ANTITUMORAL ANALOGS OF ET-743

Abstract: Antitumour compounds have the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group.

Description: ANTITUMORAL ANALOGS OF ET-743 The present invention relates to antitumoral compounds, and in particular to antitumoral analogs of ecteinascidin 743, ET-743. BACKGROUND OF THE INVENTION European Patent 309,477 relates to ecteinascidins 729, 743, 745. 759A. 759B and 770. The ecteinascidin compounds are disclosed to have antibacterial and other useful properties. Ecteinascidin 743 is now undergoing clinical trials as an antitumour agent. Ecteinascidin 743 has a complex tris(tetrahydroisoquinolinephenol) structure ofthe following formula (I): In ecteinascidin 743, the 1,4 bridge has the structure of formula (IV): Other known ecteinascidins include compounds with a different bridged cyclic ring system, such as occurs in ecteinascidin 722 and 736, where the bridge has the structure of formula (V): ecteinascidins 583 and 597, where the bridge has the structure of formula (VI): and ecteinascidin 594 and 596, where the bridge has the structure of formula (VII): The complete structure for these and related compounds is given in J. Am. Chem. Soc. (1996) 118, 9017-9023. This article is incorporated by reference. The ecteinascidins are currently prepared by isolation from extracts ofthe marine tunicate Ecteinascidin turbinata. The yield is low, and alternative preparative processes have been sought. A synthetic process for producing ecteinascidin compounds is described in US Patent 5,721,362, see also WO 9812198. The claimed method is long and complicated. By way of illustration, there are 38 Examples each describing one or more steps in the synthetic sequence to arrive at ecteinascidin 743. Claim 25 of US 5,721,362 is directed at an intermediate phenol compound of a given formula (1 1), which we refer to also as Intermediate 11 or Int- 11. It has the following bis(tetrahydroisoquinolinephenol) structure (II): where MOM is a methoxymethyl substituent and TBDPS is a tert-butyldiphenylsilyl substituent. From Intermediate 11 it is possible to synthesise another interesting antitumour agent, phthalascidin, see Proc. Natl. Acad. Sci. USA, 96, 3496-3501 , 1999. Phthalascidin is a bis(tetrahydroisoquinolinephenol) derivative of formula (III): More generally, phthalascidin and related compounds are described in WO 0018233. Claim 1 is directed at compounds of formula: wherein the substituent groups defined by Ri, R 2 . R 3 , *. R Rό. 7. R 8 and R are each independently selected from the group consisting of H, OH, ORM SH. SR\ SOR'. SO 2 RM NO 2 , NH 2 , NHRM N(R') 2 , NHC(O)R', CN, halogen =O, C(=O)H, C(=O)R\ CO 2 H, CO 2 R', Cι-Cι 2 alkyl, C 2 -Cι 2 alkenyl, C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; wherein each ofthe R' groups is independently selected from the group consisting of H, OH, NO 2 , NH 2 , SH, CN, halogen, =O, C(=O)H, C(=O)CH 3 , CO 2 H, CO 2 CH 3 , C,-C 12 alkyl, C 2 - Cj 2 alkenyl, C 2 -Cι 2 alkynyl, aryl, aralkyl, and heteroaromatic; wherein each dotted circle represents one, two or three optional double bonds; wherein R and R 8 may be joined into a carbocyclic or heterocyclic ring system; and wherein X \ and X 2 are each independently defined as above for Rι-R« and further include various permitted definitions. Further naturally occuring compounds are known which lack a bridged cyclic ring system. They include the bis(tetrahydroisoquinolinequinone) antitumor-antimicrobial antibiotics safracins and saframycins, and the marine natural products renieramicins and xestomycin isolated from cultured microbes or sponges. They all have a common dimeric tetrahydroisoquinoline carbon framework. These compounds can be classified into four types, types I to IV, with respect to the oxidation pattern ofthe aromatic rings. Type I, dimeric isoquinolinequinones, is a system of formula (VIII) most commonly occurring in this class of compounds, see the following table I. Table I Structure of Type I Saframycin Antibiotics. Substituents Compound R .4a R ,4b R 21 R 2Sa R 25b R25 C saframycin A H H CN O O CH 3 saframycin B H H H O O CH 3 saframycin C H OCH 3 H O O CH 3 saframycin G H OH CN O O CH 3 saframycin H H H CN OH CH 2 COCH 3 CH 3 saframycin S H H OH O O CH 3 saframycin Y 3 H H CN NH 2 H CH 3 saframycin Ydi H H CN NH 2 H C H 5 saframycin Adj H H CN O O C2H5 saframycin Yd H H CN NH 2 H H saframycin Y 2 H Q 6 CN NH 2 H CH 3 saframycin Y 2 b-d H Q b CN NH 2 H C2H5 saframycin AH 2 H H CN H α OH° CH 3 saframycin AH 2 Ac H H CN H OAc CH 3 saframycin AHj H H CN OH α H a CH saframycin AHi Ac H H CN OAc H CH 3 saframycin AR 3 H H H H OH CH 3 a assignments are interchangeable. b where the group Q is of formula (IX): Type I aromatic rings are seen in saframycins A, B and C; G and H; and S isolated from Streptomyces lavendulae as minor components. A cyano derivative of saframycin A, called cyanoquinonamine, is known from Japanese Kokai JP-A2 59/225189 and 60/084288. Saframycins Y 3 , Ydi, Adi, and Yd 2 were produced by S. lavendulae by directed biosynthesis, with appropriate supplementation ofthe culture medium. Saframycins Y 2 b and Y 2b -d dimers formed by linking the nitrogen on the C-25 of one unit to the C-14 ofthe other, have also been produced in supplemented culture media of S. lavendulae. Saframycins ARi (=AH 2 ,), a microbial reduction product of saframycin A at C-25 produced by Rhodococcus amidophilus, is also prepared by nonstereoselective chemical reduction of saframycin A by sodium borohydride as a 1 : 1 mixture of epimers followed by chromatographic separation [the other isomer AH] is less polar]. The further reduction product saframycin AR 3 . 21 - decyano-25-dihydro-saframycin A. (= 25-dihydrosaframycin B) was produced by the same microbial conversion. Another type of microbial conversion of saframycin A using a Nocardia species produced saframycin B and further reduction by a Mycobacterium species produced saframycin AH 1 Ac. The 25-O-acetates of saframycin AH 2 and AHi have also been prepared chemically for biological studies. Type I compounds of formula (X) have also been isolated from marines sponges, see Table II. Table II Structures of Type I Compounds from Marine Sponges. Substituents R !4a R 14b R 2 ' R renieramycin A OH H H -C(CH 3 )=CH-CH 3 renieramycin B OC2H5 H H -C(CH 3 )=CH-CH 3 renieramycin C OH O O -C(CH 3 )=CH-CH 3 renieramycin D OC 2 H 5 O O -C(CH 3 )=CH-CH 3 renieramycin E H H OH -C(CH 3 )=CH-CH 3 renieramycin F OCH 3 H OH -C(CH 3 )=CH-CH 3 xestomycin OCH 3 H H -CH 3 Renieramycins A-D were isolated from the antimicrobial extract of a sponge, a Reniera species collected in Mexico, along with the biogenetically related monomeric isoquinolines renierone and related compounds. The structure of renieramycin A was initially assigned with inverted stereochemistry at C-3, C-11, and C-13. However, careful examination ofthe 1H NMR data for new, related compounds renieramycins E and F, isolated from the same sponge collected in Palau, revealed that the ring junction of renieramycins was identical to that of saframycins. This result led to the conclusion that the formerly assigned stereochemistry of renieramycins A to D must be the same as that of saframycins. Xestomycin was found in a sponge, a Xestospongia species collected from Sri Lancan waters. Type II compounds of formula (XI) with a reduced hydroquinone ring include saframycins D and F, isolated from S. lavendulae. and saframycins Mx-1 and Mx-2, isolated from Myxococcus xanthus. See table III. Table III Type II Compounds Substituents Compound R .4a R .4b R 2 ' R 25a R 25b R 25c saframycin D O O H O O CH 3 saframycin F O O CN O O CH 3 saframycin Mx-1 H OCH 3 OH H CH 3 NH 2 saframycin Mx-2 H OCH3 H H CH 3 NH 2 The type III skeleton is found in the antibiotics safracins A and B, isolated from cultured Pseudomonas fluorescens. These antibiotics of formula (XII) consist of a tetrahydroisoquinoline-quinone subunit and a tetrahydroisoquninolinephenol subunit. NH, where R ,21 is -H in safracin A and is -OH in safracin B. Saframycin R, the only compound classified as the Type IV skeleton, was also isolated from S. lavendulae. This compound of formula (XIII), consisting of a hydroquinone ring with a glycolic ester sidechain on one ofthe phenolic oxygens, is conceivably a pro-drug of saframycin A because of its moderate toxicity. All these known compounds have a fused system of five rings (A) to (E) as shown in the following structure of formula (XIV): The rings A and E are phenolic in the ecteinascidins and some other compounds, while in other compounds, notably the saframycins, the rings A and E are quinolic. In the known compounds, the rings B and D are tetrahydro, while ring C is perhydro. SUMMARY OF THE INVENTION The present invention provides new compounds with the fused system of five rings (A) to (E). In particular, it provides new compounds which can be made from intermediates described in WO 9812198 or by a new process which is part of this invention. In this latter respect, we refer to our WO 0069862 published 23 November 2000, and which relates to hemisynthetic methods and new compounds. The present application claims priority from that PCT filing, and we incorporate that text by reference to the extent that there is disclosure therein which is not in the present specification. In WO 0069862, various routes are described for the preparation of ecteinascidin compounds, including ecteinascidin 743, as well as ecteinascidin analogs including phthaliscidin. The present invention is founded partly on the use of intermediates of WO 0069862 to prepare further analogs ofthe ecteinasacidins. PREFERRED EMBODIMENTS We have found that compounds ofthe invention have exceptional activity in the treatment of cancers, such as leukaemias, lung cancer, colon cancer, kidney cancer and melanoma. Thus, the present invention provides a method of treating any mammal, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a compound ofthe invention, or a pharmaceutical composition thereof. The present invention also relates to pharmaceutical preparations, which contain as active ingredient a compound or compounds ofthe invention, as well as the processes for their preparation. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally. Administration ofthe compounds or compositions ofthe present invention may be by any suitable method, such as intravenous infusion, oral preparations, intraperitoneal and intravenous administration. We prefer that infusion times of up to 24 hours are used, more preferably 2-12 hours, with 2-6 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of say 2 to 4 weeks. Pharmaceutical compositions containing compounds ofthe invention may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means. The correct dosage ofthe compounds will vary according to the particular formulation, the mode of application, and the particular situs, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition ofthe host, drug combinations, reaction sensitivities and severity ofthe disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose. The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition for administration at the same time or a different time. The identity ofthe other drug is not particularly limited, and suitable candidates include: a) drugs with antimitotic effects, especially those which target cytoskeletal elements, including microtubule modulators such as taxane drugs (such as taxol, paclitaxel. taxotere. docetaxel), podophylotoxins or vinca alkaloids (vincristine, vinblastine); b) antimetabolite drugs such as 5-fluorouracil, cytarabine, gemcitabine, purine analogues such as pentostatin, methotrexate); c) alkylating agents such as nitrogen mustards (such as cyclophosphamide or ifosphamide); d) drugs which target DNA such as the antracycline drugs adriamycin. doxorubicin, pharmorubicin or epirubicin; e) drugs which target topoisomerases such as etoposide; f) hormones and hormone agonists or antagonists such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, fiutamide, leuprorelin. goserelin. cyprotrone or octreotide; g) drugs which target signal transduction in tumour cells including antibody derivatives such as herceptin; h) alkylating drugs such as platinum drugs (cis-platin, carbonplatin. oxaliplatin, paraplatin) or nitrosoureas; i) drugs potentially affecting metastasis of tumours such as matrix metalloproteinase inhibitors; j) gene therapy and antisense agents; k) antibody therapeutics; 1) other bioactive compounds of marine origin, notably the didemnins such as aplidine; m) steroid analogues, in particular dexamethasone; n) anti-inflammatory drugs, in particular dexamethasone; o) anti-emetic drugs, in particular dexamethasone; p) skeletal muscle protectors, such as L-carnitine or precursor amino acids. The present invention also extends to the compounds ofthe invention for use in a method of treatment, and to the use ofthe compounds in the preparation of a composition for treatment of cancer. In one aspect ofthe invention, we make no claim to the compounds 2.3, 5. 8-OH-2. and 14 to 21 described in one or more ofthe GB priority patent applications for our PCT application published as 0069862. In a related aspect, the present invention extends to compounds which differ in respect of one or more ofthe substituents present at C-1, C-5, C- 7, C-8, or C-18 in the compounds of these GB priority patent applications. The compounds of this invention include compounds which do not have a hydroxy group at the C-18 position. Furthermore, the compounds of this invention include compounds which do not have a dicarboximidomethyl substituent, such as phthalimidomethyl, at the C-1 position. In particular, we provide active compounds where the subsituent Xi is not as shown in the penultimate line at page 19 of WO0018233. In one aspect, the analogs of this invention are typically ofthe formula (XVIIa): or formula (XVIIb): where R 1 is an optionally protected or derivatised aminomethylene group, an optionally protected or derivatised hydroxymethylene group; R 4 is -H; R 5 is -H or -OH ; R 7 is -OCH 3 and R 8 is -OH or R 7 and R 8 together form a group -O-CH 2 -O-; R ,4a and R 14b are both -H or one is -H and the other is -OH, -OCH 3 or -OCH 2 CH . or R ,4a and R 14b together form a keto group; and R 15 is -H or -OH; R 21 is -H, -OH or -CN; and derivatives including acyl derivatives thereof especially where R ' is acetyloxy or other acyloxy group of up to 4 carbon atoms. In the present invention, a key class of products includes phthalascidin and has the general formula (XX): where R 1 is an amidomethylene group; R 5 is a small oxy-sidechain; and R 21 is a cyano group or a hydroxy group. For phthalascidin, R 1 is a phthalimidomethylene group; R 5 an acetoxy 1 1 group; and R is a cyano group. Other groups for R include mono- and di-N-substituted amidomethylenes as well as other cyclic amidomethylenes, and other groups for R 5 include further Cι-C 4 acyl groups, as well as Cι-C 4 alkyl groups. In the present invention, a key class of intermediates and analogs includes Intermediate 11 and has the general formula (XXI): where Prot' and Prot 2 are hydroxy protecting groups, preferably different. For Intermediate 11 itself, the group Prot is a methoxymethyl group, and Prot is a t-butyldiphenylsilyl group. In the light ofthe preceding explanations, it can be seen that the present invention provides novel analogs and novel intermediate compounds. Depending on ring A, the compounds include those of formula (XXIIa): or of formula (XXIIb): where: R 1 is -CH 2 NH 2 or -CH 2 OH, or a protected or derivatised version of such a group and R 4 is - H; R 5 is -OH or a protected or derivatised version of such a group; R 14a and R 14b are both -H or one is -H and the other is -OH or a protected or derivatised version of such a group, -OCH 3 or -OCH 2 CH 3 , or R 14a and R 14b together form a keto group; R 12 is -H-, -CH 3 - or -CH 2 CH 3 -; R 15 is -H, -OH or a protected or derivatised version of such a group; and R 18 is -OH or a protected or derivatised version of such a group. In one embodiment, preferably at least of R 1 , R 5 . R 14a , R l4b . R 15 or R 18 is a protected or derivatised group. In one variation of this invention, the group R 1 is not a tert-butyldiphenylsilyl substituent and/or the group R is not a methoxymethyloxy group. Preferably R 1 is -CH 2 NH2 or -CH2OH, or a protected or derivatised version of such a group and R 4 is — H. Preferably R 14a and R 14b are both -H. Preferably R 12 is -CH 3 . One preferred class of intermediates includes the compound which we identify as compound 25, of formula: 25 The preferred class is thus ofthe general formula where the group MOM is replaced by any other protecting group, and/or the allyl is replaced by any other protecting group. Other preferred intermediates includes the compounds which we identify as compounds 17, 43 and 45. 17 43 45 Other N-acyl derivatives may readily be made from compound 45 and are an important part of this invention. Suitable acyl groups include those previously mentioned. The corresponding 21 -hydroxy compounds are also useful and are among the active compounds which we have found. From the activity data and other considerations, it can be seen that the active compounds of this invention include a preferred class of compounds of the general formula (XXIII): where R 1 is as previously defined for formula (XVIIb) and is preferably a derivatised aminomethylene group of moderate bulk; R 5 is as previously defined for formula (XVIIb) and is preferably a derivatised hydroxy group of low bulk; R 12 is as previously defined and is preferably -CH 3 -; and R is a hydroxy or cyano group. R 1 is suitably a hydrophobic group and which thus lacks free amino, hydroxy or other hydrophilic function. Typically R 1 is a group -CH 2 -NH 2 -CO-R a , where R a is as defined but preferably has a linear chain length of less than 20 atoms, more preferably less than 15 or 10 atoms, where a 1,4-phenyl is counted as a chain length of four atoms and similar considerations apply to other cyclic groups (for example, 1,2-cyclohexyl is chain length of two), and the linear chain of less than 10, 15 or 20 atoms can itself be substituted. In particular, the data suggests there is a balance to be achieved between having no such group R a -CO- and having a large, bulky group. In one variation, we prefer that R 1 is free from cyclic groups, especially aromatic groups. In a related variation, the present invention does not prepare the compounds which are described in the article Proc. Natl. Acad. Sci. USA, 96, 3496-3501, 1999, incorporated by reference. Our preferred groups for R 1 exclude the corresponding substituents CH 2 R 2 shown in Table 1 of that article, specifically the groups A, B, C and D for R 2 . R 5 is preferably an acetyl group. In particularly preferred compounds, the group R , 1 is acylated on an -NH 2 group, and for example N-acyl derivatives can be formed from groups -CH 2 NH 2 and -CH 2 -NH-aa. The acyl derivatives can be N-acyl or N-thioacyl derivatives thereof. The acyl groups can be of formula -CO-R a , where R a is as defined and is chosen to meet the indicated criteria. Suitable acyl groups include alanyl, arginyl, aspartyl, asparagyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, hydroxyprolyl., isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, thyronyl, tryptophyl, tyrosyl, valyl, as well as other amino acid acyl groups, which may be L- or D-. Such amino acid acyl groups are preferred derivatised on the amino group to give hydrophobicity. In a variation, the group R 1 is a derivatised hydroxymethylene group. Similar considerations apply as with the derivatised aminomethylene group. The invention extends to compounds where the various substituents around the ring are as defined in the WO 0018233, which we incorporate by reference. Thus, as appropriate, substituents in the present compounds can be chosen, among other possibilites from H, OH, ORM SH, SR\ SOR ' , SO 2 RM NO 2 , NH 2 , NHRM N(R') 2 , NHC(O)R ' , CN, halogen, =O, Cι-C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; wherein each ofthe R ' groups is independently selected from the group consisting of H, OH, NO 2 , NH 2 , SH, CN, halogen, =O, C(=O)H, C(=O)CH 3 , CO 2 H, CO 2 CH 3 . C,-C 6 alkyl. phenyl. benzyl and heteroaromatic. Suitable halogen substituents in the compounds ofthe present invention include F, Cl, Br and I. Alkyl groups preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most prefereably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members. Preferred alkenyl and alkynyl groups in the compounds ofthe present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more prefereably 2 to about 6 carbon atoms, even more prefereably 1, 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refere to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred. Preferred alkoxy groups in the compounds ofthe present invention include groups having one or more oxygem linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Preferred alkylthio groups in the compounds ofthe present invention have one or more thioether linkages and from 1 to about 12 carbon atoms, more prefereably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1 , 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfinyl groups in the compounds ofthe present invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfonyl groups in the compounds ofthe present invention include those groups having one or more sulfonyl (SO 2 ) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties. Suitable heteroaromatic groups in the compounds ofthe present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic groups in the compounds ofthe present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups. Suitable carbocyclic aryl groups in the compounds ofthe present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arykl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3- substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2.3.5-substituted and 2,4,5-substituted phenyl, including where one or more ofthe phenyl substituents is an electron-withdrawing group such as halogen, cyano, nitro. alkanoyl, sulfinyl. sulfonyl and the like; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl: and anthracyl. Any references herein to substituted groups in the compounds ofthe present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e.g., halogen such as fluoro. chloro. bromo and iodide; cyano; hydroxyl; nitro; azido; alkanoyl such as a Cl-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about °2 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbo atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl (e.g., R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl. Without being exhaustive, in terms ofthe formula: preferred compounds of this invention have one or more ofthe following definitions: Ri is -OR, where R is H, acyl, especially acetyl, alkyl-CO- (alkyl being up to about 20 carbon atoms, more preferably from 1 to about 12 carbon atoms, and especially an odd number of carbon atoms such as 3, 5, 7 and 9), cycloalkyl-alkyl-CO- and especially alkyl groupings with a terminal cyclohexyl group and up to six additional carbon atoms in the sidechain, or a protecting group, especially methoxymethyl. and is more especially OH. R 2 is methoxy. R 3 is methyl. Ri is hydrogen. R 5 is methyl or hydrogen, especially methyl. R ό is -CN or -OH. Xi is -NHR', -NH-aa-R' or -OR' where aa is an optionally protected amino acid acyl group, especially alanine, phenylalanine, cysteine, proline, valine, arginine, tryptophan or other amino acid. Other possibilities for Xi include -N(R') 2 , -N(R')-aa-R', and -N-(aa-R') 2 . In the case of any group -aa-R', the R' is usually on the amino group ofthe amino acid, and there may be two such substituents. R' is preferably H; alkyl-CO- (alkyl being up to 25 carbon atoms, such as up to 17, 19 or 21 carbon atoms and preferably an odd number of carbon atoms corresponding to a fatty acid carboxylic acid of even number of carbon atoms or else a low number of carbon atoms such as 1 to 6), especially CH 3 -(CH )n-CO- where n is for example 1, 2, 4, 12 or 16; alkenyl, especially allyl; haloalkyl-CO-, especially CF 3 -CO-; cycloalkyl-alkyl-CO-, preferably alkyl groupings with a terminal cyclohexyl group and up to six additional carbon atoms in the sidechain, especially cyclohexyl-(CH 2 ) n -CO- where n is for example 1 or 2; haloalkyl-O-CO-, especially trichloroethoxycarbonyl: arylalkyl-CO- or arylalkenyl-CO- especially phenyl-methyl/ethyl/vinyl-CO-, where aryl may be substituted as in trifluoromethylcinnamoyl; optionally substituted heteroaryl-CO-, where the substituents and heterocyclic group are as elsewhere discussed, as in 2-chloronicotinoyl; alkenyl-CO- especially crotonyl; opitionally subsituted aminoalkyl-CO-, particularly amino acid acyl, especially alanine, phenylalanine, cysteine, proline, valine, arginine, tryptophan or other amino acid, or a derivative thereof, as in Boc- phenylalanine, valine, proline. arginine or tryptophan, or as in phenethylalanine, trifluoroethylacetylalanine, trifluorodiacetylalanine and isomers thereof, or diacetyl- or dipropionyl- trifluoroacetyl, or as in or as in Cbz-Val- or a group notionally derived from cysteine and being of general formula Prot SH -S-CH 2 -C(=NOProt OH )-CO- or Prot SH -S-CH=C(-OProt OH )-CO-, where Prot SH and Prot are protecting groups for thiol and for hydroxy, especially where Prot H is Fm and Prot OH is methoxy for the first formulaor MOM for the second formula;or other possibilities such as a protecting group as in an alkoxycarbonyl such as Boc, or PhNR'CS. The various groups may be susbtituted as indicated elsewhere in this specification. R 7 and R 8 are -O-CH 2 -O- or R is =O and R 8 is OMe. especially R 7 and R 8 are -O-CH 2 -O-. R 9 is methyl. X 2 is -OR", where R" is preferably H; alkyl-CO-, especially acetyl; alkenyl especially allyl; alkenyl-O-CO-, especially allyl-O-CO-; haloalkyl-CO-, especially trifluoromethylcarbonyl or chlorornethylcarbonyl or 2-chloroethylcarbonyl or perfluoropropylcarbonyl. Of special interest are compounds wherein: Ri is -OR, where R is H or acetyl, alkyl-CO-, especially n-propyl-CO-, and Ri is more especially OH. R 2 is methoxy. R 3 is methyl. i is hydrogen. R 5 is methyl. Re is -CN or -OH. Xi is -NHR', where R' is preferably alkenyl, especially allyl, alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH 3 -(CH 2 )n-CO- where n is for example 1 to 6, and more especially 1 to 4); cycloalkyl-alkyl-CO-, especially cyclohexyl-(CH 2 ) n -CO where n is 1 or 2; arylalkyl-CO- or arylalkenyl-CO- especially phenethylcarbonyl, phenylvinylcarbonyl or benzylcarbonyl, alkenyl-CO- especially CH 3 -CH=CH-CO-; amino acid acyl, especially Cbz- Val-; optionally substituted heteroaryl-CO-, especially 2-chloropyridinylcarbonyl; or Xi is -NH-aa-R' where aa is alanine, phenylalanine, tryptophan or valine; R * is an amino subsituent and is arylalkyl-CO- especially phenethylcarbonyl or benzylcarbonyl; alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH 3 -(CH 2 )n-CO- where n is for example 1 to 6 and more especially 1, 2 or 4; alkenyl-CO- especially CH 3 -CH=CH-CO-; or protecting group especially alkyloxy-CO as in Boc; or X \ is -OR' where R' is preferably alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH 3 -(CH 2 )n-CO- where n is for example 1 to 6, and more especially 2; arylalkyl-CO- or arylalkenyl-CO- especially phenethylcarbonyl, phenylvinylcarbonyl or trifluoromethylcinnamoyl. R 7 and Rs are -O-CH 2 -O-. R 9 is methyl. X 2 is -OR", where R" is H; acetyl, allyloxycarbonyl, chloromethylcarbonyl or perfluoropropylcarbonyl; and R " is more especially H; acetyl or allyloxycarbonyl. Especially preferred embodiments ofthe present invention are the novel ecteinascidin-like compounds with the following general structures I, II and III that have been prepared from compounds 17, 25, 43 and 45 derived from cyanosafracin B. Compound 25 corresponds to the synthetic intermediate 3 described in US patent No 6,124,292. (I) (II) (III) Wherein R', X 2 , Rj and Re are each independently selected from the groups defined below: H OH OH CN CH 2 CH=CH 2 OAc OAc OH COCH 2 CH 3 OCH 2 CH=CH 2 OMOM COCH 2 CH 2 CH 3 OCOOCH 2 CH=CH 2 OCOCH2C 6 H,, CO(CH 2 ) 4 CH 3 OCOCF 3 OCOCH 2 CH 2 C 6 H, , CO(CH 2 ) 12 CH 3 OCOCH 2 Cl OCOCH 2 CH 2 CH 3 CO(CH 2 ) 16 CH 3 OCOCH 2 CH 2 Cl OCO(CH 2 ) 4 CH 3 COCH2C6H11 OCOCF 2 CF 2 CF 3 OCO(CH 2 ) 8 CH 3 COCH2CH2C6H11 OCO(CH 2 )ι 6 CH 3 COOCH 2 CCl 3 COCH 2 Ph COCH 2 CH 2 Ph COCH=CHCH 3 COCH=CHPh COCH=CHArCF 3 COCH(CH 3 )NHCOCH 2 CH 2 Ph CO-(S)-CH(CH 3 )NHCOCF 3 CO-(R)-CH(CH 3 )NHCOCF 3 CO-(S)-CH(NHCbz)CH(CH 3 ) 2 Boc CSNHPh A. NHBoc I Boc In the formulae (XVIIa) or (XVIIb), R 1 is typically aminomethylene, amidomethylene or R 1 with R 4 forms a group (IV) or (V). Suitable amidomethylene groups include those of formula -CH 2 -NH-CO-CHCH 3 -NH 2 derived from alanine, and similar groups derived from other amino acids, notably , both D and L, glycine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, methionine, cysteine, aspartate, asparagine, glutamatic acid, glutamine, lysine, arginine, proline, serine, threonine, histidine and hydroxyproline. A general formula for the group R 1 is then -CH 2 -NH -aa, where aa indicates an acyl amino acid group. The group R 1 can be acylated on an -NH group, and for example N-acyl derivatives can be formed from groups -CH 2 NH 2 and -CH 2 -NH-aa. The acyl derivatives can be N-acyl or N-thioacyl derivatives thereof, as well as cyclic amides. The acyl groups can illustratively be alkanoyl, haloalkanoyl, arylalkanoyl, alkenoyl, heterocyclylacyl. aroyl. arylaroyl, haloaroyl, nitroaroyl, or other acyl groups. The acyl groups can be of formula - CO-R a , where R a can be various groups such as alkyl, alkoxy, alkylene, arylalkyl. arylalkylene, amino acid acyl, or heterocyclyl, each optionally substituted with halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy. alkyl, amino or substituted amino. Other acylating agents include isothiocyanates, such as aryl isothiocyanates, notably phenyl isocyanate. The alkyl, alkoxy or alkylene groups of R a suitably have 1 to 6 or 12 carbon atoms, and can be linear, branched or cyclic. Aryl groups are typically phenyl, biphenyl or naphthyl. Heterocyclyl groups can be aromatic or partially or completely unsaturated and suitably have 4 to 8 ring atoms, more preferably 5 or 6 ring atoms, with one or more heteroatoms selected from nitrogen, sulphur and oxygen. Without being exhaustive, typical R a groups include alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylakylene, acyl, haloacyl, arlyalkyl. alkenyl and amino acid. For example, R a -CO- can be acetyl, trifluoroacetyl, 2,2,2- trichloroethoxycarbonyl, isovalerylcarbonyl, trans-3-(trifluoromethyl)cinnamoylcarbonyl, heptafluorobutyrylcarbonyl, decanoylcarbonyl, trans-cinnamoylcarbonyl, butyrylcarbonyl, 3- chloropropyonylcarbonyl, cinnamoylcarbonyl, 4-methylcinnamoylcarbonyl, hydrocinnamoylcarbonyl, or trans-hexenoylcarbonyl, or alanyl, arginyl, aspartyl. asparagyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, hydroxyprolyl., isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, thyronyl, tryptophyl, tyrosyl, valyl, as well as other less common amino acid acyl groups, as well as phthalimido and other cyclic amides. Other examples may be found among the listed protecting groups. Compounds wherein -CO-R a is derived from an amino acid and include an amino group can themselves form acyl derivatives. Suitable N-acyl commands include dipeptides which in turn can form N-acyl derivatives. In an important aspect of this invetnion, there are provided preferred compounds ofthe formula: wherein: R 1 is -CH 2 -N(R a ) 2 or -CH 2 -OR a , where R a is H; alkyl-CO-; haloalkyl-CO-; cycloalkylalkyl- CO-; haloalkyl-O-CO-; arylalkyl-CO-; arylalkenyl-CO-; heteroaryl-CO-; alkenyl-CO-; alkenyl; amino acid acyl; or a protecting group; R 5 is -OR", where R" is H; alkyl-CO-; cycloalkyl-CO-; haloalkyl-CO- or a protecting group; R 18 is -OR, where R is H, alkyl-CO-; cycloalkylalkyl-CO-; or a protecting group; R 21 is -CN or -OH. Typically such a compound is ofthe formula: wherein R 1 , R 5 , R 18 , and R 21 are as defined. In such preferred compounds of this invention, R 1 can be -C -NHR 3 R a can be -aa-R b where aa is amino acid acyl and R b is as defined for R a . The amino acid acyl is optionally further substituted with one or more R a groups. In further preferred comopunds, R 1 is -CH 2 -NH-aa-R b where aa is an amino acid and R b is hydrogen; protecting group; arylalkenyl-CO-; haloalkyl-CO-; alkyl-CO-: arylalkyl-CO-; or amino acid acyl. Such comopunds include those wherein R 1 is -CH2-NH-aa-R b where aa is alanine and R b is hydrogen, Boc, PhNHCS-. CF 3 CO-, PhNAcCS-, trifluorocinnamoyl, cinnamoyl, C 3 F 7 CO-, butyryl, 3-chloroproprionoyl, hydrocinnamoyl. hexanoyl. phenylacetyl, h h K Cbz-val or acetyl; -CH 2 -aa-R where aa is valine and R is Cbz or Boc; -CH 2 -aa-R where aa is phenylalanine and R is Boc; -CH2-aa-R where aa is proline and R is Boc; -CH 2 -aa- R b where aa is arginine and R b is Boc; or -CH 2 -aa-R b where aa is tryptophan and R b is Boc. R 1 can be -CH 2 -NR a -aa-R b where aa is an amino acid, R a is alkyl-CO- and R b is haloalkyl-CO-. Such compounds include those wherein R 1 is -CH 2 -NR a -aa-R b where aa is acetylalanine, R a is acetyl or butyryl, and R b is CF 3 -CO-. R 1 can be -CH 2 -NHR a where R a is hydrogen, protecting group, alkyl-CO-; alkenyl- CO-; arylalkenyl-CO-; arylalkyl-CO-; heteroaryl-CO-; cycloalkylalkyl-CO-; or alkenyl. Such compounds include those wherein R 1 is -CH 2 -NHR a where R a is hydrogen, Troc, acetyl; isovaleroyl, decanoyl, cinnamoyl, hydrocinnamoyl, phenylacetyl, propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, chloronicotinoyl, cyclohexylacetyl, cyclohexylpropionyl or allyl. R 1 can be -CH 2 -OR a where R a is hydrogen; a protected cysteine; a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(NHProt NH )-CO-, where Prot SH and Prot NH are protecting groups for thiol and for amino; a protecting group; alkyl-CO-; arylalkyl-CO-; arylalkenyl- CO-; a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(=NOProt OH )-CO- where Prot SH and Prot OH are protecting groups for thiol and