MXPA99001454A - Cytotoxic amino sugar and related sugar derivatives of indolopyrrolocarbazoles - Google Patents

Abstract

The present invention concerns novel amino sugar and related sugar derivatives of indolopyrrolocarbazoles, their use as antitumor agents, and pharmaceutical formulations.

Description

/ / AMINOAZÚCAR CITOTÓXICA AND DERIVADOS DE AZÚCAR RELATED OF INDOLOPIRROLOCARBAZOLES I. Field of the Invention The present invention relates to ammoazucar and other sugar derivatives of indolopyrrolocarbazoles, their salts and hydrates, some of which compounds show topoisomerase I activity, which are useful for inhibiting the proliferation of tumor cells, are useful in showing antitumor effect, and a process for preparing them.

II. Description of the Previous Technique The alkaloids of indole [2, 3-a] carbazole such as rebeccamycin (US Patents Nos. 4.46"7.925 and 4.552.642) and its clinically active analogue, soluble in water, the 6- (2-diethylamethyl) rebeccamycin ( 1) (U.S. Patent No. 4,785,085) are useful antimicrobial agents which target DNA.

REF. 29231 The topoisos erasas are vital nuclear enzymes which work to solve the topological dilemmas in the DNA, such as overenrolment, unwinding and concatenation, which normally arise during replication, transcription and perhaps during other DNA processes. These enzymes allow the DNA to relax by forming strand breaks with enzymatic bridges that act as transient bridges or as pivot points for the passage of other strands of DNA. Drugs that target the topoisomerase appear to interfere with this break-reunion reaction of the DNA topoisomerases. In the presence of topoisomerase active agents, an aborted reaction intermediate called "cleavable complex" accumulates and results in the arrest of replication / transcription which ultimately leads to cell death. The development of topoisomerase I active agents, therefore, offers a new procedure for the arsenal of multiple regimen therapies currently used in clinics for the treatment of cancer. The article in Cancer Chemother. Pharmacol (1994), 34 (suppl): S 41-S 45 discusses the active compounds of topoisomerase I that are in clinical studies and it is found that these agents are effective in clinical antitumor studies. Naturally, these clinical candidates are related to the alkaloid Camptothecin (2).

Camptothecin The publications of European Patent Application 0,545,195 Bl published on November 22, 1995 and 0,602,597 A2 published on June 22, 1994 and in Cancer Research 1993, 5_3, 490-494 and 1995, 55, 1310-1315 described the derivatives ( 3) of indolo [2,3-a] -carbazole related to the class of rebeccamycin and claimed antitumor activity; however, the major mechanism of action may not be similar to camptothecin. The camptothecins act by the mechanism of topoisomerase I. International Patent Application WO 95/30682 also described the molodocarbazoles related to compound (3) and claimed antitumor activity.

Hudkins et al. In International Patent Application W096 / 11933 published April 25, 1996 and its corresponding US Patent No. 5,475,110 described a series of fused pyrrolocarbazoles and displayed in vitro biological data such as the inhibition of neuronal choline acetyltransferase ( ChAT), the inhibition of protein kinase C (PKC) for some compounds. U.S. Patent No. 5,468,849 discloses certain fluororrebecamycin analogs as useful anti-tumor agents, together with a process for their production by feeding the f luorotripytophan analog of a strain of Sacchdrothrix aerocolonigenes that produces rebeccamycin, preferably Saccharothrix aerocclomgenes C38,383 -RK2 (ATCC 39243). Glicksman and co-workers in the North American Patent No. 5,468,872 disclose the indolocarbazole alkaloids which are different in structure from those of the formula I of the present invention. Kojiri et al. In International Application WO96 / 04293 published February 15, 1996 discloses the mdolopyrrolocarbazoles having a disaccharide substituent which is different from the present amino substituted sugar compounds. There is nothing in any of the above references, or in the general prior art, which suggests the novel cytotoxic amino sugar and other sugar derivatives of indole pyrrolocarbazoles, some of which are topoisomerase I active agents, of the present invention.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide the new sugar derivatives of the polyolcarboxyles which inhibit the. proliferation of the antitumor cells and some of the derivatives show increased solubility in water, and topoisomerase I activity. This invention relates to the novel animal compounds represented by the formula. I, or a pharmaceutically acceptable salt of the isms wherein: R. and R.β are independently hydrogen, a pentose group (A) or a hexose group (B) of the formulas with the proviso that one of R- and R: ß is hydrogen and the other is not hydrogen; R, R, R, R. and R., R. ,, R .., R ... and R, are independently hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 1 to 7 carbon atoms, OR , azido, halogen, NR9R10. NHC (0) NR9R10. NHC (0) 0R, OR, -C (0) Ra, SR, -OS02Rc > or together they form = N-0H, = 0, = NR, with the proviso that R2, R3, R4, R5 and R2-, R3., R4-, R? ", and R5 'are not all simultaneously hydrogen, OH , alkoxy or alkyl, and with the proviso further that R3 or R.- is not -NH2, except when R6 is - (CH) .NHC (= NH) NH, said alkyl of 1 to 7 carbon atoms is optionally substituted with one to six of the same or different substituents halogen, CN, NO;, aryl or heteroaryl, the aryl or heteroaryl substituted with one or two groups independently selected from NRaR.o, OH, C00R9, SO R, SO R or OCOR R is H, OH, alkoxy of 1 to 7 carbon atoms or NR R, R is alkyl of 1 to 7 carbon atoms or aryl, R and R .. are independently hydrogen, alkyl of 1 to 7 carbon atoms , cycloalkyl of 1 to 7 carbon atoms, heteroapium, ring of 5 to 8 members, cyclic, non-aromatic, containing either one or two heteroatoms selected from oxygen or nitrogen, (CH.). NR.R;, (CH; ) -OR-. O { CH:). COOR-. , the alkyl of 1 to 7 carbon atoms is optionally substituted with one to six of the same or different halogen, OH, CN, NO, aryl or heteroaryl substituents, the aryl or the heteroaryl are substituted with one or two independently selected groups of NR9R? 0, OH, COOR ?, S03R9 or OCOR9; R <0> and R <10> are independently hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 1 to 7 carbon atoms, benzyl, aryl, heteroaryl, any of which groups except hydrogen may be substituted with one to six thereof or different substituents halogen, OH, NH2, CN, N02, -C (= NH) NH2, 0 -CH (= NH), CH (Rc) (CH.) - COOH or CH (Rb) (CH2) nNH2 or COOR. ., or R and R. together with the nitrogen atom to which they are attached, form a cyclic 5- to 8-membered non-aromatic ring, containing either one or two heteroatoms of oxygen, nitrogen or sulfur, or R9 and - R with just form = CHRR -.- .. R. is H or COOH; R is hydrogen, alkyl of 1 to 7 carbon atoms, aplo, aplaxyl, OR, NR.R-. , or OCO (CHr) r.NR_R :,, the alkyl of 1 to 7 carbon atoms is optionally substituted with one to six of the same or different substituents halogen, NR ^ R; , CN, N02, aryl, the aryl is substituted with one or two groups independently selected from NR.Ri-j, OH, COORo, SO R or OCOR; R-? and R8 are independently OH or hydrogen, or taken together is oxygen; X :, X'i, X2 and X'2 are independently hydrogen, halogen, OH, -CN, -NC, CF3, -CORa, N02, OR, 0 (CH2) -NRoR10, 0 (CH2) nORa or O ( CH2) nCOOR9; with the proviso that X;, X'2, X. and X '. Do not be 1,11-dichloro; with the additional condition that when X2 and X '; are each hydrogen, X: and X'_ are each independently hydrogen or halogen, R. is hexose, R- and Rt together are oxygen, and each of R.-, R ?, and R4 are OH, R2- , R2-, R4-, and R5. and Rosean each hydrogen, Q is NH, and then each of R. and R; do not be NH; and R3 is not methoxy when R is heterogeneous; W is carbon or nitrogen; C is oxygen, NR, sulfur or CH; and r. is an integer from 0 to 4. Yet another aspect of the present invention provides a method for inhibiting tumor growth in a mammalian host, which comprises administering to said host an amount that inhibits the tumor growth of a compound of the formula Yet another aspect of the present invention provides a pharmaceutical formulation comprising an effective anti-tumor amount of a compound of the formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the novel amino sugar and related derivatives of the dipopyrrolocarbazoles and salts thereof, some of which are topoisomerase I active agents. These compounds are useful for inhibiting the proliferation of antitumor cells and show antitumor effect. In the request, unless explicitly specified otherwise or in the context, the following definitions apply. The numbers in the subscript after the "C" symbol define the number of carbon atoms that a particular group can contain. For example "alkyl C: -." (alkyl of 1 to 6 carbon atoms) means a saturated, linear or branched carbon chain having from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl and n-hexyl. Depending on the context "alkyl of 1 to 6 carbon atoms" can also refer to alkylene of 1 to 6 carbon atoms which bridges two groups; examples include 5-propan-1,3-diyl, butan- ?, 4-diyl, 2-methyl-butan-1, 4-diyl, etc. "C2 -C6 alkenyl" means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; the 0 examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. Depending on the context, "alkenyl of 2 to 6 carbon atoms" can also refer to alkenediyl of 2 to 6 carbon atoms which bridges two groups; examples include ethylene-1,2-diyl (vinylene), 2-met i 1 -2-buten- 1, 4 -dii lo, 2-hexen-l, 6-diyl, etc. "Alkynyl of 2 to 6 carbon atoms" means a straight or branched carbon chain having at least one carbon-carbon triple bond, '. and from two to six carbon atoms; examples include ethmyl, propynyl, butyl, and hexinyl. "Aryl" means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl. "Substituted aryl" means aryl independently substituted with one to five (but preferably one to three) groups selected from alkanoyloxy of 1 to 6 carbon atoms, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkoxy of 1 to 6 carbon atoms, aryl, alkenyl of 2 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, nitro, amino, cyano, azido, alkylamino of 1 to 6 carbon atoms, di (alkylamino of 1 to 6 carbon atoms), and amido. "Halogen" means fluorine, chlorine, bromine, and iodine; fluorine being the preferred one. "Heteroaryl" means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heterolalk include thienyl, furyl, pyrrolyl, imidazoyl, pyrazyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tpazolyl, thiadiazolyl, oxadiazoyl, tetrazolyl, thiatriazolyl, oxa triazolyl, pyridyl, pipmidyl, pyrazinyl, pi r idazinium, triazinyl, tetrazmyl, and similar rings. The compounds of the present invention have the general formula (I) Where Ri represents a pentose group (A) or a hexose group (B) of the formulas Preferred compounds of formula I are those wherein in Ri or Ria all substituents are hydrogen except R2, R3 and R4 are each OH; and R5 is NR9R? 0.

Other preferred compounds of formula I are those wherein in Rx or Ria all substituents are hydrogen except R2, R and R5 are each OH; and R 4 is NR 9 R 10, halogen or N 3 (for example azido). Other preferred compounds of formula I are those wherein in Rx or R? A all substituents are hydrogen except R2 R3 and R4 are each OH; and R5 is halogen. Other preferred compounds of formula I are those wherein in Ri or Ria all substituents are hydrogen except R5, R3 and R4 are each OH; and R2 is halogen. Other preferred compounds of formula I are those wherein in R 1 or R α all substituents are hydrogen, except R 2, R 3 are each OH; and R5 is halogen and R4 is azido or NR9R? 0 or OR. Other preferred compounds of the formula I are those wherein in Ri or R? A all substituents are hydrogen, except R2, R3 are each OH; and R5 is halogen and R4 is halogen or hydrogen or alkyl. Other preferred compounds of formula I are those wherein in Ra or Ria all substituents are hydrogen, except R2, R3 are each hydrogen or hydroxyl; and R is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R 4 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR 9 R 0. Other preferred compounds of formula I are those wherein in Ri or Ria all substituents are hydrogen, except R3 and R4 are each hydrogen or hydroxyl; R 2 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R5 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R? 0. Other compounds of formula I are those wherein in Ri or Ria all substituents are hydrogen, except R3 and R5 are each hydrogen or hydroxyl; R 2 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R4 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R? or - Other preferred compounds of formula I are those wherein in Rx or Rl all substituents are hydrogen, except R2 and R4 are each one hydrogen or hydroxyl; R3 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R5 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R10.

Other preferred compounds of the formula I are those wherein R7 and e taken together is oxygen. Other preferred compounds of formula I are those wherein Xi, X'i. X2 and X'2 are independently halogen (preferably fluoro). The pharmaceutically acceptable salts and / or solvates of the compounds of the formula I also comprise the present invention, which also includes the stereoisomers such as enantiomers which may arise as a consequence of the structural asymmetry in the selected compounds of the formula I, and the anomers that arise from the stereochemistry of the Ri substitution. The compounds of this invention may exist in the form of pharmaceutically acceptable salts. Such salts include the addition salts with the inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluene sulfonic acid, tartaric acid, and acid maleic In addition, in the case of the compounds of this invention which contain an acid group, the acid group may exist in the form of alkali metal salts such as, for example, a potassium salt and a sm salt; the alkaline earth metal salts such as, for example, a magnesium salt and a calcium salt; and salts with organic bases such as an ethylammonium salt and an arginine salt. The compounds of the present invention are useful pharmacological agents with antitumor properties. With the active properties of topoisomerase I, the compounds may also be useful as antitumor agents. In recent years, numerous reports have been added to the literature suggesting the role of drugs that target topoisomerase I, to stabilize a covalent complex of DNA-topoisomerase I to produce the breaks of a single strand of DNA, linked to enzyme . From a pharmacological point of view, there are advantages in targeting topoisomerase I; Firstly, the relatively high levels of its presence in proliferating and resting cells suggest that its function may be independent of the rate or rate of cell growth and secondly, the active agents of topoisomerase I may be effective in slow development as well as in the rapid proliferation of tumors. Cells in colon tumors have been shown to contain higher intracellular levels of topoisomerase I than normal mucosal cells, suggesting the possibility for selective cytotoxic advantage. Thus, the inhibition of the proliferation of tumor cells by the compounds of formula I was initially demonstrated by the effective inhibition of topoisomerase I. Selected compounds of formula I, which usually have EC5o values less than 10 μM in the topoisomerase I assay, they were also tested in an inhibition of the proliferation assay of human / mouse tumor cells. The compounds of this invention were also examined for their therapeutic effect against the mouse tumor (P388) and the results are shown in the following examples of pharmacological tests (Table 1).

Anti-tumor efficacy Jn Vi vo The anti-tumor experiments were initiated by implanting mice (BDF1 or CDF1) intraperitoneally with 10 (6) P388 leukemia cells. The treatments were initiated one day after the implant and involved an intraperitoneal injection by dose level; Several dose levels were evaluated per compound. Six mice were typically used per dose level in the treatment groups, and eight to ten mice were used as untreated, parallel leukemic controls. The evaluation of the activity was carried out based on the comparison of the mean survival time (MST) of the treated mice (T) with the MST of the control mice (C). The activity was defined as a% T / C > o = 125%, calculated as: MST (T) / MST (C) x 100 =% T / C Table 1 Dose Elaborated Compound Using the Example Tumor (mg / kg / dose) MST T / C (%) No. 19 P388 200 9.0 82 100 20.0 182 50 18.5 168 25 17.0 155 29 P388 200 10 91 100 16.5 150 50 12.0 109 25 14.0 127 Topoisomerase I Activity (In Vi tro) The activity of topoisomerase I was measured as described below: the procedure for evaluating the compound induced the formation of the single strand break, mediated by topoisomerase I, in the DNA, was essentially as described by Hsiang et al. which appears in J. Biol. Chem. 260: 14873-14878 (1985). The samples dissolved in 100% DMSO either as 10 μM or 10 mg / ml solutions, unless otherwise stated, were diluted in Tris-EDTA buffer. The marine bacteriophage PM2 DNA (Boehringer Mannheim) was also diluted in Tris-EDTA buffer at a concentration of 0.02 μg / μl. Different dilutions of the compound that was evaluated were mixed with the diluted DNA and this mixture was added to 1000 units (one unit of enzymatic activity is defined as the amount capable of relaxing 100 ng of supercoiled DNA in approximately 30 minutes at 37 ° C) of aliquots of purified human topoisomerase I (Topogen) in 2X reaction buffer to start the reaction. The compound-DNA-enzyme mixture was incubated for 30 minutes at 37 ° C before stopping the reaction with warm stop buffer containing sodium dodecyl sulfate and proteinase K (Sigma). These mixtures were allowed to incubate at 37 ° C for another 10 minutes, at which time the mixtures were removed from the water bath and extracted with a 24: 1 mixture of chloroform / isoamyl alcohol. After centrifugation, the aliquots of the aqueous phases were placed in 0.9% agarose gel (SeaKem) wells in Tris-borate buffer containing 0.5 μg / ml ethidium bromide, and subjected to electrophoresis for 15 hours to separate the different topological isomers and the cleaved and broken DNAs. After destaining the gel in water, the reaction products of the DNA stained with ethidium bromide were visualized by exposure of the gel to the ultraviolet irradiation. The negatives of the photographs of the irradiated gels were explored with a densitometer and the areas under the peaks were calculated, in order to obtain the percentage formation of the breakage of the single-strand DNA for each sample. An average effective concentration (EC50) was obtained for each compound by interpolation between the points of the resulting dose-effect curve, which defines the potency of the compound for its effect for the induction of single strand breaks mediated by topoisomerase I in the DNA The topoisomerase I activity for the selected compounds of the present invention is shown below in Table II.

Table II Example No. EC50 (μM) 15 0.03 18 > 100 19 0.04 29 0.01 30 < 0.01 31 < 0.01 33 0.23 34 0.23 35 0.75 45 0.28 47 0.10 48 0.40 68 0.03 69 0.03 The novel compounds of the present invention, as exemplified by the amino derivatives and other sugar derivatives in Table II, show the remarkable activity of topoisomerase I even in the sub-chromosomal concentration range. A priori, this activity, however, is unexpected and unpredictable by someone with experience in the technique, since a small change in substitution patterns seems to result in a highly unexpected change in activity. This is exemplified by the difference in the activity of topoisomerase I for the compounds prepared by Examples 18 and 19. Example 19 is an effective antitumor agent with sub-micromolar Topo-I activity while Example 18 did not show the activity of Topo-I even more than the concentration of 100 micromolar. The only difference between the compounds of Examples 18 and 19 is that in Example 18 Xa and XX is 2,10-difluoro and R 6 is amino, while in Example 19 Xi and X'i is 3,9-difluoro and R6 is hydrogen. In addition, rebeccamycin, where Xi and X'i is 1,11-dichloro, R is methoxy and R 5 is hydroxyl, is also not Topo-I active.

Cytotoxicity activity based on Cells, In Vi tro The activity of inhibiting proliferation against the human colon cell line was measured as follows. Cytotoxicity was evaluated in HCT116 human colon carcinoma cells by XTT (2, 3-bis (2-methoxy-4-nitro-5-sulfophenyl) -5 - [(phenylamino) carbonyl] -2H- hydroxide assay tetrazolium as described in the literature by Scudiero, DA, Shoemaker, RH, Paull, KD, Monks, A, Tierney, S, Nofziger, TH, Currens, MJ, Seniff, D, and Boyd, MR. soluble tetrazolium / formazan for cell growth and drug sensitivity in the culture using human and other tumor cell lines was performed according to the procedure described in Cancer Res. 48: 4827-4833, 1988. The cells were placed in plaque at 4000 cells / well in 96-well microtiter plates and 24 hours later the drugs were added and serially diluted.The cells were incubated at 37 ° C for 72 hours, at which time the tetrazolium dye was added, XTT , containing phenazine methosulfate An enzyme dehydrogenase in living cells reduces the XTT to a form that absorbs light at 450 nm, which can be quantified spectrophotometrically. The greater the absorbance, the greater the number of living cells. The results are expressed as an IC50 which is the concentration of the drug required to inhibit cell proliferation (eg, absorbance at 450 nm) at 50% of that of untreated control cells. The results for the selected compounds of the present invention are shown in Table III.

Table III Example No IC50 (μM) 15 0.26 18 > 1.45 19 0.11 29 0.09 33 0.17 35 0.50 45 0.37 58 0.07 60 0.17 Table III (continued) Example No. IC5o (μM; 62 0 ... 5 6 63 0 ... 7 7 67 0 ... 7 4 One aspect of the present invention involves the administration of the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof, to a mammal implanted with tumor or susceptible to cancer formation. In general, the compound could be administered in a dose range of about 0.01 mg / kg to about the MTD (maximum tolerated dose). Although the dosage and dosing regimen and programming of a compound of formula I must in each case be carefully adjusted, using sound professional judgment and considering the age, weight and condition of the patient, the route of administration and the nature or the degree of condition of the cancer disease. The term "systemic administration" as used herein refers to the oral, sublingual, buccal, transnasal, transdermal, rectal, intramuscular, intravenous, and traventricular, intrathecal, and subcutaneous routes. In accordance with good clinical practice, it is preferred to administer the present compounds at a concentration level which will produce beneficial beneficial effects without causing any harmful or unwanted side effects.

DESCRIPTION OF THE SPECIFIC MODALITIES The process for the preparation of the compounds of the formula I is illustrated in Scheme I, and the preparation of the key materials is illustrated in Scheme II.

