Domino knoevenagel-intramolecular cyclization reactions using five-membered aromatic heterocycles with one heteroatom as a diene or dienophile

Abstract

The present invention relates to a novel synthetic procedure utilizing domino Knoevenagel- cyclization reactions, in which the furan, thiophene or pyrrole subunits of the substrates undergo a Diels-Alder cycloaddition as either a diene or a dienophile producing novel condensed tetra- penta- or hexacycles with bridged or spirocyclic dihydrofuran, -thiophene or -pyrrole moiety. The five-membered aromatic heterocyclic subunit reacts intramolecularly as a diene with the double bond in a [4+2] or [4+4] cycloaddition (1,4-addition to five-membered heterocycle) producing bridged scaffolds. The cyclization step can also be an intramolecular hetero Diels- Alder reaction, in which a heterodiene reacts intramolecularly with the π-excessive five- membered heterocycles acting as a dienophile in the 1,2-addition. Some of the novel condensed heterocyclic products have antiproliferative activity and thus both the compounds and their therapeutic application are subject of the invention.

Description

[0001] P142074 – 1423 TEP

[0002] Domino Knoevenagel-intramolecular cyclization reactions using five-membered aromatic heterocycles with one heteroatom as a diene or dienophile THE FIELD OF THE INVENTION

[0003] The present invention relates to a novel synthetic procedure utilizing domino Knoevenagel-cyclization reactions, in which the furan, thiophene or pyrrole subunits of the substrates undergo a Diels-Alder cycloaddition as either a diene or a dienophile producing novel condensed tetrapenta- or hexacycles with bridged or spirocyclic dihydrofuran, -thiophene or -pyrrole moiety. The five-membered aromatic heterocyclic subunit reacts intramolecularly as a diene with the double bond in a [4+2] or [4+4] cycloaddition (1,4-addition to the five-membered heterocycle) producing bridged scaffolds. The cyclization step can also be an intramolecular hetero Diels-Alder reaction, in which a heterodiene reacts intramolecularly with the π-excessive five-membered heterocycles acting as a dienophile in the [4+2] cycloaddition. Some of the novel condensed heterocyclic products have antiproliferative activity and thus both the compounds and their therapeutic application are subject of the invention.

[0004] TECHNICAL BACKGROUND

[0005] Variously substituted furan, thiophene and pyrrole rings are frequent motifs in bioactive natural heterocycles. The preparation of chiral scaffolds containing five-membered, condensed heteroaryl subunits or their partially saturated analogues is a challenging task. In order to avoid lengthy multi-step convergent syntheses, domino sequences can be utilized, in which complex molecules can be assembled from relatively simple starting materials with atom- and stepefficient ways, higher overall yields and lower reaction time. The domino Knoevenagel-intramolecular cycloadditions, using hetero Diels-Alder (HD A) reactions for the cyclization, were found a powerful tool for the preparation of chiral condensed or spirocyclic heterocycles. In our previous work on the domino synthesis of chiral condensed heterocycles (S. B. Király, A. Bényei, E. Lisztes, T. Biró, B. I. Tóth, T. Kurtán, Eur. J. Org. Chem. 2021 6161–6170; S. B. Király, L. Tóth, T. Kovács, A. Bényei, E. Lisztes, I. B. Tóth, T. Biró, A. Kiss-Szikszai, K. E. Kövér, A. Mándi, T. Kurtán, Adv. Synth. Catal. 2023, 365, 3301–3319, M. Kajtár, S. B. Király, A. Bényei, A. Kiss-Szikszai, A. Kónya-Ábrahám, N. Zhang, L. B. Horváth, Sz. Bősze, D. Li, A. Kotschy, A. Paczal, T. Kurtán J. Org. Chem., 2024, 89, 6937-6950, M. Kajtár, S. B. Király, A. Bényei, A. Kiss-Szikszai, A. Kónya-Ábrahám, L. B. Horváth, S. Bősze, A. Kotschy, A. Paczal, T. Kurtán, RSC Adv. 2025, 15, 1230.), diastereoselective domino Knoevenagel-cyclization reactions of substituted 5,6-dihydro-27 / -pyran, 27 / -chromenes and N- arylcinnamylamine derivatives containing an o-formylaryl amine or ether moiety were carried out with active methylene reagents. The cyclization step could occur with different mechanisms such as intramolecular hetero Diels-Alder reaction, stepwise polar [2+2] cycloaddition, a [1,5]-hydride shift-6-endo cyclization, a multi-step nitro hetero Diels- Alder-ring opening-Cadogan-type cyclization sequence or styryl or aza Diels- Alder reactions.

[0006] When we extended our substrates to derivatives containing furan, thiophene or pyrrole subunits instead of the styryl one, surprisingly we found that according to the present invention, the furan, thiophene and pyrrole subunits reacted in an intramolecular HDA reaction as a dienophile with the a, P-unsaturated carbonyl, thiocarbonyl, or pyridyl moieties in the cyclization step. If the active methylene reagents did not contain a reactive carbonyl group, the furan subunit reacted as a diene in a DA reaction resulting in oxygen-bridged heterocycles with three or four contiguous chirality centers. In this case, the DA reaction of the domino sequence produced a bicyle bridged with a heteroatom and condensed with another benzene-condensed heterocycle, representing a novel chiral heterocyclic ring system. With some cyclic active methylene reagent, a formal [4+4] cycloaddition prevailed as the cyclization step of the domino sequence, which also involved a 1,4-addition to the five-membered aromatic heterocyclic subunit and it occurred with ionic step-wise mechanism.

[0007] π-Excessive five-membered heteroarenes with one heteroatom usually act as dienes in Diels-Alder reactions (DA) and there are only a few examples when they react as dienophiles in HDA reactions. The synthetic potential of π-excessive five-membered heteroarenes as dienophile in HDA reactions has not been explored yet in detail and it is underutilized for the construction of condensed spirocyclic heterocycles containing dihydrofuran, -pyrrole and -thiophene moieties. To facilitate these DA or HDA reactions, highly reactive sterically hindered dienes such as ortho-quinone methides or forcing conditions were used in limited number of examples [Zhang, Y.; Wei, Y., Shi, M., Chem. Comm. 2021, 57, (29), 3599-3602; Bagutski, V., de Meijere, A., Adv. Synth. Catal. 2007, 349, (7), 1247-1255; Jones, R. M.; Selenski, C., Pettus, T. R. R., J. Org. Chem. 2002, 67, (20), 6911-6915; Drew, M. G. B.; George, A. V.; Isaacs, N. S., Rzepa, H. S., J. Chem. Soc., Perkin trans. 1, 1985, 1277-1284.]

[0008] According to the state of the art (S. B. Király, A. Bényei, E. Lisztes, T. Biró, B. I. Tóth, T. Kurtán, Eur. J. Org. Chem. 20216161-6170) the six-membered 5,6-dihydro-2 / / -pyran subunit reacts as a dienophile in the domino Knoevenagel -hetero Diels-Alder reaction. This is a partially unsaturated heterocyclic subunit with a single isolated carbon-carbon double bond (two Ti electrons), in which case, based on the examples generally known from the state of the art, it is expected and predictable that it will react as a dienophile in a hetero Diels-Alder reaction. Contrary to these structures when we have aromatic five-membered heterocyclic units (furan, pyrrole, thiophene) in the analogous position, which include a 6 π-electron aromatic system, a person skilled in the art would expect in the light of the state of the art a completely different reactiviy, and would not expect that the five-membered aromatic system will react as a dienophile in the domino reactions.

[0009] The Kiraly et al. publication (S. B. Király, A. Bényei, E. Lisztes, T. Biró, B. I. Tóth, T. Kurtán, Eur. J. Org. Chem. 2021 6161–6170) disclose compounds containing six-membered condensed oxane (tetrahydropyran) ring, while the aim according to the present invention is to prepare spirocyclic compounds, which contain dihydrofuran, dihydrothiophene, or dihydropyrrole units instead of the six-membered condensed oxane ring. These structural differences are highly significant and determining both in terms of the possible method of preparation and the biological activity of the compounds.

[0010] BRIEF DESCRIPTION OF THE INVENTION

[0011] The present invention relates to a process for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged or spiro dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted in an intramolecular cyclization step of a domino Knoevenagel-cyclization sequence.

[0012] In a second aspect, the invention relates to compounds of formula (V)

[0013]

[0014] wherein

[0015] X is O, S or NR6wherein R6is Ts or other electron-withdrawing group;

[0016] Y is NR7or O, wherein R7is alkyl or C(O)-alkyl;

[0017] R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group;

[0018] R11is CN, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group R1is NO2, halogen, alkyl or CF3, and n is an integer selected from 0, 1, 2; In a third aspect the invention relates to compounds of formula (VII)

[0019]

[0020] wherein

[0021] X is O

[0022] Y is O or NR7, wherein R7is alkyl or C(O)-alkyl;

[0023] B is a 5-membered monocyclic carbocycle or a 9-membered bicyclic carbocycle; R1is NO2, halogen, alkyl, CF3; and n is an integer selected from 0, 1, 2.

[0024] In a fourth aspect, the invention relates to compounds of formula (IB)

[0025]

[0026] wherein

[0027] X is O, S or NR6, wherein R6is Ts or other electron-withdrawing group;

[0028] Y is NR7or O, wherein R7is alkyl, preferably methyl;

[0029] Z is O or S;

[0030] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)-N(alkyl)2, -C(O)-H, or another electron- withdrawing group; and

[0031] R3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; or

[0032] R2and R3form together a carbocyclic or heterocyclic ring which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensation

[0033]

[0034] to form a compound of formula (IBA)

[0035]

[0036] wherein A is a 5-6 membered carbocycle or heterocycle or a 9-10-membered bicyclic carbocycle or heterocycle, which can be optionally substituted by one or more substituent independently selected from the following: alkyl, alkoxy, and aryl; and

[0037] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2. In a fifth aspect, the invention relates to the compounds of formula (IC)

[0038]

[0039] wherein

[0040] X is O;

[0041] Y is NR7or O, wherein R7is alkyl, preferably methyl;

[0042] R2is CN, ester, -SO2-aryl, -CONH-aryl, or another electron-withdrawing group, preferably CN;

[0043] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2; In a sixth aspect, the invention relates to the above compounds for therapeutic use, specifically due to their antiproliferative activity for use in the treatment of cancer.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] The production of chiral condensed heterocycles often requires many steps and complex synthetic pathways. These generally require expensive catalysts or the use of protecting groups, which typically also significantly increases the number of synthetic steps and purification procedures.

[0046] The aim of the present invention was to provide an atom- and step-economic process for the preparation of tetra-, penta- or hexacyclic condensed heterocycles to avoid lengthy multistep synthesises, and thus allow the preparation of the target compounds diastereoselectively in an effective way, i.e. in less steps, shorter time and from readily available starting materials and reagents to produce complex heterocycles.

[0047] In a specific embodiment, the invention relates to a process for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with the double bond of the Knoevenagel intermediate in an intramolecular a [4+2] or [4+4] cycloaddition to form the bridged bicyclic scaffold.

[0048] In a more specific embodiment the invention relates to a process for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged dihydrofuran moiety, wherein the furan subunit of the corresponding substrate is reacted with the double bond of the Knoevenagel intermediate in a [4+2] or [4+4] cycloaddition to produce an oxygen-bridged scaffold.

[0049] In an even more specific embodiment the invention relates to a process for the preparation of a compound of formula (V)

[0050]

[0051] wherein

[0052] X is O, S or NR6wherein R6is Ts or other electron-withdrawing group;

[0053] Y is NR7or O, wherein R7is alkyl or C(O)-alkyl;

[0054] R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group;

[0055] R11is CN, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group; R1is NO2, halogen, alkyl or CF3and n is an integer selected from 0, 1, 2;

[0056] by reacting a compound of formula (IIB)

[0057]

[0058] wherein X, Y, R1and n are as defined above, with a compound of formula (VI)

[0059] R11___R10

[0060]

[0061] wherein R10and R11are as defined above.