for hydroxy; or a cysteine derivative of formula Prot SH -S-CH=C(-OProt OH )-CO-, where Prot SH and Prot OH are protecting groups for thiol and for hydroxy. Such compounds include those wherein R 1 is -CH 2 -OR 3 where R a is hydrogen; S-Fm-O-TBDMS-cysteine;a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(NHProt NH )- CO-, where Prot SH is Fm and Prof° H is Troc; TBDPS; butyryl; trfiluormethylcinnamoyl; cinnamoyl; hydrocinnamoyl; a cysteine derivative ofthe formula Prot SH -S-CH - C(=NOProt OH )-CO- where Prot SH is Fm and Prot OH is methoxy; or a cysteine derivative of formula Prot SH -S-CH=C(-OProt OH )-CO-, where Prot SH is Fm and Prot OH is MOM. In these preferred compounds, R 5 is suitably -OR", where R" is H; alkyl-CO where the alkyl has an odd number of carbon atoms, ω-cyclohexylalkyl-CO-; or a protecting group. In these preferred compounds, R 18 is suitably -OR, where R is H, alkyl-CO-; or a protecting group; In one variation which relates to intermediate products, the ring A is modified to incorporate the substructure shown as formula (XX) or (XXI), discussed later. In another variation relating to intermediates, the group R 1 can be -CH 2 O-CO-CFu-CH 2 -S-Prot 3 , derived from a compound of formula (XIX), where Prot 3 and Fu have the indicated meanings. In such a case, R 7 and R 8 from the oxymethyleneoxy group. The group R is usually protected. Usually R is cyano. Preferably R 14a and R 14b are hydrogen. Preferably R 15 is hydrogen. The O-acyl derivatives are suitably aliphatic O-acyl derivatives, especially acyl derivatives of 1 to 4 carbon atoms, and typically an O-acetyl group, notably at the 5-position. Suitable protecting groups for phenols and hydroxy groups include ethers and esters, such as alkyl, alkoxyalkyl, aryloxyalkyl, alkoxyalkoxyalkyl, alkylsilylalkoxyalkyl, alkylthioalkyl, arylthioalkyl, azidoalkyl, cyanoalkyl, chloroalkyl, heterocyclic, arylacyl, haloarylacyl, cycloalkylalkyl, alkenyl, cycloalkyl, alyklarylalkyl, alkoxyarylalkyl, nitroarylalkyl, haloarylalkyl, alkylaminocarbonylarylalkyl, alkylsulfinylarylalky, alkylsilyl and other ethers, and arylacyl, aryl alkyl carbonate, aliphatic carbonate, alkylsulfinylarlyalkyl carbonate, alkyl carbonate, aryl haloalkyl carbonate, aryl alkenyl carbonate, aryl carbamate, alkyl phosphinyl, alkylphosphinothioyl, aryl phosphinothioyl, aryl alkyl sulphonate and other esters. Such groups may optionally be substituted with the previously mentioned groups in R 1 . Suitable protecting groups for amines include carbamates, amides, and other protecting groups, such as alkyl, arylalkyl, sulpho- or halo- arylalkyl, haloalkyl, alkylsilylalkyl, arylalkyl, cycloalkylalkyl, alkylarylalkyl. heterocyclylalkyl, nitroarylalkyl, acylaminoalkyl, nitroaryldithioarylalkyl. dicycloalkylcarboxamidoalkyl, cycloalkyl. alkenyl. arylalkenyl, nitroarylalkenyl, heterocyclylalkenyl, heterocyclyl, hydroxyheterocyclyl. alkyldithio, alkoxy- or halo- or alkylsulphinyl arylalkyl. hetercyclylacyl, and other carbamates, and alkanoyl, haloalkanoyl, arylalkanoyl. alkenoyl, heterocyclylacyl. aroyl. arylaroyl, haloaroyl, nitroaroyl, and other amides, as well as alkyl, alkenyl. alkylsilylalkoxyalkyl, alkoxyalkyl, cyanoalkyl, heterocyclyl, alkoxyarylalkyl. cycloalkyl. nitroaryl, arylalkyl, alkoxy- or hydroxy- arylalkyl, and many other groups. Such groups may optionally be substituted with the previously mentioned groups in R 1 . Examples of such protecting groups are given in the following tables. protection for -OH group ethers abbreviation methyl methoxymethyl MOM benzyloxymethyl BOM methoxyethoxymethyl MEM 2-(trimethylsilyl)ethoxymethyl SEM methylthiomethyl MTM phenylthiomethyl PTM azidomethyl cyanomethyl 2,2-dichloro- 1 , 1 -difluoroethyl 2-chloroethyl 2-bromoethyl tetrahydropyranyl THP 1-ethoxyethyl EE phenacyl 4-bromophenacyl cyclopropylmethyl allyl propargyl isopropyl cyclohexyl t-butyl benzyl 2,6-dimethylbenzyl 4-methoxybenzyl MPM or PMB o-nitrobenzyl 2,6-dichlorobenzyl 3 ,4-dichlorobenzyl 4-(dimethylamino)carbonylbenzyl 4-methylsuflinylbenzyl Msib 9-anthrylmethyl 4-picolyl heptafluoro-/7-tolyl tetrafluoro-4-pyridyl trimethylsilyl TMS t-butyldimethylsilyl TBDMS t-butyldiphenylsilyl TBDPS triisopropylsilyl TIPS esters aryl formate aryl acetate aryl levulinate aryl pivaloate ArOPv aryl benzoate aryl 9-fluorocarboxylate aryl methyl carbonate 1 -adamantyl carbonate t-butyl carbonate BOC-OAr 4-methylsulfinylbenzyl carbonate Msz-Oar 2,4-dimethylpent-3-yl carbonate Doc-Oar aryl 2,2,2-trichloroethyl carbonate aryl vinyl carbonate aryl benzyl carbonate aryl carbamate dimethylphosphinyl Dmp-OAr dimethylphosphinothioyl Mpt-OAr diphenylphosphinothioyl Dpt-Oar aryl methanesulfonate aryl toluenesulfonate aryl 2-formylbenzenesulfonate protection for the -NH 2 group carbamates abbreviation methyl ethyl 9-fluorenylmethyl Fmoc 9-(2-sulfo)fluroenylmethyl 9-(2,7-dibromo)fluorenylmethyl 17-tetrabenzo [a, c, g, i] fluorenylmethyl Tbfmoc 2-chloro-3-indenylmethyl Climoc benz[ ]inden-3-ylmethyl Bimoc 2,7-di-t-butyl[9-( 10,10-dioxo- 10,10,10,10- tetrahydrothioxanthyl)] methyl DBD-Tmoc 2,2,2-trichloroethyl Troc 2-trimethylsilylethyl Teoc 2-phenylethyl hZ 1 -( 1 -adamantyl)- 1 -methylethyl Adpoc 2-chlooethyl 1 , 1 -dimethyl-2-chloroethyl 1 , 1 -dimethyl -2-bromoethyl 1 , 1 -dimethyl-2,2-dibromoethyl DB-t-BOC 1 , 1 -dimethyl-2,2,2-trichloroethyl TCBOC 1 -methyl- 1 -(4-biphenyl)ethyl Bpoc 1 -(3,5-di-t-butylphenyl)- 1 - 1 -methylethyl t-Burmeoc 2-(2'-and 4'-pyridyl)ethyl Pyoc 2,2-bis(4'-nitrophenyl)ethyl Bnpeoc «-(2-pivaloylamino)- 1 , 1 -dimethylethyl 2-[(2-nitrophenyl)dithio]-l-phenylethyl NpSSPeoc 2-(«,«-dicyclohexylcarboxamido)ethyl t-butyl BOC 1 -adamantyl 1-Adoc 2-adamantyl 2-Adoc vinyl Voc allyl Aloe or Alloc 1-isopropylallyl Ipaoc cinnamyl Coc 4-nitrocinnamyl Noc 3-(3'-pyridyi)prop-2-enyl Paloc 8-quinolyl H-hydroxypiperidinyl alkyldithio benzyl Cbz or Z j3-methoxybenzyl Moz p-nitrobenzyl PNZ j -bromobenzyl /?-chlorobenzyl 2,4-dichlorobenzyl 4-methylsulfinylbenzyl Msz 9-anthrylmethyl diphenylmethyl phenothiazinyl-( 10)-carbonyl n '-p-toluenesulfonylaminocarbonyl n -phenylaminothiocarbonyl amides formamide acetamide chloroacetamide trifluoroacetamide TFA phenylacetamide 3 -phenylpropanamide pent-4-enamide picolinamide 3 -pyridylcarboxamide benzamide />-phenylbenzamide R-phthalimide «-tetrachlorophthalimide TCP 4-nitro-H-phthalimide w-dithiasucciiiimide Dts «-2,3-diphenylmaleimide «-2,5-dimethylpyrrole «-2,5-bis(triisopropylsiloxyl)pyrrole BIPSOP n-1,1 ,4,4-tetramethyldisiliazacyclopentante adduct STAB ASE l,l,3,3-tetramethyl-l,3-disilaisoindoline BSB special -NH protective groups «-methylamine w-t-butylamine M-allylamine «-[2-trimethylsilyl)ethoxy]methylamine SEM n-3 -acetoxypropylamine «-cyanomethylamine n-( 1 -isopropyl-4-nitro-2-oxo-3 -pyrrolin-3 -yl)amine ?-2,4-dimethoxybenzylamine Dmb 2-azanorbornenes «-2,4-dinitrophenylamine «-benzylamine Bn «-4-methoxybenzylamine MPM «-2,4-dimethoxybenzylamine DMPM «-2-hydroxybenzylamine Hbn «-(diphenylmethyl)amino DPM 7-bis(4-methoxyphenyl)methylamine M-5-dibenzosuberylamine DBS w-triphenylmethylamine Tr «-[(4-methoxyphenyl)diphenylmethyl]amino MMTr «-9-phenylflurenylamine Pf «-ferrocenylmethylamine Fcm H-2-picolylamine n -oxide n-1,1 -dimethylthiomethyleneamine n-benzylideneamine tt- -methoxybenzylideneamine «-diphenylmethyleneamine «-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine «-nitroamine w-nitrosoamine diphenylphosphinamide Dpp dimethylthiophosphinamide Mpt diphenylthiophosphinamide Ppt dibenzyl phosphoramidate 2-nitrobenzenesulfenamide Nps n- 1 -(2,2,2-trifluoro- 1 , 1 -diphenyl)ethylsufenamide TDE 3-nitro-2-pyridinesulfenamide Npys j toluenesulfonamide Ts benzenesulfonamide Examples of preferred methods of this invention will firstly be considered with reference to starting compunds 45, 43 and 25. It will be appreicated that the particular substituents, notably at positions C-5 and C-18. can be varied in the light ofthe present disclosure. The preferred methods of producing the compounds of formula I, II and III are described below in the following reaction schemes with examples of typical substituent groups. Scheme 1 45 I (Re = CN) 1 (Re = OH) As illustrated in Scheme 1 the first step for producing the preferred compounds (I) (where Ri = OH, X 2 = OAc and Re = CN or OH) ofthe present invention from compound 45 is the high yielding conversion ofthe amino group to the amide group. After acylation ofthe amino group the second step is the transformation ofthe CN group into an OH group by reaction with silver nitrate in AcCN/T^O. The preparation of other compounds ofthe general formula I ofthe present invention starting from compound 17 is described below (Scheme 4). Scheme 2 As illustrated in Scheme 2 another group of interesting derivatives with formula II (where R\ = OH, X 2 = OAc and R 6 = CN or OH) can be obtained from compound 43 using the following sequence. Acylation ofthe amino group to provide the corresponding amide and transformation ofthe CN group into an OH group by reaction with silver nitrate in AcCN/H2O. The preparation of other compounds ofthe general formula II ofthe present invention starting from compound 17 is described below (Scheme 4). Scheme 3 The preferred procedure for producing compounds of formula III is the transformation of compound 25 into the corresponding ester derivatives by acylation ofthe OH group, deprotection ofthe phenol group followed by acetylation and deprotection ofthe MOM group to provide the corresponding ester followed by transformation of the CN group to the OH group by reaction with silver nitrate in ACCN/H2O to give the compound of formula III (where R] = OH, X 2 = OAc and Re = CN or OH) . Other compounds ofthe general formulae I and II ofthe present invention can be prepared from compound 17 via the amine intermediate 120 as described in Scheme 4. Scheme 4 The following additional compounds ofthe present invention (including for example 140 and 141) have been prepared starting from cyanosafracin B (2) as described in detail in the examples (Scheme 5). Scheme 5 141 As the skilled artisan will readily appreciate, the reaction schemes described herein may be modified and/or combined in various ways, and the compounds generated therefore are to be considered as being part of this invention. In particular the starting material and/or reagents and reactions can be varied to suit other combinations ofthe substituent groups in the formulae I, II and III. In a related aspect, the present invention is directed at the use of a known compound, safracin B, also referred to as quinonamine, in hemisynthetic synthesis. More generally, the invention relates to a hemisynthetic process for the formation of intermediates, derivatives and related structures of ecteinascidin or other tetrahydroisoquinolinephenol compounds starting from natural bis(tetrahydroisoquinoline) alkaloids. Suitable starting materials for the hemi-synthetic process include the classes of saframycin and safracin antibiotics available from different culture broths, and also the classes of reineramicin and xestomycin compounds available from marine sponges. A general formula (XV) for the starting compounds is as follows: where: R 1 is an amidomethylene group such as -CH 2 -NH-CO-CR 25a R 25b R 25c where R 25a and R ,2 2 5 b form a keto group or one is -OH, -NH 2 or -OCOCH 3 and the other is -CH 2 COCH 3 , -H, -OH or -OCOCH 3 , provided that when R 25a is -OH or -NH 2 then R 25b is not -OH, and R 25c is -H, ■ CH 3 or -CH2CH 3 , or R 1 is an acyloxymethylene group such as -CH 2 -O-CO-R. where R is - C(CH 3 )=CH-CH 3 or -CH 3 ; R 5 and R 8 are independently chosen from -H, -OH or -OCOCH OH, or R 5 and R 8 are both keto and the ring A is a p-benzoquinone ring; R 14a and R 14b are both -H or one is -H and the other is -OH, -OCH 3 or -OCH 2 CH 3 , or R 14a and R together form a keto group; R 15 and R 18 are independently chosen from -H or -OH. or R 5 and R 8 are both keto and the ring A is a p-benzoquinone ring; and R 21 is -OH or -CN. A more general formula for these class of compounds is provided below: wherein the substituent groups defined by Ri, R2, R 3 , R t , R 5 , R & R 7 , Rs, R 9 , Rio are each independently selected from the group consisting of H, OH, OCH 3 , CN, =O, CH 3 ; wherein X are the different amide or ester functionalities contained in the mentioned natural products; wherein each dotted circle represents one, two or three optional double bonds. Thus, according to the present invention, we now provide hemisynthetic routes for the production of intermediates including Intermediate 11 and thus for the production of the ecteinascidin compounds as well as phthalascidin and additional compounds. The hemisynthetic routes ofthe invention each comprise a number of transformation steps to arrive at the desired product. Each step in itself is a process in accordance with this invention. The invention is not limited to the routes that are exemplified, and alternative routes may be provided by, for example, changing the order ofthe transformation steps, as appropriate. In particular, this invention involves the provision of a 21 -cyano starting material of general formula (XVI): where R 5 , R 8 , R 14a , R 14b R 15 and R 18 are as defined. Other compounds of formula (XVI) with different substituents at the 21 -position may also represent possible starting materials. In general, any derivative capable of production by nucleophilic displacement ofthe 21 -hydroxy group of compounds of formula (XV) wherein R 21 is a hydroxy group cis a candidate. Examples of suitable 21 -substituents include but are not limited to: a mercapto group; an alkylthio group (the alkyl group having from 1 to 6 carbon atoms); an arylthio group (the aryl group having from 6 to 10 carbon atoms and being unsubstituted or substituted by from 1 to 5 substituents selected from, for example, alkyl group having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, mercapto groups and nitro groups); an amino group; a mono-or dialkylamino (the or each alkyl group having from 1 to 6 carbon atoms); a mono-or diarylamino group (the or each aryl group being as defined above in relation to arylthio groups); an α-carbonylalkyl group of formula -C(R a )(R b )-C(=O)R c , where R a and R b are selected from hydrogen atoms, alkyl groups having from 1 to 20 carbon atoms. aryl groups (as defined above in relation to arylthio groups) and aralkyl groups (in which an alkyl group having from 1 to 4 carbon atoms is substituted by an aryl group a defined above in relation to arylthio groups), with the proviso that one of R a and R b is a hydrogen atom; R c is selected from a hydrogen atom, an alkyl group having from 1 to 20 carbon atoms, aryl groups (as defined above in relation to arylthio groups), an aralkyl group (in which an alkyl group having from 1 to 4 carbon atoms is substituted by an aryl group a defined above in relation to arylthio groups), an alkoxy group having from 1 to 6 carbon atoms, an amino group or a mono- or dialkylamino group as defined above. Thus, in a more general aspect, the present invention relates to processes where the first step is to form a 21-deriviative using a nucleophilic reagent. We refer to such compounds as 21-Nuc compounds. The presence ofthe 21 -cyano group is required for some ofthe end-products, notably ecteinascidin 770 and phthalascidin, while for other end-products it acts as a protecting group which can readily be converted to another substituent, such as the 21 -hydroxy group of ecteinascidin 743 or of 21 -hydro xyphthalascidin. The adoption ofthe 21 -cyano compound as the starting material effectively stabilises the molecule during the ensuing synthetic steps, until it is optionally removed. Other 21-Nuc compounds can offer this and other advantages. In one important aspect, the present invention consists in the use of a 21 -cyano compound ofthe general formula (XVI) in the preparation of a bis- or tris- (tetrahydroisoquinolinephenol) compounds. Products which may be prepared include intermediates such as Intermediate 11 , and the ecteinascidins and phthalascidin, as well as new and known compounds of related structure. Preferred starting materials include those compounds of formula (XV) or (XVI) where R 14a and R 14b are both hydrogen. Preferred starting materials also include compounds of formula (XV) or (XVI) where R 15 is hydrogen. Furthermore, the preferred starting materials include compounds of formula (XV) or (XVI) where ring E is a phenolic ring. Preferred starting materials further include compounds of formula (XV) or (XVI) where at least one, better at least two or three of R 5 , R 8 , R 15 and R 18 is not hydrogen. Examples of suitable starting materials for this invention include saframycin A, saframycin B, saframycin C, saframycin G, saframycin H, saframycin S, saframycin Y 3 , saframycin Ydi, saframycin Adi, saframycin Yd 2 , saframycin AH 2 , saframycin AH 2 AC, saframycin AHi, saframycin AHjAc, saframycin AR 3 , renieramycin A, renieramycin B, renieramycin C, renieramycin D. renieramycin E. renieramycin F, xestomycin, saframycin D, saframycin F, saframycin Mx-1, saframycin Mx-2, safracin A, safracin B and saframycin R. Preferred starting materials have a cyano group in position 21, for the group R 21 . In a particularly preferred aspect, the invention involves a hemisynthetic process wherein the transformation steps are applied to safracin B: SAFRACIN B Safracin B presents a ring system closely related to the ecteinascidins. This compound has the same pentacycle structure and the same substitution pattern in the right- hand aromatic ring, ring E. Also, safracin B presents very close similarities to some ofthe synthetic intermediates in the total synthesis of ΕT-743, particularly to the intermediate 1 1. Such intermediate can be transformed into Εt-743 using a well established method. Synthetic conversion of safracin B into intermediate 11 will therefore provide an hemisynthetic method to obtain ET-743. Thus, we provide Intermediate 11 made from this compound safracin B. and compounds derived from Intermediate 11 , particularly ecteinascidin compounds. We further provide phthalascidin made from safracin B. The invention also relates to use of safracin B in the production of Intermediate 11, phthalascidin, ecteinascidin compounds and the other intermediates ofthe invention. The invention also relates to compounds described herein derived from the other suggested starting materials, and use of those compounds in the production of such compounds. The more preferred starting materials of this invention have a 21 -cyano group. The currently most preferred compound ofthe present invention is the compound of Formula 2. This compound is obtained directly from safracin B and is considered a key intermediate in the hemisynthetic process. compound 2 In a related aspect, we provide cyanosafracin B by fermentation of a safracin B- producing strain of Pseudomonas fluorescens, and working up the cultured broth using cyanide ion. The preferred strain of Pseudomonas fluorescens is strain A2-2, FERM BP-14, which is employed in the procedure of EP 055,299. A suitable source of cyanide ion is potassium cyanide. In a typical work-up, the broth is filtered and excess cyanide ion is added. After an appropriate interval of agitation, such as 1 hour, the pH is rendered alkaline, say pH 9.5, and an organic extraction gives a crude extract which can be further purified to give the cyanosafracin B. Safracin B includes an alanyl sidechain. In one aspect ofthe invention, we have found that protection ofthe free amino group with a Boc group can give strong advantages. In general, the conversion ofthe 21 -cyano starting compound to an ecteinascidin analog of this invention can be carried out in accordance with our copending PCT patent application, attorney reference wpp83894, which also claims priority from the PCT filing published as WO 0069862 published 23 November 2000, and which relates to hemisynthetic methods and new compounds. We incorporate the text ofthe copending PCT application, attorney reference wpp83894, by reference to the extent that there is disclosure therein which is not in the present specification. Typically the hemisynthesis of an analog of this invention involves: a) conversion if necessary of a quinone system for the ring E into the phenol system b) conversion if necessary of a quinone system for the ring A into the phenol system; c) conversion ofthe phenol system for the ring A into the methylenedioxyphenol ring; and d) derivatisation as appropriate, such as acylation. Step (a), conversion if necessary of a quinone system for the ring E into the phenol system, can be effected by conventional reduction procedures. A suitable reagent system is hydrogen with a palladium-carbon catalyst, though other reducing systems can be employed. Step (b), conversion if necessary of a quinone system for the ring A into the phenol system is analogous to step (a), and more detail is not needed. Step (c), conversion ofthe phenol system for the ring A into the methylenedioxyphenol ring, can be effected in several ways, possibly along with step (b). For example, a quinone ring A can be demethylated in the methoxy substituent at the 7- position and reduced to a dihydroquinone and trapped with a suitable electrophilic reagent such as CH 2 Br 2 , BrCH2Cl, or a similar divalent reagent directly yielding the methylenedioxy ring system, or with a divalent reagent such as thiocarbonyldiimidazol which yields a substituted methylenedioxy ring system which can be converted to the desired ring. Derivatisation in step (d) can include acylation, for instance with a group R a -CO- as well as conversion ofthe 12-NCH 3 group to 12-NH or 12-NCH 2 CH 3 . Such conversion can be effected before or after the other steps, using available methods. By way of illustration, it is now feasible to transform cyanosafracin B in a shorter and more straightforward way to make new analogs. Cyanosafracin B can be transformed into Intermediate 25; INT-25 and from this derivative it is possible to introduce further analogs of this invention. One method of this invention transforms cyanosafracin B into intermediate 25 through a sequence of reactions that involves essentially (1) removal of methoxy group placed in ring A, (2) reduction of ring A and formation of methylene-dioxy group in one pot, (3) hydrolysis of amide function placed over carbon 1, (4) transformation ofthe resulting amine group into hydroxyl group. The conversion ofthe 2-cyano compound into Intermediate 25 usually involves the following steps (see scheme II): formation ofthe protected compound of Formula 14 by reacting 2 with tert-butoxycarbonyl anhydride; converting of 14 into the di-protected compound of Formula 15 by reacting with bromomethylmethyl ether and diisopropylethylamine in acetonitrile; selectively elimination ofthe methoxy group ofthe quinone system in 15 to obtain the compound of Formula 16 by reacting with a methanolic solution of sodium hydroxide; transforming of 16 into the methylene-dioxy compound of Formula 18 by employing the next preferred sequence: (1) quinone group of compound 16 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylenedioxy compound of Formula 17 by reacting with bromochloromethane and caesium carbonate under hydrogen atmosphere; (3) 17 is transformed into the compound of Formula 18 by protecting the free hydroxyl group as a OCH 2 R group. This reaction is carried out with BrCH 2 R and caesium carbonate, where R can be aryl, CH=CH 2 , OR' etc. elimination ofthe tert-butoxycarbonyl and the methyloxymethyl protecting groups of 18 to afford the compound of Formula 19 by reacting with a solution of HCl in dioxane. Also this reaction is achieved by mixing 18 with a solution of trifluoroacetic acid in dichloromethane; formation ofthe thiourea compound of Formula 20 by reacting 19 with phenylisothiocyanate; converting compound of Formula 20 into the amine compound of Formula 21 by reacting with a solution of hydrogen chloride in dioxane; transforming compound of Formula 21 into the N-Troc derivative 22 by reacting with trichloroethyl chloroformate and pyridine; formation ofthe protected hydroxy compound of Formula 23 by reacting 22 with bromomethylmethyl ether and diisopropylethylamine; transforming compound of Formula 23 into the N-H derivative 24 by reacting with acetic acid and zinc; conversion of compound of Formula 24 into the hydroxy compound of Formula 25 by reaction with sodium nitrite in acetic acid. Alternatively, it can be used nitrogen tetroxide in a mixture of acetic acid and acetonitrile followed by treatment with sodium hydroxide. Also, it can be used sodium nitrite in a mixture of acetic anhydride-acetic acid, followed by treatment with sodium hydroxide. Scheme II The conversion ofthe Intermediate 25 compound into other analogs of this invention is then readily achieved, as illustrated for example in Scheme III, which usually involves the following steps: transforming compound of formula 24 into the derivative 30 by protecting the primary hydroxyl function with (S)-N-2,2,2-tricloroethoxycarbonyl-S-(9H-fluoren-9- ylmethyl)cysteine 29; converting the protected compound of formula 30 into the phenol derivative 31 by cleavage ofthe allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine). transforming the phenol compound of Formula 31 into compound of formula 32 by oxidation with benzeneseleninic anhydride at low temperature; The route described above to transform Intermediate 25 can be conveniently modified to form other derivatives. In more detail, the conversion ofthe starting 21 -cyano compound to a related product of this invention, such as one of formula (XX), usually involves the following steps: a) conversion if necessary of a quinone system for the ring E into the phenol system b) formation ofthe -R 5 group at the 5-position in ring A; c) formation ofthe R 1 group at the 1 -position in ring B; and d) conversion if necessary of a quinone system for the ring A into the phenol system; e) conversion ofthe phenol system for the ring A into the methylenedioxyphenol ring. These steps have many similarities with the steps given previously. Step (c) typically involves forming a group -CH2NH2 at the 1 -position and acylating it. Phthlascidin can be made using Intermediates described in the conversion of cyanosafracin B into Intermediate 25. For example, Intermediates 21 and 17 are suitable starting materials to make Phthlascidin and other analogs of this invention. As shown in scheme V, the process for the synthetic formation of phthlascidin starting from Intermediate 21 comprises the sequential steps of: transforming of 21 into the compound of Formula 27 by reaction with phthalic anhydride in dichloromethane and carbonyldiimidazole. converting of 27 into phthlascidin by reacting with tributyltin hydride and dichloro palladium-bis(triphenylphosphine) or basic media, followed by reaction with acetyl chloride. Scheme V As shown in scheme VI, the process for the synthetic formation of phthlascidin starting from Intermediate 17 comprises the sequential steps of: acetylation ofthe hydroxyl group of compound of formula 17 with acetyl chloride and pyridine to give the acetylated intermediate compound of formula 42; removal ofthe tert-butoxycarbonyl and the methyloxymethyl protecting groups of 42 to afford the compound of Formula 43 by reacting with a solution of HCl in dioxane. Also this reaction is achieved by mixing 42 with a solution of trifluoroacetic acid in dichloromethane; formation ofthe thiourea compound of Formula 44 by reacting 43 with phenylisothiocyanate; converting compound of Formula 44 into the amine compound of Formula 45 by reacting with a solution of hydrogen chloride in dioxane; transforming of 45 into phthlascidin by reaction with phthalic anhydride in dichloromethane and carbonyldiimidazole. Other analogs can be made for example from 43 or 45 by a similar manner. Scheme VI The conversion ofthe 21 -cyano compound to Intermediate 1 1 or a related intermediate of formula (XXI) usually involves the following steps: a) conversion if necessary of a quinone system for the ring E into the phenol system b) formation ofthe -OProt 1 group at the 18-position, in ring E; c) formation ofthe -CH 2 -OProt 2 group at the 1 -position, in ring B; and d) conversion if necessary of a quinone system for the ring A into the phenol system; e) conversion ofthe phenol system for the ring A into the methylenedioxyphenol ring. Step (b), formation ofthe -OProt 1 group at the 18-position in ring E, is a typical protection reaction for a phenol group, and no special comments need to be made. Appropriate conditions are chosen depending on the nature ofthe protecting group. The other steps are similar to the other reactions. Step (b), formation ofthe -CH 2 -OProt 2 group at the 1 -position in ring B, is normally carried out by forming a group -CH 2 NH2 at the 1 -position and then converting the amine function to a hydroxy function and protecting. Thus, where the starting material has a group R 1 which is -CH 2 -NH-CO-CR 25a R 25b R 25c then it is matter of removing the N-acyl group. Where the starting material has a group R 1 which is -CH -O-CO-R then no change may be needed for an ecteinascidin product where the substituent R 1 is the same. For other products, it is matter of removing the O-acyl group. Various procedures are available for such de-acylations. In one variation, the deacylation and conversion to a hydroxy function are performed in one step. Thereafter, the hydroxy group can be acylated or otherwise converted to give the appropriate R 1 group. U.S. Patent N° 5,721,362 describe synthetic methods to make ET-743 through a long multistep synthesis. One ofthe Intermediates of this synthesis is Intermediate 1 1. Using cyanosafracin B as starting material it is possible to reach Intermediate 1 1 providing a much shorter way to make such Intermediate and therefor improving the method to make ET-743 Cyanosafracin B can be converted into Intermediate 25 by the methods described above. From Intermediate 25 is possible to reach Intermediate 11 using the following steps, see scheme VII. formation ofthe protected hydroxy compound of Formula 26 by reacting 25 with tert- butyldiphenylsilyl chloride in the presence of a base; final cleavage ofthe allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine) in 26 that leads to the formation ofthe intermediate 11. Scheme VII 25 26 Bu 3 SnH One embodiment ofthe synthetic process ofthe present invention to transform safracin B into intermediate 11 is a modification and extension of Scheme VIII and comprises the sequential steps of: stereospecifically converting the compound Safracin B to the compound of Formula 2 by selective replacement of OH by CN by reacting with KCN in acid media; forming the thiourea compound of Formula 3 by reacting compound of Formula 2 with phenyl isothiocyanate; converting the thiourea compound of Formula 3 into the acetamide of Formula 5 by an hydrolysis in acid media followed by addition of acetic anhydride; The intermediate amine compound of Formula 4 can be isolated by quenching the hydrolysis in acid media with sodium bicarbonate, but this intermediate is highly unstable, and is transformed quickly into a five member cyclic imine, named compound 6; forming the protected compound of Formula 7 by reacting with bromomethylmethyl ether and diisopropylethylamine in dichloromethane; selectively de-methylating the methoxy group ofthe quinone system of compound of Formula 7 into the compound of Formula 8 by reacting with methanolic solution of sodium hydroxide; transforming the compound of Formula 8 into methylenedioxy-compound of Formula 9 by the preferred following sequence: (1) quinone group of compound 8 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylene-dioxy compound of Formula 9 by reacting with bromochloromethane and cesium carbonate under hydrogen atmosphere; (3) compound of Formula 9 is transformed into compound of Formula 10 by protecting the free hydroxyl group as a OCH 2 R group, by reacting with BrC^R and cesium carbonate, where R can be aryl, CH=CH 2 . OR ' etc.; converting the acetamide group of compound of Formula 10 into the corresponding hydroxyl group of Formula 11 by reaction with nitrogen tetroxide in a mixture of acetic acid and acetic acetate followed by treatment with sodium hydroxide; alternatively can be used sodium nitrite in a mixture of acetic anhydride acetic acid, followed by treatment with sodium hydroxide; alternatively the acetamide group of compound of Formula 10 can be converted into the primary amine group by reacting with hydrazine or with B0C 2 O. DMAP followed by hydrazine; such primary amine can be converted into the corresponding hydroxyl group (compound of Formula 11) by an oxidative conversion of the primary amine into the corresponding aldehyde with 4-formyl-l-methylpyridinium benzenesulphonate or other pyridinium ion, followed by DBU or other base treatment and further hydrolization, and followed by the reduction ofthe aldehyde to the corresponding hydroxyl group with lithium aluminium hydride or other reducing agent; forming the protected compound of Formula 26 by reacting with t-butyldiphenylsilyl chloride and dimethylaminopyridine in dichloromethane; transforming the silylated compound of Formula 26 into the intermediate 11 by deprotection ofthe OCH 2 R protecting group, by reacting under reductive conditions or acid conditions. Typical procedures are with palladium black under hydrogen atmosphere, or aqueous TFA, or tributyltin hydride and dichlorobis (triphenylphosphine palladium). In yet another preferred modification, the cyano compound of Formula 2 can be transformed into Intermediate 11 using an extension ofthe scheme II, involving the further steps of. formation ofthe protected hydroxy compound of Formula 26 by reacting 25 with tert- butyldiphenylsilyl chloride in the presence of a base; final cleavage ofthe allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine) in 26 that leads to the formation ofthe intermediate 11. Thus, it is possible to transform cyanosafracin B into a number of intermediates and derivatives with potential antitumor therapeutic activity. These intermediates can be made starting from already described compounds, or using alternative routes. Intermediates described herein comprise