Scheme I Synthesis of the Products of the formula I where: y = B r o C 1; R '= H; R "'= H or a monosaccharide derivative; R" = H or aryl or heteroaryl Scheme II Key Intermediaries In Schemes I and II, R2 to R6, Xi, X2, Xi, X2- and Q are as defined above. PG is a synthetic organic "protecting group" of the type generally used to "protect" a hydroxyl functional group, for example an acyl group such as an acetyl group, trifluoroacetyl or an arylalkyl group such as the benzyl group or the like. Suitable "protecting" or "blocking" groups used in organic synthesis are well known to the practitioner and are suitably described in the appropriate literature. See, for example, Theodora Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York. The starting materials in Scheme I are di-halomaleimide (II) derivatives, such as 3,4-dibromomaleimide; and the substituted indole derivatives of formula III. The addition of the indole derivatives III (R "= H or AR) to the maleimide II in the presence of a base such as ethylmagnesium bromide or the like in organic solvents such as THF (for example tetrahydrofuran), benzene or toluene or combinations of the at -20 ° C up to the reflux temperature, could result in the mono and bis derivatives V and IV respectively The amount of the reagents can be controlled to vary the proportion of the product of V versus IV in favor of one Intermediate IV can be further transformed into the core of indolopyrrolocarbazole VI by the use of oxidative cyclization conditions such as dicyanodichloroquinone (DDQ) / acid / heat or palladium acetate / acid or iodide, light and the like. with reactive sugar derivatives such as 1,2-epoxide described in the publications J. Org. Chem. 1993, 58, 343-349 and J. American Chemical Society 1989, 111, 6661-6666 or 1-halo and others in presence of a Suitable base such as diisopropylethylamine, hexamethyldisilazide, to form the mono- or di- or tri-anion of the indolopyrrolocarbazole nucleus VI in organic solvent such as tetrahydrofuran, DMF (for example dimethylformamide), dioxane, benzene, DME (for example dimethoxyethane) produces fully protected derivative VIII. Alternatively, more preferably, glycosylation can also be carried out by the reaction of the 1-hydroxyl form of a sugar derivative appropriately protected with the core VI under the well-known Mitsunobu process [PPh3 / dialkyl lazidodicarboxylate] in solvent ethereal such as tetrahydrofuran or chlorinated solvent such as methylene chloride. The sugar derivative suitable for glycosylation can be obtained by selective modification of the different hydroxyl groups using the methods of the literature. For example, the article that appears in J. Carbohydrate Chemistry (1995), 14 (9), p 1279-94 describes the 6-halo-6-deoxyglucose derivative. Yet another method to obtain compound VIII involves glycosylation of the mono adduct, first under the conditions described above to give intermediate VII, followed by dehydrohalogenation and cyclization using a number of well known methods published in the art, for a transformation of this type, including heat or irradiation with ultraviolet light to a solution of intermediate VII in solvents such as dioxane, ethanol or an appropriate mixture of solvents. Compound VIII is a protected form of Formula I. The judicious choice of the protecting group in the sugar would allow selective manipulation of the primary hydroxyl group. For example, when the 6'-primary hydroxyl group was protected with the p-methoxybenzyl protecting group (PMB) and the rest of the hydroxyls were protected with simple benzyl groups (Bn), it is possible for one skilled in the art to eliminate the PMB group without deprotecting the benzyl group. In this way, the primary 6-hydroxyl group is oxidized to the corresponding acid, and its ester and amide derivatives. Further, under conditions of controlled oxidation using the Dess-Martin reagent or the like, the 6-hydroxyl group is oxidized to the corresponding aldehyde. The treatment of the aldehyde with the fluorination reagent well known as DAST, resulted in the 6-difluoromethyl derivative. Similarly, other hydroxyl groups were also modified. For example, when the 4-hydroxyl group of the sugar-galactose derivative (hexose sugar in the form of pyranose in which the 4-hydroxyl group is oriented in the axial position) can be used to modify the 4-position. Oxidation of group 4 -hydroxyl of the appropriately protected sugar derivative, provided the ketone which could be further functionalized to different derivatives including the 4-difluoro derivative using the known procedures. If the 4-hydroxyl group is activated, for example in the case of 4-mesylate, this is susceptible to nucleophilic displacement by agents such as an azide (for example sodium azide) to provide the 4-azido derivative. On the other hand, when the sugar derivative with the unprotected 4-hydroxyl group is treated with the fluorinating agent, DAST, the 4-fluoro derivative is obtained. Similarly, other hydroxyl groups are also selectively modified. For example, the modification of the procedure published in the literature allows the introduction of a fluorine atom in position 2 of sugar (Bioorg, Med.

Chem., Vol. 5, No. 3, pp. 497-500 (1997). This is illustrated in Example 90. The manipulation of the simple protective group such as hydrogenation or transfer hydrogenation with the Pearlman catalyst to remove the benzyl protecting groups from the sugar moiety, or if necessary, the hydrolysis with potassium hydroxide or sodium hydroxide of the nitrogen-protecting group of the maleimide to give the anhydride after an acid treatment followed by heating with an appropriate amine, could produce the desired compound of the formula la with the correct substitution pattern. Selective derivatization of each hydroxyl group in the sugar portion of the compound can be achieved by the use of the protective group manipulation and removal of the primary hydroxyl protecting group, in the presence of the secondary naphthyl protecting groups. For example, when the compound of the formula la, in a glucopyranosyl form (for example the hexose formula (B)), wherein all hydroxyl groups of the sugar are free, treated with a silyl reagent such as trimethylsilyl or t-butyl-d-phenylsilyl or preferably t-butyl-di-methylsilyl triflate in the presence of a base in a solvent such as methylene chloride or tetrahydrofuran at cold or ambient temperature, derivatives are obtained wherein positions 3 and 6 are protected as silyl ethers. Selective deprotection of the silyl ether in the 6-position can be achieved under controlled conditions of inorganic or aqueous organic acid such as trifluoroacetic acid, and an aqueous mixture as a solvent at a cold temperature such as -25 ° C to 0 ° C in a 30 minute period up to 3 hours, or until the reaction is complete as is followed by thin layer chromatography. This intermediate is now ready for further derivatization at position 6, to activate the 6-hydroxyl to a good leaving group as mesylate or halide. Thus, methanesulfonyl or toluenesulfonyl chloride or trifluoromethanesulfonyl in the presence of a base such as triethylamine or pyridine could produce the corresponding mesylate or tosylate. Alternatively, selective mesylation of the primary 6-hydroxyl group can be carried out directly from the compound of the formula la wherein all the hydroxyl groups of the sugar are deprotected, under pyridine and mesyl chloride in pyridine at 0 ° C. Nucleophilic displacement with an appropriate amine or other nucleophiles such as azide, followed by reduction of the azide to amine could then produce the desired compounds of the formula I such as the 6'-aminocarbon derivatives Ib. In this manner, the 6-methyl sulfide derivative was prepared using either the sodium salt of the thiol derivative or the thiol, and a base such as potassium carbonate in dimethylformamide or an organic amine base such as triethylamine or the base of Hunig at varying temperatures from room temperature to 150 ° C. The 6-alkyl sulfide, for example 6-methyl sulfide, is further oxidized by oxidation agents known as Oxone or m-chloroperbenzoic acid or, preferably, the magnesium salt of monoperoxyphthalic acid (MMPP) to its sulfoxides and sulfone under controlled conditions. Similarly, other hydroxyl groups may be derivatized as desired. A further modification of formula I could result in the indolopyrrolocarbazole derivatives substituted with N-maleimide (for example R6) For example, the anhydride obtained from the basic hydrolysis of the appropriately protected form of formula I is it could be reactivated with a number of amine derivatives to produce the desired N-substituted maleimides As described in Scheme II, the N-substituted maleimide derivative can be obtained either directly from the dihalomaleic anhydride after treatment with a appropriate amine derivative or halogenation of the maleimide, followed by alkylation. The initial indole derivatives, which do not have substitution in the 2-position can be obtained following the published procedures, and the 2-arylindoles can be prepared from the aryl-methyl-ketones following the synthetic procedures of Fisol's Indole, either known. The compounds constituting this invention and their methods of preparation will appear more fully from a consideration of the following examples, which will be for purposes of illustration only and are not intended to be limiting of the invention in scope or in scope. The various intermediate compounds as well as other conventional starting materials, for example, II, III and IX; used in the preparation of final products I, were generally commercially available. The representative synthesis of some of the final compounds of the formula I (wherein in Ri all substituents are hydrogen unless otherwise mentioned) are given hereinafter. The syntheses of some of the intermediates are also provided as in Examples 1-11, 14, 91-96, 98-102, 104 and 105. All anhydrous reactions were carried out under a nitrogen or argon atmosphere using anhydrous solvents , from Aldrich bottles of hermetic sealing or freshly distilled solvents. Column chromatography was performed with silica gel 60 (E M Science, 230-400 mesh) using the aforementioned solvent system as eluent. Thin layer chromatography was conducted on silica gel plates Anatech GFLH or Whatman MK6F. The melting points were determined in an open capillary tube with a Thomas-Hoover melting point apparatus, unless otherwise stated and not corrected. The infrared spectra were recorded in a Perkin-Elmer 1800 Fourier transformation spectrophotometer, such as thin films or potassium bromide pellets. The proton nuclear magnetic resonance spectra (1H NMR) and the carbon 13 nuclear magnetic resonance spectra (13C NMR) were recorded on either Bruker AM-300 or JEOL 300 or Bruker AC-300 nuclear magnetic resonance instruments or 500 MHz, and are expressed as parts per million (ppm od) from the solvent mentioned as the internal standard. The coupling constants are in hertz and the signals are cited as singlet (s), triplet (t), quartet (q), multiplet (m), and broad (br). The low resolution mass spectra were determined on either a Finnigan Model 4500 quadrapolar mass spectrometer by direct chemical ionization (DCI) with isobutane as the positive Cl gas, a Finnigan Model SSQ-7000 instrument (negative or positive ESI) or a Kratos MS-25 or Finnigan TSQ-70 (FAB) instrument. High resolution mass spectra (HRMS) were determined on either a Kratos MS-50 mass spectrometer using rapid bombardment of atoms with cesium iodide in glycerol as the reference agent or on a Finnigan MAT-900 instrument using ionization Electro-debris with polypropylene glycol as the reference agent.

Example 1 3, 4-dibromomaleimide (II; R6 = H, y = Br).

To a magnetically stirred solution of maleimide (25.0 g, 0.258 mol) in deionized water (250 ml) Bromine (100 g, 0.626 mol) was added rapidly followed by benzoyl peroxide (300 mg). The reaction mixture was heated at 50 ° C for 6.5 hours, and then stirred at room temperature for 11.5 hours. The reaction mixture was cooled in an ice / water bath for 45 minutes, and the solid precipitate was filtered, washed with water, and dried with air to give 36.35 g (55.4%) of the title compound as a white solid. 13 C NMR at 75 MHz (d6-acetone): d 165.08, 130.73; mass spectrum of fast atom bombardment (FAB), m / e 253 (M +); Analysis Calculated for C4HBr2N02: C, 38.30; H, 2.05; N, 4.06; Br 46.32. Found: C, 38.28; H, 2.06; N, 4.07; Br, 46.24.

Example 2 1- (tert-butylbenzyl) -3,4-dibromomaleimide (II; e = tert-butylbenzyl, y = Br) To a magnetically stirred solution of 3,4-dibromomaleimide (20.0 g, 78.5 mmol) in acetone (1200 mL) was added potassium carbonate (132 g, 0.954 mol). Then 4- (t-butyl) benzyl bromide (24.98 g, 20.2 ml, 110 mmol) was slowly added in 15 minutes and the reaction mixture was stirred for 6 hours in the dark. The reaction mixture was filtered on a pad of Celite and washed with acetone (250 ml). Evaporation in vacuo, followed by flash chromatography on silica gel with 50% hexane in dichloromethane, gave 22.5 g (71.5%) of the title compound as a white solid. 1 H NMR at 300 MHz (CDC13) d 7.45-7.25 (m 4 H), 4.75 (s, 2 H), 1.32 (s, 9 H); DCI mass spectrum, m / e 399 (M +); Analysis Calculated for C? 5H15Br2N02: C, 44.92; H, 3.77; N, 3.49. Found: C, 45.04; H, 3.81; N, 3.38.

Example 3 2- (2-benzo [b] thienyl) -5-fluoro-lH-indole (III: Xi = 5F; X2 = H; R "= 2-benzo [b] thienyl, R '= H) N-Butyllithium in hexanes (1.6 M, 255 mL, 0.41 mmol) was added in 5 mL portions to a cold (4 ° C) solution of tianaphthene (47.8 g, 0.36 mol) in anhydrous tetrahydrofuran / diethyl ether (1 : 1, 400 ml) under a nitrogen atmosphere. The lithium alkyl was added at such a rate that the internal reaction temperature never exceeded 8 ° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature, where it was stirred for 1 hour before it was cooled again to 4 ° C and carefully treated with an acetaldehyde solution (50 ml) in anhydrous tetrahydrofuran (50 ml). The mixture was allowed to warm to room temperature for 0.5 hours before it was quenched with water and diluted with ethyl acetate. The organic phase was separated, washed with brine, dried and concentrated. The aqueous phase was extracted twice more with ethyl acetate and combined with the original organic extract before further work. Purification of the resulting residue by flash chromatography on silica gel (gradient elution with 7% ethyl acetate in hexanes, followed by 15% ethyl acetate in hexanes) provided 29.25 g (46%) of the intermediate alcohol as a solid pale yellow which was then treated directly. The alcohol (29.15 g, 0.16 mol) was dissolved in anhydrous dichloromethane (800 ml) and the reaction mixture was treated with Celite (36 g) and pyridinium chlorochromate (35 g). After one hour at room temperature, additional dichloromethane (400 ml), Celite (36 g) and PCC were added. (35 g). The mixture was further stirred for an additional 1 hour at room temperature, before it was diluted with ether (1 L), filtered through suction through a pad of silica gel and concentrated.

Methyl ketone (27.6 g, 96%) was isolated as a white, pure solid. Anhydrous sodium acetate was added (16.6 g, 0.20 mole) in one portion to a stirred suspension of 4-fluorophenyrazine hydrochloride (32.98 g, 0.20 mole) and methyl ketone (27.5 g, 0.156 mole) in absolute ethanol (150 ml). The mixture was heated to reflux for 2 hours before it was cooled, to be diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, IN hydrochloric acid and brine. After drying and evaporation of the solvent, the residue was recrystallized from hot ethanol to give the pure hydrazone (40.08 g, 90%) as a yellow solid. The hydrazone (18.3 g, 64.4 mmol) was placed in a 500 ml single-neck round bottom flask (equipped with a reflux condenser) which contained freshly fused zinc chloride, under a nitrogen atmosphere. The flask was then placed in a preheated oil bath (180 ° C) for 1 hour. After 1 hour, the temperature of the oil bath was allowed to cool to 140 ° C before the flask was carefully charged with absolute ethanol. The mixture was heated to reflux for 6 hours before it was cooled, diluted with ethyl acetate and washed with IN hydrochloric acid and brine, before drying and concentration of the solvent to 1/3 of the volume. Suction filtration gave the title compound (22.4 g, 65%) as a white solid, m.p. 263-264 ° C; XR NMR (300 MHz, DMSO-dβ) d 11.91 (s, ÍH), 7.99-7.96 (, ÍH), 7.89-7.86 (m, 2H), 7.83 (s, ÍH), 7.43-7.29 (series of m, 4H), 7.03-6.96 (m, HH), 6.81 (d, J = 1.5 Hz, HH), 13C NMR (75 MHz, DMSO-d6) ppm 158.79, 155.72, 140.01, 138.35, 134.92, 133.92, 133.79, 128.64 , 128.50, 124.93, 124.79, 123.70, 122.44, 119.73, 112.35, 112.22, 110.76, 110.41, 104.90 104.59, 100.90, 100.84; IR (KBr, cm "1) 3421, 1625, 1586, 1567, 1501, 1448, 1412, 1286, 1201, 1188, 1128, 862, 825, 783, 744, 725, 559, 515 ms (NEG. Esi, MH ") m / z 266. Analysis Calculated for d6H10FNS: C, 71.89; H, 3.77; N, 5.24. Found: C, 71.82; H, 3.76; N, 5.13.

Example 4 (E) -4-fluoro-2-nitro-β-dimethylaminoes tireno A mixture of 4-fluoro-2-nor trotoluene (185.0 1. 19 mol) dimethylacetal of the N, N-dimethylformamide (500 ml, 3.77 mol) in anhydrous dimethylformamide was heated at reflux for 2 hours under nitrogen atmosphere before the azeotropic distillation of methanol from the reaction mixture. Another tandem reaction was performed (169.2 g of 2-fluoro-2-trotoluene). A combined weight of 450 g (95%) of the title compound was isolated as a red solid (solidified upon cooling) which was pure enough to be used subsequently. Distillation from Kugeirohr provided the title compound (analytically pure for characterization purposes) as a reddish black crystalline solid, m.p. 54-55 ° C; NMR XH (300 MHz, DMS0-d6) d 7.72-7.62 (m, 2H), 7.37-7.32 (m, 1H), 7.33 (d, J = 13.4 Hz, ÍH), 5.58 (d, J = 13.4 Hz, ÍH), 2.58 (s, 6H); 13 C NMR (75 MHz, DMSO-d 6) ppm 158.19, 154.99, 146.16, 143.13, 143.02, 132.57, 132.54, 126.14, 126.04, 120.98, 120.69, 111.41, 111.07, 88.23; IR (KBr, cm "1) 3446, 1622, 1570, 1508, 1386, 1270, 1092, 940, 822, 798; MS (MH +) m / z 211. Analysis Calculated for C 10 HnFN 2 O 2: C, 57.14; H, 5.27; N, 13.33, Found: C, 57.09; H, 5.16; N, 13.46.

Example 5 6-fluoroindole (III: Xa = F, X2 = R "= R '= H) The (E) -4-fluoro-2-nitro-β-dimethylaminostyrene (120 g, 0.5 mol) was dissolved in tetrahydrofuran (1 L) and subjected to Parr hydrogenation (3.51 kg / cm2 (50 psi) of H2 , at room temperature, 24 hours) using 10% palladium on carbon (30 g). The mixture was filtered through Celite (washed with tetrahydrofuran, methanol and methylene chloride) and concentrated to dryness. This reaction was performed three additional times in order to consume the initial material mentioned above. Steam distillation of the residue afforded the title compound (192.6 g, 62%) as white needles, m.p. 73-75 ° C; NMR XH (300 MHz, DMSO-ds) d 11.14 (broad s, HI), 7.51 (dd, J = 8.6, . 5 Hz, ÍH), 7.32 (t, J = 2.9 Hz, ÍH), 7.16 (dd, J = . 1, 2.3 Hz, ÍH), 6.87-6.80 (m, ÍH), 6.43-6.41 (m, ÍH); 13 C NMR (75 MHz, DMSO-d 6) ppm 160.26, 157.16, 135. 79, 135.63, 125.94, 125.89, 124.42, 120.97, 120.83, 107.43, 107.10, 101.17, 97.47, 97.13; GO (KBr, c "1) 3392, 3072, 1626, 1508, 1448, 1342, 114, 954, 846, 802, 728, 508; MS (MH +) m / z 136. Analysis Calculated for C8H6FN: C, 71.10; H, 4.47; N, 10.36.

Found: C, 71.28; H, 4.69; N, 10.24.

Example 6 3, 4-bis (5-fluoro-l-indol-3-yl) -N- [4- (t-butyl) -benzyl] -pyrrole-2, 5-dione (IV: Xx = F; X2 = R 'or R "= H; R6 = 4- (t-butyl) benzyl) To a magnetically stirred solution of 5-fluoroindole (7.0 g, 51.8 mmol) in anhydrous benzene (125 ml) was added under an argon atmosphere with stirring, methyl magnesium iodide (3.0 M in ether; 18. 0 ml, 54.0 mmol). The mixture was stirred at room temperature for 30 minutes and then this solution was added via a cannula in a period of 10 minutes, to a rapidly stirred solution of N- [4- (t-butyl) benzyl] -3.4 -dibromomaleimide (6.50 g, 16.2 mmol) in anhydrous benzene (60 ml). The resulting dark purple solution was stirred at room temperature under an argon atmosphere for 16 hours, and was poured into a mixture of 20% aqueous citric acid (350 ml) and ethyl acetate (500 ml). The organic layer was washed with water (200 ml) and brine (200 ml), and dried (sodium sulfate). Evaporation in vacuo followed by flash chromatography on silica gel with 100% dichloromethane, followed by 10% ethyl acetate in dichloromethane, gave 3.68 g (44%) of the title compound as a red solid. XH NMR at 300 MHz (CDC13) d 8.63 (broad s, 2H), 7.87 (d, 2H, J = 2.9 Hz), 7.46-7.34 (m, 4H), 7.23 (dd, 2H, J = 8.9, 4.4 Hz ), 6.79 (ddd, 2H, J = 9.1, 8.9, 2.5 Hz), 6.48 (dd, 2H, J = 10.2, 2.5 Hz), 4.83 (s, 2H), 1.30 (s, 9H); 75 MHz 13 C NMR (CDC13) d 172.15 (s), 157.73 (d, J = 235 Hz), 150.82 (s), 133.79 (s), 132.27 (s), 129.92 (s), 128.32 (s), 127.14 (s) s), 126.16 (d, J = 10.4 Hz), 125.72 (s), 112.19 (d, J = 9.8 Hz), 111.10 (d, J = 26.6 Hz), 106.95 (d, J = 4.3 Hz), 106.43 ( d, J = 25.1 Hz), 41.68 (s), 34.55 (s), 31.33 (s); mass spectrum FAB, m / e 509 (M +).

Example 7 3-bromo-4- (6-fluoro-lH-indol-3-yl) - lH-pyrrole-2, 5-dione (V: Xi = 6F; R '= R "= R6 = H; y = Br) and 3,4-bis (6-fluoro-1H-indo-3-yl) -lH-pyrrole-2, 5-dione (IV: Xa = F; X2 = R '= R "= R6 = H) To a solution of 6-fluoroindole (50.0 g, 0.37 mol) in anhydrous benzene (1 L) under nitrogen atmosphere was added by means of a syringe, ethylmagnesium bromide (3M, 130 ml, 0.43 mol) at a rate that maintained the internal temperature between 45-50 ° C. The mixture was then heated to 50-55 ° C for 0.5 hours before a suspension of 2,3-dibromomaleimide (24.9 g, 0.093 mol) in anhydrous benzene was drained into the reaction mixture. The mixture was refluxed for 22 hours, cooled, diluted with ethyl acetate, and acidified to pH = 1 with IN HCl. The organic phase was then separated, washed with brine, dried and concentrated. The aqueous phase was diluted once more with ethyl acetate and separated. The resulting organic phase was treated in an identical manner as mentioned above and combined with the original. Another 50 g reaction was performed and combined before chromatography. Purification of the combined residues by flash chromatography on silica gel (gradient elution with 10% acetate in hexanes followed by 20% and finally 40% ethyl acetate in hexane) provided two main products. The title compound of formula V was isolated (12.31 g, 21.5% as a brick red solid and the title compound of formula IV (31.5 g, 41%) as a reddish-orange foam. title of formula V: mp 73-75 ° C; XH NMR a (300 MHz, DMSO-d6) d 11.14 (s broad, ÍH), 7.51 (dd, J = 8.6-5.5 Hz, ÍH), 7.32 (t, J = 2.9 Hz, ÍH), 7.16 (dd, J = 10.1, 2.3 Hz, ÍH), 6. 87-6.80 (m, ÍH), 6.43-6.41 (m, ÍH); 13 C NMR (75 MHz, DMSO-de) PPm 160.26, 157.16, 135.79, 135.63, 125.94, 125.89, 124.42, 120.97, 120.83, 107.43, 107.10, 101.17, 97.47, 97.13; IR (KBr, cm "1) 3392, 3072, 1626, 1508, 1448, 1342, 1144, 954, 846, 802, 728, 508; MS (MH +) m / z 136. Analysis Calculated for C8H6FN: C, 71.10; H, 4.47; N, 10.36, Found: C, 71.28; H, 4.69; N, 10.24.

For the title compound of formula IV: p.f. 207-208 ° C (decomposes); X H NMR (300 MHz, DMSO-d 6) d 12.10 (s, ÍH), 11.37 (s, ÍH), 8.03 (d, J = 2.9 Hz, 1H), 7.86 (dd, J = 8.9, 5.4, 2.3 Hz, ÍH), 7.28 (dd, J = 9.6, 2.3 Hz, 1H), 7.00 (dt, J = 9.3, 2.3 Hz, ÍH); 13 C NMR (75 MHz, DMSO-d 6) ppm 170.12, 167.35, 160.70, 157.56, 137.65, 136.62, 136.45, 131.58, 131.56, 123.51, 123.38, 121.27, 115.40, 109.03, 108.70, 103.89, 98.47, 98.14; IR (KBr, cm "1) 3328, 3222, 1726, 1604, 1450, 1338, 1240/1192, 1148, 840, 794; MS (MH +) m / z 309, 311. Analysis Calculated for C? 2H6NrFN202: C, 46.63; H, 1.96; N, 9.06, Found: C, 46.70; H, 2.00; N, 8.94.

