon, breast lung, pancreas, and prostate cancers as well as melanomas are particularly desired because of the lack of any particular effective therapy at the present time.
SUMMARY
The present invention provides new anti-cancer agents which are effective against a variety of cancer cells in particular, against all liquid and solid cancers that may arise in a subject, including cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver,

brain, testis, ovary, cervix, skin, vulva, small intestine, lymph glands, and blood cells. More particularly, the present invention relates to certain substituted lactams which exhibit a high degree of selectivity in killing cancer cells.
DETAILED DESCRIPTION
The invention relates to pharmaceutical compounds that are useful for the treatment of cancer of the formula I:

wherein
n is 0,1 or 2;
R1 is H, Xr(C^) alky!-, (CM2)alkyl0(O)-, Xr(C2-4) alkenylene-, X2-(C2^) alkynylene-, XHC3-9)cycloalkyh X2-(C3.9)cycloa[kene-, Xraryh Xr(C3-7)cycloalkane-(C1^)alkylene-, XrCQj-rJcycloalkene-fCi-eJalkyiene-, or XraryKC^alkylene-;
X, is H, (C-M4)alkyl, (C^cycloalkyl, (CL^alkyl substituted by (C^cycloalkyl, -ORa, -SRa, -N02, halo or (C^)alkylC(O)-; aryl, aryl-(C1.12)alkyl-J -ORai -SRa, -N02, halo, (C^alkyl-C(O)-, mono- or di-fC^alkylamino, amino(C1.i6)alkyl-) or mono- or di-(C1^)alkylamino(Ci_ ie)alkyl;
X2 is H, (Chalky!, (C^cycloalkyl, (d.14)alkyl substituted by (C^cycloalkyl, -ORa -SRa, -N02, halo or (C-^alkyi-CfO)-; aryl, aryKd.^aikyl-, amino(Ci.16)alkyl- or mono- or di-(Ci. 4)aIkylamino(C1.16)alkyl;

F*2, R3, R4 and R5 independently are hydrogen or methyl;
R6 is hydrogen;
R7 is H or (C^alkyi;
RB is H; and
n is 2.
In another embodiment, the invention provides pharmaceutical compositions, especially for the treatment of cancer in subjects, especially human, comprising a pharmaceutical^ acceptable carrier or diluent and an antitumorally effective dose of a compound of formula 1 above, or a pharmaceuticalfy acceptable salt thereof, where possible.
In still another embodiment, the current invention provides a method for treating cancer comprising administering to a subject, especially human, in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutical^ acceptable salt thereof, where possible. The effective dosage of the compounds of the invention for such treatment may encompass a range of from about 0.01 milligrams per kilogram body weight per day to about 0.02 grams per kilogram of body weight per day.
In another embodiment, the current invention relates to the use of a compound of formula I or of a pharmaceuticaliy acceptable salt of such a compound for the preparation of a pharmaceutical composition for use in the chemotherapy of cancer.
Furthermore, the current invention relates to the use of a compound of formula I or of a pharmaceuticaliy acceptable salt of such a compound for the chemotherapy of cancer.
In the above definitions:
The alky! groups, including any alkyl portion of a substituent, such as alkoxy, are either straight or branched chain, of which examples of the latter include isopropyl, isobutyl, f-butyl, isopentyl, neopentyl, isohexyl, 3-methylpentyI, 2,2-dimethylbutyl, 2,3-dimethyIbutyI and 1,1,2,2-tetramethyIethyI unless otherwise noted.
The term "alkyiene" as used herein refers to a straight or branched chain consisting solely of carbon and hydrogen. Examples of "alkylene" groups include methylene, ethylene, propylene, butylene, pentylene, and 3-methypentylene.

The term "alkenylene" as used herein refers to a straight or branched chain consisting solely of carbon and hydrogen, containing at least one garbon-carbon double bond. Examples of "alkenylene" groups include ethenyiene, propenylene, butenylene, 3,3,-dimethylbut-l-enylene, 3-methylbut-1-enylene, pentenylene, 3-methylpentenylene, and butadiene.
The term "alkynylene" as used herein refers to a straight or branched chain divalent group consisting solely of carbon and hydrogen containing at least one carbon-carbon triple bond. Examples of "alkynylene" groups include acetylene, propynylene, butynylene, pentynylene, 3-methylpentynylene.
If R2 and R4 together or R3 and R5 together form an acetal group, R2 and R4 together or R3 and R5 together preferably form a group of the formula -C(R')(R"K wherein R' and Rn are selected independently of each other from Xr(Ci^) alkyl-, X2-(C2-4) alkenyl-, Xr(C3-7)cycloafkyh or Xr(C3.7)cycloaIkane-(Ci^)aIkyI- wherein X^ is as defined herein.
The term "direct bond" as herein described refers to a single, double, or triple, covalent atomic bond which links together two moieties.
Halo is chloro, bromo, iodo or fluoro, especially chloro, bromo or iodo.
The substituent het is preferably a 3 to 9 membered aliphatic ring, such as a 4 to 7 membered aliphatic ring, containing from one to three heteroatoms selected from nitrogen, sulfur and oxygen, or het is a 5 to 7 member aromatic ring containing one or more heteroatoms, for example from 1 to 4 heteroatoms, selected from N, O and S, or het is a bicyclic and tricyclic fused ring system where each ring can independently be 5 or 6 membered and contain one or more heteroatoms, for example, 1, 2, 3, or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic. Examples of suitable het substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, and pyrroloquinoline. Het is preferably pyridyl.

In the instance where het is a nitrogen containing ring, N-substituted compounds are included- Suitable N-substituents include (Chalky!, such as N-methyl or N-ethyl, -C(0)Ci-12alkyl, such as methyiamido or ethyiamido, -C(OVO-(C1.u)alkyl, such as carbomethoxy or carboethoxy, or phenyl.
het also includes the above rings with substitution on one or more carbons. Suitable C-substituents include (Chalky), such as methyl or ethyl, -ORa, such as methoxy and ethoxy, -SRa, halo, -N(RX)2 and the like.
Aryl includes phenyl and naphthyl substituents.
A "heteroaryT group is mono-, bi- or tri-cyclic, and comprises 3-24, preferably 4-16 ring atoms, and is most preferably mono-cyclic comprising 5-7 ring atoms, wherein at least one or more, preferably one to four ring carbons are replaced by a heteroatom selected from O, N or S such as azirinyl, imidazolyl, thienyl, furyl, indolyl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, 2f/-pyrrolyl, pyrrolyl, benzimidazolyl, pyrazofyl, pyrazinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3/-/-indolyI, benzimidazolyl, benzothiazolyl and benzo[1,2,5] thiadiazolyl, thiacumaryl, indazolyl, triazolyl, tetrazoiyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyi, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and chromanyl, each of these radicals being unsubstituted or substituted by one to two substituents.
"Heterocyclic" refers to a heterocyclic radical containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. piperazinyl, lower alkyl-piperazinyl, azetidinyl, pyrrolidinyl, piperidino, morpholinyl, imidazolinyl). The heterocyclic radical is preferably unsaturated, saturated or partially saturated in the bonding ring; has 3-24, more preferably 4-16 ring atoms, wherein at least in the bonding ring one or more, preferably 1-4, especially one or two carbon ring atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the bonding ring preferably having 4-12, especially 4-7 ring atoms; the heterocyclic radical is unsubstituted or substituted by one or more, especially 1-4

substituents and is especially selected from the group consisting of indoly, tetrahydrofuranyl, benzofuranyl, thienyl, pyridyl, imidazolinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidino, piperidyl, pyrrolidinyl, oxiranyl, 1,2-oxathiolanyI, pyrrolinyl, imidazolidinyl, pyrazolidinyl and azetidinyl, with piperazinyl being especially preferred.
In view of the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, hereinbefore and hereinafter any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient.
Salts are especially the pharmaceutical^ acceptable salts of compounds of formula I.
Salts of the compounds of formula I may be pharmaceutical^ acceptable acid or base addition salts with organic or inorganic acids or bases. Although the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, for example, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid may also be utilized.
Preferably, R2, R* R4 and R5 are in the relative stereochemical conformation to each other depicted in stereochemical formulae la and lb:

The lactams of formula I may be prepared as depicted below:

where each of R1, R5, R7 and R8 is as defined above.
As to the individual steps, Step A involves the acylation of an aminolactam of formula VI with a lactone compound of formula VII to obtain a diamide compound of formula VIII. The acylation is conducted in a polar, organic solvent preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.