compound 47, and a numbers of amide derivatives made using compounds 45 or 43. In Scheme VIII is described formation of compound 47 using the following sequence: forming the thiourea compound of Formula 3 by reacting compound of Formula 2 with phenyl isothiocyanate; converting the thiourea compound of Formula 3 into the acetamide of Formula 5 by an hydrolysis in acid media followed by addition of acetic anhydride; The intermediate amine compound of Formula 4 can be isolated by quenching the hydrolysis in acid media with sodium bicarbonate, but this intermediate is highly unstable, and is transformed quickly into a five member cyclic imine, named compound 6; forming the protected compound of Formula 7 by reacting with bromomethylmethyl ether and diisopropylethylamine in dichloromethane; selectively de-methylating the methoxy group ofthe quinone system of compound of Formula 7 into the compound of Formula 8 by reacting with methanolic solution of sodium hydroxide; transforming the compound of Formula 8 into methylenedioxy-compound of Formula 10 by the preferred following sequence: (1) quinone group of compound 8 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylene-dioxy compound of Formula 9 by reacting with bromochloromethane and cesium carbonate under hydrogen atmosphere; (3) compound of Formula 9 is transformed into compound of Formula 10 by protecting the free hydroxyl group as a allyloxy group, by reacting with allyl-bromide and cesium carbonate; transforming the compound of formula 9 into acetyl-derivative 46 by reaction with acetyl chloride in pyridine; transforming compound of formula 46 into de-protected compound 47 by reaction with hydrochloric acid in dioxane. Scheme VIII Other useful amide intermediate derivatives are made starting from already described intermediate 45 using the next scheme: Scheme fX The second step is optional. This process is an important part ofthe invention, particularly where the group R is a group R a as previously defined. Furthermore, the Scheme VIII can be readily broadened to enable preparation of compounds of formula (XXIII), by inclusion in the starting material of a different group at the 5-position, either a group directly intended for the product or a group which can be removed or otherwise modified to give the desired group. From compound 45 can be made a group of analogs through the following sequence: acylation in the amino group of compound of Formula 45 by a wide range of acyl derivatives to provide the corresponding amides, where preferred acyl groups are acetyl, cinnamoyl chloride, p-trifluorocinnamoyl chloride, isovaleryl chloride phenylisothiocyanate or aminoacids, or the other examples previously given of groups R a CO-. transforming the CN group into an OH group by reaction with silver nitrate in a mixture AcN H 2 O. Other useful amide intermediate derivatives are made starting from already described intermediate 43 using the next scheme: Scheme X From Compound 43 can be obtained another group of interesting derivatives using the following sequence: (a) acylation in the amino group of compound of Formula 43 by a wide range of acyl derivatives to provide the corresponding amides, where preferred acyl groups are acetyl, cinnamoyl chloride, p-trifluorocinnamoyl chloride, isovaleryl chloride or aminoacids, or the other examples previously given of groups R a CO-. (b) transforming the CN group into an OH group by reaction with silver nitrate in a mixture AcN/H 2 O Reflecting the active compounds, an important process in accordance with this invention is as follows: where R 5 for the end product is as defined for the compound (XXII) and may be different in the starting material and converted thereto as part ofthe process, R 18 is a hydroxy group in the end product but may be a protected hydroxy group in the starting material and converted thereto as part ofthe process, R 12 for the end product may be the same as in the starting material or may be converted thereto as part ofthe process, R 21 for the end product is as defined and if a hydroxy group may be formed from a cyano group as part ofthe process, R a is as defined, and may be further acylated as part ofthe process to give an end product with an acylated R a group as discussed. R 5 is preferably oxyacetyl or other small oxyacyl group in the starting material and is not changed in the reaction. R 18 is preferably a hydroxy group in the starting material and is not changed in the reaction. R 12 is preferably -NCH - in the starting material and is not changed in the reaction. R 21 the end product is as defined and if a hydroxy group may be formed from a cyano group as part ofthe process. R a is in the final product is preferably as defined in relation to the compound of formula (XXIII). Another important method of this invention includes the reaction: Another important method of this invention includes the reaction: Another important method of this invention includes the reaction includes the reaction where a group R 1 is aminomethylene is converted to a hydroxymethylene group. Another important method of this invention includes the reaction for preparing a 21- cyano compound of formula (XVI) which comprises reacting a compound of formula (XV): where R 1 . R 5 , R 8 , R 14a , R 14b R 15 and R 18 are as defined and R 21 is a hydroxy group, with a source of cyanide ion, to give the desired 21 -cyano compound. In addition, processes using other nucleophile-containing compounds, to produce similar compounds of formula (XVI) wherein the 21 -position is protected by another nucleophilic group, a 21-Nuc group, are also envisaged. For example, a 21 -Nuc compound of formula (XVI) with an alkylamino substituent at the 21 -position can be produced by reacting the compound of formula (XV) wherein R is a hydroxy group with a suitable alkylamine. A 21 -Nuc compound of formula (XVI) with an alkylthio substituent at the 21 - position can also be produced by reacting the compound of formula (XV) wherein R 21 is a hydroxy group with a suitable alkanethiol. Alternatively, a 21-Nuc compound of formula (XVI) with an α-carbonylalkyl substituent at the 21 -position can be produced by reacting the compound of formula (XV) wherein R 21 is a hydroxy group with a suitable carbonyl compound, typically in the presence of a base. Other synthetic routes are available for other 21-Nuc compounds. Another important reaction of this invention involves treatment of a 21 -cyano product of this invention to form a 21 -hydroxy compound. Such compounds have interesting in vivo properties. For the avoidance of doubt, the stereochemistries indicated in this patent specification are based on our understanding ofthe correct stereochemistry ofthe natural products. To the extent that an error is discovered in the assigned stereochemistry, then the appropriate correction needs to be made in the formulae given throughout in this patent specification. Furthermore, to the extent that the syntheses are capable of modification, this invention extends to stereoisomers. CYTOTOXIC ACTIVITIY CYTOTOXIC ACTIVITY (M) EXAMPLES OF THE INVENTION The present invention is illustrated by the following examples. Example 1 14 To a solution of 2 (21.53 g, 39.17 ml) in ethanol (200 ml), tert- butoxycarbonyl anhydride (7.7 g, 35.25 ml) was added and the mixture was stirred for 7 h at 23 °C. Then, the reaction was concentrated in vacuo and the residue was purified by flash column chromatography (SiO 2 , hexane:ethyl acetate 6:4 ) to give 14 (20.6 g, 81 %) as a yellow solid. Rf: 0.52 (ethyl acetate:CHCl 3 5:2). 1H NMR (300 MHz, CDC1 3 ): δ 6.49 (s, 1H), 6. 32 (bs, 1H), 5.26 (bs. 1H). 4.60 (bs, 1 H), 4.14 (d, J= 2.4 Hz, 1H), 4.05 (d, J= 2.4 Hz, 1H), 3.94 (s, 3H), 3.81 (d, J= 4.8 Hz. 1H). 3.7 (s, 3H), 3.34 (br d, J= 7.2 Hz, 1H), 3.18-3.00 (m. 5H), 2.44 (d, J= 18.3 Hz. 1H). 2.29 (s, 3H), 2.24 (s, 3H), 1.82 (s, 3H), 1.80-1.65 (m, 1H). 1.48 (s, 9H), 0.86 (d. J= 5.7 Hz, 3H) I3 C NMR (75 MHz, CDC1 3 ): δ 185.5, 180.8, 172.7. 155.9, 154.5. 147.3. 143.3. 141.5. 135.3. 130.4, 129.2, 127.5, 120.2, 1 17.4, 1 16.9, 80.2. 60.7, 60.3, 58.5, 55.9, 55.8. 54.9. 54.4, 50.0, 41.6, 40.3, 28.0, 25.3, 24.0, 18.1. 15.6, 8.5. ESI-MS m/z: Calcd. for C 34 H4 3 N 5 O 8 : 649.7. Found (M+H) + : 650.3. Example 2 14 15 To a stirred solution of 14 (20.6 g, 31.75 ml) in CH 3 CN (159 ml), diisopropylethylamine (82.96 ml, 476.2 ml), methoxymethylene bromide (25.9 ml, 317.5 ml) and dimethylaminopyridine (155 mg, 1.27 ml) were added at 0 °C. The mixture was stirred at 23 °C for 24h. The reaction was quenched at 0 °C with aqueous 0. IN HCl (750 ml) (pH = 5), and extracted with CH 2 C1 2 (2 x 400 ml). The organic phase was dried (sodium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient hexane:ethyl acetate 4:1 to hexane:ethyl acetate 3:2) to give 15 (17.6 g. 83 %) as a yellow solid. Rf: 0.38 (hexane:ethyl acetate 3:7). Η NMR (300 MHz, CDC1 3 ): δ 6.73 (s, IH), 5.35 (bs. IH), 5.13 (s, 2H), 4.50 (bs. I H). 4.25 (d, J= 2.7 Hz, IH), 4.03 (d, J= 2.7 Hz, IH), 3.97 (s, 3H), 3.84 (bs, IH), 3.82-3.65 (m. IH). 3.69 (s, 3H), 3.56 (s, 3H), 3.39-3.37 (m, IH), 3.20-3.00 (m, 5H), 2.46 (d, J= 18 Hz. IH), 2.33 (s, 3H), 2.23 (s, 3H), 1.85 (s, 3H), 1.73-1.63 (m, IH), 1.29 (s, 9H). 0.93 (d, J= 5.1 Hz, 3H) 13 C NMR (75 MHz, CDCl 3 ): δ 185.4, 180.9, 172.4, 155.9, 154.5, 149.0, 148.4. 141.6. 135.1 , 131.0, 129.9, 127.6, 124.4, 123.7, 117.3, 99.1, 79.3, 60.7, 59.7, 58.4, 57.5, 56.2. 55.9, 55.0, 54.2, 50.0, 41.5, 39.9, 28.0, 25.2, 24.0. 18.1, 15.6, 8.5. ESI-MS m/z: Calcd. for CseELπ sOo: 693.8. Found (M+H) + : 694.3. Example 3 16 15 To a flask containing 15 (8 g, 1.5 ml) in methanol (1.6 1) an aqueous solution of 1M sodium hydroxide (3.2 1) was added at 0 °C. The reaction was stirred for 2h at this temperature and then, quenched with 6M HCl to pH = 5. The mixture was extracted with ethyl acetate (3 x 1 1) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient CHC1 3 to CHCl 3 :ethyl acetate 2:1) to afford 16 (5.3 mg, 68 %). Rf: 0.48 (CH 3 CN:H 2 O 7:3, RP-C18) 1H NMR (300 MHz, CDC1 3 ): δ 6.73 (s, IH), 5.43 (bs, IH), 5.16 (s, 2H), 4.54 (bs, IH), 4.26 (d, J= 1.8 Hz, IH), 4.04 (d, J= 2.7 Hz IH), 3.84 (bs, IH), 3.80-3.64 (m, IH). 3.58 (s, 3H). 3.41-3.39 (m, IH), 3.22-3.06 (m, 5H), 2.49 (d, J= 18.6 Hz IH), 2.35 (s. 3H). 2.30-2.25 (m, IH), 2.24 (s, 3H), 1.87 (s, 3H), 1.45-1.33 (m, IH), 1.19 (s, 9H), 1.00 (br d. J= 6.6 Hz 3H) 13 C NMR (75 MHz, CDCl 3 ): δ 184.9, 180.9, 172.6, 154.7, 151.3, 149.1, 148.6. 144.7. 132.9. 131.3, 129.8, 124.5, 123.7, 117.3, 116.8, 99.1, 79.4, 59.8, 58.6, 57.7, 56.2, 55.6, 54.9. 54.5, 50.1, 41.6, 40.1, 28.0, 25.3, 24.4, 18.1, 15.7, 8.0. ESI-MS m/z: Calcd. for C 35 H 45 N 5 O 9 : 679.7. Found (M+H) + : 680.3. Example 4 16 17 To a degassed solution of compound 16 (1.8 g, 2.64 ml) in DMF (221 ml) 10 % Pd/C (360 mg) was added and stirred under H 2 (atmospheric pressure) for 45 min. The reaction was filtered through celite under argon, to a flask containing anhydrous Cs 2 CO 3 (2.58 g, 7.92 ml). Then, bromochloromethane (3.40 ml 52.8 ml), was added and the tube was sealed and stirred at 100 °C for 2h. The reaction was cooled, filtered through a pad of celite and washed with CH 2 C1 2 . The organic layer was concentrated and dried (sodium sulphate) to afford 17 as a brown oil that was used in the next step with no further purification. Rf: 0.36 (hexane-.ethyl acetate 1:5, SiO 2 ). 1H NMR (300 MHz, CDC1 3 ): δ 6.68 (s, IH), 6.05 (bs, IH), 5.90 (s, IH), 5.79 (s, IH), 5.40 (bs, IH), 5.31-5.24 (m, 2H), 4.67 (d, J= 8.1 Hz, IH), 4.19 (d, J= 2.7 Hz, IH), 4.07 (bs, IH), 4.01 (bs, IH), 3.70 (s, 3H), 3.67 (s, 3H), 3.64-2.96 (m, 5H), 2.65 (d, .7=18.3 Hz, IH), 2.33 (s, 3H), 2.21 (s, 3H), 2.04 (s, 3H), 2.01-1.95 (m, IH), 1.28 (s, 9H), 0.87 (d, J= 6.3 Hz, 3H) 13 C NMR (75 MHz, CDC1 3 ): δ 172.1, 162.6, 154.9, 149.1, 145.7, 135.9, 130.8, 130.7, 125.1, 123.1, 117.8, 100.8, 99.8, 76.6, 59.8, 59.2, 57.7, 57.0, 56.7, 55.8, 55.2, 49.5. 41.6. 40.1. 36.5. 31.9, 31.6, 29.7, 28.2, 26.3, 25.0, 22.6, 18.2, 15.8, 14.1, 8.8. ESI-MS m/z: Calcd. for C 36 H 47 N 5 O 9 : 693.34. Found (M+H) + : 694.3. Example 5 To a flask containing a solution of 17 (1.83 g, 2.65 ml) in DMF (13 ml). Cs 2 CO 3 (2.6 g, 7.97 ml), and allyl bromide (1.15 ml, 13.28 ml) were added at 0° C. The resulting mixture was stirred at 23 °C for lh. The reaction was filtered through a pad of celite and washed with CH C1 2 . The organic layer was dried and concentrated (sodium sulphate). The residue was purified by flash column chromatography (SiO , CHCl 3 :ethyl acetate 1 :4) to afford 18 (1.08 mg, 56 %) as a white solid. Rf: 0.36 (CHCl 3 :ethyl acetate 1 :3). 1H NMR (300 MHz, CDC1 3 ): δ 6.70 (s, IH), 6.27-6.02 (m, IH), 5.94 (s, IH), 5.83 (s, IH), 5.37 (dd, J / = 1.01 Hz, J 2 = 16.8 Hz, IH), 5.40 (bs, IH), 5.25 (dd, J,= 1.0 Hz, J 2 = 10.5 Hz, IH), 5.10 (s, 2H), 4.91 (bs, IH), 4.25-4.22 (m, IH), 4.21 (d, J= 2.4 Hz, IH), 4.14-4.10 (m, IH), 4.08 (d, J=2.4 Hz, IH), 4.00 (bs, IH), 3.70 (s, 3H), 3.59 (s, 3H), 3.56-3.35 (m, 2H), 3.26-3.20 (m, 2H), 3.05-2.96 (dd, J/= 8.1 Hz, J 2 =18 Hz, IH), 2.63 (d, J=18 Hz, IH), 2.30 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H), 1.91-1.80 (m, IH), 1.24 (s, 9H), 0.94 (d, J= 6.6 Hz, 3H) 13 C NMR (75 MHz, CDC1 3 ): δ 172.0, 154.8, 148.8, 148.6, 148.4, 144.4, 138.8, 133.7, 130.9, 130.3, 125.1, 124.0, 120.9, 117.8, 117.4, 112.8, 112.6, 101.1, 99.2, 73.9, 59.7, 59.3. 57.7. 56.9, 56.8, 56.2, 55.2, 40.1, 34.6, 31.5, 28.1, 26.4, 25.1, 22.6, 18.5, 15.7, 14.0, 9.2. ESI-MS m/z: Calcd. for C 39 H 5 ,N 5 O 9 : 733.4. Found (M+H) + : 734.4. Example 6 18 19 To a solution of 18 (0.1 g, 0.137 ml) in dioxane (2 ml), 4.2M HCI/dioxane (1.46 ml) was added and the mixture was stirred for 1.2h at 23 °C. The reaction was quenched at 0 °C with sat. Aqueous sodium bicarbonate (60 ml) and extracted with ethyl acetate (2x70 ml). The organic layers were dried (sodium sulphate) and concentrated in vacuo to afford 19 (267 mg, 95 %) as a white solid that was used in subsequent reactions with no further purification. Rf: 0.17 (ethyl acetate :methanol 10:1, SiO 2 ) 1H NMR (300 MHz, CDC1 3 ): δ 6.49 (s, IH), 6.12-6.00 (m, IH), 5.94 (s, IH), 5.86 (s, IH), 5.34 (dd, J= 1.0 Hz, J= 17.4 Hz, IH), 5.25 (dd, J= 1.0 Hz, J= 10.2 Hz, IH), 4.18-3.76 (m, 5H), 3.74 (s, 3H), 3.71-3.59 (m, IH), 3.36-3.20 (m, 4H), 3.01-2.90 (m, IH), 2.60 (d, J= 18.0 Hz, IH), 2.29 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 1.97-1.86 (m, IH), 0.93 (d, J= 8.7 Hz, 3H) 13 C NMR (75 MHz, CDC1 3 ): δ 175.5, 148.4, 146.7, 144.4, 142.4, 138.9, 133.7, 131.3, 128.3, 120.8, 117.9, 117.4, 113.8, 112.4, 101.1, 74.2, 60.5, 59.1, 56.5, 56.1, 56.3, 56.0, 55.0, 50.5, 41.6, 39.5, 29.5, 26.4, 24.9, 21.1, 15.5, 9.33. ESI-MS m/z: Calcd. for C 32 H 39 N 5 O 6 : 589. Found (M+H) + : 590. Example 7 19 20 To a solution of 19 (250 mg, 0.42 ml) in CH 2 C1 2 (1.5 ml), phenyl isothiocyanate (0.3 ml, 2.51 ml) was added and the mixture was stirred at 23° C for lh. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography (SiO , gradient Hexane to 5:1 hexane:ethyl acetate) to afford 20 (270 mg, 87 %) as a white solid. Rf: 0.56 (CHCl 3 :ethyl acetate 1 :4). Η NMR (300 MHz, CDC1 3 ): δ 8.00 (bs, IH), 7.45-6.97 (m, 4H), 6.10 (s, IH), 6.08-6.00 (m, IH), 5.92 (s, IH), 5.89 (s, IH), 5.82 (s, IH), 5.40 (dd, J= 1.5 Hz, J= 17.1 Hz, IH), 3.38 (bs, IH), 5.23 (dd, J= 1.5 Hz, J= 10.5 Hz, IH), 4.42-4.36 (m, IH), 4.19-4.03 (m, 5H), 3.71 (s, 3H), 3.68-3.17 (m, 4H), 2.90 (dd. J=7.8 Hz, J= 18.3 Hz, IH), 2.57 (d, J= 18.3 Hz, IH), 2.25 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 1.90 (dd, J= 12.3 Hz, J= 16.5 Hz. IH), 0.81 (d, J= 6.9 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ): δ 178.4, 171.6, 148.6, 146.8, 144.3, 142.7, 138.7, 136.2, 133.6, 130.7, 129.8, 126.6, 124.2, 124.1, 120.9, 120.5, 117.7, 1 17.4, 1 16.7, 112.6. 1 12.5. 101.0, 74.0, 60.6, 59.0, 57.0, 56.2, 56.1, 55.0, 53.3, 41.4, 39.7, 26.3, 24.8, 18.3, 15.5, 9.2. ESI-MS m/z: Calcd. for C 39 H4 4 N 6 O 6 S: 724.8 Found (M+H) + : 725.3. Example 8 20 21 To a solution of 20 (270 mg, 0.37 ml) in dioxane (1 ml), 4.2N HCI/dioxane (3.5 ml) was added and the reaction was stirred at 23 °C for 30 min. Then, ethyl acetate (20 ml) and H 2 O (20 ml) were added and the organic layer was decanted. The aqueous phase was basified with saturated aqueous sodium bicarbonate (60 ml) (pH = 8) at 0 °C and then, extracted with CH C1 2 (2 x 50 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo. The residue was purified by flash column chromatography (SiO , ethyl acetate:methanol 5:1) to afford compound 21 (158 mg, 82%) as a white solid. Rf: 0.3 (ethyl acetatermethanol 1 :1). Η NMR (300 MHz, CDC1 3 ): δ 6.45 (s, IH), 6.12-6.03 (m, IH), 5.91 (s, IH). 5.85 (s, IH), 5.38 (dd, 10.5 Hz, IH), 4.23-4.09 (m, 4H), 3.98 (d, J= 2.1 Hz, IH), 3.90 (bs, IH), 3.72 (s, 3H), 3.36-3.02 (m. 5H), 2.72-2.71 (m, 2H), 2.48 (d, J= 18.0 Hz, 1 H), 2.33 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.85 (dd, J,= 1 1.7 Hz, J 2 = 15.6 Hz, IH) ). 13 C NMR (75 MHz, CDC1 3 ): δ 148.4, 146.7, 144.4, 142.8, 138.8, 133.8, 130.5, 128.8, 121.5, 120.8, 118.0, 117.5, 116.9, 113.6, 112.2, 101.1, 74.3, 60.7, 59.9, 58.8, 56.6, 56.5, 55.3, 44.2, 41.8, 29.7, 26.5, 25.7, 15.7, 9.4. ESI-MS m z: Calcd. for C 29 H 34 N 4 O 5 : 518.3. Found (M+H) + : 519.2. Example 9 To a solution of 21 (0.64 g, 1.22 ml) in CH 2 C1 2 (6.13 ml), pyridine (0.104 ml, 1.28 ml) and 2,2,2-trichloroethyl chloroforrnate (0.177 ml, 1.28 ml) were added at -10 °C. The mixture was stirred at this temperature for lh and then, the reaction was quenched by addition of 0.1N HCl (10 ml) and extracted with CH 2 C1 2 (2 x 10 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , (hexane:ethyl acetate 1 :2) to afford 22 (0.84 g, 98%) as a white foam solid. Rf: 0.57 (ethyl acetate:methanol 5:1). Η NMR (300 MHz, CDC1 3 ): δ 6.50 (s, IH), 6.10-6.00 (m, IH), 6.94 (d, J= 1.5 Hz, IH), 5.87 (d, J= 1.5 Hz, IH), 5.73 (bs, IH), 5.37 (dq, J ; = 1.5 Hz, J 2 = 17.1 Hz, IH), 5.26 (dq, J / = 1.8 Hz, J 2 = 10.2 Hz, IH), 4.60 (d, J= 12 Hz, IH), 4.22-4.10 (m, 4H), 4.19 (d, J= 12 Hz, IH), 4.02 (m, 2H), 3.75 (s, 3H), 3.37-3.18 (m, 5H), 3.04 (dd, J,= 8.1 Hz, J 2 = 18 Hz, IH), 2.63 (d, J= 18 Hz, IH), 2.31 (s, 3H), 2.26 (s, 3H), 2.1 1 (s, 3H), 1.85 (dd, J,= 12.3 Hz, J 2 = 15.9 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 154.3, 148.5, 146.7, 144.5, 142.8, 139.0, 133.8, 130.7, 128.7, 121.3, 120.8, 117.8, 117.7, 116.8, 112.7, 101.2, 77.2, 74.3, 60.7, 59.9, 57.0, 56.4, 55.3, 43.3, 41.7, 31.6, 26.4, 25.3, 22.6, 15.9, 14.1, 9.4. ESI-MS m/z: Calcd. for C 32 H 35 Cl 3 N 4 O 7 : 694.17. Found (M+H) + : 695.2. Example 10 To a solution of 22 (0.32 g, 0.46 ml) in CH 3 CN (2.33 ml), diisopropylethylamine (1.62 ml, 9.34 ml), bromomethyl methyl ether (0.57 ml, 7.0 ml) and dimethylaminopyridine (6 mg, 0.046 ml) were added at 0 °C. The mixture was heated at 30 °C for 1 Oh. Then, the reaction was diluted with dichloromethane (30 ml) and poured in an aqueous solution of HCl at pH = 5 (10 ml). The organic layer was dried over sodium sulphate and the solvent was eliminated under reduced pressure to give a residue which was purified by flash column chromatography (SiO 2 , hexane:ethyl acetate 2:1) to afford 23 (0.304 g, 88%) as a white foam solid. Rf: 0.62 (hexane: ethyl acetate 1 :3). 1H NMR (300 MHz, CDC1 3 ): δ 6.73 (s, IH), 6.10 (m, IH), 5.94 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, lH), 5.39 (dq, J / = 1.5 Hz, J 2 = 17.1 Hz, IH), 5.26 (dq, J / = 1.8 Hz, J = 10.2 Hz, IH), 5.12 (s, 2H), 4.61 (d, J= 12 Hz, IH), 4.55 (t, J= 6.6 Hz, IH), 4.25 (d, J= 12 Hz, IH), 4.22-4.11 (m, 4H), 4.03 (m, 2H), 3.72 (s, 3H), 3.58 (s, 3H), 3.38-3.21 (m, 5H). 3.05 (dd, J,= 8.1 Hz, J 2 = 18 Hz, IH), 2.65 (d, J= 18 Hz, IH), 2.32 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H), 1.79 (dd, J ; = 12.3 Hz, J 2 = 15.9 Hz, IH); I3 C NMR (75 MHz, CDC1 3 ) δ 154.3, 148.6, 148.4, 144.5, 139.0, 133.6, 130.6, 130.1, 125.07, 124.7, 124.0, 121.1, 117.7, 112.6. 101.2, 99.2, 77.2, 74.4, 74.1 , 59.8, 59.8, 57.7, 57.0, 56.8, 56.68, 55.3, 43.2, 41.5, 26.4, 25.2, 15.9, 9.3. ESI-MS m z: Calcd. for C 34 H 39 Cl 3 N 4 O 8 : 738.20. Found (M+H) + : 739.0. Example 11 To a suspension of 23 (0.304 g, 0.41 ml) in 90% aqueous acetic acid (4 ml), powder zinc (0.2 g, 6.17 ml) was added and the reaction was stirred for 7 hour at 23 °C. The mixture was filtered through a pad of celite which was washed with CH 2 C1 2 . The organic layer was washed with an aqueous sat. solution of sodium bicarbonate (pH = 9) (15 ml) and dried over sodium sulphate. The solvent was eliminated under reduced pressure to give 24 (0.191 g, 83%) as a white solid. Rf: 0.3 (ethyl acetate:methanol 5:1). 1H NMR (300 MHz, CDC1 3 ): δ 6.68 (s, IH), 6.09 (m. IH), 5.90 (d, J= 1.5 Hz, IH), 5.83 (d, J= 1.5 Hz, IH), 5.39 (dq, 10.2 Hz, IH), 5.10 (s, 2H), 4.22-4.09 (m, 3H), 3.98 (d, J= 2.4 Hz, IH), 3.89 (m, IH), 3.69 (s, 3H), 3.57 (s, 3H), 3.37-3.17 (m, 3H), 3.07 (dd, J/= 8.1 Hz, J?= 18 Hz, IH), 2.71 (m, 2H), 2.48 (d, J= 18 Hz, IH), 2.33 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.80 (dd, J / = 12.3 Hz, J 2 = 15.9 Hz, IH) I3 C NMR (75 MHz, CDCl 3 ): δ 148.5, 148.2, 144.3, 138.7, 133.7, 130.7, 129.9, 125.0, 123.9, 121.3, 117.9, 117.5, 113.6, 112.0, 101.0, 99.2, 74.0, 59.8, 59.7, 58.8, 57.6, 57.0, 56.2, 55.2, 44.2, 41.5, 31.5, 26.4, 25.6, 22.5, 16.7, 14.0, 9.2. ESI-MS m/z: Calcd. for C 31 H 38 N 4 O 6 : 562.66. Found (M+H) + : 563.1. Example 12 To a solution of 24 (20 mg, 0.035 ml), in H 2 O (0.7 ml) and THF (0.7 ml). NaNO 2 (12 mg, 0.17 ml) and 90% aqueous. AcOH (0.06 ml) were added at 0 °C and the mixture was stirred at 0 °C for 3h. After dilution with CH 2 C1 (5 ml), the organic layer was washed with water (1 ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO , hexane:ethyl acetate 2:1) to afford 25 (9.8 mg, 50%) as a white solid. Rf: 0.34 (hexane:ethyl acetate 1 :1). Η NMR (300 MHz, CDC1 3 ): δ 6.71 (s, IH), 6.1 1 (m, IH), 5.92 (d, J= 1.5 Hz. lH), 5.87 (d, J= 1.5 Hz, IH), 5.42 (dq, J,= 1.5 Hz, J 2 = 17.1 Hz, IH), 5.28 (dq, J / = 1.5 Hz. J ? = 10.2 Hz, IH), 5.12 (s, 2H), 4.26-4.09 (m, 3H), 4.05 (d, J= 2.4 Hz, IH), 3.97 (t, J= 3.0 Hz. I H). 3.70 (s, 3H), 3.67-3.32 (m, 4H), 3.58 (s, 3H), 3.24 (dd, J / = 2.7 Hz, J 2 = 15.9 Hz. IH). 3.12 (dd, J/= 8.1 Hz, J 2 = 18.0 Hz, IH), 2.51 (d, J= 18 Hz, IH), 2.36 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.83 (dd, J;= 12.3 Hz, J 2 = 15.9 Hz, IH) 13 C NMR (75 MHz, CDC1 3 ) δ 148.7, 148.4, 138.9, 133.7, 131.1, 129.4, 125.1 , 123.9, 120.7, 117.6, 117.5, 113.2, 112.3, 101.1, 99.2, 74.0, 63.2, 59.8, 59.7, 57.9, 57.7, 57.0, 56.5, 55.2, 41.6, 29.6, 26.1, 25.6, 22.6, 15.7, 9.2. ESI-MS m/z: Calcd. for C 3 ,H 37 N 3 O 7 : 563.64. Found (M+H) + : 564.1. Example 13 2,2,2-Trichloroethyl chloroformate NaH, THF, reflux 29 The starting material (2.0 g, 5.90 ml) was added to a suspension of sodium hydride (354 mg, 8.86 ml) in THF (40 ml) at 23 °C, following the suspension was treated with allyl chloroformate (1.135 ml, 8.25 ml) at 23 °C and then refluxed for 3 hours. The suspension was cooled, filtered off, the solid washed with ethyl acetate (100 ml), and the filtrate was concentrated. The oil crude was ground with hexane (100 ml) and kept at 4°C overnight. After, the solvent was decanted and the light yellow slurry was treated with CH 2 C1 (20 ml), and precipitated with hexane (100 ml). After 10 minutes, the solvent was decanted again. The operation was repeated until appearing a white solid. The white solid was filtered off and dried to afford compound 29 (1.80 g, 65%) as a white solid. Η-NMR (300 MHz, CDC1 3 ): δ 7.74 (d, J= 7.5 Hz. 2H), 7.62 (d, J= 6.9 Hz, 2H). 7.33 (t, J= 7.5 Hz, 2H), 7.30 (t, J= 6.3 Hz, 2H), 5.71 (d, J= 7.8 Hz, IH), 4.73 (d, J= 7.8 Hz, 2H), 4.59 (m, IH), 4.11 (t, J= 6.0 Hz, IH), 3.17 (dd, J= 6.0 Hz, J= 2.7 Hz, 2H), 3.20 (dd. J= 5.4 Hz, J= 2.1 Hz, 2H). 13 C-NMR (75 MHz, CDCl 3 ): δ 173.6, 152.7, 144.0, 139.7, 137.8, 126.0, 125.6. 123.4, 1 18.3, 73.4, 52.4, 45.5, 35.8, 33.7. ESI-MS m/z: Calcd.. for C 20 Hι 8 Cl 3 NO 4 S: 474.8. Found (M+Na) + : 497.8 Example 14 EDC.HCI, CH 2 CI 2 , 23°C, 3h A mixture of compound 25 (585 mg, 1.03 ml) and compound 29 (1.47 mg, 3.11 ml) were azeotroped with anhydrous toluene (3 x 10 ml). To a solution of 25 and 29 in anhydrous CH 2 C1 2 (40 ml) was added DMAP (633 mg, 5.18 ml) and EDC-HCl (994 mg, 5.18 ml) at 23 °C. The reaction mixture was stirred at 23 °C for 3 hours. The mixture was partitioned with saturated aqueous solution of sodium bicarbonate (50 ml ) and the layers were separated. The aqueous layer was washed with CH C1 (50 ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography (ethyl acetate/hexane 1 :3) to obtain 30 (1.00 g. 95%) as a pale cream yellow solid. 1H-NMR (300 MHz, CDC1 3 ): δ 7.72 (m, 2H), 7.52 (m, 2H), 7.38 (m, 2H), 7.28 (m, 2H), 6.65 (s, IH), 6.03 (m, IH), 5.92 (d, J= 1.5 Hz, IH), 5.79 (d, J= 1.5 Hz, IH), 5.39 (m, IH), 5.29 (dq, J= 10.3 Hz, J= 1.5 Hz, IH), 5.10 (s, 2H), 4.73 (d, J= 11.9 Hz, IH), 4.66 (d, J= 11.9 Hz, IH), 4.53 (m, IH), 4.36-3.96 (m, 9H), 3.89 (t, J= 6.4 Hz, IH), 3.71 (s, 3H), 3.55 (s, 3H), 3.33 (m, IH), 3.20 (m, 2H), 2.94 (m, 3H), 2.59 (m, IH), 2.29 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H), 1.83 (dd, J= 16.0 Hz, J= 1 1.9 Hz, IH). 13 C-NMR (75 MHz, CDC1 3 ): δ 169.7. 154.0, 148.8, 148.4, 145.7, 144.5, 140.9. 139.0, 133.7, 130.9, 130.6, 127.6, 127.0, 124.8, 124.6, 124.1, 120.8, 119.9, 118.2, 117.7. 117.3. 112.7, 112.1, 101.3, 99.2, 74.7, 73.9, 64.4, 59.8, 57.7, 57.0, 56.8, 55.4, 53.3, 46.7, 41.4, 36.5, 34.7, 31.5, 26.4, 24.9, 22.6, 15.7, 14.0, 9.1. ESI-MS m/z: Calcd.. for C 5 ,H 53 C1 3 N 4 O, 0 S: 1020.4. Found (M+H) + : 1021.2 Example 15 30 31 To a solution of 30 (845 mg, 0.82 ml), acetic acid (500 mg, 8.28 ml) and (PPh 3 ) 2 PdCl 2 (29 mg, 0.04 ml) in anhydrous CH 2 C1 2 20 ml at 23 °C was added, dropwise, Bu 3 SnH (650 mg, 2.23 ml). The reaction mixture was stirred at this temperature for 15 min., bubbling was. The crude was quenched with water (50ml) and extracted with CH C1 2 (3 x 50 ml). The organic layers were dried over sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography (ethyl acetate hexane in gradient from 1 :5 to 1 :3) to obtain compound 31 (730 mg, 90%) as a pale cream yellow solid. Η-NMR (300 MHz, CDC1 3 ): δ 7.72 (m, 2H), 7.56 (m, 2H), 7.37 (m, 2H), 7.30 (m. 2H), 6.65 (s, IH), 5.89 (s, IH), 5.77 (s, IH), 5.74 (s, IH), 5.36 (d, J= 5.9 Hz, IH), 5.32 (d, J= 5.9 Hz, IH), 5.20 (d, J= 9.0, IH), 4.75 (d, J= 12.0 Hz, IH), 4.73 (m, IH), 4.48 (d. J= 11.9 Hz. IH), 4.08 (m, 4H), 3.89 (m, IH), 3.86, (t, J= 6.2 Hz, IH), 3.70 (s, 3H), 3.69 (s. 3H). 3.38 (m, IH), 3.25 (m, IH), 3.02-2.89 (m, 4H), 2.67 (s, IH), 2.61 (s, IH ), 2.51 (dd, J= 14.3 Hz, J= 4.5 Hz, IH), 2.29 (s, 3H), 2.23 (s, 3H), 1.95 (s, 3H), 1.83 (m, IH). 13 C-NMR (75 MHz, CDC1 3 ): δ 168.2, 152.5, 148.1, 146.2, 144.4, 144.3, 143.3. 139.6, 134.6, 129.7, 129.6, 126.2, 125.6, 123.4, 123.3, 121.6, 118.5, 116.3, 110.7, 110.2, 105.1 , 99.4, 98.5, 75.2, 73.3, 61.7, 58.4, 57.9, 56.3, 56.1, 55.1, 54.7, 53.9, 51.9, 45.2, 40.1, 35.6, 33.3, 24.8, 23.3., 14.5, 7.3. ESI-MS m/z: Calcd.. for C 48 H4 9 CI 3 N 4 O10S: 980.3. Found (M+H) + : 981.2 Example 16 31 32 To a solution of 31 (310 mg, 0.32 ml), in anhydrous CH 2 C1 2 (15 ml) at -10 °C was added a solution of benzeneseleninic anhydride 70 % (165 mg, 0.32 ml), in anhydrous CH 2 C1 2 (7 ml), via cannula, keeping the temperature at -10 °C. The reaction mixture was stirred at -10 °C for 5 min. A saturated solution of sodium bicarbonate (30 ml) was added at this temperature. The aqueous layer was washed with more CH 2 C1 2 (40 ml). The organic layers were dried over sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography (ethyl acetate/hexane in gradient from 1 :5 to 1 : 1 ) to obtain 32 (287 mg, 91%, HPLC: 91.3%) as a pale cream yellow solid and as a mixture of two isomers (65:35) which were used in the next step. Η-NMR (300 MHz, CDC1 3 ): δ (Mixture of isomers) 7.76 (m, 4H), 7.65 (m, 4H). 7.39 (m, 4H), 7.29 (m, 4H), 6.62 (s, IH), 6.55 (s, IH), 5.79-5.63 (m, 6H), 5.09 (s, IH). 5.02 (d, J= 6.0 Hz, IH), 4.99 (d, J= 6.0 Hz, IH), 4.80-4.63 (m, 6H), 4.60 (m, IH), 4.50 (m, IH). 4.38 (d, J= 12.8 Hz, J= 7.5 Hz, IH), 4.27 (dd, J= 12.8 Hz, J= 7.5 Hz, IH), 4.16-3.90 (m, 10H), 3.84 (s, 3H), 3.62 (s, 3H), 3.50 (s, 3H), 3.49 (s, 3H), 3.33-2.83 (m, 14H), 2.45-2.18 (m, 2H). 2.21 (s. 6H), 2.17 (s, 6H ), 1.77 (s, 6H), 1.67 (m. 2H). 13 C-NMR (75 MHz, CDC1 3 ): δ (Mixture of isomers) 168.6, 168.4, 158.6. 154.8, 152.8, 152.5, 147.3, 147.2, 146.8, 144.1, 144.0, 140.8, 139.7, 137.1, 129.8, 129.3, 128.4, 128.7, 126.5, 125.5, 123.7, 123.6, 123.5, 123.4, 122.2, 121.3, 118.3, 115.8, 115.5, 110.2, 106.9, 103.5, 103.2, 100.1, 99.6, 97.9, 97.7, 93.8, 73.4, 70.9, 69.2, 64.9, 62.5, 59.3, 58.9, 58.4, 56.7, 56.3, 56.2, 55.4, 55.2, 55.1, 54.9, 54.7, 54.3, 54.1, 53.8, 52.8, 45.5, 40.5, 40.0, 39.8, 35.8, 35.5, 33.9, 33.7, 30.1, 28.8, 24.2, 24.1, 21.2, 14.5, 14.4, 12.7, 6.0, 5.7. ESI-MS m z: Calcd.. for C 48 H 49 Cl 3 N O, ,S: 996.3. Found (M+H) + : 997.2 Example 17 32 33 The reaction flask was flamed twice, purged vacuum/ Argon several times and kept under Argon atmosphere for the reaction. To a solution of DMSO (39.1 ml, 0.55 ml. 5 equivalents.) in anhydrous CH C1 2 (4.5 ml) was dropwise added triflic anhydride (37.3 ml, 0.22 ml, 2 equivalents.) at -78 °C . The reaction mixture was stirred at -78 °C for 20 minutes, then a solution of 32 (1 10 mg, 0.1 1 ml, HPLC: 91.3%) in anhydrous CH 2 C1 2 (1 ml, for the main addition and 0.5 ml for wash) at -78 °C was added, via cannula. During the addition the temperature was kept at -78 °C in both flasks and the colour changed from yellow to brown. The reaction mixture was stirred at -40 °C for 35 minutes. During this period of time the solution was turned from yellow to dark green. After this time, 'Pr 2 NEt (153 ml, 0.88 ml, 8 equivalents.) was dropwise added and the reaction mixture was kept at 0 °C for 45 minutes, the colour ofthe solution turned to brown during this time. Then t- butanol (41.6 ml, 0.44 ml, 4 equivalents.) and 2- l Butyl-l,l,3,3-tetramethylguanidine (132.8 ml, 0.77 ml, 7 equivalents.) were dropwise added and the reaction mixture was stirred at 23 °C for 40 minutes. After this time, acetic anhydride (104.3 ml, 1.10 ml, 10 equivalents.) was dropwise added and the reaction mixture was kept at 23 °C for 1 hour more. Then the reaction mixture was diluted with CH 2 C1 2 (20ml) and washed with aqueous saturated solution of NHL 4 CI (50ml), sodium bicarbonate (50ml), and sodium chloride (50ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane gradient from 1 :3 to 1 :2) to afford compound 33 (54 mg, 58%) as a pale yellow solid. Η-NMR (300 MHz, CDC1 3 ): δ 6.85 (s, IH), 6.09 (s, IH), 5.99 (s, IH), 5.20 (d, J= 5.8 Hz. IH), 5.14 (d, J= 5.3 Hz, IH), 5.03 (m, IH), 4.82 (d, J= 12.2, IH), 4.63 (d, J= 12.0 Hz, IH), 4.52 (m, IH), 4.35-4.17 (m, 4H), 3.76 (s, 3H), 3.56 (s, 3H), 3.45 (m, 2H). 2.91 (m. 2H). 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.12 (m, 2H), 2.03 (s, 3H). 13 C-NMR (75 MHz, CDC1 3 ): δ 168.5, 167.2, 152.7. 148.1, 147.1, 144.5, 139.6. 139.1. 130.5. 129.0, 123.7, 123.5, 123.3, 118.8, 116.5, 112.1, 100.6, 97.8, 73.3, 60.5, 59.4. 59.2. 58.3. 57.6, 57.4, 56.1, 53.3, 53.1, 40.6, 40.0, 31.0, 22.2, 18.9, 14.4, 8.1. ESI-MS m/z: Calcd.. for C 36 H 39 Cl 3 N 4 OnS: 842.1. Found (M+H) + : 843.1 Example 18 33 34 To a solution of 33 (12 mg, 0.014 ml)in dry dichloromethane (1.2 ml) and HPLC grade acetonitrile (1.2 ml) was added at 23 °C sodium iodide (21 mg, 0.14 ml) and freshly distilled (over calcium hydride at atmospheric pressure) trimethylsilyl chloride (15.4 mg, 0.14 ml). The reaction mixture turned to orange colour. After 15 min the solution was diluted with dichloromethane (10 ml) and was washed with a freshly aqueous saturated solution of Na 2 S 2 O (3 x 10 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. It was obtained compound 34 (13 mg, quantitative) as pale yellow solid which was used without further purification. Η-NMR (300 MHz, CDC1 3 ): δ 6.85 (s, IH), 6.09 (s, IH), 5.99 (s, IH), 5.27 (d, J= 5.8 Hz, IH), 5.14 (d, J= 5.3 Hz, IH), 5.03 (d, J= 11.9 Hz, IH), 4.82 (d, J= 12.2, IH), 4.63 (d, J= 13.0 Hz, IH), 4.52 (m, IH), 4.34 (m, IH), 4.27 (bs, IH), 4.18 (m, 2H), 3.76 (s, 3H), 3.56 (s, 3H), 3.44 (m, IH), 3.42 (m, IH), 2.91 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.03 (s, 3H). ESI-MS m/z: Calcd.. for C 34 H 35 N 4 Oι 0 S: 798.1. Found (M+H) + : 799.1 Example 19 34 35 To a solution of 34 (13 mg, 0.016 ml) in a mixture of acetic acid/H 2 O (90:10, 1 ml) was added powder Zinc (5.3 mg, 0.081 ml) at 23 °C. The reaction mixture was heated at 70 °C for 6 h. After this time, was cooled to 23 °C, diluted with CH 2 C1 2 (20 ml) and washed with aqueous saturated solution of sodium bicarbonate (15 ml) and aqueous solution of Et 3 N (15 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography with Silica-NH 2 (eluent: ethyl acetate/hexane gradient from 0:100 to 50:50) to afford compound 35 (6.8 mg, 77% for two steps) as a pale yellow solid. Η-NMR (300 MHz, CDC1 3 ): δ 6.51 (s, IH), 6.03 (dd, J= 1.3 Hz, J= 26.5 Hz, 2H), 5.75 (bs, IH), 5.02 (d, J= 11.6 Hz, IH), 4.52 (m, IH), 4.25 (m, 2H), 4.18 (d, J= 2.5 Hz, IH), 4.12 (dd, J= 1.9 Hz, J= 11.5 Hz, IH), 3.77 (s, 3H), 3.40 (m, 2H), 3.26 (t, J= 6.4 Hz, IH), 2. 88 (m, 2H), 2.30-2.10 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 2.02 (s, 3H). 13 C-NMR (75 MHz, CDC1 3 ): δ 174.1, 168.4, 147.8, 145.4, 142.9, 140.8, 140.1, 131.7, 130.2, 129.1, 128.3, 120.4, 118.3, 117.9, 113.8, 111.7, 101.7, 61.2, 59.8, 59.2, 58.9, 54.4, 53.8, 54.4, 41.3, 41.5, 34.1, 23.6, 20.3, 15.5, 9.4. ESI-MS m/z: Calcd.. for C 3 ,H 34 N 4 O 8 S: 622.7. Found (M+H) + : 623.2. Example 20 35 36 A solution of N-methyl pyridine-4-carboxaldehyde iodide (378 mg, 1.5 mmol) in anhydrous DMF (5.8 mL) was treated with anhydrous toluene (2 x 10 mL) to eliminate the amount of water by azeotropic removal ofthe toluene. A solution of 35 (134 mg, 0.21 mmol), previously treated with anhydrous toluene (2 x 10 mL), in anhydrous CH C1 (distilled over CaH 2ι 7.2 mL) was added, via cannula, at 23 °C to this orange solution. The reaction mixture was stirred at 23 °C for 4 hours. After this time DBU (32.2 μL, 0.21 mmol) was dropwise added at 23 °C and it was stirred for 15 minutes at 23 °C. A freshly aqueous saturated solution of oxalic acid (5.8 mL) was added to the reaction mixture and was stirred for 30 minutes at 23 °C. Then the reaction mixture was cooled to 0 °C and ΝaHCO 3 was portionwise added followed by addittion of aqueous saturated solution of NaHCO 3 . The mixture was extracted with Et 2 O. K CO 3 was added to the aqueous layer and it was extrated with Et 2 O. The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The crude was purified by flash column chromatography (AcOEt/hexane from 1/3 to 1/1) to afford compound 36 (77 mg, 57%) as pale yellow solid. 