Example 8 3, 9-difluoro-12, 13-dihydro-5H-indole [2,3-a] pyrrolo [3,4-c] carbazole-5, 7 (6-N- [4- (t-butyl) encyl] ) -dione (VI: Xi = Xx. = F; X2 = X2 '= R' = H; R6 = 4- (t-butyl) benzyl; Q = NH).

To a magnetically stirred solution of the product of Example 6 (11.6 g, 22.8 mmol) in anhydrous benzene (1700 ml) was added under stirring argon, p-toluenesulfonic acid monohydrate (170 mg) and DDQ (10.9 g, 48.0) mmol). The mixture was heated to reflux under an argon atmosphere with stirring for 1 hour, and stirred at room temperature for 16 hours. The resulting dark precipitate was collected by filtration, washed with cold ethyl acetate (50-70 ml), and dried for 1-2 hours under vacuum to give 12.80 g (94%) of the title compound as a yellow brown solid. (monoethyl acetate complex by proton NMR, further vacuum drying can reduce the ethyl acetate content by a two-thirds means). Recrystallization from tetrahydrofuran / ethyl acetate gives the analytically pure product as a bright yellow solid (monoethyl acetate complex by proton NMR). XH NMR at 300 MHz (d6-DMSO) d 11.83 (broad s, 2H), 8.46 (dd, 2H, J = 9.7, 2.6 Hz), 7.69 (dd, 2H, J = 8.9, 4.6 Hz), 7.36 (ddd) , 2H, J = 9.1, 8.9, 2.6 Hz), 7.34-7.22 (, 4H), 4.63 (s, 2H), 1.22 (s, 9H); mass spectrum FAB, m / e 507 (M +); Analysis Calculated for C3? H23F2N302 • C4H802: C, 70.58; H, 5.25; F, 6.38; N, 7.06. Found C, 70.52; H, 5.31; F, 6.14; N, 7.00.

Example 9 2,10-difluoro-12, 13-dihydro-5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazol-5, 7 (6H) -dione (VI: Xi = Xi- = F; X2 = X2 '= R' = R6 = H; Q = NH) The 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (15.81 g, 0.70 mol) was added in one portion to a stirred suspension of 3, -bis (6-fluoro-1H-indol-3). il) -lH-pyrrole-2, 5-dione (11.5 g, 0.032 mol) and toluenesulfonic acid monohydrate (0.44 g) in benzene (1 L) under nitrogen atmosphere and the mixture was heated to reflux for 2 hours before it was cooled, stored at room temperature for 16 hours, and filtered by suction through a sintered glass funnel. The precipitate was washed successfully with benzene, with ethyl acetate and with ether until a colorless filtrate was observed. Another 20.0 g reaction was performed in tandem using proportionally the same amount of reagents used in the first reaction. The title compound (15.51 g, 40%) was isolated as a yellowish green solid, m.p. > 305 ° C; NMR XH (300 MHz, DMS0-d6) d 11.67 (broad s, 2H), 10.93 (s broad, ÍH), 8.84 (dd, J = 8.8, 5.8 Hz, 2H), 7.55 (dd, J = 10.0, 2.3 Hz, 2H), 7.11 (dt, J = 9.2, 2.3 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 1.96 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, DMSOde) ppm 171.09, 170.32, 163.27, 160.08, 141.00, 140.83, 129.25, 125.69, 125.55, 119.54, 118.23, 115. 09, 108.51, 108.19, 98.64, 98.28, 59.74, 20.74, 14.07; IR (KBr, cm "1) 3320, 1748, 1690, 1572, 1404, 1376, 1312, 1232, 1144, 1116, 840; MS (M +) m / z 361. Calculated Analysis for C20H9F2N3O2 • 1. OEtOAc • 0.1H20 : C, 63.89; H, 3.84; N, 9.31, Found: C, 64.12; H, 3. 76; N, 9.55.

Example 10 3, 9-di fluoro-12, 13-dihydro-13 - [3, 4, 6-tris-0 (phenylmethyl) -β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6N- [4- (t-butyl) benzyl]) -dione (VIII: Xi = X? - = F; X2 = X2. = R '= R "' = H; R6 = 4 (t-butyl) encyl, Q = NH, PG = benzyl).

To a magnetically stirred suspension of the core of Example 8 (9.50 g, 17.7 mmol) in anhydrous tetrahydrofuran (450 ml) was added sodium bis (trimethylsilyl) amide (5-10 minutes) under argon with stirring. 1.0 M in tetrahydrofuran, 50.0 ml, 2.82 equiv.). The resulting dark red solution was stirred at room temperature for 45 minutes, treated by means of a syringe with chlorotrimethylsilane (5.06 ml, 40.0 mmol), and stirred at room temperature for an additional 1 hour. The reaction mixture was then heated to reflux, and refluxed while adding a solution of 1,2-anhydro-sugar IX (13.5 g, 31.2 mmol, see J. Org. Chem. 1993, 5_8 343-349). ) in anhydrous tetrahydrofuran (200 ml) over a period of 3.5 hours by means of a constant addition funnel. After the addition was complete, the reaction was heated to reflux for 10 hours under an argon atmosphere, treated with a solution of 1,2-anhydro-sugar IX (800 mg) in anhydrous tetrahydrofuran (40 ml) and heated to reflux for 2.5 additional hours. The mixture was cooled to room temperature over a period of 45 minutes, treated with hydrochloric acid (1.0 N, 280 ml), and stirred for 75 minutes. The mixture was partitioned between ethyl acetate (2000 ml) and 0.5 N HCl (600 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (300 ml), water (350 ml) and brine (400 ml). The original acidic aqueous layer was extracted with fresh ethyl acetate (600 ml) which was then washed with water (100 ml), and brine (150 ml). The combined organic extracts were dried (sodium sulfate) and rotary evaporated to a volume of about 300 ml, after which the resulting yellow precipitate was collected by filtration, washed with ethyl acetate (300 ml), and dried vacuum to give 3.00 g (31.6%) of the recovered pure core. The filtrate was concentrated in vacuo, dissolved in methylene chloride / hexane, and purified by flash chromatography on silica gel using 5-10% ethyl acetate in hexanes. The yellow fractions containing the less polar spot were evaporated to a volume of about 300 ml and allowed to stand overnight to produce 625 mg (3.8%) of beautiful yellow prisms of the N12 product, N? 3-double glycosylated (structure determined by X-ray crystallography). An additional portion of 380 mg (2.3%) thereof was obtained from the mother liquor. Additional elution with 10-15% ethyl acetate in hexanes gave 9.23 g (55.5%, 81% based on the recovered core) of the analytically pure title compound of formula VIII as a yellow solid. XH NMR at 500 MHz (d6-DMS0) d 10.85 (s broad, ÍH), 8.84 (dd, ÍH, J = 9.6, 2.7 Hz), 8.75 (dd, ÍH, J = 9.6, 2.5 Hz), 7.54 (ddd , ÍH, J = 9.1, 9.1, 2.7 Hz), 7.42-7-18 (m, 21H), 6.43 (d, ÍH, J = 8.8 Hz, l'H), 5.38 (d, ÍH, J = 6.3 Hz , 2'OH), 4.94-4.56 (m, 8H), 4.30-4.15 (m, 2H), 3.98-3.72 (m, 4H), 1.24 (s, 9H); mass spectrum FAB, m / e 939 (M +); Analysis Calculated for C58H5iF2N3? 7: C, 74.11; H, 5.47; F, 4.04; N, 4.47. Found C, 73.89; H, 5.51; F, 3.77; N, 4.26.

Example 11 2, 10-di fluoro-12, 13-dihydro-13 - [3, 4, 6-tris-O- (f-enylmethyl-β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3 , 4-c] carbazole-5, 7 (6H) -dione (A = VIII: Xa = Xi '= F; X2 = X2? = R6 = R "'= H; Q = NH; PG = benzyl) and 2, 10-di fluoro-12, 13-dihydro- 13 - [2-0- [3, 4, 6-tris-O- ( phenylmethyl) -β-D-glucopyranosyl] -3,4,6-tris-O- (phenylmethyl) -β-D-glucopyranosyl 1] - 5H-indolo [2,3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (B = VIII: XI = XI '= F; X2 = X2 '= R6 = H; Q = NH; PG = benzyl; R "'= 3, 4, 6-tris-0 (phenylmethyl) -β-D-glucopyranosyl).

A solution of sodium bis (trimethylsilyl) amide (IM, 9.1 ml, 3.3 eq.) In tetrahydrofuran was added via syringe to a solution of 2, 10-difluoro-12,13-dihydro-5H-indolo [2]. , 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6H) -dione (11.17 g, 32.38 mmol) in anhydrous tetrahydrofuran (600 mL) at room temperature. After 25 minutes, an epoxide solution (24.27 g, 56.11 mmol, 1.7 eq.) In anhydrous tetrahydrofuran (50 ml) was cannulated into the reaction mixture. The mixture was refluxed for 6 hours before it was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The organic phase was separated, washed with brine, dried and evaporated. Purification of the residue by flash chromatography on silica gel (gradient elution with 15% tetrahydrofuran in hexanes, followed by 20% and 40% tetrahydrofuran in hexanes) provided the title compound A of formula VIII (6.1 g, %) as a yellow foam, the unreacted aglycone (4.00 g) and the bis-sugar compound B (10.9 g, 34%, MS (M +) calculated for C? 4 HssF2N30? 2 1226.4615, observed 1226.4566) as a yellow foam which was converted directly to the title compound A of formula VIII as described below. For the title compound of the formula A = VIII: p.f. 140-147 ° C; 1 H NMR (300 MHz, CDCl 3) d 10.50 (s, HH), 8.79-8.74 (dd, J = 8.8, 5.8 Hz, ÍH), 8.21 (dd, J = 8.8, 5.6 Hz, ÍH), 7.59-7.33 ( m, 11H), 7.28-7.12 (2m, 11H), 7.06-7.00 (m, ÍH), 6.81 (dd, J = 9.1, 2.2 Hz, ÍH), 6.61-6.58 (m, ÍH), 5.83 (d, J = 9.0 Hz, ÍH), 5.12 (d, J = 5.3 Hz, ÍH), 5.08 (d, J = 5.2 Hz, ÍH), 5.01-4.98 (, ÍH), 4. 85 (d, J = 10.8 Hz, ÍH), 4.73-4.72 (m, HH), 4.55-4.35 (m, 4H), 4.07-3.93 (m, 3H), 3.76-3.72 (m, HH); 3 C NMR (75 MHz, CDCl 3) ppm 169.55, 169.10, 164.43, 164.25, 161.18, 161.00143.00, 142.83, 141.68, 141.50, 137.69, 137.59, 136.32, 130.45, 128.91, 128.74, 128.63, 128.56, 128.43, 128.06, 127.02, 126.89, 126.15, 126.01, 120.00 119.01, 118.44, 118.17, 118.09, 110.33, 110.02, 109.48, 109.16, 98.04, 97.70, 97.34, 85.89, 85.62, 76.35, 75.36, 75.05, 74.09, 73.74, 66.75; IR (KBr, cm "1) '3430, 3334, 2914, 2870, 1752, 1702, 1580, 1452, 1328, 1232, 1140, 1062, 698; MS (M +) calculated for C47H38F2N3? 7 794.2678, observed 794.2687. Calculated for C47H37F2 3.O7-l.OH2O: C, 69.54; H, 4.84; N, 5.17; H20, 2.2 Found: C, 69.57; H, 4.70; N, 5.10; H20, 0.4, Compound B becomes to compound A by stirring a solution of 2, 10-difluoro-12, 13-dihydro-13- [2-0- [3, 4,6-tris-0- (phenylmethyl) -β-D-glucopyranosyl) ] -3,4,6-tris-O- (phenylmethyl) -β-D-glucopyranosyl] -5H-indole [2,3-a] pyrrolo [3,4-c] carbazole-5, 7 (6H ) -dione (10.9 g, 8.89 mmol) in anhydrous ethyl acetate (25 ml) and treatment with a solution of anhydrous methanolic hydrogen chloride (8M, 500 ml) in a sealed flask for 96 hours at room temperature. The solvents were then removed in vacuo and the resulting residue was diluted with ethyl acetate and tetrahydrofuran and neutralized to pH = 8 with saturated sodium hydrogen carbonate solution. The organic phase was separated and washed with brine before drying and the concentration of the solvent. Purification of the residue by flash chromatography on silica gel (as described below) yielded the title compound A of formula VIII (5.7 g, 81%) as a yellow foam, as well as the initial aglycone material (0.7 g). ).

Example 12 3, 9-difluoro-12, 13-dihydro-13- [β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6N- [ 4- (t-butyl) benzyl] -) -dione (la: Xx = X? »= F; X2 = 2- = H; R6 = 4- (t-butyl) benzyl; Q = NH; R2-R5 = OH). To a magnetically stirred solution of the compound of Example 10 (2.10 g, 2.23 mmol) in 95% ethanol (450 ml) and cyclohexane (175 ml) was added 20% palladium hydroxide on carbon (0.49 g) and the mixture was stirred. heated to reflux under nitrogen atmosphere with vigorous stirring for 20 hours. The mixture was filtered hot through Celite and washed with methanol. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel using 3-5% methanol in methylene chloride to give 1.35 g (90%) of the pure title compound as a yellow-orange solid. The analytical sample was evaporated from ethyl acetate, dried in vacuo, and obtained as 1/2 ethyl acetate complex per molecule. XH NMR at 300 MHz (d6-DMSO) d 11.81 (s broad, ÍH), 8.84 (dd, ÍH, J == 9.7, 2.7 Hz), 8.76 (dd, ÍH, J = 9.7, 2.6 Hz), 8.04 (dd, ÍH, J = 9.3, 4.4 Hz), 7.70 (dd, ÍH, J = 8.9, 4.6 Hz), 7.55-7.46 (m, 2H), 7.40-7.33 (m, 4H), 6.31 (d, ÍH, J = 8.9 Hz), 6.12 (s broad, ÍH), 5.43 (d, ÍH, J = 4.4 Hz), 5.17 (d, ÍH, J = 5.5 Hz), 4.93 (d, ÍH, J = 5.4 Hz), 4.90 (s, 2H), 4.13-4.07 (m, ÍH), 4.00-3.96 (m, 2H), 3.87-3.80 (m, 1H), 3.63-3.46 (m, 2H), 1.24 (s, 9H); mass spectrum FAB, m / e 669 (M +); Analysis Calculated for • 1/2 C4H802: C, 65.63; H, . 22; F, 5.32; N, 5.89. Found: C, 65.04; H, 5.20; F, 5.32; N, 5.91.

Example 13 2, 10-difluoro-12, 13-dihydro-13- [β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (the: Xi = Xi '= F; X2 = X2- = R6 = H; Q = NH; R2-R5 = OH).

A solution of 2, 10-difluoro-12, 13-dihydro-13- [3, 4, 6-tris-0- (phenylmethyl) -β-D-glucopyranosyl] -5H-indolo [2,3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (4.36 g, 5.49 mmol)) in a mixture of ethanol and ethyl acetate (1: 1, 100 ml) was subjected to hydrogenation of Parr (H2) , 4.22 kg / cm2 (60 psi)) for 6 hours at room temperature with 20% Pd (0H) 2 on carbon (4.4 g) as catalyst. After filtration by suction through Celite, the filtrate was concentrated to dryness to yield an orange-yellow residue which was purified by flash chromatography on silica gel (elution with 50% tetrahydrofuran in hexanes) to provide the title compound. Title (2.33 g, 77%) as a yellow solid, m.p. 255-260 ° C; NMR XH (300 MHz, DMS0-d6) d 11.77 (s, ÍH), 11. 19 (s, ÍH), 9.14-9.03 (m, 2H), 7.89 (dd, J = 11.0, 2.0 Hz, ÍH), 7.41 (dd, J = 9.8, 2.3 Hz, ÍH), 7.27-7.19 (m, 2H), 6.26 (d, J = 8.9 Hz, 1H), 6.14-6.12 (, 1H), 5.43 (d, J = 4.0 Hz, ÍH), 5.17 (d, J = 5.5 Hz, ÍH), 4.98 (d , J = 5.5 Hz, HH), 4.24-3.94 (m, 3H), 3.83-3.81 (m, HH), 3.59-3.57 (m, HH), 3.50-3.42 (m, HH); 13 C NMR (75 MHz, DMSO-d6) ppm 170.99, 170.91, 163.43, 160.24, 143.12, 141.63, 130.09, 128.74, 126.02, 120.90, 119.35, 118.22, 118.14, 117.74, 116.54, 108.78, 108.57, 98.77, 98.55, 98.20 , 86.64, 78.56, 76.44, 73.06, 67.51, 58.29; IR (KBr, cm "1) 3326, 1744, 1700, 1578, 1452, 1328, 1232, 1114, 1074, 828; MS (M +) m / z 523. Analysis Calculated for C26H? 9F2N3O7» 0.25EtOAc »0.40H2O: C, 58.68, H, 3.98, N, 7.60, H20, 1.30, Found: C, 58.55, H, 4.18, N, 7.38, H20, 1.20.

Example 14 2, 10-di fluoro-12, 13-dihydro-13 - [2-0- (triethylsilyl) -3,4,6-tris-0- (phenylmethyl) -β-D-glucopyranosyl] -6-triethylsilyl-5H -indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5,7-dione (A = VIII: X? = Xj. = F; X2 = X2- = H; R6 = R "'= triethylsilyl, Q = NH, PG = benzyl) and 2,10-difluoro-12, 13-dihydro-13- [2-0- (triethylsilyl) -3,4,6-tris-O- (phenylmethyl) -β -D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (B = VIII: Xx = Xi- = F; X2 = X2. = R6 = H; R "'triethylsilyl; Q = NH; PG = benzyl). Triethylsilyl triflate (9.0 ml, 40.0 mmol, 20 eq.) Was added in one portion to a solution of 2., 10-di-fluoro-12, 13-dihydro-13- [3, 4,6-tris-0- (phenylmethyl) -β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (1.60 g, 2.0 mmol) in anhydrous pyridine (100 ml). The mixture was stirred in a sealed flask at room temperature for 48 hours before absolute ethanol (5 ml) was added. After 10 minutes, the solvent was removed under vacuum at room temperature. The residue was then diluted with ethyl acetate and tetrahydrofuran, and acidified with 0.1N hydrochloric acid until acidic. After separation of the organic phase, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The attempted purification of the residue by flash chromatography (2 times) on silica gel (elution with 10% tetrahydrofuran in hexanes for the first time and 40% ether in hexanes the second time) yielded the title compound A (1.4 g) like a slightly impure yellow foam. The impurity proved to be B. The complete conversion from A to B could be achieved by dissolving A (1.4 g, 1.37 mmol) in absolute ethanol (20 ml) and treating the solution with ammonium acetate (0.11 g, 1.40 mmol ) at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed successively with saturated sodium hydrogen carbonate solution and brine before drying and concentration to dryness. The title compound B (1.19 g, 96%) was isolated as a yellow foam. For A: p.f. 77.79 ° C; NMR XH (300 MHz, CDC13) d 10.64 (s, ÍH), 9.29 (dd, J = 8.8, 5.8 Hz, ÍH), 9.23-9.20 (m, ÍH), 7.33-7.20 (m, 15H), 7.13- 7.04 (, 4H), 5.77 (d, J = 8.8 Hz, ÍH), 5.05 (d, J = 11.6 Hz, ÍH), 4.89-4.79 (m, 2H), 4.67-4.63 (m, 2H), 4.54 ( d, J = 12.4 Hz, HH), 4.28 (m, HH), 4.16 (m, HH), 3.97 (m, 2H), 3.79-3.76 (m, 2H), 1.23-1.16 (m, 6H), 1.11 -1.06 (m, 9H), 0.24 (t, J = 8.0 Hz, 9H), -0.29- (-0.50) (m, 6H); 13 C NMR (75 MHz, CDC13) ppm 175.34, 142.70, 141.88, 138.08, 137.40, 136.28, 128.72, 128.56, 128.27, 128.13, 128.05, 127.52, 127.40, 127.17, 126.73, 121.40, 118.12, 109.84, 109.84, 109.53, 109.21 , 98.26, 97.52, 86.12, 77.71, 77.44, 77.01, 76.72, 76.59, 75.53, 75.25, 74.26, 66.82, 6.91, 6.12, 4.03, 3.95; IR (KBr, c "1) 3458, 3334, 2954, 2876, 1692, 1454, 1328, 1300, 116, 1072, 732, 696; MS (M +) calculated for C59H66F2 307Si2 1022.4407, observed 1022.4377 For B: pf not determined; 1 H-NMR (300 MHz, CDC13) d 10.65 (s, HH), 9.25-9.22 (m, HH), 9.14 (d, J = 8.8, 5.6 Hz, HH), 7.72 (s, HH), 7.33- 7.21 (m, 14. H, 7.16-7.03 (m, 4H), 5.77 (d, J = 8.8 Hz, ÍH), 5.05 (d, 'j = 11.5 Hz, ÍH), 4.87-4.78 (m, 2H), 4.69-4.63 (m, 2H), 4.59-4.51 (m, ÍH), 4.28 (t, J = 8.8 Hz, ÍH), 4.15 (t, J = 8.8 Hz, ÍH), 4.02-3.91 (, 2H), 3.79-3.73 (m, 2H), 0.23 (t, J = 8.0 Hz, 9H), -0.28- (-0.52) (m, 6H); 13 C NMR (75 MHz, CDC13 ppm 169.70, 169.66, 164.39, 161.18, 142.80, 142.64, 142.16, 141.99, 138.05, 137.37, 136.26, 130.65, 130.65-126-71 (11 lines, olefinic), 121.11, 119.48, 119.11, 118.93, 118.68, 118.44, 110.04, 109.74, 109.44, 98.39, 98.04, 97.63, 97.26, 86.11, 86.06, 77.76, 77.21, 76.74, 75.52, 75.25, 74.30, 66.86, 6.10, 4.03; IR (KBr, cm "1) 3434, 2876, 1754, 1718, 1624, 1582, 1454, 1326, 1116, 1086, 738; MS (FAB, MH +) m / z calculated for C53H52F2N307Si 908.3543, observed 908.3547.