Alternatively, the acylation of an aminolactam of formula VI, or an acid addition salt thereof, with the lactone compound of formula VII in Step A may be earned out with in the presence of: 1) a weak base, preferably a carboxylate salt such as sodium 2-ethylhexanoate, and 2) a polar, organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between 0°C and 50°C, preferably at 25°C, for a period of between 1 hour and 7 days, preferably for 20 hours.
Step B concerns the hydrolysis of the 1,3-dioxane group common to a diamide compound of formula VIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.
Alternatively, the diamide compounds of formula Villa may be prepared according to the following 3-step reaction scheme:

As to the individual steps, Step 1 involves the acylation of an aminolactam of formula IX with a lactone compound of formula VII to obtain a diamide compound of formula X. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step 2 concerns the hydrolysis of the group P2 common to a diamide compound of formula X to obtain a hydroxylactam compound of formula XI. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutyf-ammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.
Step 3 concerns the acylation of a hydroxylactam compound of formula XI by reacting it with an acid chloride of formula R12COCI where R12, is defined above, to obtain a diamide compound of formula Villa. The acylation is conducted in the presence of a base, preferably an alkylamine base such as triethylamine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours.
Alternatively, the acylation of a hydroxylactam compound of formula XI in Step 3 may be carried out with a carboxylic acid of formula R12COCI where R12, is defined above, in the presence of a carboxylic acid coupling reagent, preferably a diimide such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, preferably a substituted pyridine such a 4-dimethylaminopyridine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours.
The aminolactam compounds of formula la may be prepared as depicted below;

As to the individual steps, Step 1a involves the cyclization of hydroxylysine (or any salt or hydrate preparation thereof) XII to obtain hydroxycyclolysine XIIL The cyclization is typically carried out in the presence of a coupling reagent, preferably a diimide such as 1-(3-dimethylaminopropyl)-3^thylcarbodiimide hydrochloride, and a suitable actuating agent common to diimide coupling reactions, preferably an AZ-hydroxy compound such as 1-hydroxybenztriazole hydrate, and a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 12 and 72 hours.
Step 1b involves the A^acylation of hydroxycyclolysine XIII to obtain an N-acylhydroxycyclolysine compound of formula XIV. The acylating agent is typically an acid chloride or an anhydride. When Pi is f-butyloxycarbonyl, the acylating agent is di-ferf-butyldicarbonate. The reaction is carried out in the presence of a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours.
Step 1c involves the Osilylation of an W-acylhydroxycyclolysine compound of formula XIV to obtain a silyl ether compound of formula XV, The silylating agent is typically a silyl chloride or trifluoromethanesutfonate. When P2 is ferf-butyldimethylsilyl, the silylating agent is ferf-butyldimethylsilylchloride. The reaction is carried out in the presence of a base, preferably a mild base such as imidazole, and a polar organic solvent, preferably an amide such as N,N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours.
Step 1d involves the /V-alkylation of a silyl ether compound of formula XV with an alkyl (defined as R7 above) halide or sulfonate to obtain an N-alkyl lactam compound of formula XVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsilyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 2 hours.

Step 1e concerns the hydrolysis of the group P^ on an N-alkyl lactam compound of formula XVI. The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethyisifyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours-Step 1f involves the acylation of an aminolactam of formula XVII with a lactone compound of formula VII to obtain a diamide compound of formula X. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step 1g concerns the hydrolysis of the group P2 common to an N-alkyl lactam compound of formula X, to obtain a hydroxylactam compound of formula XI. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutylammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 6 hours.
Step 1h concerns the acylation of a hydroxylactam compound of formula XI by reacting it with an acid chloride of formula R12COCl where R12, is defined above, to obtain a diamide compound of formula VIII. The acylation is conducted in the presence of a base, preferably an alkylamine base such as triethylamine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours.
Step 1i concerns the hydrolysis of the 1,3-dioxane group of compound formula VIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.

Alternatively, the acylation of a hydroxylactam compound of formula XI in Step 1h may be carried out with a carboxyDc add of formula R12COOH where Ri2, is defined, in the presence of a carbolic acid coupling reagent, preferably a dfimide such as 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, preferably a substituted pyridine such a 4-dimethylaminopyridine, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -78 °C and 25 °C for a period of between 1 and 24 hours.
The aminolactam compounds of formula lib may be prepared as depicted below:

R14 is a leaving group.
where each R1, Rs» Rzand R12 is as defined above, and Pi is a carbonyl-containing group. Preferably, Pi is alkoxycarbonyl such as f-butyloxycarbonyl. P2 is an alcohol protective group. Preferably, P2 is a silyf group such as fert-butytdimethylsilyl.

Step 2a concerns the hydrolysis of the group P2 common to an N-alkyl lactam compound of formula XVI, to obtain a hydroxylactam compound of formula XVII. The hydrolysis is typically carried out in the presence of fluoride, preferably a fluoride salt such as tetrabutylammonium fluoride, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 6 hours.
Step 2b involves the O-alkylation of a compound of formula XVII with an alkyl (defined as R12 above) halide or sulfonate to obtain an O-alkyl lactam compound of formula XVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsifyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 6 hours.
Step 2c concerns the hydrolysis of the group P1 on an N-alkyl lactam compound of formula XVIII. The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethylsilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours.
Step 2d involves the acylation of an aminoladam of formula XIX with a lactone compound of formula VII to obtain a diamide compound of formula XX. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step 2e concerns the hydrolysis of the 1,3-dioxane group of compound formula XX, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.

The aminolactam compounds of formula He may be prepared as depicted below:

where each R1, R5, R7 is as defined above, R13 is an appropriate substituent based on the definition of Rs above and P% is a carbonyl-containing group.
Preferably, P^ is alkoxycarbonyl such as f-butyloxycarbonyL
Step 3a involves the substitution of the hydroxy group of the compound of formula XVI! for a heteroatom (defined as Y above) preferably with inversion of configuration and most preferably by a Mitsunobu type reaction (reference) involving a trialkyl or triaryi substituted phosphine, an azodicarboxylate diester and a nucleophile source such as diphenyiphosphoryl azide. Alternatively the hydroxy group can be converted to a sulfonate or haiide suitable for displacement.
Step 3b concerns the hydrolysis of the group P^ on an N-alkyl lactam compound of formula XXI. The hydrolysis is typically carried out in the presence of a protic acid, preferably an

organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethyisilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours.
Step 3c involves the acylation of an aminoiactam of formula XXII with a lactone compound of formula VII to obtain a diamide compound of formula XXIII. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropylethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step 3d concerns the hydrolysis of the 1,3-dioxane group of compound formula XXIII, to obtain a substituted lactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.
The aminoiactam compounds of formula lid may be prepared as depicted below:

where each R1, R5, and R7 is as defined above, and P-i is a carbonyl-containing group. Preferably. Pi is alkoxvcarbonvl such as f-butvloxvcarhonvl.
Step 4a involves the A/-acyiation of cyclolysine XXIV to obtain an AJ-acylcycloIysine compound of formula XXV. The acylating agent is typically an acid chloride or an anhydride. When Pi is f-butyloxycarbonyl, the acylating agent is di-te/f-butyldicarbonate. The reaction is carried out in the presence of a base, preferably an alkylamine base such as triethylamine, and a polar organic solvent, preferably an amide such as N7N-dimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours.
Step 4b involves the W-alkylation of an N-acylcyclolysine compound of formula XXV with an alkyl (defined as R7 above) halide or sulfonate to obtain an A/-alkyl lactam compound of formula XXVI. The alkylation is conducted in the presence of a strong base, preferably an alkali metal amide such as sodium bis(trimethylsilyl)amide, and an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -100 °C and 25 °C for a period of between 5 minutes and 2 hours.