[0062] Another specific embodiment of the invention is a process for the preparation of a compound of formula (VII)

[0063]

[0064] wherein

[0065] X is O

[0066] Y is O or NR7, wherein R7is alkyl or C(O)-alkyl;

[0067] B is a 5-membered monocyclic carbocycle or a 9-membered bicyclic carbocycle; R1is NO2, halogen, alkyl, CF3; and n is an integer selected from 0, 1, 2; by reacting a compound of formula (IIB)

[0068]

[0069] wherein X, Y, R1and n are as defined above;

[0070] with a compound of formula (VIII),

[0071]

[0072] wherein B is as defined above, in the presence of a Lewis-acid such as InCl3, NiCl2, specifically MgCl2. The reactions are diastereoselective and result in a single diastereomer.

[0073] The reaction can be carried out as follows: In a dry vial the substrate IIb and 1,2 equivalent of the active methylene reagent (VIII) were dissolved in 2 ml dry dichloromethane under nitrogen atmosphere. Then anhydrous MgCl2(1.5 eq) were added to the solution and the reaction was stirred at room temperature for 2 days. For the work-up, 3 ml of water and 1 ml of dichloromethane were added to the reaction mixture, and the organic phase was purified with flash column chromatography (hexane / ethyl acetate 1:1).

[0074] In an other embodiment of the invention, it relates to a process for the preparation of condensed tetra-, penta- or hexacyclic compounds containing a spirocyclic dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted in an intramolecular cyclization step of a domino Knoevenagel-cyclization sequence.

[0075] The targeted spirocyclic compounds contain a 'spirocyclic dihydrofuran, dihydrothiophene, or dihydropyrrole' moiety, which is formed by the ring closure of 'furan, thiophene, or pyrrole' units. In the compounds prepared according to the state of the art (S. B. Király, A. Bényei, E. Lisztes, T. Biró, B. I. Tóth, T. Kurtán, Eur. J. Org. Chem. 2021 6161–6170) such structural elements are not present, and based on the reaction of 5,6-dihydro-27 / -pyran moiety at an analogous position according to the cited prior art, the reaction according to the present invention cannot be expected or predicted as a partially saturated heterocyclic moiety cannot be compared with five-membered aromatic moieties in terms of reactivity.

[0076] Thus, when we extended our substrates to derivatives containing furan, thiophene or pyrrole subunits instead of the styryl one, surprisingly we found that according to the present invention, the furan, thiophene and pyrrole subunits reacted as a dienophile with the a, P-unsaturated carbonyl, thiocarbonyl, or pyridyl moieties in the cyclization step. Domino Knoevenagel-oxa / thia / aza Diels-Alder reactions took place, respectively, affording condensed tetra-, penta-or hexacyclic condensed spiro heterocycles. In these intramolecular HDA reactions, the furan, thiophene and pyrrole rings acted as a dienophile, contributing to the cycloaddition reaction with two π-electrons, which resulted in the loss of aromaticity and formation of dihydro derivatives. By this domino process, novel chiral heterocyclic scaffolds can be assembled from readily available starting materials under mild conditions using a wide range of regular heterodienes. Thus harsh conditions or the use of reactive ortho-quinone methides required for the reported few analogue intermolecular examples can be avoided.

[0077] In a specific embodiment the invention relates to a process for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a spirocyclic dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with a carbonyl, thiocarbonyl or vinyl-N-heterocyclic subunit in an intramolecular hetero-Diels-Alder reaction to form the spirocyclic scaffold.

[0078] In a more specific embodiment, the invention relates to a process wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with an a, P-unsaturated carbonyl subunit in an intramolecular oxa-Diels-Alder reaction.

[0079] In another more specific embodiment, the invention relates to a process wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with an a, P-unsaturated thiocarbonyl subunit in an intramolecular thia-Diels-Alder reaction

[0080] With carbonyl and thiocarbonyl reagents, a domino Knoevenagel-oxa / thia Diels- Alder reaction took place, respectively, affording the condensed tetra- penta- or hexacyclic spiro heterocycles of formula (IB) or (IBA). In these reactions, the furan, thiophene and pyrrole rings acted as dienophiles, taking part in the cycloaddition reactions with two π-electrons, resulting in the loss of aromaticity.

[0081] In another even more specific embodiment, the invention relates to a process wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with a vinyl-N-heterocyclic subunit, such as vinyl-2-pyridyl subunit, in an intramolecular aza-Diels-Alder reaction.

[0082] In an even more specific embodiment, the invention relates to a process for the preparation of a compound of formula (I)

[0083]

[0084] wherein

[0085] a)

[0086] X is O, S or NR6, wherein R6is Ts or another electron-withdrawing group;

[0087] Y is NR7, or O, wherein R7is alkyl, preferably methyl, or -C(O)-alkyl;

[0088] Z is O or S;

[0089] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)-N(alkyl)2, -C(O)-H, or another electron-withdrawing group; and R3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; or

[0090] R2and R3form together a carbocyclic or heterocyclic ring, which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensation

[0091]

[0092] to form a compound of formula (IA)

[0093]

[0094] wherein

[0095] Ais a 5-6 membered carbocycle or heterocycle, or a 9-10 membered bicyclic carbocycle or heterocycle, each of which can be optionally substituted by one or more substituent independently selected from the following: alkyl, alkoxy, and aryl;

[0096] R4and R5are H, or form together with the carbon atoms, to which they are attached an optionally substituted arene moiety;

[0097] with the proviso that when R4and R5mean both H, R2and R3form together with the carbon atoms to which they are linked group (A); or

[0098] b)

[0099] Z is NR9, wherein R9forms together with R3and N an optionally substituted N- heterocycle such as pyridine, and

[0100] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group, and

[0101] X, Y, R4, R5are as defined above,

[0102] wherein the process comprises

[0103] for the preparation of a compound of formula (I) as defined under a) above, reacting a compound of formula (II)

[0104]

[0105] wherein X, Y and R4and R5are as defined above under point a),

[0106] with a compound of formula (III)

[0107]

[0108] wherein Z, R2and R3are as defined above under point a); or

[0109] for the preparation of a compound of formula (I) as defined under point b) above; reacting a compound of formula (II)

[0110]

[0111] wherein X, Y and R4and R5are as defined under point b) above,

[0112] with a compound of formula (IV)

[0113] R2-CH2-Het (IV)

[0114] wherein R2is as defined under point (b) above, and

[0115] Het is an optionally substituted V-heterocycle, such as pyridine.

[0116] In a further more specific embodiment, the invention relates to a process for the preparation of a compound of formula (IB)

[0117]

[0118] wherein X is O, S or NR6, wherein R6is Ts or an electron-withdrawing group;

[0119] Y is NR7or O, wherein R7is alkyl, preferably methyl;

[0120] Z is O or S;

[0121] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)-N(alkyl)2, -C(O)-H, or another electron-withdrawing group; and

[0122] R3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; or

[0123] R2and R3form together a carbocyclic or heterocyclic ring, which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensation

[0124]

[0125] to form a compound of formula (IBA)

[0126]

[0127] wherein

[0128] A is a 5-6 membered carbocycle or heterocycle or a 9-10 membered bicyclic carbocycle or heterocycle, which can be optionally substituted by one or more substituents independently selected from the following alkyl, alkoxy, and aryl; and

[0129] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2; by reacting a compound of formula (II)

[0130]

[0131] wherein X, Y, R1and n and are as defined above;

[0132] with a compound of formula (III)

[0133]

[0134] wherein Z is O or S, and R2and R3are as defined above.

[0135] A specific embodiment of the above processes is wherein X is O.

[0136] A further embodiment of the invention relates to a process for the preparation of a compound of formula (IC)

[0137]

[0138] wherein

[0139] X is O,

[0140] Y is NR7or O, wherein R7is alkyl, preferably methyl;

[0141] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, - C(O)-N(alkyl)2, -C(O)-H, or another electron-withdrawing group, preferably CN;

[0142] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2; by reacting a compound of formula (IIB),

[0143]

[0144] wherein X, Y, R1and n are as defined above,

[0145] with a compound of formula (IV’)

[0146]

[0147] wherein R2is as defined above.

[0148] The above aza-Diels-Alder reaction is novel and unexpected in view of the prior art not only from the side of the aromatic 'furan, thiophene or pyrrole' units but also from the side of 2-vinylpyridine as a diene. Pyridine is an aromatic heterocycle, and it is not obvious for a skilled person that it contributes two π electrons to the dienophile. There is no analogy with the alpha-beta-unsaturated carbonyl unit, as the pyridine is a heteroaromatic system and contains no carbonyl group. The formal double bond is part of a heteroaromatic system and it is not localized. The transformation cannot be predicted from either reacting partner.

[0149] NC^O

[0150] In a specific embodiment the compound of formula (IV’) isN

[0151] The process according to the invention can be carried out under basic catalysis in case of thiophene or pyrrole subunits, i.e. when X is S or NR6.

[0152] In some specific embodiments in the above formulae X and Y are O and the reaction is carried out under acid catalysis.

[0153] The intramolecular hetero Dieal-Alder reactions are diastereoselective and result in a single diastereomer.

[0154] In a second aspect the invention relates to the novel compounds of formula (V)

[0155]

[0156] wherein

[0157] X is O, S or NR6wherein R6is Ts or other electron-withdrawing group;

[0158] Y is NR7or O, wherein R7is alkyl or C(O)-alkyl;

[0159] R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group;

[0160] R11is CN, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group R1is NO2, halogen, alkyl or CF3, and n is an integer selected from 0, 1, 2. Specific embodiments of the above compounds are, wherein

[0161] X is O; and / or

[0162] Y is NR7, wherein R7is C1-4alkyl; and / or

[0163] R10is CN, SO2-Ph, CO-NH2, CO-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl; and / or R11is CN, C(O)-alkyl, C(O)-O-alkyl, and / or

[0164] R1is NO2, F, C1-4alkyl or CF3; and n is an integer selected from 0, 1, 2, preferably n is 1. More specific group of compounds is, wherein

[0165] X is O; and / or

[0166] Y is N-Me; and / or

[0167] R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(Me)2. C(O)-OEt, C(O)OMe, C(O)-Me; and / or

[0168] R11is CN, C(O)-OMe, C(O)-Me;

[0169] R1is NO2and n is 1.

[0170] Specific compounds according to the invention are selected from the following:

[0171]

[0172] In a third aspect the invention relates to the novel compounds of formula (VII)

[0173]

[0174] wherein

[0175] X is O

[0176] Y is O or NR7, wherein R7is alkyl or C(O)-alkyl;

[0177] B is a 5-membered monocyclic carbocycle or a 9-membered bicyclic carbocycle; R1is NO2, halogen, alkyl, CF3; and n is an integer selected from 0, 1, 2.

[0178] Specific group of the above compounds is, wherein

[0179] X is O and / or Y is O or N-ME; and / or

[0180] B is selected from

[0181]

[0182] wherein dashed line indicates the place of condensation; and / or R1is NO2, and n is 0 or 1.

[0183] Specific compounds according to the above embodiment of the invention are selected from

[0184]

[0185] In a fourth aspect the invention relates to the novel compounds of formula (IB), which showed antiproliferative effect on human cell line,

[0186]

[0187] wherein

[0188] X is O, S or NR6, wherein R6is Ts or other electron-withdrawing group;

[0189] Y is NR7or O, wherein R7is alkyl, preferably methyl;

[0190] Z is O or S;

[0191] R2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)-N(alkyl)2, -C(O)-H, or another electron-withdrawing group; and

[0192] R3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; or

[0193] R2and R3form together a carbocyclic or heterocyclic ring which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensation

[0194]

[0195] to form a compound of formula (IBA)

[0196]

[0197] wherein

[0198] A is a 5-6 membered carbocycle or heterocycle or a 9-10 membered bicyclic carbocycle or heterocycle, which can be optionally substituted by one or more substituent independently selected from the following alkyl, alkoxy, and aryl; and

[0199] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2. The claimed compounds are different from the compounds of the state of the art. While in the prior art document Kiraly et al. (S. B. Király, A. Bényei, E. Lisztes, T. Biró, B. I. Tóth, T. Kurtán, Eur. J. Org. Chem. 2021 6161–6170) some of the disclosed spirocyclic compounds have identical structural subunit in the upper part of the structure (see e.g. Fig.1, Table 1 and Table 2), there are major structural differences as compared to the spirocyclic compounds according to the present invention: there is a five-membered heterocycle instead of a six-membered one, the position of the heteroatom is different, and the heterocyclic portion is partially unsaturated - in contrast to the fully saturated heterocycle described in the Kiraly et al. prior art. These differences are decisive in terms of bioactivity and may require a completely different synthetic strategy for the preparation of the compounds according to the present invention as compared to the prior art.