Example 15 3,9-difluoro-12, 13-dihydro-13- [6-0- (methylsulfonyl) -β-D-glucopyranosyl] -5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole- 5, 7 (6H) -dione (Ib: Xx = Xlf = F; X2 = X2. = H = R6; R2-R4 = OH; R5 = mesylate) To a magnetically stirred solution of 3,9-difluoro-12,13-dihydro-13- [β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6H) -dione (330 mg, 0.630 mmol) in anhydrous pyridine (8 ml) at 0 ° C under nitrogen atmosphere was added by means of a syringe, methanesulfonyl chloride (80 μl, 1.03 mmol). The reaction mixture was stirred at 0 ° C for 3.25 hours and checked periodically by thin layer chromatography on silica gel. (elution with ethyl acetate) to show the new highest Rf product stain in addition to the initial material. The additional methanesulfonyl chloride (20 μl, 0.26 mmol) was added and the reaction was stirred at 0 ° C for 1.25 hours, and then worked up using ethyl acetate (350 ml) and saturated, aqueous copper (II) sulfate ( 100 ml). The ethyl acetate layer was washed with saturated aqueous copper (II) sulfate (3 x 150 ml), 0.1 N HCl (200 ml), water (200 ml) and brine (200 ml), and dried over sulfate. of sodium. Evaporation in vacuo, followed by flash chromatography on silica gel with 4-6% methanol in dichloromethane, gave 146 mg (39%) of the title compound as a yellow solid: XH NMR at 500 MHz COZY (CD3COCD3) d 10.40 (s, ÍH), 10.00 (s broad, ÍH), 8.97-8.86 (m, 2H), 8.02-7.96 (m, 2H), 7.42-7.33 (m, 2H), 6.43 (d, ÍH, J = 9.2 Hz, l'H), 4.98 (d, ÍH, J = 11.0 Hz, 6'H), 4.76 (d, ÍH, J = 11.0 Hz, 6"H), 4.48 (d, ÍH, J = 10.0 Hz, 5'H), 4.22 (t, ÍH, J = 9.7 Hz, 4'H), 4.00 (t, ÍH, J = 9.3 Hz, 2'H), 3.89 (t, ÍH, J = 9.0 Hz, 3 ' H), 3.23 (s, 3H), mass spectrum FAB, m / e 601 (M +).

Example 16 2, 10-di fluoro-12, 13-dihydro-13- [6-deoxy-6- (1,3-dihydro-1,3-dioxo-2-isoquinolinyl) -β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (A = Ib: Xi = Xlf = F; X2 = X2- = R2 = R6 = h; R2-R4 = OH; R5 = phthalimide).

The potassium phthalimide (0.45 g, 2.43 mmol) was added in one portion to a stirred solution of 2,10-di-fluoro-12, 13-dihydro-13- [6-0- (met ilsul foni 1) -β- D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione (200 mg, 0.33 mmol) in anhydrous dimethylformamide (10 ml) before The mixture was heated at 130 ° C for 3 hours, cooled to room temperature, and concentrated in vacuo overnight. The residue was then taken up in ethyl acetate (some tetrahydrofuran was added) and washed with 0.1 N hydrochloric acid and brine. After drying and concentration of the solvent, the residue was purified by flash chromatography on silica gel (elution with 7% methanol in chloroform) to give the title compound (46 mg, 21%) as a yellow solid. p.f. > 300 ° C; NMR? E (500 MHz, DMSO-d6) d 11.21 (m), 10.80 (s), 9.15-9.13 (m), 9.07-9.02 (m), 7.97 (d, J = 8.8 Hz, ÍH), 7.86 ( d, J «11.1 Hz, ÍH), 7.74-7.69 (m), 7.40 (d, J = 10.3 Hz, ÍH), 7.31-7.23 (m), 7.20-7.17 (m), 6.09 (d, J = 9.1 Hz, ÍH), 5.73 (m), 5.64 (m), 5.30 and 5.26 (2m), 4.99 (m), 4.36-4.27 (m), 4.21 (m), 4.14-4.10 (m), 4.01-3.96 ( m), 3.83-3.72 (2m), 3.57-3.53 (m); IR (KBr, cm "1) 3426, 1752, 1706, 1624, 1579, 1452, 1397, 1328, 1113, 1035; MS (negative ESI, M-H") m / z 651.

Example 17 13- [6- (Azido-6-deoxy-β-D-glucopyranosyl) -2,10-difluoro-12,13-dihydro-5H-indole [2,3-a] pyrrolo [3,4-c] carbazole -5, 7 (6H) -dione (Ib: Xx = Xi »= F; X2 = X2. = H = R6; R2-R4 = OH; R5 = N3).

Sodium azide (0.29 mg, 0.44 mmol) in one portion was added to a stirred solution of 2,10-difluoro-12,13-dihydro-13- [6-0- (methylsulfonyl) -β-D-glucopyranosyl] - 5H-indole [2, 3-a pyrrolo [3,4-c_] carbazole-5, 7 (6H) -dione (132 mg, 0.22 mmol) and powdered molecular sieves of 4 A (50 mg) in anhydrous dimethylformamide ( 3 ml) before the mixture was heated to 60 ° C for 6 hours, cooled to room temperature, diluted with ethyl acetate (some tetrahydrofuran added) and washed with saturated sodium hydrogen carbonate solution and brine. . After drying and concentration of the solvent, the residue was purified by flash chromatography on silica gel (elution with 10% methanol in chloroform) to yield the title compound (40 mg, 33%) as a yellow solid, decomposition point 265 ° C; NMR XH (500 MHz, DMSO-d6) d 11.89 (broad s, 1H), 11.21 (broad s, ÍH), 11.14 (broad s, ÍH), 10.82 (s, ÍH), 9.19 (dd, J = 8.8 Hz , ÍH), 9.13-9.06 (m, 3H), 7.90 (dd, J = 10.8, 2.1 Hz, HH), 7.71 (dd, J = 10.5, 2.1 Hz, HH), 7.49 (dd, J = 9.6, 2.1 Hz, HH), 7.35 (dd, J = 9.4, 2.3) Hz, ÍH), 7.30-7.22 (m, 4H), 6.33 (d, J -8.7 Hz, ÍH), 6.27 (d, J = 8.6 Hz, ÍH), 5.72 (d, J = 5.2 Hz, ÍH), 5.61 (d, J = 4.9 Hz, ÍH), 5.33 (s broad, ÍH), 5.23-5.21 (m, 2H), 5.11 (d, J = 5.0 Hz, ÍH), 4.20-4.10 (m, 4H), 4.02-3.94 (m, 3H), 3.85-3.83 (m, ÍH), 3.79-3.69 (m, 3H), 3.63-3.58 (m, 3H), IR (KBr, cm "1) 3422, 2110, 1740, 1700, 1622, 1580, 1450, 1381, 1329, 1231, 1170, 1115, 1074, 829, 763; HRMS (negative ESI, M-H ") calculated for C26Hi7F2Ns06 547.1256, observed 547.1199.

Example 1 6-amino-13- (6-amino-6-deoxy-β-D-glucopyranosyl) -2, 10-difluoro-12, 13-dihydro-5H-indolo [2,3-a] pyrrolo [3, 4 -c] carbazole-5, 7 (6H) -dione (le: Xi = Xi-F, X2 = X2, = H, R2-R4 = OH, R5 = NH2 = R6).

Hydrazine hydrate (2 ml) was added to 2, 10-difluoro-12,13-dihydro-13- [6-deoxy-6- (1,3-dihydro-1,3-dioxo-2-isoquinolinyl) -β) -D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (19 mg, 0.029 mmol) and the mixture was stirred at room temperature by 1 hour and at 50 ° C for 1 hour, before concentrating in vacuum for 24 hours. Purification of the residue by HPLC on a C? 8 YMC Pack ODS column (30% isocratic flow using methanol / water / 0.1% trifluoroacetic acid) gave the title compound (10 mg, 27%) as an orange yellow solid, pf > 300 ° C; NMR? E (500 MHz, DMS0-d6 / D20) d 8.94-8.89 (2m), 8.81 (m), 8.68 (m), 7.93 (m), 7.82 (d, J = 10.0 Hz, ÍH), 7.73 ( d, J = 10.2 Hz, HH), 7.39 (d, J = 9.5 Hz, 1H), 7.12-7.11 (m), 6.93 (m), 6.20 (d, J = 8.9 Hz, HH), 6.07 (d, J = 7.7 Hz, ÍH), 4.22 (m), 4.16-4.12 (m), 4.14 (t, J = 8.9 Hz, ÍH), 3.79 (t, J = 8.9 Hz, 1H), 3.75-3.73 (m) , 3.61-3.52 (m), 3.40-3.34 (m), 3.31-3.27 (m); IR (KBr, cm "1) 3415, 1757, 1706, 1676, 1623, 1581, 1451, 1404, 1330, 1203, 1112, 839; HRMS (negative ESI, M-H") calculated for C2sH? 9F2N505 536.1460, observed 536.1349.

Example 19 13 -. 13 - [6- (amino-6-deoxy-β-D-glucopyranosyl) -3, 9-difluor or-12, 13-dihydro-5H-indo lo [2, 3-a] pyrrolo [3, 4- c] carbazole-5, 7 (6H) -dione (Ib: Xi = X? < = F; X2 = X2 > = H = R6; R2-R4 = OH; R5 = NH2).

To a solution of the compound 13- [6- (azido-6-deoxy-β-D-glucopyranosyl) -3,9-di-fluoro-12,13-dihydro-5H-indole [2,3-aJpirrolo [3, 4 -c] carbazole-5, 7 (6H) -dione (98.9 mg, 0.180 mmol) in absolute methanol (125 ml) under nitrogen atmosphere in a Parr apparatus, palladium (II) chloride (90 mg, 0.51 mmol ). The mixture was sonicated for 10 minutes and then placed on a Parr shaker at a hydrogen pressure of 4.92 kg / cm2 (70 psi) for 45 hours. The mixture was filtered through a small pad of Celite, washed with methanol and concentrated in vacuo. Purification on Sephadex LH 20 column with elution with methanol (0.4-0.5 ml / minute flow rate), gave 69.6 mg (70%) of the title compound cpmo an orange yellow solid: 500 MHz COZY NMR (d6) -DMSO) d 11.20 (s broad, ÍH), 8.92 (dd, ÍH, J = 9.7, 2.6 Hz), 8.81 (dd, ÍH, J = 9.7, 2.6 Hz), 8.05 (dd, ÍH, J = 9.0, 4.6 Hz), 7.95 (broad s, 3H), 7.88 (dd, ÍH, J = 8.9, 4.6 Hz), 7.48 (ddd, ÍH, J = 2.5, 8.9, 9.1 Hz), 7.41 (ddd, ÍH, J = 2.5, 8.9, 9.1 Hz), 6.41 (d, ÍH, J = 8.8 Hz, l'H), 5.70 (s broad, ÍH), 5.36 (broad d, 2H, 2 ', 3' OH) , 4.23-4.19 (m, ÍH, 5'H), 4.06-4.02 (m, ÍH, 2'H), 3.89-3.84 (m, ÍH, 3'H), 3.56 (t, ÍH, J = 8.9 Hz , 4'H), 3.32-3.25 (m, ÍH, 6'H), 3.13-3.08 (m, ÍH, 6"H), mass spectrum FAB, m / e 522 (M +).

Example 20 4- [2- (Benzo [b] thien-2-yl) -5-fluoro-lH-indol-3-yl] -3-chloro-l-methyl-lH-pyrrolo-2, 5-dione (V: Xx = 5F; X2 = H = R ': R6 = Me; R "= benzo [b] thienyl, y = Cl).

To a solution of 2- (2-benzo [b] thienyl) -5-fluoroindole (10.0 g, 0.37 mol) in anhydrous tetrahydrofuran (250 ml) under nitrogen atmosphere was added by means of a syringe ethylmagnesium bromide (3M, 13.1 ml, 0.39 mol) at a rate that maintained the internal temperature between 45-50 ° C. The mixture was then heated to 50-55 ° C for 0.5 hour and cooled again to room temperature before a solution of 3,4-dichloro-1-methylmaleimide (7.41 g, 0.41 mol) in anhydrous tetrahydrofuran was cannulated, to the reaction mixture. The mixture was refluxed for 2 hours, cooled, diluted with ethyl acetate, washed with saturated ammonium chloride solution and with brine, before drying and the concentration of the solvent to 1/4 volume. Filtration by suction of the suspension gave the title compound (12.65 g, 82%) as a red-violet solid, m.p. 250-251 ° C; 1 H NMR (300 MHz, DMSO-ds) d 12.50 (s, ÍH), 8.03-7.99 (m, ÍH), 7.93-7.89 (m, ÍH), 7.83 (s, ÍH), 7.52 (dd, J = 8.9 , 4.4 Hz, HH), 7.46-7.36 (m, 2H), 7.29 (dd, J = 9.9, 2.5 Hz, HH), 7.16-7.09 (m, HH), 3.37 (s, 3H); 13 C NMR (75 MHz, DMSO-d6) ppm 167.71, 165.34, 159.10, 156.00, 139.48, 134.18, 133.76, 133.19, 133.06, 132.66, 127.41, 127.27, 125.20, 125.02, 124.22, 123.64, 122.55, 113.23, 113.10, 111.89 , 111.54, 105.40, 105.07, 100.56, 24.61; IR (KBr, cm "1) 3336, 1778, 1706, 1636, 1490, 1441, 1383,? 297, 1170, 1010, 982, 881, 822, 800, 750, 736; MS (negative ESI, MH") m / z 409. Analysis Calculated for C2? H? 2FN202S: C, 61.39; H, 2.94; N, 6.82. Found; C, 61.08; H, 2.88; N, 6.62.

Example 21 3-f luoro-6-methyl-5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7-dione (VI: Xi = F; X2 = X = X2 = R '= H; Q = S; R6 = Me).

A suspension containing 4- [2- (benzo [b] thien-2-yl) -5-fluoro-lH-indol-3-yl] -3-chloro-l-methyl-lH-pyrrolo-2, 5 -dione (12.6 g, 30.7 mmol) in anhydrous absolute ethanol / dioxane (60%, 1 liter) was placed in a 2-liter pyrex flask equipped with a reflux condenser. The mixture was stirred and irradiated (Hanovia medium pressure mercury lamp 450 W) for 14 hours before it was cooled to room temperature and refrigerated for an additional 24 hours at -5 ° C. Filtration by suction of the suspension afforded the title compound (12.7 g, 95%) as a glass fiber-like, yellowish green fluorescent solid, m.p. > 305 ° C; NMR XH (500 MHz, DMS0-d6) d 9.50 (d, J = 7.8 Hz, HH), 8.39 (d, J = 9.7 Hz, HH), 8.05 (d, J = 7.8 Hz, HH), 7.55-7.47 (m, 3H), 7.33-7.29 (m, ÍH), 3.55 (s, 0.3 dioxane, 3H), 2.96 (s, 3H); 13 C NMR (125 MHz, DMSO-de at 40 ° C) ppm 168.99, 168.73, 158.05, 138.98, 138.93, 137.97, 134.13, 129.91, 127.73, 127.07, 126.59, 125.40, 125.22, 122.99, 121.18, 118.50, 115.75, 115.55 , 114.81, 112.85, 112.78, 109.87, 109.67, 66.45 (dioxane), 23.66; IR (KBr, cm "1) 3263, 1756, 1702, 1694, 1629, 1494, 1455, 1374, 1291, 1256, 1222, 1168, 1156, 1110, 982, 869, 806, 755, 745, 704, 613; MS (negative ESI, MH ") m / z 373.

Analysis Calculated for C2? HnFN2O2S »0.3dioxane * l .5H20: C, 65.93; H, 3.44; N, 6.93; H20, 0.89. Found: C, 65.86; H, 3.43; N, 6.68; H20, 0.56.

Example 22 3-fluoro-6-methyl-l 3- [2, 3,4,6-tetra-0- (phenylmethyl) -β-D-glucopyranosyl-5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione (VIII: X2 = F; X2 = X = X2- = H; Q = S; R6 = Me; PG = R "'= benzyl) .

Diisopropyl azodicarboxylate (4.6 ml, 24.0 mmol, 4.5 eq.) Was added dropwise to a slightly cool (0 ° C) suspension of 3-fluoro-6-methyl-5H, 13H-benzo [b] thienyl [2 , 3-a] pyrrolo [3,4-c] -carbazole-5,7-dione (2.0 g, 5.34 mmol), 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose (8.67 g, 16.03 mmol, 3.0 eq.) And triphenylphosphine (6.31 g, 24.0 mmol, 4.5 eq.) In anhydrous tetrahydrofuran (200 ml). The mixture was stirred at 0 ° C for 1 hour before it was diluted with ethyl acetate and washed with 0.1N hydrochloric acid and brine. After drying and evaporation of the solvent, the residue was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in hexanes, followed by 15% ethyl acetate in hexanes) to give the title compound (4.60. g, 96%) as a yellow foam, mp 64-70 ° C; X H NMR (500 MHz, DMSO-de, 1: 1 mixture of rotational isomers) d 9.87 and 9.78 (2m, ÍH), 9.00-8.99 and 8.85-8.83 (2m, ÍH), 8.11-8.02 (2m, 1.5H) , 7.73 (d, J = 7.2 Hz, 0.5H), 7.58-7.54 (m, 2.5H), 7.38-7.23 (m, 15H), 7.18 (d, J = 7.9 Hz, 0.5 H), 6.84 (t, J = 7.4 Hz, 0.5H), 6.78-6.75 (m, 0.5H), 6.67 (t, J = 7.6 Hz, ÍH), 6.55 (t, J = 7.5 Hz, ÍH), 6.51 (d, J = 8.8 Hz, 0.5H), 6.43 (d, J = 9.2 Hz, 0.5H), 6.12-6.10 (m, 2H), 4.95 (d, J = 10.9 Hz, 0.5H), 4.88-4.79 (m, 3H), 4.74-4.65 (m, ÍH), 4.58-4.48 (m, 2.5H), 4.36-4.29 (m, 1.5H), 4.24-4.20 (m, 0.5H), 4.14 (s broad, 0.5H), 4.11- 4.00 (m, 3H), 3.93 (d, J = 10.6 Hz, 0.5H), 3.87 (broad s, HI), 3.18 (s, 3H); IR (KBr, cm "1) 3423, 2920, 2866, 1759, 1699, 1622, 1481, 1453, 1380, 1283, 1255, 1213, 1180, 1160, 1089, 744, 697; MS (FAB, M") m / z 896.

Example 23 3-fluoro-6-methyl-l 3- [β-D-glucopyranosyl] -5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6H diona (la; Xi = F; X2 = X2- = X = H; Q = S; R5 = Me; R2-R5 = OH).

To a cold stirred solution (0 ° C) of 3-fluoro-6-methyl-l 3- [2, 3,4,6-tetra-O- (phenylmethyl) -β-D-glucopyranosyl] -5H, 13H- benzo [b] thienyl [2, 3-a] -pyrrolo [3, 4-c] carbazole-5, 7- (6H) -dione (4.5 g, 5.02 mmol) in ethanethiol (30 ml) was added trifluoride etherate of cold boron (0 ° C) (6.36 ml, 50.2 mmol). The mixture was stirred at 0 ° C for 1 hour before it was allowed to stir at room temperature for a total of 48 hours. Additional boron trifluoride etherate (3.2 ml) was added after 12 hours and 24 hours. The solvent was removed in vacuo and the remaining residue was taken up in ethyl acetate / tetrahydrofuran and washed with 1N hydrochloric acid and brine, before drying and concentration of the solvent. Purification of the residue by flash chromatography on silica gel (gradient elution with 10% methanol in chloroform followed by 15% methanol in chloroform) afforded the title compound (2.53 g, 94%) as a yellow solid, m.p. > 305 ° C; NMR XH (500 MHz, DMSO-d6) d 9.85 and 9.71 (2d, J = 7.4 and 7.5 Hz, ÍH), 8.96 and 8.89 (2d, J = 9.6 and 9.6 Ha, ÍH), 8.13-8.05 (m, 1.25 H), 7.99 (dd, J = 9.0, 4.5 Hz, 0.75H), 7.61-7.41 (3m, 3H), 6.29 and 6.09 (2d, 8.8 and 9.3 Hz, ÍH), 5.36- 5.33 (3H), 4.84-4.72 (m, 1.5H), 4.04-3.98 (m, ÍH), 3. 92-3.86 (m, 1.75H), 3.76-3.68 (m, 2H), 3.63-3.54 (m, 1.75H), 3.16 (s, 3H); 13 C NMR (125 MHz, DMSO-d 6) ppm 169.34, 169.19, 169.04, 158.81, 156.95, 140.06, 138. 48, 137.05, 133.12, 131.70, 131.49, 130.85, 129. 75, 128.36, 127.40, 127.20, 126.52, 125.78, 125. 71, 125.39, 122.80, 122.66, 122.35, 119.81, 116.33, 116.08, 115.94, 115.74, 110.70, 110.50, 105. 28, 87.77, 81.36, 77.72, 70.89, 69.86, 61.28, 24. 33; IR (KBr, cm "1) 3428, 1756, 1694, 1622, 1481, 1460, 1448, 1384, 1084, 745; MS (negative ESI, M-H ") m / z 535.

Example 24 3-fluoro-13- (β-D-glucopyranosyl) -5H, 13H-benzo [b] -thienyl [2,3-a] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione ( the: R2-R5 = OH, R6 = X2 = Xv = X2- = H, Q = S). 3-Fluoro-6-methyl-l 3- (β-D-glucopyranosyl) -5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 ( 6H) -dione (0.20 g, 0.37 mmol) was suspended in a potassium hydroxide solution 10% aqueous (30 ml) under nitrogen atmosphere. The mixture was heated to reflux gently for 3 hours before it was titrated with concentrated hydrochloric acid until a dense precipitate formed. The precipitate was taken up in ethyl acetate / tetrahydrofuran and washed with 1N hydrochloric acid and brine before drying and concentration of the solvent. The residue was dissolved in absolute methanol (1 ml) and solid ammonium acetate (3.0 g) was added. The mixture was melted at 150 ° C for 3 hours before it cooled, was diluted with ethyl acetate / tetrahydrofuran, washed with 1 N sodium hydroxide with brine, dried and concentrated. Purification of this residue by flash chromatography on silica gel (gradient elution with 30% tetrahydrofuran in chloroform followed by 50% tetrahydrofuran in chloroform) afforded the title compound (69.5 mg, 36%) as a yellow solid, m.p. >305 ° C; NMR XH (500 MHz, DMSO-d6) d 11.67 (s, 0.25H), 11.53 and 11.51 (2s, ÍH), 9.95-9.93 and 9.91-9.89 (2m, ÍH), 0.02 and 8.97 (2dd, J = 9.8 , 2.7 Hz and 9.7, 2.8 Hz, ÍH), 8.24-8.23 and 8.18-8.16 (2M, ÍH), 8.08 and 8.01 (2dd, J = 9.4 4.4 Hz and 9.1, 4.6 Hz, ÍH), 7.69-7.63 (m , 2H), 7.54-7.48 (m, ÍH), 6.34 and 6.09 (2d, J = 8.9, 9.4 Hz, ÍH), 5.37-5.35 (m, ÍH), 5.28 and 5.22 (2m wide, 2H), 4.75 ( m broad, 0.75H), 4.04 and 3.87-3.75 (2m, 3H), 3.68-3.58 (, 2H), 3.55-3.52 (m, 2H); 13 C NMR (125 MHz, DMSO-d 6) ppm 170.39, 170.16, 158.76, 156.89, 140.05, 138.34, 136.87, 133.09, 131.76, 128.32, 127.28, 126.62, 125.64, 122.64, 120.60 > • 116.16, 115.95, 115.84, 110.76, 110.56, 107.35, 87.71, 81.13, 77.45, 70.74, 69.79, 67.01, 61.23; IR (KBr, cm "1) 3392, 1747, 1705, 1625, 1481, 1462, 1430, 1326, 1284, 1262, 1180, 1087, 804, 758, 747; HRMS (negative ESI, MH") calculated for C2eH? 8FN207S 521.0897, observed 521.0802.