Step 4c concerns the hydrolysis of the group Pi on an N-alkyl lactam compound of formula XXVI, The hydrolysis is typically carried out in the presence of a protic acid, preferably an organic acid such as trifluoroacetic acid, hydrogen or a silyl halide, preferably a silyl iodide such as trimethylsilyl iodide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between -100 °C and 25 °C for a period of between 1 minute and 2 hours.
Step 4d involves the acylation of an aminolactam of formula XVII with a lactone compound of formula XXVII to obtain a diamide compound of formula XXIX. The acylation is conducted in the presence of a base, preferably an alkylamine base such as diisopropyiethylamine, and a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step 4e concerns the hydrolysis of the 1,3-dioxane group of compound formula XXIX, to obtain a substituted lactam compound of formula Id. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0 °C and 25 °C for a period of between 5 minutes and 2 hours.
The lactone compounds of formula VII may be prepared as depicted below.

where R1 and R5 are as defined above.
As to the individual steps, Step 5a involves the diketalization of polyhydroxylated lactone of formuia XXX with acetone io obtain bis(acetonide) XXXi. The diketalization is conducted in acetone as solvent using a catalyst such as iodine at a temperature of between 0 °C and the reflux temperature for a period of between 2 and 48 hours.
Step 5b involves the alkylation of b/s(acetonide) XXXI with an alkylating agent such as an alkyl (defined as R5 above) halide, sulfonate or sulfate ester to obtain the ether XXXII. The alkylation is conducted in the presence of water and a base, preferably a metal oxide such as silver oxide, and an inert organic solvent, preferably a chlorinated alkane such as dichloromethane, at a temperature of between 0 °C and the reflux temperature for a period of between 12 hours and 7 days.
Step 5c involves the hydrolysis of alkyl ether XXXII to obtain the dihydroxy compound of formula XXXIII. The hydrolysis is conducted in the presence of water and a protic acid, preferably a carboxylic acid such as acetic acid, at a temperature of between 5 °C and 35 C for a period of between 1 and 24 hours.

Step 5d involves the oxidative cleavage of dihydroxy compound XXXIII to obtain the aldehyde XXXIV. The reaction is conducted in the presence of an oxidant preferably a periodate salt such as sodium periodate, in a protic solvent, preferably an alkanol such as methanol, at a temperature of between 0 °C and 25 °C for a period of between 10 minutes and 4 hours.
Step 5e involves the olefination of aldehyde XXXIV to obtain a lactone compound of formula VII. The olefination is conducted in the presence of an organometaliic compound, preferably an organochromium compound such as the transient species generated from chromium(H)chloride and a diiodoalkane (defined as f^CH^ where Ri is as defined above), in the presence of a solvent mixture consisting of 1) a polar organic solvent, preferably an amide such as ty/V-dimethylformamide, and 2) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between -80 °C and 25 °C for a period of between 5 minutes and 4 hours.
Alternatively the lactone compounds of formula Vila may be prepared as depicted below:

where R5 is defined above and R' is C^) alkyl
Step 6a involves the conversion of XXXIII to an ortho ester XXXV by acid catalyzed transesterification with an alkyl orthoester, preferably triethylorthoformate and p-toluenesulfonic acid. The reaction can be run with excess alkyl orthoester as the solvent or an inert organic solvent may be used at a temperature of between 20 °C and 80 °C for a period between 1 and 24 hours.

Step 6b involves the elimination of the orthoester XXXV to give alkene Vila. The reaction is conducted in an organic acid anhydride, preferably acetic anhydride at a temperature of 20 °C and 100 °C for a period between 1 and 24 hours.
Alternatively the lactams of formula I may be prepared as depicted below:

where each R1, R5, R7, R9* and X are defined above, R" is a C^9) branched alkyl or phenyl substituted C(1^j alkyl, preferably benzyl and Rm is a C(i-6) alkyl, preferably ethyl. P2 and P3 are alcohol protective groups, preferably silyl groups such as terf-butyldimethylsilyl and trimethylsilyl respectively. P4 is an alcohol protective group, preferably benzyl or 2-naphthlmethyl ethers.
Step 7a involves an Evans type aldol condensation of oxyimide XXXVI with an aldehyde to give XXXVII. The reaction is conducted in the presence of a Lewis acid, preferably diethylborontriflate and an organic base, preferably diisopropylethylamine in an inert organic solvent such as CH2CI2at a temperature of between -100 °C and 0 °C for a period of 1-24 hours.
Step 7b involves the O-siiylation of compound XXXVII to obtain a silyl ether compound of formula XXXVIIL The siiylating agent is typically a silyl chloride or trifluoromethanesulfonate.

When P2 is fe/t-butyldimethylsilyl, the silylating agent is fert-butyldimethylsilylchloride. The reaction is carried out in the presence of a base, preferably a mild base such as imidazole, and a polar organic solvent, preferably an amide such as tyAWimethylformamide, at a temperature of between 0 °C and 40 °C for a period of between 1 and 24 hours.
Step 7c involves the formation of thioester XXXIX from XXXVIII by reaction with an alkali metal salt of a thioether, preferably LiSEt, in an inert solvent, preferably THF, at a temperature of between -100 °C and 0 °C for a period of 1-24 hours.
Step7d involves conversion of thioester XXXIX to the aldehyde XL by reduction with a metal hydride, preferably diisobutylaluminum hydride, in an inert solvent, preferably CH2CI2J at a temperature of between -100 °C and 0 °C for a period of 10 minutes to 1 hour.
Step 7e involves a Gennari type coupling of aldehyde XL with a thiovinylether to give the thioester XLI. The reaction is conducted in the presence of a Lewis acid, preferably SnCU, in an inert solvent, preferably a mixture of CH2CI2 and heptane, at a temperature of between -100 °C and 0 °C for a period of 1-24 hours.
Step 7f involves the acylation of thioester XLI with amine VI to give diamide XLII. The reaction is conducted in an inert solvent, preferably dioxane, at a temperature of between room temperature and 100 °C for a period of 1-48 hours.
Step 7g involves the deprotection of diamide XLII to give compound I. The method employed is dependant on the P2 and P5 groups utilized, preferably when P2 is terf-butyldimethyisilyl and P4 is 2-naphthlmethyi ether a two step procedure is employed using DDQ in a mixture of wet CH3OH and CH2CI2 followed by treatment with tetrabutylammonium fluoride in THF to give compound I.
The following specific examples are intended to further illustrate, but not limit, the invention.
EXAMPLES

EXAMPLE 1: Tetradecanoic acid (3R,6SHK)XI>1-pyridine
3,4,5-trihydroxy-2-methoxy-8,8^ ester

a) Preparation of 3,5:6 J4)is-0-(1-iTiethylethylidene}-a-D-glucoheptonic y-Iactone. a-D-Glucoheptonic y-Iactone (500 g, 2.4 mol) is added into 9 L of acetone in a 5 gal plastic drum. The mixture is agitated mechanically until most of the solid dissolved (15-20 min). Iodine (60g, 0.236 mol) is added portion wise into the lactone solution over 5-10 min. The resulting mixture is stirred overnight. A saturated solution of Na2S203 (1.3 L) is added to the iodine solution to quench the reaction. The resulting solution is concentrated to about half of its original volume in vacuum, and brine solution (5 L) is added. The resulting mixture is extracted with 3 x 1.2 L EtOAc. AH organic layers are combined and evaporated to dryness. The solid is slurried with a mixture of ether and hexane (3:7), and filtered. The filter cake is washed with Et20 (50 mL) and air dried, giving 599 g of the desired compound as a white powder (86.5%): 1H NMR (CDCl3) 5 4.62 (m, 1H), 4.50 (m, 1H), 4.35 (m, 2H), 4.07 (m, 1H), 3.93 (m, 1H), 3.82 (dd, 1H), 3.08 (d, 1H), 1.51 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCI3) 5 174.4, 109.4, 98.6, 72.8, 71.4, 69.3, 68.4, 67.8, 66.7, 28.6, 26.7, 24.6, 19.3.
Preparation of 2-Omethyl-3,5:6,7-bis-0-(1-methylethylidene)-a-D-glucoheptonic y-lactone. 3,5:6,7-bis-0(1-methylethylidene)-a-D-gIucoheptonicy-lactone (719 g, 2.49 mol) is added into 4.5 L of CH2CI2 in a 5 gal plastic drum. The mixture is stirred under N2. lodomethane (2500 g, 17.6 mol) is added immediately followed by addition of siiver(l) oxide (1750 g, 7.58 mol). Water (30 mL) is added to the reaction mixture. Ice bath is used to maintain the reaction temperature at 15-30 °C. The reaction is stirred in the absence of light for 18 h. After diluting the reaction mixture with 1.5 L of CH2CI2, the solid is filtered and washed with an additional 2.2 L of CH2CI2. The undesired solid is discarded and the filtrate is evaporated