[0200] In a specific embodiment of the invention in the above formula

[0201] Z is O or S; and / or

[0202] X is O, S or NTs; and / or

[0203] Y is NMe or O; and / or

[0204] R1is NO2 or CF3, and n is 0 or 1; and / or

[0205] R2is CN, -COOMe, methyl, NH-Ph-4-Cl, or SO2Ph; and

[0206] R3is amino, -N(Me)2, -N(Ci-4alkyl)2, methyl, phenyl, -OMe, or -OEt; or R2and R3form together with the carbon atoms to which they are linked group A selected from the following, wherein dashed line indicates the place of condensation:

[0207]

[0208] In a more specific embodiment X is O.

[0209] In further specific embodiment Y is O.

[0210] In a very specific embodiment, the compound is selected from the following:

[0211]

[0212]

[0213]

[0214] In a fifth aspect the invention relates to a compound of formula (IC)

[0215]

[0216] wherein

[0217] X is O;

[0218] Y is NR7or O, wherein R7is alkyl, preferably methyl; R2is CN, ester, -SO2-aryl, -CONH-aryl, or another electron-withdrawing group, preferably CN;

[0219] R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2;

[0220] In a further aspect the invention relates to the use of the above compounds in the treatment of cancer.

[0221] The antiproliferative effect of the compounds was investigated against human U87 glioblastoma (brain tumour) cell line.

[0222] Several of the tested compounds showed promising antiproliferative effect on the above mentioned human cancer cell line.

[0223] In the context of the present invention certain terms have the following definitions.

[0224] A domino Knoevenagel-cyclization sequence means the following. In domino reactions, several bond-forming steps take place under the same conditions, with the reacting bonds always being formed in the preceding step. The domino Knoevenagel-cyclization sequence is a tandem reaction, in which the double bond formed in the Knoevenagel condensation is part of the heterodiene and will react with a diene or dienophile subunit of the molecule in an intramolecular cyclization reaction.

[0225] In the domino Knoevenagel -DA sequence the double bond initially formed in the Knoevenagel condensation reacts as a dienophile with the diene subunit of the five-membered aromatic heterocycle in an intramolecular DA reactionas shown on Scheme 1 A, wherein the compound of formula K is the Knoevenagel intermediate.

[0226]

[0227] Scheme 1A

[0228] An example of a domino Knoevenagel-cyclization sequence, in which the double bond formed in the Knoevenagel condensation is part of the heterodiene and will react with the dienophile subunit of the molecule in an intramolecular cyclization reaction is shown on Scheme IB.

[0229]

[0230] Scheme IB

[0231] An a, P-unsaturated carbonyl subunit means a part of a compound wherein there is a double bond in the a, P-positions relating to the carbonyl group of the compound, for example O=C(R3)-C(R2)=CH- in the following compound:

[0232]

[0233] An a, P-unsaturated thiocarbonyl subunit means a part of a compound wherein there is a double bond in the a, P-positions relating to the thiocarbonyl group of the compound, for example S=C(R3)-C(R2)=CH- in the following compound:

[0234]

[0235] In the present case, an intramolecular hetero-Diels-Alder reaction reaction means that the double bond formed in the Knoevenagel condensation is part of the heterodiene and will react with a dienophile in the molecule in an intramolecular hetero-Diels-Alder reaction, i.e. in an oxa-Di els- Alder reaction, according to the present invention the heterodiene is the a, P-unsaturated carbonyl subunit as defined above, and it reacts with the dienophilic furan, thiophene or pyrrole subunit of the compound in an intramolecular reaction; in a thia-Diels-Alder reaction, according to the present invention the heterodiene is the a, P-unsaturated thiocarbonyl subunit as defined above, and it reacts with the dienophilic furan, thiophene or pyrrole subunit of the compound in an intramolecular reaction; in an aza-Diels-Alder reaction, according to the present invention the heterodiene is formed by the nitrogen atom and one carbon atom of the A-heterocycle, such as a pyridine ring and by the double bond formed in the Knoevenagel condensation, and it reacts with the dienophilic furan, thiophene or pyrrole subunit of the compound in an intramolecular reaction.

[0236] An electron-withdrawing group means a substituent, which has the ability to draw electron density toward itself and away from other adjacent atoms. This electron density transfer is often achieved by negative resonance and / or negative inductive effects. Particular electronwithdrawing groups according to the invention are those, which contain a carbonyl group, such as -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)-N(alkyl)2, or -C(O)-H. Further particular electron-withdrawing groups are -CN, -SO2-aryl, wherein aryl is as defined below, or -NO2.

[0237] An alkyl group means, an aliphatic hydrocarbon group, which may be unbranched or branched and having about one to about 15 carbon atoms in the chain. Particular alkyl groups have from 1 to about 6 carbon atoms. More particular alkyl groups have 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, zz-propyl, z-propyl, zz-butyl,.s-butyl, / -butyl, zz-pentyl, 3-pentyl, zz-hexyl, a particular example of alkyl group is methyl.

[0238] An aryl group means a monocyclic or multicyclic aromatic carbocyclic group of about 6 to about 14 carbon atoms such as phenyl or naphthyl. The aryl group is optionally substituted by one or more aryl group substituents selected independently form the followings: halogen, alkyl, NO2, CF3.

[0239] An ester means a COO-alkyl group, wherein alkyl is as defined above.

[0240] An alkoxy means -O-alkyl wherein alkyl is as defined above.

[0241] A 5-6-membered carbocycle means a 5- or 6-membered ring, which is unsaturated or partially saturated, e.g.: cyclopentene, cyclohexene. A specific group is a 5-membered monocyclic carbocycle, which means a cyclopentane ring, which is partially unsaturated, having carbonyl groups and it can be condensed with another ring. A 9-10-membered bicyclic carbocycle means a 9-10-membered carbocyclic ring, which is unsaturated, partially saturated, and one of the cycles can be aromatic. Such as a 9-membered bicyclic carbocycle, which means a condensed bicycle with nine carbons, which is unsaturated, partially saturated, and one of the cycles can be aromatic, for example indane.

[0242] A 9-10-membered bicyclic heterocycle means a heterocyclic ring containing 1, 2. 3 or 4 heteroatoms, which is unsaturated or partially saturated and one of the cycles can be aromatic.

[0243] An arene means a benzene ring that can be optionally substituted by one or more groups such as NO2, halogen, alkyl or CF3

[0244] Halogen means chlorine, fluorine, bromine or iodine.

[0245] Ts means a -toluenesulfonyl group. An optionally substituted A -heterocycle means a 6-membered aromatic heterocycle containing 1 or 2 N atoms, such as pyridine. The A-heterocycle may be optionally substituted by one or more alkyl or halogen.

[0246] EXAMPLES

[0247] Methods and materials

[0248] Chemicals were purchased puriss p.a. from commercial suppliers, and solvents were purified by distillation before use. For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 were used and compounds were visualized by irradiation with UV light or by staining with vanillin stain (15 g vanillin in 250 mL ethanol and 2.5 mL concentrated sulfuric acid) and heating with a heating gun. Column chromatography was performed using silica gel Merck 60 (particle size 0.063-0.200 mm). Melting points were determined on a Kotler hot-stage apparatus and are uncorrected. The NMR spectra were recorded on Bruker Avance DRX 360 MHz (1H: 360 MHz;13C: 90 MHz), Bruker Avance II 400 (1H: 400 MHz.13C: 100 MHz) and Bruker Avance II 500 MHz (1H: 500 MHz.13C: 125 MHz) spectrometers using TMS as internal standard. The Nuclear Overhauser effects were detected with offset-compensated and zeroquantum suppressed ROESY experiments, developed by Batta etal. S. Boros, G. Batta, Magn. Reson. Chem. 2016, 54, 947-952). Chemical shifts were reported as 5 in ppm and H. H coupling constants in Hz. IR spectra were recorded on a JASCO FT / IR-4100 spectrometer and absorption bands are presented as wavenumber in cm-1. Electrospay Quadrupole Time-of-Flight HRMS measurements were performed with a MicroTOF-Q type QqTOF MS instrument equipped with an ESI source from Bruker (Bruker Daltoniks, Bremen, Germany). Preparation of the starting materials

[0249] The starting compounds and reactants used in the processes according to the present invention, i.e. compounds of formulae (II), (IIB), (III), (IV), (VI), and (VIII) are known in the art, are commercially available and / or can be prepared by known methods.

[0250] The corresponding furan, thiophene and pyrrole subunits of formula (II) or (IIB) were prepared starting from furfural, thiophene-2-carbaldehyde and N-tosylpyrrole-2-carbaldehyde as shown on Scheme 2 ( L. Yu, S. Huang, T. Cai, K. Du, C. Wu, H. Dong, R. Shen, J. Org. Chem. 2022, 87, 15114-15119).

[0251]

[0252] i. MeNH2, MeOH, r.t. 1 h. ii. NaBH40 °C 3 h. iii. anhydrous K2CO3and dry toluene 60 °C 3 h. iv. anhydrous K2CO3, water r.t overnight.

[0253] Scheme 2

[0254] General method of the reductive amination:

[0255] In a flame-dried, three-necked round-bottom flask, equipped with a reflux condenser and a CaCh drying tube, arylaldehyde S1a,b, S5c (20 mmol) was dissolved in 20 ml dry MeOH. Methylamine solution (2.05 ml, 20 mmol, 1.0 equivalent, 9.8 M in methanol) was added, and the reaction was stirred for one hour at room temperature. The mixture was then cooled to 0 °C in an ice bath, and sodium tetrahydridoborate (25 mmol, 1.25 equivalent) was added to the reaction mixture in two portions. The mixture was stirred at 0 °C for three hours, filtered through a celite plug, and it was washed with methanol. The methanol was removed in vacuo and the resulting crude oil was dissolved in dichloromethane and extracted three times with water. The organic phase was dried over MgSO4, filtered, washed, and concentrated in vacuo, affording secondary amines S2a-c, which were used without further purification.

[0256] 1-(furan-2-yl)-N-methylmethanamine (S2a) (Y. Yang, L. Huang, K. Jiang, X. Cao, B. Yin, Org. Let. 2022, 24, 3275-3280): S2a was prepared from freshly vacuum distilled furfural according to the general reductive amination method, affording the amine S2a as pale yellow liquid (72 %). Rf = 0.33 [hexane / acetone 3:1 with 1% EtsN, staining with vanillin stain (15 g vanillin in 250 mL ethanol and 2.5 mL concentrated sulfuric acid) and heating with a heating gun]. Spectral data is identical to that reported in literature.

[0257] N-m ethyl- l-(thi ophen-2 -yl)methanamine (S2b) (M. Rajadurai, E. R. Reddy, RSC Adv. 2021, 11, 14862-14870.):

[0258] S2b was prepared from thiophene-2-carbaldehyde according to the general reductive amination method, affording the amine S2b as pale yellow liquid (85 %). Rf= 0.60 (hexane / acetone 3:1 with 1% EtsN, visualized by vanilin). Spectral data is identical to that reported in literature.

[0259] N-methyl-1-(1-tosyl-1H-pyrrol-2-yl)methanamine (S2c):

[0260] S2c was prepared from 1-tosyl-1H-pyrrole-2-carbaldehyde7S2c according to the general reductive amination method, affording the amine S2c as orange oil (89 %). Rf = 0.07 (hexane / ethyl acetate 3:1 with 1% EtsN).