1H-NMR (300 MHz, CDC1 3 ): δ 6.48 (s, IH), 6.11 (d, J= 1.3 Hz, IH), 6.02 (d, J= 1.3 Hz, IH), 5.70 (bs, IH), 5.09 (d, J= 11.3 Hz, IH), 4.66 (bs, IH), 4.39 (m, IH), 4.27 (d, J= 5.6 Hz, IH), 4.21 (d, J= 10.5 Hz, IH), 4.16 (d, J= 2.6 Hz, IH), 3.76 (s, 3H), 3.54 (d, J= 5.1 Hz, IH), 3.42 (d, J= 8.5 Hz, IH), 2.88-2.54 (m, 3H), 2.32 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H). 13 C-NMR (75 MHz, CDC1 3 ): δ 186.7, 168.5, 160.5, 147.1, 146.4, 142.9, 141.6, 140.7, 130.4, 129.8, 121.7 (2C), 120.0, 117.8, 117.1, 113.5, 102.2, 61.7, 61.4, 60.3, 59.8, 58.9, 54.6, 41.6, 36.9, 29.7, 24.1, 20.3, 15.8, 14.1, 9.6. ESI-MS m z: Calcd.. for C 3 ιH 3 ιN 3 O 9 S: 621.7. Found (M+H) + : 622.2. Example 21 36 Et-770 To a solution of 36 (49mg, 0.08 ml) and 2-[3-hydroxy-4-methoxyphenyl]ethylamine (46.2 mg, 0.27 ml) in ethanol (2.5 ml) was added silica gel (105 mg) at 23 °C. The reaction mixture was stirred at 23 °C for 14 h. It was diluted with hexane and poured into a column of chromatography (ethyl acetate hexane from 1/3 to 1/1) to afford Et-770 (55 mg. 90%) as a pale yellow solid. 1H-NMR (300 MHz, CDC1 3 ): δ 6.60 (s, IH), 6.47 (s, IH), 6.45 (s, IH), 6.05 (s, IH), 5.98 (s, IH), 5.02 (d, J=11.4 Hz, IH), 4.57 (bs, IH), 4.32 (bs, IH), 4.28 (d, J= 5.3 Hz, IH), 4.18 (d, J= 2.5 Hz, IH), 4.12 (dd, J= 2.1 Hz, J= 11.5 Hz, IH), 3.78 (s, 3H), 3.62 (s, 3H), 3.50 (d, J= 5.0 Hz, lH), 3.42 (m, IH), 3.10 (ddd, J= 4.0 Hz, J= 10.0 Hz, J= 11.0 Hz, IH), 2.94 (m, 2H), 2.79 (m, IH), 2.61 (m, IH), 2.47 (m, IH), 2.35 (m, IH), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 2.09 (m, IH), 2.04 (s, 3H). ESI-MS m/z: Calcd.. for C 40 H 42 N 4 O K ,S: 770.7. Found (M+H) + : 771.2 Example 22 To a solution of 21 (22 mg, 0.042 ml) in CH 2 C1 2 (0.8 ml) was added phthalic anhydride (6.44 mg, 0.042 ml) and the reaction mixture was stirred for 2h at 23 °C. Then, carbonyldiimidazole (lmg, 0.006 ml) was added and the mixture was stirred at 23 °C for 7h. Then, carbonyldiimidazole (5.86mg, 0.035 ml) was added and the reaction was stirred at 23 °C for an additional 17h. The solution was diluted with CH 2 C1 2 (15 ml) and washed with 0.1 N HCl (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , hexane:ethyl acetate 2:1) to afford 27 (26.4 mg, 96%) as a white solid. Rf: 0.58 (ethyl acetate). 'H NMR (300 MHz, CDC1 3 ): 7.73-7.64 (m, 4H), 6.40 (s, IH), 6.12-6.01 (m, IH), 5.63 (s, IH), 5.58 (d, J= 1.5 Hz, IH), 5.37 (dd, J,= 1.8 Hz, J 2 = 17.4 Hz), 5.23 (dd, J,= 1 -8 Hz, J 2 = 10.5 Hz, IH), 5.12 (d, J= 1.5 Hz, IH), 4.22-4.15 (m, 3H), 4.08 (d, J= 1.8 Hz, IH), 3.68 (s, 3H), 3.59-3.55 (m 2H), 3.35 (d, J= 8.1 Hz, IH), 3.27-3.16 (m, 2H), 3.05 (dd, J,= 8.1 Hz, J 2 = 18.3 Hz, IH), 2.64 (d, J= 18.0Hz, IH), 2.30 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H), 1.80 (dd, J 7 = 11.4 Hz, J 2 = 15 Hz, IH); 13 C NMR (75 MHz, CDCl 3 ): δ 167.7, 148.9, 146.4, 144.2, 142.6, 139.5, 134.0, 133.5, 132.0, 131.0, 128.3, 123.0, 121.3, 120.9, 118.1, 117.5, 116.8, 113.6, 112.4, 100.8, 74.5, 60.6, 60.5, 57.7, 56.6, 55.6, 55.5, 42.3, 41.7, 26.6, 25.5, 15.9, 9.46. ESI-MS m/z: Calcd. for C 37 H 35 N 4 O 7 : 648.79. Found (M+H) + : 649.3. Example 23 To a solution of 27 (26 mg, 0.041 ml) in CH 2 C1 2 (11 ml), acetic acid (1 1 ml), (PPh 3 ) 2 PdCl 2 (2.36 mg) and Bu 3 SnH (28 ml, 0.10 ml) were added at 23 °C. After stirring at that temperature for 2h the reaction was poured into a pad of flash column (SiO , gradient Hex to hexane:ethyl acetate 2:1) to afford 28 (24.7 mg, 99 %) as a white solid. Rf: 0.33 (hexane: ethyl acetate 2: 1). Η NMR (300 MHz, CDC1 3 ): δ 7.75-7.70 (m, 2H), 7.69-7.65 (m, 2H), 6.39 (s. IH), 5.82 (bs, IH), 5.50 (d, J= 1.5 Hz, IH), 5.0 (d, J= 1.5 Hz, IH), 4.45 (bs, IH), 4.23-4.19 (m, 2H), 4.10- 4.09 (m, IH), 3.73 (s, 3H), 3.60-3.48 (m, 2H), 3.36-3.33 (m, IH), 3.26-3.20 (m, I H), 3.14- 3.08 (m, IH), 3.98 (d, J= 14.4 Hz, IH), 2.61 (d, J= 18.3 Hz, IH), 2.30 (s, 3H). 2.23 (s, 3H), 2.06 (s, 3H), 1.85 (dd, J/= 12 Hz, J 2 = 15.3 Hz); 13 C NMR (75 MHz, CDC1 3 ): δ 167.8. 146.4, 145.1, 143.9, 142.7, 137.1, 133.5, 131.9, 130.8, 128.4, 122.9, 120.8, 118.0, 116.8, 114.0, 1 13.4, 106.4, 100.4, 60.6, 60.5, 57.8, 56.6, 55.5, 55.2, 42.6, 41.5, 25.6, 25.5, 15.8, 8.9. ESI-MS m/z: Calcd. for C 34 H 32 N 4 O 7 : 608.6. Found (M+H) + : 609.2. Example 24 To a solution of 28 (357 mg, 0.058 ml) in CH 2 C1 2 (3 ml), acetyl chloride (41.58 ml, 0.58 ml) and pyridine (47.3 ml, 0.58 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (15 ml) and washed with 0.1 N HCl (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN:H 2 O 60:40) to afford phthalascidin (354 mg, 94%) as a white solid. Rf: 0.37 (CH 3 CN:H 2 O 7:3, RP-18). 1H NMR (300 MHz, CDC1 3 ): δ 7.72-7.68 (m, 2H), 7.67-7.63 (m, 2H), 6.38 (s, IH), 5.69 (d, J= 1.2 Hz, IH), 5.64 (d, J= 1.2Hz, IH), 5.30 (bs, IH), 4.25-4.21 (m, 2H), 4.02 (d, J= 2.1 Hz, IH), 3.64-3.62 (m, 5H), 3.33 (d, J= 8.4 Hz, IH), 3.21-3.16 (m, IH), 3.02 (dd, J / = 8.1 Hz, J 2 = 18 Hz, IH), 2.76 (dd, 17.7 Hz, IH), 2.29 (s, 3H), 2.28 (s,3H), 2.21 (s, 3H), 2.0 (s, 3H), 1.73 (dd, J/= 12.0 Hz, J 2 = 15.3 Hz, IH) ) 13 C NMR (75 MHz, CDCl 3 ) ): δ 168.5, 167.6, 146.2, 144.2, 142.5, 141.0, 140.5, 133.4, 131.8, 130.7, 128.2, 120.9, 120.8, 1 17.9, 116.4, 113.6, 101.1, 60.4, 60.0, 57.0, 56.3, 55.6, 55.4, 41.6, 41.5, 26.5, 25.2, 20.2, 15.7, 9.4. ESI-MS m/z: Calcd. for C 36 H 34 N 4 O 8 : 650. Found (M+H) + : 651.2. Example 25 17 42 To a solution of 17 (300 mg, 0.432 ml) in CH 2 C1 2 (2 ml), acetyl chloride (30.7 ml, 0.432 ml) and pyridine (34.9 ml, 0.432 ml) were added at 0 °C. The reaction mixture was stirred for 2h at that temperature and then, the solution was diluted with CH 2 C1 2 (15 ml) and washed with 0.1 N HCl (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 42 (318 mg. 100%) as a white solid that was used in subsequent reactions with no further purification. Rf: 0.5 (ethyl acetate:methanol 5:1). Η NMR (300 MHz, CDC1 3 ). δ 6.66 (s, IH), 5.93 (d, J= 1.2 Hz, IH), 5.83 (d, J= 1.2 Hz, IH), 5.42 (t, J= 6.6 Hz, IH), 5.07 (d, J= 5.7 Hz, IH), 4.98 (d, J= 5.7 Hz, IH). 4.16 (d, J= 1.8 Hz, IH), 4.11 (d, J= 2.7 Hz, IH), 3.98 (bs, IH), 3.73-3.61 (m, 2H), 3.64 (s, 3H), 3.52-3.48 (m, IH), 3.50 (s, 3H), 3.33 (d, J= 9.6 Hz, IH), 3.17-3.14 (m, IH), 2.97-2.87 (m, IH), 2.75- 2.70 (d, J= 16.8 Hz, IH), 2.26 (s, 6H), 2.16 (s, 3H), 1.96 (s, 3H), 1.70 (dd, J,= 1 1.7 Hz, Jf= 15.6 Hz, IH), 1.33 (s, 9H), 0.59 (d, J= 6.0 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) ): δ 172.0, 168.3, 162.3, 148.2, 144.4, 140.4, 140.2, 130.9, 130.5, 125.3, 123.4, 120.8, 117.6, 1 12.7, 1 11.7, 101.4, 99.1, 79.2, 59.5, 58.8, 57.5, 57.4, 56.4, 55.5, 55.0, 41.3, 39.0, 28.2, 26.4, 24.6, 19.9, 18.4, 15.4, 9.1. ESI-MS m/z: Calcd. for C SS H^N S O K ,: 735.82. Found (M+H) + : 736.3. Example 26 To a solution of 42 (318 mg, 0.432 ml) in CH 2 C1 2 (2.16 ml), trifluoroacetic acid (1.33 ml, 17.30 ml) was added and the reaction mixture was stirred for 3.5h at 23 °C. The reaction was quenched at 0 °C with saturated aqueous sodium bicarbonate (60 ml) and extracted with CH 2 C1 2 (2 x 70 ml). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , ethyl acetate:methanol 20:1) to afford 43 (154 mg, 60%) as a white solid. Rf: 0.22 (ethyl acetate:methanol 5:1). Η NMR (300 MHz, CDC1 3 ). δ 6.47 (s, IH), 6.22 (bs, IH), 5.95 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 4.08-4.06 (m, 2H), 4.01 (bs, IH), 3.69 (s, 3H), 3.49 (d, J= 3.6 Hz, IH), 3.33 (d, J= 8.1 Hz, IH), 3.26-3.22 (m, IH), 2.95 (dd, 18 Hz, IH), 2.80-2.76 (m, 2H), 2.58 (d, J=18Hz, IH), 2.29 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.96 (s, 3H), 1.77 (dd, J/= 12.3 Hz, Jr= 15.6 Hz, IH), 0.90 (d, J=6.9 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) ): δ 174.8, 169.0, 146.8, 144.4, 142.8, 140.5, 140.2, 131.1, 128.8, 120.8, 120.5, 117.1, 112.9, 111.6, 101.5, 60.3, 59.0, 56.5, 56.3, 55.6, 55.1, 50.2, 41.6, 39.5, 26.8, 26.3, 24.9, 20.2, 15.4, 9.2. ESI-MS m/z: Calcd. for C 31 H 37 N 5 O 7 : 591.65. Found (M+H) + : 592.3. Example 27 43 44 To a solution of 43 (154 mg, 0.26 ml) in CH 2 C1 2 (1.3 ml), phenyl isothiocyanate (186 ml, 1.56 ml) was added and the mixture was stirred at 23° C for 2h. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography (SiO 2 . gradient Hexane to hexane:ethyl acetate 1 :1) to afford 44 (120 mg, 63 %) as a white solid. Rf: 0.41 (ethyl acetate:methanol 5:1). 1H NMR (300 MHz, CDC1 3 ). δ 8.17 (s, IH), 7.49-7.44 (m, 3H), 7.31-7.24 (m, 3H), 7.05 (d, J= 6.9 Hz, IH), 5.98 (d, J= 1.2 Hz, IH), 5.87 (d, J= 1.2 Hz, IH), 5.52 (bs, I H). 4.54 (t, J= 6.6 Hz, IH), 4.15 (d, J= 2.1 Hz, IH), 4.03 (d, J= 2.7 Hz, 2H), 3.80 (bs, IH), 3.66 (s, 3H), 3.40 (bs, IH), 3.32 (d, J= 7.8 Hz, IH), 3.16 (d, J= 11.7 Hz, IH), 2.82-2.61 (m, 3H), 2.29 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.80 (dd, J ; = 12.0 Hz, J 2 = 15.9 Hz, IH), 0.62 (d, J= 6.0 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 178.5, 171.9, 168.7, 146.7, 144.5, 142.6, 140.6, 140.3, 136.3, 131.0, 129.9, 128.9, 126.7, 124.4, 120.9, 120.6, 1 17.7, 116.6, 1 12.7, 11 1.9, 101.4, 60.4, 58.7, 57.5, 56.1, 55.7, 55.1, 53.3, 41.4, 38.8, 26.3, 24.4, 20.2, 18.1, 15.3, 9.2. ESI-MS m z: Calcd. for C 38 H 42 N 6 O 7 S: 726.3. Found (M+H) + : 727.3. Example 28 To a solution of 44 (120 mg, 0.165 ml) in dioxane (0.9 ml), 5.3N HCI/dioxane (1.8 ml) was added and the reaction was stirred at 23 °C for 2.5h. Then, CH 2 C1 2 (10 ml) and H 2 O (5 ml) were added to this reaction and the organic layer was decanted. The aqueous phase was basified with saturated aq sodium bicarbonate (20 ml) (pH = 8) at 0 °C and then, extracted with CH 2 C1 2 (2x15 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo to afford 45 (75 mg, 87%) as a white solid that was used in subsequent reactions with no further purification. Rf: 0.23 (ethyl acetatemethanol 5:1). Η NMR (300 MHz, CDC1 3 ): δ 6.43 (s, IH), 5.94 (d, J= 1.2 Hz, IH), 5.87 (d, J= 1.2Hz, IH), 4.10 (d, J= 2.1 Hz, IH), 3.98 (d, J= 2.4 Hz, IH). 3.91 (bs, IH), 3.69 (s, 3H), 3.34-3.25 (m, 2H), 3.05 (dd, J;= 1.8 Hz, J 2 = 8.1 Hz, IH), 2.80-2.73 (m, 3H), 2.46 (d, J= 18 Hz, IH), 2.30 (s, 3H), 2.28 (s,3H), 2.20 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J / = 12.6 Hz, J 2 = 16.2 Hz, IH); 13 C NMR (75 MHz, CDCl 3 ) ): δ 168.7, 146.7, 144.4. 142.9, 140.4, 130.4, 128.9, 121.1, 120.8, 117.8, 116.8, 113.6, 111.5, 101.4, 67.6, 60.5, 59.8, 58.4, 56.6, 55.8, 55.3, 43.6, 41.8, 31.3, 25.6, 20.2, 15.6, 9.2. ESI-MS m/z: Calcd. for C 28 H 32 N O 6 : 520.58. Found (M+H) + : 521.3. Example 29 To a solution of 45 (10 mg, 0.02 ml) in CH 2 C1 2 (0.4 ml) was added phthalic anhydride (2.84 mg, 0.02 ml) and the reaction mixture was stirred for 2 h at 23 °C. Then, carbonyldiimidazole (0.5 mg, 0.003 ml) was added and the mixture was stirred at 23 °C for 7h. Then, carbonyldiimidazole (2.61 mg, 0.016 ml) was added and the reaction was stirred at 23 °C for an additional 17h. The solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN:H 2 O 60:40) to afford phthalascidin (1 1.7 mg, 93%) as a white solid. Rf: 0.37 (CH 3 CN:H 2 O 7:3, RP-18). Η NMR (300 MHz, CDC1 3 ): δ 7.72-7.68 (m, 2 h), 7.67-7.63 (m, 2 h), 6.38 (s, 1 H), 5.69 (d, J= 1.2 Hz, IH), 5.64 (d, J= 1.2 Hz, IH), 5.30 (bs, IH), 4.25-4.21 (m, 2 h), 4.02 (d, J= 2.1 Hz, IH), 3.64-3.62 (m, 5H), 3.33 (d, J= 8.4 Hz, IH), 3.21-3.16 (m, IH), 3.02 (dd, J/= 8.1 Hz, J 2 = 18 Hz, IH), 2.76 (dd, J / = 1.8 Hz, J 2 = 15.6 Hz, IH), 2.63 (d, J= 17.7 Hz, IH), 2.29 (s, 3H), 2.28 (s,3H), 2.21 (s, 3H), 2.0 (s, 3H), 1.73 (dd, J,= 12.0 Hz, J = 15.3 Hz, IH) ); 13 C NMR (75 MHz, CDC1 3 ) ): δ 168.5, 167.6, 146.2, 144.2, 142.5, 141.0, 140.5, 133.4, 131.8, 130.7, 128.2, 120.9, 120.8, 117.9, 116.4, 113.6, 101.1, 60.4, 60.0, 57.0, 56.3, 55.6, 55.4, 41.6, 41.5, 26.5, 25.2, 20.2, 15.7, 9.4. ESI-MS m z: Calcd. for C 36 H 34 N O 8 : 650. Found (M+H) + : 651.2. Example 30 25 26 To a solution of 25 (18 mg, 0.032 ml) in DMF (0.05 ml), cat. DMAP (0.5 mg. 0.004 ml), imidazole (5 mg, 0.08 ml) and tert-Butyldiphenylsilyl chloride (12.5 ml, 0.048 ml) were added at 0 °C and the reaction mixture was stirred for 6h at 23 °C. Water (10 ml) was added at 0 °C and the aqueous phase was extracted with hexane:ethyl acetate 1 : 10 (2 x 10 ml). The organic layer was dried (sodium sulphate), filtered, and the solvent was removed under reduced pressure. The crude was purified by flash column chromatography (SiO 2 . hexane:ethyl acetate 3:1) to afford 26 (27 mg, 88 %) as a white solid. Rf: 0.29 (hexane:ethyl acetate 3:1). Η NMR (300 MHz, CDC1 3 ) δ 7.61-7.58 (m, 2 h), 7.42-7.28 (m, 8H), 6.71 (s, IH), 6.19-6.02 (m, IH), 5.78 (d, J= 1.2 Hz, IH), 5.64 (d, J= 1.2 Hz, IH), 5.40 (dd, J / = 1.2 Hz. J 2 = 17.1 Hz, IH), 5.27 (dd, J,= 1.2 Hz, J 2 = 10.2 Hz, IH), 5.13 (s, 2 h), 4.45 (d, J= 2.4 Hz, IH), 4.24 (d, J= 2.1 Hz, IH), 4.17-4.06 (m, 3H), 3.75 (s, 3H), 3.64 (dd, J,= 2.4 Hz, J 2 = 9.9 Hz, IH), 3.59 (s, 3H), 3.42-3.21 (m, 4H), 3.10 (dd, Jy= 8.1 Hz, J 2 = 17.7 Hz, IH), 2.70 (d, J= 17.7 Hz, IH), 2.33 (s, 3H), 2,26 (s, 3H), 2.11 (s, 3H), 2.08-1.89 (m, IH), 0.87 (s, 9H); 13 C NMR (75 MHz, CDC1 3 ): δ 148.5, 148.3, 148.1, 144.0, 139.0, 135.6, 135.4, 133.8, 133.1, 132.6, 130.5, 130.3, 129.6, 129.4, 127.5, 127.4, 125.1, 124.3, 121.6, 118.5, 1 17.5, 1 12.9, 111.7, 100.8, 99.2, 74.0, 67.7, 61.5, 59.6, 59.0, 57.7, 57.1, 55.4, 41.6, 29.6, 26.6, 25.5, 18.8, 15.8, 9.2. ESI-MS m z: Calcd. for C 47 H 55 N 3 O 7 Si: 801.3. Found (M+H) + : 802.3. Example 31 26 ET-11 To a solution of 26 (7 mg, 0.0087 ml) in CH 2 C1 2 (0.15 ml), acetic acid (2.5 ml, 0.044 ml), (PPh 3 ) 2 PdCl 2 (0.5 mg, 6.96 x 10 "4 ml) and Bu 3 SnH (3.5 ml, 0.013 ml) were added at 23 °C. The reaction mixture was stirred at that temperature for lh. The solution was diluted with a mixture of hexane: ethyl acetate 5:1 (0.5 ml) and poured into a pad of flash column (SiO 2 , gradient 5:1 to 1:1 hexane:ethyl acetate) affording ET-11 (5 mg, 75 %) as a white solid. Rf: 0.36 (hexane:ethyl acetate 1 :5, silica). Η NMR (300 MHz, CDC1 3 ): δ 7.56 (m, 2 h), 7.41-7.25 (m, 8H), 6.67 (s, IH), 5.72 (d, J= 1.0 Hz, IH), 5.58 (d, J= 1.0 Hz, IH), 5.51 (s, IH), 5.38 (d, J= 5.75 Hz, IH), 5.16 (d, J= 5.7 Hz, IH), 4.57 (d, J= 2.9 Hz, IH), 4.21 (m, IH), 4.09 (m, IH), 3.72 (s, 3H), 3.71 (s, 3H), 3.68 (dd, 15.7 Hz, IH), 3.01 (dd, J;= 8.9 Hz, J2= 17.9 Hz, IH), 2.70 (d, J= 17.9 Hz, IH), 2.31 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 1.89 (dd, J / = 12.1 Hz, J 2 „ 15.7 Hz, IH), 0.9 (s, 9H). ); I3 C NMR (75 MHz, CDC1 3 ): δ 149.0, 147.4, 145.3, 144.3, 136.3, 135.7, 135.4, 133.2, 130.9, 130.5, 129.6, 129.5, 127.5, 125.0, 118.6, 112.5, 1 12.1, 105.7, 100.5, 99.8, 68.5, 61.5, 59.7, 58.8, 57.7, 56.9, 56.5, 55.4, 41.7, 26.6, 26.2, 25.5, 18.9, 15.8, 14.2, 8.7. ESI-MS m/z: Calcd. for 761. Found (M+H) + : 762. Example 32 A solution of 2 (3.0 g, 5.46 ml) and phenyl isothiocyanate (3.92mL. 32.76 ml) in CH 2 C1 2 (27 ml) was stirred at 23° C for 1.5h. The reaction mixture was partitioned between CH 2 C1 (10 ml) and H 2 O (5 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , gradient Hex to 2:3 hexane:ethyl acetate) to give 3 (3.29 g, 88%) as a yellow solid. Rf: 0.27 (ACN:H 2 O 3:2, RP-C18); Η NMR (300 MHz, CDC1 3 ): δ 7.77 (bs, IH), 7.42-7.11 (m, 5H), 6.65 (d, IH), 6.29 (s, IH), 5.6-5.5 (m, IH), 4.19-4.14 (m, 2 h), 4.08 (d, IH), 3.92 (s, 3H), 3.87-3.65 (m, 6H), 3.77 (s, 3H), 3.37-2.98 (m, 8H), 2.50 (d, IH), 2.31 (s, 3H), 2.20 (s, 3H), 1.96 (d, IH), 1.87 (s, 3H), 1.81-1.75 (m, IH), 0.96 (d, 3H); 13 C NMR (75 MHz, CDCl 3 ):δ 185.7, 180.9, 178.9, 172.0, 155.7, 147.1, 143.2, 142.4, 136.0, 135.1, 130.5, 129.9, 129.3, 128.5, 126.9, 124.4, 120.2, 117.4, 1 16.3, 77.1 , 60.9, 58.6, 56.2, 55.8, 55.0, 54.6, 53.5, 41.7, 40.3, 25.1, 24.5, 18.4, 15.8, 8.7 ESI-MS m/z: Calcd. for C 36 H 40 N 6 O 6 S: 684.8. Found (M+H) + : 685.2. Example 33 A solution of 3 (0.143 g, 0.208 ml) in 6.5 M HCI/dioxane (150 ml) was stirred at 23 °C for 6h. Then, toluene (3 ml) was added to this reaction and the organic layer was decanted. The residue was partitioned between saturated aqueous sodium bicarbonate (3 ml) and CHC1 3 (3x3 ml) The organic layers were dried and concentrated to afford title compound as a mixture of 4 and 6 (4:6 90:10) which slowly cyclizes to 6 on standing. Rf: 0.4 (ethyl acetate:methanol5:l, silica); Η NMR (300 MHz, CDC1 3 ): δ 6.45 (s, IH), 4.16 (m, IH), 4.02 (d, IH), 3.96 (s. 3H), 3.79 (m, 2 h), 3.75 (s, 3H), 3.35 (m, IH), 3.20-3.00 (m, 3H), 2.87 (d, IH), 2.75 (d. IH). 2.43 (d, IH), 2.34 (s, 3H), 2.30 (s, 3H), 1.93 (s, 3H), 1.72-1.5 (m, 3H); ESI-MS m/z: Calcd. for C 26 H 30 N 4 O 5 : 478.5. Found (M+H) + : 479.2 Example 34 A solution of 3 (0.143 g, 0.208 ml) in 6.5M HCI/dioxane (150 ml) was stirred at 23 °C for lh. Evaporation ofthe solvent gave a residue which was purified by flash column chromatography (ethyl acetate/methanol/triethylamine 100:25:0.1) to give 6 (80 mg, 83%) as a yellow solid. Rf: 0.26 (ACN:H 2 O 3:2, RP-C18); Η NMR (500 MHz, CDC1 3 ): δ 6.46 (s, IH), 5.9 (bs, IH) 4.67 (dd, J=18.3 Hz, J= 7.8 Hz, IH), 4.24 (d, IH), 4.16 (s, 3H), 3.93 (d, J=2.7 Hz, IH), 3.8 (m, 2 h). 3.77 (s. 3H). 3.45 (m. 2 h), 3.08 (dd, J=17.9 Hz, J=3.6 Hz, IH), 2.78 (m, IH), 2.55 (d, IH), 2.3 (m, IH), 2.3 (s. 3H), 2. 28 (s, 3H), 1.90 (s, 3H); 13 C NMR (75 MHz,CDCl 3 ):δ 186.2, 162.1, 154.9, 146.9, 145.3, 143.0, 130.1, 129.4, 128,1, 125.0, 121.4, 116.4, 116.2, 66.6, 60.7, 60.7, 60.1, 59.6, 58.8, 55.6, 54.9, 41.9, 25.3, 24.7, 15.7, 8.9. ESI-MS m/z: Calcd. for C 26 H 28 N 4 O 4 : 460.5. Found (M+H) + : 461.1 Example 35 To a solution of 3 (2.38 g, 3.47 ml) in dioxane (5 ml) 5.3M HCl in dioxane (34 ml) was added and the reaction was stirred at 23 °C for 45 minutes. Then Ac 2 O (51 ml, 539.5 ml) was added and the mixture was stirred for 4h. The reaction was cooled at 0 °C and partitioned between aqueous saturated Na 2 CO 3 (300 ml) and ethyl acetate (300 ml) at this temperature. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , gradient CH 2 C1 2 to CH 2 Cl 2 :ethyl acetate 1:2) to give 5 (1.75 g, 97%) as a yellow solid. Rf: 0.53 (ACN:H 2 O 3:2, RP-C18); Η NMR (300 MHz, CDC1 3 ): δ 6.51 (s, IH), 5.98 (bs, IH), 4.84 (dd, IH), 4.17 (d, IH), 4.00 (d, IH), 3.99 (s, 3H), 3.85 (bs, IH), 3.81 (m, IH), 3.74 (s, 3H), 3.70 (d, IH), 3.23 (m, IH), 3.11 (dd, IH), 3.09 (m, IH), 2.93 (m, 2 h), 2.44 (d, IH), 3.67 (s, 3H), 2.25 (s, 3H), 1.70 (s, 3H), 1.60-1.50 (m, 2 h), 1.29 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ): δ 185.9, 180.8, 169.9, 160.2, 156.2, 147.0, 143.1, 140.4. 136.1. 130.6, 129.6, 127.9, 120.4, 117.2, 61.0, 60.7, 58.6, 56.1, 55.7, 55.1, 54.3.41.8, 41.1. 25.7, 23.9, 22.2, 15.7, 8.7. ESI-MS m/z: Calcd. for C 28 H 32 N 4 O 6 : 520.6. Found (M+H) + : 521.1 Example 36 To a solution of 5 (1.75 g, 3.36 ml) in CH 2 C1 2 (17 ml) diisopropylethylamine (1 1.71 ml, 67.23 ml), DMAP (20 mg, 0.17 ml) and bromomethyl methyl ether (4.11 ml, 50.42 ml) were added at 0 °C. After 6 h at 23 °C the reaction was partitioned between CH 2 C1 2 (50 ml) and aqueous saturated sodium bicarbonate (25 ml). The organic layer was dried over sodium sulphate and the solvent was eliminated under reduced pressure. The crude was purified by flash column chromatography (RP-18, CH 3 CN/H 2 O 1/1) to give 7 (1.32 g, 70%) as a yellow solid. Rf: 0.34 (ACN:H 2 O 2:3, RP-C18); 1H NMR (300 MHz, CDC1 3 ): δ 6.74 (s, IH), 5.14 (s, 2 h), 4.82 (m, IH), 4.22 (d, IH), 4.00 (s, 3H), 4.0 (m, IH), 3.83 (m, 2 h), 3.7 (s, 3H), 3.58 (s, 3H), 3.4 (m, IH), 3.2-2.95 (m, 6H), 2.43 (d, IH), 2.37 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.5-1.4 (m, 2 h), 1.31 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ): δ 185.9, 180.7, 169.6, 156.2, 148.9, 148.5, 140.3, 136.2, 131.3, 130.1, 127.7, 124.6, 123.7, 117.3, 99.5, 99.2, 60.9, 59.7, 58.8, 57.7, 56.4, 55.7, 55.0, 54.2, 51.0, 41.6, 41.0, 40.5, 25.5, 23.9, 22.3, 19.3, 15.6, 14.6, 8.6. ESI-MS m z: Calcd. for C 30 H 36 N 4 O 7 : 564.6. Found (M+H) + : 565.3 Example 37 To a solution of 7 (0.37 g, 0.65 ml) in methanol (74 ml) at 0 °C was added 1 M sodium hydroxide (130 ml). The reaction was stirred for 15 minutes and then, quenched at 0 °C with 6M HCl to pH = 5. The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (RP-C18 CH 3 CN:H 2 O 1 /: 1 ) to afford 8 (232 mg, 65%) as a yellow oil. Rf: 0.5 (ACN:H 2 O 3 :2, RP-C 18); 1H NMR (300 MHz, CDC1 3 ): δ 6.75 (s, IH), 5.15 (s, 2 h), 4.86 (m, IH), 4.26 (d, IH), ), 4.01 (d, IH), 3.88-3.81 (m, 2 h), 3.70 (s, 3H), 3.58 (s, 3H), 3.39 (m, IH), 3.27-3.21 (m, IH), 3.18- 3.08 (m, 2 h), 3.03-2.97 (m, IH) 2.47 (d, IH), 2.37 (s, 3H), 2. 22 (s, 3H), 1.90 (s, 3H), 1.57- 1.46 (m, 2 h), 1.33 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ): δ 185.3, 180.6, 175.9, 170.1, 151.5, 148.9, 148.6, 143.3, 133.7, 131.5, 129.9, 124.7, 123.5, 117.1, 117.0, 99.2, 59.8, 58.7, 57.8, 56.3, 55.3, 54.9, 54.3, 41.5, 40.7, 29.6, 25.5, 24.4, 22.2, 20.7, 15.7, 8.0. ESI-MS m z: Calcd. for C 29 H 34 N 4 O 7 : 550.6. Found (M+H) + : 551.2 Example 38 To a degassed solution of compound 8 (240mg, 0.435 ml) in DMF (30 ml) 10 % Pd/C (48 mg) was added and the reaction was stirred under H 2 (atmospheric pressure.) for lh. The reaction was filtered through a pad of celite under Argon to a Schlenk tube, as a colourless solution, containing anhydrous Cs 2 CO 3 (240 mg, 0.739 ml). Then, bromochloromethane (0.566 ml, 8.71 ml) was added. The tube was sealed and stirred at 90 °C for 3h. The reaction was cooled and filtrated through celite and washed with CH 2 C1 2 . The organic layer was concentrated and dried (sodium sulphate) to afford 9 as a brown oil that was used in the next step with no further purification. Rf: 0.36 (SiO 2 , hexane:ethyl acetate 1 :5) 'H NMR (300 MHz, CDCl 3 ): δ 6.71 (s, 3H), 5.89 (d, IH), 5.81 (d, IH), 5.63 (bs. IH), 5.33 (d, IH), 5.17 (d, IH), 4.97 (m, IH), 4.20 (d, IH), 4.09 (m, IH), 3.99 (m, IH), 3.68 (m, IH), 3.65 (s, 6H), 3.59-3.47 (m, 4H), 3.37-3.27 (m, 2 h), 3.14- 2.97 (m, 2 h), 2.62 (d, IH), 2.32 (s, 3H), 2.20 (s, 3H), 2.08 (s, 3H), 1.72 (m, IH), 1.36 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ): δ 169.8, 149.1, 147.4, 145.5, 136.2, 130.9, 130.8, 125.0, 122.9, 117.7, 112.6, 111.8, 106.4, 100.8, 99.8, 59.8, 58.9, 57.7, 56.6, 56.4, 55.5, 55.2, 41.6, 40.1, 29.6, 25.9, 25.0, 22.6, 15.6, 8.8. ESI-MS m/z: Calcd. for C 30 H 36 SiN 4 O 7 : 564.6. Found (M+H) + : 565.3. Example 39 To a flask containing 9 (245 mg, 0.435 ml) in DMF, (4 ml), cesium carbonate (425 mg, 1.30 ml) and allyl bromide (376 ml, 4.35 ml) were added at 0 °C and the mixture was stirred at 23 °C for lh. The reaction was filtered though a pad of celite and partitioned between CH C1 2 (25 ml) and H O (10 ml). The organic phase was dried (sodium sulphate) and concentrated at reduced pressure to afford a residue that was purified by flash column chromatography (SiO 2 , CHCl 3 :ethyl acetate 1 :2) to give 10 as a yellow oil. (113 mg. 43 %). Rf: 0.36 (hexane: ethyl acetate 1 :5) Η NMR (300 MHz, CDC1 3 ): δ 6.74 (s, IH), 6.3-6.0 (m, IH), 5.94 (d, IH), 5.87 (d, IH), 5.43-5.36 (m, 2 h), 5.22 (s, 2 h), 5.00 (m, IH), 4.22 (m, IH), 4.17-4.01 (m, IH), 3.98 (m, 2 h), 3.71-3.67 (m, IH), 3.69 (s, 3H), 3.62-3.51 (m, 3H), 3.58 (s, 3H), 3.39-3.37 (m, IH), 3.31- 3.26 (m, 3H), 3.09 (dd, IH), 2.56 (d, IH), 2.36 (s, 3H), 2.21 (s, 3H), 2.1 1 (s, 3H), 2.24-2.10 (m, IH), 1.82-1.73 (m, IH), 1.24 (bs, 3H) 13 C NMR (75 MHz, CDC1 3 ): δ 169.4, 148.8, 148.3, 139.1, 133.7, 130.9, 130.3, 125.2, 120.2, 117.7, 113.1, 112.6, 101.3, 99.3, 74.1, 59.7, 59.3, 57.8, 57.0, 56.1, 56.1, 55.2, 41.6, 41.0, 40.9, 29.7, 26.3, 22.5, 15.6, 9.3 ESI-MS m z: Calcd. for 604.7. Found (M+H) + : 605.3. Example 40 46 To a solution of 9 (22 mg, 0.039 ml) in CH 2 C1 2 (0.2 ml), acetyl chloride (2.79 ml, 0.039 ml) and pyridine (3.2 ml, 0.039 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 46 (22 mg, 93%) as a white solid. Rf: 0.4 (hexane:ethyl acetate 1 :5). 1H NMR (300 MHz, CDC1 3 ). δ 6.74 (s, IH), 5.97 (d, J= 0.9 Hz, IH), 5.91 (d, J= 0.9 Hz, IH), 5.12 (d, J= 5.7 Hz, 2 h), 5.04 (d, J= 5.7 Hz, IH) 4.90 (t, J= 6 Hz, IH), 4.17 (d, J= 2.7 Hz, IH), 4.05 (d, J= 2.7 Hz, IH), 4.01 (bs, IH), 3.71 (s, 3H), 3.57 (s, 3H), 3.50-3.44 (m, 2 h), 3.38-3.36 (m, IH), 3.30-3.26 (m, IH), 3.00 (dd, J,= 7.8 Hz, J 2 = 18.0 Hz, IH), 2.79 (d, J= 12.9 Hz, IH), 2.60 (d, J=18.0 Hz, IH), 2.35 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.68 (dd, J;=l 1.7 Hz, J 2 = 15.6 Hz, 1 H). ESI-MS m/z: Calcd. for C 32 h38 N 4 O 8 : 606.67. Found (M+H) + : 607.3. Example 41 46 47 To a solution of 46 (8 mg, 0.013 ml) in dioxane (0.1 ml), 5.3N HCI/dioxane (0.5 ml) was added and the reaction was stirred at 23 °C for lh. Then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 47 (5 mg. 70%) as a white solid. Rf: 0.4 (hexane:ethyl acetate 1:5). Η NMR (300 MHz, CDC1 3 ). δ 6.51 (s, IH), 5.97 (d, J= 1.2 Hz, IH), 5.91 (d. J= 1.2 Hz, IH), 4.97 (bs, IH), 4.11 (bs, IH), 4.04-4.02 (m, 2 h), 3.75 (s, 3H), ), 3.65 (d, J= 2.1 Hz, 2 h), 3.56-3.30 (m, 2 h), 3.04 (dd,J/= 7.5 Hz, J 2 = 18 Hz, IH), 2.80 (d, J= 14.4 Hz, IH), 2.59 (d, J= 18.3 Hz, IH), 2.33 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.76 (dd, J,= 12.0 Hz, J 2 = 15.9 Hz, IH), 1.33 (s, 3H), 1.25 (s, 3H). ESI-MS m/z: Calcd. for C 30 H 34 N 4 O 7 : 562.61. Found (M+H) + : 563.3. Example 42 To a solution of 45 (10 mg, 0.0192 ml) in CH 2 C1 2 (0.3 ml), isovaleryl chloride (2.34 ml, 0.0192 ml) and pyridine (1.55 ml, 0.0192 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 1:2) to afford 48 (11 mg, 95%) as a white solid. Rf: 0.12 (Hex: ethyl acetate 1:2). 'H NMR (300 MHz, CDC1 3 ): δ 6.50 (s, IH), 5.98 (d, J= 1.5Hz, IH), 5.91(d, J= 1.5 Hz, IH), 5.75 (s, IH), 5.02 (t, J= 5.4 Hz, IH), 4.10 (d, J= 1.5 Hz, IH), 4.06 (d, J= 2.7 Hz, IH), 4.02 (d, J= 2.7 Hz, IH), 3.77 (s, 3H), 3.76-3.71 (m, IH), 3.86-3.28 (m, 3H), 3.04 (dd, J,= 8.1 Hz, J 2 = 18.3Hz, IH), 2.78 (d, J=15.9 Hz, IH), 2.55 (d, J=18 Hz, IH), 2.32 (s, 6H), 2.26 (s, 3H), 1.98 (s, 3H), 1.84-1.68 (m, 2 h), 1.36 (d, J= 7.2 Hz, 2 h), 0.69 (d, J= 6.6 Hz, 3H). 0.62 (d, J=6.6 Hz, 3H). ESI-MS m z: Calcd. for C 33 H4 0 N 4 O 7 : 604.69. Found (M+H) + : 605.3. Example 43 To a solution of 45 (10 mg, 0.0192 ml) in CH 2 C1 2 (0.3 ml), isovaleryl chloride (3.98 ml, 0.0192 ml) and pyridine (1.55 ml, 0.0192 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 1:2) to afford 49 (12.4 mg, 96%) as a white solid. Rf: 0.7 (ethyl acetate:methanollO:l). 1HNMR (300 MHz, CDC1 3 ): δ 6.50 (s, IH), 5.98 (d, J= 1.5Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.73 (s, IH), 5.08 (t, J= 5.4 Hz, IH), 4.10 (d, J= 1.5 Hz, IH), 4.05 (m., IH), 4.01 (m, IH), 3.76 (s, 3H), 3.65-3.61 (m, IH), 3.40-3.27 (m, 3H), 3.03 (dd, 18.6 Hz, IH), 2.78 (d, J=13.2 Hz, IH), 2.57 (d, J=18.3 Hz, IH), 2.32 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H), 1.79 (dd, J/= 12.0 Hz, J 2 = 16.5 Hz, IH), 1.73-1.42 (m, 4H), 1.33-1.18 (m, 10H), 1.03 (m, 2 h), 0.87 (t, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 38 H 50 N 4 O 7 : 674.83. Found (M+H) + : 675.5. Example 44 To a solution of 45 (14.5 mg, 0.0278 ml) in CH 2 C1 2 (0.3 ml), trans-3-trifluoromethyl cinnamoyl chloride (4.76 ml, 0.0278 ml) and pyridine (2.25 ml, 0.0278 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 1 :1) to afford 50 (18.7 mg, 94%) as a white solid. Rf: 0.64 (ethyl acetate:methanol5:l ). 1H NMR (300 MHz, CH 3 OD). δ 7.74-7.55 (m, 4H), 7.23 (d, J= 16.0 Hz, IH), 6.34 (s, IH), 6.12 (d, J= 16.0 Hz, IH), 6.07 (d, J= 0.9 Hz, IH), 5.96 (d, J= 0.9 Hz, IH), 4.39 (d, J= 2.4 Hz, IH), 4.07-4.05 (m, 1 H), 3.81 (bs, IH), 3.46-3.51 (m, 3H), 3.42 (s, 3H), 3.09 (br d, J= 12.0 Hz, IH), 2.94-2.85 (m, 2 h), 2.74 (d, J=18.3 Hz, IH), 2.38 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H), 1.80 (s, 3H), 1.84-1.75 (m, IH). 13 C NMR (75 MHz, CDCl 3 ) ): δ 168.7, 165.3, 146.5, 144.7, 142.6, 140.6, 138.0, 135.9, 131.0, 130.9, 129.1, 128.6, 125.8, 125.7, 124.5, 124.4, 122.7, 121.2, 117.8, 116.5, 113.0, 112.0, 101.7, 60.4, 59.1, 56.5, 56.4, 55.6, 55.3, 41.8, 40.3, 26.6, 25.1, 20.3, 15.4, 9.3. ESI-MS m/z: Calcd. for C 38 H 37 F 3 N 4 O 7 : 718.72. Found (M+H) + : 719.3. Example 45 To a solution of 43 (33 mg, 0.0557 ml) in CH 2 Cl 2 (0.4 ml), isovaleryl chloride (6.79 ml, 0.0557 ml) and pyridine (4.5 ml, 0.0557 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 1 :2) to afford 51 (34 mg, 91%) as a white solid. Rf: 0.09 (Hex: ethyl acetate 1:2). 1H NMR (300 MHz, CDC1 3 ): δ 6.46 (s,lH), 6.10 (bs, IH), 5.99 (d, J= 0.9Hz, IH), 5.90 (d, J= 0.9 Hz, IH), 5.30 (t, J= 6.0 Hz. IH), 4.10-4.05 (m, 3H),3.81 (bs, IH), 3.74 (s, 3H), 3.54 (bs,lH), 3.38-3.36 (m, IH), 3.29-3.21 (m, IH), 3.00 (dd, J / = 8.0 Hz, J : = 18.0 Hz, IH), 2.25 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H), 1.95-1.90 (m, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.76 (d, J=6.0 Hz, 3H). ESI-MS m/z: Calcd. for 675.77. Found (M+H) + : 676.3. Example 46 To a solution of 43 (33 mg, 0.0557 ml) in CH 2 C1 2 (0.4 ml), trans-3-trifluoromethyl cinnamoyl chloride (9.52 ml, 0.0557 ml) and pyridine (4.5 ml, 0.0557 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 1 :2) to afford 52 (40 mg, 92%) as a white solid. Rf: 0.21 (hexane:ethyl acetate 1 :2). Η NMR (300 MHz, CD 3 OD). δ 7.74-7.47 (m, 4H), 6.49 (s, IH), 6.40 (d, J= 15.6 Hz, IH), 6.00 (d, J= 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, IH), 5.47 (t, J= 6 Hz, IH), 4.12-4.09 (m, 3H), 3.93 (bs, IH), 3.71 (s, 3H), 3.59-3.58 (m, IH), 3.38 (d, J=7.8 Hz, IH), 3.29 (d, J=12.0 Hz, IH), 3.00 (dd, J/= 8.1 Hz, J 2 = 18.3 Hz, IH), 2.79-2.78 (m, IH), 2.65 (d, J=18.3 Hz, IH) 2.29 (s, 6H), 2.28 (s, 3H), 2.22 (s, 3H), 1.84-1.80 (m, IH), 0.85-0.84 (m, 3H). ,3 C NMR (75 MHz, CDCl 3 ) δ 171.9, 168.8, 164.4, 146.9, 144.6, 143.0, 140.5, 140.5, 139.3, 135.7, 131.1, 131.0, 129.4, 129.1, 126.0, 124.1, 124.0, 122.4, 121.1, 120.7, 120.6, 1 17.7, 116.9, 112.8, 112.0, 101.6, 60.6, 59.3, 57.1, 56.3, 55.9, 55.2, 49.0, 41.7, 49.9, 26.5, 25.1, 20.2, 18.4, 15.7, 9.3. ESI-MS m/z: Calcd. for C 4 ιH 42 F 3 N 5 O 8 : 789.8. Found (M+H) + : 790.3. Example 47 To a solution of 43 (10 mg, 0.0169 ml) in CH 2 C1 2 (0.2 ml) trifluoroacetic anhydride (2.38μl, 0.0169 ml) was added at 23 °C. The reaction mixture was stirred for 5h and then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 3:2) to afford 53 (10.7 mg, 93%) as a white solid. Rf: 0.57 (ethyl acetate:methanol5:l). Η NMR (300 MHz, CDC1 3 ) δ 6.45 (s, IH), 6.00 (d, J= 1.2 Hz, IH), 5.90 (d, J= 1.2 Hz, lH), 5.87 (bs, lH), 5.32 (bs, lH), 4.12(d, J= 2.1 Hz, IH), 4.08 (d, J= 1.8 Hz. IH), 3.78-3.56 (m, 3H), 3.72 (s, 3H), 3.40 (d, J= 8.1 Hz, IH), 3.25 (d, J= 9.3 Hz, IH), 3.00 (dd, Jr 8.4 Hz, J 2 = 18.0 Hz, IH), 2.77 (dd, J / = 2.1 Hz, J = 15.9 Hz, IH), 2.68 (d, J= 18.6 Hz, I H), 2.30 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.75 (dd, J/= 1 1.4 Hz, J 2 = 15.9 Hz, IH), 0.69 (d, J= 6.3 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 170.1, 168.6,156.0, 147.0, 144.6, 143.0, 140.6, 140.4, 131.0, 129.4, 120.9, 120.7, 117.6, 116.8, 112.4, 112.1, 101.6, 60.5, 59.0, 57.1, 56.3, 55.6, 55.2, 48.7, 41.6, 39.4, 26.5, 24.9, 20.2, 17.8, 15.4, 9.2. ESI-MS m z: Calcd. for Css^FsNsOs: 687.63. Found (M+H) + : 688.66. Example 48 To a solution of 19 (11 mg, 0.0169 ml) in CH C1 2 (0.2 ml) trifluoroacetic anhydride (2.38 ml, 0.0169 ml) was added at 23 °C. The reaction mixture was stirred for 5h and then, the solution was diluted with CH 2 C1 2 (5 ml) and washed with 0.1 N HCl (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: ethyl acetate 3:2) to afford 54 (10.7 mg, 93%) as a white solid. Rf: 0.6 (ethyl acetate:methanol5:l). ! H NMR (300 MHz, CDC1 3 ) δ 7.33 (d, J= 6.3 Hz, IH), 6.45 (s, IH), 6.04 (m, IH), 5.95 (d, J= 1.5 Hz, IH), 5.84 (d, J= 1.5 Hz, IH), 5.32 (m, 2 h), 5.21 (m, IH), 4.1 1 (m, 4H), 3.73 (s, 3H), 3.64 (m, 2 h), 3.51 (m, IH), 3.37 (d, J- 7.8 Hz, IH), 3.22 (m, 2 h), 3.03 (dd, IH, J / = 8.1 Hz, J 2 = 18.3 Hz, IH), 2.60 (d, J= 18.3 Hz, IH), 2.29 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.86 (dd, J / = 12 Hz, J 2 = 16.2 Hz, IH), 0.82 (d, J= 7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 170.0, 156.0, 148.4, 147.1, 144.3, 143.0, 138.7, 133.8, 130.5, 129.4, 120.6, 120.4, 117.6, 117.5, 117.0, 1 13.5, 1 12.5, 112.4, 101.1, 74.1, 66.8, 60.4, 59.3, 56.9, 56.6, 56.3, 55.4, 48.7, 41.6, 40.1, 26.2, 25.0, 17.6, 15.4, 9.1. ESI-MS m z: Calcd. for C 35 H 39 F 3 N 5 O 7 : 685.69. Found (M+H) + : 686.3. Example 49 To a solution of 54 (100 mg, 0.415 ml) in CH 2 C1 2 (4 ml), acetic acid (40 ml), (PPh 3 ) 2 PdCl 2 (8.4 mg, 0.012 ml) and Bu 3 SnH (157 ml, 0.56 ml) were added at 23 °C. After stirring at that temperature for 2 h the reaction was poured into a pad of flash column (SiO 2 , gradient Hex to hexane:ethyl acetate 2:1) to afford 55 (90 mg, 96%) as a white solid. Rf: 0.6 (hexane:ethyl acetate 1 :2). Η NMR (300 MHz, CDC1 3 ) δ 7.55 (d, J= 7.2 Hz, IH), 6.45 (s, IH). 5.90 (d, J= 1.2 Hz, IH), 5.82 (d, J= 1.2 Hz, IH), 5.37 (t, J= 6.0 Hz, IH), 4.15 (d, J= 2.1 Hz, 1H), 4.04 (d, J= 1.8 Hz, IH), 3.70 (s, 3H), 3.66-3.53 (m, 2 h), 3.37-3.31 (m, 2 h), 3.19-3.15 (d, J= 1 1.7 Hz, IH), 3.08- 3.00 (m, 2 h), 2.56 (d, J=18.3 Hz, IH), 2.30 (s, 3H), 2.24 (s, 3H), 2.04 (s, 3H), 1.91 (dd, J / = 12.0 Hz, J 2 = 15.6 Hz, IH), 0.84 (d, J= 6.9 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 170.1, 156.3, 147.3, 144.9, 144.4, 143.3, 136.7, 130.7, 129.3, 120.6, 117.6, 117.4, 114.4, 112.1, 107.7, 101.0, 85.8, 60.5, 59.3, 56.5, 56.4, 56.2, 55.2, 48.9, 41.6, 40.9, 25.7, 25.3, 18.0, 15.6, 8.7. ESI-MS m z: Calcd. for C 32 h35 F 3 N 5 O 7 : 645.63. Found (M+H) + : 646.2. Example 50 17 56 To a solution of 17 (200 mg, 0.288 ml) in CH 2 C1 2 (1.44 ml), trifluoroacetic acid (888 ml, 11.53 ml) was added and the reaction mixture was stirred for 4h at 23 °C. The reaction was quenched at 0 °C with saturated aqueous sodium bicarbonate (60 ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo to afford 56 (147 mg, 93%) as a white solid that was used in subsequent reactions with no further purification. Rf: 0.19 (ethyl acetate:methanol5:l). Η NMR (300 MHz, CD 3 OD). δ 6.48 (s, IH), 5.88, d, J= 0.9 Hz, IH), 5.81 (d, J= 0.9 Hz, IH), 4.35 (d, J= 2.4 Hz, 1H),4.15 (d, J= 1.8 Hz, IH), 3.99-3.98 (m, IH), 3.70 (s, 3H), 3.52- 2.96 (m, 7H), 2.68 (d, J= 18.3 Hz, IH), 2.24 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.85 (dd, J,= 11.7 Hz, J 2 = 15.6 Hz, IH), 0.91 (d. J= 6.6 Hz, 3H). 