Example 25 3, 9-di-fluoro-12, 13-dihydro-13- [3, 6-0- (t-but i Idime ti 1-silyl) -β-D-glucopyranosyl] -5H-indole [2, 3-a ] pyrrolo- [3, 4-c] carbazole-5, 7 (6N- [4- (t-but i 1) benzyl] -) -dione (Ib: Xa = Xv = F; X 2 = X 2 - = H; R6 = 4- (t-butyl) benzyl, Q = NH, R2 = R4 = OH, R3 = R5 = t-butyldimethylsilyloxy).

To a magnetically stirred solution of the product of Example 12 (750 mg, 1.12 mmol) and imidazole (1.9 g, 28 mmol) in anhydrous dimethylformamide (14 mL) under nitrogen with stirring, trifluoromethanesulfonate was added via a syringe. of t-butyldimethylsilyl (2.96 g, 2.57 ml, 11.2 mmol). The reaction was stirred at room temperature for 1 hour and quenched with absolute ethanol (5 ml). The mixture was diluted with ethyl acetate (150 ml) and washed with water (6 x 100 ml), and brine (100 ml), and dried over sodium sulfate. This material was used directly in the next step without further purification. The analytical sample was purified by flash chromatography on silica gel with hexane / methylene chloride: 300 MHz tE NMR (CDC13) d 10.06 (broad s, ÍH), 9.12 (dd, ÍH, J = 9.2, 2.7 Hz), 7.88-7.81 (m, ÍH), 7.72 (dd, ÍH, J = 9.2, 3.9 Hz), 7.41 (ddd, ÍH, J = 8.9, 8.9, 2.6 Hz), 7.25 (dd, ÍH, J = 9.0, 4.1 Hz), 7.20-6.99 (m, 4H), 6.92 (ddd, ÍH, J = 8.7, 8.7, 2.4 Hz), 5.97 (d, ÍH, J = 8.9 Hz), 4.58-3.90 (m, 8H), 1.18 (s, 9H), 0.91 (s, 9H), 0.83 (s, 9H), 0.27 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), -0.02 (s, 3H); mass spectrum FAB, m / e 897 (M +).

Example 26 3, 9-difluoro-12, 13-dihydro-13- [3-0- (t-butyldimethyl-silyl) -β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo- [3 , 4-c] carbazole-5, 7 (6N- [4- (t-butyl) benzyl] -) -dione (Ib: Xa = Xv = F; X2 = X2- = H; R6 = 4- (t -butyl) benzyl, Q = NH, R 2 = R 4 = OH, R 3 = t-butyldimethylsilyloxy).

To a magnetically stirred solution of the crude product of Example 25 at -5 ° C was added a mixture of trifluoroacetic acid: water 9: 1 precooled at -5 ° C. The reaction was stirred at -5 ° C for 45 minutes, diluted with ethyl acetate (200 ml), and washed with saturated sodium hydrogen carbonate solution (6 x 150 ml), with water (1 x 150 ml) , and brine (1 x 150 ml), and dried over sodium sulfate. Evaporation in vacuo, followed by flash chromatography on silica gel with 1-10% methanol in methylene chloride gave 59 mg (6%) of the starting material (eg compound of Example 25), 78 mg (10%) of the completely desilylated product (for example compound of Example 12), and 585 mg (74%) of the pure title compound as a yellow solid: XH NMR at 500 MHz COZY (d6-DMSO) d 11.80 (broad s, ÍH), 8.82 (dd, ÍH, J = 9.6-2.7 Hz), 8.76 (dd, ÍH, J = 9.7, 2.7 Hz), 8.03 (dd, ÍH, J = 9.2, 4.4 Hz), 7.68 (dd, ÍH, J = 8.9, 4.5 Hz), 7.51-7.45 (m, 2H), 7.38-7.31 (m, 4H), 6.28 (d, ÍH, J = 9.1 Hz, l'H), 6.08 (t, ÍH, J = 3.9 Hz , 6'0H), 5.35 (d, ÍH, J = 6.8 Hz, 4'0H), 4.88 (s, 2H), 4.81 (d, ÍH, J = 6.8 Hz, 2'0H), 4.12-4.08 (, ÍH, 6'H), 3.98-3.93 (m, ÍH, 5'H), 3.93-3.90 (m, ÍH, 4'H), 3.86-3.82 (m, ÍH, 6'H), 3.73 (t, ÍH, J = 8.8 Hz, 3'H), 3.39 (ddd, ÍH, J = 9.1, 8.8, 6.8 Hz, 2'H), 1.23 (s, 9H), 0.76 (s, 9H), 0.07 (s, 3H), -0.03 (s, 3H); mass spectrum m / e 783 (M +).

Example 27 3, 9-difluoro-12, 13-dihydro-13- [3-0- (t-butyldimethyl-silyl) -6-0- (methanesulfonyl) -β-D-glucopyranosyl] -5H-indo lo [2, 3-a] pyrrolo (3,4-c] carbazole-5, 7 (6N- [4- (t-butyl) benzyl] -) -dione (Ib: X x = X v = F; X 2 = X 2 - = H; R6 = 4- (t-butyl) benzyl, Q = NH, R 2 = R 4 = OH, R 3 = t-butyldimethylsilyloxy, R 5 = methanesulfonyloxy) To a magnetically stirred solution of the pure product of Example 26 (403 mg, 0.514 mmol) in anhydrous pyridine (7 ml) at -10 ° C under an argon atmosphere was added via a syringe in 1 minute, methanesulfonyl chloride (46 g. μl, 0.594 mmol). After 70 minutes at -10 ° C, an aliquot was removed, added to a mixture of ethyl acetate and saturated aqueous copper (II) sulfate, and analyzed by thin layer chromatography on silica gel using 1-2 % methanol in methylene chloride. It appeared mainly indicated the initial material by a small amount of the stain of the product of higher Rf. Additional methanesulfonyl chloride (32 μl) was added and the reaction was maintained at -10 ° C for 1 hour. In 30 minute intervals, the reaction was treated successively with additional methanesulfonyl chloride (33 μl, 31 μl, 31 μl and 24 μl). After a total of 5 hours at -10 ° C, thin layer chromatography showed the largest product spot and a little of the initial material of the lowest Rf. In the last 1.5 hours, the temperature of the reaction was allowed to rise to -1 ° C from -10 ° C. The reaction mixture was quenched by the addition of 200 μl of absolute ethanol, stirred for 5 minutes, and partitioned with ethyl acetate (600 ml) and saturated aqueous copper (II) sulfate (250 ml). The organic layer was washed with saturated aqueous copper (II) sulfate (200 ml), water (200 ml) and brine (200 ml), and dried over sodium sulfate. Evaporation in vacuo, followed by flash chromatography on silica gel with 1% methanol in methylene chloride gave 404 mg (91%) of the pure title compound and 40 mg of the recovered starting material: XH NMR at 300 MHz, (CDC13 ) d 9.83 (s broad, ÍH), 9.08 (dd, ÍH), 7.80-7.71 (m, ÍH), 7.68 (dd, ÍH), 7.52 (dd, ÍH), 7.40 (ddd, ÍH), 7.21-7.13 (m, 2H), 7.03-6.86 (m, 3H), 5.94 (d, ÍH), 5.15-3.92 (m, 10H), 3.02 (s, 3H), 1.19 (s, 9H), 0.84 (s, 9H) ), 0.23 (s, 3H), -0.01 (s, 3H); mass spectrum FAB, m / e 861 (M +.

Example 28 3, 9-difluoro-12, 13-dihydro-13 - [3 -O- (t-but i Idimeti 1-silyl) -6- (4N-morpholino) -β-D-glucopyranosyl] -5H-indolo [ 2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6N- [4- (t-butiD-benzyl] -) -dione (Ib: Xi = Xv = F; X2 = X2 < = H; R6 = R- (t-butyl) benzyl; Q = NH; R2 = R4 = OH; R3 = t-butyldimethylsilyloxy; R5 = morpholino) To a magnetically stirred solution of the pure product of Example 27 (193 mg, 0.224 mmol) in anhydrous DMSO (5 mL) under nitrogen atmosphere was added morpholine (210 μL, 2.41 mmol). The resulting red reaction mixture was stirred for 69 hours at 47 ° C and partitioned with ethyl acetate (350 ml) and saturated aqueous sodium hydrogen carbonate solution (75 ml). The organic layer was washed with water (4 x 70 ml) and brine (75 ml), and dried over sodium sulfate. Evaporation in vacuo, followed by flash chromatography on silica gel with 20-25% ethyl acetate in methylene chloride gave 9 mg (5%) of the recovered starting material and then 102 mg (53%, 56% based on the initial material recovered) of the pure title compound as a yellow solid: 2 H NMR at 300 MHz, (CDC13) d 10.03 (broad s, HI), 9.09 (dd, ÍH), 8.02-7.96 (m, 1H), 7.69 (dd, ÍH), 7.39 (ddd, ÍH), 7.30-7.23 (m, ÍH), 7.21-7.17 (m, 2H), 7.07-6.98 (m, 3H), 5.96 (d, ÍH), 4.53-3.93 (m, 6H), 3.72-3.57 (m, 4H), 3.19-2.98 (, 2H), 2.82-2.71 (m, 2H), 2.68-2.58 (m, 2H), 1.19 (s, 9H), 0.88 ( s, 9H), 0.27 (s, 3H), 0.08 (s, 3H); ESI (NEGATIVE) mass spectrum, m / e 851 (M-H) ".

Example 29 3, 9-difluoro-12, 13-dihydro-3- [6- (4N-morphino) -β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] ] carbazole-5, 7 (6H) -dione (la: Xi = Xv = F; X2 = X2- = R6 = H; R5 = 4N-morpholino; Q = NH; R2-R4 = OH).

To a magnetically stirred solution of the pure product of Example 28 (205 mg, 0.240 mmol) in absolute ethanol (160 mL) was added aqueous potassium hydroxide (4.45 M, 42 mL, 187 mmol). The resulting dark red solution was heated in an open flask until all the ethanol was evaporated and a solid gum was obtained (approximately 1.5 hours). The mixture was cooled under a stream of nitrogen and concentrated hydrochloric acid (12 N, 17 mL, 204 mmol) was added. The mixture was stirred 5 minutes and absolute ethanol (90 ml) was added, followed by solid ammonium acetate (85 g). The mixture was heated with stirring in an open flask just below the boiling point, for 2.5-3 hours and then at 180 ° C (internal melt temperature) in about 2 hours. The mixture was further heated to 200 ° C in 10-15 minutes, cooled rapidly under a stream of nitrogen to about 50-60 ° C, and digested with water (200 ml), with saturated aqueous sodium carbonate solution (200 ml), and with ethyl acetate (800 ml). The organic layer was washed with brine (200 ml), the combined aqueous layers were extracted with fresh ethyl acetate (300 ml), and the last extract was washed with brine (100 ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was dissolved in methanol (400 ml) and treated with anhydrous potassium carbonate (2.0 g) and potassium fluoride dihydrate (1.03 g), and stirred at room temperature for 15 hours. The solvent was evaporated in vacuo, the residue redissolved in methanol (250 ml), treated with 1 N hydrochloric acid (15 ml), and evaporated in vacuo. The residue was dissolved in absolute ethanol (500 ml), evaporated in vacuo, and this process was repeated again. Recrystallization from 95% ethanol gave 79.6 mg (53%, 2 crops) of the pure title compound as its hydrochloride salt: NMR? E at 500 MHz, COZY (d6-DMSO) d 12.67 (broad s, ), 11.19 (s, 1H), 8.92 (dd, ÍH, J = 9.7, 2.6 Hz), 8.79 (dd, ÍH, J = 9.8, 2.3 Hz), 8.05 (dd, ÍH, J = 9.0, 4.5 Hz) , 7.94 (dd, ÍH, J = 8.7, 4.5 Hz), 7.46 (ddd, ÍH, J = 2.5, 8.9, 9.0 Hz), 7.41 (ddd, ÍH, J = 2.6, 9.0, 9.1 Hz), 6.61 (d , HH, J = 8.6 Hz, HH), 3.97 (t, HH, J = 8.8 Hz, 2'H), 3.91-3.16 (m, 13H).

Example 30 3, 9-difluoro-12, 13-dihydro-13- [6-azido-β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 ( 6-hydroxy) dione (le) To a magnetically stirred solution of 3,9-difluoro-12,13-dihydro-13- [6-azido-β-D-glucopyranosyl] -5H-indole [2, 3-a] pyrrolo [3, 4-c] ] carbazole-5, 7 [6 (4-t-butylbenzyl)] -dione (20 mg, 0.029 mmol) in absolute ethanol (5 ml) was added aqueous potassium hydroxide (4.45 M, 1.1 ml, 4.9 mmol). The resulting dark red solution was heated in an open flask until all the ethanol was evaporated and a solid gum formed (approximately 1.5 hour). This mixture was cooled under a stream of nitrogen and absolute ethanol (5 ml) was added, followed by solid hydroxylamine hydrochloride (685 mg). The mixture was heated to reflux with stirring for 4 hours, then heated to 110 ° C (internal temperature of the melt after the boiling solvent) for about 3 hours. The mixture was cooled under a stream of nitrogen at room temperature, and digested with 1 N HCl (80 ml) and ethyl acetate (400 ml). The organic layer was washed with 1 N hydrochloric acid (3 x 50 ml), water (2 x 50 ml), and brine (100 ml), and dried over sodium sulfate, evaporation in vacuo, followed by purification on a Sephadex LH 20 column with elution with methanol 0.4-0.5 ml / minute flow rate) gave 4.3 mg (27%) of the title compound as a yellowish red solid: IR (KBr) 2114 cm "1; XH NMR at 500 MHz COZY (CD3OD) d 8.53 (dd, ÍH, J = 9.6, 2.1 Hz), 8.36 (dd, ÍH, J = 9.5, 1.9 Hz), 7.68 (dd, ÍH, J = 8.8, 3.7 Hz ), 7.36 (dd, ÍH, J = 8.8, 4.2 Hz), 7.24 (ddd, ÍH, J = 8.7, 8.7, 2.0 Hz), 7.14 (ddd, 1H, J = 8.9, 8.8, 2.3 Hz), 5.98 ( d, ÍH, J = 9.0 Hz, l'H), 4.47 (d, ÍH, J = 12.1 Hz, 6'H), 4.28 (d, ÍH, J = 12.1 Hz, 6"H), 4.11 (d, ÍH, J = 9.4 Hz, 5'H), 3.91 (t, ÍH, J = 9.4 Hz, 4'H), 3.61 (t, ÍH, J = 9.0 Hz, 2'H), 3.46 (dd, ÍH, J = 9.4, 9.0 Hz, 3'H), mass spectrum FAB, m / e 564 (M +).

Example 31 3, 9-difluoro-12, 13-dihydro-13- [6-amino-β-D-glucopyranosyl] -5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole-5, 7 (6-hydroxy) dione (le) To a solution of the product of Example 30 (3.0 mg, 0.0053 mmol) in absolute methanol (2 ml) under nitrogen atmosphere in a Parr apparatus was added palladium (II) chloride (15 mg , 0.09 mmol). The mixture was sonicated for 10 minutes and then placed on a Parr shaker at 4.57 kg / cm2 (65 psi) of hydrogen pressure for 24 hours. The mixture was filtered through a small pad of Celite, washed with methanol, and concentrated in vacuo to give 2.0 mg (66%) of the title compound as a yellowish orange solid: mass spectrum FAB, m / e 538 (M +). Additional examples of compounds of formula I, which can be synthesized by modifications of the above synthetic methods, are described in Table IV, wherein the substituents are the same as in Example 29 unless mentioned above. another way.

Table IV E j emp l o R2 R5 R6 O Do not . 32 OH N3 4 -t-butyl-? H benzyl Table IV E j emplo R Rs RÉ O No. 33 OH N3 H NH 34 OH imidazole H NH OH 4-Me-piperazine H 'NH 36 OH 4N-morpholino H S 37 OH NH2 H S 38 OH 4N-morpholino H O 39 OH NH2 H O 40 OH N3 H O 41 OH N (CH2CH2OH) 2 H S 42 OH CN H S 43 OH COOH H NH 44 OH N? ORNITHINE H NH 45 0 OH H NH 46 N-OH OH H NH 47 OH R H NH 48 OH F OH NH The analytical data for some of the Examples shown in Table IV are given below: Example 32: IR (KBr) 2110 c "1; XH NMR at 500 MHz COZY (CD3OD) d 8.81-8.8.79 (m, 2H), 7.68 (dd, ÍH, J = 9.1, 4. 0 Hz), 7.56 (dd, ÍH, J = 8.8, 4.2 Hz), 7.38-7.25 (m, 6H), 6.05 (d, ÍH, J = 8.5 Hz, l'H), 4.75 (s, 2H), 4.29 (d, ÍH, J = 12.8 Hz, 6'H), 4.17-4.06 (m , 2H, ', 6"H), 4.00 (t, ÍH, J = 8.9 Hz, 4'H), 3.70-3.65 (m, 2H, 2'3'H), 1.27 (s, 9H); mass spectrum FAB, m / e 694 (M +).

Example 33: Yellow solid: IR (KBr) 2112, 1750, 1700 cm "1; XH NMR at 500 MHz COZY (CD30D) d 8.78-8.72 (m, 2H), 7.77 (dd, ÍH, J = 9.1, 4.1 Hz ), 7.55 (dd, ÍH, J = 8.8, 4.2 Hz), 7.33-7.26 (m, 2H), 6.12 (d, ÍH, J = 8.5 Hz, l'H), 4.27 (d, ÍH, J = 11.5 Hz, 6'H), 4.15-4.07 (, 2H, 5 ', 6"H), 4.01 (t, ÍH, J = 8.7 Hz, 4'H), 3.74-3.67 (, 2H, 2', 3 ' H); mass spectrum FAB, m / e 548 (M +).

Example 34: Yellow-orange solid: 500 MHz XH NMR, CD3OD) d 8.81-8.61 (m, 2H), 7.88-7.04 (m, 7H), 6. 32 (d, ÍH, J = 8.9 Hz, l'H), 4.20-3.30 (m, 6H); mass spectrum FAB, m / e 574 (MH +).

Example 35: Yellow solid; mass spectrum FAB, m / e 605 (M +).

Example 36: Yellow solid, m.p. 257-2730C; NMR? E (500 MHz, DMSO-d6) d 11.73 (broad s, ÍH), 9.53-9.40 (2m, ÍH), 8.65-8.63 (m, ÍH), 8.25-7.91 (4m, 2H), 7.52-7.25 (3m, 2H), 6.21 and 6.10 (2d, J = 8.8, 9.3 Hz, ÍH), 5.47-4.99 (series of m, 3H), 4.10-3.86 (3m, 3H), 3.56-3.53 (m, 7H) , 2.99-2.57 (series of m, 4H); IR (KBr, cm "1) 3412, 2924, 2800, 1706, 1653, 1602, 1567, 1481, 1463, 1425, 1321, 1301, 1198, 1110, 1067, 916, 804, 764, 742; MS (+ ESI) , M + H +) m / z 610.

Example 37: 12 - [6-amino-6-deoxy-β-D-glucopyranosyl) -3-fluoro-5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 (6H) -dione Triphenylphosphine (107 mg, 0.41 mmol) was added in one portion to a stirred solution of 12- [6- (azido-6-deoxy-β-D-glucopyranosyl) -3-fluoro-5H, 13H-benzo [b] thienyl. [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7 (6H) -dione (75 mg, 0.14 mmol) in wet tetrahydrofuran (3 ml) under nitrogen atmosphere before the mixture was heated to 50 ° C for 28 hours, cooled to room temperature and treated with aqueous solution of ammonium hydroxide for 1 hour at room temperature and for 1 hour at 50 hours. ° C. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was taken up in methanol, acidified with 1 N HCl / Et20 and evaporated to dryness. Purification of this residue by HPLC on a YMC Pack ODS column (20x100) operating at 87% B, afforded the title compound (54 mg, 71%) as a yellow solid, decomposition point 290 ° C (sealed tube); NMR? E (500 MHz, DMSO-d6) d 11.55 (s broad, ÍH), 9.94-9.90 (m, ÍH), 9.03-8.96 (2m, ÍH), 8.30-8.26 (m, 4H), 8.12-8.08 (m, ÍH), 7.71-7.29 (series of m, 6H), 6.36 and 6.15 (2d, J = 8.9, 9.3 Hz, ÍH), 5.81 and 5.55 (2m, 2H), 4.23-3.70 (5m, 2H) , 3.60-3.57 and 2.94 (2m, 2H), 1.68-1.41 (3m, 2H); IR (KB r, cm "1) 3401, 1702, 1624, 1482, 1460, 1328, 1284, 1209, 1182, 1087, 757, 746; MS (FAB, MH +) m / z 522.

Example 39 3, 9-di-fluoro-12- (6 -ami non-6-deoxy-β-D-glucopyranosyl) benzofurane [2, 3-a] -pyrrolo [3,4-c] -carbazole-5, 7- diona To a magnetically stirred solution of 3,9-di-fluoro-12- (β-D-glucopyranosyl] benzofuran [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7-dione (50 mg, 0.09 mmol) and powdered molecular sieves of 4 angstrom (100 mg) in anhydrous pyridine (3 ml) at -30 ° C under an argon atmosphere, methanesulfonyl chloride (10 μl, 0.12 mmol) was added via syringe. The reaction mixture was stirred at -30 ° C for 1 hour, then at -10 ° C for 0.5 hours followed by an additional portion of methanesulfonyl chloride (10 μL, 0.12 mmol) This resulting mixture was then stirred at 0 ° C. for 1 hour, it was filtered by suction and concentrated.The residue was taken up in ethyl acetate / tetrahydrofuran and washed with water, dried over sodium sulfate and evaporated.The resulting residue was washed with toluene to give a yellow product. crude oil which was used directly for the next reaction-without further purification.Sodium azide (62 mg, 0.95 mmol) was added to a stirred solution of 3,9-difluoro-12- (6-0- (methylsul fonyl) -β-D-glucopyranosyl) benzo furan- [2,3-a] pyrrolo [3,4- c] -carbazole-5, 7-dione (54 mg, 0.09 mmol) in anhydrous dimethylformamide (3 ml) before the mixture was heated to 70 ° C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, dried over sodium sulfate and concentrated in vacuo. The crude yellow product was used directly for the next reaction without further purification. A mixture of 3,9-difluoro-12- (6-azido-deoxy-β-D-glucopyranosyl) benzofuran- [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione (Example 40) (49 mg, 0.09 mmol) and 10% palladium on carbon (50 mg) in a mixture of ethanol (3 ml) and tetrahydrofuran (1 ml) was hydrogenated at 1 atmosphere for 21 hours. The reaction mixture was filtered, washed with methanol and tetrahydrofuran, and concentrated in vacuo. The crude product was subjected to chromatography (60% methylene chloride: 20% tetrahydrofuran and 20% a solution of 90% methanol and 10% ammonium hydroxide) to provide the title compound (20 mg, 42% ) as a yellow solid: IR (KBr) 1753, 1701, 1479 cm "1: XH NMR (DMSO-d6, 400 MHz) d 8.87-8.82 (m, HH), 8.56-8.49 (m, HH), 8.10- 7.99 (m, 2H), 7.67-7.50 (m, 2H), 6.53 (d, 0.7 H, J = 9.0 Hz), 6.14 (d, 0.3H, J = 9.0 Hz), 5.44-5.30 (m, 2H) , 4.28-2.86 (m, 7H): HPLC: 90.4% (247 nm).