[0261] Preparation of the starting materials of the domino sequences

[0262] 1 Preparation of IIBa:

[0263] 2-[(furan-2-ylmethyl)(methyl)amino]-5-nitrobenzaldehyde (IIBa):

[0264]

[0265] In a three-necked round-bottom flask, equipped with a reflux condenser, 2-fluoro-5-nitrobenzaldehyde S3 (8.5 mmol) was dissolved in 15 ml of dry toluene. To the stirred solution, dry K2CO3 (25 mmol, 2.5 equivalent) was added, and the suspension was warmed up 40 °C and l-(furan-2-yl)-N-methylmethanamine S2a (10.2 mmol 1.2 equivalent) was added to the reaction mixture. The reaction was stirred at 60 °C for three hours and it was monitored with TLC. The mixture was filtered and washed with di chloromethane and the solvents were removed in vacuo. The resulting oil was triturated with chilled (-15 °C) ether. The crystals were filtered and washed with chilled ether and the filtrate was concentrated and purified by column chromatography (hexane / ethyl acetate 20:1) on Brockmann 1 neutral AI2O3. The filtered crystals and the product obtained from chromatography were mixed, affording Ila as yellow powder (54 %), mp 40-41 °C. Rf = 0.28 (hexane / ethyl acetate 3:1). It was stored at -15 °C.

[0266] 1H-NMR (400 MHz, CDCl3) δ 3.05 (s, 3 H, NCH3), 4.53 (s, 2 H, 2-H), 6.29-6.33 (m, 1 H, 3”-H), 6.36 (dd, J= 3.2, 1.8 Hz, 1 H, 4”-H), 7.14 (d, J= 9.3 Hz, 1 H, 3’-H), 7.39 (dd, J= 1.8, 0.8 Hz, 1 H, 5”-H), 8.23 (dd, J= 9.3, 2.8 Hz, 1 H, 4’-H), 8.60 (d, J= 2.8 Hz, 1 H, 6’-H), 10.12 (s, 1 H, CHO).

[0267] 13C-NMR (100 MHz, CDCl3) δ 41.0 (NCH3), 53.7 (C-2), 109.62 (C-3’), 110.5 (C-3”), 117.7 (C-4”), 124.2 (C-H), 128.9 (C-6’), 129.3 (C-4’), 139.6 (C-5’), 143.0 (C-5”), 149.5 (C-2”), 156.7 (C-2’), 188.4 (CHO).

[0268] IR(KBr) v: 3070, 2849,1680, 1598, 1497, 1321, 1265. HRMS: calcd. for C13H13N2O4 [M+H+] 261.0875, found 261.0870.

[0269] 2 Preparation of IIBb:

[0270] 2-[methyl(thi ophen-2 -ylmethyl)amino]-5-nitrobenzaldehy de (IIBb):

[0271]

[0272] In a three-necked round-bottom flask, equipped with a reflux condenser, N-methyl-1-(thiophen-2-yl)methanamine S2b (1 mmol) and 2-fluoro-5-nitrobenzaldehyde S3 (0.9 mmol, 0.9 equivalent) were dissolved in 5 ml water. To the stirred solution, K2CO3 (2.5 mmol, 2.5 equivalent) was added, and the reaction was stirred overnight at room temperature. The mixture was diluted with 10 ml water and extracted with dichloromethane (3x10 ml). The combined organic phase was dried over MgSO4, filtered, washed with dichloromethane and the solvent was removed in vacuo. The resulting oil was purified by column chromatography (hexane / ethyl acetate 10:1), affording IIBb as yellow oil (77 %). Rf= 0.22 (hexane / acetone 5:1). It was stored at -15°C1H-NMR (400 MHz, CDCl3) δ 3.07 (s, 3 H, NCH3), 4.75 (s, 2 H, 2-H), 6.97 (s, 2 H, 3”-H, 4”-H), 7.09 (d, J= 9.1 Hz, 1 H, 3’-H), 7.26 (bs, 1 H, 5”-H), 8.18-8.27 (m, 1 H, 4’-H), 8.60 (s, 1 H, 6’-H), 10.10 (s, 1 H, CHO).

[0273] 13C-NMR (100 MHz, CDCl3) δ 41.1 (NCH3), 55.5 (C-2), 117.6 (C-3’), 124.0 (C-V), 125.5 (C-3”), 126.5 (C-5”), 126.6 (C-4”), 128.6 (C-6’), 129.0 (C-4), 138.3 (C-5’), 139.3 (C-2”), 156.3 (C-2’), 188.0 (CHO).

[0274] IR (KBr) v: 2945, 2867, 1599, 1541, 1432, 1297, 1268. HRMS: calcd. for C13H13N2O3S [M+H+] 277.0646, found 277.0643

[0275] 3 Preparation of IIBc:

[0276] 2-{methyl[(1-tosyl-1H-pyrrol-2-yl)methyl]amino}-5-nitrobenzaldehyde (IIBc):

[0277]

[0278] In a three-necked round-bottom flask, equipped with a reflux condenser, N-methyl-1-(1-tosyl-1H-pyrrol-2-yl)methanamine S2c (10 mmol) and 2-fluoro-5-nitrobenzaldehyde S3 (9 mmol, 0.9 equivalent) were dissolved in 25 ml water. To the stirred solution, K2CO3 (25 mmol, 2.5 equivalent) was added, and the reaction was stirred overnight at room temperature. The mixture was diluted with 50 ml water and extracted with dichloromethane (3x20 ml). The combined organic phase was dried over MgSO4, filtered, washed with dichloromethane and the solvent was removed in vacuo. The resulting oil was triturated with chilled (-15 °C) ether, affording IIBc as yellow powder (69 %), mp 116-117 °C. Rf = 0.28 (hexane / ethyl acetate 3:1).

[0279] 1H-NMR (500 MHz, CDCl3) δ 2.45 (s, 3 H, C-CH3), 3.02 (s, 3 H, N-CH3), 4.66 (s, 2 H, 2-H), 6.14 (dd, J= 3.3, 1.6 Hz, 1 H, 3”-H), 6.27 (t, J= 3.3 Hz, 1 H, 4”-H), 6.76 (d, J= 9.3 Hz, 1 H, 3’-H), 7.31-7.38 (m, 3 H, 5”-H, 2”’-H, 6”’-H), 7.55-7.62 (m, 2 H, 3”’-H, 6”’-H), 8.08 (dd, J= 9.3, 2.8 Hz, 1 H, 4’-H), 8.56 (d, J= 2.8 Hz, 1 H, 6’-H), 9.85 (s, 1 H, CHO).13C-NMR (125 MHz, CDCl3) δ 21.7 (C-CH3), 42.3 (N-CH3), 111.9 (C-2), 114.9 (C-4”), 116.9 (C-3’), 123.3 (C-3”), 124.1 (C-l’), 126.6 (C-5”), 128.7 (C-2”’, C-6’”), 128.7 (C-l”’), 129.4 (C-6’), 129.4 (C-4’), 130.4 (C-3’”, C-5’”), 135.7 (C-2”), 139.0 (C-5”), 145.8 (C-4’”), 156.3 (C-2’), 188.0 (CHO).

[0280] IR (KBr) v: 2968, 2886, 1675, 1594, 1574, 1328, 1263, 1169, 1149. HRMS: C20H19N3O5SNa [M+Na+] 436.0943, found 436.0940.

[0281] 4 Preparation of IIBd:

[0282] 2-(furan-2-ylmethoxy)benzaldehyde (IIBd):

[0283]

[0284] To a flame-dried three-necked round-bottom flask equipped with a reflux condenser 5 g (31 mmol) of freshly prepared 2-(bromomethyl)-furan (S4)8, 20 ml of dry ACN: DMF 9:1, salicylaldehyde (S5) (1.5 equivalent) and dry K2CO3 (3 equivalent) were added. The reaction mixture was refluxed for 2 hours after which it was filtered and washed with ethyl acetate. The solvent was removed in vacuo and the crude product was purified using column chromatography (hexane: ethyl acetate 9:1) affording IIBd as brown oil (47%) Rf = 0.37 (hexane / ethyl acetate 9:1). It was stored at 4 °C.

[0285] 1H-NMR (500 MHz, CDCl3) δ 5.10 (s, 2 H, l’-H), 6.37 (dd, J= 3.2, 1.9 Hz, 1 H, 4”-H), 6.44 (d, J= 3.2 Hz, 1 H, 3”-H), 7.02 (t, J= 7.5 Hz, 1 H, 5-H), 7.10 (d, J= 8.4 Hz, 1 H, 3-H), 7.43 (dd, J= 1.9, 0.8 Hz, 1 H, 5”-H), 7.52 (ddd, J= 8.4, 7.5, 1.8 Hz, 1 H, 4-H), 7.81 (dd, J= 7.5, 1.8 Hz, 1 H, 6-H), 10.44 (s, 1 H, CHO).

[0286] 13C-NMR (125 MHz, CDCl3) δ 63.1 (C-l’), 110.5 (C-3”), 110.6 (C-4”), 113.4 (C-3), 121.3 (C-5), 125.5 (C-l), 128.3 (C-6), 135.8 (C-4), 143.4 (C-5”), 149.4 (C-2”), 160.8 (C-2), 189.0 (CHO).

[0287] IR (KBr) v: 2867, 1681, 1594, 1480, 1461, 1448, 1286, 1233. HRMS: calcd. for C12H10O3Na [M+Na+] 225.0527, found 225.0522. 5 Preparation of IIBe:

[0288] N-(furan-2-ylmethyl)-N-(3-oxopropyl)acetamide (IIBe):

[0289] Amberlyst 15 acetone:water

[0290]

[0291] 1:1

[0292] overnight

[0293]

[0294] 150 mg amide derivative (0.49 mmol) was dissolved in 4 ml water / acetone 1:1 and 200 mg of Amberlyst 15 resin was added to the mixture. The reaction was stirred for overnight than it was filtered with a celite plug and washed with acetone. The volatiles were removed in vacuo and the crude product was purified with column chromatography (hexane / acetone 2:1) affording IIBe as pale yellow oil (66 % for three steps) Rf = 0.26 (hexane / aceton 2: 1).

[0295] 1H NMR (400 MHz, CDCl3) δ 2.16 and 2.20 (s, 3 H, 2”-H), 2.65 - 2.78 (m, 2 H, 2’-H), 3.57 -3.69 (m, 2 H, l’-H), 4.49 (s, 2 H, 1-H), 4.56 (s, 1 H, 1-H), 6.22 - 6.28 (m, 1 H, 2”’-H), 6.31 -6.37 (m, 1 H, 3”’-H), 7.37 - 7.42 (m, 1 H, 4”’-H), 9.70 - 9.82 (m, 1 H, CHO).

[0296] 13C NMR (100 MHz, CDCl3) δ 21.7 (C-2”), 40.3 and 41.5 (C-2’), 42.6 and 42.8 (C-1'), 46.5 (2xC-l), 108.1 and 108.7 (C-2’”), 110.4 and 110.5 (C-3’”), 142.7 (C-4’”), 150.1 (C-T”), 171.0 (C-l”), 199.4 and 200.9 (CHO).

[0297] IR: (KBr) v: 2935, 1719, 1636, 1473, 1420, 1372, 1267, 1209, 1165, 1146, 1071, 1010.

[0298] HRMS: calcd. for C10H14NO3[M+H+] 196.0974, found 196.0979.

[0299] General procedure of domino Knoevenagel cyclization reactions

[0300] Method A-B: In a flame-dried three-necked round-bottom flask, equipped with a reflux condenser and a CaCh drying tube, benzaldehyde derivative IIBa-c (100 mg) and active methylene reagent of formula III (1.2 equivalent) were dissolved in dry 1,2-di chloroethane (5 ml). Triethylamine (1.2 equivalent) was added to the solution, and it was stirred overnight at room temperature (method A) or refluxed for 4 hours (method B). The reaction mixture was concentrated in vacuo, and the crude product was triturated with cold ether or acetone / ether 1:4 and the filtrate was purified by column chromatography.