13 C NMR (75 MHz, CD 3 OD): δ 173.2, 149.1, 145.6, 144.9, 138.0, 132.2. 130.6, 121.4, 119.6, 117.4, 114.3, 109.2, 102.5, 82.3, 60.4, 58.4, 58.3, 57.8, 56.6, 50.1, 42.3, 41.6, 27.8, 26.2, 19.5, 15.5, 9.8. ESI-MS m/z: Calcd. for C 29 H 35 N 5 O 6 : 549.62. Found (M+H) + : 550.3. Example 51 To a solution of 56 (10 mg, 0.018 ml) in CH 2 C1 2 (0.4 ml), phenyl isothiocyanate (13 ml, 0.109 ml) was added and the reaction was stirred at 23° C for 1.5h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (SiO 2 , gradient Hexane to 1 :1 hexane:ethyl acetate) to afford 57 (8 mg, 65%) as a white solid. Rf: 0.57 (ethyl acetate:methano!10:l). Η NMR (300 MHz, CDC1 3 ): δ 7.88 (bs, IH), 7.41-7.36 (m, 2 h), 7.27-7.22 (m, I H), 7.02- 7.00 (d, J= 7.8 Hz, 2 h), 6.71 (d, J= 7.2 Hz, IH), 6.31 (s, IH), 6.17 (bs, IH), 5.93 (d, J=1.2 Hz, IH), 5.83 (d, J= 1.2 Hz, IH), 5.55 (bs, IH), 5.20-5.17 (m, IH), 4.16 (d, J= 1.8 Hz, IH), 4.05 (bs, IH), 4.02 (d, J= 2.4 Hz, IH), 3.79 (s, 3H), 3.75-3.71 ( , IH), 3.35 (d, J= 7.8 Hz, IH), 3.28-3.19 (m, 2 h), 3.12-2.97 (m, 2 h), 2.50 (d, J=18.3 Hz, IH), 2.32 (s, 3H), 2.21 (s, 3H), 2.15-2.09 (dd, J / = 11.4 Hz, J = 15.9 Hz, IH), 1.95 (s, 3H), 0.88 (d, J=6.9 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ): δ 178.5, 171.7, 147.2, 145.0, 144.3, 143.3, 137.0, 135.7, 130.6, 130.4, 129.6, 127.5, 124.3, 120.6, 117.7, 1 17.2, 1 15.3, 1 12.1, 108.3, 100.9, 60.9, 59.5, 56.7, 56.5, 56.2, 55.2, 54.1, 41.7, 41.1, 26.3, 25.4, 18.5, 15.8, 9.0. ESI-MS m/z: Calcd. for C^FLrøNeOeS: 684.81. Found (M+H) + : 685.3. Example 52 57 58 To a solution of 57 (45 mg, 0.065 ml) in CH 2 C1 2 (0.5 ml), acetyl chloride (4.67 ml, 0.065 ml) and pyridine (5.3 ml, 0.065 ml) were added at 0 °C. The reaction mixture was stirred for 3h and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 40:60) to afford 58 (14 mg, 28%) as a white solid. Rf: 0.34 (CH 3 CN: H 2 O 7:15). Η NMR (300 MHz, CDC1 3 ). δ 1 1.90 (d, J= 6.6 Hz, IH), 7.45-7.40 (m, 3H). 7.18-7.15 (m, 2 h), 6.58 (s, IH), 6.00 (d, J= 1.2 Hz, IH), 5.89 (d, J= 1.2 Hz, IH), 5.70 (s. IH). 5.37 (t, J= 4.8 Hz, IH), 4.48 (m, IH), 4.23 (bs, IH), 4.07 (bs, 2 h), 3.85-3.75 (m, IH), 3.70 (s, 3H), 3.46-3.41 (m, 2 h), 3.24-3.20 (m, IH), 3.00-2.95 (m, IH), 2.87-2.75 (m, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.85 (dd, J,= 11.4 Hz, J 2 = 15.6 Hz, IH), 1.66 (s, 3H), 0.82 (d, J= 6.0 Hz, 3H). I3 C NMR (75 MHz, CDC1 3 ) ): δ 182.6, 174.3, 171.0, 146.6, 144.6, 142.7, 142.3, 140.7, 140.2, 131.3, 129.8, 129.3, 128.9, 128.8, 121.5, 120.4, 117.3, 116.6, 112.8, 112.0, 111.3, 101.5, 60.5, 59.0, 57.6, 56.2, 55.9, 55.3, 55.1, 41.6, 39.4, 27.8, 26.5, 24.8, 20.2, 17.1, 15.5, 9.3. ESI-MS m/z: Calcd. for oHψ t NeOsS: 768.88. Found (M+H) + : 769.2. Example 53 A solution of 57 (130 mg, 0.189 ml) in dioxane (1 ml), 5.3N HCI/dioxane (1.87 ml) was added and the reaction was stirred at 23 °C for 4h. Then, CH 2 C1 2 (15 ml) and H 2 O (10 ml) were added to this reaction and the organic layer was decanted. The aqueous phase was basified with saturated aq sodium bicarbonate (60 ml) (pH = 8) at 0 °C and then, extracted with ethyl acetate (2x50 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo to afford 59 (63 mg, 70%) as a white solid. Rf: 0.15 (ethyl acetate:methanol5:l). 1H NMR (300 MHz, CDC1 3 ). δ 6.67 (s, IH), 5.99 (d, J= 0.9 Hz. IH), 5.91 (d, J= 1.2 Hz, IH), 5.10 (bs, IH), 4.32 (d, J= 7.2 Hz, IH), 4.25 (dd, J,= 3.6 Hz, J 2 = 9.3 Hz, IH), 3.7 (s, 3H), 3.71-3.64 (m, 2 h), 3.50 (dd, J / = 2.4 Hz, J 2 = 15.9 Hz, IH), 3.42-3.37 (m, 2 h), 3.16 (dd, J/=3.6 Hz, J 2 = 12.9 Hz, IH), 2.57 (dd, J,= 9.3 Hz, J 2 = 12.9 Hz, IH), 2.27 (s, 3H), 2.11 (s, 3H), 1.91 (dd, Jr= 12.0 Hz, J = 15.9 Hz, IH). ESI-MS m/z: Calcd. for C 26 H 30 N 4 O 5 : 478.5. Found (M+H) + : 479.3. Example 54 A solution of 43 (20 mg, 0.0338 mmol) in CH 2 C1 2 (0.3 ml), cinnamoyl chloride (5.63 mg , 0.0338 mmol) and pyridine (2.73 ml, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 Cl 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 60 (22 mg, 90%) as a white solid. Rf: 0.56 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ). 7.51 (s, IH), 7.50-7.47 (m, 2H), 7.36-7.35 (m, 2H), 6.43 (s, IH), 6.36 (brd, J= 15.9 Hz, 2H), 6.01 (d, J= 1.5 Hz, IH), 5.90 (brd, J= 1.5 Hz, 2H), 5.42 (t, J= 6.0 Hz IH), 4.12-4.07 (m, 3H), 3.96-3.95 (m, IH), 3.73 (bs, 3H), 3.58 (bs, 2H), 3.39 (d, J= 8.7 Hz, IH), 3.25 (d, J= 11.7 Hz, IH), 3.0 (dd, J,= 7.5 Hz, J 2 = 17.7 Hz, IH), 2.78 (d, J= 15.9 Hz, IH), 2.67 (d, J= 16.5 Hz, IH), 2.29 (s, 6H), 2.23 (s, 3H), 1.99 (s, 3H), 1.82 (dd, J ; = 11.4 Hz, J 2 = 15.6 Hz, IH), 0.83 (d, J= 6.0 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) ): δ. 172.0, 165.0, 146.9, 144.6, 143.1, 141.0, 140.5, 134.8, 131.0, 129.7, 129.1, 128.8, 127.8, 125.5, 123.8, 123.0, 121.1, 120.5, 117.7, 1 16.9, 1 12.8, 112.0, 101.9, 60.6, 59.2, 57.1, 56.4, 55.9, 55.3, 48.8, 41.7, 40.0, 26.5, 25.1, 20.3, 18.5, 15.7, 9.3. ESI-MS m/z: Calcd. for GtoHoNsOg: 721.8. Found (M+H) + : 722.3. Example 55 A solution of 45 (19 mg, 0.0364 mmol) in CH 2 C1 2 (0.3 ml), heptafluorobutyryl chloride ( 5.44 ml, 0.0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 61 (1 1.7 mg, 45%) as a white solid. Rf: 0.76 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.46 (s, IH), 6.12 (bs, IH), 5.98 (d, J= 1.2 Hz. IH), 5.93 (d, J= 1.2 Hz, IH), 5.72 (bs, IH), 4.13-4.1 1 (m, 2H), 4.0 (d, J= 2.4 Hz, IH), 3.98-3.96 (m, IH), 3.73 (s, 3H), 3.39 (d, J= 7.5 Hz, I H), 3.39-3.28 (m, 2H), 3.09 (dd, J ; = 8.1 Hz, .Λ= 18.0 Hz, IH), 2.80 (d, J= 16.2 Hz, IH), 2.46 (d, J= 18.3 Hz, IH), 2.32 (s, 6H), 2.21 (s, 3H), 1.99 (s, 3H), 1.80 (dd, J ; = 12.0 Hz, J 2 = 16.2 Hz, IH). ESI-MS m/z: Calcd. for C 32 H 3 ,F 7 N 4 O 7 : 716.6. Found (M+H) + : 717.2. Example 56 A solution of 43 (24 mg, 0.04 mmol) in CH 2 C1 2 (0.3 ml), butyryl chloride (4.15 ml, 0.04 mmol) and pyridine (3.28 ml, 0.04 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 62 (24 mg, 90%) as a white solid. Rf: 0.35 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.47 (s, IH), 6.10 (d, J= 6.5 Hz, IH), 6.0 (d, J= 1.5 Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.86 (bs, IH), 5.31 (d, J= 6.9 Hz, IH), 4.11-4.06 (m, 3H), 3.85-3.81 (m, IH), 3.75 (s, 3H), 3.59-3.53 (m, 2H), 3.38 (d, J= 7.5 Hz, IH), 3.27-3.22 (m, IH), 3.0 (dd, Jr 7.8 Hz, J 2 = 17.4 Hz, IH), 2.79 (d, J= 15.3 Hz, IH), 2.63 (d, J= 17.7 Hz, IH), 2.31 (s, 3H), 2.0 (s, 3H), 1.80 (dd, 15.9 Hz, IH), 1.58 (q, J= 7.2 Hz, 2H), 0.89 (t, J= 7.2 Hz, 3H), 0.76 (d, J= 6.6 Hz, 3H). ESI-MS m z: Calcd. for C 35 H 43 N 5 O 8 : 661.64. Found (M+H) + : 662.3 Example 57 A solution of 43 (19 mg, 0.0364 mmol) in CH 2 C1 2 (0.3 ml), cinnamoyl chloride (6.06 mg , 0.0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 63 (20.1 mg. 85%) as a white solid. Rf: 0.65 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.39-7.29 (m, 5H), 6.42, (s, IH), 6.01 (d, J= 1.5 Hz, IH), 5.92 (d, J= 1.5 Hz, IH), 5.73 (bs, IH), 5.24 (t, J= 6.8 Hz, IH), 4.12-4.08 (m, 3H), 3.66-3.64 (m, 2H), 3.58 (bs, 3H), 3.36 (d, J= 8.7 Hz, IH), 3.29 (d, J= 12.0 Hz, IH), 2.98 (dd, J,= 8.1 Hz, J 2 = 18 Hz, IH), 2.33 (s, 6H), 2.29 (s, 3H), 2.01 (s, 3H), 1.84 (dd, J,= 12.0 Hz, J 2 = 15.9 Hz, IH). ). ESI-MS m/z: Calcd. for C 37 H 38 N 4 O 7 : 650.72. Found (M+H) + : 651.2. Example 58 43 64 A solution of 43 (20 mg, 0.0338 mmol) in CH 2 C1 2 (0.3 ml), 3-chloropropionyl chloride (3.22 ml , 0.0338 mmol) and pyridine (2.73 ml, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 64 (20.5 mg, 89%) as a white solid. Rf: 0.32 (EtOAc-.Hexane 5:1). 'H NMR (300 MHz, CDC1 3 ) 6.48 (s, 3H), 6.28 (m, IH), 5.99 (d. J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.86 (bs, IH), 5.31 (m, IH), 4.08-4.07 (m, 3H), 3.75 (s, 3H), 3.72-3.53 (m, 5H), 3.39 (d, J= 8.1 Hz, IH), 3.24 (d, J= 12.0 Hz, IH), 3.00 (dd, J/= 8.1 Hz, J 2 = 18.0 Hz, IH), 2.79 (d, J= 13.5 Hz, IH), 2.50 (t, J= 6.3 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H). 2.25 (s, 3H), 2.0 (s, 3H), 1.79 (dd, J / = 12.3 Hz, J = 14.8 Hz, IH), 0.81 (d, J= 6.3 Hz, 3H). Example 59 45 65 A solution of 43 (19 mg, 0.0364 mmol) in CH 2 C1 2 (0.3 ml), butyryl chloride (3.78 ml , 0.0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 ml) and washed with 0.1 N HCl (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 20:1) to afford 64 (19 mg, 87%) as a white solid. Rf: 0.60 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC1 3 ) 6.50 (s, IH), 5.98 (d, J= 1.5 Hz, IH), 5.91 (d. J= 1.5 Hz, IH), 5.75 (s,lH), 5.01 (t, J= 6.4 Hz, IH), 4.10 ^1.09 (m, IH), 4.06 (d, J= 2.1 Hz, IH), 4.03-4.02 (m, IH), 3.76 (s, 3H), 3.67-3.60 (m, IH), 3.42-3.35 (m, 2H), 3.29 (d, J= 12.0 Hz. IH), 3.02 (dd, J / = 7.8 Hz, J 2 = 17.7 Hz, IH). 2.79 (d, J= 14.1 Hz, IH), 2.56 (d, J= 18.3 Hz, IH), 2.32 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.78 (dd, 15.9 Hz, IH), 1.63 (s, 3H), 1.53-1.46 (m, 2H), 1.28-1.16 (m, 2H), 0.68 (t, J= 7.2 Hz, 3H). ESI-MS m/z: Calcd. for C 32 H 38 N 4 O 7 : 590.67. Found (M+H) + : 591.2. Example 60 66 To a solution of 50 (31.7 mg, 0.044 mmol) in CH 3 CN/H 2 O (1.5 ml/0.5 ml), AgNO 3 (225 mg, 1.32 mmol) was added and the reaction was stirred at 23°C for 17 h. Then brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:1) to afford 66 (16 mg, 51%) as a white solid. Rf: 0.26 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.66-7.42 (m, 4H), 7.20 (bs. IH), 6.44 (s. IH). 5.97 (b. J= 1.2 Hz, IH), 5.90 (d, J= 1.2 Hz, IH). 5.76 (bs, IH), 5.28 (bs, IH), 4.54 (bs, IH), 4.43 (bs. IH). 4.00 (bs, IH), 3.68-3.57 (m, 4H), 3.47 (d, J= 3.3 Hz, IH), 3.40 (d, J= 1 1.7 Hz. IH). 3.17 (d, J= 6.9 Hz, IH), 2.92 (dd, J/= 8.1 Hz, J 2 = 17.7 Hz, lH), 2.74 (d, J= 17.1 Hz, IH), 2.48 (d, J= 18.6 Hz, IH), 2.32 (s, 6H), 2.28 (s. 3H), 1.99 (s, 3H), 1.76 (dd, J,= 12.0 Hz. J 2 = 16.2 Hz, IH). ESI-MS m/z: Calcd. for C 37 H 38 F 3 N 3 O 8 : 709. Found (M + -17): 692.3. Example 61 53 67 To a solution of 53 (57 mg, 0.0828 mmol) in CH 3 CN/H 2 O (1.5 mL/0.5 ml), AgNO 3 (650 mg, 3.81 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:1) to afford 67 (28 mg, 50%) as a white solid. Rf: 0.28 (EtOAc:MeOH 10:1). Η NMR (300 MHz, CDC1 3 ) d 6.47 (s, IH), 5.97 (s, IH), 5.88 (s, IH), 5.35 (bs, IH), 4.51 (bs, IH), 4.41 (bs, IH), 4.12-4.05 (m, IH), 4.00 (d, J= 2.7 Hz, IH), 3.77 (s, 3H), 3.64 (bs, IH), 3.46 (d, J= 3.3 Hz, IH), 3.34 (d, J= 11.4 Hz, IH), 3.18 (d, J= 7.5 Hz, IH), 2.95 (dd, J,= 8.4 Hz, J 2 = 18.3 Hz. IH), 2.70 (d. J= 15.6 Hz, IH), 2.48 (d, J= 17.7 Hz, IH), 2.28 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H). 1.98 (s, 3H), 1.68 (dd, J,= 12 Hz, J 2 = 15.6 Hz, IH), 0.86 (d, J= 6.3 Hz, 3H). ESI-MS m/z: Calcd. for C 32 H 37 F 3 N 4 O 9 : 678.66. Found (M + -17): 661.2. Example 62 48 68 To a solution of 48 (32 mg, 0.0529 mmol) in CH 3 CN/H 2 O (1.5 ml/0.5 ml), AgNO 3 (270 mg, 1.58 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:1) to afford 68 (18 mg, 56%) as a white solid. Rf : 0.40 (EtOAc-.MeOH 5:1). 1H NMR (300 MHz, CDC1 3 ) d 6.50 (s, IH), 5.95 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 5.23 (d, J= 6.9 Hz, IH), 4.45 (d, J= 3.3 Hz, IH), 4.38 (s, IH), 4.01 (d, J= 2.4 Hz, IH), 3.78 (m, IH), 3.77 (s, 3H), 3.41-3.37 (m, IH), 3.17-3.15 (m, IH), 2.96 (dd, J,= 7.8 Hz, Jf= 18.0 Hz, IH), 2.70 (d, J= 15.3 Hz, IH), 2.40 (d, J= 18.0 Hz, IH), 2.30 (s, 6H), 2.27 (s, 3H), 1.76- 1.65 (m, IH), 1.35-1.25 (m, 2H), 0.89-0.82 (m, IH), 0.69 (d, J= 6.6 Hz, 3H), 0.58 (d, J= 6.6 Hz, 3H) Example 63 To a solution of 51 (27 mg, 0.04 mmol) in CH 3 CN/H 2 O (1.5 ml/0.5 ml). AgNO 3 (204 mg, 1.19 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:1) to afford 69 (10 mg, 38%) as a white solid. Rf: 0.38 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDCl 3 ) d 6.48 s, lH), 6.16 (bs, IH), 5.98 (d, J= 1.5 Hz, IH), 5.89 (d, J= 1.5 Hz, IH), 5.33 (t, J= 6.0 Hz, IH), 4.50 (m, IH), 4.40 (m, IH), 4.11-4.09 (m, IH), 4.00 (d, J= 2.6Hz, IH), 3.78 (s, 3H), 3.41-3.32 (m, 3H), 3.18 (d, J= 8.4 Hz, IH), 2.94 (dd, J,= 8.4 Hz, J 2 = 18.3 Hz, IH), 2.70 (d, J= 14.4 Hz, IH), 4.45 (d, J= 18.3 Hz, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.04 (s, 3H), 2.00-1.86 (m, 3H), 1.73 (m, IH), 0.87 (d, J= 6.3 Hz, 6H). Example 64 63 70 To a solution of 63 (15 mg, 0.023 mmol) in CH 3 CN/H 2 O (1.5 ml/0.5 ml). AgNO 3 (118 mg, 0.691 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc-.MeOH 5:1) to afford 70 (20.1 mg, 85%) as a white solid. Rf: 0.43 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) d 7.38-7.28 (m, 5H), 6.48 (s, IH), 5.98 (d, J=l .5 Hz, IH), 5.91 (d, J=1.5 Hz, IH), 5.75 (bs, IH), 5.38 (brd, IH), 5.30 (bs, IH), 4.53 (m, IH), 4.42 (m, IH), 4.02 (d, J=2.7 Hz, IH), 3.78-3.65 (m, 5H), 3.46-3.40 (m, 2H), 3.17 (d, J=7.8 Hz, IH), 2.94 (dd, J ; =7.8 Hz, J 2 =17.7 Hz, IH), 2.73 (d, J=16.8 Hz, IH), 2.45 (d, J=18.0 Hz, 1H), 2.31 (s, 6H), 2.28 (s, 3H), 1.97 (s, 3H), 1.77 (dd, J,=12.0 Hz, J 2 =15.3 Hz, IH). Example 65 65 71 To a solution of 65 (25 mg, 0.042 mmol) in CH 3 CN/H 2 O (1.5 ml/0.5 ml), AgNO 3 (215.56 mg, 1.269 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHCO 3 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:2) to afford 71 (16mg« 65%) as a white solid. Rf: 0.0.5 (EtOAc:MeOH 5:2). Η NMR (300 MHz, CDC1 3 ) d 6.50 (s, IH), 5.95 (d, J=1.5 Hz, IH), 5.78 (s, IH), 5.19 (bs, IH), 4.45 (d, J=3.3 Hz, IH), 4.37 (bs, IH), 4.11 (brd, J=4.8 Hz, IH), 4.01 (d, J=2.1 Hz, IH), 3.76 (s, IH), 3.71-3.69 (m, IH), 3.49-3.35 (m, IH), 3.24 (d, J=13.5 Hz, IH), 3.15 (d, J=9.3 Hz, IH), 2.95 (dd, J / =8.1 Hz, J 2 =17.7 Hz, IH), 2.70 (d, J=15.6 Hz, IH), 2.40 (d, J=18.0 Hz, IH), 2.31 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 1.96 (s, 3H), 1.75-1.66 (m, IH), 1.52-1.17 (m, 2H), 0.66 (t, J=7.2 Hz, 3H). Example 66 To a solution of 45 (35 mg, 0.0672 mmol) in CH 2 C1 2 (0.3 mL), hydrocinnamoyl chloride ( 11.58 μl, 0.0672 mmol) and pyridine (5.43 μL, 0.0672 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex: ethyl acetate 2:1 to ethyl acetate) to afford 72 (30 mg, 68%) as a white solid. Rf: 0.51 (ethyl acetate:MeOH 10:1). Η NMR (300 MHz, CDC1 3 ) δ 7.23-7.12 (m. 3H), 7.05-7.00 (m, 2H). 5.97 (d. J= 1.2 Hz. IH), 5.91 (d, J= 1.2 Hz, IH), 5.73 (s, IH), 5.04 (brt, IH), 4.08 (d, J= 2.4 Hz. IH), 4.02 (bs. IH), 4.00 (d, J= 2.4 Hz, IH), 3.58 (dd, J,= 4.5 Hz, J 2 = 13.8 Hz, IH), 3.47 (bs, 3H), 3.33 (d. J= 7.5 Hz, IH), 3.29 (dt, Jr 2.7 Hz, J 2 = 11.7 Hz, IH), 3.00 (dd, J,= 7.8 Hz, J 2 = 18.3 Hz, IH), 2.79 (d, J= 14.1 Hz, IH), 2.58-2.50 (m, 3H), 2.32 (s, 3H), 2.29 (s, 3H), 2.03 (s. 3H), 2.01 (s, 3H), 1.94-1.76 (m, 4H). ESI-MS m/z: Calcd. for C 37 H4oN 4 O 7 : 652.7. Found (M+Na) + : 675.3. Example 67 To a solution of 45 (45 mg, 0.0576 mmol) in CH C1 2 (0.3 mL), phenyl acetyl chloride ( 7.61 μl, 0.0576 mmol) and pyridine (4.6 μL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 3:1 to Hex:ethyl acetate 1 : 1 ) to afford 73 (25.8 mg, 70 %) as a white solid. Rf: 0.5 (Hex:ethyl acetate:MeOH 5:10:2). Η NMR (300 MHz, CDC1 3 ) δ 7.18-7.17 (m, 3H), 6.85 (bs, 2H), 6.54 (s, IH), 5.89 (d, J= 1.5Hz, IH), 5.83 (d, J= 1.5 Hz, IH), 5.76 (s, IH), 5.08 (bs, IH), 4.12 (d, J= 2.1 Hz, IH), 4.09 (d, J= 2.1 Hz, IH), 3.98 (bs, IH), 3.73 (s, 3H), 3.51-3.46 (m, 2H), 3.35 (d, J= 8.4 Hz, IH), 3.25 (dt, J } = 2.7 Hz, J 2 = 12.0 Hz, IH), 3.03 (d, J= 8.7 Hz, IH), 3.02-2.94 (m, 2H), 2.75 (d, J= 16.8 Hz, IH), 2.63 (d, J= 18.0 Hz, IH), 2.35 (s, 3H), 2.30 (s, 3H), 2.22 (s. 3H9, 1.98 (s, 3H), 1.80 (dd, J,= 12.0 Hz, J = 16.2 Hz, IH). ESI-MS m/z: Calcd. for C 36 H 38 N 4 O 7 : 638.7. Found (M+l) + : 639.2. Example 68 45 74 To a solution of 45 (30 mg, 0.0576 mmol) in CH 2 C1 2 (0.3 mL), propyonyl chloride ( 5 μL, 0.0576 mmol) and pyridine (4.6 μL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 5:1 to Hex:ethyl acetate 1 :1 to ethyl acetate) to afford 74 (23 mg, 70 %) as a white solid. Rf: 0.59 ((Hex:ethyl acetate:MeOH 5:10:2). 1H NMR (300 MHz, CDC1 3 ) δ 6.50 (s,lH), 5.97 (d, J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.76 (s, IH), 5.00 (t, IH), 4.09 (d, J= 1.2 Hz, IH), 4.04 (bs, 2H), 3.74 (s, 3H), 3.62 (dd, J,= 6.6 Hz, J2= 13.2 Hz, IH), 3.43 (bs, IH), 3.37 (d, J= 8.4 Hz, IH), 3.29 (d, J= 12.0 Hz, IH), 3.02 (dd, J/= 8.1 Hz, Jf= 18.3 Hz, IH), 2.80 (d, J= 14.4 Hz, IH), 2.55 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.78 (dd, J,= 12.0 Hz, J 2 = 15.6 Hz, IH), 1.64-1.50 (m, 2H), 0.70 (t, J= 7.8 Hz, 3H). ESI-MS m/z: Calcd. for C 3 ιH 36 N 4 O 7 : 576.6. Found (M+l) + : 577.2. Example 69 To a solution of 45 (15 mg, 0.0288 mmol) in CH 2 C1 2 (0.25 mL), myristoyl chloride ( 7.83 μL, 0.0288 mmol) and pyridine (2.3 μL, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 6:1 to Hex:ethyl acetate 1 :1) to afford 75 (15 mg, 71 %) as a white solid. Rf: 0.65 (Hex:ethy acetate:MeOH 10:10:1). 1H NMR (300 MHz, CDC1 3 ) δ 6.49 (s, IH), 5.97 (d, J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.72 (s, IH), 4.99 (t, IH), 4.09 (d, J= 1.5 Hz, IH), 4.05 (d, J= 1.5 Hz, IH), 4.02 (bs, IH), 3.76 (s, 3H), 3.61-3.59 (m, IH), 3.39 (bs, IH), 3.35 (d, J= 7.8 Hz, IH), 3.29 (d, J= 12.3 Hz, IH), 3.04 (dd, Jf= 8.1 Hz, J 2 = 18.3 Hz, IH), 2.78 (d, J= 15.6 Hz, IH), 2.55 (d, J= 18.3 Hz, IH), 2.32 (s, 6H), 2.25 (s, 3H), 1.99 (s, 3H), 1.78 (dd, J,= 12.3 Hz, J 2 = 15.0 Hz, IH), 1.25- 1.24 (m, 12H), 0.87 (d, J= 6.0 Hz, 3H). ESI-MS m/z: Calcd. for C 42 H 58 N 4 O 7 : 730.9. Found (M+l) + : 731.4. Example 70 To a solution of 45 (15 mg, 0.0288 mmol) in CH 2 C1 2 (0.25 mL), stearoyl chloride ( 9.7 μL, 0.0288 mmol) and pyridine (2.3 μL, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 3:1 to Hex:ethyl acetate 1 :1) to afford 76 (16 mg, 70 %) as a white solid. Rf: 0.46 (Hex:ethyl acetate:MeOH 10:10:1). Η NMR NMR (300 MHz, CDC1 3 ) δ 6.49 (s, IH), 5.98 (d, J= 1.5 Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.73 (s, IH), 4.99 (t, J= 5.7 Hz, IH), 4.09 (d, J= 1.8 Hz, IH), 4.05 (d, J= 2.4 Hz, IH), 4.01 (bs, IH), 3.76 (s, 3H), 3.61-3.59 (m, IH), 3.38 (bs, IH), 3.36 (d, J= 7.2 Hz, IH), 3.28 (d, J= 12.0 Hz, IH), 3.03 (dd, J / = 7.8 Hz, J 2 = 18.3 Hz, IH), 2.78 (d, J- 15.9 Hz, IH), 2.57 (d, J= 18.3 Hz, IH), 2.32 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J / = 11.7 Hz, J 2 = 15.6 Hz, IH), 1.25-1.24 (m, 16H), 0.87 (d, J= 6.3 Hz, 3H). ESI-MS m/z: Calcd. for C 46 H 66 N 4 O 7 : 786.4. Found (M+22) + : 809.5. Example 71 To a solution of 45 (31 mg, 0.0595 mmol) in CH 2 C1 2 (0.3 mL), hexanoyl chloride ( 8.32 μL, 0.0595 mmol) and pyridine (4.8 μL, 0.0595 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO . filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 3:2 to ethyl acetate) to afford 77 (26 mg, 70 %) as a white solid. Rf: 0.65 (ethyl acetate MeOH 10: 1). 'H NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 5.98 (d, J= 1.5 Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.74 (s, IH), 5.00 (t, J- 5.4 Hz, IH), 4.09 (d, J= 2.7 Hz, IH), 4.05 (d, J= 2.4 Hz, IH), 4.01 (bs, IH), 3.76 (s, 3H), 3.61-3.58 (m, IH), 3.02 (dd, 18.3 Hz, IH), 2.78 (d, J= 14.4 Hz, IH), 2.56 (d, J= 18.3 Hz, IH), 2.31 (s, 6H), 2.25 (s, 3H), 2.00 (s, 3H), 1.78 (dd, J / = 12.0 Hz, J 2 = 15.9 Hz, IH), 1.53-1.40 (m, 2H), 1.29-1.12 (m, 4H), 1.07-0.97 ( , 2H), 0.81 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 3 H 42 N 4 O 7 : 618.7. Found (M+l) + : 619.3. Example 72 45 78 To a solution of 45 (20 mg, 0.0384 mmol) in CH 2 C1 2 (0.3 mL), trans-crotonyl chloride (3.68 μL, 0.0384 mmol) and pyridine (3.1 μL, 0.0384 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:ethyl acetate 4:1 to ethyl acetate) to afford 78 (16 mg, 71 %) as a white solid. Rf: 0.55 (ethyl acetate:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.50-6.40 (m, IH), 6.46 (s, IH), 5.97 (d, J= 1.5 Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.77 (s, IH), 5.08 (bst, IH), 4.10 (d, J= 1.5 Hz, IH), 4.05 (m, 2H), 3.78 (s, 3H), 3.67 (bs, IH), 3.42-3.29 (m, 3H), 3.04 (dd, J,= 8.1 Hz, J 2 = 18.3 Hz, IH), 2.78 (d, J= 15.3 Hz, IH), 2.53 (d, J= 18.3 Hz, IH), 2.32 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J / = 12.0 Hz, J 2 = 15.6 Hz, IH), 1.70 (dd, J,= 1.2 Hz, J 2 = 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 32 H 36 N 4 O 7 : 588.6. Found (M+l) + : 589.3. Example 73 45 79 To a solution of 45 (50 mg, 0.096 mmol) in CH 2 C1 2 (0.5 mL), Cbz-L-Val-OH (24.12 mg, 0.096 mmol) and carbonyl diimidazole (18.7 mg, 0.115 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH 2 C1 2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 4:1) to afford 79 (25 mg, 34 %) as a white solid. Rf: 0.7 (EtOAc:MeOH 5:l). Η NMR (300 MHz, CDC1 3 ) δ 7.33-7.28 (m, 5H), 6.45 (s, IH), 5.96 (s, IH), 5.90 (bs, IH), 5.82 (s, IH), 5.53 (bs, IH), 5.09 (bs, IH), 5.05 (d, J= 3.3 Hz, 2H), 4.16 (bs, IH), 4.09 (d, J= 2.4 Hz, IH), 4.02 (bs, IH), 3.75 (s, 3H), 3.74 (m, IH), 3.37-3.35 (m, 2H), 3.26-3.21 (m, 3H), 3.00 (dd, J / = 8.1 Hz, J 2 = 18.3 Hz, IH), 2.77 (d, J= 15.6 Hz, IH), 2.55 (d, J= 18.0 Hz, IH), 2.30 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 1.98 (s, 3H), 1.70-1.66 (m, IH), 0.65 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 41 H 47 N 5 O 9 : 753.8. Found (M+l) + : 754.2. Example 74 To a solution of 72 (18 mg, 0.0275 mmol) in CH 3 CN H 2 O (1.5 mL/0.5 mL). AgNO 3 (140.5 mg, 0.827 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH C1 2 (20 L). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 10:1) to afford 80 (13 mg, 74 %) as a white solid. Rf: 0.37 (EtOAc:MeOH 5:1). 'HNMR (300 MHz, CDC1 3 ) δ 7.23-7.11 (m, 3H), 7.06-7.01 (m, 2H), 6.43 (s, IH), 5.95 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 5.71 (bs, IH), 5.19 (bs, IH), 4.45 (d, J= 3.0 Hz, IH), 4.37 (bs, IH), 4.02-3.96 (m, IH), 3.75-3.68 (m, 2H), 3.48 (s, 3H), 3.41-3.36 (m, 2H), 3.28- 3.24 (m, IH), 3.15 (d, J= 7.5 Hz, IH), 3.01-2.88 (m, 2H), 2.70 (d, J= 15.9 Hz, IH), 2.57-2.51 (m, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (s, 6H), 1.77-1.68 (m, IH). ESI-MS m/z: Calcd. for CseFLu^Os: 643.3. Found (M- 17) + : 626.2. Example 75 73 81 To a solution of 73 (23 mg, 0.036 mmol) in CH 3 CN H 2 O (1.5 mL/1 mL), AgNO 3 (183 mg, 1.08 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH C1 2 (20 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc:MeOH 5:1 to MeOH) to afford 81 (9.3 mg, 41 %) as a white solid. Rf: 0.3 (EtOAc:MeOH 5:l). 'HNMR (300 MHz, CDC1 3 ) δ 7.17-7.13 (m, 3H), 6.85 (m, 2H), 6.54 (s, IH), 5.90 (d, J= 1.5 Hz, IH), 5.84 (d, J= 1.5 Hz, IH), 5.22 (m, IH), 4.43 (bs, IH), 4.39 (d, J= 2.4 Hz, IH), 4.00 (d, J= 2.4 Hz, IH), 3.71 (s, 3H), 3.64-3.29 (m, 2H), 3.16 (d, J= 8.7 Hz, IH), 2.98-2.88 (m, 3H), 2.67 (d, J= 14.8 Hz, IH), 2.45 (d, J= 18.3 Hz, IH), 2.33 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H), 1.68 (dd, J,= 12.8 Hz, J 2 = 14.7 Hz, IH). ESI-MS m/z: Calcd. for C 35 H 39 N 3 O 8 : 629.7. Found (M + - OH): 612.3. Example 76 74 82 To a solution of 74 (20 mg, 0.0346 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (176.6 mg, 1.04 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 mL). The solution was extracted and the organic layer was dried over Na 2 SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 1 : 1 ) to afford 82 (12.9 mg, 66 %) as a white solid. Rf: 0.3 (EtOAc:MeOH 5:l). 1H NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 5.95 (d, J= 1.2 Hz, IH), 5.89 (d, J= 1.2 Hz, IH), 5.19 (d, IH), 4.46 (d, J= 3.0 Hz, IH), 4.38 (d, J= 1.8 Hz, IH), 4.00 (d, J= 2.1 Hz, IH), 3.74 (s, 3H), 3.70-3.66 (m, IH), 3.38 (dt, J,= 2.7 Hz, J 2 = 13.2 Hz, IH), 3.25 (d, J= 13.8 Hz, IH), 3.16 (d, J= 7.5 Hz, IH), 2.96 (dd, J,= 7.2 Hz, J = 17.7 Hz, IH), 2.71 (d, J= 15.6 Hz, IH), 2.40 (d, J= 18.0 Hz, IH), 2.30 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.97 (s, 3H), 1.71 (dd, J ; = 11.7 Hz, J 2 = 15.3 Hz, IH), 1.60-1.48 (m, 2H), 0.67 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 30 H 37 N 3 O 8 : 567.6. Found (M- 17) + : 550.2. Example 77 83 77 To a solution of 77 (14 mg, 0.0226 mmol) in CH 3 CN H 2 O (1.5 mL/1 mL), AgNO 3 (115.3 mg, 0.68 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc:MeOH 5:1) to afford 83 (9 mg, 65 %) as a white solid. Rf: 0.25 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 5.96 (d, J= 1.5 Hz, IH), 5.89 (d, J= 1.5 Hz, IH), 5.73 (bs, IH), 4.44 (d, J= 3.6 Hz, IH), 4.37 (s, IH), 4.01 (d, J= 2.4 Hz, IH), 3.77 (s, 3H), 3.73-3.64 (m, IH), 3.39 (dt, J / = 3.0 Hz, J 2 = 9.3 Hz, IH), 3.22 (d, J= 14.5 Hz, IH), 3.16 (d, J= 7.5 Hz, IH), 2.95 (dd, J,= 8.1 Hz, J = 17.4 Hz, IH), 2.70 (d, J= 14.5 Hz, IH), 2.41 (d, J= 18.3 Hz, IH), 2.30 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.71 (dd, J,= 12.0 Hz, J 2 = 15.6 Hz, IH), 1.48-1.46 (m, 2H), 1.24-1.10 (m, 4H), 1.00-0.95 (m, 2H), 0.80 (t, J- 7.2 Hz, 3H). ESI-MS m z: Calcd. for C 33 H 3 N 3 O 8 : 609.7. Found (M-17) + : 592.3. Example 78 78 84 To a solution of 78 (15 mg, 0.025 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (130 mg, 0.764 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq satNaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 1:1) to afford 84 (10 mg, 71 %) as a white solid. Rf: 0.19 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.49 (s, IH), 6.47-6.37 (m, IH), 5.94 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, IH), 5.77 (bs, IH), 5.26 (d, J= 5.7 Hz, IH), 4.93 (d, J= 14.7 Hz, IH), 4.48 (d, J= l l.l Hz, lH), 4.38 (d, J= 2.7 Hz, 1 H), 4.02 ((d, J= 2.1 Hz, IH), 3.79 (s, 3H), 3.76-3.72 (m, IH), 3.42 (dt, J,= 2.7 Hz, J 2 = 12.0 Hz, IH), 3.28 (d, J= 13.2 Hz, IH), 3.15 (d, J= 6.6 Hz, IH), 2.96 (dd, Jf= 8.7 Hz, J 2 = 18.0 Hz, IH), 2.70 (d, J= 15.0 Hz, IH), 2.38 (d, J= 18.0 Hz, IH), 2.30 (s, 3H), 2.28 (s, 3H), 1.95 (s, 3H), 1.72 (dd, J/= 12.3 Hz, J 2 = 17.4 Hz, IH), 1.98 (dd, J / = 1.5 Hz, J 2 = 6.9 Hz, 3H). ESI-MS m z: Calcd. for C 3 ιH 37 N 3 O 8 : 579.6. Found (M-17) + : 562.3. Example 79 To a solution of 43 (25 mg, 0.422 mmol) in CH 2 C1 2 (0.3 mL), hydrocinnamoyl chloride (6.27 μL, 0.422 mmol) and pyridine (3.41 μL, 0.422 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 CI 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex: EtOAc 4:1 to EtOAc) to afford 85 (30 mg, 68 %) as a white solid. Rf: 0.54 (EtOAcMeOH 10:1). Η NMR (300 MHz, CDC1 3 ) δ 7.28-7.14 (m, 5H), 6.45 (s, IH), 6.07 (brd, IH), 5.99 (d, J= 1.2 Hz, IH), 5.90 (d, J= 1.2 Hz, IH), 5.88 (s, IH), 5.31 (brt, IH), 4.09-4.06 (m, 3H), 3.80- 3.75 (m, IH), 3.73 (s, 3H), 3.57-3.51 (m, 2H), 3.38 (d, J= 7.5 Hz, IH), 3.24 (m, IH), 3.00 (dd, J / = 8.4 Hz, J 2 = 18.0 Hz, IH), 2.89-2.85 (m, 2H), 2.79 (d, J= 16.5 Hz, IH), 2.61 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.79 (dd, J,= 12.3 Hz, J 2 = 16.2 Hz, IH), 0.72 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 40 H 45 N 5 O 8 : 723.8. Found (M+23) + : 746.3. Example 80 86 43 To a solution of 43 (20 mg, 0.0338 mmol) in CH 2 C1 2 (0.25 mL), hexanoyl chloride (4.72 μL, 0.0338 mmol) and pyridine (2.73 μL, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 1 :1 to EtOAc) to afford 86 (10 mg, 43 %) as a white solid. Rf: 0.74 (EtOAc:MeOH 10:1). Η NMR (300 MHz, CDC1 3 ) δ 6.47 (s, IH), 6.12 (brd, IH), 6.00 (d, J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.30 (m, IH), 4.09-3.99 (m, 3H), 3.84-3.82 (m, IH), 3.75 (s, 3H), 3.57-3.55 (m, 2H), 3.39 (d, J= 6.9 Hz, IH), 3.24 (d, J= 12.0 Hz, IH), 3.04 (dd, J,= 9.0 Hz, J 2 = 18.3 Hz, IH), 2.77 (d, J= 115.3Hz, IH), 2.63 (d, J= 18.0 Hz, IH), 2.32 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J/= 11.7 Hz, J 2 = 15.6 Hz, IH), 1.55-1.50 (m, 2H), 1.30-1.22 (m, 6H), 0.87 (t, J= 6.9 Hz, 3H), 0.75 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 37 H 7 N 5 O 8 : 689.8. Found (M+l) + : 690.3. Example 81 To a solution of 43 (33 mg, 0.0557 mmol) in CH 2 C1 2 (0.4 mL), phenyl acetyl chloride (7.36 μL, 0.0557 mmol) and pyridine (4.5 μL, 0.0557 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 2:1) to afford 87 (13 mg, 32 %) as a white solid. Rf: 0.63 (Hex:EtOAc:MeOH 5:10:2). Η NMR (300 MHz, CDC1 3 ) δ 7.37-7.20 (m, 5H), 6.26 (s, IH), 6.14 (d, J= 6.6 Hz, IH), 5.98 (d, J= 1.2 Hz, IH), 5.83 (s, IH), 5.27 (t, J= 6.2 Hz, IH), 4.11 (d, J= 2.1 Hz, IH), 4.07 (d, J= 3.0 Hz, IH), 4.04 (s, IH), 3.86-3.81 (m, IH), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.44 (bs, 2H), 3.36 (d, J= 8.1 Hz, IH), 3.22 (dt, J / = 2.7 Hz, J 2 = 12.0 Hz, IH), 2.93 (dd, J,= 7.2 Hz, J 2 = 18.3 Hz, IH), 2.77 (d, J= 14.4 Hz, IH), 2.59 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 2.01 (s, 3H), 1.78 (dd, J,= 10.8 Hz, J = 15.6 Hz, IH), 0.65 (d, J= 6.3 Hz, IH). ESI-MS m/z: Calcd. for C 39 H 3 N 5 O 8 : 709.8. Found (M+l) + : 710.3. Example 82 To a solution of 43 (30 mg, 0.05 mmol) in CH 2 C1 2 (0.3 mL), propionyl chloride (4.40 μL, 0.05 mmol) and pyridine (4.04 μL, 0.05 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 1 :1 to EtOAc) to afford 88 (18 mg, 56 %) as a white solid. Rf: 0.49 (Hex:EtOAc:MeOH 1 :10:2). 'H NMR (300 MHz, CDC1 3 ) δ 6.46 (s, IH), 6.16 (brd, IH), 5.99 (d, J= 1.2 Hz, IH), 5.95 (s, IH), 5.90 (d, J= 1.2 Hz, IH), 5.34 brt, IH), 4.12-4.06 (m, 3H), 3.84 (bs, IH), 3.74 (s, 3H), 3.63 (dd, J ; = 6.3 Hz, J 2 = 12.9 Hz, IH), 3.50-3.48 (m, IH), 3.39 (d, J= 8.1 Hz, IH), 3.23 (d, J= 11.7 Hz, IH), 3.00 (dd, J/= 8.4 Hz, J2= 18.3 Hz, IH), 2.78 (d, J= 15.6 Hz, IH), 2.63 (d, J= 18.3 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 1.87-1.80 (m, IH), 1.06 (t, J= 7.5Hz, 3H), 0.74 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd, for 647.7. Found (M+l) + : 648.2. Example 83 To a solution of 43 (20 mg, 0.0338 mmol) in CH 2 C1 2 (0.3 mL), propionyl chloride (3.238 μL, 0.0338 mmol) and pyridine (2.73 μL, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO , gradient Hex:EtOAc 3:1 to AcOEt) to afford 89 (1 1.5 mg, 52 %) as a white solid. Rf: 0.57 (EtOAc:MeOH 10:1). 1H NMR (300 MHz, CDC1 3 ) δ 6.82-6.70 (m, IH), 6.46 (s, IH), 6.11 (d, IH), 6.00 (d, J= 1.5 Hz, IH), 5.89 (d, J= 1.5 Hz, IH), 5.85 (s, IH), 5.77 (dd, J/= 1.5 Hz, J 2 = 15.3 Hz, IH), 5.37 (bst, IH), 4.13-4.06 (m, 3H), 3.19 (m, IH), 3.73 (s, 3H), 3.55 (m, 2H), 3.38 (d, J= 1.5 Hz, IH), 3.23 (d, J= 11.4 Hz, IH), 3.00 (dd, J ; = 8.4 Hz, J 18.3 Hz, IH), 2.78 (d, J= 15.0 Hz, IH), 2.65 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.85-1.82 (m, 4H), 0.77 (d, J= 6.3 Hz, 3H). ESI-MS m/z: Calcd. for C 35 H 4 1N 5 O J5 : 659.7. Found (M+l) + : 660.3. Example 84 90 43 To a solution of 43 (15 mg, 0.0253 mmol) in CH 2 C1 2 (0.3 mL), Cbz-L-Val-OH (6.39 mg, 0.0253 mmol) and carbonyl diimidazole (4.86 mg, 0.03 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH 2 CI 2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 1 :1 to EtOAc) to afford 90 (6.7 mg, 32 %) as a white solid. Rf: 0.79 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDCI 3 ) δ 7.35 (bs, 5H), 6.46 (s, IH), 6.28 (d, J= 6.0 Hz, IH), 5.98 (d, J= 1.2 Hz, IH), 5.89 (d, J- 1.2 Hz, IH), 5.77 (s, IH), 5.44 (bs, IH), 5.30 (bs, IH), 5.08 (s, 2H), 4.09-4.06 (m, 3H), 3.94-3.89 (m, IH), 3.70-3.66 (m, 5H), 3.38 (d, J= 11.7 Hz, IH), 3.01 96 (dd, Jι= 7.8 Hz, Jf= 18.3 Hz, IH), 2.79 (d, J= 14.1 Hz, IH), 2.63 (d, J= 18.0 Hz, IH), 2.30 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H9, 1.97-1.81 (m, 2H), 0.83 (d, J= 6.6 Hz, 3H), 0.80 (d, J= 6.6 Hz, 3H), 0.75 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for GWH S Z O OK): 824.9. Found (M +1) + : 825.4. Example 85 62 91 To a solution of 62 (20 mg, 0.030 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (154 mg, 0.90 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 CI 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 3:1) to afford 91 (13 mg, 66 %) as a white solid. Rf: 0.18 (EtOAc:MeOH 10:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.49 (s, IH), 6.16 (d, IH), 5.98 (d, J= 1.5 Hz, IH), 5.89 (d, J= 1.5 Hz, IH), 5.32 (bs, IH), 4.41 (bs, IH), 4.00 (bs, IH), 3.79 (s, 3H), 3.70-3.65 (m, 2H), 3.37-3.32 (m, 2H), 3.19-3.17 (m, IH), 2.94 (dd, J/= 9.0 Hz, J = 15.0 Hz, IH), 2.74 (d, J= 15.9 Hz, IH), 2.46 (d, J= 17.1 Hz, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.04-2.01 (m, 2H), 1.98 (s, 3H), 1.64-1.62 (m, IH), 1.54-1.52 (m, 2H), 0.89-0.84 (m, 6H). ESI-MS m z: Calcd. for 652.7. Found (M-17) + : 635.3. Example 86 To a solution of 85 (10 mg, 0.0138 mmol) in CH 3 CN H 2 O (1.5 mL/1 mL), AgNO 3 (70.4 mg, 0.414 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 4:1) to afford 92 (7 mg, 71 %) as a white solid. Rf: 0.20 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.25-7.13 (m, 5H), 6.47 (s, IH), 6.13 (brd, IH), 5.97 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 5.34 (brt, IH), 4.50 (bs, IH), 4.40 (bs, IH), 4.00 (bs, IH), 3.76 (s, 3H), 3.70-3.65 (m, 3H), 3.34 (d, J= 11.7 Hz, IH), 3.17 (d, J= 5.1 Hz, IH), 2.98- 2.83 (m, 3H), 2.72 (d, J= 14.4 Hz, IH), 2.44 (d, J= 19.2 Hz, IH), 2.30 (s, 3H), 2.27 (s, 6H), 1.97 (s, 3H), 1.72 (m, IH), 0.82 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C 39 H 46 N 4 O 9 : 714.8. Found (M-17) + : 697.3. Example 87 93 86 To a solution of 86 (6 mg, 0.0087 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (44 mg, 0.26 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 5:1) to afford 93 (5 mg, 85 %) as a white solid. Rf: 0.018 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.48 (s, IH), 6.17 (d, IH), 5.98 (d, J= 1.5 Hz, IH), 5.89 (d, J= 1.5 Hz, IH), 5.33 (bs, IH), 4.51 (d, IH), 4.40 (d, IH), 4.00 (d, IH), 3.78 (s, 3H), 3.76-3.65 (m, 2H), 3.36-3.32 (m, 2H), 3.18 (d, J= 6.9 Hz, IH), 2.98-2.89 (m, IH), 2.71 (d, J= 15.0 Hz, IH), 2.45 (d, J= 17.7 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.68-1.50 (m, 3H), 1.29-1.19 (m, 6H), 0.88-0.84 (m, 6H). ESI-MS m z: Calcd. for C 36 H 48 N 4 O 9 : 680.7. Found (M-17) + : 663.3. Example 88 87 94 To a solution of 87 (12 mg, 0.0169 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (86 mg, 0.507 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCU 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 5:1) to afford 94 (8.8 mg, 74 %) as a white solid. Rf: 0.28 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDCl 3 ) δ 7.34-7.18 (m, 5H), 6.37 (s, lH), 6.20 (d, IH), 5.96 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, IH), 5.30 (t, IH), 4.50 (bs, IH), 4.39 (d, J= 1.8 Hz, IH), 3.99 (d, J= 2.1 Hz, IH), 3.73 (s, 3H), 3.69-3.60 (m, 3H), 3.37-3.30 (m, 3H), 3.17 (d, J= 18.1 Hz, IH), 2.89 (dd, J / = 7.5 Hz, J 2 = 18.3 Hz, IH), 2.31 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H), 1.71 (dd, J= 11.7 Hz, Jf= 15.0 Hz, IH), 0.77 (d, J= 6.6 Hz, IH). ESI-MS m/z: Calcd. for 700.7. Found (M-17) + : 683.2. Example 89 88 95 To a solution of 88 (14 mg, 0.0216 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (110 mg, 0.648 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 5:1) to afford 95 (9.7 mg, 70 %) as a white solid. Rf: 0.16 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.48 (s, IH), 6.10 (d, IH), 5.97 (d, J= 1.2 Hz, IH), 5.89 (d, J= 1.2 Hz, IH), 5.36 (bs, IH), 4.51 (bs, IH), 4.40 (d, J= 2.1 Hz, IH), 4.00 (d, J= 2.1 Hz, IH), 3.78 (s, 3H), 3.76-3.62 ( , 3H), 3.33 (d, J= 11.7Hz, IH), 3.18 (d, J= 8.4 Hz, I H), 2.94 (dd, Jι= 8.4 Hz, J 2 = 16.5 Hz, IH), 2.72 (d, J= 15.0 Hz, IH), 2.45 (d, J= 18.3 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H), 1.86 (m, 2H), 1.73 (dd, J,= 12.0 Hz, J 2 = 15.0 Hz, IH), 1.05 (t, J= 7.8 Hz, 3H), 0.83 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C 33 H 42 N 4 O 9 : 638.7. Found (M-17) + : 621.2. Example 90 89 96 To a solution of 89 (10 mg, 0.015 mmol) in CH 3 CN H 2 O (1.5 mL/1 mL), AgNO 3 (77.2 mg, 0.454 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO , gradient EtOAc to EtOAc:MeOH 1:1) to afford 96 (9 mg, 92 %) as a white solid. Rf: 0.016 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.76-6.69 (m, IH), 6.47 (s, IH), 6.18 (brd, IH), 5.97 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, IH), 5.71 (dd, J/= 1.5 Hz, J 2 = 16.2 Hz, 3H), 5.32 (bs, IH), 4.50 (m, IH), 4.41 (m, IH), 3.99 (m, IH), 3.78 (m, 4H), 3.64-3.58 (m, 2H), 3.34 (d, J= 11.1 Hz, IH), 3.17 (d, J= 8.6 Hz, IH), 2.95 (dd, J,= 7.5 Hz, J 2 = 17.4 Hz, IH), 2.70 (d, J= 16.2 Hz, IH), 2.48 (d, J= 17.7 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 2.17 (s, 6H), 1.97 (s, 3H), 1.82- 1.74 (m, 4H), 0.88 (t, J= 5.2 Hz, 3H). ESI-MS m/z: Calcd. for C 34 H 42 N 4 O 9 : 650.7. Found (M-17) + : 633.3. Example 91 25 97 To a solution of 25 (100 mg, 0.177 mmol) in CH 2 C1 2 (0.5 mL), butyryl chloride (24 μL, 0.23 mmol) and pyridine (17 μL, 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH 2 C1 2 (30 mL) and washed with 0.1 N HCl (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex:EtOAc 3:1) to afford 97 (99 mg, 88 %) as a colorless oil. Rf: 0.64 (Hex:EtOAc l :l). 