to dryness. The residue is slurried in Et20 (1.5 L), filtered, and dried to give 618 g product (82 %): 1H NMR (CDCI3) 5 4.75 (m, 1H), 4-33 (m, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 4.07 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.65 (s, 3H), 1.57 (s, 3H), 1.42 (s, 6H), 1.35 (s, 3H); 13C NMR (CDCI3) 8 172.5,109.6, 98.5, 79.0, 73.1, 69.5, 68.6, 67.5, 66.9, 59.1, 28.9, 26.9, 24.9, 19.4.
Preparation of 2-0-Methyl-3,5-CK1-methylethyiidene)-a-D»glucoheptonic y-lactone.
2-(>methyl-3,5:6t7-bis-(>(1-m^ (618 g, 2.05 mol)
is dissolved in 8 L of a mixture of acetic add and water (1:1) over 30 min. The solution is stirred at ambient temperature overnight The solution is evaporated to dryness in vacuum. The solid is slurried in 3-5 L of hot acetone and filtered. After oven drying at 20-30 °C, 363 g of the desired compound is obtained (67.6 %). 1H NMR(CDCU): 5 4.92 (d, 1H), 4.80 (m, 1H), 4.47 (d, 1H), 4.42 (t, 1H), 4.39 (m, 1H), 3.95 (dd, 1H), 3.75 (m, 2H), 3.4 (s, 3H), 2.5 (m, 1H), 1.42 (s,3H), 1.22 (s,3H).
d) Preparation of 2,4-0-(1-methylethyiidene)-5-OmethyI-L-glucuronic y-lactone. 2-0-Methyl-3,5-0-(1-methylethylidene)-a-D-glucoheptonic y-lactone (200 g, 0.76 mol) is dissolved into a 1:1 mixture of methanol and water (3.6 L). The stirred mixture is cooled in an ice water bath to about 8 °C. Solid NaI04 (213 g, 0.98 mol) is added portion wise. Reaction is complete within 40 min as indicated by thin layer chromatography (TLC) (silica gel, 5% methanol, 15% EtOAc in CH2CI2). Solid NaCI is added into the reaction mixture to saturate the methanolic solution. The solid is filtered and washed with 2 L CH2CI2. The filtrate is extracted with 7x500 mL ChfeCfe. Combined organic layers are dried over Na2S04, filtered and concentrated to a syrup, which formed a precipitate upon addition of hexane. The solid is filtered and rinsed with Et20. A portion of the crude product (50 g) is dissolved in 3 L CHCI3 and heated to reflux. After rotary evaporation of 2.1 L of CHCI3at atmospheric pressure (methanol is driven out of the system by co-evaporation with CHCI3) the residue is evaporated to dryness. 44 g of the desired product is obtained as a solid after drying in vacuum overnight. 1H NMR (CDCI3): 59.60 (s, 1H),4.78(m, 1H), 4.42 (s, 2H), 4.15 (dd, 1H)f 3.65 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H); 13C NMR (CDCI3) 5 198.8, 171.9, 99.0, 78.4, 74.4, 72.9, 68.4, 67.4, 59.2, 28.7, 19.0.
e) Preparation of (6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-0-methyl-3,5-0-(1-methylethylidene)-gu!o-non-6-enonic acid lactone.

Into a 2 L round bottom flask, is added CrCI2 (50 g, 41 mmol), anhydrous THF (750 mL), and DMF (32 mL). The mixture is stirred under N2 for 1 h. A solution of 2,4-0-(U methylethy!idene)-5-0-methyl-L-gIucuronicY-lactone (12 g, 50 mmol), 1,1-diiodo-2,2-dimethylpropane (15 mL), and 500 mL of anhydrous THF is added slowly into the reaction mixture. After the addition, the reaction mixture is stirred at ambient temperature for 1.5 h. The reaction is quenched with saturated aqueous NhUCI. The residue is partitioned with EtOAc/water and chromatographed (5% EtOAc - CH2C!2) to give 9 g (63%) of the desired compound as a white crystalline solid: 1HNMR (CDCI3) 5 5.82 (d, 1H), 5.58 (q, 1H), 4.71 (m, 1H), 4.46 (m, 1H), 4.10 (dd, 1H), 4.0 (m, 1H), 3.66 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H), 1.07 (s, 9H); 13C NMR (CDCI3) 5 172.5, 147.0,120.2, 98.7, 79.1, 71.9, 70.3, 67.6, 59.2, 33.2, 29.3, 19.3.
Preparation of (3S, 6/?)-3-(te/t-butoxycarbonyl)aminohexahydro-6-hydroxy-2W-azepin-2-one In a 1 L flask (5R)-5-hydroxy-L-lysine (10 g, 0.040 mol), 1-hydroxybenzotriazole hydrate (8.2 g, 0.060 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-HCI (11.6 g, 0.060 mol) are added to 500 mL DMF with stirring. After 0.5 h triethylamine (16.8 mL, 0.120 mol) is added. The reaction is stirred at room temperature for 48 h. Di-terf-butyl dicarbonate (17.6 g, 0.080 mol) and triethylamine (16.8 mL, 0.120 mol) are added. Stirring is continued for 16 h. The reaction mixture is filtered to remove triethylamine-HCI and the solvent is removed by rotary evaporation under high vacuum to give a thick oil. The oil is dissolved in 150 mL CH2CI2 and applied to a silica gel column (150 g, 40 x 250 mm). The column is eluted with 3% methanol in CH2CI2 to give the crude product as a solid. The crude solid is dissolved in 120 mL hot CH2CI2 and cooled to -20 °C for 1 h. The resulting solid is filtered and washed with 50 mL CH2CI2. The combined filtrates are evaporated to dryness. CH2CI2 (40 mL) is added to this residue and the resulting slurry is stirred for 0.5 h at room temperature. The slurry is filtered and the solid washed with 25 mL CH2CI2. The solids are combined to give 5.57 g of (3S, 6R)-3-(fert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one. 300 MHz 1H NMR (DMSO) 8 7.42 (1 H, t, J = 5.1 Hz), 6.38 (1 H, d, J = 6.6 Hz), 4.60 (1 H, d, J = 4.2 Hz), 4.07 (1 H, m), 3.74 (1 H, m), 3.32 (1 H, m), 3.03 (1 H, m), 1.8-1.5 (4 H, m), 1.39 (9 H,s).
g) Preparation of (3S, 6ft)-3-(fe/^butoxycarbonyl)aminohexahydro-6+butyl-dimethylsilyloxy-2H-azepin-2-one.