[0301] Method C and D: In a flame-dried three-necked round-bottom flask, equipped with a reflux condenser and a CaCh drying tube, benzaldehyde derivative IIBa-c (100 mg) and active methylene reagent of formula III (1.2 equivalent) were dissolved in dry ethanol (5 ml). Piperidine (1.2 equivalent) was added to the solution, and it was stirred overnight at room temperature (method C) or refluxed for 4 hours (method D). The precipitate was filtered and washed with cold ethanol. If no precipitate formed, the solution was concentrated in vacuo, and purified by column chromatography.

[0302] Method E: In a flame-dried three-necked round-bottom flask, equipped with a reflux condenser and a CaCl₂ drying tube, benzaldehyde derivative IIBd (100 mg) and active methylene reagent of formula III (1.2 equivalent) were dissolved in dry 1,2-dichloroethane (5 ml). Acetic acid (1.2 equivalent) was added to the solution, and it was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the crude product was triturated with cold ether and the filtrate was purified by column chromatography.

[0303] Method F: In a flame-dried three-necked round-bottom flask equipped with a reflux condenser and a CaCl₂ drying tube, benzaldehyde derivative IIBe (100 mg) and active methylene reagent of formula III (1.2 equivalent) were dissolved in dichloromethane (5 ml). L-proline (1.2 equivalent) was added to the solution, and it was stirred for 3 hours. After the reaction the solution was concentrated in vacuo, and purified by column chromatography.

[0304] Example 1:

[0305] rac-(6aR*,9aS*, 15bA*)-5-methyl-2-nitro-9a, 15b-dihydro-5JT-furo[3',2':2,3]indeno[2',l':5,6]pyrano[3,4-c]quinolin-15(6J7)-one [rac-(6aR*,9a5*,15b7?*)-example 1]

[0306]

[0307] rac-(6aS*,9aR*,15bR*)-Example 1

[0308] The reaction of IIBa with indan- 1,3 -di one was carried out according to method A, and the crude product was triturated with 3 ml of cold acetone. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the product from crystallization and chromatography afforded the compound of Example 1 as yellow powder (60 %), mp 189-190 °C. Rr 0.14 (hexane / acetone 3:1).

[0309] ¹H-NMR (400 MHz, CDCl₃) δ 3.10 (s, 3 H, l’-H), 3.35 (d, J= 13.2 Hz, 1 H, 6-Hb), 3.97 (d, J = 13.2 Hz, 1 H, 6-Ha), 4.22 (s, 1 H, 15b-H), 6.05 (d, J= 5.8 Hz, 1 H, 9-H), 6.47 (d, J= 5.8 Hz, 1 H, 8-H), 6.53-6.64 (m, 2 H, 9a-H, 4-H), 7.17 (d, J = 6.8 Hz, 1 H, 11-H), 7.30-7.35 (m, 1 H, 13-H), 7.35-7.41 (m, 1 H, 12-H), 7.51 (d, J= 6.8 Hz, 1 H, 14-H), 7.68 (bs, 1 H, 1-H), 8.03 (d, J= 9.1 Hz, 1 H, 3-H).

[0310] ¹³C-NMR (100 MHz, CDCl₃) δ 38.9 (C-1'), 43.7 (C-15b), 56.3 (C-6), 88.4 (C-6a), 107.7 (C-9a), 109.3 (C-4), 110.8 (C-15a), 119.2 (C-ll), 121.4 (C-15c), 121.8 (C-14), 124.9 (C-l), 125.0 (C-3), 125.6 (C-9), 130.1 (C-13), 131.6 (C-14a), 133.0 (C-12), 137.9 (C-2) 138.1 (C-8), 140.3 (C-lOb), 149.5 (C-4a), 169.0 (C-lOa), 195.7 (C-15).

[0311] IR (KBr) v: 3093, 2905, 1692, 1603, 1578, 1389,1295, 1264.

[0312] HRMS: calculated, for C22H17N2O5 [M+H+] 388.1059, found. 388.1062.

[0313] Example 2:

[0314] / ac-m ethyl (6a / ? *,95*, 105*, 10a5*)- 10-acetyl-5-methyl-2-nitro-5,9, 10, 1 Oa-tetrahydro-67 / -6a,9-epoxyphenanthridine-10-carboxylate [rac-(6a / ?*,95*,105*,10a5*)-example 2]

[0315]

[0316] rac-(6aR*,9S*,10aS*)-Example 2

[0317] The reaction of IIBa with methyl acetoacetate was carried out according to method B, and the crude product was purified by column chromatography (hexane / acetone 3:1), affording the compound of Example 2 as amorphous yellow powder (23 %). Rr 0.11 (hexane / acetone 3:1).

[0318] 'H-NMR (400 MHz, CDCh) 62.25 (s, 3 H, 2’-C), 3.09 (s, 3 H, 4’-H), 3.41 (s, 3 H, 3’-H), 3.73 (d, J= 13.1 Hz, 1 H, 7-Hb), 3.81 (d, J= 13.1 Hz, 1 H, 7-Ha), 4.01 (s, 1 H, 12b-H), 5.38 (s, 1 H, 3a-H), 6.41 (d, J= 5.7 Hz, 1 H, 4-H), 6.51 (d, J= 5.7 Hz, 1 H, 5-H), 6.63 (d, J= 9.3 Hz, 1 H, 9-H), 7.89 (bs, 1 H, 12-H), 7.93-8.04 (m, 1 H, 10-H). ¹³C-NMR (100 MHz, CDCl₃) δ 28.4 (C-2’), 40.2 (C-4’), 45.0 (C-12b), 51.6 (C-7), 52.7 (C-3’), 75.5 (C-l), 82.0 (C-3a), 86.8 (C-6a), 111.4 (C-9), 119.6 (C-12a), 124.4 (C-10), 127.0 (C-12), 133.9 (C-4), 137.6 (C-ll), 140.0 (C-5), 151.1 (C-8a), 169.5 (C-2), 199.3 (C-l’).

[0319] IR (KBr) v: 2990, 1747, 1712, 1603, 1579, 1474, 1317, 1292. HRMS: calcd. for C18H19N2O6 [M+H+] 359.1243 found 359.1239.

[0320] Example 3:

[0321] Rac-(6aR *,9S*, 1 OS*, 10a5*)- 10-cyano-7V,7V,5-trimethyl-2-nitro-5,9, 10, 1 Oa-tetrahydro-67 / -6a,9-epoxyphenanthridine-10-carboxamide [rac-(6a7?*,95'*,105'*,10a5'*)-example 3]

[0322]

[0323] rac-(6aR*,9S*, 10S*,1 OaS*)-Example 3

[0324] The reaction of IIBa with 2-cyano-7V,7V-dimethylacetamide was carried out according to method B, and the crude product was purified by column chromatography (hexane / acetone 3:1), affording the compound of Example 3 as yellow powder (73 %), mp 124-126 °C. Rr 0.05 (hexane / acetone 3:1).

[0325] 1H-NMR (400 MHz, CDCl3) δ 3.07 (s, 3 H, l’-H), 3.10 (s, 3 H, 3’-H), 3.39 (s, 3 H, 2’-H), 3.72 (d, J= 13.3 Hz, 1 H, 7-Hb), 3.86 (d, J = 13.3 Hz, 1 H, 7-Ha), 4.37 (s, 1 H, 12b-H), 5.54 (bs, 1 H, 3a-H), 6.28 (dd, J = 5.8, 1.5 Hz, 1 H, 4-H), 6.60 (d, J= 5.8 Hz, 1 H, 5-H), 6.70 (d, J = 9.3 Hz, 1 H, 9-H), 7.93 (dd, J= 2.6, 1.0 Hz, 1 H, 12-H), 8.05 (dd, J= 9.3, 2.6 Hz, 1 H, 10-H).

[0326] °C-NMR (100 MHz, CDCh) 638.1 (C-l’), 38.3 (C-2’), 40.0 (C-3’), 48.6 (C-12b), 51.3 (C-7), 84.2 (C-3a), 87.3 (C-6a), 111.6 (C-9), 117.7 (C-CN), 119.5 (C-12a), 119.6 (C-l), 125.0 (C-10), 128.1 (C-12), 131.7 (C-4), 138.3 (C-ll), 140.3 (C-5), 150.3 (C-8a), 162.6 (C-2).

[0327] IR (KBr) v: 2955, 2908, 2233, 1655, 1604, 1579, 1519, 1492, 1318, 1296, 1261, 1209, 1158, 1128, 1084. HRMS: calcd. for C18H19N4O4 [M+H+] 355.1406, found 355.1401.

[0328] Example 4: Rac-(6aR *,95*, 105*, 10a5*)- 10-cy ano-5-methyl-2-nitro-5,9, 10,10a-tetrahydro-67 / -6a,9-epoxyphenanthridine-10-carboxamide [rac-(6a / ?*,95*, 105*, 10a5*)-example 4]

[0329]

[0330] rac-(6aR*,9S*, 10S*,1 OaS*)-Example 4

[0331] The reaction of IIBa with 2-cyanoacetamide was carried out according to method B, and the crude product was triturated with 5 ml of cold ether. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 2:1). Unifying the product from crystallization and chromatography afforded the compound of Example 4 as yellow powder (93 %), mp 148-150 °C. Rr 0.11 (hexane / acetone 2:1).

[0332] 'H-NMR (400 MHz, DMSO-d6) 83.07 (s, 3 H, 3’-H, 3.72-3.80 (m, 2 H, 12b-H, 7-Hb), 3.97 (d, J = 13.7 Hz, 1 H, 7-Ha), 5.67 (bs, 1 H, 3a-H), 6.47 (dd, J = 5.7, 1.4 Hz, 1 H, 4-H), 6.72-6.76 (m, 1 H, 5-H), 6.83 (d, J = 9.4 Hz, 1 H, 9-H), 7.79-7.82 (m, 1 H, 12-H), 7.85 (s, 1 H, 2’-H), 7.97-8.04 (m, 1 H, 10-H), 8.17 (s, 1 H, 2’-H).

[0333] °C-NMR (100 MHz, DMSO-d6) 639.2 (C-3’), 45.6 (C-12b), 50.1 (C-7), 59.5 (C-l), 83.5 (C-3a), 87.0 (C-6a), 111.4 (C-9), 119.4 (C-1'), 119.7 (C-12a), 124.4 (C-10), 127.1 (C-12), 132.6 (C-4), 136.2 (C-ll), 140.8 (C-5), 150.6 (C-4a), 165.1 (C-2).

[0334] IR (KBr) v:3393, 3347, 3187, 2911, 2237, 1701, 1604, 1320, 1267, 1255, 1127, 1093. HRMS: calcd. for C16H15N4O4 [M+H+] 327.1093, found 327.1087.

[0335] Example 5:

[0336] rac-(6a7?*,95*,10a5*)-5-methyl-2-nitro-9,10a-dihydro-5H-6a,9-epoxyphenanthridine- 10,10(6J7)-dicarbonitrile [rac-(6a / ?*,95*,10a5*)-example 5]

[0337]

[0338] rac-(6aR*,9S*,10aS*)-Example 5

[0339] The reaction of IIBa with malonitrile was carried out according to method A, and the crude product was triturated with 3 ml of cold methanol. The precipitate was filtered and washed with 5 ml of cold methanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the product from crystallization and chromatography afforded the compound of Example 5 as orange powder (79 %), mp 155-157 °C. Rr 0.13 (hexane / acetone 3:1).

[0340] ¹H-NMR (500 MHz, DMSO-d₆) δ 3.09 (s, 3 H, l’-H), 3.89 (d, J= 14.1 Hz, 1 H, 6-Hb), 4.03 (d, J= 14.1 Hz, 1 H, 6-Ha), 4.05 (s, 1 H, lOa-H), 5.99 (d, J= 1.8 Hz, 1 H, 9-H), 6.79 (dd, J= 5.6, 1.8 Hz, 1 H, 8-H), 6.89 (d, J= 9.3 Hz, 1 H, 4-H), 6.97 (d, J = 5.6 Hz, 1 H, 7-H), 7.94 (d, J = 2.7 Hz, 1 H, 1-H), 8.07 (dd, J= 9.3, 2.7 Hz, 1 H, 3-H).