'H NMR (300 MHz, CDC1 3 ) δ 6.66 (s, IH), 6.16-6.05 (m, IH), 5.93 (d, J= 1.2 Hz, IH), 5.87 (d, J= 1.2 Hz, IH), 5.40 (dd, J,= 1.2 Hz, J = 17.1 Hz, IH), 5.26 (dd, J,= 1.2 Hz, J 2 = 10.2 Hz, IH), 5.13-5.08 (m, 2H), 4.44 (dd, 11.1 Hz, IH), 4.21-4.07 (m, 5H), 3.74 (m, IH), 3.72 (s, IH), 3.57 (s, 3H), 3.35 (d, . J= 10.5 Hz, IH), 3.26-3.21 (m, 2H), 3.98 (dd, J,= 8.7 Hz, J 2 = 18.0 Hz, IH), 2.54 (d, J= 18.0 Hz), 2.30 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 1.92- 1.65 (m, 3H), 1.42-1.34 (m, 2H), 0.80 (t, J= 7.5 Hz, 3H). ESI-MS m z: Calcd. for 633.7. Found (M+l) + : 634.3. Example 92 To a solution of 25 (100 mg, 0.177 mmol) in CH 2 C1 2 (0.4 mL), trans-3- (trifluoromethyl)cinnamoyl chloride (35 μL, 0.23 mmol) and pyridine (17 μL. 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for lh at room temperature and then, the solution was diluted with CH 2 C1 2 (30 mL) and washed with 0.1 N HCl (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , gradient Hex:EtOAc 6:1 to Hex:EtOAc 1:1) to afford 98 (122 mg, 90 %) as a white solid. Rf: 0.478 (Hex:EtOAc l :l). 'H NMR (300 MHz, CDC1 3 ) δ 7.64-7.48 (m, 4H), 7.37 (d, J= 15.6 Hz, IH), 6.62 (s, IH), 6.16-6.07 (m, IH), 6.12 (d, J= 15.6 Hz, IH), 5.94 (d, J= 1.2 Hz, IH), 5.89 (d, J= 1.2 Hz, IH), 5.41 (dd, J/= 1.8 Hz, J 2 = 17.1 Hz, IH), 5.28 (dd, J / = 1.8 Hz, J 2 = 12.0 Hz, IH), 5.04 (q, J= 6.0 Hz, IH), 4.60 (dd, J ; = 3.3 Hz, J 2 = 11.1 Hz, IH), 4.22-4.15 (m, 5H), 3.90 (dd, J,= 4.2 Hz, Jf= 11.1 Hz, IH), 3.55 (s, 3H), 3.38 (s, 3H), 3.35-3.34 (m, IH), 3.27-3.25 (m, IH), 3.22 (bs, IH), 2.98 (dd, J ; = 7.8 Hz, J = 18.0 Hz, IH), 2.61 (d, J= 17.7 Hz, I H), 2.29 (s, 3H), 2.16 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J,= 11.7 Hz, J 2 = 15.6 Hz, IH). ESI-MS m/z: Calcd. for G H H^F S ^O U : 761.7. Found (M+l) + : 762.3. Example 93 To a solution of 25 (68 mg, 0.12 mmol) in CH 2 C1 2 (0.4 mL), hydrocynnamoyl chloride (20 μL, 1.12 mmol) and pyridine (10 μL, 1.01 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH 2 C1 2 (30 mL) and washed with 0.1 N HCl (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO , gradient Hex:EtOAc 5:1 to Hex:EtOAc 2:1) to afford 99 (41 mg, 49 %) as a white solid. Rf: 0.47 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.29-7.18 (m, 3H), 7.04-7.02 (m, 2H), 6.66 (s, IH), 6.16-6.07 (m, IH), 5.93 (d, J= 1.2 Hz, IH), 5.87 (d, J= 1.2 Hz, IH), 5.40 (dd, J,= 1.7 Hz, J 2 = 17.4 Hz, IH), 5.26 (dd, J,= 1.7 Hz, J?= 10.2 Hz, IH), 5.09 (dd, J,= 6.0 Hz, J 2 = 8.7 Hz, 2H), 4.43 (dd, J / = 3.3 Hz, J 2 = 11.1 Hz, IH), 4.20-4.14 (m, 3H), 4.06 (t, J= 3.7 Hz, IH), 4.02 (d, J= 2.4 Hz, IH), 3.72 (dd, 11.1 Hz, IH), 3.56 (s, 3H), 3.55 (s, 3H), 3.32 (brd, J= 8.7 Hz, IH), 3.26 (dd, J;= 1.9 Hz, J 2 = 8.1 Hz, IH), 3.23-3.20 (m, IH), 3.01 (brd, J= 8.1 Hz, IH), 3.23-3.20 (m, IH), 3.26 (dd, J,= 1.9 Hz, J = 8.1 Hz, IH), 2.95 (d, J= 1.8 Hz, IH), 2.71-2.64 (m, 3H), 2.53 (d, J= 17.7 Hz, IH), 2.26 (s, 3H), 2.14 (s, 6H), 1.83 (dd, J / = 12.3 Hz, J 2 = 15.9 Hz, IH). ESI-MS m/z: Calcd. for GrøJLsFsNaOs: 695.3. Found (M+l) + : 696.3. Example 94 To a solution of 25 (100 mg, 0.177 mmol) in CH 2 C1 2 (0.4 mL), cynnamoyl chloride (35 mg, 0.21 mmol) and pyridine (17 μL, 0.21 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH C1 2 (30 mL) and washed with 0.1 N HCl (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 6:1) to afford 100 (94 mg, 76 %) as a white solid. Rf: 0.49 (Hex:EtOAc 1 :1). 'H NMR (300 MHz, CDC1 3 ) δ 7.42-7.33 (m, 6H), 6.62 (s, IH), 6.16-6.05 (m, IH), 6.10 (d, J= 15.9Hz, IH), 5.94 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 5.43 (dd. Jr= 3.0 Hz, J 2 = 17.1 Hz, IH), 5.27 (dd, J ; = 3.0 Hz, J 2 = 12.0 Hz, IH), 5.04 (q, J= 6.0 Hz, IH). 4.55 (dd, J,= 3.9 Hz, J2= 11.1 Hz, IH), 4.22-4.15 (m, 5H), 3.87 (dd, 1 1.1 Hz, IH), 3.55 (s, 3H), 3.39 (s, 3H), 3.36-3.33 (m, IH), 3.26-3.22 (m, 2H), 2.98 (dd, J / = 8.1 Hz, J 2 = 17.7 Hz, IH), 2.63 (d, J= 17.7 Hz, IH), 2.29 (s, 3H), 2.03 (s, 3H), 1.82 (dd, J,= 1 1.7 Hz, J 2 = 15.3Hz, IH). ESI-MS m/z: Calcd. for C 40 H4 3 N 3 O 8 : 693.3. Found (M+l) + : 694.3. Example 95 97 101 To a solution of 97 (40 mg, 0.063 mmol) in CH 2 Cl 2 (0.7 mL), acetic acid (17.8 μL), Pd(PPh 3 ) 2 Cl 2 (3.64 mg, 0.0052 mmol) and Bu 3 SnH (67.9 μL, 0.252 mmol ) were added at 23 °C. The reaction mixture was stirred for 2h at that temperature and then, the solution was poured into a pad of flash column (SiO 2 , gradient Hex:EtOAc 5:1 to Hex:EtOAc 3:1) to afford 101 (30 mg, 80 %) as a white solid. Rf: 0.4 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 6.65 (s, IH), 5.90 (d, J= 1.5 Hz, IH), 5.82 (d, J= 1.5 Hz, IH), 5.54 (s, IH), 5.33 (d, J= 6.0 Hz, IH), 5.13 (d, J= 6.0 Hz, IH), 4.54 (dd, J,= 3.6 Hz, J 2 = 11.4 Hz, IH), 4.18 (d, J= 2.1 Hz, IH), 4.13 (d, J= 2.4 Hz, IH), 4.07 (t, J= 3.3 Hz, IH), 3.75 (dd, J / = 3.9 Hz, J 2 = 11.1 Hz, IH), 3.70 (s, 3H), 3.35 (d, J= 8.4 Hz, IH), 3.24 (dd, J,= 2.7 Hz, J 2 = 8.7 Hz, IH), 3.10 (dd, J;= 2.4 Hz, J 2 = 15.0 Hz, IH), 3.01 (d, J= 8.1 Hz, IH), 2.95 (d, J= 7.8 Hz, IH), 2.58 (d, J= 18.3 Hz, IH), 2.29 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.89-1.66 (m, 3H), 1.36-1.25 (m, 2H), 0.77 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 32 H 39 N 3 O 8 : 593.6. Found (M+l) + : 594.8 Example 96 To a solution of 98 (37 mg, 0.0485 mmol) in CH 2 Cl (0.7 mL), acetic acid (20 μL), Pd(PPh 3 ) 2 Cl 2 (4 mg, 0.0057 mmol) and Bu 3 SnH (53 μL, 0.194 mmol ) were added at 23 °C. The reaction mixture was stirred for 5h at that temperature and then, the solution was poured into a pad of flash column (Siθ2, gradient Hex:EtOAc 6:1 to Hex:EtOAc 2:1) to afford 102 (25 mg, 71 %) as a white solid. Rf: 0.38 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.63-7.60 (M, 2H), 7.50-7.49 (M, 2H), 7.24 (d, J= 15.9 Hz, IH), 6.59 (s, IH), 5.98 (d, J= 15.9 Hz, IH), 5.92 (d, J= 1.5 Hz, IH), 5.84 (d, J= 1.5 Hz, IH), 5.66 (s, IH), 5.20 (d, J= 6.0 Hz, IH), 4.87 (d, J= 6.0 Hz, IH), 4.71 (dd, J,= 2.7 Hz, J 2 = 10.8 Hz, IH), 4.16-4.15 (m, 3H), 3.93 (dd, J,= 3.3 Hz, J 2 = 11.1 Hz, IH), 3.66 (s, 3H), 3.36 (brd, J= 10.2 Hz, IH), 3.26 (brd, J= 1 1.7 Hz, IH), 3.10 (brd, J= 15.0 Hz, IH), 2.96 (dd, J,= 7.8 Hz, J = 17.7 Hz, IH), 2.62 (d, J= 17.7 Hz, IH), 2.27 (s, 3H), 2.14 (s, 3H), 1.97 (s, 3H), 1.79 (dd, J,= 12.0 Hz, J = 15.8 Hz, IH). ESI-MS m z: Calcd. for C 38 H 38 F 3 N 3 O 8 : 721.7. Found (M+l) + : 722.2. Example 97 To a solution of 99 (41 mg, 0.059 mmol) in CH 2 C1 2 (1 mL), acetic acid (25 μL), Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.0071 mmol) and Bu 3 SnH (63 μL, 0.235 mmol ) were added at 23 °C. The reaction mixture was stirred for 4.5 h at that temperature and then, the solution was poured into a pad of flash column (SiO 2 , gradient Hex:EtOAc 6:1 to Hex:EtOAc 1:1) to afford 103 (34.2 mg, 89 %) as a white solid. Rf: 0.49 (Hex:EtOAc 1:1). Η NMR (300 MHz, CDC1 3 ) δ 7.24-7.15 (m, 3H), 7.03-7.01 (m, 2H), 6.65 (s, IH), 5.89 (bs, lH),5.82(bs, lH),5.49(s, IH), 5.31 (d,J=6.0Hz, IH), 5.12 (d,J=6.0 Hz. lH),4.53(dd, J,= 3.3 Hz,J 2 = 11.1 Hz, IH), 4.18 (d,J= 2.7 Hz, IH), 4.07 (m, 2H), 3.75 (dd,J / = 3.9 Hz, J 2 = 11.1 Hz, IH), 3.69 (s, 3H), 3.62 (s, 3H), 3.32 (d,J= 7.8 Hz, IH), 3.25 (d,J= 10.8 Hz, IH), 3.12 (d,J= 14.7Hz, IH), 3.00 (d,J= 7.8 Hz, IH), 2.94 (d,J= 8.1 Hz, IH), 2.66-2.60 (m, 3H), 2.57 (d,J= 18.0 Hz, IH), 2.28 (s, 3H), 2.14 (s, 3H), 2.10 (bs, 3H), 1.83-1.74 (m, IH). ESI-MS m/z: Calcd. for C 37 H 4) N 3 O 8 : 655.7. Found (M+l) + : 656.3. Example 98 To a solution of 100 (40 mg, 0.0576 mmol) in CH 2 C1 2 (1 mL), acetic acid (25 μL), Pd(PPh 3 ) 2 Cl 2 (4.8 mg, 0.007 mmol) and Bu 3 SnH (62 μL, 0.23 mmol ) were added at 23 °C. The reaction mixture was stirred for 5 h at that temperature and then, the solution was poured into a pad of flash column (Siθ 2 , gradient Hex:EtOAc 4:1 to Hex:EtOAc 1:1) to afford 104 (30 mg, 82 %) as a white solid. Rf: 0.41 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.36 (s, 5H), 7.30 (d, J= 16.2 Hz, IH), 6.59 (s, IH), 5.99 (d, J= 16.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.84 (d, J= 1.2 Hz, IH), 5.60 (s, IH), 5.20 (d, J= 5.6 Hz, IH), 4.94 (d, J= 5.6 Hz, IH), 4.63 (dd, J / = 3.3 Hz, J 2 = 11.4 Hz, IH), 4.18-4.15 (m, 3H), 3.91 (dd, J;= 3.9 Hz, J 2 = 11.1 Hz, IH), 3.66 (s, 3H), 3.49 (s, 3H), 3.35 (brd, J= 15.0 Hz, IH), 3.26 (brd, J= 11.4 Hz, IH), 3.10 (brd, J= 15.0 Hz, IH), 2.96 (dd, J,= 8.4 Hz, J 2 = 18.0 Hz, IH), 2.63 (d, J= 18.0 Hz, IH), 2.27 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J,= 12.0Hz, J 2 = 14.4 Hz, IH). ESI-MS m/z: Calcd. for C 37 H 39 N 3 O 8 : 653.7. Found (M+ 23) + : 676.2. Example 99 101 105 To a solution of 101 (24 mg, 0.041 mmol) in CH 2 C1 2 (0.4 mL), acetyl chloride (3 μL, 0.041 mmol), and pyridine (3.3 μL, 0.041 mmol ) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH 2 C1 2 (15 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 5:1 to Hex:EtOAc 1 :1) to afford 105 (23 mg. 88 %) as a white solid. Rf: 0.40 (Hex:EtOAc 1 :1). 'HNMR (300 MHz, CDCl 3 ) δ 6.66 (s, IH), 5.97 (d, J= 1.2 Hz, 1H), 5.91 (d, J= 1.2 Hz. IH), 4.58 (d, J= 3.0 Hz, IH), 4.54 (d, J= 3.0 Hz, IH), 4.07 (t, J= 3.3 Hz, IH), 3.77 (dd, J,= 3.9 Hz, J 2 = 11.4 Hz, IH), 3.73 (s, 3H), 3.57 (s, 3H), 3.35 (d, J= 10.2 Hz, IH), 3.22 (dt, J / = 2.7 Hz, J 2 = 11.7 Hz, IH), 2.98 (dd, J ; = 8.1 Hz, J 2 = 18.0 Hz, IH), 2.80 (d, J= 13.5 Hz. IH), 2.58 (d, J= 18.0 Hz, IH), 2.33 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.02 (s, 3H), 1.89-1.76 (m, 2H), 1.72-1.66 (m, IH), 1.37-1.25 (m, 2H), 0.78 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 34 H ,N 3 O 9 : 635.7. Found (M+l) + : 636.8. Example 100 To a solution of 102 (16 mg, 0.022 mmol) in CH 2 C1 (0.2 mL), acetyl chloride (1.9 μL, 0.0266 mmol), and pyridine (2.15 μL, 0.0266 mmol ) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 4:1 toEtOAc) to afford 106 (12 mg, 71 %) as a white solid. Rf: 0.60 (Hex:EtOAc 1 :1). l H NMR (300 MHz, CDC1 3 ) δ 7.83 (bs, IH), 7.65-7.58 (m, 2H), 7.49-7.44 (m, IH), 7.14 (d. J= 16.2 Hz, IH), 6.62 (s, IH), 6.06 (d, J= 16.2 Hz, IH), 6.00 (d, J= 1.2 Hz, IH), 5.95 (d, J= 1.2 Hz, IH), 5.02 (d, J= 5.7 Hz, IH), 4.96 (bs, IH), 4.92 (d, J= 5.7 Hz. IH). 4.15-4.11 (m, 3H), 3.88 (dd, J,= 3.3 Hz, J f = 11.1 Hz, IH), 3.08 (bs, 3H), 2.93 (dd, J,= 8.1 Hz. J 2 = 18.3 Hz. IH), 2.80 (d, J= 13.2 Hz, IH), 2.64 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.91 (s, 3H), 1.69 (dd, J 7 = 11.7 Hz, J = 15.9 Hz, IH). ). ESI-MS m/z: Calcd. for C 4 oH 40 F3N 3 O 9 : 763.7. Found (M+l) + : 764.2. Example 101 To a solution of 103 (34 mg, 0.052 mmol) in CH 2 C1 2 (0.2 mL), acetyl chloride (4.4 μL, 0.062 mmol), and pyridine (5 μL, 0.062 mmol ) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 CI 2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , gradient Hex:EtOAc 4:1 toEtOAc) to afford 107 (25.5 mg, 70 %) as a white solid. Rf: 0.48 (Hex.ΕtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.25-7.14 (m, 3H), 7.06-7.04 (m, 2H), 6.66 (s, IH), 5.96 (d, J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.11 (d, J= 5.4 Hz, IH), 4.14 (d, J= 3.3 Hz, IH), 4.07 (d, J= 3.6 Hz, IH), 4.04 (d, J= 2.7Hz, IH), 3.78 (dd, J,= 3.3 Hz, Jf= 10.8 Hz, IH), 3.55 (s, 3H), 3.51 (s, 3H), 3.33 (brd, J= 8.1 Hz, IH), 3.23 (dt, J,= 2.7 Hz, J = 11.7 Hz, IH), 2.97 (dd, J / = 8.1 Hz, J 2 = 18.0 Hz, IH), 2.81 (d, J= ll.l Hz, IH), 2.63-2.52 (m, 3H), 2.33 (s. 3H), 2.29 (s, 3H), 2.26-202 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.74 (dd, J,= 12.0 Hz, J2= 15.6 Hz, IH). ESI-MS m/z: Calcd. for C 39 H4 3 N 3 O 9 : 697.7. Found (M+l) + : 698.3. Example 102 To a solution of 104 (29 mg, 0.0443 mmol) in CH 2 C1 2 (0.3 mL). acetyl chloride (3.77 μL, 0.053 mmol), and pyridine (4.3 μL, 0.053 mmol ) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH 2 C1 2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ2, gradient Hex:EtOAc 4:1 toEtOAc) to afford 108 (21.6 mg, 70 %) as a white solid. Rf: 0.58 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.47-7.44 (m, 2H), 7.35-7.34 (m, 3H), 7.29 (d, J= 15.9 Hz, IH), 6.62 (s, IH), 5.99 (d, J= 1.2 Hz, IH), 5.93 (d, J= 1.2 Hz, IH), 5.05 (d, J= 5.7 Hz, IH), 4.94 (d, J= 5.7Hz, IH), 4.81 (d, J= 11.5 Hz, IH), 4.16-4.11 (m, 3H), 3.34 (brd, J= 5.4 Hz, IH), 3.24 (bs, 3H), 3.22-3.20 (m, 2H), 2.94 (dd, J/= 8.1 Hz, J 2 = 18.0 Hz, IH), 2.80 (d, J= 14.1 Hz, IH), 2.64 (d, J= 18.0 Hz, IH), 2.32 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.71 (dd, J,= 11.7 Hz, J f = 15.6 Hz, IH). ESI-MS m/z: Calcd. for C 39 K nN 3 O 9 : 695.7. Found (M+l) + : 696.2. Example 103 105 109 To a solution of 105 (16 mg, 0.025 mmol) in CH 2 C1 (0.2 mL), trifluoroacetic acid (77 μL, 1 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate ( 15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex:EtOAc 1 : 1 ) to afford 109 (12 mg, 81 %) as a white solid. Rf: 0.32 (Hex:EtOAc 1 :1). 'H NMR (300 MHz, CDC1 3 ) δ 6.43 (s, IH). 5.97 (d, J= 1.5 Hz, IH), 5.91 (d, J= 1.5 Hz, IH), 5.69 (s, IH), 4.51 (dd, J ; = 3.3 Hz, J 2 = 11.1 Hz, IH), 4.10-4.05 (m, 3H), 3.78-3.77 (m, IH), 3.75 (s, 3H), 3.33 (d, J= 8.1 Hz, IH), 3.22 (dt, J,= 2.7 Hz, J 12.0 Hz, IH), 2.96 (dd, J,= 8.4 Hz, J 2 = 17.7 Hz, IH), 2.80 (d, J= 15.6 Hz, IH), 2.55 (d, J= 18.0 Hz, I H). 2.33 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.87-1.66 (m, 3H), 1.37-1.27 (m, 2H), 0.77 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 32 H 31 N 3 O 8 : 591.6. Found (M+l) + : 592.8. Example 104 To a solution of 106 (90 mg, 0.1178 mmol) in CH 2 C1 2 (0.3 mL), trifluoroacetic acid (750 μL, 4.71 mmol) was added at 0 °C and the reaction mixture was stirred for 7 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 1 : 1 ) to afford 110 (71 mg, 84 %) as a white solid. Rf: 0.6 (Hex:EtOAc 1:1). 'H NMR (300 MHz, CDC1 3 ) δ 7.76 (bs, IH), 7.62-7.57 (m, 2H), 7.48-7.45 (m, IH), 7.12 (d, J= 16.2 Hz, IH), 6.37 (s, IH), 6.00 (d, J= 16.2 Hz, IH), 5.98 (d, J= 1.2 Hz, IH), 5.92 (d, J= 1.2 Hz, IH), 5.60 (bs, 1H), 4.88 (d, J= 10.2 Hz, IH), 4.14 (bs, IH), 4.10 (d, J= 2.4 Hz, IH), 4.03 (d, J= 2.4 Hz, IH), 3.89 (dd, J y = 2.7 Hz, Jf= 11.4 Hz, IH), 3.32 (d, J= 8.4 Hz, IH), 3.26-3.21 (m, 4H), 2.91 (dd, J / = 8.1 Hz, J = 18.0 Hz, IH), 2.82 (d, J= 13.8 Hz, IH), 2.58 (d, J= 18.0 Hz, IH), 2.33 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H), 1.84 (dd, J / = 12.0 Hz, J?= 15.6 Hz, IH). ESI-MS m/z: Calcd. for C 38 H 36 F 3 N 3 O 8 : 719.7. Found (M+l) + : 720.3. Example 105 To a solution of 107 (20 mg, 0.286 mmol) in CH 2 C1 (0.2 mL), trifluoroacetic acid (88 μL, 1.144 mmol) was added at 0 °C and the reaction mixture was stirred for 4 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 1 :1) to afford 111 (18 mg, 96 %) as a white solid. Rf: 0.39 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.23-7.16 (m, 3H), 7.06-7.04 (m, 2H), 6.43 (s, IH). 5.96 (d. J= 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, IH), 6.66 (s, IH), 4.52 (dd, J ; = 3.3 Hz. J = 11.1 Hz, IH). 4.07 (s, lH), 4.05 (d, J= 3.3 Hz, 1H), 4.03 (d, J= 2.4 Hz, IH), 3.76 (dd, J,= 3.6 Hz. J 2 = 11.1 Hz, IH), 3.56 (s, 3H), 3.31 (d, J= 7.5 Hz, IH), 3.23 (d, J= 12.0 Hz, IH), 2.95 (dd, J / = 8.1 Hz, J 2 = 18.0 Hz, IH), 2.80 (d, J= 15.3 Hz, IH), 2.63-2.58 (m, 2H), 2.53 (d, J= 18.0 Hz, IH), 2.33 (s, 3H), 2.61 (s, 3H), 2.21-2.09 (m, 2H), 2.13 (s, 3H), 2.02 (s, 3H). 1.85 (dd. J,= 1 1.7 Hz, J 2 = 115.3Hz, IH). ESI-MS m/z: Calcd. for C 37 H 39 N 3 O 8 : 653.7. Found (M+l ) + : 654.3. Example 106 To a solution of 108 (14 mg, 0.02 mmol) in CH 2 C1 2 (0.4 mL), trifluoroacetic acid (61.5 μL, 0.8 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 2:1) to afford 112 (12 mg, 92 %) as a white solid. Rf: 0.36 (Hex:EtOAc 1:1). 'H NMR (300 MHz, CDC1 3 ) δ 7.46-7.45 (m, 2H), 7.35-7.20 (m, 4H), 6.38 (s, IH), 6.05 (d, J= 15.9 Hz, IH), 5.98 (d, J= 1.2 Hz, IH), 5.93 (d, J= 1.2 Hz, IH), 5.57 (s, IH), 4.71 (d, J= 9.3 Hz, IH), 4.17-4.13 (m, 2H), 4.08 (d, J= 1.9 Hz, IH), 3.89 (dd. J,= 3.6 Hz. J 2 = 11.4 Hz, IH), 3.33 (m, 5H), 3.26-3.22 (m, IH), 2.93 (dd, J/= 9.0 Hz, J 2 = 17.4 Hz. IH), 2.34 (s. 3H), 2.25 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.81 (dd, J,= 12.0 Hz, J = 15.6 Hz, IH). ESI-MS m/z: Calcd. for C 37 H 37 N 3 O 8 : 651. Found (M+l) + : 652.2. Example 107 109 113 To a solution of 109 (10 mg, 0.017 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (86 mg, 0.5 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI 2 (15 mL). The solution was extracted and the organic layer was dried over Na SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 3:1) to afford 113 (7 mg, 71 %) as a white solid. Rf: 0.41 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.45 (s, IH), 5.95 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, IH), 5.65 (bs, IH), 4.50-4.48 (m, 2H), 4.44 (d, J- 2.1 Hz, IH), 3.96 (d, J= 3.0 Hz, IH), 3.76 (s, 3H), 3.74-3.70 (m, IH), 3.30 (d, J= 12.3 Hz, IH), 3.13 (d, J= 7.5 Hz, IH), 2.86 (dd, J,= 5.7 Hz, J2= 18.3 Hz, IH), 2.73 (d, J= 14.7 Hz, IH), 2.48 (d, J= 17.7 Hz, IH), 2.33 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86-1.55 (m, 3H), 1.42-1.23 (m, 2H), 0.75 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 3 ιH 38 N 2 O 9 : 582.6. Found (M-17) + : 565.3. Example 108 To a solution of 110 (42.8 mg. 0.059 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL). AgNO 3 (303 mg, 1.78 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 5:1) to afford 114 (30 mg, 71 %) as a white solid. Rf: 0.30 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 7.75 (bs, IH), 7.61-7.56 (m, 2H), 7.45-7.42 (m, IH), 7.12 (d, J= 16.2 Hz, IH), 6.38 (s, IH), 6.02 (d, J= 16.2 Hz, IH), 5.97 (d, J= 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, IH), 5.50 (bs, IH), 4.87 (bs, IH), 4.56 (m, IH), 4.45 (bs, IH), 3.92 (d, J= 2.4 Hz, IH), 3.31 (dt, J / = 3.6 Hz, J 2 = 12.9 Hz, IH), 3.21 (bs, 3H), 3.13 (d, J= 7.8 Hz, IH), 2.82 (dd, J / = 8.1 Hz, J 2 = 18.0 Hz, IH), 2.75 (d, J= 14.7 Hz, IH), 2.49 (d, J= 18.0 Hz, IH), 2.33 (s, 3H), 2.21 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H), 1.78 (dd, J,= 12.0 Hz, J 2 = 15.6 Hz, IH). ESI-MS m z: Calcd. for C 37 H 37 F 3 N 2 O 9 : 710.6. Found (M-17) + : 693.2. Example 109 To a solution of 111 (12 mg, 0.018 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (93.5 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 CI 2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Siθ 2 , gradient EtOAc to EtOAc:MeOH 1:1) to afford 115 (10 mg. 86 %) as a white solid. Rf: 0.43 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.23-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.45 (s, IH), 5.93 (d, J= 1.2 Hz, IH), 5.88 (d, J= 1.2 Hz, IH), 5.63 (brd, IH), 4.55-4.49 (m, 2H), 4.43 (d, J= 2.7 Hz, IH), 3.96 (d, J= 3.1 Hz, IH), 3.80-3.73 (m, IH), 3.56 (bs, 3H), 3.32 (dt, J,= 3.3 Hz, Jf= 12.6 Hz, IH), 3.13 (d, J= 6.0 Hz, IH), 2.86 (dd, J/= 7.5 Hz, J = 18.3 Hz, I H), 2.74 (d, J= 14.7 Hz, IH), 2.61-2.56 (m, 2H), 2.47 (d, J= 18.0 Hz, IH), 2.33 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.99-1.94 (m, 2H), 1.78 (dd, J/= 1 1.7 Hz, J = 15.0 Hz, I H). ESI-MS m/z: Calcd. for C 36 H 40 N 2 O 9 : 644.7. Found (M-17) + : 627.2. Example 110 To a solution of 112 (12 mg, 0.018 mmol) in CH 3 CN H 2 O (1.5 mL/1 mL), AgNO 3 (93 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 CI 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Siθ 2 , gradient EtOAc to EtOAc:MeOH 1:1) to afford 116 (8 mg, 70 %) as a white solid. Rf: 0.41 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.44-7.43 (m, 2H), 7.34-7.27 (m, 4H), 6.39 (s, I H), 6.03 (d, J= 15.9 Hz, IH), 5.96 (d, J= 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, IH), 5.55 (m, IH), 4.47 (m, IH), 4.50 (m, IH), 3.94 (d, J= 3.6 Hz, IH), 3.85 (dd, J,= 3.3 Hz, J 2 = 1 1.1 Hz. IH), 3.66 (bs, 3H), 3.34-3.31 (m, 2H), 3.13 (d, J= 5.1 Hz, IH), 2.93-2.73 ( , 2H). 2.53 (d. J= 18.0 Hz, IH), 2.33 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.94-1.82 (m, IH). ESI-MS m/z: Calcd. for C 36 H 38 N 2 O 9 : 642.7. Found (M-17) + : 625.2. Example 111 17 117 To a solution of 17 (6.28 g, 9.06 mmol) in CH 2 C1 2 (45.3 mL), allyl chloroformiate ( 3.85 mL, 36.24 mmol) and pyridine (2.93 mL, 36.24 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at 23°C and then, the solution was diluted with CH 2 C1 2 (150 mL) and washed with 0.1 N HCl (2 x 100 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure to give 117 (5.96 g, 84 %) which was used in following steps with no further purification. Rf: 0.56 (CH 2 Cl 2 :EtOAc 1:1). Η NMR (300 MHz, CDC1 3 ) δ 6.72 (s, IH), 6.05-5.94 (m, IH), 6.01 (s, IH), 5.91 (s, IH), 5.44 (dd, J7 = 1.2 Hz, J2 = 17.1 Hz, IH), 5.35 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, IH), 5.34 (m, IH), 5.10 (d, J = 5.7 Hz, IH), 5.05 (d, J = 5.7 Hz, IH), 4.68 (d, J = 5.7 Hz, IH), 4.65 (dt, Jl = 1.2 Hz, J2 = 6 Hz, IH), 4.18 (brd, J = 9 Hz, 2H), 4.04 (bs, IH), 3.70 (s, 3H), 3.67-3.60 (m, IH), 3.55 (s, 3H), 3.43-3.41 (m, 2H), 3.29-3.25 (m, 2H), 3.00 (dd, Jl = 8.7 Hz, J2 = 18.3 Hz, IH), 2.90 (dd, J7 = 2.4 Hz, J2 = 16.2 Hz, IH), 2.75 (d, J = 18.3 Hz, IH), 2.35 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H), 1.83 (dd, Jl = 11.4 Hz, J2 = 15.9 Hz, IH), 1.39 (s, 9H). 0.73 (d, J = 6.9 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 152.8, 148.6, 148.3, 144.6, 140.7, 140.6, 131.5, 131.2, 131.1, 130.4, 125.3, 125.0, 123.3, 120.9, 119.1, 118.8, 117.6, 112.9, 1 12.0, 101.6, 99.2, 71.8, 69.0, 68.4, 59.7, 59.2, 57.6, 57.3, 56.7, 55.8, 55.2, 41.4, 39.9, 28.2, 26.0, 25.0, 18.6, 15.6, 9.0. ESI-MS m/z: Calcd. for C 40 H 51 N 5 O 11 : 777.8. Found (M+l) + : 778.3 Example 112 118 117 To a solution of 117 (3.96 g, 5.09 mmol) in MeOH (37.4 mL), trimetylchlorosilane ( 6.5 mL, 50.9 mmol) was added at 0 °C. The reaction mixture was stirred for 4 h at 23°C and then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (70 mL) and washed with a saturated aqueous solution of NaHCO 2 (2 x 45 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated in vacuo to give 118 (2.77 g, 86 %) which was used in following steps with no further purification. Rf: 0.61 (Hex:EtOAc l :l). Η NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 6.45 (m, IH), 6.10-6.03 (m, IH), 6.00 (s, IH), 5.93 (s, IH), 5.47 (dd, Jl = 1.2 Hz, J2 = 17.1 Hz, IH), 5.38 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, IH), 4.81-4.64 (m, 2H), 4.10-4.03 (m, 3H), 3.75 (s, 3H), 3.70-3.44 (m, 2H), 3.35 (d, J = 8.1 Hz, IH), 3.28 (dt, J7 = 2.7 Hz, J2 = 9 Hz, IH), 2.98 (dd, J7 = 7.8 Hz, J2 = 18 Hz, IH), 2.90 (dd, J7 = 2.7 Hz, J2 = 16.2 Hz, IH), 2.78 (dd, Jl = 6.9 Hz, J2 = 14.1 Hz, IH), 2.63 (d, J = 18.3 Hz, IH), 2.30 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.88 (dd, J7 = 13.2 Hz, J2 = 15.6 Hz, IH), 0.95 (d, J = 6.9 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 175.8, 152.9, 146.6, 144.6, 142.5, 140.8, 140.6, 131.5, 131.3, 128.5, 121.1, 120.8, 118.9, 117.8, 117.0, 113.2, 111.9, 101.7, 68.9, 60.6, 59.1, 56.6, 56.4, 55.7, 55.2, 50.5, 41.7, 39.4, 26.1, 25.0, 21.0, 15.6, 9.2. ESI-MS m/z: Calcd. for C 33 H 39 N 5 O 8 : 633.6. Found (M+l) + : 634.2. Example 113 118 119 To a solution of 118 (3.52 g, 5.56 mmol) in CH2CI2 (28 mL), phenylisothiocyanate ( 3.99 mL, 33.36 mmol) was added at 23 °C. The reaction mixture was stirred for 3 and then, the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography to afford 119 (3.5 g, 82 %) as a white solid. Rf: 0.52 (CH 2 Cl 2 :EtOAc 1:5). Η NMR (300 MHz, CDC1 3 ) δ 7.69 (bs, IH), 7.49-7.46 (m, 2H), 7.34-7.21 (m, 2H), 6.96 (d, J = 6.9 Hz, IH), 6.06-5.97 (m, IH), 6.03 (s, IH), 5.96 (bs, IH), 5.91 (s, IH), 5.66 (s, IH), 5.47 (dd, J7 = 1.5 Hz, J2 = 17.1 Hz, IH), 5.37 (dd, J7 = 1.5 Hz, J2 = 10.5 Hz, IH), 5.36 (s, IH), 4.75-4.70 (m, 2H), 4.54-4-49 (m, 1H), 4.14 (d, J = 2.4 Hz, IH), 4.07-4.06 (m, 2H), 3.70 (s, 3H), 3.44 (m, IH), 3.35 (d, J = 8.1 Hz, IH), 3.21 (dt, J7 = 2.7 Hz. J2 = 6.6 Hz, IH), 2.94-2.82 (m, 2H), 2.63 (d, J = 18 Hz, IH), 2.24 (s, 3H), 2.06 (s, 3H), 2.06 (s, 3H), 1.90 (dd, J7 = 11.7 Hz, J2 = 15.9 Hz, IH), 0.71 (d, J = 6.9 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 178.6, 171.9, 152.8, 146.7, 144.5, 142.6, 140.8, 140.5, 136.3, 131.3, 131.0, 129.9, 129.8, 128.9, 126.7, 125.2, 124.3, 121.1, 120.6, 1 18.9, 117.7, 1 16.5, 112.8, 112.1, 101.6, 68.9, 60.5, 58.9, 57.3, 56.1, 55.9, 55.1, 53.3, 41.5, 39.2, 25.9, 24.6, 20.9, 15.4, 9.1. ESI-MS m/z: Calcd. for doH^NsOsS: 768.8. Found (M+l) + : 769.3. Example 114 119 To a solution of 119 (3.38 g, 4.4 mmol) in MeOH (22 mL), trimetylchlorosilane ( 2.3 mL, 22 mmol) was added at 0 °C. The reaction mixture was stirred for 1.5 h at 23°C and then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with 0.1 N HCl (2 x 75 mL). The aqueous phase was basified with a saturated aqueous solution of NaHCO2 and extracted with CH 2 CI2 (2 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure to afford 120 (2.47 g, 100 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC1 3 ) δ 6.45 (s, IH), 6.05-5.98 (m, IH), 5.97 (d, J = 1.2 Hz, IH), 5.90 (d, J= 1.2 Hz, IH), 5.44 (dd, J7 = 1.2 Hz, J2 = 17.1 Hz, IH), 5.35 (dd, J7 = 1.2 Hz, J2 = 10.2 Hz, IH), 4.75-4.71 (m, 2H), 4.12-4.10 (m, IH), 3.99 (d, J = 2.4 Hz, IH), 3.92 (bs, IH), 3.73 (s, 3H), 3.36-3.26 (m, 2H), 3.06 (dd, J7 = 8.4 Hz, J2 = 18 Hz, IH), 2.89 (dd, J7 = 2.7 Hz, J2 = 15.9 Hz, IH), 2.75-2.73 (m, 2H), 2.48 (d, J = 18 Hz, IH), 2.32 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.85 (dd, J7 = 11.7 Hz, J2 = 15.6 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 153.0, 146.6, 144.5, 142.8, 140.7, 131.5, 130.5, 128.9, 121.3, 120.9, 119.1, 117.9, 116.7, 113.8. 111.6, 101.5, 69.0, 60.6, 59.8, 58.7, 56.5, 56.0, 55.3, 44.2, 41.8, 31.6, 26.1, 25.7, 15.7, 9.2. ESI-MS m/z: Calcd. for C 30 H 34 N 4 O 7 : 562.6. Found (M+l) + : 563. 2. Example 115 To a solution of 120 (2.57 g, 4.4 mmol) in CH 2 C1 2 (44 mL), TrocCI ( 0.91 mL, 6.6 mmol) and pyridine (0.53 mL, 6.6 mmol) were added at -20 °C. The reaction mixture was stirred for 30 min at 0°C and then, the solution was diluted with CH 2 C1 2 (50 mL) and washed with 0.1 N HCl (2 x 25 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure to give 121 (3.24 g, 100 %) which was used in following steps with no further purification. Rf: 0.62 (EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 6.07-6.01 (m, IH), 5.99 (d, J = 1.2 Hz, IH), 5.93 (d, J = 1.2 Hz, IH), 5.68 (s, IH), 5.46 (dd, J7 = 1.2 Hz, J2 = 17.1 Hz, IH), 5.37 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, IH), 4.74 (t, J = 5.7 Hz, 2H), 4.63-4.62 (m, IH), 4.54 (d, J = 12 Hz, IH), 4.30 (d, J = 12 Hz, IH), 4.14-4.11 (m, 2H), 4.02-4.01 (m, 2H), 3.75 (s, 3H), 3.36- 3.26 (m, 3H), 3.04 (dd, J7 = 8.1 Hz, J2 = 17.7 Hz, IH), 2.91 (dd, J7 = 2.4 Hz, J2 = 15.6 Hz, IH), 2.60 (d, J = 17.7Hz, IH), 2.31 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.84 (dd, J7 = 12 Hz, J2 = 15.9 Hz, IH). ESI-MS m/z: Calcd. ' for C33H35CI3N4O9: 738.0. Found (M+l) + : 737.2. Example 116 121 122 To a solution of 121 (0.45 g, 0.60 mmol) in CH 3 CN (4 mL), diisopropylethylamine (2.17 mL, 12.46 mmol), bromomethyl methyl ether (0.76 mL, 9.34 mmol) and dimethylaminopyridine (8 mg, 0.062 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH 2 CI 2 (50 mL) and washed with 0.1 N HCl (2 x 25 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure to give 122 (0.453 g, 95 %) which was used in following steps with no further purification. Rf: 0.31 (RP-18 CH 3 CN-H 2 O 8:2). 'H NMR (300 MHz, CDC1 3 ) δ 6.70 (s, IH), 6.05-5.99 (m, IH), 5.97 (s, IH), 5.92 (s, IH), 5.43 (dd, J7 = 1.2 Hz, J2 = 17.1 Hz, IH), 5.34 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, IH), 5.10- 5.04 (m, 2H), 4.72-4.68 (m, 2H), 4.60 (t, J = 5.7 Hz, IH), 4.49 (d, J = 12.3 Hz, IH), 4.38 (d, J = 12.3 Hz, IH), 4.18 (d, J = 2.7 Hz, IH), 4.03-4.00 (m, 2H), 3.71 (s, 3H), 3.54 (s, 3H), 3.38-3.22 (m, 4H), 3.04 (dd, J7 = 7.8 Hz, J2 = 18.3 Hz, IH), 2.91 (dd, J7 = 2.4 Hz, J2 = 15.9 Hz, IH), 2.61 (d, J = 18 Hz, IH), 2.31 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 1.76 (dd, J7 = 11.7 Hz, J2 = 15.6 Hz, IH). ESI-MS m/z: Calcd. for C 33 H 39 Cl 3 N 4 Oι 0 : 782.0. Found (M+l) + : 783.2. Example 117 To a suspension of 122 (0.45 g, 0.579 mmol) in 90 % aqueous acetic acid (6 mL), powder zinc (0.283 g, 4.34 mmol) was added and the reaction was stirred for 6 h at 23 °C. Then, the mixture was filtered through a pad of celite which was washed with CH 2 CI 2 (25 mL). The organic layer was washed with an aqueous sat. solution of sodium bicarbonate (pH= 9) (2 x 15 mL), dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure to give 123 (0.351 g, 100 %) which was used in following steps with no further purification. Rf: 0.38 (SiO 2 , EtOAc:MeOH 5:1). 'H NMR (300 MHz, CDC1 3 ) δ 6.68 (s, IH), 6.06-5.99 (m, IH), 5.97 (d, J = 1.5 Hz, IH), 5.91 (d, J = 1.25 Hz, IH), 5.44 (dd, J7 = 1.5 Hz, J2 = 17.4 Hz, IH), 5.36 (dd, J7 = 1.5 Hz, J2 = 10.2 Hz, IH), 5.08 (q, J = 5.7 Hz, 2H), 5.74-4.70 (m, 2H), 4.02 (d, J = 3 Hz, IH), 4.00 (d, J = 2.4 Hz, IH), 3.91 (m, IH), 3.71 (s, 3H), 3.56 (s, 3H), 3.37-3.35 (m, IH), 3.29 (t, J = 2.7 Hz, IH), 3.08 (dd, J7 = 7.5 Hz, J2 = 18 Hz, IH), 2.90 (dd, J7 = 2.7 Hz, J2 = 15.9 Hz, IH), 2.74 (dd, J7 = 2.4 Hz, J2 = 5.1 Hz, 2H), 2.48 (d, J = 18 Hz, IH), 2.35 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H), 1.80 (dd, J7 = 12 Hz, J2 = 15.9 Hz, 2H). ESI-MS m/z: Calcd. for C 32 H 38 N 4 O 8 : 606.6. Found (M+l) + : 607.3. Example 118 To a solution of 120 (100 mg, 0.177 mmol) in CH 2 CI2 (0.7 mL), cinnamoyl chloride ( 29.5 mg, 0.177 mmol) and pyridine (14.37 μL, 0.177 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ2, gradient Hex.ΕtOAc 2:1 to Hex:EtOAc 1 :3) to afford 124 (86 mg, 70 %) as a white solid. Rf: 0.77 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.39-7.26 ( , 5H), 7.25 (d, J = 15.6 Hz, IH), 6.44 (s, IH), 6.01 (d, J = 1.2 Hz, IH), 5.94 (d, J = 1.2 Hz, IH), 5.68 (s, IH), 5.65 (d, J = 15.6 Hz, IH), 5.44 (dd, Jl = 1.2 Hz, J2 = 17.1 Hz, IH), 5.35 (dd, Jl = 1.2 Hz, J2 = 10.5 Hz, IH), 5.18 (t, J = 6 Hz, IH), 4.73-4.69 (m, 2H), 4.11-4.09 (m, 3H), 3.66-3.58 (m, 2H), 3.65 (s, 3H), 3.38- 3.31 (m, 3H), 3.02 (dd, Jl = 8.4 Hz, J2 = 18.3 Hz, IH), 2.92 (dd, Jl = 2.7 Hz, J2 = 15.6 Hz, IH), 2.59 (d, J = 18.3 Hz, IH), 2.31 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.89 (dd, Jl = 12.3 Hz, J2 - 16.2 Hz, IH). 13 C NMR (75 MHz, CDCI 3 ) δ 165.5, 152.7, 146.6, 144.4, 142.6, 140.7, 140.5, 140.1, 134.7, 131.2, 130.6, 129.3, 128.7, 128.4, 127.6, 120.8, 120.5, 120.3, 118.9, 117.6, 116.5, 113.2, 111.8, 101.6, 68.8, 60.4, 59.0, 56.2, 56.1, 55.7, 55.0, 41.5, 40.6, 25.9, 25.1, 15.5, 9.0. ESI-MS m/z: Calcd. for C 39 H 40 N 4 O 8 : 692.7. Found (M+l) + : 693.2. Example 119 To a solution of 124 (495 mg, 0.713 mmol) in CH 2 C1 2 (28 mL), acetic acid (163 μL), Pd(PPh 3 ) 2 C1 2 (50 mg, 0.0713 mmol) and Bu 3 SnH (384 μL, 1.42 mmol ) were added at 0 °C. The reaction mixtme was stirred for 2 h at 23°C and then, the solution was poured into a pad of flash column (SiO 2 , gradient Hex:EtOAc 1:1 to EtOAc) to afford 125 (435 mg, 100 %) as a white solid. Rf: 0.22 (Hex:EtOAc 1 :2). 'H NMR (300 MHz, CDC1 3 ) δ 7.36-7.33 (m, 5H), 7.28 (d, J = 15.9 Hz, IH), 6.45 (s, IH), 5.90 (s, IH), 5.83 (s, IH), 5.55 (d, J = 15.6 Hz, IH), 5.24 (t, J = 12.9 Hz, IH), 4.17 (d, J = 1.8 Hz, IH), 4.10-4.07 (m, 2H), 3.72 (s, 3H), 3.46-3.32 (m, 3H), 3.14-3.00 (m, 2H), 2.54 (d, J = 18 Hz, IH), 2.32 (s, 3H), 2.05 (s, 6H), 1.89 (dd, J / = 12 Hz, J2 = 15.3 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 165.7, 146.9, 145.1, 144.2, 143.0, 140.8, 136.5, 134.5, 130.6, 129.4, 128.9, 127.9, 127.7, 120.8, 119.8, 1 17.8, 1 14.1, 112.9, 107.1, 100.8, 60.5, 59.2, 56.4, 56.0, 55.1, 41.4, 30.7, 25.5, 25.3, 15.5, 8.9. ESI-MS m/z: Calcd. for C 35 H 36 N 4 O 6 : 608. 