To a stirred solution of (3S, 6/?)«3-(tert-butoxycarbonyI)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol) in DMF (60 mL) is added te/f-butyldimethylsiiyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol). The reaction is stirred at room temperature for 18 h, diluted with 1 L of water and extracted with a 1:1 (2 x 200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine, dried with NaS04, and concentrated under vacuum. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S, 6/?)-3-(terf-butoxycarbonyI) aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin»2»one as a white solid, melting point: 65 - 66 °C; 1H NMR (CDCI3) 5 5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H)f 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H).
h) Preparation of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2HDxo-1 -pyridin-3-yImethyI-azepan-3-yI]-carbamic acid tert-butyl ester
To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (4.0 g, 11.1 mmol) in THF (30 mL) at -78 °C is added KN(Si(CH3)3)2 (45.0 mL 1M THF, 45.0 mmol) slowly. The mixture is stirred at room temperature for 20 min, cooled to -78 °C, and 3-chloromethyl-pyridine hydrochloride (2.75 g, 16.7 mmol) is added in portions. The reaction is warmed to room temperature and stirred for 16 h, H20 (20 mL) is added and the mixture is partitioned with H20/ether, the organic layer is separated, dried with Na2S04 and evaporated to give a white solid, 5.0 g (quantitative) of [(3S,6R)-6-(tert-butyl-dimethy^silanylox^^ acid tert-butyl ester. MS (ESI) 899.3 (2M+H)+
i) Preparation of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1 -pyridin-3-ylmethyI-azepan-2-one
To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethy[-azepan-3-yI]-carbamic acid tert-butyl ester (5.0 g, 11.1 mmol) in CH2CI2 (50 mL) at-78 °C is added trimethylsilyl iodide (2.8 g, 14.0 mmol) neat After 30 min the reaction solution is warmed to 0 °C and stirred for 15 min. The reaction is quenched with a solution of CH3OH (25 mL) and NH4HC03 (10 mL, saturated in H20), and partitioned with H20/CH2CI2. The CH2CI2 fraction is dried over Na2S04 and evaporated to a gum and chromatographed on

a) Preparation of [(3S,6R}-6-(tert-butyf-dimethyl-siianyloxy)-1 -methyl-2-oxo-azepan-3-yi]-
carbamic acid tert-butyl ester
Following the procedure of Example 1(f)-1(h), except CH3-I is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 is used in step 1(h) to give the product as an oil. 1H NMR (CDCI3) 5 0.05 (s( 3H), 0.07 (sf 3H), 0.87 (s, 9H), 1.44 (s, 9H), 1.8 (m, 4H), 3.06 (s, 3H), 3.2 (dd, 1H), 3.7 (d, 1H), 4.0 (m, 1H). 4.28 (dd, 1H), 6.0 (d, 1H).
b) Preparation of ((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-y[)-carbamic acid tert-
butyl ester
To a solution of [(3S,6R)-6-(tert-butyWimethyl-silany^ carbamic add tert-butyl ester (0.85 g, 2.27 mmol) in THF (40 mL) is added tetrabutylammonium fluoride (3 mL 1M THF, 3 mmol) at room temperature. The reaction solution is stirred for 4 h, then H20 (40 mL) is added and the solution concentrated under vacuum to 34 its volume and extracted 3x with CH2CI2 (40 mL). The combined CH2CI2 extracts are adsorbed on silica and chromatographed (5% CH3OH/ CH2CI2) to give 0.568 g (72%) of ((SS.eRJ-e-hydroxy-l-meth^-oxo-azepan-S-ylJ-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCI3) 5 1.44 (s, 9H)t 1.7-2.05 (m, 4H), 3.1 (s, 3H), 3.37 (dd, 1H), 3.73 (d, 1H), 4.07 (m, 1H), 4.31 (m, 1H), 6.0 (d, 1H).
Preparation of [(3S,6R)-6-(6-azido-hexyloxy)-1«methyl-2-oxo-azepan-3-yll-carbamic acid tert-butyl ester
To a stirred solution of ((3S,6R)-6-hydroxy-1-methyi-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester (0.70 g, 2.6 mmol) in THF (5 mL) cooled to -78 °C is added NaN(Si(CH3)3)2 (2.8 mL 1M THF, 2.8 mmol). After 10 min trifluoro-methanesulfonic acid 6-azido-hexyI ester (0.76

gf 3.1 mmol) is added neat and stirred for 10 min at -78 °C then warmed and stirred at room temperature for 1 h. NaHC03 (5 mL 1M H20) is added and the solution is partitioned with H20/EtOAc, the EtOAc extract is dried with Na2S04 and evaporated to an oil. The oil is adsorbed on silica and chromatographed (20% EtOAc/ CH2CI2) to give 0.32 g (32%) of [(3S,6R)^(6-azido-hexyloxy)-1-methyl-2K)Xo-azepan-3-yI]-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCI3) 5 1.34 (st 9H), 124-2.1 (m, 12H), 2.95 (s, 3H), 3.1-3.35 (rn, 6H), 3.44 (m, 1H), 3.55 (d, 1H), 4.2 (m, 1H).
Preparation of (3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-a2epan-2-one To a stirred solution of [(3S,6R)-6-(6-azido-hexyioxy)-1-methyl-2-oxo-azepan-3-yl]-carbarnic acid tert-butyl ester (0.32 g, 0.83 mmol) in CH2CI2 (4 mL) is added TFA (1 mL) at room temperature. After 1 h, the reaction is evaporated under vacuum, toluene (20 mL) is added and evaporated under vacuum to remove remaining TFA. The residue is dissolved in CH2CI2 (20 mL) saturated with NH3 adsorbed on silica and chromatographed (50% EtOAc/CH2CI2/NH3 then 10% CH3OH/CH2CI2/NH3) to give 0.207 g (88%) of (3S,6R)-3-amino-6-(6-azido-hexyIoxy)-1-methyl-azepan-2-one as an oil. MS (ESI) 284.2 (M+H)+
Preparation of (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1 -methyI-2-oxo-azepan-3-yI]-2-
[(4R,5R,6R)-6-((E)-3,3-dime^
methoxy-acetamide
To a solution of (3S,6R)-3-amino-6-(6-aado-hexyloxy)-1-methyl-azepan-2-one (0.207 g, 0.73
mmol) in isopropanol (1 mL) is added (4R,4aR)-4-((E)-3,3-dimethyl-but-1-enyl)-7-methoxy-
2,2-dimethyl-tetrahydro-furo[3l2"d][1l3]dioxin-6-one (0.3 g, 1 mmol) and heated to reflux for
18 h. The solution is evaporated under vacuum adsorbed on silica and chromatographed
(CH2CI2 to EtOAc gradient) to give 0.245 g (59%) of (R)-N-[(3S,6R)-6-(6-azido-hexyIoxy)-1-
methyi-2-oxo-azepan-3-yl]-2~[^
dimethy!-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a solid. (ESi) 568.1 (M+H)+
f) Preparation of (EJ^R^R^S.SR^S^^-trihydroxy^-methoxy-S^-dimethyl-non-e-enoic acid [(3SI6R)-6-(6-azido-hexyloxy)-1 -methyl-2-oxo-azepan-3-yl]-amide Following the procedure of Example 1 m) except (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyi-2-oxo-azepan-3-yl]"2-[(4R,5R,6R)-6-((E)-3r3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-fl^Jdioxan^yll^-methoxy-acetamide is substituted for tetradecanoic acid

(3R,6S)^(R)-2-[(4R,5R,6R)-6-((E)-3,3Ki'^
[1,3](Soxarv4-yl]-2-methoxy-acet^^ ester.
MS (ESI) 528.0 (M+H)+
g) Preparation of title compound (E)-(2RI3Rl4S,5R)-3,4I5-trihydroxy-2-methoxy«8I8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-amino-hexyloxy)-1 -methyl-2-oxo-azepan-3-yl]-amide To a stirred solution of (EH2R3R,4Sf5R)-3,4)5-trihydroxy-2-methoxy-8,8KJimethyl-non-6-enoic acid [(3S,6R)-5-(6-a2ido-hexyloxy)-1-methyl-2HDxo-a2epan-3-yIl"amide (0.13 g, 0.25 mmol) in THF (2 mL) is added H2O and triphenylphosphine (0.120 g, 0.5 mmol). After 8 h the reaction solution is evaporated under vacuum to give a semisolid residue that is dissolved in CH2CI2 (10 mL), adsorbed on silica and chromatographed (CH2CI2/NH3 to 25% CH3OH/CH2CI2/NH3 gradient) to give 0.106 g (85%) of (EM2R,3R,4S,5R)-3,4,54rihydroxy-2-methoxy-8f8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-amino-hexyloxy)-1 -methyl-2-oxo-azepan-3-y!]-amide as a white solid. MS (ESI) 502.1 (M+H)+
EXAMPLE 3: (E)-(2R,3Rt4S,5R)-314I5-Trihydroxy-2-methoxy-8I8-dimethyl-non»6-enoic acid ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-amide