Example 45: XH NMR at 300 MHz d6-acetone) d 11.97 (broad s, ÍH), 9.91 (s, ÍH), 9.12 (dd, ÍH), 8.88 (dd, ÍH), 7.92 (dd, ÍH), 7.69 (dd, ÍH) 7.47-7.23 (m, 2H), 7.48 (ddd, ÍH, J = 2.5, 8.9, 9.1 Hz), 7.41 (ddd, ÍH, J = 2.5, 8.9, 9.1 Hz), 6.73 (s, ÍH, l'H), 4.60-3.95 (m, 6H).

Example 47: Yellow-orange solid: 500 MHz 1E NMR (CDC13 with one drop of d6-DMSO) d 10.36 (d, HH, JH-F = 4.2 Hz), 9.98 (broad s, HH), 8.81 (dd, HH, J = 9.5, 2.6 Hz), 8.68 (dd, ÍH, J = 9.5, 2.5 Hz), 7.47 (dd, ÍH), 7.30-7.40 (m, ÍH), 7.15-7.04 (, 2H), 5.84 (d, ÍH) , J = 8.5 Hz), 5.02 (dd, ÍH, JH-F = 45.2 Hz, JH-H = 10.1 Hz), 4.72 (dd, ÍH, JH-F = 49.6 Hz, JH-H = 10.1 Hz), 4.03 -3.82 (m, 2H), 3.71-3.60 (, 2H); ESI negative mass spectrum, m / e 524 (M-H) -.

Example 48: H-NMR at 500 MHz (d6-DMSO) d 8.80-7.20 (m, 6H), 6.38 (d, ÍH), 5.15-3.45 (, 6H). mass spectrum (ESI (NEG), m / e 540 (M-H) ".

Additional examples of the compounds of formula I, which can be synthesized by modifications of the above synthetic procedures, are described in Table V, wherein the substituents are the same as in Example 19 unless mentioned above. another way.

Table V E jmplo í Rs O No. 49 OH Cl H NH 50 OH Cl H S 51 OH Cl H O 52 OH F H S 53 OH F H O 54 OH SCH3 H NH 55 OH SCH3 H S 56? OH N3 N S 57 OH S (0) CH3 H S 8 OH S (0) CH3 H NH 59 OH SCH2COOH H NH 60? OH l-piperidine H S 61? OH Tiomorf olin-S-HS oxide 2 OH S- (2-pyridine) HS 3 OH S- (2-pyridine-N-HS oxide) 64 OH S- (2- (4-OH) - H pyrimidinyl) 5 OH SCH2CF3 HS 6 OH S (0) CH2CF3 HS Table V (continued) E j emplo R * * 1 1 No. 67 OH S- (2- -imidazole) H S 68 OH Net2 OH NH 69 OH F OH S 0 N3 F H NH 1 + R 4 = = R 4 'OH H NH = F 2 F F H NH 3 NH 2 F H NH 4 CH 3 F H NH 5 N 3 H H NH 6 * R 4 = = R 4 'OH H NH = 0 7 R 4 = = R 4' F H NH -H 8 OH -CH 2 CH 2 NH-NH (-C (NH) NH 2) 9 NH 2 H H NH 0 F H H NH 1 R 4 = R 4 'H H 0 -F Table V (continued) Example k R * No. 82 R4 = R4 'HH = F 83 FHHS 84 CH3 FHS 85 OCH3 FHS 86 OCH3 FH NH 87 N3 OH H NH 88 NH2 OH H NH Note that in Examples 56, 60 and 61, X'i It is hydrogen. Note that in Example 89, X2 and X'2 are, respectively 2- and 10-fluoro, also R5. and R5- taken together is = 0. Note that in Examples 71 and 76, X2 and X'2 are respectively 2- and 10-fluoro.

The analytical data for some of the examples shown in Table V are given below.

Example 50: yellow solid, m.p. 242-248 ° C decomposes; NMR XH (500 MHz, DMS0-d6) d 11.55 (broad m, ÍH), 9.75-9.57 (2m, ÍH), 9.01-8.87 (2m, ÍH), 8.23-7.98 (3m, 2H), 7.57-7.34 ( 2m, 2H), 6.33 and 6.21 (2d, J = 8.8, 9.4 Hz, ÍH), 5.69-5.61 (2m, ÍH), 5.44-5.17 (2m, 2H), 4.12-3.96 (, 4H), 3.66-3.55 (2m, 2H); IR (KBr, cm "1) 3392, 2926, 1703, 1622, 1602, 1567, 1481, 1463, 1426, 1324, 1198, 1085, 915, 806, 763, 742; MS (-ESI, MH") m / z 557.

Example 52: yellow solid, m.p. 248-250 ° C; H NMR (500 MHz, DMSO-dβ) d 11.73, 11.65 and 11.62 (3s, ÍH), 9.81-9.68 (2m, ÍH), 9.07-8.99 (2m, ÍH), 8.27-8.00 (m, 2H), 7.61 -7.50 (m, ÍH), 6.38 and 6.26 (2d, J = 8.8, 9.3 Hz, ÍH), 5.69-5.21 (series of m, 3H), 5.05-4.82 (m, 2H), 4.25-3.82 (m, 2H), 3.72-3.61 (m, ÍH); IR (KBr, cm "1) 3384, 1706, 1622, 1602, 1568, 1481, 1463, 1325, 1198, 1086, 916, 806, 763, 742; MS (-ESI, M-H") m / z 541.

Example 54: 300 MHz * H NMR (CD3OD) d 8.80 (dd, 1H, J = 9.6, 2.3 Hz), 8.72 (dd, 1H, J = 9.9, 2.8 Hz), 7.84-7.73 (m, 2H), 7.37-7.26 (m, 2H), 6.15 (d, ÍH, J = 9.5 Hz), 4.34-4.27 (m, ÍH), 4.14 (t, ÍH, J = 9.5 Hz), 3.97 (t, ÍH, J = 9.0 Hz), 3.74 (t, ÍH, J = 9.0 Hz), 3.45 (dd, ÍH, J = 14.8, 1.8 Hz), 3.15 (dd, ÍH, J = 14.8, 3.9 Hz), 2.19 (s, 3H); ESI negative mass spectrum, m / e 552 (M-H).

Example 56 12- [6- (Azido-6-deoxy-β-D-glucopyranosyl) -3-fluoro-5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3, 4-c] carbazole-5 , 7 (6H) -dione.

Sodium azide (216 mg, 3.30 mmol) was added in one portion to a stirred solution of 3-fluoro-13- [6-0-. { methylsulfonyl) -β-D-glucopyranosyl] -5H, 13H-benzo [b] thienyl [2, 3-a] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione (0.20 g, 0.33 mmol ) in anhydrous dimethylformamide (3 ml) before the mixture was heated to 120 ° C for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 40% tetrahydrofuran in hexanes) to give the title compound (141 mg, 78%) as a yellow solid, decomposition point 265 ° C; NMR JH (500 MHz, DMSO-d6) 8 11.51 (broad s, ÍH), 9.94-9.87 (2m, ÍH), 9.03-8.95 (2m, ÍH), 8.20-7.99 (3m, 2H), 7.67-7.63 ( m, 2H), 7.53-7.49 (m, ÍH), 6.37 and 6.20 (2d, J = 8.9 and 9.4 Hz, ÍH), 5.54-5.14 (series of m, 3H), 4.10-3.76 (4m, 3H), 3.67-3.26 (m, 3H); IR (KBr, cm "1) 3332, 2103, 1702, 1481, 1461, 1431, 1372, 1324, 1283, 1230, 1211, 1178, 1079, 746; MS (-ESI, M-H") m / z 546.

Example 57 Yellow solid, m.p. 268-277 ° C (decomposes); NMR XH (500 MHz, DMSO-d6) d 11.52 (broad s, ÍH), 9.75-9.51 (3m, ÍH), 9.00-8.88 (2m, ÍH), 8.30-7.97 (3m, 2H), 7.66-7.22 ( 3m, 2H), 6.35-6.20 (2m, ÍH), 5.86-5.56 (m, ÍH), 5.42-5.35 (m, 2H), 4.28-3.89 (m, 2H), 3.72-3.56 (m, 2H), 3.50-3.32 (m, ÍH), 3.27-3.14 (m, ÍH), 2.61-2.53 (4s, 3H); IR (KBr, cm "1) 3412, 2950, 1707, 1625, 1605 1481, 1464, 1385, 1324, 1198, 1086, 916, 764, 742; LCMS (-ESI, M-H") m / z 685.

Example 58: yellow-orange solid (mixture of diastereoisomers in sulfur): JH NMR at 500 MHz, (d6-DMSO, mixture of 2 diastereoisomers and rotamers) d 8.85-8.74 (m, 2H), 8.15-7.75 (, 2H) , 7.55-7.35 (, 2H), 6.45-6.10 (m, ÍH), 5.80-5.25 (m, 3H), 4.60-3.10 (m, 6H), 2.76, 2.74, 2.58 and 2.56 (all s, 3H); Negative ESI mass spectrum, m / e 568 (M-H) ".

Example 59 XH NMR at 300 MHz (CD3OD) d 8.87 (dd, ÍH, J = 9.6, 2.6 Hz), 8.78 (dd, ÍH, J-9.8, 2.6 Hz), 7.94 (dd, ÍH, J = 8.9, 4.4 Hz) , 7.83 (dd, ÍH, J = 9.0, 4.1 Hz), 7.38-7.27 (m, 2H), 6.14 (d, ÍH, J = 9.3 Hz), 4.34-4.18 (m, 2H), 3.94 (t, ÍH , J - 9.2 Hz), 3.73 (t, ÍH, J = 8.9 Hz), 3.51-3.22 (m, 4H). Negative ESI mass spectrum, m / e 596 (M-H) ".

Example 60: yellow solid, m.p. 228-232 ° C; NMR 1E (500 MHz, DMSO-de) 5 11.88 and 11.76 (2m wide, ÍH), 9.75-9.69 (2m, HH), 8.73-8.62 (2m, HH), 8.18 and 8.09 (2d, J = 4.8, 4.7 Hz, ÍH), 7.99-7.92 (2m, ÍH), 7.65-7.35 (m, 3H), 6.28 and 6.07 (2d, J = 8.9, 9.2 Hz, ÍH), 5.29-4.97 (3m, 3H), 4.10- 3.85 (3m, 2H), 3.60-3.48 (m, 2H), 2.97-2.70 (3m, 2H), 2.58 (m, 3H), 1.56-1.44 (m, 5H), 1.34 (m, 2H); IR (KBr, cm "1) 3406, 2934, 1705, 1622, 1481, 1461, 1430, 1374, 1321, 1284, 1179, 1081, 1038, 758, 747; MS (+ ESI, M + H *) m / z 590.

Example 61: yellow solid, m.p. 228-232 ° C; NMR * H (500 MHz, DMSO-de) d 11.88 and 11.76 (2m wide, ÍH), 9. 75-9.69 (2m, ÍH), 8.73-8.62 (2m, ÍH), 8.18 and 8.09 (2d, J = 4.8, 4.7 Hz, ÍH), 7.99-7.92 (2m, ÍH), 7.65-7.35 (m, 3H ), 6.28 and 6.07 (2d, J = 8.9, 9.2 Hz, ÍH), 5.29-4.97 (3m, 3H), 4.10-3.85 (3m, 2H), 3.60-3.48 (, 2H), 2.97-2.70 (3m, 2H), 2.58 (m, 3H), 1.56-1.44 (m, 5H), 1.34 (, 2H); IR (KBr, cm "1) 3406, 2934, 1705, 1622, 1481, 1461, 1430, 1374, 1321, 1284, 1179, 1081, 1038, 758, 747; MS (+ ESI, M + H +) m / z 590.

Example 62: yellow solid, m.p. 280-282 ° C; NMR lE (500 MHz, DMSO-de) d 11.64 (broad s, ÍH), 9.83-9.68 (2m, ÍH), 9.08-8.97 (2m, ÍH), 8.45-7.10 (series of m, 8H), 6.37 and 6.25 (2d, J = 8.8, 9.1 Hz, HH), 5.74-5.68 (2m, HH), 5.50-5.21 (2m, 2H), 4.20-4.04 (2m, 4H), 3.71-3.60 (m, 2H); IR (KBr, cm'1) 3369, 2918, 1752, 1712, 1601, 1580, 1558, 1482, 1456, 1413, 1319, 1256, 1197, 1094, 1020, 914, 805, 762; MS (-ESI, M-H ") m / z 632.

Example 63: yellow solid, decomposition point 248 ° C; NMR 'H (500 MHz, DMSO-d6) d 11.65 (s broad H), 9.78-9.73 (2 m, H), 9.07-8.97 (2 m, H), 8.30-7.95 (m series, 3 H), 7.61- 7.42 (2m, 3H), 7.15-7.06 (m, 2H), 6.37 and 6.25 (d, J = 8.8, 9.3 Hz, ÍH), 5.81-5.22 (series of m, 3H), 4.32-4.12 (3m, 3H) ), 3.77, 3.63 (m, 3H); IR (KBr, cm "1) 3401, 2963, 1752, 1707, 1475, 1465, 1424, 1261, 1198, 1092, 1021, 801; LCMS (+ ESI, M + H +) m / z 650.

Example 64 Obtained 15.1 mg (49%), yellow solid, m.p. 254-265 ° C (decomposes); NMR XH (500 MHz, DMSO-d6) d 11.61 (broad s, ÍH), 9.76-9.66 (2m, ÍH), 9.01-8.92 (2m, ÍH), 8.31-7.96 (3m, 2H), 7.78 (s broad , ÍH), 7.58-7.45 (m, 2H), 6.30 and 6.19 (2d, J = 8.9, 9.4 Hz, ÍH), 5.99 (s broad, ÍH), 5.50-5.16 (series of, 3H), 4.12-3.92 (3m, 3H), 3.61-3.39 (, 3H); IR (KBr, c "1) 3392, 2927, 1706, 1661, 1604, 1567, 1532, 1480, 1463, 1384, 1324, 1085, 916, 826, 807, 764, 742; MS (-ESI, MH") m / z 649.

Example 65: yellow solid, m.p. 244-246 ° C; NMR XH (500 MHz, DMSO-dβ) d 11.63 (broad s, ÍH), 9.75-9.67 (2m, ÍH), 9.00-8.94 (2m, ÍH), 8.28-8.20 (2m, ÍH), 8.11-7.97 ( 2m, ÍH), 7.57-7.50 (m, 2H), 6.30 and 6.16 (2d, J = 8.8, 9.3 Hz, ÍH), 5.63-5.19 (series of m, 3H), 4.05-4.02 (m, ÍH), 3.61-3.07 (m, 6H); IR (KBr, cm "1) 3412, 1762, 1703, 1602, 1482, 1464, 1425, 1315, 1259, 1199, 1082, 916, 807, 763, 742; MS (-ESI, MH") m / z 637 .

Example 66: Obtained 4.7 mg (55%), yellow solid, m.p. 252-254 ° C (decomposes); NMR H (500 MHz, DMSO-dβ) d 11.60 (broad s, ÍH), 9.83-9.71 (2m, ÍH), 9.07, 9.01 (2m, ÍH), 8.30-8.07 (3m, 2H), 7.65-7.56 ( 2m, 2H), 6.43-6.30 (2m, 1H), 5.73-5.71 (m, 1H), 5.55-5.20 (2m, 2H), 4.21-4.07 (m, 4H), 3.81-3.52 (2m, 4H); IR (KBr, cm "1) 3384, 2926, 1706, 1622, 1602, 1568, 1482, 1464, 1426, 1384, 1309, 1259, 1230, 1081, 916, 805, 763, 742; LCMS (-ESI, MH ") m / z 653.

Example 67 Obtained 10.5 mg (26%), yellow solid, decomposition point 290 ° C; NMR 1E (500 MHz, DMS0-d6) d 12.34 and 12.23 (2s, ÍH), 11.58 (s, ÍH), 9.75-9.63 (2m, ÍH), 9.01-8.92 (2m, ÍH), 8.23-8.15 (m , ÍH), 8.17-7.96 (m, ÍH), 7.53-7.46 (m, 2H), 7.11-6.85 (series of m, 2H), 6.32 and 6.15 (2d, J = 8.9, 9.3 Hz, ÍH), 5.85 -5.14 (series of m, 3H), 4.11-3.98 (m, 2H), 3.71-3.49 (m, 4H); IR (KBr, cm "1) 3242, 2926, 1751, 1705, 1602, 1481, 1463, 1426, 1325, 1198, 1086, 915, 763, 742; MS (-ESI, M-H") m / z 621.

Example 71 2,3,9, 10-tetrafluoro-12- (4-deoxy-4,4-difluoro-b-D-glucopyranosyl) indole [2, 3-a] pyrrolo [2, 3-c] carbazole-5, 7-dione To a solution of Dess-Martin periodinane (0.470 g, 1.11 mmol) in 30 ml of dichloromethane was added dropwise a solution of 6- (4-tert-butylbenzyl) -2,3,9,10-tetrafluoro-12 - (2,3,6-tri-0-benzyl-bD-glucopyranosyl) indole [2, 3-a] pyrrolo [3,4-c] -carbazole-5,7-dione (0.540 g, 0.55 mmol) in 20 ml of dichloromethane and the mixture was stirred at room temperature under argon atmosphere for 1 hour. Another 0.470 g (1.11 mmol) of the Dess-Martin reagent was added and stirring was continued for 2 hours. The resulting mixture was diluted with dichloromethane, washed (with saturated NaHCO3-Na2S203, saturated NaHC03, and brine), dried over sodium sulfate and evaporated. The residue was subjected to chromatography (Si02 / hexane-ethyl acetate, 2: 1) to give the ketone (0.360 g, 67%) as a dark yellow solid.

To a portion of the ketone (0.067 g, 0.07 mmol) in 2 ml of dichloromethane was added DAST (0.036 ml, 0.28 mmol) and the mixture was stirred at room temperature under argon atmosphere for 18 hours. The mixture was then diluted with saturated sodium hydrogen carbonate solution in dichloromethane and the organic phase was separated, washed with brine, dried over sodium sulfate and evaporated to a gum. Flash chromatography (Si02 / hexane-ethyl acetate, 3: 1) gave 6- (4-tert-butylbenzyl) -2, 3, 9, 10-tetrafluoro-12- (4-deoxy-4, 4-difluoro -2, 3, 6-tri-O-benzyl-bD-glucopyranosyl) -indolo [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione as a yellow solid: 1H NMR (CDC13 , 400 MHz) d 10.21 (s, ÍH), 9.14 (dd, J = 10.6, 8.4 Hz, ÍH), 9.02 (dd, J = 10.7, 8.2 Hz, ÍH), 7.53 (d, J = 8.7 Hz, 2H ), 7.40 (d, J = 8.7 Hz, 2H), 7.34 (m, 5H), 7.20-7.12 (m, 6H), 6.97 (dd, J = 10.0, 6.6 Hz, ÍH), 6.80 (t, J = 7.4 Hz, HH), 6.72 (t, J = 7.6 Hz, 2H), 6.13 (d, J = 7.2 Hz, 2H), 5.82 (d, J = 8.6 Hz, HH), 4.97 (m, 3H), 4.80 (d, J = 11.1 Hz, ÍH), 4.65 and 4.61 (ab q, J = 12.0 Hz, 2H), 4.24-4.01 (m, 6H), 3.37 (d, J = 10.6 Hz, ÍH), 1.28 (s) , 9H). This material was deprotected in the usual manner (i) aqueous sodium hydroxide, tetrahydrofuran-ethanol, concentrated HCl, ii) ammonium acetate (NH4OAc), D, iii, H2, Pd (OH) 2-C, chloroform-methanol) to give the title compound (24% complete yield) as a yellow solid: IR (KBr) 3410, 1747, 1704, 1596, 1478, 1323 cm "1; XH NMR (400 MHz, DMS0-d6) d 11.39 (s, ÍH), 11.34 (s, ÍH), 8.93 (, 2H), 8.03 (dd, J = 11.8, 6.8 Hz, ÍH), 7. 62 (dd, J = 10.7, 6.9 Hz, ÍH), 6.54 (d, J = 9.2 Hz, ÍH), 6.08 (m, 2H), 5.48 (d, J - 5.9 Hz, ÍH), 4.43 (m, ÍH), 4.22 (m, ÍH), 4.06 (, 2H), 3.66 (m, ÍH). MS (ESI) m / e 578 (M-H). HPLC: 91.1% (320 nm).

Example 75: yellow solid: XH NMR at 500 MHz (d6-DMSO) d 11.85 (s, ÍH), 11.18 (s, ÍH), 8.92 (dd, ÍH), 8.81 (dd, ÍH), 8.06 (dd, ÍH) ), 7.78 (dd, ÍH), 7.49-7.39 (m, 2H), 6.28 (d, ÍH, l'H, J = 8.8 Hz), 5.85 (d, ÍH, 3'OH), 5.45 (d, ÍH) , 2'0H), 4.25-3.89 (m, 3H, 2'H, 3'H, 5'H), 3.68 (t, ÍH, 4'H), 1.42 (d, 3H, 6'H); ESI negative mass spectrum, m / e 531 (M-H). "IR (KBr) 2112 cm" 1.

Example 79 Yellow solid: NMR 'H at 500 MHz (d6-DMSO) d 12.72 (s, ÍH), 11.18 (s broad, ÍH), 8.92 (dd, ÍH), 8.80 (dd, ÍH), 8.21 (s broad, 2H ), 8.07 (dd, ÍH), 7.94 (dd, ÍH), 7.48-7.39 (m, 2H), 6.60 (d, ÍH, J = 7.8 Hz, l'H), 5.98 (s broad, ÍH, 3 ' OH), 5.48 (s broad, ÍH, 2'OH), 4.55-4.50 (m, ÍH, 5'H), 4.07-4.02 (m, 2H, 2'H, 3'H), 3.19 (t, ÍH , 4'H), 1.43 (d, 3H, 6'CH3); ESI negative mass spectrum 505 (M-H) ".