6. Found (M+l) + : 609.2. Example 120 To a solution of 125 (86 mg, 0.124 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (632 mg, 3.72 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI 2 (20 mL). The solution was extracted and the organic layer was dried over Na 2 SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Siθ 2 , gradient EtOAc to EtOAc:MeOH 2:1) to afford 126 (70 mg, 83 %) as a white solid. Rf: 0.07 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.40-7.28 (m, 5H), 7.25 (d, J = 15.6 Hz, IH), 6.48 (s, IH), 6.00-5.94 (m, IH), 5.96 (s, IH), 5.92 (s, IH), 5.89 (s, IH), 5.53 (d, J = 15.6 Hz, IH), 5.42- 5.36 (m, 2H), 5.31 (dd, J, = 1.2 Hz, J2 = 10.8 Hz, IH), 4.71-4.65 (m, 2H), 4.51 (d, J = 3 Hz, IH), 4.42 (bs, IH), 4.07 (bs, IH), 3.79 (dd, J, = 6.9 Hz, J2 = 12.9 Hz, IH), 3.68 (s, 3H), 3.62-3.59 (m, IH), 3.41-3.37 (m, IH), 3.16 (d, J = 7.8 Hz, IH), 2.95 (dd, J, = 7.5 Hz, J2 = 17.4 Hz, IH), 2.88-2.83 (m, IH), 2.43 (d, J = 18 Hz, IH), 2.28 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.81 (dd, J/ = 11.7 Hz, J2 = 15.3 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 165.5, 152.9, 146.7, 144.5, 144.4, 142.7, 141.0, 140.0, 134.6, 131.4, 130.7, 129.2, 128.8, 128.5, 127.8, 127.7, 124.6, 121.2, 120.9, 118.9, 116.5, 114.9, 114.7, 111.3, 101.6, 93.3, 92.3, 83.2, 68.9, 60.6, 57.8, 56.8, 56.6, 56.3, 52.5, 52.2, 41.6, 26.1, 24.6, 15.6, 9.1. ESI-MS m/z: Calcd. for C 38 H 41 N 3 O 9 : 683.7. Found (M-17) + : 666.3 Example 121 To a solution of 120 (1.61 g, 2.85 mmol) in CH 2 CI 2 (4 mL), hydrocinnamoyl chloride ( 423 μL, 2.85 mmol) and pyridine (230 μL, 2.85 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (50 mL) and washed with 0.1 N HCl (30 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 2:1 to EtOAc) to afford 127 (1.64 g, 83 %) as a white solid. Rf: 0.63 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 7.26-7-14 (m, 3H), 7.04-7.01 (m, 2H), 6.44 (s, IH), 6.07-5.99 (m, IH), 5.97 (d, J = 1.5 Hz, IH), 5.91 (d, J = 1.5 Hz, IH), 5.75 (bs, IH), 5.45 (dd, J; = 1.5 Hz, J2 = 17.4 Hz, IH), 5.36 (dd, J, = 1.5 Hz, J2 = 10.2 Hz, IH), 5.03 (t, J = 5.7 Hz, IH), 5.74-5.66 (m, 2H), 4.09 (d, J = 2.4 Hz, IH), 4.01 (bs, IH), 3.97 (d, J = 2.7 Hz, IH), 3.62 (dd, J; = 8.4 Hz, J2 = 13.5 Hz, IH), 3.42 (s, 3H), 3.37-3.28 (m, 3H), 3.04-2.87 (m, 3H), 2.67-2.46 (m, 4H), 2.29 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.83-1.79 (m, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 171.8, 152.8, 146.7, 144.5, 144.4, 142.7, 140.9, 140.8, 140.6, 131.4, 130.7, 128.9, 128.4, 128.2, 128.1, 126.0, 120.8, 120.4, 118.9, 117.6, 1 16.6, 1 13.0, 111.9, 101.6, 68.9, 60.3, 59.0, 56.3, 56.2, 55.6, 55.1, 41.6, 40.3, 37.7, 31.0, 25.9, 25.2, 15.5, 9.1. ESI-MS m/z: Calcd. for C 39 H42N4O 8 : 694.3. Found (M+l) + : 695.3. Example 122 To a solution of 127 (50 mg, 0.072 mmol) in CH 3 CN/H 2 O (1.5 mL/1 mL), AgNO 3 (444 mg, 2.16 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 C1 2 (15 mL). The solution was extracted and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , gradient EtOAc to EtOAc:MeOH 3:1) to afford 128 (30 mg, 61 %) as a white solid. Rf: 0.65 (EtOAc:MeOH 5:1). 'H MR (300 MHz, CDCI 3 ) δ 7.22-7.11 (m, 3H), 7.06-7.03 (m, 2H), 6.43 (s, IH), 6.08-5.98 (m, IH), 5.96 (d, J = 1.5 Hz, IH), 5.90 (d, J = 1.5 Hz, IH), 5.66 (bs, IH), 5.44 (dd, J, = 1.5 Hz, J2 = 17.4 Hz, IH), 5.36 (dd, J, = 1.5 Hz, J2 = 10.5 Hz, IH), 4.78-4.65 (m, 2H), 4.44 (d, J= 3 Hz, IH), 4.36 (bs, IH), 3.99 (td, J7 = 2.1 Hz, J2 = 9.9 Hz, IH), 3.78-3.67 (m, IH), 3.56 (dt, Jl = 1.5 Hz, J2 = 11.1 Hz, IH), 3.43 (s, 3H), 3.30-3.12 (m, 2H), 3.02-2.89 (m, IH), 2.83 (dd, J7 = 2.7 Hz, J2 = 15.9 Hz, IH), 2.62-2.51 (m, 2H), 2.36 (d, J = 18.6 Hz, IH), 2.27 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.86-1.66 (m, 3H). 13 C NMR (75 MHz, CDCI 3 ) δ 171.6, 146.7, 141.2, 141.1, 131.5, 130.5, 128.9, 128.3, 128.2, 128.2, 125.9, 124.7, 121.1, 121.0, 118.8, 111.3, 101.6, 94.0, 83.2, 68.8, 60.3, 57.9, 56.6, 56.3, 52.3, 52.0, 41.7, 41.6, 41.1, 37.9, 31.1, 31.0, 26.1, 24.6, 15.5, 9.2. . ESI-MS m/z: Calcd. for C 38 H43N3O : 685.7. Found (M-17) + : 668.3. Example 123 To a solution of 127 (1.64 g, 2.36 mmol) in CH 3 CN (12 mL), diisopropylethylamine (8.22 mL, 47.2 mmol), bromomethyl methyl ether (2.89 mL, 35.4 mmol) and dimethylaminopyridine (29 mg, 0.236 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH 2 CI 2 (80 mL) and washed with 0.1 N HCl (3 x 25 mL). The organic layer was dried over Na 2 SO . filtered, and the solvent was eliminated under reduced pressure to give 129 (1.46 g, 84 %) which was used in following steps with no further purification. Rf: 0.24 (RP-18 CH 3 CN-H 2 O 8:2). Η NMR (300 MHz, CDC1 3 ) δ 7.27-7.1 1 (m, 3H), 7.05-7.02 (m, 2H), 6.67 (s, IH), 6.08-5.98 (m, IH), 5.96 (d, J = 1.2 Hz, IH), 5.90 (d, J = 1.2 Hz, IH), 5.44 (dd, J7 = 1.2 Hz, J2 = 17.1Hz, IH), 5.34 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, IH), 5.05 (d, J = 6 Hz, IH), 5.00 (d, J = 6 Hz, IH), 4.97 (t, J = 5.1 Hz, IH), 4.75-4.68 (m, 2H), 4.16 (d, J = 2.7 Hz, IH), 3.98-3.97 (m, IH), 3.68-3.67 (m, IH), 3.65-3.61 (m, IH), 3.52 (s, 3H), 3.35 (s, 3H), 3.32-3.26 (m, 3H), 3.05-2.86 (m, 3H), 2.59-2.48 (m, 2H), 2.30 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.91-1.67 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 171.4, 152.7, 148.5, 148.3, 144.5, 140.9, 140.8, 140.4, 131.1, 130.9, 130.4, 130.1, 128.4, 128.2, 126.0, 124.6, 123.7, 120.3, 119.0, 112.9, 111.8, 101.6, 99.1, 68.9, 59.4, 59.1, 57.5, 56.7, 56.3, 55.4, 55.1, 41.5, 40.2, 37.7, 30.9, 25.8, 25.2, 15.5, 9.0. ESI-MS m/z: Calcd. for C 41 H 46 N 4 O 9 : 738.8. Found (M+ 23) + : 761.2. Example 124 To a solution of 129 (1.46 g, 1.97 mmol) in CH 2 C1 2 (40 mL), acetic acid (450 μL), Pd(PPh 3 ) 2 Cl 2 (138 mg, 0.197 mmol) and Bu 3 SnH (1.06 mL, 3.95 mmol ) were added at 0 °C. The reaction mixture was stirred for 5 h at 23°C and then, the solution was poured into a pad of flash column (SiO 2 , gradient Hex:EtOAc 1:1 to EtOAc) to afford 130 (1.1 g, 85 %) as a white solid. Rf: 0.22 (Hex:EtOAc 1 :2). 'H NMR (300 MHz, CDC1 3 ) δ 7.21-7.12 (m, 3H), 6.98-6.95 (m, 2H), 5.86 (s, IH), 5.84 (s, IH), 5.79 (bs, IH), 5.26 (d, J = 6 Hz, IH), 5.11 (d, J = 6 Hz, IH), 5.05 (t, J = 5.7 Hz, IH), 4.19 (d, J = 2.4 Hz, IH), 4.03 (d, J = 2.4 Hz, IH), 3.99 (bs, IH), 3.65 (s, 3H), 3.56 (s, 3H), 3.53-3.42 (m, 2H), 3.34 (d, J = 8.7 Hz, IH), 3.27 (brd, J = 11.7 Hz, IH), 3.11 (d, J = 15 Hz, IH), 2.99 (dd, J7 = 8.4 Hz, J2 = 18.3 Hz, IH), 2.64-2.52 (m, 3H), 2.29 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.84 (t, J = 7.8 Hz, 2H), 1.71 (dd, J7 = 12.9 Hz, J2 = 13.5 Hz, IH). 13 C NMR (75 MHz, CDCl 3 ) δ 171.7, 149.0, 147.6, 140.6, 132.1, 131.9, 130.9, 130.5, 128.5, 128.4, 128.3, 128.0, 126.0, 124.9, 124.6, 123.1, 117.6, 100.8, 99.6, 59.6, 58.9, 57.6, 56.6, 56.5, 55.6, 55.1, 41.5, 37.8, 31.5, 31.1, 25.9, 25.1, 22.6, 15.5, 8.8. ESI-MS m/z: Calcd. for C 37 H 2 N 4 O 7 : 654.7. Found (M + + Na): 655.1 Example 125 To a solution of 130 (130 mg, 0.198 mmol) in CH 2 C1 2 (1 mL), trifluoroacetyl anhydride ( 41.9 μL, 0.297 mmol) and pyridine (24 μL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 2.5 h and then, the solution was diluted with CH 2 CI 2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over Na 2 SO . filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 4:1 to Hex:EtOAc 1 :4) to afford 131 (93 mg, 62 %) as a white solid. Rf: 0.30 (Hex:EtOAc 1 :2). Η NMR (300 MHz, CDC1 3 ) δ 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.78 (s, IH), 6.02 (d, J = 1.2 Hz, IH), 5.95 (d, J = 1.2 Hz, IH), 5.11 (d, J = 6.6 Hz, IH), 4.98 (d, J = 6.6 Hz, IH), 4.95 (t, J = 6.3 Hz, IH), 4.61 (bs, IH), 4.30 (s, IH), 4.08 (s, IH), 3.96 (d, J = 7.2 Hz, IH), 3.66-3.54 (m, IH), 3.50 (s, 3H), 3.39 (s, 3H), 3.19 (dd, Jl = 7.8 Hz, J2 = 18.3 Hz, IH), 2.88 (d, J = 18.6 Hz, IH), 2.79 (dd, Jl = 2.7 Hz, J2 = 15.9 Hz, IH), 2.66-2.62 (m, IH), 2.57 (s, 3H), 2.06 (s, 6H), 1.94-1.87 (m, IH), 1.77-1.68 (m, 2H). ESI-MS m/z: Calcd. for C 39 H 4 iF 3 N 4 O 8 : 750.7. Found (M+Na) + : 751.2. Example 126 To a solution of 130 (130 mg, 0.198 mmol) in CH 2 Cl2 (2 mL), chloroacetyl chloride ( 23.65 μL, 0.297 mmol) and pyridine (24 μL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 CI 2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , gradient Hex:EtOAc 2:1 to Hex:EtOAc 1 :1) to afford 132 (130 mg, 90 %) as a white solid. Rf: 0.31 (Hex:EtOAc 1:2). Η NMR (300 MHz, CDC1 3 ) δ 7.24-7.15 (m, 3H), 7.07-7.05 (m, 2H), 6.69 (s, IH), 6.00 (d, J = 1.5 Hz, IH), 5.94 (d, J = 1.5 Hz, IH), 5.11 (d, J = 5.7 Hz, IH), 5.04 (d, J - 5.7 Hz, IH), 4.93 (m, IH), 4.36 (s, 2H), 4.16 (d, J = 2.7 Hz, IH), 4.01 (m, 2H), 3.64 (dd, J7 = 6.9 Hz, J2 = 12.3 Hz, IH), 3.54 (s, 3H), 3.40 (s, 3H), 3.38-3.35 (m, 2H), 2.29 (dt, J7 = 3 Hz, J2 = 12 Hz, IH), 3.03 (dd, J7 = 7.8 Hz, J2 = 18 Hz, IH), 2.77 (dd, J7 = 2.4 Hz, J2 = 16.2 Hz, IH), 2.58-2.52 (m, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.92-1.85 (m, IH), 1.76-1.65 (m, 2H). 13 C NMR (75 MHz, CDC1 3 ) δ 171.6, 164.9, 148.3, 144.6, 140.9, 140.8, 139.8, 132.1, 131.9, 131.1, 130.0, 128.2, 126.0, 125.0, 124.6, 123.5, 120.1, 1 17.5, 1 13.0, 1 1 1.5, 101.7, 99.1, 64.9, 59.7, 58.9, 57.7, 56.6, 56.4, 55.2, 55.1, 41.5, 40.2, 39.9, 37.7, 30.9, 26.3, 25.1, 15.4, 9.1. ESI-MS m z: Calcd. for C 39 H 43 ClN 4 O 8 : 730.2. Found (M+l) + : 731.1. Example 127 To a solution of 130 (130 mg, 0.198 mmol) in CH 2 CI 2 (2 mL), chloropropionyl chloride ( 28.35 μL, 0.297 mmol) and pyridine (24 μL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex:EtOAc 1 : 1 ) to afford 133 (94 mg, 64 %) as a white solid. Rf: 0.43 (Hex:EtOAc 1:2). Η NMR (300 MHz, CDC1 3 ) δ 7.23-7.12 (m, 3H), 7.06-7.04 (m, 2H), 6.69 (s, IH), 5.97 (s, IH), 5.92 (s, IH), 5.08 (d, J = 6 Hz, IH), 5.00 (d, J = 6 Hz, IH), 4.97 (m, IH), 4.16 (bs, IH), 4.00 (m, IH), 3.88 (t, J = 6.9 Hz, 2H), 3.75 (t, J = 6.9 Hz, 2H), 3.59 (dd, J7 = 6.3 Hz, J2 = 12.3 Hz, IH), 3.53 (s, 3H), 3.37 (s, 3H), 3.03-3.26 (m, IH), 3.17-2.97 ( , 3H), 2.83- 2.73 (m, 2H), 2.58-2.52 (m, 3H), 2.31 (s, 3H), 2.03 (s, 6H), 1.93-1.86 (m, IH), 1.79-1.64 (m, 2H). 13 C NMR (75 MHz, CDCI 3 ) δ 171.9, 167.8, 148.3, 144.7, 140.8, 132.1, 132.0, 131.1, 130.2, 128.2, 126.1, 125.2, 124.6, 123.7, 122.2, 120.2, 117.6, 114.7, 112.9, 111.8, 101.7, 99.3, 74.9, 65.0, 59.6, 59.0, 57.7, 56.7, 56.4, 55.4, 55.1, 41.5, 38.5, 37.8, 37.2, 31.0, 26.4, 25.2, 15.5, 9.3. ESI-MS m/z: Calcd. for C 4 0H 45 CTN4O 8 : 744.2. Found (M+l) + : 745.0. Example 128 To a solution of 130 (160 mg, 0.244 mmol) in CH 2 CI 2 (2 mL), heptafluorobutyryl chloride ( 54.5 μL, 0.366 mmol) and pyridine (40 μL, 0.49 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH 2 CI 2 (15 mL) and washed with 0.1 N HCl (10 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , gradient Hex:EtOAc 2:1 to Hex:EtOAc 1 :4) to afford 134 (120 mg, 63 %) as a white solid. Rf: 0.40 (Hex:EtOAc 1:2). Η NMR (300 MHz, CDC1 3 ) δ 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.77 (s, IH), 6.02 (d, .7 = 1.5 Hz, IH), 5.96 (d, J = 1.5 Hz, IH), 5.1 1 (d, J = 6.6 Hz, IH), 4.95 (d, J = 6.6 Hz, IH), 4.94 (m, IH), 4.58 (m, IH), 4.25 (bs, IH), 4.06 (bs, IH), 3.88 (d, J = 6.9 Hz, IH), 3.64 (dd, J7 = 7.5 Hz, J2 = 12.9 Hz, IH), 3.55-3.53 (m, IH), 3.49 (s, 3H), 3.38 (s, 3H), 3.17 (dd, J7 = 8.1 Hz, J2 = 18.9 Hz, IH), 2.85 (d. J = 18.3 Hz, IH), 2.77 (dd, J7 = 2.7 Hz, J2 = 16.2 Hz, IH), 2.60-2.57 ( , 3H), 2.56 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.96-1.88 (m, IH), 1.79- 1.69 (m, 2H). ESI-MS m/z: Calcd. for C 41 H 4 iF 7 N 4 O 8 : 850.7. Found (M+l) + : 851.3. Example 129 To a solution of 131 (93 mg, 0.123 mmol) in CH C1 2 (1 mL), trifluoroacetic acid (381 μL, 4.95 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate ( 15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 135 (65 mg, 75 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (Hex.'EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.24 - 7.15 (m, 3H), 7.04 - 7.01 (m, 2H), 6.45 (s, IH), 6.03 (d, J = 1.5 Hz, IH), 5.97 (d, J = 1.5 Hz, IH), 5.62 (s, IH), 4.97 (m, IH), 4.09 (d, J = 1.8 Hz, IH), 4.03 (bs, IH), 3.99 (d, J = 2.4 Hz, IH), 3.73 (dd, Jl= 7.5 Hz, J2 = 12 Hz, IH), 3.38 (s, 3H), 3.34 - 3.28 (m, 3H), 3.05 (dd, Jl= 8.4 Hz, J2 = 18.3 Hz, IH), 2.75 (dd, Jl= 3.3 Hz, J2 = 16.5 Hz, IH), 2.60 - 2.47 (m, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.91 - 1.65 (m, 3H). ESI-MS m/z: Calcd. for C 37 H 37 F 3 N 4 O 7 : 706.2. Found (M+l) + : 707.2. Example 130 To a solution of 132 (130 mg, 0.177 mmol) in CH 2 C1 2 (1 mL), trifluoroacetic acid (545 μL, 7.08 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 136 (118 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf: 0.27 (Hex:EtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.23 - 7.13 (m, 3H), 7.06 - 7.03 (m, 2H), 6.45 (s, IH), 5.98 (d, J = 1.2 Hz, IH), 5.91 (d, J = 1.2 Hz, IH), 5.04 (t, J = 4.5 Hz, IH), 4.37 (bs, 2H), 4.13 (d, J = 2.1 Hz, IH), 4.03 (bs, 2H), 3.68 - 3.61 (dd, Jl= 7.2 Hz, J2 = 12.3 Hz IH), 3.40 (s 3H), 3.37 - 3.28 (m, 3H), 3.02 (dd, Jl= 8.4 Hz, J2 = 18.6 Hz IH), 2.75 (dd, Jl= 2.7 Hz, J2= 15.9 Hz IH), 2.58 - 2.50 (m, 3H), 2.32 (s, 3H), 2.01 (s, 6H), 1.94 - 1.67 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 171.8, 165.0, 146.8, 144.6, 142.9, 141.0, 140.9, 139.8, 132.0, 130.3, 129.4, 128.5, 128.3, 126.0, 120.8, 120.1, 117.4, 116.1, 113.0, 11 1.5, 101.7, 60.5, 58.7, 56.3, 56.2, 55.2, 55.0, 41.5, 40.4, 39.5, 37.7, 31.0, 29.6, 26.4, 25.3, 15.5, 9.2. ESI-MS m/z: Calcd. for C 37 H 39 ClN 4 O 7 : 686.2. Found (M+l) + : 687.2. Example 131 To a solution of 133 (94 mg, 0.126 mmol) in CH 2 Cl2 (1 mL), trifluoroacetic acid (385 μL, 5.0 mmol) was added at 0 °C and the reaction mixture was stirred for 2.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate ( 15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 137 (118 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf: 0.24 (Hex.ΕtOAc 1 :1). Η NMR (300 MHz, CDC1 3 ) δ 7.25-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.44 (s, IH), 5.98 (d, J = 1.5 Hz, IH), 5.92 (d, J = 1.5 Hz, IH), 5.82 (s, IH), 5.20 (t, J = 4.8 Hz, IH), 4.07 (d, J = 2.1 Hz, IH), 5.82 (s, IH), 5.20 (t, J = 4.8 Hz, IH), 4.07 (d, J = 2.1 Hz, IH), 4.01 (bs, IH), 3.98 (d, J = 2.4 Hz, IH), 3.93-3.84 (m, 2H), 3.63 (ddd, J7 = 1.5 Hz, J2 = 6.9 Hz, J3 = 12 Hz, IH), 3.44 (bs, 3H), 3.37-3.26 (m, 3H), 3.11-3.06 (m, 2H), 3.01 (dd, J7 = 8.4 Hz, J2 = 18.3 Hz, IH), 2.80 (brd, J = 13.8 Hz, IH), 2.58-2.47 (m, 3H), 2.29 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.93-1.68 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 171.7, 168.0, 146.7, 144.6, 142.8, 142.1, 141.0, 140.8, 140.1, 130.7, 129.0, 128.2, 126.0, 122.2, 120.9, 1 16.7, 114.7, 113.1, 111.7, 102.3, 101.7, 72.0, 60.4, 59.1, 56.4, 56.3, 55.7, 55.2, 41.7, 40.3, 38.8, 37.8, 37.1, 31.0, 26.4, 25.2, 15.5, 9.4. ESI-MS m z: Calcd. for C 38 H 4 ιClN 4 O 7 :J00.2. Found (M+23) + : 723.1. Example 132 To a solution of 134 (46 mg, 0.054 mmol) in CH 2 CI 2 (1 mL), trifluoroacetic acid (166 μL, 2.16 mmol) was added at 0 °C and the reaction mixture was stirred for 10 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 138 (35 mg, 80 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (Hex:EtOAc 1:1). Η NMR (300 MHz, CDC1 3 ) δ 7.23 - 7.12 (m, 3H), 7.04 - 7.01 (m, 2H), 6.45 (s, IH), 6.03 (d, J = 1.5 Hz, IH), 5.97 (d, J = 1.5 Hz, IH), 5.64 (s, IH), 4.98 (m, IH), 4.09 (d, J = 2.1 Hz, IH), 4.03 (bs, IH), 3.98 (d, J = 2.4 Hz, IH), 3.75 (dd, Jl= 9.6 Hz, J2 = 14.1 Hz, IH), 3.35 (s, 3H), 3.29 - 3.24 (m, 3H), 3.04 (dd, Jl= 7.8 Hz, J2 = 18.0 Hz, IH), 2.74 (dd, Jl= 3.0 Hz, J2 = 16.8 Hz, IH), 2.57 - 2.45 (m, 3H), 2.30 (s, 3H), 2.03 (s, 6H), 1.92 - 1.64 (m, 3H). ESI- MS m z: Calcd. for C 39 H 37 F 7 N 4 O 7 : 806.7. Found (M+l) + : 807.3. Example 133 139 136 To a solution of 136 (45 mg, 0.065 mmol) in CH 2 C1 2 (0.3 mL), acetyl chloride (4.65 μL, 0.065 mmol), and pyridine (5.2 μL, 0.065 mmol ) were added at 0 °C. The reaction mixture was stirred for 4 h and then, the solution was diluted with CH 2 Cl 2 (15 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , gradient Hex:EtOAc 5:1 to EtOAc) to afford 139 (27 mg, 57 %) as a white solid. Rf: 0.36 (Hex:EtOAc 1:2). 'H NMR (300 MHz, CDC1 3 ) δ 7.26 - 7.14 (m, 3H), 7.07 - 7.04 (m, 2H), 6.84 (s, IH), 6.00 (d, J= 1.2 Hz, IH), 5.94 (d, J= 1.2 Hz, IH), 4.94 (t, J= 5.1 Hz, IH), 4.39 - 4.38 (m, 2H), 4.02 (bs, 2H), 3.67 (d, J= 3 Hz, IH), 3.60-3.54 (m, IH), 3.47-3.35 (m, 3H), 3.42 (s, 3H), 3.26 (dt, J, = 4.8 Hz, J 2 = 8.7 Hz IH), 3.02 (dd, J, = 8.1 Hz, J 2 = 18.3 Hz, IH), 2.64 - 2.38 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.95 - 1.69 (m, 3H). ESI-MS m/z: Calcd. for 729.2. Found (M+23) + : 752.3. Example 134 To a solution of 2 (15 mg, 0.0273 mmol) in CH 2 C1 2 (0.2 mL), acetyl chloride (1.94 μL, 0.0273 mmol), and pyridine (2.20 μL, 0.0273 mmol ) were added at 0 °C. The reaction mixture was stirred for 20 minutes and then, the solution was diluted with CH 2 CI 2 (15 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , gradient EtOAc to EtOAcMeOH 5: 1 ) to afford 140 (9 mg, 56 %) as a light yellow solid. Rf: 0.56 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.52 (s, IH), 6.40 (s, IH), 5.73 (d, J= 7.5 Hz, IH), 4.95 (d, J= 6.9 Hz, IH), 4.20 (d, J= 1.5 Hz, IH), 4.00 (s, 3H), 3.86 (d, J= 4.5 Hz, IH), 3.79 (s, 3H), 3.78-3.77 (m, IH), 3.40-3.35 (m, 2H), 3.24 (dt, , J,= 3.6 Hz, J 2 = 1 1.4 Hz, IH), 3.17 (d, J= 7.8 Hz, IH), 3.11 (d, J= 7.5 Hz, IH), 3.04 (dd, J,= 3.6 Hz, J 2 = 18.6 Hz, IH), 2.92 (dt, , J,= 3.3 Hz, J 2 = 14.1 Hz, IH), 2.43 (d, J= 18.0 Hz, IH), 2.37 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.79 (s, 3H), 1.75 (dd, 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C 3 ιH 37 N 5 O 7 : 591.6. Found (M+l) + : 592.3. Example 135 To a solution of 2 (15 mg, 0.0273 mmol) in CH 2 C1 2 (0.2 mL), trifluoroacetyl anhydride (3.85 μL, 0.0273 mmol was added at 23 °C. The reaction mixture was stirred for 30 minutes and then, the solution was diluted with CH 2 C1 2 (15 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO , gradient EtOAc to EtOAcMeOH 4:1) to afford 141 (12.1 mg, 69 %) as a light yellow solid. Rf: 0.73 (EtOAc:MeOH 5:1). Η NMR (300 MHz, CDC1 3 ) δ 6.90 (d, J= 6.6 Hz, IH), 6.56 (s, IH), 5.1 1 (d, J= 6.6 Hz, IH), 4.47 (bs, IH), 4.23 (bs, IH), 3.97 (s, 3H). 3.93 (bs, IH), 3.85-3.81 (m, IH), 3.77 (s, 3H), 3.40-3-36 (m, 2H), 3.23 (dd, J,= 7.2 Hz, J 2 = 18.6 Hz, IH), 3.13-3.08 (m, 3H), 1.86 (s, 3H), 1.74 (dd, J;= 10.8 Hz, J 2 = 16.8 Hz, IH), 1.07 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C 31 H 34 F 3 N 5 O 7 : 645.6. Found (M+l) + : 646.3. Example 136 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 C1 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), N-Boc-Phenylalanine (22.9 mg. 0.086 mol) and DMAP (0.7 mg, 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4h. Then, the solution was diluted with CH2CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :2) to afford 174 (17 mg, 38%) as a white solid. Rf= 0.35 Hex: AcOEt 1:2. 'H NMR (300 MHz, CDC1 3 ) 7.24-7.15 (m, 3H), 7.05-7.02 (m, 2H), 6.43 (s, IH), 5.88 (s, IH), 5.78 (s, IH), 5.64 (s, IH), 5.63 (bs, IH), 4.80 (bs, IH), 3.98 (s, IH), 3.85 (bs, 2H), 3.75 (bs, IH), 3.58 (bs, IH), 3.53 (bs, 3H), 3.38 (m, IH), 3.17-3.10 (m, 3H) 2.90 (dd, J / = 8.7 Hz, J 2 = 17.7 Hz, IH), 2.73 (d, J= 14.4 Hz, IH), 2.57 (m, IH), 2.43-2.37 (m, IH), 2.25 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H), 1.94 (s, 3H), 1.76 (dd, J, = 12.3 Hz, J 2 = 15.6 Hz, IH), 1.19 (bs, 9H). 13 C NMR (75 MHz, CDC1 3 ) 171.2, 168.8, 146.6, 144.6, 142.8, 140.6, 137.0, 130.7, 129.5, 129.0, 128.4, 126.8, 121.1, 121.0, 1 17.8, 1 16.7, 113.3, 1 11.8, 101.5, 60.5, 59.7, 57.0, 56.4, 55.3, 41.9, 41.6, 38.7, 31.6, 29.7, 28.2, 26.5, 25.2, 22.6, 20.3, 15.7, 14.1, 9.3. ESI-MS m/z: Calcd. for C^H^NsOg: 767.87. Found (M+l) + : 768.3. Example 137 45 175 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 C1 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), N-Boc-Valine (18.8 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CH2CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ2, Hex: EtOAc 1 :2) to afford 175 (18 mg, 43%) as a white solid. Rf= 0.25 Hex:EtOAc 1:1. 'H NMR (300 MHz, CDC1 3 ) δ 6.42 (s, IH), 5.97 (s, IH), 5.82 (s, IH), 5.73 (bs, IH), 5.50 (bs, IH), 4.82 (bs, IH), 4.15 (bs, IH), 4.03 (bs, IH), 3.96 (bs, IH), 3.72 (s, 3H), 3.61 (m, IH), 3.41-3.15 (m, 3H), 2.96 (dd, J/ = 8.4 Hz, J 2 = 18.3 Hz, IH), 2.72 (d, J= 16.5 Hz, IH), 2.53 (d, J= 18 Hz, IH), 2.25 (s, 3H), 2.21 (s, 3H), 1.93 (s, 3H), 1.81 (dd, J = 14.1 Hz, J 2 = 14.7 Hz, IH), 1.34 (s, 9H), 0.83-0.76 (m, 2H), 0.61 (d, J= 6.3 Hz, 3H), 0.54 (d, J= 6.3 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 171.6, 168.7, 155.4, 146.8, 144.5, 142.9, 140.7, 130.7, 128.8, 121.0, 120.6, 117.7, 116.8, 113.3, 111.9, 101.4, 60.6, 60.0, 59.3, 57.2, 56.3, 55.2, 41.7, 29.7, 29.3, 28.2, 26.2, 25.2, 22.6, 20.3, 18.9, 17.7, 15.7, 14.1, 9.3. ESI-MS m/z: Calcd. for C 38 H 49 N 5 O : 719.82. Found (M+l) + : 720.3. Example 138 45 176 To a solution of 45 (38 mg, 0.073 mmol) in CH 2 Cl 2 (1.09 mL), DIPEA (19.0 mL, 0.109 mmol), EDC-HCl (34.9 mg, 0.182 mmol), N-Boc-Proline (23.5 mg, 0.109 mmol) and DMAP (0.8 mg, 0.007 mmol) were added at 23 °C and the reaction mixture was stirred for 4.5 h. Then, the solution was diluted with CH 2 CI2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :1) to afford 176 (33 mg, 63%) as a white solid. Rf= 0.14 Hex:EtOAc 1 :2. 'H NMR (300 MHz, CDC1 3 ) δ 6.49 (s, IH), 6.02 (bs, IH), 5.90 (s, IH), 5.74 (s, IH), 4.19 (bs, IH), 4.09 (bs, IH), 3.98 (bs, IH), 3.76 (s, 3H), 3.38 (d, J= 6 Hz, 2H), 3.22 (d, J= 1 1.7 Hz, IH), 3.15-2.99 (m, 2H), 2.80 (d, J= 15.3 Hz, IH), 2.63-2.58 (m, IH), 2.32 (s. 3H), 2.26 (s, 6H), 1.99 (s, 3H), 1.78-1.62 (m, IH), 1.50-0.83 (m, 7H), 1.21 (s, 9H). ESI-MS m/z: Calcd. for C 3 8H 4 7N5O 9 : 717.81. Found (M+l) + : 718.3. Example 139 To a solution of 45 (50 mg, 0.144 mmol) in CH 2 C1 2 (0.96 mL), DIPEA (41.8 mL. 0.240 mmol), EDC-HCl (46.0 mg, 0.240 mmol), N-Boc-Arginine hidrochloride hydrate (47.2 mg, 0.144 mmol) and DMAP (1.1 mg, 0.01 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solvent was removed under vacuum and the residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :2) to afford 177 (58 mg, 78%) as a white solid. Rf = 0.40 MeOH:EtOAc 1 :5. Η NMR (300 MHz, CDC1 3 ) δ 7.53 (bs, IH), 6.95 (bs, 3H), 6.54 (bs, IH), 6.48 (s, IH), 6.07 (s, IH), 6.00 (bs, IH), 5.88 (s, IH), 5.11 (bs, IH), 4.23 (s, IH), 4.08 (s, IH), 4.02 (s, IH), 3.76 (s, 3H), 3.70 (bs, IH), 3.48 (bs, IH), 3.37 (d, J= 6.9 Hz, IH), 3.18 (d, J= 10.2 Hz, IH), 3.00-2.94 (m, 3H), 2.82-2.70 (m, 2H), 2.34 (s, 3H), 2.25 (s, 6H), 1.99 (s, 3H), 1.73 (bit, J= 14.1 Hz, IH), 1.40 (s, 9H), 1.25 (bs, 3H), 0.95-0.85 (m, 2H). ESI-MS m/z: Calcd. for C 39 H 52 N 8 O 9 : 776.88. Found (M+l) + : 777.3. Example 140 To a solution of 45 (50 mg, 0.096 mmol) in CH 2 C1 2 (1.44 mL), DIPEA (25.8 mL, 0.144 mmol), EDC-HCl (46.0 mg, 0.240 mmol), N-Boc-Tryptophan (43.8 mg, 0.144 mmol) and DMAP (1.2 mg, 0.009 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CH2CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na2SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: EtOAc 1 :2) to afford 178 (57 mg, 74%) as a white solid. Rf= 0.12 Hex:EtOAc 1 :1. 'H NMR (300 MHz, CDC1 3 ) δ 8.50 (bs, IH), 7.73-7.71 (m, IH), 7.13-7.12 (m. 3H), 6.51 (s, IH), 5.72 (s, IH), 5.36 (bs, IH), 5.28 (bs, IH), 4.95 (bs, IH), 4.41 (bs, IH), 4.05 (s, IH), 3.70 (s, 3H), 3.50 (bs, 2H), 3.30-3.17 (m, 4H), 2.89-2.82 (m, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 2.03 (s, 3H), 1.49 (s, 9H), 1.26-1.25 (m, 2H). ESI-MS m/z: Calcd. for 806.90. Found (M+l) + : 807.3. Example 141 To a solution of 178 (43 mg, 0.053 mmol) in CH 3 CN H 2 O (3 mL/2 mL), AgNO 3 (271 mg, 1.60 mmol) was added and the reaction was stirred at 23°C for 17 h. Then, Aq sat NaCl (10 mL) and Aq sat NaHCO 3 (10 mL) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 CI 2 (20 mL). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Siθ 2 , EtOAc:MeOH 5:1) to afford 179 (24 mg, 56%) as a white solid. Rf = 0.38 EtOAc:MeOH 5:1. 'H NMR (300 MHz, CDC1 3 ) δ 8.40 (s, IH), 7.66 (bs, IH), 7.25-7.21 (m, IH), 7.16-7.09 (m, 2H), 6.45 (s, IH), 5.75 (bs, IH), 5.55 (bs, IH), 5.45 (s, IH), 5.25 (bs, IH). 4.36 (bs, IH), 4.16 (bs, IH), 4.05 (bs, IH), 3.95 (s, IH), 3.69 (s, 3H), 3.35-3.02 (m, 6H), 2.83-2.73 (m, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J; = 12 Hz, J 2 = 15.3 Hz IH). ESI-MS m/z: Calcd. for C 43 H 5 ιN 5 O I0 : 797.89. Found (M-17) + : 780. Example 142 To a solution of 45 (50 mg, 0.0960 mmol) in CH C1 2 (0.7 mL), 2-Chloronicotinoyl chloride (17.7 mg, 0.101 mmol) and pyridine (8.1mL, 0.101 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH 2 C1 2 (5 mL) and washed with 0.1 N HCl (3 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiU 2 , Hex: EtOAc 1:1) to afford 180 (45 mg, 71%) as a white solid. Rf= 0.18 Hex:EtOAc l:2. Η NMR (300 MHz, CDC1 3 ) δ 8.32-8.29 (m, IH), 7.38-7.34 (m, IH), 7.14-7.09 (m, IH), 6.14 (s, IH), 5.97 (d, J= 1.2 Hz, IH), 5.92-5.91 (m, 2H), 5.75 (d, J= 2.1 Hz, IH), 4.18 (d, J = 2.1 Hz, IH), 4.15 (s, IH), 4.07 (s, IH), 3.91-3.73 (m, 2H), 3.68 (s, 3H), 3.36 (d, J= 7.5 Hz, IH), 3.31 (dt, J; = 2.4 Hz, J 2 = 11.7 Hz, IH), 2.92 (dd, J, = 8.1 Hz, J 2 = 18 Hz, IH), 2.80 (d, J= 16.2 Hz, IH), 2.58 (d, J= 18 Hz, IH), 2.31 (s, 3H), 2.27 (s, 3H), 1.99 (s, 3H), 1.91 (s, 3H) 1.97-1.83 (m, IH). I3 C NMR (75 MHz, CDC1 3 ) δ 168.6, 164.8, 150.3, 147.2, 146.5, 144.6, 142.5, 140.6, 139.0, 130.9, 130.5, 128.8, 122.3, 120.8, 120.3, 117.6, 116.3, 112.7, 112.1, 101.6, 60.6, 58.8, 56.5, 56.3, 55.6, 55.1, 41.6, 39.8, 31.5, 26.2, 24.9, 20.3, 15.5, 9.3. ESI-MS m/z: Calcd. for C 34 H 34 ClN 5 O 7 : 659.2. Found (M+l) + : 660.1. Example 143 To a solution of 180 (39 mg, 0.059 mmol) in CH 3 CN/H 2 O (3 mL/2 mL), AgNO 3 (301mg, 1.77 mmol) was added and the reaction was stirred at 23°C for 17 h. Then, Aq sat NaCl (10 mL) and Aq sat NaHCO3 (10 mL) solutions were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH 2 CI 2 (20 mL). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , EtOAc :MeOH 5:1) to afford 181 (28 mg, 73%) as a white solid. Rf = 0.24, EtOAc:MeOH 5:1. 'H NMR (300 MHz, CDCI 3 ) δ 8.33-8.31 (m, IH), 7.40-7.35 (m, IH), 7.16-7.09 (m, 2H), 6.20 (s, IH), 5.98 (d, J= 1.2 Hz, IH), 5.96 (s, IH), 5.92 (d, J= 1.2 Hz, IH), 5.63 (bs, IH), 4.60 (bs, IH), 4.47 (bs, IH), 4.02-3.95 (m, 2H), 3.69 (s, 3H), 3.65-3.56 (m, IH), 3.48 (s, 3H), 3.43-3.38 (m, IH), 3.17 (brd, J= 7.2 Hz, IH), 2.88 (dd, J, = 8.7 Hz, J 2 = 18.3 Hz, IH), 2.74 (d, J= 15.3 Hz, IH), 2.40 (d, J= 18.3 Hz, IH), 2.32 (s, 3H), 2.26 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.77 (dd, Jj = 12 Hz, J 2 = 15 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 168.1, 165.0, 150.0, 147.2, 146.5, 144.4, 142.5, 140.9, 138.7, 131.5, 130.2, 128.9, 122.3, 121.1, 120.7, 116.1, 1 14.4, 1 1 1.4, 101.5, 82.6, 60.6, 57.8, 56.2, 52.1, 41.6, 31.5, 26.4, 24.5, 22.6, 20.3, 15.6, 14.1, 9.3. ESI-MS m/z: Calcd. for C 33 H 35 ClN 4 O 8 : 650.2 Found (M-17) + : 633.3. Example 144 45 182 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 Cl 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :2) to afford 182 (10 mg, 27%) as a white solid. Rf= 0.11 Hex:EtOAc l :l. Η NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 5.98 (d, J= 1.2 Hz, IH), 5.91 (d, J= 1.2 Hz, IH), 5.75 (s, IH), 5.02-4.91 (m, IH), 4.11 (bs, IH), 4.04 (d, J= 2.1 Hz, IH), 4.01 (bs, IH), 3.78 (s, 3H), 3.72-3.69 (m, IH), 3.38-3.29 (m, 3H), 3.05 (dd, J / = 7.8 Hz, J 2 = 18.0 Hz, IH), 2.77 (d, J= 15.6 Hz, IH), 2.54 (d, J= 18.6 Hz, IH), 2.33 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J / = 1 1.7 Hz, J 2 = 15.6 Hz, IH), 1.59-0.61 (m, 13H). ESI-MS m/z: Calcd. for C 36 H 4 N4O 7 : 644.76. Found (M+l) + : 645.3. Example 145 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 C1 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :2) to afford 183 (17 mg, 38%) as a white solid. Rf= 0.13 Hex:EtOAc 1:1. Η NMR (300 MHz, CDCI 3 ) δ 6.87 (s, IH), 5.99 (d, J= 1.2 Hz, IH), 5.92 (d, J= 1.2 Hz, IH), 4.95 (t, J= 5.7 Hz, IH), 4.08 (bs, IH), 4.00 (bs, IH), 3.71 (s, 3H), 3.64 (d, J= 1.8 Hz, 2H), 3.38 (d, J= 6.6 Hz, IH), 3.33-3.32 (m, IH), 3.27 (d, J= 1 1.7 Hz, IH), 3.06 (dd, J, = 7.8 Hz, J 2 = 18.0 Hz, IH), 2.65-2.59 (m, IH), 2.50-2.47 (m, IH), 2.35 (s, 3H), 2.27 (s, 6H), 1.99 (s, 3H), 1.78-1.74 (m, IH) 1.60-0.62 (m, 26H). ESI-MS m/z: Calcd. for C^Hse^Os: 768.94. Found (M+l) + : 769.3. Example 146 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 C1 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred at 23 °C for 6 h. Then, the solution was diluted with CH 2 C1 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex: EtOAc 1:2) to afford 184 (15 mg, 39%) as a white solid. Rf= 0.15 Hex:EtOAc 1:1. 'H NMR (300 MHz, CDC1 3 ) δ 6.50 (s, IH), 5.98 (s, IH), 5.91 (s. IH), 5.74 (s, IH), 5.01 (t, J= 5.1 Hz, IH), 4.09 (bs, IH), 4.06 (s, IH), 4.02 (bs, IH), 3.76 (s, 3H), 3.64-3.58 (m, IH), 3.42-3.41 (m, IH), 3.36 (d, J= 7.5 Hz, IH), 3.28 (d, J= 12.3 Hz, IH), 3.05 (dd, J, = 8.6 Hz, J 2 = 18 Hz, IH), 2.79 (d, J= 14.7 Hz, IH), 2.57 (d, J= 18 Hz, IH), 2.32 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J, = 12.0 Hz, J 2 = 15.9 Hz, IH), 1.62-0.71 (m, 15H). ESI-MS m/z: Calcd. for C 37 H 46 N 4 O 7 : 658.78. Found (M+l) + : 659.3. Example 147 To a solution of 45 (30 mg, 0.058 mmol) in CH 2 C1 2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 6 h. Then, the solution was diluted with CH C1 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO , Hex: EtOAc 1 :2) to afford 185 (21 mg, 46%) as a white solid. Rf= 0.17 Hex:EtOAc l :l. Η NMR (300 MHz, CDC1 3 ) δ 6.86 (s, IH), 5.99 (s, IH), 5.92 (s, IH), 4.97 (t, J= 5.4 Hz, IH), 4.10 (d, J= 2.4 Hz, IH), 4.01 (bs, IH), 3.70 (s, 3H), 3.64 (d, J= 2.4 Hz, IH), 3.51 (bs, IH), 3.37 (d, J= 8.1 Hz, IH), 3.23 (d, J= 11.1 Hz, IH), 3.02 (dd, J 7 = 7.8 Hz, J 2 = 18 Hz, IH), 2.69-2.59 (m, 4H), 2.35 (s, 3H), 2.26 (s, 6H), 2.00 (s, 3H), 1.76-0.72 (m, 30H). I3 C NMR (75 MHz, CDCl 3 ) δ 173.1, 171.5, 168.2, 147.9, 144.7, 142.5, 140.7, 140.3, 130.9, 130.6, 127.7, 123.3, 120.0, 117.5, 113.1, 111.9, 101.6, 60.5, 59.0, 57.3, 56.7, 55.2, 55.0, 41.6, 39.9, 37.2, 33.5, 33.0, 32.9, 32.9, 32.8, 32.5, 32.4, 31.9, 31.7, 29.7, 29.3, 26.6, 26.5, 26.2, 24.9, 20.3, 15.8, 14.1, 9.4. ESI-MS m/z: Calcd. for C 46 H 60 N 4 O 8 : 796.4. Found (M+l) + : 797.5. Example 148 To a solution of 72 (111 mg, 0.162 mmol) in CH 2 C1 2 (0.81 mL), DIPEA (56.3 mL, 0.324 mmol), butyryl chloride (33.6 mL, 0.324 mmol) and DMAP (1.96 mg. 0.016 mmol) were added at 0 °C and the reaction mixture was stirred for 5 h at this temperature. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na2SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 1 :1) to afford 186 (65.4 mg. 54%) as a white solid. Rf= 0.21 Hex:EtOAc l :2. 'H NMR (300 MHz, CDC1 3 ) δ 7.24-7.15 (m, 3H), 7.12-7.04 (m, 2H), 6.84 (s, IH), 5.98 (d, J = 1.2 Hz, IH), 5.92 (d, J= 1.2 Hz, IH), 4.97 (t, J= 5.7 Hz, IH), 4.03 (m, 3H), 3.63 (d, J = 2.7 Hz, IH), 3.50 (m, 2H), 3.44 (s, 3H), 3.37 (d, J= 8.4 Hz, IH), 3.24 (dt, J, = 2.7 Hz, J 2 - 11.7 Hz, IH), 3.02 (dd, J, = 8.1 Hz, J 2 = 18.3 Hz, IH), 2.65-2.54 (m, 7H), 2.35 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.87-1.75 (m, 3H), 1.08 (t, J= 7.5 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 171.7, 170.8, 168.2, 147.8, 144.7, 142.5, 140.8, 140.6, 140.3, 131.1, 130.5, 128.3, 128.2, 127.6, 126.0, 123.2, 117.5, 112.9, 111.8, 101.6, 60.2, 59.0, 57.3, 56.6, 55.1, 54.9, 41.5, 39.9, 37.8, 36.0, 31.0, 26.5, 24.8, 22.6, 20.2, 18.5, 15.6, 13.7, 9.3. ESI-MS m/z: Calcd. for C 4 ιH 46 N 4 O 8 : 722.83. Found (M+l) + : 723.2. Example 149 To a solution of 72 (80 mg, 0.122 mmol) in CH 2 C1 2 (0.61 mL), DIPEA (64.0 mL, 0.367 mmol), hexanoyl chloride (49.5 mL, 0.367mmol) and DMAP (1.50 mg, 0.012 mmol) were added at 0 °C and the reaction mixture was stirred at this temperature for 5h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 6:4) to afford 187 (86.1 mg, 94%) as a white solid. Rf= 0.25 Hex:EtOAc 1:2 Η NMR (300 MHz, CDC1 3 ) δ 7.20-7.06 (m, 3H), 6.99-6.97 (m, 2H), 6.77 (s, IH), 5.91 (s, IH), 5.85 (s, IH), 4.90 (m, IH), 3.96 (d, J = 3 Hz, 2H), 3.57-3.55 (m, IH), 3.43 (bs, 2H), 3.36 (bs, 3H), 3.29 (brd, J= 10.5 Hz, IH), 3.18 (d, J= 11.7 Hz, IH), 2.97 (dd, J / = 4.8 Hz, J = 12 Hz, IH), 2.58-2.46 (m, 6H), 2.28 (s, 3H), 2.18 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.86- 1.66 (m, 7H), 1.41-1.38 (m, 2H), 0.86-0.81 (m, 3H). I3 C NMR (75 MHz, CDC1 3 ) δ 171.7, 171.0, 168.2, 147.8, 144.7, 142.5, 140.8, 140.6, 140.3, 131.1, 130.5, 128.3, 128.2, 127.6, 126.0, 1 17.5, 1 12.9, 111.8, 101.6, 60.2, 59.0, 57.3, 56.6, 55.1, 55.0, 41.5, 39.9, 37.8, 34.1, 31.3, 31.1, 29.6, 24.8, 24.7, 22.3, 20.2, 15.6, 13.8. ESI-MS m/z: Calcd. for C 43 H 50 N 4 O 8 : 750.88. Found (M+l) + : 751.3. Example 150 85 188 To a solution of 85 (80 mg, 0.110 mmol) in CH 2 C1 2 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), butyryl chloride (34.4 mL, 0.331 mmol) and DMAP (1.30 mg, 0.01 1 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH2CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 1:1) to afford 188 (70.1 mg, 80%) as a white solid. Rf = 0.54 MeOH:EtOAc 1:5. 'H NMR (300 MHz, CDCI 3 ) δ 7.28-7.14 (m, 5H), 6.80 (s, IH), 6.07 (d, J= 6.6 Hz, IH), 6.00 (d, J= 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, IH), 5.35 (t, J= 5.4 Hz, IH), 4.12 (d, J= 2.4 Hz, IH), 4.05 (bs, IH), 3.89 (brt, J= 6.9 Hz, IH), 3.66 (s, 3H), 3.64-3.63 (m, IH), 3.59-3.45 (m, 2H), 3.40 (brd, J= 7.8 Hz, IH), 3.20 (dt, J, = 2.7 Hz, J 2 = 12 Hz, IH), 3.00 (dd, J, = 8.1 Hz, J2 = 18 Hz, IH), 2.87 (t, J= 8.1 Hz, 2H), 2.71 (d, J= 18.6 Hz, IH), 2.66-2.61 (m, IH), 2.58 (t, J= 7.2 Hz, 2H), 2.41-2.35 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.90-1.77 (m, 3H), 1.08 (t, J= 7.2 Hz, 3H), 0.69 (d, J= 6.9 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 172.0, 171.3, 170.8, 168.5, 147.7, 144.7, 142.5, 140.6, 140.5, 140.3, 131.0, 130.7, 128.4, 128.2, 127.7, 126.1, 123.1, 120.3, 117.5, 112.7, 111.8, 101.6, 60.3, 59.1, 57.3, 57.2, 55.4, 54.9, 48.2, 41.5, 39.5, 38.0, 36.0, 31.4, 26.8, 26.6, 24.6, 20.1, 18.5, 18.1, 15.7, 13.7, 9.2. ESI-MS m/z: Calcd. for GμHsiNsOα: 793.9. Found (M+l) + : 794.3. Example 151 To a solution of 85 (80 mg, 0.110 mmol) in CH 2 C1 2 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), hexanoyl chloride (46.3 mL, 0.331mmol) and DMAP (1.30 mg, 0.01 1 mmol) were added at 0 °C and the reaction mixture was stirred at 23°C for 5 h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed succesively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by column chromatography (RP-18, CH 3 CN: H 2 O 1:1) to afford 189 (80 mg, 88%) as a white solid. Rf= 0.23 Hex:EtOAc l:3. 'H NMR (300 MHz, CDC1 3 ) δ 7.21-7.08 (m, 5H), 6.74 (s, IH), 6.00 (d, J= 6.9 Hz, IH), 5.94 (d, J= 1.5 Hz, IH), 5.84 (d, J= 1.5 Hz, IH), 5.24 (t, J= 5.4 Hz, IH), 4.06 (bs, IH), 4.00 (bs, IH), 3.83 (t, J= 6 Hz, IH), 3.59 (s, 3H), 3.57 (m, IH), 3.53-3.40 (m, 2H), 3.33 (d, J = 7.8 Hz, IH), 3.14 (d, J= 11.7 Hz, IH), 2.94 (dd, J, = 8.4 Hz, J 2 = 18 Hz, IH), 2.81 (t, J= 7.5 Hz, 2H), 2.65 (d, J= 18 Hz, IH), 2.60-2.54 (m, IH), 2.52 (t, J= 7.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.27 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.95 (s, 3H), 1.76-1.60 (m, 3H), 1.35-1.29 (m, 2H), 1.84 (m, 2H), 0.85-0.78 (m, 3H), 0.62 (t, J= 6.6 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 172.0, 171.3, 171.1, 168.4, 147.8, 144.8, 142.6, 140.7, 140.5, 131.2, 130.6, 128.4, 128.3, 127.7, 126.2, 123.1, 120.3, 117.5, 112.6, 112.0, 101.7, 60.4, 59.1, 57.4, 57.2, 55.4, 54.9, 48.3, 41.5, 39.6, 38.1, 34.1, 33.6, 31.5, 31.3, 26.7, 24.7, 22.3, 20.2, 18.2, 15.7, 13.9, 9.3. ESI-MS m/z: Calcd. for C 6 H 55 N 5 O 9 : 821.96. Found (M+l) + : 822.3. Example 152 53 190 To a solution of 53 (100 mg, 0.145 mmol) in CH 2 C1 2 (0.72 mL), DIPEA (50.6 mL, 0.291 mmol) and acetyl chloride (20.7 mL, 0.291 mmol) were added at 0 °C and the reaction mixture was stirred for 4 h at 23 °C. Then, the solution was diluted with CH 2 CI 2 (10 mL), and washed successively with 0.1 N HCl (5 mL), and a solution of 10% NaHCO (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Siθ 2 , Hex: EtOAc 1 :2) to afford 190 (27 mg, 25%) as a white solid. Rf= 0.24 Hex:EtOAc l:l. 