[0341] ¹³C-NMR (125 MHz, DMSO-d₆) δ 39.0 (C-1'), 49.3 (C-6), 51.1 (C-lOa), 85.2 (C-9), 87.7 (C-6a), 111.7 (C-4), 114.5 (C-10), 114.9 (C-2’, C-3’), 116.5 (C-lOb), 125.0 (C-3), 127.6 (C-1), 133.0 (C-7), 136.0 (C-2), 141.4 (C-8), 150.3 (C-4a).

[0342] IR (KBr) v: 2918, 2684, 2250, 1604, 1587, 1524, 1495, 1321, 1300, 1125, 1080. HRMS: calcd. for C16H12N4O3 [M+H+] 309.0987, found 309.0983.

[0343] Example 6:

[0344] rac-(6a7?*,95*,10a7?*)-5-methyl-2-nitro-10-(phenylsulfonyl)-6,9,10,10a-tetrahydro-5H-6a,9-epoxyphenanthridine-10-carbonitrile [rac-(6a7?*,95*,10a7?*)-example 6]

[0345] rac-

[0346]

[0347] Example 6

[0348] The reaction of IIBa with (phenylsulfonyl)acetonitrile was carried out according to method A, and the crude product was triturated with 3 ml of cold ether. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the product from crystallization and chromatography afforded the compound of Example 6 as yellow powder (87 %), mp 175-178 °C. Rr 0.20 (hexane / acetone 2:1).

[0349] ¹H-NMR (400 MHz, DMSO-d₆) δ 3.06 (s, 3 H, l’-H), 3.83 (d, J = 13.9 Hz, 1 H, 6-Hb), 3.91 (s, 1 H, lOa-H), 4.03 (d, J= 13.9 Hz, 1 H, 6-Ha), 5.24 (s, 1 H, 9-H), 6.86 (d, J= 7.4 Hz, 3 H, 4-H, 7-H, 8-H), 7.78-7.86 (m, 2 H, 3”-H, 5”-H), 7.94-8.00 (m, 1 H, 4”-H), 8.03 (dd, J= 9.3, 2.1 Hz, 1 H, 3-H), 8.09 (d, J= 7.8 Hz, 2 H, 2”-H, 6”-H), 8.13 (s, 1 H, 1-H).

[0350] ¹³C-NMR (100 MHz, DMSO-d₆) δ 39.2 (C-1'), 46.4 (C-lOa), 50.0 (C-6), 74.9 (C-6a), 84.0 (C-9), 88.7 (C-10), 111.8 (C-4), 116.3 (C-2’), 117.5 (C-lOb), 124.8 (C-3), 128.1 (C-l), 129.8 (C-2”, C-6”), 130.3 (C-3”, C-5”), 132.8 (C-7), 134.8 (C-1'), 136.1 (C-4”), 136.5 (C-2), 139.8 (C-8), 150.8 (C-4a).

[0351] IR(KBr) v: 3097, 3073, 2897, 2240, 1581, 1522, 1493, 1476, 1320, 1158, 1082. HRMS: calcd. for C21H17N3O5S [M+H+] 424.0967, found 424.0964.

[0352] Example 7:

[0353] Ethyl rac-(6a7?*,95*,105*,10a5*)-10-cyano-5-methyl-2-nitro-5,9,10,10a-tetrahydro-6J / -6a,9-epoxyphenanthridine-10-carboxylate \rac-(6aR*,9S*, 105*, 10a5*)-example 7]

[0354]

[0355] rac-(6aR*,9S*,10aS*)-Example 7

[0356] The reaction of IIBa with ethyl cyanoacetate was carried out according to method A, and the crude product was triturated with 5 ml of cold hexane / acetone 2:1. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the product from crystallization and chromatography afforded the compound of Example 7 as orange powder (84 %), mp 124-127 °C. Rr 0.13 (hexane / acetone 3:1).

[0357] ¹H-NMR (400 MHz, CDCl₃) δ 1.41 (t, J= 7.1 Hz, 3 H, 3’-H), 3.10 (s, 3 H, 4’-H), 3.67 (s, 1 H, 12b-H), 3.74 (d, J= 13.5 Hz, 1 H, 7-Hb), 3.87 (d, J= 13.5 Hz, 1 H, 7-Ha), 4.31-4.38 (m, 2 H, 2’-H), 5.44 (d, J= 1.7 Hz, 1 H, 3a-H), 6.47 (dd, J= 5.8, 1.7 Hz, 1 H, 4-H), 6.60 (d, J= 5.8 Hz, 1 H, 5-H), 6.69 (dd, J= 8.5, 1.1 Hz, 1 H, 9-H), 8.00-8.07 (m, 2 H, 12-H, 10-H).

[0358] °C-NMR (100 MHz, CDCh) 6 14.0 (C-3’), 39.9 (C-4’), 47.7 (C-12b), 51.1 (C-7), 58.7 (C-l), 63.9 (C-2’), 84.7 (C-3a), 87.6 (C-6a), 111.7 (C-9), 117.0 (C-1'), 118.4 (C-12a), 125.1 (C-10), 127.9 (C-12), 133.8 (C-4), 138.1 (C-ll), 139.9 (C-5), 150.2 (C-8a), 165.4 (C-2).

[0359] IR (KBr) v: 2971, 2895, 2239, 1736, 1606, 1583, 1520, 1504, 1316, 1294, 1257, 1213, 1095. HRMS: calcd. for C18H17N3O5 [M+H+] 356.1246, found 356.1243.

[0360] Example 8:

[0361] rac-(5A*,7a5*,13bA*)-2,3,8,13b-tetrahydro-5,7a-epoxycyclopenta[2,3]oxocino[5,4-c]chromen-l(5H)-one [rac-(5A*,7a5*,13bA*)-example 8]

[0362] 3 2

[0363] 3a / I

[0364] 5-0 p3c O

[0365] J I 1"H 13

[0366] 78L AJ11

[0367] 0 910

[0368] rac-(5R*,7aS*,13bR*)-Example 8 In a flame-dried, three-necked round bottom flask, equipped with reflux condenser and CaCh drying tube, 100 mg (0.495 mmol) IIBd was dissolved in 5 ml of dry di chloromethane. To the stirred solution 57 mg dry MgCl2(1.2 equivalent) and 60 mg (1.2 mmol) cyclopentane-1,3-dione were added, and the solution was stirred for 48 h at room temperature. The solvent was removed in vacuo. The crude product was purified by column chromatography (hexane / ethyl acetate 3:1), affording the compound of Example 8 as white powder (47 %), mp 174-176 °C. Rr 0.11 (hexane / ethyl acetate 3:1).

[0369] ¹H-NMR (400 MHz, CDCl₃) δ 2.45-2.58 (m, 2 H, 2-H), 2.58-2.72 (m, 2 H, 3-H), 4.20 (d, J = 11.6 Hz, 1 H, 8-Hb), 4.30 (s, 1 H, 13b-H), 4.37 (dd, J= 11.6, 1.0 Hz, 1 H, 8-Ha), 6.02 (dd, J = 5.9, 1.3 Hz, 1 H, 6-H), 6.38 (d, J= 5.9 Hz, 1 H, 7-H), 6.45 (d, J= 1.3 Hz, 1 H, 5-H), 6.81-6.90 (m, 2 H, 12-H, 10-H), 6.97-7.01 (m, 1 H, 13-H), 7.09-7.16 (m, 1 H, 11-H).

[0370] ¹³C-NMR (100 MHz, CDCl₃) δ 28.2 (C-3), 33.4 (C-2), 42.6 (C-13b), 68.7 (C-8), 88.1 (C-7a), 106.9 (C-5), 116.5 (C-10), 119.2 (C-13c), 121.3 (C-12), 121.4 (C-13a), 126.0 (C-6), 128.2 (C-13), 129.0 (C-ll), 137.0 (C-7), 152.70 (C-9a), 179.9 (C-3a), 207.44 (C-l).

[0371] IR (KBr) v: 2924, 2853, 2349, 2318, 1681, 1610, 1486, 1377, 1348, 1254. HRMS: calcd. for C17H15O4 [M+H+] 283.0970, found 283.0967.

[0372] Example 9:

[0373] rac-(6a7?*,9a5*, 14b / ?*)-5-methyl-2-nitro-5,6, 11,12,13,14b-hexahydrofuro[3',2':2,3]chromeno[3,4-c]quinolin-14(9aH)-one \rac-(6aR*,9a5*,14b / ?*)-example 9]

[0374] rac-

[0375]

[0376] 9

[0377] The reaction of IIBa with cyclohexan-1, 3-dione was carried out according to method A, and the crude product was triturated with 3 ml of cold acetone / ether 1:4 mixture. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the products from crystallization and chromatography afforded the compound of Example 9 as yellow powder (87 %). mp 199-202 °C Rr 0.19 (hexane / acetone 3:1).

[0378] ¹H-NMR (400 MHz, CDCl₃) δ 1.91-2.09 (m, 2 H, 12-H), 2.32-2.38 (m, 2 H, 11-H), 2.39-2.51 (m, 1 H, 13-Ha), 2.58-2.68 (m, 1 H, 13-Hb), 3.11 (s, 3 H, l’-H), 3.20 (d, J= 12.0 Hz, 1 H, 6-Hb), 3.65 (d, J= 12.0 Hz, 1 H, 6-Hb), 4.51 (s, 1 H, 14b-H), 5.13-5.25 (m, 2 H, 9a-H, 9-H), 6.54-6.65 (m, 2 H, 8-H, 4-H), 7.68 (bs, 1 H, 1-H), 7.97 (dd, J= 9.1, 2.4 Hz, 1 H, 3-H).

[0379] ¹³C-NMR (100 MHz, CDCl₃) δ 20.8 (C-12), 29.7 (C-ll), 32.5 (C-14b), 36.5 (C-13), 39.6 (C-1’), 55.1 (C-6), 83.6 (C-9a, C-6a), 101.8 (C-9), 110.0 (C-4), 116.1 (C-14a), 123.2 (C-14c), 124.4 (C-3), 125.3 (C-l), 138.6 (C-2), 149.8 (C-4a), 151.2 (C-8), 173.0 (C-lOa), 197.5 (C-14).

[0380] IR (KBr) v: 3112, 2954, 1624, 1602, 1514, 1494, 1382, 1327, 1301, 1228, 1177.

[0381] HRMS: calculated, for C19H19N2O5, [M+H+] 355.1293, found 355.1291.

[0382] Example 10:

[0383] rac-(6a7?*,9a5*,14b7?*)-5,12-dimethyl-2-nitro-9a,14b-dihydro-5J7-furo[3',2':2,3]pyrano[3',4':5,6]pyrano[3,4-c]quinolin-14(6H)-one \rac-(6aR*,9a5*,14b7?*)-example 10]

[0384] rac-

[0385]

[0386] e 10

[0387] The reaction of IIBa with 4-hydroxy-27 / -pyran-2-one was carried out according to method A, and the crude product was triturated with 3 ml of cold ethanol. The precipitate was filtered and washed with 2 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the products from crystallization and chromatography afforded compound of Example 10 as a yellow powder (55 %), decomposes at 188 °C. Rr 0.28 (hexane / acetone 3:1).

[0388] 'H-NMR (400 MHz, CDCh) 62.25 (s, 3 H, 2’-H), 3.13 (s, 3 H, l’-H), 3.22 (d, J= 12.1 Hz, 1 H, 6-Hb), 3.68 (d, J= 12.1 Hz, 1 H, 6-Ha), 4.58 (s, 1 H, 14b-H), 5.22 (d, J= 2.6 Hz, 1 H, 9-H), 5.27 (d,.7= 2.6 Hz, 1 H, 9a-H), 5.76 (s, 1 H, 11-H), 6.59 (d, J= 2.6 Hz, 1 H, 8-H), 6.62 (d, J = 9.2 Hz, 1 H, 4-H), 7.94 (dd, J= 2.5, 1.3 Hz, 1 H, 1-H), 8.02 (dd, J= 9.2, 2.5 Hz, 1 H, 3-H).