Example 87; yellow solid: NMR 'H at 300 MHz (CD3OD) d 8.84 (dd, ÍH), 8.74 (dd, ÍH), 7.77 (dd, ÍH), 7.35-7.24 (m, 2H), 6.14 (d, ÍH, J = 9.2 Hz), 4.23-3.95 (, 4H), 3.90 (t, 1H, J = 9.2 Hz), 3.74 (t, ÍH, J = 9.0 Hz); IR (KBr) 2114 cm "1; ESI negative mass spectrum, m / e 547 (M-H)".

Example 88: yellow solid 500 MHz XH NMR (CD30D) d 8.89 (dd, ÍH), 8.77 (dd, ÍH), 7.81 (dd, ÍH), 7.63 (dd, ÍH), 7.33-7.26 (m, 2H) , 6.15 (d, ÍH, J = 8.9 Hz), 4.24-3.88 (m, 3H), 3.73 (t, ÍH, J = 8.9 Hz), 3.59 (dd, ÍH, J = 9.6, 8.9 Hz), 3.54 ( t, ÍH, J = 9.6 Hz); Negative ESI mass spectrum, m / e 521 (M-H) ".

Example 89: yellow solid: IR (KBr) 3435, 3345, 1740, 1713, 1477, 1320 cm "1; NMR lE (THF-d8, 400 MHz) d 11.50 (s, ÍH), 10.12 (s, ÍH), 9.08 (dd, J = 11.0, 8.6 Hz, ÍH), 8.99 (dd, J = 11.0, 8.4 Hz, ÍH), 7.71 (dd, J - 11.5, 6.6 Hz, ÍH), 7.63 (dd, J = 10.3, 6.7 Hz), 6.11 (d, J = 8.9 Hz, HH), 5.30 (d, J = 4.5 Hz, HH), 5.01 (d, J = 4.1 Hz, HH), 4.62 (d, J = 5.1 Hz, HH ), 4.56 (d, J = 9.7 Hz, ÍH), 4.00 (s, 3H), 3.97-3.91 (, ÍH), 3.78-3.54 (m, 2H).

Example 90 3, 9-difluoro-12, 13-dihydro-13- (2-fluoro-bD-glucopyranosyl) -5 (H) indole [2, 3-a] pyrrolo [3, 4-c] -carbazole-5, 7 -Diona.

Using the Mitsunobu procedure described at the beginning in Example 22, 250 mg (0.465 mmol) of the product of Example 6 and 210 mg (0.464 mmol) of 2-fluoro-3,4,6-tri-O-benzyl were mixed. -D-glucopyranose (prepared by treating commercially available Tri-O-benzyl-D-glucal (1.5 g, 3.6 mmol) with xenon difluoride (1.0 g, 5.91 mmol) in acetonitrile (50 ml) and water (5 ml) ) for 3 hours at room temperature The typical work followed by flash chromatography on silica gel with 5% ethyl acetate in methylene chloride gave 380 mg (23.4%) of the 2-fluoro-3,4,6-tri -O-benzyl-D-glucopyranose This procedure was a modification of a published method: see T. Hayashi, BW Murray, R. Wang, and C.-H. Wong Bioorganic and Medicinal Chemistry, 1997, 5 497-500) . After purification by flash chromatography using 20-60% methylene chloride in hexane, 120 mg (28%) of the reasonably pure glycosylated product was obtained: the removal of the benzyl protecting groups by using the hydrogenation conditions of transfer (95% ethanol / cyclohexene / 20% Pd (OH) 2 / C, reflux for 6-48 hours) followed by removal of the 4-t-bitylbenzyl protecting group under basic hydrolysis conditions (potassium hydroxide 4.45) M, ethanol / reflux, concentrated hydrochloric acid, ammonium acetate / ethanol / heat for 8-48 hours) provided, after purification by flash chromatography on silica gel with acetone: methylene chloride: ethyl acetate, followed by Further purification on Sephadex LH-20 in methanol gave 15 mg (39% for the 2 unblocking steps) of the pure title compound as a yellow-orange solid: NMR: H at 300 MHz (d6-DMSO) d 11.68 ( s broad, ÍH), 11.28 (s broad, ÍH), 8.88 (dd, ÍH), 8.78 (dd, ÍH), 8.10 (dd, ÍH), 7.68 (dd, ÍH), 7.60-7.43 (, 2H), 6.77 (dd, ÍH, J = 8.8, 2.5 Hz), 6.23 (s broad, ÍH), 5.77 (s broad, ÍH), 5.62 (s broad, ÍH), 4.32 (dt, ÍH, J = 50.7, 9.0 Hz) 4.15-3.80 (m, 5H); ESI negative mass spectrum, m / e 524 (M-H) ".

Example 91 3, 9-di f luoro- 12- (ß-D-glucopyranosyl) benzofurane [2, 3-a] pyrrolo [3,4- c] carbazole-5, 7-dione Yellow solid IR (KBr) 1757, 1706 , 1483 cm "1 NMR? E (400 MHz, DMSO-d6) d 11.45 (broad s, HI), 8. 84-8.79 (m, ÍH), 8.53-8.46 (m, ÍH), 8.08-7.81 (m, ÍH), 7.64-7.50 (m, 2H), 6.49 (d, 0.7 H, J = 8.9 Hz), 6. 07 (d, 0.3 H, J = 8.9 Hz), 5.38-5.16 (m, 3H), 4.75-4.21 (m, ÍH), 3.93-3.49 (m, 6H). HPLC: 97.5% (305 nm).

Example 92 3-bromo-9-fluoro-12- (β-D-glucopyranosyl) benzofuran- [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione Yellow solid IR (KBr) 1775, 1708 cm * 1 NMR aH (DMSO-d6, 400 MHz) 6 11.69 and 11.49 (broad 2s, ÍH), 8.97 (d, 0.3H, J = 2.0 Hz), 8.91 (d, 0.7H, J = 2.0 Hz), 8.85-8.79 (m, ÍH), 8.08-7.77 (m, 3H), 7.59-7.49 (, ÍH), 6.47 (d, 0.7H, J = 9.0 Hz), 6.07 (d, 0.3H, J = 9.0 Hz), 5.37-5.21 (m, 3H), 4.79-4.20 (m, ÍH), 3.92 -3.54 (, 6H). HPLC: 92.5% (260 nm).

Example 93 3-cyano-9-fluoro-12- (β-D-glucopyranosyl) benzofuran- [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione 3-Bromo-9-fluoro-12- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) benzofuran [2,3-a] -pyrrolo [3,4-c] carbazole -5,7-dione (189 mg, 0.2 mmol) was combined with zinc cyanide (14 mg, 0.6 mmol) and tetrakis- (triphenylphosphine) palladium (0) (12 mg, 0.01 mmol) in deoxygenated dimethylformamide (2 mL) and the yellow suspension was heated at 80 ° C under nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was chromatographed (hexane: ethyl acetate, 7: 3) to give 3-cyano-9-fluoro-12 (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) ) benzofuran [2, 3-a] pyrrolo [3,4-c] -carbazole-5, 7-dione (160 mg, 90%) as a yellow solid: IR (KBr) 2235 cm "1. To a solution of 3-cyano-9-fluoro-12- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) benzofuran [2, 3-a] pyrrolo [3, 4-c] -carbazole- 5,7-dione (58 mg, 0.06 mmol) in 5 ml of anhydrous methylene chloride was added dropwise boron trichloride (0.39 ml, 1.0 M solution in methylene chloride) at -78 ° C. The resulting solution it was warmed to 0 ° C and stirred for 2 hours and cooled again to -78 ° C before the addition of methanol (5 ml) This resulting mixture was warmed to room temperature The solvent was removed in vacuo and the The remaining residue was taken up in ethyl acetate / tetrahydrofuran and washed with 10% aqueous hydrochloric acid and brine before drying over sodium sulfate. Sodium and concentration of the solvent. Purification of the residue by preparative thin layer chromatography (THF: Hex, 9: 1) afforded the title compound (18 mg, 53%) as a yellow solid: IR (KBr) 3417, 2220, 1757, 1708, 1635, 1478 cm "1: XH NMR (DMSO-d6, 400 MHz) d 9.05 (s, 0.3H), 8.90 (s, 0.7H), 8.70-8.67 (, ÍH), 8.16-7.95 (m, 3H), 7.48 -7.45 (m, ÍH), 6.42 (d, 0.7H), J - 8.3 Hz), 6.11 (d, 0.3H, J = 8.3 Hz), 5.45-5.37 (m, 3H), 4.17-3.50 (7H) HPLC: 91.4% (260 nm).

Example 94 3-iodo-9-fluoro-12- (ß-D-glucopyranosyl) benzofuran- [2, 3-a] pyrrolo [3,4-c] carbazole-5, 7-dione 3-bromo-9-fluoro-12- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl) enzofuran [2, 3-a] -pyrrolo [3,4-c] carbazole -5,7-dione (189 mg, 0.2 mmol) was combined with bis (tributyltin) (0.2 mL, 0.4 mmol) and tetrakis- (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in deoxygenated NMP (2 mL). ) and the yellow suspension was heated at 90 ° C under nitrogen atmosphere for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was chromatographed (hexane: ethyl acetate, 4: 1) to give 3-tributylstannyl-9-fluoro-12- (2, 3, 4, 6-tetra-O-benzyl-β-D- glucopyranosyl) benzofuran [2, 3-a] -pyrrolo [3,4-c] carbazole-5,7-dione (150 mg, 90%) as a yellow solid. To a solution of this yellow oil in 5 ml of methylene chloride was added iodine (33 mg, 0.13 mmol) and the mixture was stirred at room temperature for 0.5 hour). The resulting mixture was treated with saturated NaHS03, washed with water, brine, dried and evaporated. This crude residue (118 mg, 91%) was treated with boron trichloride (0.71 ml, 1.0 M solution in methylene chloride) as previously described to give the title compound as a yellow solid: IR (KBr) 3140, 3040, 1753, 1703, 1405 cm "1: XH NMR (exchange of DMSO-d6 and D20, 400 MHz) d 9.05 (d, 0.3H, J - 1.7 Hz), 8.89 (d, 0.7H, J = 1.7 Hz), 8.67 (dd, 0.3H, J = 9.5, 2.7 Hz), 8.62 (dd, 0.7H, J = 9.5, 2.7 Hz), 7.98-7.64 (m, 3H), 7.47-7.41 (m, ÍH), 6.42 (d, 0.7H, J = 9.0 Hz), 6.00 (d, 0.3H, J = 9.0 Hz), 4.26-3.50 (m, 6H): HPLC: 94.9% (320 nm).

Example 95 6- (4-tert-butylbenzyl) -2,3,9,10-tetrafluoro-12- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) indolo- [2, 3 a] pyrrolo [3, 4-c] carbazole-5, 7-dione To a suspension of 6- (4-tert-butylbenzD-2,3,9, 10-tetrafluoroindolo [2,3-a] -pyrrol [3,4-c] carbazole-5,7-dione (1,131 g, 2.08 mmol) and anhydrous sodium sulfate (5.0 g) in 25 ml of anhydrous tetrahydrofuran was added finely powdered potassium hydroxide (0.932 g, 16.6 mmol).

The resulting mixture was stirred vigorously at room temperature under argon atmosphere for 1.5 hours. To the resulting dark purple mixture was added a solution of 2,3,4,6-tetra-0-benzyl-α-D-glucopyranosyl chloride (1450 g, 2.60 mmol) in 10 ml of anhydrous tetrahydrofuran and the stirring was continued for 24 hours. hours. An additional amount of 0.200 g (0.36 mmol) of chloro sugar was added and the stirring was continued for another 24 hours. The mixture was then diluted with ethyl acetate and quenched with 1N hydrochloric acid. The organic phase was separated, washed with brine, dried over sodium sulfate and evaporated to give a yellow foam. Flash chromatography (pre-adsorbed on silica (SiO2); eluted with hexane-ethyl acetate, 5: 1) gave the product as a bright yellow crystal. This crystal was taken up in dichloromethane and the solution was diluted with methanol. Concentration of this solution on the rotary evaporator, followed by vacuum drying, gave the title compound (1240 g, 54%) as a bright yellow solid: IR (KBr) 3307, 1748, 1694, 1593, 1473, 1072 cm. 1; H-NMR (CDC13, 400 MHz) d 10.58 (s, 1H), 9.18 (dd, J -10.7, 8.2 Hz, 1H), 9.07 (dd, J = 10.8, 8.2 Hz, ÍH), 7.53 (d, J - 8.3 Hz, 2H), 7.41 (m, 6H), 7.28 (m, 8H), 7.22 (, 4H), 6.94 (d, J - 10.1, 6.5 Hz, ÍH), 6.88 (t, J = 7.3 Hz , ÍH), 6.81 (t, J = 7.3 Hz, 2H), 6.16 (d, J = 7.2 Hz, 2H), 5.75 (d, J - 8.4 Hz, ÍH), 5.03 (d, J = 10.8 Hz, ÍH) ), 4.96 (m, 2H), 4.90 (m, 2H), 4.78 (d, J = 10.8 Hz, ÍH), 4.64 (d, J - 12.2 Hz, ÍH), 4. 58 (d, J = 12.2 Hz, ÍH), 4.29 (t, J = 10.4 Hz, ÍH), 4. 07 (d, J = 10.1 Hz, ÍH), 4.00-3.85 (m, 5H), 3.15 (d, J = 9.2 Hz, ÍH), 1.28 (s, 9H). Analysis Calculated for C65H55F4N3O: C, 73.22; H, 5.20; N, 3.94. Found: C, 72.92; H, 5.58; N, 4. 02.

Example 96 2,3,9,10-tetrafluoro-12- (β-D-glucopyranosyl) -indolo [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione IR (KBr) 3432, 3310 , 1743, 1702, 1475, 1331 cm "1; NMR aH (DMSO-dβ, 400 MHz) d 11.86 (s, ÍH), 11.31 (s, ÍH), 8.99 (dd, J = 11.1, 8.5 Hz, ÍH) , 8.92 (dd, J = 11.2, 8.3 Hz, ÍH), 8.18 (dd, J = 11.7, 6.9 Hz, ÍH), 7. 62 (dd, J = 11.0, 7.0 Hz, ÍH), 6.26 (d, J = 9.0 Hz, ÍH), 6.19 (t, J - 4.2 Hz, ÍH), 5.43 (d, J - 4.8 Hz, ÍH), 5.17 (d, J = 5.7 Hz, ÍH), 4.99 (d, J = 5.6 Hz, ÍH), 4.10 (dd, J - 10.7, 4.2 Hz, ÍH), 3.92 (m, 2H), 3.82 (m, ÍH) ), 3.57 (m, ÍH), 3.41 (m, ÍH). HPLC: 97. 1% (320 nm).

Example 97 2, 3, 9, 10-tetraf luoro-12- (6-f luoro-6-deoxy-β-D-glucopyranosyl) indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7 -dione IR (KBr) 3440, 3365, 1750, 1705, 1478 cm "1. XH NMR (DMSO-dβ, 400 MHz) d 12.04 (s, 0.5H), 11.31 (s, 0.5H), 11.27 (s, 0.5H), 10.68 (s, 0.5H), 9.07 (dd, J = 11.3, 8.8 Hz, 0.5H), 8.95 (dd, J = 19.4, 9.2 Hz, ÍH), 8.87 (dd, J = 10.9, 8.9 Hz, 0.5H), 8.17 (dd, J = 11.9, 6.9 Hz, 0.5H), 7.91 (dd, J = 11.5, 7.1 Hz, 0.5H), 7.71 (dd, J - 10.7, 6.9 Hz, 0.5H), 7.50 (dd, J = 9.6, 6.9 Hz, 0.5H), 6.34 (d, J = 8.8 Hz, 0.5H), 6.32 (d, J = 7.9 Hz, 0.5H), 5.98-4.73 (m, 5H), 4.22-3.46 (m , 4H). HPLC: 98.2% (320 nm).

'Example 98 6- (4-tert-butylbenzyl) -2,3,9, 10-tetrafluoro-12- (2,3,6-tri-O-benzyl-β-D-galactopyranosyl) indole [2, 3-a] - pyrrolo [3, 4-c] carbazole-5,7-dione A solution of 6- (4-tert-butylbenzyl) -2,3,9,10-tetrafluoro-12- (2,3,6-tri-0-benzyl-4-0- (4-methoxybenzyl) -β) -D-galactopyranosyl) indole [2, 3-a] -pyrrolo [3,4-c] carbazole-5,7-dione (0.135 g, 0.12 mmol) in 10 ml of 10% trifluoroacetic acid-methylene chloride stirred at room temperature under argon atmosphere for 20 minutes. The resulting mixture was diluted with dichloromethane and then washed (saturated sodium hydrogen carbonate), dried over magnesium sulfate and evaporated. The resulting residue was subjected to chromatography (silica / ethyl acetate-hexane, 1: 2) to give the title compound (0.107 g, 90%) as a yellow solid: NMR, H (DMSO-dβ, 400 MHz) d 12.21 (s, ÍH), 9.00 (dd, J = 11.1, 8.4 Hz, ÍH), 8.90 (dd, J = 11.2, 8.4 Hz, ÍH), 8.11 (dd, J = 12.0, 6.9 Hz, ÍH), 7.61 -7.18 (m, 15H), 6.71 (t, J = 7.4 Hz, ÍH), 6.61 (t, J - 7.7 Hz, 2H), 6.39 (d, J = 9.2 Hz, ÍH), 6.18 (d, J = 7.2 Hz, 2H), 4.89 (s, 2H), 4.87 (d, J = 13.9 Hz, ÍH), 4.71 (d, J = 12.1 Hz, ÍH), 4.58 (s, ÍH), 4.49 (s, 2H) , 4.33 (m, ÍH), 4.20 (m, 2H), 4.00-3.66 (m, 4H), 3.58 (d, J = 11.2 Hz, ÍH), 1.26 (s, 9H).

Example 99 6- (4-tert-butylbenzyl) -2,3,9, 10-tetrafluoro-12- (2,3,6-tri-O-benzyl-4-deoxy-β-D-galactopyranosyl) indolo- [2, 3-a] pyrrolo [3, 4-c] carbazole-5, 7-dione To a solution of 6- (4-tert-butylbenzyl) -2,3,9,10-tetrafluoro-12- (2,3,6-tri-O-benzyl-β-D-galactopyranosyl) indole [2, 3-a] pyrrolo [3, 4-c] carbazole-5,7-dione (0.402 g, 0.41 mmol) in 10 mL of acetonitrile was added DMAP (0.100 g, 0.82 mmol), followed by phenyl chlorothionoformate. (0.085 g, 0.49 mmol) and the mixture was heated to reflux under an argon atmosphere for 19 hours. An additional amount of 0.043 g (0.25 mmol) of phenyl chlorothionoformate and 0.030 g (0.25 mmol) of DMAP was then added, and the mixture was heated to reflux for 19 hours. The cooled mixture was partitioned with ethyl acetate and saturated sodium hydrogen carbonate and the organic phase was washed, dried and evaporated. The residue was subjected to flash chromatography (silica / ethyl acetate-hexane, 1: 3) to give the thionocarbonate (0.320 g, 0.29 mmol, 70%) as a solid. This material was dissolved in 10 ml of toluene, the solution was purged with a stream of argon bubbles for 15 minutes and then AIBN (0.010 g, 0.06 mmol) and tributyltin hydride (0.126 g, 0.43 mmol) were added. The resulting solution was heated to reflux under an argon atmosphere for 18 hours. Another 0.126 g of tributyltin hydride and 0.010 g of AIBN were added and the reflux was continued for 4 hours. The cooled mixture was evaporated and the residue was subjected to chromatography (silica / ethyl acetate-hexane, 1: 2) to give the title compound (0.215 g, 78%) as a yellow solid: IR cm "1; 2 H NMR (CDC13, 400 MHz) d 10.69 (s, ÍH), 9.15 (dd, J = 10.7, 8.4 Hz, ÍH), 9.06 (dd, J = 10.7, 8.3 Hz, ÍH), 7.53-7.24 (m, 15H) , 6.98 (dd, J = 10.1, 6.6 Hz, HH), 6.83 (m, HH), 6.78 (m, 2H), 6.18 (d, J = 7.0 Hz, 2H), 5.68 (d, J - 8.9 Hz, ÍH), 4.95-4.68 (m, 5H), 4.19-3.75 (m, 7H), 3.30 (d, J = 10.5 Hz, ÍH), 2.58 (m, ÍH), 2.35 (m, ÍH), 1.26 (s) , 9H).

Example 100 2,3,9, 10-tetrafluoro-12- (4-deoxy-β-D-glucopyranosyl) indole [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione IR (KBr) 3440, 1745, 1710, 1474 cm "1 NMR I (DMSO-dβ, 400 MHz) d 11.89 (s, ÍH), 11.31 (s, ÍH), 8.99 (dd, J-9.8, 8.9 Hz, ÍH), 8.92 (dd, J = 10.3, 9.0 Hz, HH), 8.14 (dd, J = 11.7, 6.5 Hz, HH), 7.64 (d, J = 10.5, 6.9 Hz, HH), 6.21 (t, J = 4.5 Hz , ÍH), 6.18 (d, J = 9.2 Hz, ÍH), 5.07 (d, J = 5.6 Hz, ÍH), 4.96 (d, J - 5.4 Hz, ÍH), 4.28 (d, J = 12.1 Hz, ÍH) ), 3.90-3.75 (m, 3H), 2.27 (m, HH), 2.01 (, ÍH), HPLC: 96.7% (320 nm).

Example 101 2,3,9,10-tetrafluoro-12- (2,3,4-tri-O-benzyl-β-D-glucopyranosyl) indole [2,3-a] pyrrolo [3,4-c] carbazole -5, 7-dione A solution of 2, 3, 9, 10-tetraf luoro-12- (2,3,4-tri-0-benzyl-6-0- (-me tox ibenzyl) -β-D-glucopyranosyl) indole [2, 3-a] pyrrolo [3,4-c] carbazole-5,7-dione (0.410 g, 0.43 mmol) in 10 ml of 10% trifluoroacetic acid-methylene chloride was stirred at room temperature under an argon atmosphere for 15 minutes. minutes The resulting mixture was diluted with ethyl acetate (50 ml) and then washed (sodium acid carbonate), 2 x 50 ml; H20, 2 x 50 ml; brine, 50 ml) was dried over magnesium sulphate and evaporated. The resulting residue was subjected to chromatography (silica / 2-26% ethyl acetate-hexane) to provide the title compound (0.346 g, 97%) as a yellow solid: IR (CH2C12) 3333, 1753, 1700, 1478 1093 cm "1; NMR aH NMR (DMS0-d6, 400 MHz) d 11.76 (s, ÍH), 11.33 (s, ÍH), 8.99 (dd, J = 10.8, 8.5 Hz, ÍH), 8.93 (dd, J = 10.9, 8.5 Hz, ÍH), 8.14 (dd, J - 11.8, 6.8 Hz, ÍH), 7.66 (dd, J = 10.7, 6.9 Hz, ÍH), 7.40 (m, 5H), 7.26 (m, 5H ), 6.98 (t, J - 7.4 Hz, ÍH), 6.83 (t, J = 7.6 Hz, 2H), 6.55 (d, J = 8.9 Hz, ÍH), 6.44 (m, ÍH), 6.10 (d, J = 7.6 Hz, 2H), 4.96 (d, J = 11.1 Hz, ÍH), 4.92 (d, J = 11.0 Hz, ÍH), 4.82 (m, 2H), 4.23 (t, J = 9.4 Hz, ÍH), 4.20-4.06 (m, 3H), 3.98-3.95 (m, 2H), 3.66 (t, J = 9.0 Hz, ÍH), 2.94 (d, J - 10.6 Hz, ÍH), HPLC: 98.9% (320 nm) Analysis Calculated for C47H35F4N3? 7: C, 68.03; H, 4.25; N, 5.07. Found: C, 68.00; H, 4.72; N, 4.79.