Preparation of ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester To a stirred solution of ((3S,6R)-6-hydroxy-2-oxo-azepan-3-yl>-carbamic acid tert-butyl ester (3 g, 12.3 mmol example 1 f) and triphenylphosphine (3.75 g, 14.1 mmol) in THF (200 mL) at 0°C is added diethyl azodicarboxylate (2.2 mL, 13.5 mmol) at a rate to maintain a temperature
gradient) to give 2.33 g (70%) of ((3S,6S)-6-azido-2-oxo-azepan-3-yI)-carbamic acid tert-butyl ester as a solid. MS (ESI) 270 (M+H)+
Preparation of (3S,6S)-3-amino-6-azido~azepan-2-one
Following the procedure of example 2 d) ((3Sf6S)-6-azido-2-oxo-a2epan-3-yl)-carbamic acid
tert-butyl ester is substituted for [(3S,6R)-6-(6-a2ido-hexyloxy}-1-methyl-2-oxo-a2epan-3-yI]-
carbamic acid tert-butyl ester to give (3S,6S)-3-amino-6-azido-azepan-2-one. MS (ESI) 170
(M+H)+
Preparation of (R)-hH(3S,6S)-6-aado-2^xo-^
but-1 -enyl)-5-hydroxy-2F2-dimethyl^1,3]dioxan-4-yQ-2-methoxy-acetamide
Following the procedure of example 2 e) (3S,6S)-3-amino-6-azido-azepan-2-one is
substituted for (3S,6R)-3-amino-6-(6-a2ido-hexyloxy)-1-methyl-azepan-2HDne to give (R)-N-
((3S,6S)-6-azido-2K>xo-azepan-3-yl>24(4R,5R^
hydroxy^^-dimethyl-Il^ldioxan-^yll^-methoxy-acetamide. MS (ESI) 454.2 (M+H)+
d) Preparation of title compound (E)-(2R,3RI4S,5R)-3)4l5-trihydroxy-2-methoxy-8f8-
dimethyI-non-6-enoic acid ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-amide
Following the procedure of example 1 m) (R)-N«((3S,6S)-6-azido-2-oxo-azeparH3-yl)-2-
[(4R,5R,6R)-6-((E)-3>dimethyl-but-1^nyl^^
methoxy-acetamide is substituted for tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R)5RI6R)-6-
((E)-3,3 acetylamino}-7-oxo-1-pyridin-3"ylmethyl-azepan»3-yl ester to give the title compound. MS
(ESI) 414.2 (M+H)+
EXAMPLE 4: [(S)-2-Oxo»3-((2R,3RJ4SJ5R)-(E)-3)4J5-trihydroxy-2-methoxy-8-methyl-non-6-enoylamino)-azepan-1-yl]-acetic acid benzyl ester

Preparation of (4R,4aR)-7-methoxy-2,2 Following the procedure of example 1 a) - e) except 1,1-diiodo-2-methyl-propane is
substituted for 1,1-dfiodo-2,2-dimethyl-propane to give (4R,4aR)-7-methoxy-2,2-dimethyl-4-
((E)-3-methyk>ut-1-enylMetrahydr^ as a white solid. 1HNMR
(CDCl3).5 5.85 (dd, J=15.6, 6.22 Hz, 1H), 5.64 (ddd, J= 15.6, 7.5,1.27 Hz, 1H), 4.74 (dd, J= 3.79, 2.09 Hz, 1H), 4.48 (dd, J= 7.49,178 Hz, 1H), 4.12 (d, J= 3.86 Hx, 1H), 4.02 (t, J= 2.02 Hz, 1H), 3.68 (s, 3H), 2.36 (m, 1H), 1.56 (s, 3H), 1.51 (s, 3H), 1.04 (d, J= 1.9 Hz, 3H), 1.03 (d, J~ 1.9 Hz, 3H); 13C NMR (CDCfe) 8 172.8,143.2,122.0, 98.7,79.0, 71.7, 70.0, 67.6, 59.2, 30.7, 29.2, 21.9, 21.8,19.2. HRMS: calculated for (M+Na)+ (C^H^OsNa) 293.1365, found 293.1355.
Preparation of ((S)-3-amino-2-oxo-azepan-1-yI)-aceticacid benzyl ester Following the procedure of example 1 h) except ((S)-2-oxo*azepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(tert-butyi-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester and bromo-acetic acid benzyl ester is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 base to give ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. Removal of the Boc group by procedure 2 d) gives ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester.
c) Preparation of title compound [(S)-2-oxo-3-((2R,3R,4S,5RHE)-3,4l5-trihydroxy-2-
methoxy-8-methyl-non-6-enoylamino)-azepan-1-yn"acetic acid benzyl ester
The product of 4 b) is processed as in example 2 e) - f) to give the title compound as a white
solid.
Examples 5-59

The following compounds are prepared by similar methods utilizing analogous starting materials:

The anti-tumor activity of the compounds of formula I may be demonstrated employing the Anchorage Dependent Growth Monolayer Assay (ADGMA) which measures the growth inhibitory effects of test compounds on proliferation of adherent cell monolayers. This assay was adapted from the 60 cell line assay used by the National Cancer Institute (NCI) with the following modifications: 1) cell lines representative for the important tumor types, for example, MDA-MB-435 breast and A549 non-small cell lung, are utilized; and 2) a tetrazolium derivative, wz, MTS, is utilized to determine cell density.
The ADGMA compares the number of viable cells following a 3-day exposure to a test compound relative to a number of cells present at the time the test compound is added. Cell viability is measured using a tetrazolium derivative, wz, 3-(4,5-dimettiyIthiazol-2»yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazoliumI inner salt (MTS) that is metabolically reduced in the presence of an electron coupling agent (PMS; phenazine methosulfate) by viable cells to a water-soluble formazan derivative. The absorbance at 490 nm (A490) of the formazan derivative is proportional to the number of viable cells. The IC50 for a test compound is the concentration of compound required to reduce the final cell number to 50% of the final control cell number.
The MDA-MB-435 breast carcinoma line is obtained from the American Type Culture Collection (ATCC) and used between passages 4-20 following thawing. MDA-MB-435 breast carcinoma is maintained and plated in DME/F12 medium containing 10% fetal bovine serum, 15 mM HEPES (pH=7.4), penicillin 100 units/mL, and streptomycin 100 micrograms/mL
The A549 non-small cell lung lines are obtained from the American Type Culture Collection (ATCC) and used between passages 4-20 following thawing. A549 cells are maintained in RPMI 1640 containing 5% FBS, 5 mg/mL insulin, 5 mg/mL transferring, 5 mg/mL selenous acid, 1 nM [3- estradiol, 1 nM testosterone, 100 units/mL penicillin and 100 ug/mL streptomycin.
Cell lines are trypsinized and counted using a Coulter counter to determine plating densities. Cells are then plated in their respective maintenance media (100 pL/well) in 96 well plates at the following densities: MDA-MB-435, 3,000 cells/well; A549, 700 cells/well. The number of cells plates as determined in preliminary experiments, results in cell densities of 75-90% of

confluency by 4 days after plating. Initial cell densities, assayed one day after plating, are roughly 0.15-0.20 absorbance units greater than the media blank. Ninety-six well plates are seeded on day 0 and the test compounds are added on day 1. A control plate is created for each cell Fine that receives media only in row A and cells in row B. One day following plating, test compounds are added (in a final volume of 100 pL) to the test plates. Control plates receive 10 pL MTS mixture (prepared fresh on day of addition to cell plates at a ratio of 10 pL of a 0.92 mg/mL solution of PMS to a 190 pL of a 2 mg/mL solution of MTS) and 100 pL media. A490 of control plates is read 4 h after MTS addition to determine initial cell density values for each cell line. Three days after addition of the test compound, 10 pL/wel! of MTS mixture is added to the test plates and A490 is read 4 h later. A490 values for wells containing cells are corrected for media absorbance, then normalized to initial density readings to determine percent net growth. IC50 values are determined from graphs of percent net growth as a function of compound concentration. Percent net growth is calculated as (Cell + Drug A490 - Initial A49o/Cell + Drug Vehicle A490 - Initial A490).
Each of the compounds of Examples 1-59 shows an IC50 value in the range from 0.001 pM to 100 pM in the ADGMA with at least one carcinoma cell line.