'H NMR (300MHz, CDC1 3 ) δ 6.82 (s, IH), 6.02 (d, J= 0.9 Hz, IH), 5.92 (d, J= 0.9 Hz, IH), 5.30 (bs, IH), 4.14 (d, J= 2.7 Hz, IH), 4.10 (s, IH), 3.90-3.73 (m, 2H), 3.68 (s, 3H), 3.67 (bs, IH), 3.49 (bs, IH), 3.42 (brd, J= 8.1 Hz, IH), 3.24-3.20 (m, IH), 3.01 (dd, J, = 8.4 Hz, J 2 = 18.3 Hz, IH), 2.78 (d, J= 18 Hz, IH), 2.64 (brd, J= 15.6Hz, IH), 2.36 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.77 (dd, J, = 11.7 Hz, J 2 = 15.6 Hz, lH), 0.65 (d, J= 6.6 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 170.2, 168.6, 168.1, 167.6, 147.9, 144.9, 142.8, 140.5, 131.5, 131.0, 127.7, 123.2, 120.3, 117.5, 112.3, 112.2, 101.7, 60.4, 59.0, 57.4, 57.2, 55.2, 54.9, 48.6, 41.5, 39.1, 36.6, 29.7, 26.7, 24.6, 20.7, 20.2, 17.6, 15.5, 9.2. ESI-MS m/z: Calcd. for C 3 5H 38 F3N 5 O 9 : 729.70. Found (M+l) + : 730.3. Example 153 53 191 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 CI 2 (1.09 mL). DIPEA (151.9 mL, 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h.. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 4:1) to afford 191 (20.2 mg, 12%) as a white solid. Rf= 0.3 Hex:EtOAc l :l. 'H NMR (300 MHz, CDC1 3 ) δ 6.81 (s, IH), 6.03 (d, J= 1.2 Hz, IH), 5.92 (d, J= 1.2 Hz, IH), 5.16 (t, J= 5.4 Hz, IH), 4.13 (d, J= 2.1 Hz, IH), 4.10 (bs, IH), 3.87-3.82 (m, IH), 3.80-3.74 (m, 1), 3.68 (s, 3H), 3.64 (d, J= 3 Hz, IH), 3.52-3.47 (m. IH), 3.42 (brd, J= 7.2 Hz, IH), 3.24-3.20 (m, IH), 3.02 (dd, J, = 8.1 Hz, J 2 = 18.3 Hz, IH), 2.77 (d, J= 17.7 Hz, IH), 2.64 (brd, J= 16.2 Hz, IH), 2.58 (t, J= 7.2 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H), 1.87-1.73 (m, 3H), 1.08 (t, J= 7.2 Hz, 3H), 0.68 (d, J= 6.6 Hz, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 172.8, 172.1, 170.4, 157.8, 150.0, 146.9, 144.8, 142.6, 142.5, 133.3, 132.8, 129.6, 125.3, 122.3, 119.5, 118.4, 115.7, 114.3, 114.2, 103.8, 62.4, 61.0, 59.4, 59.2, 57.2, 57.0, 50.6, 43.6, 41.2, 38.1, 31.7, 28.7, 26.6, 22.2, 20.6, 19.7, 17.5, 15.7, 11.2. ESI-MS m/z: Calcd. for C 37 H4 2 F 3 N 5 O 9 : 757.75. Found: 758.5 (M+l) + , 780.5 (M+23) + . Example 154 53 192 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 C1 2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), acetyl chloride (62.0 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 . filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H 2 O 1 :1) to afford 192 (111 mg, 62%) as a white solid. Rf= 0.25 Hex:EtOAc l:l. Η NMR (300 MHz, CDC1 3 ) δ 6.80 (s, IH), 5.87 (s, IH), 5.81 (s, IH), 4.70 (dd, J, = 2.4 Hz, J 2 = 9.9 Hz, IH), 4.20 (d, J= 6.3 Hz, IH), 4.09 (s, IH), 3.74 (s, 3H), 3.60 (s, IH), 3.28 (d, J = 7.5 Hz, IH), 3.17 (d, J= 12 Hz, IH), 3.07 (dd, J, = 7.2 Hz, J 2 = 18.3 Hz, IH), 2.93 (d, J= 13.2 Hz, IH), 2.66 (d, J= 15.3 Hz, IH), 2.53 (d, J= 17.7 Hz, IH), 2.47-2.20 (m, IH), 2.37 (s, IH), 2.33 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.72 (t, J= 14.4 Hz, IH), 1.53 (d, J= 6.9 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ 174.1, 168.6, 168.4, 167.5, 147.7, 144.8, 142.2, 140.4, 131.1, 130.5, 126.9, 123.3, 120.4, 117.5, 112.4, 111.8, 101.1, 60.7, 60.6, 57.6, 57.2, 56.6, 55.3, 52.7, 48.3, 41.5, 31.6, 29.7, 26.4, 25.5, 23.0, 22.6, 20.7, 20.5, 20.2, 17.8, 15.9, 14.1, 9.5. ESI-MS m/z: Calcd. for C 39 H 2 F 3 N 5 Oπ: 813.7. Found (M+l) + : 814.3. Example 155 53 193 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 C1 2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH 2 C1 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 4:1) to afford 193 (58 mg, 30%) as a white solid. Rf= 0.38 Hex:EtOAc l:l. 'H NMR (300 MHz, CDC1 3 ) δ 6.85 (s, IH), 5.99 (d, J= 1.2 Hz, IH), 5.90 (d, J= 1.2 Hz, IH), 5.47-5.42 (m, 2H), 4.09-4.08 (m, 2H), 3.69 (s, 3H), 3.66 (m, IH), 3.41 (d, J= 7.5 Hz, IH), 3.28-3.18 (m, 2H), 3.07 (dd, J / = 8.1 Hz, J 2 = 18 Hz, IH), 2.66 (d, J= 18.6 Hz, IH), 2.61-2.39 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.95-1.79 (m, 6H), 1.72-1.59 (m, 6H) 1.09 (t, J= 7.5 Hz, 3H), 0.99-0.94 (m, 6H), 0.85 (d, J= 6.9 Hz, 3H). I3 C NMR (75 MHz, CDC1 3 ) δ 171.2, 170.7, 169.1, 168.4, 148.1, 145.0, 142.7, 140.9, 140.6, 131.2, 130.5, 128.4, 123.4, 119.9, 117.6, 113.0, 112.1, 101.9, 60.7, 59.5, 57.6, 56.5, 55.7, 55.2, 41.8, 41.4, 36.3, 35.8, 29.9, 27.0, 25.3, 20.5, 20.0, 18.8, 18.3, 15.8, 14.0, 13.8, 13.4, 12.7, 9.6. ESI-MS m/z: Calcd. for C45H54F 3 N 5 O11: 897.93. Found (M+l) : 898.3. Example 156 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 C1 2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), hexanoyl chloride (121.9 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH 2 CI 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na2SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 4:1) to afford 194 (37.5 mg, 22%) as a white solid. Rf= 0.32 Hex:EtOAc 1:1. Η NMR (300 MHz, CDC1 3 ) δ 6.80 (s, IH), 6.02 (d, J= 1.2 Hz, IH), 5.92 (d, J= 1.2 Hz, IH), 5.22 (t, J= 5.7 Hz, IH), 4.13 (d, J= 2.4 Hz, IH), 4.09 (s, IH), 3.88-3.81 (m, 1H), 3.80- 3.71 (m, IH), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, IH), 3.52-3.43 (m, IH), 3.41 (brd, J= 6.6 Hz, IH), 3.23-3.19 (m, IH), 3.00 (dd, .// = 8.7 Hz, J 2 = 18.6 Hz, IH) , 2.77 (d, J= 18Hz, IH), 2.67-2.56 (m, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.01 (s, 3H), 1.82-1.74 (m, 4H), 1.43-1.38 (m, 3H), 0.97-0.88 (m, 3H), 0.67 (d, J= 6.9Hz, 3H). 13 C NMR (75 MHz, CDCI3) δ 171.2, 170.3, 168.6, 148.2, 145.1, 143.0, 140.8, 140.7, 131.7, 131.1, 127.8, 123.5, 120.6, 117.7, 112.5, 102.0, 60.7, 59.2, 57.6, 57.4, 55.4, 55.2, 48.9, 41.8, 34.4, 31.8, 31.6, 29.9, 26.9, 25.0, 24.8, 22.9, 22.5, 20.4, 17.9, 15.8, 14.3, 14.1, 9.5. ESI-MS m/z: Calcd. for GsgH^NsO.,: 785.81. Found: 786 (M+l) + , 805.5 (M+23) + . Example 157 DIPEA, CH 2 CI 2 53 195 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 C1 2 (1.09 mL), DIPEA (75.9 mL, 0.436 mmol), and decanoyl chloride ( 92.7mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH 2 C1 2 (10 mL) and washed successively with 0.1 N HCl (5 mL), and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 1:1) to afford 195 (75 mg, 41%) as a white solid. Rf= 0.32 Hex:EtOAc l:l. Η NMR (300 Hz, CDC1 3 ) δ 6.82 (s, IH), 6.03 (d, J= 1.5 Hz, IH), 5.93 (d, J= 1.5 Hz, IH), 5.26 (bs, IH), 4.15 (s, IH), 4.11 (s, IH), 3.89-3.75 (m, 2H), 3.68 (s, 3H), 3.65 (bs, IH), 3.52- 3.44 (m, IH), 3.43 (d, J= 8.1 Hz, IH), 3.22 (brd, J= 11.4 Hz, IH), 3.03 (dd, J, = 7.8 Hz, J 2 = 17.4 Hz, IH), 2.78 (d, J= 17.7 Hz, IH), 2.69-2.56 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 2.03 (s, 3H), 1.83-1.74 (m, 3H), 1.83-1.74 (m, 12H), 0.90-8.88 (m, 3H), 0.68 (d, J= 6 Hz, 3H). 13 C NMR (75 Hz, CDC1 3 ) δ 171.0, 170.1, 168.4, 148.0, 144.8, 142.8, 140.5, 131.5, 130.8, 127.5, 123.3, 120.3, 117.5, 112.3, 112.2, 101.7, 60.4, 59.0, 57.4, 57.2, 55.1, 55.0, 48.6, 41.5, 39.1, 34.2, 31.8, 29.4, 29.2, 26.7, 25.0, 24.6, 22.6, 20.2, 17.6, 15.5, 14.0, 9.2. ESI-MS m/z: Calcd. for C 43 H 54 F 3 N 5 O 9 : 841.91. Found (M+l) + : 842.3. Example 158 To a solution of 53 (150 mg, 0.218 mmol) in CH 2 C1 2 (1.09 mL), DIPEA (75.9 mL, 0.436 mmol), and stearoyl chloride (147.3 mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH 2 CI2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH 3 CN: H 2 O 1:1) to afford 196 (86 mg, 41%) as a white solid. Rf= 0.42 Hex:EtOAc 1:1. 'H NMR (300 MHz, CDCl 3 ) δ 6.81 (s, IH), 6.03 (s, lH), 5.92 (s, IH), 5.21 (bs, lH), 4.14 (s, IH), 4.10 (s, IH), 3.88-3.74 (m, 2H), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, IH), 3.49 (brd, J= 14.7 Hz, IH), 3.42 (d, J= 8.1 Hz, IH), 3.22 (brd, J= 11.4 Hz, IH), 3.02 (dd, J, = 8.7 Hz, J 2 = 18.6 Hz, IH), 2.78 (d, J= 18Hz, IH), 2.68-2.56 (m, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 2.02 (s, 3H), 1.82-1.73 (m, 3H), 1.42-1.19 (m, 28H), 0.87 (t, J= 7.2 Hz, 3H), 0.67 (d, J= 6.6 Hz, 3H). ,3 C NMR (75 MHz, CDC1 3 ) δ 171.0, 170.2, 168.5, 147.9, 144.8, 142.8, 140.4, 131.4, 130.9, 127.5, 123.3, 120.4, 117.5, 112.4, 112.1, 101.7, 60.4, 58.9, 57.4, 57.2, 55.2, 55.0, 48.6, 41.5, 39.0, 34.2, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2, 26.7, 25.1, 24.6, 22.7, 20.2, 17.6, 15.5, 14.1, 9.2. ESI-MS m z: Calcd. for C 5 ιH 7 oF 3 N 5 O 9 : 953.5. Found (M+l) + : 954.4. Example 159 To a solution of 45 (10 mg, 0.019 mmol) in CH 2 C1 2 (0.095 mL), triethylamine (2.94 mL, 0.021 mmol) and allyl bromide (2.0 mL, 0.023 mmol) were added at 23 °C. The reaction mixture was stirred for 6 h and then, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , MeOH: EtOAc 1:5) to afford 197 (3.8 mg, 35%) as a white solid. Rf = 0.19 EtOAc:MeOH 5:1. 'H NMR (300 MHz, CDC1 3 ) δ 6.43 (s, IH), 5.95 (s, IH), 5.89 (s, IH), 5.62-5.59 (m, IH), 4.94-4.84 (m„ 2H), 4.19 (s, IH), 4.08 (s, IH), 3.98 (t, J = 4.5 Hz, IH), 3.76 (s, 3H), 3.32- 3.26 (m, 2H), 3.07 (dd, J ; = 7.5 Hz, J 2 = 17. A Hz, IH), 2.89 (d, J= 6 Hz, 2H), 2.80 (d, J = 3.9 Hz, IH), 2.76 (d, J= 3.3 Hz, IH), 2.57-2.52 (m, 2H), 2.33 (s, 6H), 2.24 (s, 3H), 1.99 (s, 3H), 1.88-1.79 (dd, J, = 12.9 Hz, J 2 = 15.9 Hz, IH). ESI-MS m/z: Calcd. for C 31 H36 4 O 6 : 560.64. Found (M+l) + : 561.3. Example 160 To a solution of 146 (50 mg, 0.096 mmol) in CH 2 C1 2 (0.96 mL), pyridine (11.7 mL, 0.144 mmol), and cinnamoyl chloride (24.0 mg, 0.144 mmol) were added at 23 °C and the reaction mixture was stirred for 18 h at that temperature. Then, the solution was diluted with CH 2 C1 2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO 3 (5 ml). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , Hex:EtOAc 1 :2) to afford 198 (54 mg, 86%) as a white solid. Rf= 0.45 Hex:EtOAc l:l. 'H NMR (300 MHz, CDC1 3 ) δ 7.41-7.37 (m, 6H), 6.38 (s, IH), 6.19-6.03 (m, IH), 6.08 (d, J = 15.9 Hz, IH), 5.93 (d, J= 1.5 Hz, IH), 5.88 (d, J= 1.5 Hz, IH), 5.62 (s, IH), 5.38 (dd, J, = 1.5 Hz, J 2 = 17.1 Hz, IH), 5.26 (dd, J, = 1.5 Hz, J 2 = 10.5 Hz, IH), 4.47 (dd. J, = 3.6 Hz, J 2 = 10.8 Hz, IH), 4.23-4.11 (m, 5H), 3.89 (dd, J = 4.8 Hz, J 2 = 1 1.1 Hz, IH), 3.51 (s, 3H), 3.34 (brd, J= 8.4 Hz, IH), 3.27-3.21 (m, 2H), 2.97 (dd, J y = 7.8 Hz, J? = 17.7 Hz, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H), 1.91 (dd, J, = 12 Hz, J 2 = 15.6 Hz, IH). 13 C NMR (75 MHz, CDC1 3 ) δ 166.5, 148.8, 146.7, 144.7, 144.5, 142.7, 139.5, 134.4, 134.1, 131.1, 130.6, 129.1, 128.7, 128.2, 121.9, 121.2, 118.5, 117.8, 116.8, 112.9, 112.7, 101.5, 74.7, 65.2, 60.7, 60.6, 57.4, 56.8, 56.6, 55.7, 41.9, 31.8, 26.7, 25.5, 22.9, 15.9, 14.4, 9.7. ESI-MS m/z: Calcd. for C 38 H 39 N 3 O 7 : 649.7. Found (M+l) + : 650.3. Example 161 To a solution of 161 (78.5 mg, 0.146 mmol) and the cysteine derivative (81.1 mg, 0.247 mmol) in anhydrous CH2C12 (7.3 mL), DMAP (50 mg, 0.41 mmol) and EDC.HCI (78.1 mg, 0.41 mmol) were added at 23 oC. The reaction mixture was stirred at 23 oC under Argon atmosphere for 1.5 h. The mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2C12 (20 mL) and the combined organic extracts were dried over Na2SO4, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter o the column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1 :4 to 3:1 as eluent. Compound 199 (1 13 mg, 88%) was obtained as a pale yellow solid. Rf= 0.36 Hex:EtOAc 1:1. Η NMR (300 MHz, CDC1 3 ) δ: 7.76 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, j = 7.6 Hz, 2H), 6.54 (s, IH), 5.80 (s, IH), 5.74 (s, IH), 5.10 (d, J = 5.7 Hz, IH), 5.08 (d, J = 5.7 Hz, IH), 4.50 (dd, j = 4.9 Hz, j = 11.8 Hz, IH), 4.20-4.05 (m, 4H), 4.02 (s, 3H), 3.81 (s, 3H), 3.61 (d, j = 13.8 Hz, IH), 3.55 (d, J= 13.8 Hz, IH), 3.50 (s, 3H), 3.21 (m, IH), 3.06 (m, IH), 3.00 (d, j = 6.0 Hz, 2H), 2.90 (dd, J = 8.9 Hz, j = 17.4 Hz, IH), 2.79 (s, IH), 2.56 (m, IH), 2.50 (dd, j = 4.8 Hz, J = 14.9 Hz, IH), 2.21 (s, 3H), 2.18 (s, 3H), 1.80 (s, 3H), 1.75 (m, 2H). ESI-MS m/z: Calcd. for 848.3. Found: 849.3 (M+l) + , 871.3 (M+23) + . HPLC: Conditions: Column: Simmetry C18, Mobile phase: CH 3 CN/H 2 O in gradient from 50 to 100% in 25 minutes. 0 = 1 mL/min, t= 40 °C. Retention time: 16.04 minutes. HPLC purity in area: 89.29%. Example 162 To a solution of 161 (80 mg, 0.148 mmol) and the cysteine derivative (76 mg, 0.223 mmol) in anhydrous CH 2 C1 2 (6.8 mL), DMAP (45 mg, 0.37 mmol) and EDC.HCI (71 mg, 0.37 mmol) were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 2.5 h Then, the mixture was diluted with CH 2 CI 2 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH 2 CI 2 (20 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and the solvent was eliminated under reduced pressure. The crude ofthe reaction was purified by flash column chromatography (inner diameter ofthe column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in gradient from 1:4 to 3:1 as eluent. Compound 200 (83 mg, 65%) was obtained as a pale yellow solid. Rf= 0.5 Hex:EtOAc l:l. Η NMR (300 MHz, CDC1 3 ) δ: 7.71 (m, 3H), 7.49 (d, J = 7.3 Hz, IH), 7.36 (t, J = 7.3 Hz, 2H), 7.32- 7.23 (m, 2H), 6.65 (s, IH), 5.80 (s, IH), 5.79 (s, IH), 5.13 (d, J = 6.1 Hz, IH), 5.11 (d, J = 6.1 Hz, IH), 5.05 (d, J = 6.1 Hz, IH), 5.01 (d, J = 6.3 Hz, IH), 4.76 (dd, J = 3.9 Hz, J = 11.9 Hz, IH), 4.15- 4.03 (m, 4H), 3.96 (t, J = 4.0 Hz, IH), 3.87 (s, 3H), 3.55 (s, 3H), 3.51 (s, 3H), 3.34-3.29 (m, 2H), 3.24 (dd, J = 5.5 Hz, J = 13.5 Hz, IH), 3.03 (m, IH), 2.97 (t, J = 7.5 Hz, IH), 2.44-2.35 (m, 3H), 2.29 (s, 3H), 2.14 (s, 3H), 1.98 (dd, J = 8.06, J = 15.1 Hz, 2H), 1.75 (s, 3H). 13 C NMR (75 MHz, CDC1 3 ) δ 196.98, 161.13, 158.21, 149.01, 148.78, 145.05, 144.91, 141.01, 140.69, 140.07, 137.53, 132.76, 131.15, 129.41, 127.70, 127.67, 127.21, 126.83, 125.28, 125.05, 124.94, 122.51, 119.84, 119.73, 116.61, 110.26, 104, 57, 101.40, 99.23, 96.70, 70.25, 63.15, 60.40, 58.89, 57.52, 56.98, 56.72, 56.15, 55.06, 47.22, 41.37, 38.26. 35.22, 29.57, 25.34, 15.62, 7.26. ESI-MS m z: Calcd. for C47H 49 N 3 O 11 S: 863.97. Found: 865.0 (M+l) + , 887.1 (M+23) + . HPLC: Conditions: Column: Simmetry C18. Mobile phase: CH 3 CN/H 2 O in gradient from 50 to 100% in 25 minutes. 0 = 1 mL/min. t= 40 °C. Retention time: 15.36 minutes. HPLC purity in area: 91.56%. Example 163 To a solution of 161 (418 mg, 0.77 mmol) and the cysteine derivative (321 mg, 0.77 mmol) in anhydrous CH 2 C1 2 (35 mL), DMAP (235 mg, 1.92 mmol) and EDC.HCI (369 mg, 1.92 mmol) were added at 23 °C and the reaction was stirred under Argon atmosphere for 2 h. The mixture was diluted with CH2CI 2 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2CI2 (20 mL) and the combined organic extracts were dried over Na SO 4 , filtered and the solvent was eliminated under reduced pressure. The crude ofthe reaction was purified by flash column chromatography (inner diameter of the column 3 cm, height of silica 11 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1:3 to 3:1 as eluent. Compound 201 (372 mg, 52%) was obtained as a pale yellow solid. Rf= 0.41 Hex:EtOAc 1:1. 1H-RMN (CDCI3, 300 MHz) δ 7.76-7.64 (m, 4H), 7.41-7.30 (m, 4H), 6.54 (s, IH major isomer), 6.51 (s, IH, minor isomer), 5.69 (s, IH, minor isomer), 5.67 (s, IH, major isomer), 5.60 (s, IH minor isomer), 5.57 (s, IH major isomer), 5.08 (s, 2H), 4.26 (t, J = 5.1 Hz, IH minor isomer), 4.23 (t, J= 4.9 Hz, IH major isomer), 4.07-4.03 (m, 3H), 3.98- 3.88 (m, 3H), 3.84 (s, 3H), 3.71 (dt, J, = 5.6 Hz, J 2 = 10.0 Hz, IH), 3.49 (s, 3H, major isomer), 3.49 (s, 3H, minor isomer), 3.40 (dt, J, = 5.6 Hz, J 2 = 9.5 Hz, IH), 3.18 (m, 3H), 3.11 (m, IH). 2.91-2.82 (m, IH), 2.48-2.28 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H, major isomer), 2.14 (s. 3H. minor isomer), 2.03 (s, 3H), 1.91 (dt, J, = 8.8 Hz, J 2 = 14.4 Hz, IH), 1.76 (s, 3H. minor isomer). 1.76 (s, 3H major isomer), 0.85 (s, 9H minor isomer), 0.85 (s, 9H major isomer). 0.04 and 0.01 (s, 6H both isomers). ESI-MS m/z: Calcd. for C 5 ιH 6 ιN 3 O, 0 SSi: 935.4. Found: 936.4 (M+l) + , 958.3 (M+23) + . Example 164 To a solution of 25 (2 mg, 0.0035 mmol) and an excess amount ofthe cysteine derivative in anhydrous CH2CI 2 (0.2mL), an excess amounts of DMAP and EDC.HCI were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 14 h. Then, the mixture was diluted with CH 2 CI 2 (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with additional CH2CI 2 (10 mL). The combined organic layers were dried over a2SO 4 , filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (SiO 2 , Hex:EtOAc 4:1) to afford 202 as a pale yellow solid. Η NMR (300 MHz, CDC1 3 ) (poor resolution) δ 7.78.7,62 (m, 4H), 7.41-7.26 (m, 4H), 6.73 (s, IH), 6.10 (m, IH), 5.92 (d, J = 1.3 Hz, IH), 5.88 (d, J = 1.3 Hz, IH), 5.40-5.22 (m, 2H), 5.11 (s, 3H), 5.02 (d, J = 13.8 Hz, IH). 4.29-4.02 (m, 6H), 3.97 (m, IH), 3.72 (d. J = 12.5 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 3H), 3.51 (d, J = 12.3 Hz, 2H), 3.50 (s, 3H), 3.49-3.20 (m. 4H), 2.54-2.28 (m, 4H), 2.40 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H). Fermentation Procedures Example A Seed medium YMP3 containing 1% glucose; 0.25% beef extract; 0.5% bacto- peptone; 0.25% NaCl; 0.8% CaCO 3 was inoculated with 0.1% of a frozen vegetative stock of the microorganism, strain A2-2 of Pseudomonas fluorescens, and incubated on a rotary shaker (250 rpm) at 27°C. After 30 h of incubation, the seed culture was added to a agitated- vessel fermentor with a production medium composed of 2% dextrose; 4% mannitol, 2% dried brewer's yeast (Vitalevor® Bioϊux, Belgium); 1% (NH 4 ) 2 SO 4 ; 0.04% K 2 HPO 4 ; 0.8 KC1; 0.001% FeCl 3 ; 0.1% L-Tyr; 0.8% CO 3 Ca; 0.05% PPG-2000; 0.2% anti- foam silicone (ASSAF-100, RHODIA UK). The sterilisation was carried out at 122°C 30 minutes. The volume inoculated was a 2% (v/v). The temperature was 27°C (0 to 16h) and 24°C from 16h to final process (41 hours). The dissolve oxygen-pressure was upper to 25%. The pH was controlled at 6.0 with diluted sulphuric acid since 28 hours till final process. The overpressure was 0.5 bar. A 1% mannitol or sorbitol was added from 16 h to final process (for two days running) and 2% for three days fermentation-process. After 41 or 64 hours, the fermentation broth must be extracted for recovery safracin B or KCN treatment in the clarified broth for recovery safracin B - cyano. Example B Obtention of safracin B cyano from the crude extract. A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted a pH 9.5 with diluted sodium hydroxide and extracted twice with 2:1 (v/v) ethyl acetate, methylene chloride or butyl acetate. The extraction was carried out into an agitated-vessel during 20', the temperature ofthe mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous or frozen and then filtered for removing ice. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract. Example C Obtention of safracin B cyano from the clarified broth. A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted at pH 3.9 with concentrated acetic acid. 0.5 grams per litre of KCN are added to the clarified broth an incubated at 20°C during 1 hour with agitation. Then, the temperature was decreased at 15°C and the pH was adjusted at 9.5 with diluted sodium hydroxide and extracted with 2: 1.5 (v/v) ethyl acetate. The extraction was carried out into an agitated-vessel during 20 minutes, the temperature ofthe mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract. This extract was purified by flash column chromatography (SiO 2 , gradient 20:1 to 10: to 5:1 ethyl acetate:methanol) to afford quantitatively compound 2 as a light yellow solid. Rf: 0.55 (ethyl acetate:methanol5:l); .t R = 19.9 min [HPLC, Delta Pack C4, 5μm, 300 A, 150x3 mm, λ=215 nm, flow= 0.7 ml/min, temp= 50°C, grad.: CH 3 CN-aq. NaOAc (lOmM) 85% - 70% (20')]; Η NMR (300 Mhz, CDC1 3 ): δ 6.54 (dd, J, = 4.4Hz, J 2 = 8.4 Hz, 1H),6.44 (s, IH), 4.12 (d, J = 2.4 Hz, IH), 4.04 (d, J= 2.4 Hz, IH), 4.00 (s, 3H), 3.87 (bs, IH), 3.65 (ddd, J = 1.5 Hz, J 2 = 8.7 Hz, J 3 = 9.9 Hz, IH), 3.35 (br. D, J= 8.4 Hz, IH), 3.15-2.96 (m, 4H), 2.92 (q, J= 7.2 Hz, IH), 2.47 (d, J= 18.3 Hz, IH), 2.29 (s, 3H), 2.18 (s, 3H) 1.83 (s, 3H), 1.64 (ddd, J / = 2.7 Hz, J 2 = 11.1 Hz, J 3 = 14.1 Hz, IH), 0.79 (d, J= 7.2 Hz, 3H); 13 C NMR (75 Mhz, CDC1 3 ): δ 186.0 (q), 175.9 (q), 156.2 (q), 146.8 (q), 142.8 (q), 140.7 (q), 136.6 (q), 130.5 (q), 128.8 (q), 127.0 (q), 120.5 (s), 117.4 (q), 116.5 (q), 60.8 (t), 60.4 (s), 58.7 (t), 56.2 (s), 55.7 (s), 54.8 (s), 54.8 (s), 54.4 (s), 50.0 (s), 41.6 (t), 39.8 (d), 25.2 (d), 24.4 (d), 21.2 (t), 15.5 (t), 8.4 (t). ESI-MS m/z: Calcd for C 29 H 35 N 5 O 6 : 549.6. Found (M+Na) + : 572.3. Example D A medium (50 1) composed of dextrose (2%), mannitol (4%), dry brewer's yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.04%), potassium chloride (0.8%), iron (III) chloride 6-hydrate (0.001%), L-tyrosine (0.1%), calcium carbonate (0.8%), poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (FERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 64 hours (aeration of 75 1 per minute and agitation from 350 to 500 rpm). The pH was controlled by automatic feeding of diluted sulphuric acid from 27 hours to final process. A 2% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 9.5 with diluted sodium hydroxide, extracted with 25 litres of ethyl acetate twice. The mixture was carried out into an agitated-vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phases were frozen at -20°C and filtered for removing ice and evaporated ice and evaporated until obtention of a 40 g oil-dark-crude extract. After introduction ofthe cyanide group and purification, 3.0 grams of safracin B cyano were obtained. Example E A medium (50 1) composed of dextrose (2%), mannitol (4%), dry brewer's yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.02%, potassium chloride (0.2%), Iron (III) chloride 6-hydrate (0.001%, L-tyrosine (0.1%), calcium carbonate (0.8%, poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (FERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 41 hours (aeration of 75 1 per minute and agitation from 350 to 500 rpm). The pH was controlled by automatic feeding of diluted sulphuric acid from 28 hours to final process. A 1% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 3.9 with 200 ml of cone, acetic acid. 25 grams of potassium cyanide 97% were added and after 1 hour of agitation at 20°C, the pH was adjusted to 9.5 with 1500 ml of a solution 10% sodium hydroxide. Then, extracted with 35 litres of ethyl acetate. The mixture was carried out into an agitated -vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried by sodium sulphate anhydrous and evaporated until obtention of a 60 g oil-dark-crude extract. After chromatography, 4.9 grams of safracin B cyano were obtained. REFERENCES European Patent 309,477. US Patent 5,721,362. Sakai, R., Jares-Erijman, E.A., Manzanares, I., Elipe, M.V.S., and Rinehart, K.L. J. Am. Chem. Soc. (1996) 118, 9017-9023 Martinez, E.J., Owa, T., Schreiber, S.L. and Corey, E.J. Proc. Natl. Acad. Sci. USA. 1999, 96, 3496-3501. Japanese Kokai JP-A2 59/225189. Japanese Kokai JP-A2 60/084288. Arai, T,; Kubo, A. In The Alkaloids, Chemistry and Pharmacology, Brossi, A. Ed.; Academic: New York, 1983, Vol 21 ; pp 56-1 10. Remers, W. A.: In 77ze Chemistry of Antitumor Antibiotics; Vol. 2; Wiley; New York, 1988, pp 93-118. GulavitaN. K.; Scheuer, P. J.: Desilva, E. D. Abst. Indo-United States Symp. on Bioactive Compounds from Marine Organisms, Goa, India, Feb. 23-27, 1989, p 28. Arai, T; Takahashi, K; Kubo, A. J. Antibiot, 1977, 30, 1015-1018. Arai. T.; Takahashi, K.; Nakahara, S.; Kubo, A. Experientia 1980, 36, 1025-1028. Mikami, Y.; Takahashi, K; Yazawa, K.; Hour- Young, C; Arai, T.; Saito, N.; Kubo, A. J. Antibiot. 1988, 41, 734-740. Arai, T.; Takahashi, K.; Ishiguro, K.; Yazawa, K. J. Antibiot. 1980, 33, 951-960. Yazawa, K.; Takahashi, K.; Mikami, Y.; Arai, T.; Saito, N.; Kubo, A. J. Antibiot. 1986, 39, 1639-1650. Arai, T.; Yazawa, K.; Takahashi, K.; Maeda, A.; Mikami, Y. Antimicrob. Agent Chemother. 1985, 25, 5-11. Takahashi, K.; Yazawa, K.; Kishi, K.; Mikami, Y.; Arai, T.; Kubo, A. J. Antibiot. 1982. 35. 196-201. Yazawa, K.; Asaoka, T.; Takahashi, K.; Mikami, Y.; Arai, T. J. Antibiot. 1982, 35. 915-917. Frincke, J. M.; Faulkner, D. J. J Am. Chem. Soc. 1982, 104, 265-269. He, H. -Y.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5822-5824. Kubo, A.; Saito, N.; Kitahara, Y.; Takahashi, K.; Tazawa, K.; Arai, T. Chem Pharm. Bull. 1987, 35, 440-442. Trowitzsch-Kienast, W.; Irschik, H.; Reichenback, H.; Wray, V.; Hδfle, G. Liebigs Ann. Chem. 1988, 475-481. Ikeda, Y.; Idemoto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.; Asano, T.; Munakata, T. J. Antibiot. 1983, 36, 1279-1283. Asaoka, T.; Yazawa, K.; Mikami, Y. Arai, T.; Takahashi, K. J. Antibiot. 1982, 35, 1708- 1710. Lown, J. W.; Hanstock, C. C; Joshua, A. V.; Arai, T; Takahashi, K. J. Antibiot. 1983, 36, 1184-1194. Munakata et al. United States Patent 4, 400, 752, 1984. Y. Ikeda et al. The Journal of Antibiotics. VOL XXXVI, N°10, 1284, 1983. R. Cooper, S. Unger. The Journal of Antibiotics. VOL XXXVIII, N°l, 1985. Corey et al. United States Patent 5, 721, 362. 1998. Corey et al. J. Am. Chem. Soc. vol 118 pp 9202-92034, 1996. Proc. Natl. Acad. Sci. USA. Vol. 96, pp 3496-3501, 1999.

Claims: Claims 1. A compound with the five membered fused ring ecteinascidin structure of the formula (XIV): the compound lacking a 1,4-bridging group and having at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group. 2. A compound according to claim 1, where the ring structure is of formula (a), (b) or (c): (a) (b) or 3. A compound according to claim 1 or 2, wherein the C-1 substituent is a hydrophobic group of moderate bulk. 4. A compound according to claim 1 , 2 or 3, where the substituent at C-1 is an optionally protected or derivatised aminomethylene group. 5. A compound according to claim 4, where the C-1 substituent is a monosubstituted aminomethylene group. 6. A compound according to claim 5, wherein the C-1 substituent is ofthe formula - CH 2 -NH CO-R a or-CH 2 -NH CS-R a . where R a is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylakylene, acyl, haloacyl, arlyalkyl, alkenyl and amino acid. 7. A compound according to claim 4, where the C-1 substituent is an optionally protected or derivatised hydroxymethylene group. 8. A compound according to claim 7, wherein the C-1 substituent is ofthe formula - CH 2 -O CO-R a .where R a is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylakylene, acyl, haloacyl, arlyalkyl, alkenyl and amino acid. 9. A compound according to claim 1 ofthe formula: wherein: R 1 is -CH 2 -N(R a ) 2 or-CH 2 -OR a , where R a is H; alkyl-CO-; haloalkyl-CO-; cycloalkylalkyl- CO-; haloalkyl-O-CO-; arylalkyl-CO-; arylalkenyl-CO-; heteroaryl-CO-; alkenyl-CO-; alkenyl; amino acid acyl; or a protecting group; R 5 is -OR", where R" is H; alkyl-CO-; cycloalkyl-CO-; haloalkyl-CO- or a protecting group; R 18 is -OR, where R is H, alkyl-CO-; cycloalkylalkyl-CO-; or a protecting group; R 21 is -CN or -OH. 10. A compound according to claim 9, which is ofthe formula: wherein R , 1 , R , R , and R ,21 are as defined. 11. A compound according to claim 9 or 10, wherein R 1 is -CH 2 -NHR a 12. A compound according to any of claims 9 to 11, wherein R is -aa-R b where aa is amino acid acyl and R b is as defined for R a . 13. A compound according to claim 12, wherein the amino acid acyl is further substituted with one or more R a groups. 14. A compound according to any of claims 9 to 13, wherein R 1 is -CH 2 -NH-aa-R b where aa is an amino acid and R b is hydrogen; protecting group; arylalkenyl-CO-; haloalkyl- CO-; alkyl-CO-; arylalkyl-CO-; or amino acid acyl, 15. A compound according to claim 14, wherein R 1 is -CH 2 -NH-aa-R b where aa is alanine and R b is hydrogen, Boc, PhNHCS-, CF 3 CO-, PhNAcCS-, trifluorocinnamoyl, cinnamoyl, C 3 F CO-, butyryl, 3-chloroproprionoyl, hydrocinnamoyl, hexanoyl, phenylacetyl, Cbz-val or acetyl; -CH 2 -aa-R where aa is valine and R is Cbz or Boc; -CH -aa-R where aa is phenylalanine and R b is Boc; -CH 2 -aa-R where aa is proline and R b is Boc; -CH 2 -aa- R b where aa is arginine and R b is Boc; or -CH 2 -aa-R b where aa is tryptophan and R b is Boc. 16. A compound according to any of claims 9 to 13, wherein R 1 is -CH 2 -NR a -aa-R b where aa is an amino acid, R a is alkyl-CO- and R b is haloalkyl-CO-. 17. A compound according to claim 16, wherein R 1 is -CH 2 -NR a -aa-R b where aa is acetylalanine, R a is acetyl or butyryl, and R b is CF 3 -CO-. 18. A compound according to any of claims 9 to 13, wherein R 1 is -CH 2 -NHR a where R a is hydrogen, protecting group, alkyl-CO-; alkenyl-CO-; arylalkenyl-CO-; arylalkyl-CO-; heteroaryl-CO-; cycloalkylalkyl-CO-; or alkenyl. 19. A compound according to claim 18, wherein R 1 is -CH 2 -NHR a where R a is hydrogen, Troc, acetyl; isovaleroyl, decanoyl, cinnamoyl, hydrocinnamoyl, phenylacetyl, propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, chloronicotinoyl, cyclohexylacetyl, cyclohexylpropionyl or allyl. 20. A compound according to any of claims 9 to 13, wherein R 1 is -CH 2 -OR a where R a is hydrogen; a protected cysteine; a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(NHProt NH )-CO-, where Prot SH and Prot NH are protecting groups for thiol and for amino; a protecting group; alkyl-CO-; arylalkyl-CO-; arylalkenyl-CO-; a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(=NOProt OH )-CO- where Prot SH and Prot OH are protecting groups for thiol and for hydroxy; or a cysteine derivative of formula Prot SH -S-CH=C(-OProt OH )-CO-, where Prot SH and Prot OH are protecting groups for thiol and for hydroxy. 21. A compound according to claim 20, wherein R 1 is -CH 2 -OR a where R a is hydrogen; S-Fm-O-TBDMS-cysteine;a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(NHProt NH )-CO-, where Prot SH is Fm and Prot OH is Troc; TBDPS; butyryl; trfiluormethylcinnamoyl; cinnamoyl; hydrocinnamoyl; a cysteine derivative ofthe formula Prot SH -S-CH 2 -C(=NOProt OH )-CO- where Prot SH is Fm and Prot OH is methoxy; or a cysteine derivative of formula Prot SH -S-CH=C(-OProt OH )-CO-, where Prot SH is Fm and Prot OH is MOM. 22. A compound according to any of claims 9 to 21, wherein R 5 is -OR", where R" is H; alkyl-CO where the alkyl has an odd number of carbon atoms, ω-cyclohexylalkyl-CO-; or a protecting group; 23. A compound according to any of claims 9 to 22, wherein R 18 is -OR, where R is H, alkyl-CO-; or a protecting group; 24. A compound according to any of claims 9 to 22, wherein R 2 ' is -CN. 25. A compound according to any of claims 9 to 22, wherein R 21 is -OH 26. A compound according to claim 1, which is ofthe formula (XVIIa): or formula (XVIIb): where R 1 is an optionally protected or derivatised aminomethylene group, or an optionally protected or derivatised hydroxymethylene group; R 4 is -H; R 5 is -H or -OH; R 7 is -OCH 3 and R 8 is -OH or R 7 and R 8 together form a group -O-CH 2 -O-; R 14a and R 14b are both -H or one is -H and the other is -OH, -OCH 3 or -OCH 2 CH 3 , or R 14a and R 14b together form a keto group; and R 15 is -H or -OH; R 21 is -H, -OH or -CN; and derivatives. 27. A compound according to claim 26, where R 5 is acetyloxy or other acyloxy group of up to 4 carbon atoms. 28. A compound according to claim 1, ofthe general formula (XX): where R 1 is a monosubstituted amidomethylene group; R 5 is a small oxy-sidechain; and R 2 is a cyano group or a hydroxy group. 29. A compound according to claim 1, ofthe general formula (XXI): where Prot 1 and Prot 2 are hydroxy protecting groups, preferably different. 30. A compound according to claim 1, of formula (XXIIa): or of formula (XXIIb): where: R 1 is -CH 2 NH 2 or -CH 2 OH, or a protected or derivatised version of such a group and R 4 is - H; R 5 is -OH or a protected or derivatised version of such a group; R 14a and R 14b are both -H or one is -H and the other is -OH or a protected or derivatised version of such a group, -OCH 3 or -OCH 2 CH 3 , or R 14a and R 14b together form a keto group; R 12 is -NCH 3 -; R 15 is -OH or a protected or derivatised version of such a group; and R 18 is -OH or a protected or derivatised version of such a group. 31. A compound according to claim 30, wherein at least of R 1 , R 5 , R 14a , R 14b , R 15 or R 18 is a protected or derivatised group. 32. A compound according to claim 30, wherein R I4a and R 14b are both -H. 33. A compound according to claim 1, ofthe general formula (XXIII): where R 1 is a derivatised aminomethylene group of moderate bulk; R 5 is a derivatised hydroxy group of low bulk; R 12 is -NCH 3 - and R 2 ' is a hydroxy or cyano group. 34. A compound according to claim 33, where R 1 is a hydrophobic group and lacks a free hydrophilic function. 35. A compound according to claim 33 or 34, wherein R 1 is a group -CH 2 -NH 2 -CO-R a , where R a has a linear chain length of less than 20 atoms. 36. A compound according to claim 33, 34 or 35 where R 5 is an acetyl group. 37. A compound according to any of claims 33 to 36, where the group R 1 is acylated on an -NH 2 group, and is an N-acyl derivative formed from a group -CH 2 NH 2 or -CH 2 -NH-aa. 38. A compound according to claim 37, where the acyl group is of formula -CO-R a , where R a is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylakylene, acyl, haloacyl, arlyalkyl, alkenyl or amino acid. 39. A compound according to claim 33 or 34, where the group R 1 is a derivatised hydroxymethylene group. 40. A pharmaceutical composition comprising a comound according to any preceding claim, together with a pharmaceutically acceptable carrier. 41. The use of a compound according to any of claims 1 to 39, in the preparation of a pharmaceutical composition for use in the treatment of a tumour. 42. A method of treating a tumour, which comprises administering an effective amount of a compound according to any of claims 1 to 39.

Inventors: CUEVAS CARMEN, MANZANARES IGNACIO, MARTIN MARIA JESUS, MUNT SIMON, PEREZ MARTA, RODRIGUEZ ALBERTO, CUEVAS, CARMEN, MANZANARES, IGNACIO, MARTIN, MARIA JESUS, MUNT, SIMON, PEREZ, MARTA, RODRIGUEZ, ALBERTO
Applicants: CUEVAS CARMEN, MANZANARES IGNACIO, MARTIN MARIA JESUS, MUNT SIMON, PEREZ MARTA, PHARMA MAR SA, RODRIGUEZ ALBERTO, CUEVAS, CARMEN, MANZANARES, IGNACIO, MARTIN, MARIA JESUS, MUNT, SIMON, PEREZ, MARTA, PHARMA MAR, S.A., RODRIGUEZ, ALBERTO
Application year: 2001
Main classification: C07D515
IPC codes: A61K31, A61K35, A61P31, A61P35, C07D221, C07D241, C07D291, C07D317, C07D471, C07D487, C07D491, C07D515