Example 102 2,3,9, 10-tetrafluoro-12- ((2,3,4-tri-O-benzyl-β-D-glucopyranoside) uronate) indolo- [2,3-a] pyrrolo [3, 4-c] ] -carbazole-5, 7-dione To a solution of 2, 3, 9, 10-tetrafluoro-12- (2, 3, -tril-O-benzyl-β-D-glucopyranosyl) indolo- [2, 3-a] pyrrolo [3, 4- c] carbazole-5,7-dione (0.125 g, 0.15 mmol) in 12 ml of anhydrous dimethylformamide was added pyridinium dichromate (PDC) (0.282 g, 0.75 mmol) and the mixture was stirred at room temperature for 4 hours. Then another 0.282 g (0.75 mmol) of PDC was added and the stirring was continued for 16 hours. An additional portion of PDC (0.282 g, 0.75 mmol) was added and this was repeated after 24 hours. A total of 1128 g (3.0 mmol) of PDC was added and the reaction was run for 4 days. The resulting mixture was cooled to 5 ° C, treated with 10 ml of saturated NaHS03 and then diluted with water (25 ml). This mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1, 4 x 25 ml) and the combined extract was washed (2 x 25 ml of saturated NaHS03, and 25 ml of brine), dried over magnesium sulfate and dried. evaporated The resulting residue was subjected to chromatography (silica / 0-20% methanol-methylene chloride) to give the title compound (0.069 g, 55%) as a yellow solid: IR (KBr) 3412, 3260, 1746, 1710 , 1597, 1477, 1320 c "1; XH NMR (DMSO-de, 400 MHz) d 11.21 (s, ÍH), 9.02 (dd, J = 10.8, 8.8 Hz, ÍH), 8.57 (s broad, ÍH), 8.00 (m, HH), 7.85 (m, HH), 7.45 (d, J = 7.0 Hz, 2H), 7.33 (m, 3H), 7.19 (s, 5H), 7.00 (t, J - 7.4 Hz, 1H ), 6.86 (t, J = 7.5 Hz, 2H), 6.38 (d, J - 7.2 Hz, ÍH), 6.07 (d, J = 7.3 Hz, 2H), 4.93 (d, J = 10.8 Hz, ÍH), 4.77 (d, J = 11.2 Hz, ÍH), 4.73 (d, J = 10.8 Hz, ÍH), 4.64 (d, J = 11.2 Hz, HH), 4.29 (d, J = 8.8 Hz, HH), 4.04 ( m, ÍH), 3.89 (m, 2H), 3.35 (m, ÍH), 2.82 (m, ÍH).

Example 103 2,3,9, 10-tetrafluoro-12- [[(β-D-glucopyranoside) uronic acid] indole [2, 3-a] pyrrolo [3,4-c] -carbazole-5,7-dione A mixture of 2, 3, 9, 10-tetrafluoro-12 - [(2, 3, 4-tri-O-benzyl-β-D-glucopyranoside) uronate] indolo was hydrogenated at 20 hours for an hour [2, 3 -a] -pyrrolo [3, 4-c] carbazole-5, 7-dione (0.030 g, 0.035 mmol) and 20% palladium hydroxide on mineral carbon (0.030 g) in a methanol mixture (5 ml) and tetrahydrofuran (5 ml). Another 30 mg of 20% palladium hydroxide was added over mineral coal and the hydrogenation was continued for another 24 hours. The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran-methanol-water (10: 10: 1, 4 x 5 ml) and the filtrate was evaporated to give a solid residue. Flash chromatography (silica / 2-20% methanol-tetrahydrofuran and then 20% methanol-tetrahydrofuran containing 1-4% water) provided the title compound (0.006 g, 30%) as a yellow solid: IR ( KBr) 3425, 3260, 1740, 1707, 1600, 1475, 1322 cm "1; 1N-NMR (DMSO-dβ, 400 MHz) d 13.11 (s broad, ÍH), 10.96 (s broad, ÍH), 9.02-7.51 ( m, 5H), 6.21 (d, J = 8.9 Hz, ÍH), 5.4-4.0 (m, 8H).

Example 104 3-carboxy-9-f luoro-12- (β-D-glucopyranosyl) -benzofurano [2,3-a] pyrrolo [3,4-c] carbazole-5,7-dione 3-Cyano-9-fluoro-12- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl) benzo fu [2, 3-a] -pyrrolo [3, 4- c] carbazole-5,7-dione (380 mg, 0.43 mmol) in ethanol: tetrahydrofuran (10 ml: 5 ml) was added to a 4.0 M sodium hydroxide solution (10 ml). The mixture was refluxed gently for 24 hours. This resulting mixture was cooled to 0 ° C and treated with concentrated hydrochloric acid (15 ml). This solution was stirred at room temperature for 24 hours before it was taken up in ethyl acetate: tetrahydrofuran and washed with water and brine before drying and concentration of the solvent. To this residue was added solid ammonium acetate (5.0 g) and the mixture was melted at 150 ° C for 1 hour before it was cooled, diluted with ethyl acetate: tetrahydrofuran, washed with water, brine, dried on sodium sulfate and concentrated. A portion of this crude product (60 mg) was hydrogenated (Pd / C) as previously described to give the title compound (18 mg, 50%) as a yellow solid; IR (KBr) 3420, 1756, 1710, 1561, 1395 cm "1: NMR" H (exchange of DMS0-d6 and D20, 400 MHz) d 9.26 (s broad, ÍH), 8.83-8.76 (, ÍH), 8.22 (s broad, ÍH), 7.99-7.96 (m, ÍH), 7.83-7.68 (m, ÍH), 7.55-7.45 (m, ÍH), 6.51 (d, 0.6H, J = 8.9 Hz), 5.99 (d , 0.4H, J - 8.9 Hz), 4.31-3.43 (m, 6H): HPLC: 94.0% (320 nm).

Example 105 3, 9-difluoro-6 - [(2-guanidino-ethyl] -12, 13-dihydro-13- (bD-glucopyranosyl) -5 (H) indole [2, 3-a] pyrrolo [3, 4-c] ] -carbazole-5, 7-dione To a magnetically stirred solution of the pure product of Example 10 (3.35 g, 3.25 mmol) in absolute ethanol (600 ml) was added aqueous potassium hydroxide (4.45 M, 60.0 ml, 267 mmol). The resulting dark red solution was heated in an open flask until about half of the ethanol was evaporated (approximately 3 hours). The mixture was cooled under a nitrogen atmosphere and concentrated hydrochloric acid (12 N, 175 ml) was added. The mixture was stirred 15 minutes and then partitioned with water (300 ml) and ethyl acetate (800 ml). The organic layer was washed with water (300 ml), with saturated aqueous sodium hydrogen carbonate solution (300 ml), and with brine (300 ml), dried over sodium sulfate and evaporated in vacuo. The resulting solid anhydride was treated with ethylenediamine (50 ml) and heated to boiling for about 4-5 hours, dissolved in absolute ethanol (175 ml), heated to reflux for about 6 hours, and then concentrated in vacuo. Purification by flash chromatography on silica gel with 2-10% methanol in methylene chloride gave 1.72 g (55%) of the pure 6N- (2-amino) ethyl derivative of the starting compound as a yellow-orange solid: NMR lE at 300 MHz (CDC13) d 10.65 (broad s, ÍH), 9.05 (dd, 1H), 8.94 (dd, ÍH), 7.55 (dd, ÍH), 7.45-7.14 (m, 18H), 7.00 (t , ÍH), 6.87 (t, 2H), 6.14 (d, 2H), 5.95 (d, ÍH), 5.05-4.58 (m, 6H), 4.40-4.34 (m, ÍH), 4.12-3.85 (m, 8H ), 3.22-3.15 (m, 2H), 2.96 (d, ÍH): ESI positive mass spectrum, m / e 927 (M + H) +. To a magnetically stirred solution of the pure product described above (1.72 g, 1.86 mmol) in anhydrous tetrahydrofuran (20 ml) was added N, N-diisopropylethylamine (314 ml), and N, N'-bis (benzyloxycarbonyl) -S-methylisothiourea (800 mg, 2.23 mmol: K. Nowak, L. Kania Rocz, Chem. 1969, 4_3 1953) and the reaction was heated in an oil bath at 70 ° C for 24 hours. The solution was cooled to room temperature, evaporated in vacuo, and purified by flash chromatography on silica gel using 5% ethyl acetate in methylene chloride to give 1.57 g (68%) of the pure guanidine derivative protected with di. -CBz of the initial amide, as a yellow solid: 1 H NMR at 300 MHz, (CDC13) d 11.80 (broad s, ÍH), 10.70 (broad s, ÍH), 9.18 (s broad, ÍH), 9.08 (dd, ÍH), 8.92 (dd, ÍH), 7.62-7.10 (m, 24H), 6.96 (t, ÍH), 6.85 (t, 2H), 6.13 (d, 2H), 5.95 (d, ÍH), 5.20-4.60 (m, 10H), 4.36 (t, ÍH), 4.20-3.85 (m, 10H), 3.02 (d, ÍH). To a solution of the product described above (1.58 g, 1.38 mmol) in methanol / ethyl acetate 3: 1 (120 ml) and IN hydrochloric acid (18 ml) under nitrogen atmosphere was added 20% palladium hydroxide (II) on carbon (722 mg). The mixture was placed on a Parr shaker under a hydrogen pressure of 4.57 kg / cm2 (65 psi) for 3 days, and then filtered through a small pad of Celite. The pad was washed with ethanol (3 x 50 ml) and concentrated in vacuo to give an orange solid. Purification on Sephadex LH-20 with elution with methanol gave 754 mg (91%) of the pure title compound as an orange-red solid: NMR: H at 500 MHz (CD3OD) d 8.83 (dd, 1H, J-9.7, 2.8 Hz), 8.73 (dd, ÍH, j = 8.9, 2.5 Hz), 7.77 (dd, ÍH, J = 9.2, 4.1 Hz), 7.63 (dd, ÍH, J - 8.9, 4.4 Hz), 7.34-7.25 (m , 2H), 6.15 (d, ÍH, J = 8.5 Hz), 4.32-4.17 (m, 2H), 4.11-3.97 (m, 2H), 3.91-3.84 (m, 2H), 3.78-3.66 (m, 2H) ), 3.60-3.53 (, 2H). Mass spectrum FAB, m / e 609 (M + H) *.

Example 106 2, 3, 9, 10-tetrafluoro-12- ((6-deoxy-6,6-difluoro-bD-glucopyranosyl) indole [2, 3-a] pyrrolo [3,4-c] carbazole-5,7- diona (R5, R5. = F, R2-R4 = OH, Xx, Xa-, X2, X2. = F, Q = NH) A solution of 2, 3, 9, 10-tetrafluoro-12- (2, 3, 4-tri-O-benzyl-bD-glucopyranosyl) indole [2,3-a] -pyrrolo [3,4-c] carbazole -5,7-dione (0.166 g, 0.20 mmol) in 5 ml of dichloromethane was added to a cold solution (5 ° C) of the Dess-Martin periodinane (0.106 g, 0.25 mmol) in 5 ml of dichloromethane. The resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction mixture was subsequently diluted with ethyl acetate (25 ml), washed (sodium acid carbonate 1M-30% Na2S203, 2 x 10 ml; sodium carbonate acid sodium, 2 x 10 ml; water, 10 ml; brine, 10 ml), dried over magnesium sulfate and evaporated. The resulting residue was subjected to chromatography (silica / 2-30% ethyl acetate-hexane) to give 2,3,9,10-tetrafluoro-12- ((2,3,4-tri-O-benzyl) bD-glucopyranoside) uronaldehyde) indole [2, 3-a] pyrrolo [3,4-c] carbazole-5,7-dione (0.118 g, 71%) as a pale yellow solid: IR (CH2C12), 3344, 2930 , 1753, 1724, 1597, 1479, 1322 cm "1; XH NMR (CDC13, 400 MHz) d 11.08 (s, 0.3H), 10.68 (s, ÍH), 3.85 (s, 0.3H), 8.97 (m, 0.3H), 8.79 (m, 0.3H), 8.43 (m, ÍH), 7.99 (s broad, 0.7H), 7.83 (m, ÍH), 7.68 (m, 0.3H), 7.53-6.73 (, 14H) , 6.27 (m, 1H), 6.05 (d, J = 7.2 Hz, 2H), 5.80 (d, J = 9.0 Hz, ÍH), 5.61 (s, 2H), 5.09 (d, J = 11.1 Hz, ÍH) , 4.91 (m, 3H), 4.29-3.85 (m, 4H), 3.74 (t, J = 8.8 Hz, ÍH), 2.92 (d, J = 10.3 Hz, ÍH) To a cold solution (5 ° C) of the aldehyde (0.053 g, 0.085 mmol) in 5 ml of dichloromethane under argon atmosphere was added DAST (0.022 ml, 0.17 mmol) dropwise The resulting mixture was stirred at room temperature for 18 hours. The reaction was then diluted with ethyl acetate (20 ml), washed (1 M sodium hydrogen carbonate, 2 x 10 ml; water, 2 x 10 ml; brine, 10 ml), dried over magnesium sulfate and evaporated. The residue was subjected to chromatography (silica / 2-24% ethyl acetate-hexane) to give 2, 3, 9, 10-tetrafluoro-12- (2, 3, -tri-0-benzyl-6-deoxy). 6,6-difluoro-bD-glucopyranosyl) indole [2, 3-a] pyrrolo [3,4-c] carbazole-5,7-dione (0.046 g, 85%) as a pale yellow solid: IR (CH2C12) , 3400, 1757, 1728, 1596, 1478, 1320 cm "1; NMR lE (CDC13, 400 MHz) d 9.98 (s, ÍH), 8.89 (m, 2H), 7.71 (m, ÍH), 7.51-7.26 ( m, 11H), 7.09 (m, ÍH), 7.00 (t, J = 7.4 Hz, ÍH), 6.85 (t, J = 7.5 Hz, 2H), 6.24 (t, J = 53.7 Hz, ÍH), 6.13 ( d, J = 7.2 Hz, 2H), 5.80 (d, J = 9.0 Hz, ÍH), 5.04 (d, J = 11.2 Hz, HH), 4.89 (s, 2H), 4.84 (d, J = 11.2 Hz, ÍH), 4.23 (m, ÍH), 4.3 (m, 2H), 3.95 (d, J = 10.3 Hz, ÍH), 3.81 (m, ÍH), 3.04 (m, ÍH), MS (ESI) m / e 848 (MH) A mixture of tri-O-benzylglucopyranoside (0.035 g, 0.041 mmol) and 20% Pd (OH) 2-C in a mixture of methanol (5 ml) and chloroform (2 ml) was hydrogenated under pressure of 1 atmosphere for 16 hours. The resulting mixture was filtered and the cake of the filtrate was washed with tetrahydrofuran-methanol (1: 1). The filtrate was evaporated and the residue was subjected to chromatography (silica / 2-12% methanol-methylene chloride) to give the title compound (0.019 g, 80%) as a yellow solid: IR (KBr) 3385, 1748, 1713, 1595, 1476, 1326 crn "1; NMR: H (THF-dβ, 400 MHz) d 10.55 (s, ÍH), 10-18 ( s-ÍH), 9.14 (dd, J - 10.6, 8.8 Hz, ÍH), 9.04 (dd, J = 10.6, 8.6 Hz, ÍH), 7.79 (dd, J = 11.5, 6.6 Hz, ÍH), 7.44 (dd , J - 9.8, 7.1 Hz, ÍH), 6.56 (t, J - 53.7 Hz, ÍH), 6.18 (d, J = 7.9 Hz, ÍH), 5.52 (s broad, ÍH), 5-10 (s broad, ÍH), 4.71 (s broad, ÍH), 4.27 (m, ÍH), 3.95 (m, ÍH), 3.69 (, 2H), HPLC: 95.2% (230 nm).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (17)

CLAIMS Having described the invention as antecede, the content of the following is claimed as property:

1. A compound of formula I, or a pharmaceutically acceptable salt thereof characterized in that Ri and Ria are independently hydrogen, a pentose group (A) or a hexose group (B) of the formulas B with the proviso that one of Ri and R? A is hydrogen and the other is not hydrogen; R2, R3, R4. Rs and R2"R R3 'R4' / 5" and 5 'are independently hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 1 to 7 carbon atoms, 0, azido, halogen, NR9R? 0, NHC (0) ) NR9R10, NHC (0) 0R, OR, -C (0) Ra, SR, -0S02Rc, or together form = N-0H, = 0, = NR, with the proviso that R2, R3, R4, R5 and R2-R3., R4., R5", and R5 'are not all simultaneously hydrogen, OH, alkoxy or alkyl, and with the proviso further that R3 or R3 > is not -NH2, except when Rβ is - (CH2) nNHC (= NH) NH2, said alkyl of 1 to 7 carbon atoms is optionally substituted with one to six of the same or different substituents halogen, CN, N02, aryl or heteroaryl, the aryl or heteroaryl substituted with one or two groups independently selected from NR9R10, OH, COORg, Ra is H, OH, alkoxy of 1 to 7 carbon atoms or NRqR10; Rc is alkyl of 1 to 7 carbon atoms or aryl; R and Ru are independently hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 1 to 7 carbon atoms, heteroaryl, ring of 5 to 8 membered cyclic, non-aromatic, containing either one or two heteroatoms selected from oxygen or nitrogen, (CH2) nNR9R10, (CH2) nOR9 or (CH2) nCOOR9, the alkyl of 1 to 7 carbon atoms is optionally substituted with one to six of the same or different halogen, OH, CN, N02, aryl or heteroaryl substituents , the aryl or the heteroaryl are substituted with one or two groups independently selected from NR9R10, OH, COOR9, SO3R9 or OCOR9; Rg and Rio are independently hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 1 to 7 carbon atoms, benzyl, aryl, heteroaryl, any of which groups except hydrogen can be substituted with one to six of the same or different substituents halogen, OH, NH2, CN, N02, -C (= NH) NH2, -CH (-NH), CH (Rb) (CH2) nCOOH or CH (Rb) (CH2) nNH2 O COORn, OR R9 and R10 together with the nitrogen atom to which they join, they form a cyclic 5- to 8-membered non-aromatic ring containing either one or two heteroatoms of oxygen, nitrogen or sulfur, or Rg and Rio together form = CHRRn. Rb is H or COOH; Rβ is hydrogen, alkyl of 1 to 7 carbon atoms, aryl, arylalkyl, OR10, NR9R10, or OCO (CH2) nNR9R? 0, alkyl of 1 to 7 carbon atoms is optionally substituted with one to six thereof or different halogen substituents, NR9R? 0, CN, N02, aryl, the aryl is substituted with one or two groups independently selected from NR9R10, OH, COORg, R7 and R? are independently OH or hydrogen, or taken together is oxygen; Xi, X'i, X2 and X'2 are independently hydrogen, halogen, OH, -CN, -NC, CF3, -CORa, N02, OR, 0 (CH2) nNR9R? Or 0 (CH2) nORg or 0 (CH2 ) nCOOR9, * with the proviso that X2, X'2, Xi and X'i are not 1,11-dichlor; with the additional proviso that when X2 and X'2 are each hydrogen, Xi and X'i are each independently hydrogen or halogen, Rx is hexose, R7 and Re together are oxygen, and each of R2, R5, and R4 are OH, R2. , R3. , R4., And R5. and R5-are each hydrogen, Q is NH, and then each of R3 and R4 are not NH2 and R3 is not methoxy when Re is hydrogen; W is carbon or nitrogen; Q is oxygen, NR9, sulfur or CH2; and n is an integer from 0 to 4.

2. A compound according to claim 1, characterized in that in Ri or R? A all substituents are hydrogen, except R2, R3 and R4 which are each OH; and R5 is NR9R10.

3. A compound according to claim 1, characterized in that in Ri or R? A all substituents are hydrogen, except R2, R3 and R5 are each OH; and R4 is NR9R10.

4. A compound according to claim 1, characterized in that in Ri or Ria all substituents are hydrogen, except R2, R3 and R4 are each OH; and R5 is halogen.

5. A compound according to claim 1, characterized in that R7 and Rβ taken together is oxygen.

6. A compound according to claim 1, characterized in that:? , X'i, X2 and X'2 are independently halogen.

7. A compound according to claim 1, characterized in that the halogen group is fluoro.

8. A compound according to claim 1, characterized in that Q is 0, S or NH.

9. A compound according to claim 1, characterized in that R2, R3, and R5 are each OH; and R4 is NR9R10, halogen or N3.

10. A compound according to claim 1, characterized in that in Ri or R? A all substituents are H except R5, R3 and R4 are each OH; and R2 is halogen.

11. A compound according to claim 1, characterized in that in Ri or R? A all substituents are H except R2, R3 are each OH; R5 is halogen; and R4 is azido, NRgRX0 or OR.

12. A compound according to claim 1, characterized in that in Rx or R? A all substituents are H except R2, R3 are each OH; and R5 is halogen; and R is halogen, H or alkyl.

13. A compound according to claim 1, characterized in that in R: or R? A all substituents are H except R2 and R3 are each hydrogen or hydroxyl; R 4 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R5 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R? 0.

14. A compound according to claim 1, characterized in that in Ri or R? A all substituents are H except R3 and R4 are each hydrogen or hydroxyl; R 2 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and Ri is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R? 0.

15. A compound according to claim 1, characterized in that in Ri or R? A all substituents are H except R3 and R5 are each hydrogen or hydroxyl; and R2 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms; and R is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R? 0.

16. A compound according to claim 1, characterized in that in Ri or R? A all substituents are H except R2 and R are each hydrogen or hydroxyl; R3 is hydrogen, halogen, alkyl of 1 to 7 carbon atoms or azido; and R5 is hydroxyl, azido, alkyl of 1 to 7 carbon atoms, halogen or NR9R10.

17. A pharmaceutical formulation characterized in that it comprises an effective anti-tumor amount of a compound of the formula I, according to any of claims 1 to 16.