What is claimed is:
1. A compound of the formula I:

or a salt thereof, wherein
n is 0,1 or 2;
R1 is H, Xr(d-e) alkyl-, (Ci.12)aIkylC(0)-, XHCM) alkenylene-, X^CM) alkynylene-, Xr(Cs.
9)cycloaIkyh X^C^cycloalkene-, X-i-aryl-, XHQw)cycloalkane-(d-6)alkytene-, X2-
(C3-7)cycloalkene-(C1^)alkylene-, or Xraryl-(d-e)alkytenes Xi is H, (Ci-i4)alkyl, (d-7)cycloalkyI, (d.14)alkyl substituted by (C^cycloalkyl, -ORa, -SRa,
-N02, halo or (C^)alkylC(O)-; aryl, aryi~(d-i2)alkyh -ORa, -SRa, -N02, halo, (d-
iiOatkyl-CfO)-, mono- or di-(C1^)a!kyiamino, amino(d-i6)aIkyh or mono- or di-(Ci.
4)alkylamino(C1.16)alkyl; X2 is H, (Ci.i4)alkyl> (C^cycloalkyl, (d-i4)alkyl substituted by (C^cycloalkyl, -ORa -SRa,
-N02, halo or (d-6)alkyl-C(0)-; aryl, aryl-(d-i2)alkyh amino(d-i6)a!kyl- or mono- or di-
(CM)alkylamino(Ci-i6)alkyl; Ra is H, (d-is)aikyl, aryl, or (Ci.i8)alkyl substituted by (C^cycloalkyl, aryl, -OH, -0-(d-6)alkyl
or halo; R2, R3» R4 and R5 are independently hydrogen or (Ci.i8)alkyl, R5 is also phenyl or (d-ie)alkyl
which is substituted by phenyl, wherein there is no more than a total of 18 carbon
atoms in the combined R2, R3, R4 and R5 alkyl substituents, or R2 and R* together or R3
and R5 together form an acetal group; R6 is hydrogen or (d.6) alkyl; R7 is H, (d-i8)alkyl, phenyl, pyridyl, (Ci.i8)alkyl substituted by (C^cycloalkyl, -ORx, N3l
halo, -N(RX)2, Rx, -0-(d-6)alkyl, -OC(OHd-i6)alky! or pyridyl; -Y-Rb or a substituent of
formula lla or Ilia

wherein R7 and Re are defined above, with the compound of formula VII

wherein Ri and R5 are defined above, to form a compound of formula VIII

(b) hydrolyzing the compound of formula VIII.
11. The process as claimed in claim 10, wherein step (a) is conducted in a polar organic solvent or in the presence of a weak base and a polar organic solvent.
12. The process as claimed in claim 10, wherein the compound of VIII is prepared by reacting the compound of XI

wherein Ru R5 and R7 are defined in claim 10, with an acid chloride in the presence of a base and a solvent.
13. The process as claimed in claim 12, wherein the acid chloride is of the formula R12COCt,
wherein R12 is an appropriate substituent based on the definition of Re; the base is
triethylanime and the solvent is dichloromethane.

14. The process as claimed in claim 10, wherein the compound of VIII is prepared by
reacting the compound of XI

wherein Ri, R5 and R7 are defined in claim 11, with a carboxyiic acid in the presence of a carboxylic acid coupling agent and an activating agent.
15. The process as claimed in claim 14, wherein the carboxylic acid is of the formula
R12COOH wherein R12 is an appropriate substituent based on the definition of R%, the
carboxylic acid coupling reagent is 1-{3-dimethylaminopropyI)-3-ethylcarbodiimide
hydrochloride and the activating agent is 4-dimethyaminopyridine.
16. The process as claimed in claim 10 wherein the compound of formula VII is prepared by
cleaving the compound of formula XXXIII

wherein R5 is defined in claim 10, to obtain the compound XXXIV

reacting the compound of XXXIV with an organometallic compound in the presence of a solvent mixture.
17. The process as claimed in claim 16, wherein cleaving the compound of formula XXXlll is
carried out in the presence of a periodate salt in a solvent.

18. The process as claimed in claim 17, wherein the periodate salt is sodium periodate and the solvent is methanol.
19. The process as claimed in claim 16, wherein the organometallic compound is an organochromium compound, and the solvent mixture comprises of a polar organic solvent and an inert organic solvent
20. The process as claimed in claim 19, wherein the polar organic solvent is N,N-dimethytformamide and the inert organic solvent is tetrahydrofuran.
21. A process to prepare the compound of the formula I:

or a salt thereof, wherein
n is 0,1 or 2;
R1 is H, XHd-e) alkyh (Ci.t2)alkylC(Oh XHC2-4) aikenyiene-, X^QM) alkynyiene-, XHd-
9)cycloalkyh X^C^cycloalkene-, Xraryt-, X^KCwJcycloalkane-^^Jalkylene-, X2-
(d-7)cycloalkene-(d-6)alkytene-, or X-t-aryHC^alkylene-; X1 is H, (d-i4)alkyl, (C^cydoalkyl, (C1.14)alkyl substituted by (d-rjcycloalkyl, -ORa, -SRa,
-N02l halo or (d-e)aikylC(O)-; aryl, aryl-(d-i2)alkyl-, -ORa, -SRat -N02, halo, (d-
i2)alky!-C(0)-, mono- or di-(Ci-4)alkylamino, amino(Ci.16)alkyh or mono- or di-(d-
4)alkylamino(C1.16)alkyl; X2 is H, (Ci-i4)atkyl, (C^cycloalkyl, (d-i4>alkyl substituted by (Cs^cycioalkyl, -OR3 -SRa,
-N02) halo or (d-6)alkyl-C(0)-; aryl, aryl-(d-i2)alkyh amino(d-i6)alkyl- or mono- or di-
(d^)alkylamino(Ci.i6)alkyl; Ra is H, (d-is)alkyl, aryl, or (d-is)alkyl substituted by (C^cycloalkyl, aryl, -OH, -0-(d-e)aIkyl
or halo;

R* R3. R4 and R5 are independently hydrogen or (Ci.i8)alkylv R5 is also phenyl or (Cv16)alkyI which is substituted by phenyl, wherein there is no more than a total of 18 carbon atoms in the combined R2, R3, R4 and R5 alkyl substituents, or R2 and R4 together or R3 and R5 together form an acetal group;
R6 is hydrogen or (d-e) alkyl;
R7 is H, (CvisJaikyI, phenyl, pyridyi, (d-ia)a!kyi substituted by (C^cydoalkyl, -0RX, N3,
halo, -N(RX)2, Rx, -0-(d.6)alkyi, -OC(OHCi.i6)alkyl or pyridyi; -Y-Rt> or a substituent of formula Ha or Ilia