[0389] °C-NMR (100 MHz, CDC13) 520.2 (C-2’), 34.5 (C-14b), 39.8 (C-E), 55.1 (C-6), 83.2 (C-6a), 84.2 (C-9a), 101.6 (C-ll), 101.8 (C-9), 102.6 (C-14a), 110.4 (C-4), 122.1 (C-14c), 124.9 (C-3), 125.6 (C-l), 139.0 (C-2), 149.8 (C-4a), 151.6 (C-8), 162.2 (C-12), 165.4 (C-14), 165.9 (C-10a).

[0390] IR (KBr) v: 3097, 2915, 2496, 1705, 1581, 12 1330, 1302, 1264. HRMS: calcd. for C19H17N2O6 [M+H+] 369.1086, found 369.1081.

[0391] Example 11:

[0392] rac-(6a7?*,9a5*, 16b / ?*)-l 1, 12,13-trimethoxy-5-methyl-2-nitro-9a, 16b-dihydro-5H-chromeno[3',4':5,6]furo[3',2':2,3]pyrano[3,4-c]quinolin-16(6H)-one \rac-(6aR*,9a5*,16b / ?*)-example 11]

[0393] rac-

[0394]

[0395] 11

[0396] The reaction of IIBa with 4-hydroxy-5,6,7-trimethoxy-27 / -chromen-2-one was carried out according to method A, and the crude product was purified by column chromatography (hexane / acetone 3:1), affording the compound of Example 11 as yellow powder (44 %), mp 137-140 °C. Rr 0.21 (hexane / acetone 2:1).

[0397] ¹H-NMR (400 MHz, CDCl₃) δ 3.16 (s, 3 H, l’-H), 3.30 (d, J= 12.1 Hz, 1 H, 6-Hb), 3.77 (d, J = 12.1 Hz, 1 H, 6-Ha), 3.82 (s, 3 H, 3’-H), 3.85 (s, 3 H, 2’-H), 3.93 (s, 3 H, 4’-H), 4.72 (s, 1 H, 16b-H), 5.29 (t, J= 2.6 Hz, 1 H, 9-H), 5.53 (d, J= 2.6 Hz, 1 H, 9a-H), 6.56-6.66 (m, 2 H, 8-H, 4-H), 6.72 (s, 1 H, 14-H), 7.82 (dd, J = 2.5, 1.3 Hz, 1 H, 1-H), 7.97 (dd, J = 9.2, 2.5 Hz, 1 H, 3-H). ¹³C-NMR (100 MHz, CDCl₃) δ 35.0 (C-16a), 39.6 (C-U), 54.9 (C-6), 56.4 (C-4’), 61.2 (C-3’), 62.1 (C-2’), 83.4 (C-6a), 84.9 (C-9a), 96.7 (C-14), 101.5 (C-9), 103.7 (C-16a), 104.7 (C-lOb), 110.3 (C-4), 121.9 (C-16c), 124.8 (C-3), 124.9 (C-l), 138.6 (C-2), 140.1 (C-12), 149.9 (C-4a), 150.5 (C-ll), 150.6 (C-14a), 151.9 (C-8), 157.1 (C-13), 162.8 (C-lOa), 163.3 (C-16).

[0398] IR (KBr) v: 3083, 2940, 1708, 1636, 1613, 1398, 1301, 1050. HRMS: cacld for. C25H23N2O9 [M+H+], 495.1403, found 495.1400.

[0399] Example 12:

[0400] rac-(6a / ?*,9a5*, 12 / ?*, 14b / ?*)- and rac-(6a / ?*,9a5*, 125*, 14bA*)-5-methyl-2-nitro-12-phenyl-5,6,ll,12,13,14b-hexahydrofuro[3',2':2,3]chromeno[3,4-c]quinolin-14(9aH)-one \rac-(6a / ?*,9a5'*,12 / ?*,14b / ?*)-example 12 and rac-(6a / ?*,9aS'*,125'*,14b / ?*)-epi-example 12]

[0401] rac-(6aR*,9aS

[0402]

[0403] The reaction of IIBa with 4-phenylcyclohexan-l, 3-dione was carried out according to method A, and the crude product was triturated with 3ml of cold acetone:ether 1:2. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the products from crystallization and chromatography afforded the mixture of rac- 6aR*,9a5*,121?*,14b / ?*)-example 12 and rac-(6al?*,9a5*,125'*,14bl?*)- ep / -example 12 as yellow powder (68 %). Rr 0.23 (hexane / acetone 3:1).

[0404] ¹H-NMR (400 MHz, CDCl₃) δ 2.54-2.64 and 2.64-2.71 (m, 2 H, 11-H), 2.71-2.78 and 2.82-2.93 (m, 2 H, 13-H), 3.10 and 3.12 (s, 3 H, 1”-H), 3.15-3.23 (m, 2 H, 6-Hb), 3.27-3.39 (m, 1 H, 12-H), 3.46-3.56 (m, 1 H, 12-H), 3.61-3.72 (m, 2 H, 6-Ha), 4.57 (s, 1 H, 14b-H), 5.20 (bs, 2 H, 9-H, 9a-H), 5.24 (bs, 1 H, 9-H), 6.61 (d, J= 9.4 Hz, 4 H, 4-H, 8-H), 7.18-7.39 (m, 9 H, Ph-H), 7.61 (bs, 1 H, 1-H), 7.79 (bs, 1 H, 1-H), 7.98 (d, J= 9.2 Hz, 1 H, 3-H), 8.02 (d, J= 9.2 Hz, 1 H, 3-H).

[0405] ¹³C-NMR (100 MHz, CDCl₃) δ 32.8 (C-14b), 36.4 and 37.5 (C-ll), 38.0 and 38.2 (C-12), 39.7 (C-l”), 43.2 and 43.7 (C-13), 55.2 (C-6), 83.3 and 83.8 (C-6a), 83.8 and 84.0 (C-9), 101.8 and 102.2 (C-9a), 110.1 and 110.2 (C-4), 116.0 (C-14a), 123.0 and 123.3 (C-14c), 124.5 and 124.6 (C-3), 125.5 and 125.7 (C-l), 126.9 (C-2’, C-6’), 127.1 and 127.2 (C-4’), 128.9 (C-3’, C-5’), 138.9 and 139.0 (C-2), 142.3 and 142.5 (C-l’), 149.8 and 149.9 (C-4a), 151.3 and 151.4 (C-8), 171.6 and 172.2 (C-lOa), 196.6 and 196.7 (C-14).

[0406] IR (KBr) v: 2954, 2898, 1625, 1602, 1581, 1331, 1297, 1229. HRMS: calcd. for C25H23N2O5 [M+H+] 431.1606, found 431.1602.

[0407] Example 13:

[0408] rac-(3a5*,6a7?*, 12bA*)-8-methyl-l l-nitro-2-phenyl-3a,7,8, 12b-tetrahydrofuro[3', 2':2,3]pyrano[3,4-c]quinoline-l -carbonitrile \rac-(3aS*,6aR*,12b / ?*)-example 13]

[0409] rac-

[0410]

[0411] 13

[0412] The reaction of IIBa with benzoylacetonitrile was carried out according to method A, and the crude product was triturated with 5 ml of cold ether. The precipitate was filtered and washed with 5 ml of cold ether. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the products from crystallization and chromatography afforded the compound of Example 13 as yellow powder (80 %), mp 105-108 °C. Rr 0.13 (hexane / acetone 3:1).

[0413] ¹H-NMR (400 MHz, CDCl₃) δ 3.14 (s, 3 H, 1”-H), 3.34 (d, J= 12.3 Hz, 1 H, 7-Hb), 3.68 (d, J = 12.3 Hz, 1 H, 7-Ha), 4.06 (s, 1H), 5.34 (s, 2 H, 3a-H, 4-H), 6.64 (d, J = 9.2 Hz, 1 H, 9-H), 6.68 (s, 1 H, 5-H), 7.35-7.51 (m, 3 H, 3’-H, 5’-H, 4’-H), 7.80 (d, J= 7.6 Hz, 2 H, 2’-H, 6’-H), 8.06 (d, J= 9.2 Hz, 1 H, 10-H), 8.23-8.27 (m, 1 H, 12-H).

[0414] ¹³C-NMR (100 MHz, CDCl₃) δ 39.7 (C-l”), 41.0 (C-12b), 54.8 (C-7), 84.83 (C-6a), 86.1 (C-3a), 89.4 (C-l), 100.9 (C-4), 110.5 (C-9), 120.0 (C-CN), 120.8 (C-12a), 124.9 (C-12), 125.4 (C-10), 128.4 (C-3’, C-5’), 128.7 (C-2’, C-6’), 131.8 (C-4’), 132.4 (C-l’), 138.7 (C-ll), 149.8 (C-8a), 152.1 (C-5), 167.1 (C-2).

[0415] IR (KBr) v: 2952, 2913, 2854, 2206, 1620, 1601, 1580, 1517, 1493, 1331, 1296, 1255. HRMS: calcd. for C22H18N3O4 [M+H+] 388.1297 found 388.1294.

[0416] Example 14:

[0417] rac-(3a7?*,9bf?*,15a5*)-5-methyl-8-nitro-4,5,9b,15a-tetrahydrobenzo[f]furo[2,3-j]pyrido[l,2-b][2,7]naphthyridine-10-carbonitrile [rac-(3a7?*,9b / ?*,15a5'*)-example 14]

[0418]

[0419] rac-(3aR*,9bR*,15aS*)-Example 14

[0420] The reaction of IIBa with 2-pyridylacetonitrile was carried out according to method B, stirring for six days. The crude product was purified by column chromatography (hexane / acetone 2:1) affording the compound of Example 14 as brown powder, mp 145-148 °C. (44 %). Rr 0.05 (hexane / acetone 2:1).

[0421] 'H-NMR (400 MHz, DMSO-d6) 63.09 (s, 3 H, l’-H), 3.45 (d, J= 12.7 Hz, 1 H, 4-Ha), 3.60 (d, J = 12.7 Hz, 1 H, 4-Hb), 3.93 (s, 1 H, 9b-H), 4.90 (s, 1 H, 14b-H), 5.39 (t, J= 2.5 Hz, 1 H, 1-H), 5.89-5.98 (m, 1 H, 13-H), 6.71-6.82 (m, 3 H, 2-H, 6-H, 11-H), 6.84-6.94 (m, 1 H, 12-H), 7.27 (d, J= 6.9 Hz, 1 H, 14-H), 7.96 (dd, J= 9.2, 2.7 Hz, 1 H, 7-H), 8.10 (dd, J= 2.7, 1.0 Hz, 1 H, 9-H).

[0422] ¹³C-NMR (100 MHz, DMSO-d6) 6 37.3 (C-9b), 38.9 (C-l’), 54.2 (C-4), 64.0 (C-10), 66.2 (C- 14b), 82.2 (C-3a), 103.6 (C-l), 107.1 (C-13), 110.2 (C-6), 119.9 (C-ll), 122.2 (C-9a), 123.6 (C-2’), 124.2 (C-9), 124.7 (C-7), 133.3 (C-12), 136.5 (C-8), 137.5 (C-14), 149.1 (C-2), 149.5 (C-lOa), 150.1 (C-5a). IR(KBr) v: 2993, 2923, 2163, 1637, 1603, 1579, 1550, 1524, 1492, 1301, 1160. HRMS: calcd. for C20H17N4O3 [M+H+] 361.1300, found 361.1297.

[0423] Example 15:

[0424] rac-(3a5*,6a7?*,12b5*)-2-amino-8-methyl-ll-nitro-3a,7,8,12b-tetrahydrofuro[3', 2':2,3]thiopyrano[3,4-c]quinoline-l -carbonitrile \rac-(3aS*,6aR*,12b5*)-example 15]

[0425]

[0426] rac-(3aS*,6aR*,12bS*)-Example 15

[0427] The reaction of IIBa with 2-cyanothioacetamide was carried out according to method C, and the product precipitated during the reaction. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 2:1). Unifying the products from crystallization and chromatography afforded the compound of Example 15 as yellow powder (72 %), mp 222-225 °C. Rr 0.24 (hexane / acetone 2:1).