wherein
R9 is from 0 to 3 substituents selected from (d-e)alkyl, -ORa, -SRa, -NO;*, halo, -N3, (d-i2)alkylC(0)-, mono- or di«(d^)alkylamino, amino(d-i6)alkyi-, mono- or di-(d-4)alkylamino(d.i6)alkyl. (CH2)o.2-C&.7cycloalkylI (CH2)o-2-heterocyclic1 (CH^-C^aryl, or (CH2)o.rheteroaryl;
Y is a linking group selected from -(d.10)alkyl-, KCo-io)aIkyiene-CO-N(RxHCo-io)alkyIene-, -(CCMo)alkylene-N(Rx)-CO-(Co-1o)alkylene-, -(d-ioJalkylene-CO-O-Cd-toJalkylene-, -(Cv io)alkylene-0-C(0>(C1.io)aIkylene^-(Co-io)alkyiene-CO-(C0.io)alkyJene-l-(Co. 10)alkylene-(Rx)N-CO-0-(Co.10)alkylene-, -(Co.io)alkylene-0-CO-(Rx)N-(Co.io)alkylene-or -(Co.i8)alkylene-arylene-(Co-i8)alkylene-;
Rx is H, (C-^alkyl or phenyl;
Rh is (d.16)alkyi or (Ci.ie)alkyl which is substituted by (C^cycloalkyl, -ORx, N3, halo, -N(RX)2, -0-(C^)alkyl, -OC(OHd.16)aIkyl or pyridyi;
R8 is H, halo, -N3, (CM6)alkyI> -Z-(d-i6)alkyl, (Ci.16)alkyl substituted by (C^cycloalkyi, -N3l -N(RX)2( -Z-het, -ORa or -SRa, -Z-(Ci.16)alkyl substituted by (d^cycloalkyl, -N3) -N(RX)2, -Z-het, -ORa or -SRa, -0(d-ie)alkylene-N3, -0(d_16)alky)ene-N(Rx)2l -(C0.6)a)kylene-OCCOHd-ieJalkyl, -(Cw)alkylene-(0)C-0-(Ci.16)alkyl1 ~(Co.6)alkytene-OC(OHd. 7)cycloalkyl, -(Co^alkyleneKOJC-O-CC^cycloalkyl, pyridyi, -OC(0)0(d.i2)aikyIt -O-C0-X-R2, or -0-CO-(CH2)m-0-(CH2)m-X-Rz wherein X is a direct bond, (d.i2)alkylene, (Ci.12)alkenylene or (d.12)alkynylene and R2 is H, (C^cycloatkyi, phenyl, phenyl

substituted by one or more of chloro, methoxy, (Ci.18)alkyl or (Ci-i8)alkoxy, pyrroiyl, furanyl, thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13, -Z-het, -ORa, -SRa, mono- or dHC-u 4)a!kylamino, amino(Ci.i6)alkyl-, mono- or di-(C1J()alkylamino(Ci.i6)alkylI -Z-Si((Ci. 6)alkyF)3 or a substituent selected from the following two formulae:

Z is a direct bond, -(C^alkylene-, -(d.^alkylene-O-, -0-(Ci.12)alkylene-, -(Cj.12)alkylene-N(RX)-, -N(Rxh -WxHCi-^alkytene-, -N(Rx>C(0)-, -NfRxJ-CfOHCL^alkylene-, -(C1.12)alkylene-N(Rx)-C(0)-,-(C1-6)aIkylene-N(Rx)-C(OHC14)a!kylene-,-(C1.12)alkylene-CO-N(Rx)-, -CO-N(Rx)-(C1.12)alkylene-, -(d^alkylene-CO-NfRxHC^Jalkylene-, -CO-N(RX)-, -(d.^alkylene-CO-O-, -(d.^alkylene-O-CKO)-, -OC(0.)-(Ci-i2)alkylene-, -CKOJ-O-fCviaJalkylene-, -(d-u^alkylene-CO-, -{C^Jalkylene-CO-tC^^alkylene-, -CO-(d-i2)alkylene-, -C(O)-, -N(Rx)-C(0)-0-, -N(Rx)-C(0)-0-(C1.12)alkylene-1 -(d. 12)alkylene-N(Rx)-C(0)-O-)-(C1^)alkylene-N(Rx)-C(0)-0-(C^)alkylene-,-(C1. 12)alkylene-0-CO-N(Rx)-,-O-CO-NtRO-CCvizialkytene-, -(d-e)alkylene-0-CO-N(Rx)-(C^)alkylene-, -0-CO-N(Rx)-, -O-CO-O-, -(d-i2)alkylene-0-CO-0-, -0-CO-O-(d-12)a!kylene- or -(d^)a(kylene-O-C(0)-0-(d-8)alkylene-;
Zt is a direct bond, -(d-i2)alkytene-, -0-(d-i2)alkylene-, -N(RxMd-i2)alkylene-, -N(Rx)-C(0)-(Cvizialkytene-.^C^Jal^eTO-NCRxKltOKC^ialkylene-.-CO-NtRxHCi.-isJalkylene-, ~(C1^)alkylene-CO-N(Rx)-(C1^)alkylene-, -OC(OHd.i2)alkylene-, -C(0)-O-(Ci-12)alkylene-, -(d-8>alkytene-CO-(d-8))alkytene-. -CO-(Ci-i2)alkylene-, -C(OK -N(RX>-C(0)-0-(Ci.12)alkylene-, -(Ci^)alkylene-N(Rx)-C(0}-0-(C1^)alkylene-, -0-CO-N(Rx>-(d-i2)alkyiene-, -(C1^)alkylene-0-CO-N(Rx)-(C1^)alkylene-I-O-CO-O^Ci.^Jalkylene-or-(d*)alkylene-0-C(0)-0-(d-8)alkylene-;
R10 is from 0 to 3 substituents selected from hydroxy, halo, -(C1.17)alkyl, -0-(d-i7)alkyl, -(CHz)m-C3.7 -cycloalkyl, -(CH2)o-io-aryl or -(CH2)o-io -het;
het is a heterocyclic or heteroaromatic ring;
pis 1-18;
with the proviso that when n is 2 and Rn is (d-6)a!kyI-CH=CH- or (C3.6)cycloalkyl-CH=CH-then R7 is not H or (Chalky! or R8 is not -0-CO-X-R2 or -0-CO-(CH2)m-0-(CH2)m-X-

R2 where X is a direct bond, (C^alkylene, (C^alkenylene or (C1.12)alkynyiene and R2 is H, (C^cycloalkyi, phenyl, phenyl substituted by one or more of chloro, methoxy (Ci.i8)alkyl or (Ci.18)aIkoxyJ pyrrolyl, furanyl, thbfuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13^ and with the further proviso that Re is not -OH when n is 2, R7 is H or methyl and R, is 3-methyIbut-1 -enylene; comprising the following steps:
(a) reacting a compound of formula XLI

wherein R^ and R5 are defined above, P2 and P4 are protective groups, and Rm is a (Chalky], with the compound of formula VI

wherein R7 and Re are defined above, to form the compound of formula XLI I

(b) deprotecting the compound of formula XLII.
22. The process as claimed in claim 21, wherein R'" is ethyl, P2 is fert-butyldimethylsilyl, and P4 is selected from benzyl or naphthlmethy! ethers.

Documents:

0290-chenp-2006-abstract.pdf

0290-chenp-2006-assignement.pdf

0290-chenp-2006-claims.pdf

0290-chenp-2006-correspondnece-others.pdf

0290-chenp-2006-description(complete).pdf

0290-chenp-2006-form 1.pdf

0290-chenp-2006-form 26.pdf

0290-chenp-2006-form 3.pdf

0290-chenp-2006-form 5.pdf

0290-chenp-2006-pct.pdf

290-CHENP-2006 ABSTRACT.pdf

290-CHENP-2006 CLAIMS.pdf

290-CHENP-2006 CORRESPONDENCE OTHERS.pdf

290-CHENP-2006 CORRESPONDENCE PO.pdf

290-CHENP-2006 DESCRIPTION (COMPLETE).pdf

290-CHENP-2006 FORM 18.pdf

290-CHENP-2006 FORM 3.pdf

290-CHENP-2006 PETITIONS.pdf

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Patent Number

231180

Indian Patent Application Number

290/CHENP/2006

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

03-Mar-2009

Date of Filing

24-Jan-2006

Name of Patentee

NOVARTIS AG

Applicant Address

Lichtstrasse 35, CH-4056 Basel,

Inventors:

#	Inventor's Name	Inventor's Address
1	KINDER, Frederick, Ray, Jr	37 Olyphant Drive, Morristown, NJ 07960,
2	BAIR, Kenneth, Walter	5924 McAndrew Drive, Oakland, CA 94611,
3	VERSACE, Richard, William	69 Townsend Road, Wanaque, NJ 07465,

PCT International Classification Number

C07D 401/06

PCT International Application Number

PCT/EP04/08284

PCT International Filing date

2004-07-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/490,415	2003-07-25	U.S.A.