[0428] 'H-NMR (400 MHz, DMSO-d6) 83.09 (s, 3 H, 3’-H), 3.54 (d, J= 13.2 Hz, 1 H, 7-Hb), 3.72 (d, J= 13.2 Hz, 1 H, 7-Ha), 3.87 (s, 1 H, 12b-H), 4.38 (s, 1 H, 3a-H), 5.00-5.09 (m, 1 H, 4-H), 6.57 (s, 1 H, 5-H), 6.75 (d, J= 9.3 Hz, 1 H, 9-H), 6.91 (s, 2 H, 2’-H), 7.96-8.04 (m, 1 H, 12-H), 8.15 (s, 1 H, 10-H).

[0429] ¹³C-NMR (100 MHz, DMSO-d6) δ 39.1 (C-3’), 43.1 (C-12b), 55.8 (C-7), 56.5 (C-3a), 70.8 (C- 1), 86.0 (C-6a), 103.0 (C-4), 109.9 (C-9), 118.7 (C-12a), 118.8 (C-l’), 124.1 (C-12), 125.3 (C- 10), 135.3 (C-ll), 147.5 (C-5), 150.3 (C-8a), 162.0 (C-2).

[0430] IR (KBr) v: 3451, 3300, 3205, 2923, 2188, 1628, 1606, 1578, 1558, 1524, 1491, 1294, 1265, 1251, 1156. HRMS: calcd. for C16H15N4O3S [M+H+] 343.0864, found 343.0860. Example 16:

[0431] rac-(6aR*,9aS*, 14b / ?*)-5-methyl-2-nitro-5,6, 11, 12, 13, 14b-hexahydrothieno[3',2':2,3]chromeno[3,4-c]quinolin-14(9aH)-one [rac-(6a7?*,9a5*,14b / ?*)-example 16]

[0432] rac-

[0433]

[0434] le 16

[0435] The reaction of IIBb with cyclohexan-1, 3-dione was carried out according to method C, and the product precipitated during the reaction. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 3:1). Unifying the products from crystallization and chromatography afforded the compound of Example 16 as yellow powder (62 %), mp 215-217 °C. Rr 0.25 (hexane / acetone 3:1).

[0436] ¹H-NMR (400 MHz, DMSO-d6) δ 1.71-1.81 (m, H, ll-Ha), 1.90-2.01 (m, 2 H, ll-Hb), 2.29-2.55 (m, 4 H, 13-H, 12-H), 3.08 (s, 3 H, l’-H), 3.41 (d, J = 12.9 Hz, 1 H, 6-Hb), 4.09 (d, J = 12.9 Hz, 1 H, 6-Ha), 4.51 (s, 1 H, 14b-H), 5.17 (d, J= 3.0 Hz, 1 H, 9a-H), 5.78 (dd, J= 5.9, 3.0 Hz, 1 H, 9-H), 6.75 (d, J= 9.2 Hz, 1 H, 4-H), 6.89 (d, J= 5.9 Hz, 1 H, 8-H), 7.58 (s, 1 H, 1-H), 7.93 (dd, J= 9.2, 2.4 Hz, 1 H, 3-H).

[0437] ¹³C-NMR (100 MHz, DMSO-d6) δ 20.0 (C-ll), 28.8 (C-12), 30.7 (C-14b), 36.1 (C-13), 38.8 (C-U), 56.9 (C-6a), 83.9 (C-9a), 110.5 (C-4), 113.8 (C-14a), 120.89 (C-9), 122.9 (C-14c), 124.1 (C-3), 124.7 (C-l), 135.0 (C-8), 136.5 (C-2), 149.7 (C-4a), 174.8 (C-lOa), 196.7 (C-14).

[0438] IR (KBr) v: 3067, 2952, 2924, 2883, 2861, 1644, 1618, 1600, 1579, 1517, 1495, 1330, 1289, 1246, 1169. HRMS: calcd. for C19H19N2O4S [M+H+] 371.1065, found 371.1065

[0439] Example 17:

[0440] rac-(3a5*,6a7?*,12b5*)-2-amino-8-methyl-ll-nitro-3a,7,8,12b-tetrahydrothieno[3',2':2,3]thiopyrano[3,4-c]quinoline-l-carbonitrile [rac-(3a5*,6a7?*,12b5*)-example 17]

[0441] rac-

[0442]

[0443] le 17

[0444] The reaction of IIBb with 2-cyanothioacetamide was carried out according to method C, and the product precipitated during the reaction. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 5:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 17 as orange powder (55 %), mp 167- 169 °C. Rr 0.24 (hexane / acetone 2:1).

[0445] ¹H-NMR (500 MHz, DMSO-d6) δ 3.12 (s, 3 H, 3’-H), 3.71 (d, J= 12.7 Hz, 1 H, 7-Hb), 3.99 (d, J = 12.7 Hz, 1 H, 7 -Ha), 4.11 (s, 1 H, 12b-H), 4.57-4.64 (m, 1 H, 3a-H), 5.46 (dd, J= 6.1, 2.8 Hz, 1 H, 4-H), 6.41 (d,.7= 6.1 Hz, 1 H, 5-H), 6.77 (dd, J= 9.5, 2.1 Hz, 1 H, 9-H), 7.15 (s, 2 H, 2’-H), 8.00 (dd, J= 9.5, 2.8 Hz, 1 H, 10-H), 8.12 (dd, J= 2.8, 2.1 Hz, 1 H, 12-H).

[0446] ¹³C-NMR (125 MHz, DMSO-d6) δ 39.7 (C-3’), 45.9 (C-12b), 60.3 (C-7), 61.1 (C-3a), 64.7 (C-6a), 73.9 (C-l), 110.4 (C-9), 118.8 (C-1'), 119.1 (C-12a), 124.2 (C-4), 124.6 (C-10), 125.1 (C- 12), 127.6 (C-5), 135.6 (C-ll), 150.2 (C-8a), 162.8 (C-2).

[0447] IR (KBr) v: 3412, 3308, 3191, 3078, 2896, 2178, 1602, 1574, 1542, 1518, 1487, 1471 1284, 1268, 1234, 1173, 1136. HRMS: calcd. for C23H22N5O4S2 [M+H+] 496.1113, found 496.1109.

[0448] Example 18:

[0449] rac-(6aR*,9aS*, 14b7?*)-5-methyl-2-nitro-7-tosyl-7,9a, 11, 12, 13, 14b-hexahydro-5H-pyrrolo[3',2':2,3]chromeno[3,4-c]quinolin-14(6H)-one [rac-(6a7?*,9a5*,14b7?*)-example 18]

[0450] rac

[0451]

[0452] 18

[0453] The reaction of IIBc with cyclohexan-1, 3-dione was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / acetone 2:1). Unifying the products from crystallization and chromatography afforded the compound of Example 18 as yellow powder (83 %), mp 220-223 °C. Rr 0.24 (hexane / acetone 2:1).

[0454] ¹H-NMR (400 MHz, CDCl₃) δ 1.65-1.86 (m, 3 H, 12-H, 13-Hb), 2.12-2.23 (m, 2H, 11-H), 2.26-2.36 (m, 1 H, 13-Ha), 2.43 (s, 3 H, 2’-H), 3.08 (s, 3 H, l’-H), 3.18 (d, J= 12.2 Hz, 1 H, 6-Hb), 4.31 (d, J= 12.2 Hz, 1 H, 6-Ha), 5.10 (s, 1 H, 14b-H), 5.13 (d, J= 3.0 Hz, 1 H, 9a-H), 5.29 (ddd, J= 4.1, 3.0, 0.8 Hz, 1 H, 9-H), 6.58 (d, J= 9.2 Hz, 1 H, 4-H), 6.85 (d, J= 4.1 Hz, 1 H, 8-H), 7.29 (d, J= 8.3 Hz, 2 H, 3’-H, 5’-H), 7.61 (d, J = 8.3 Hz, 2 H, 2’-H, 6’-H), 7.70 (dd, J = 2.6, 1.3 Hz, 1 H, 1-H), 7.96 (dd, J= 9.2, 2.6 Hz, 1 H, 3-H).

[0455] ¹³C-NMR (100 MHz, CDCl₃) δ 20.3 (C-12), 21.6 (C-2’), 29.3 (C-ll), 29.4 (C-14b), 36.1 (C-13), 39.5 (C-1'), 55.0 (C-6), 68.5 (C-6a), 83.7 (C-9a), 105.5 (C-9), 110.1 (C-4), 114.7 (C-14a), 123.2 (C-14c), 124.3 (C-3), 125.8 (C-l), 127.2 (C-2’, C-6’), 130.0 (C-3’, C-6’), 135.8 (C-8), 137.2 (C-1'), 138.7 (C-2), 144.0 (C-4’), 149.3 (C-4a), 172.1 (C-lOa), 196.4 (C-14).

[0456] IR(KBr) v: 2889, 1624, 1604, 1580, 1494, 1329, 1304, 1275, 1260, 1162, 1129. HRMS: calcd. for C26H26N3O6S [M+H+] 508.1542, found 508.1539.

[0457] Example 19:

[0458] rac-(6a7?*,9a5'*,14b / ?*)-5,12-dimethyl-2-nitro-7-tosyl-5,6,9a,14b-tetrahydropyrano[3',4':5,6]pyrrolo[3',2':2,3]pyrano[3,4-c]quinolin-14(7H)-one \rac-(6a7?*,9a5*,14b / ?*)-example 19]

[0459]

[0460] rac-(6aR*,9aS*,14bR*)-Example 19

[0461] The reaction of IIBc with 4-hydroxy-2J / -pyran-2-one was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 5:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 19 as yellow powder (77 %), mp decomposes at 225 °C. Rr 0.45 (hexane / chloroform / acetone 5:5:1).

[0462] 'H-NMR (400 MHz, DMSO-d6) 82.12 (s, 3 H, 2”-H), 2.40 (s, 3 H, 3”-H), 3.07 (s, 3 H, 1”-H), 3.29 (d, J= 12.5 Hz, 1 H, 6-Hb), 4.04 (d, J= 12.5 Hz, 1 H, 6-Ha), 5.04 (s, 1 H, 14b-H), 5.30 (d, J= 2.9 Hz, 1 H, 9a-H), 5.44-5.50 (m, 1 H, 9-H), 5.96 (s, 1 H, 11-H), 6.80 (d, J= 9.4 Hz, 1 H, 4-H), 7.14 (d, J= 4.3 Hz, 1 H, 8-H), 7.35 (d, J= 8.3 Hz, 2 H, 2’-H, 6’-H), 7.62 (d, J= 8.3 Hz, 2 H, 3’-H, 5’-H), 7.75 (dd, J= 2.6, 1.3 Hz, 1 H, 1-H), 7.96 (dd, J= 9.4, 2.6 Hz, 1 H, 3-H).

[0463] ¹³C-NMR (100 MHz, DMSO-d6) δ 19.2 (C-2”), 21.1 (C-3”), 30.7 (C-14b), 38.9 (C-l”), 53.7 (C-6), 67.5 (C-6a), 83.9 (C-9a), 100.3 (C-ll), 100.8 (C-14a), 106.4 (C-9), 111.0 (C-4), 121.3 (C-14c), 124.0 (C-l), 124.5 (C-3), 126.3 (C-3’, C-5’), 129.8 (C-2’, C-6’), 136.0 (C-8), 136.7 (C-4’), 136.9 (C-2), 143.9 (C-l’), 149.6 (C-4a), 162.5 (C-12), 163.7 (C-14), 164.7 (C-lOa).

[0464] IR (KBr) v: 3111, 2925, 1703, 1650, 1604, 1579, 1523, 1497, 1301, 1267, 1160, 1134.

[0465] HRMS: calcd. for C26H24N3O7S [M+H+] 522.1334, found 522.1330.

[0466] Example 20:

[0467] rac-(6a7?*,9a5'*,13b / ?*)-5-methyl-2-nitro-7-tosyl-5,6,9a,ll,12,13b-hexahydrocyclopenta[5,6]pyrrolo[3',2':2,3]pyrano[3,4-c]quinolin-13(7H)-one \rac-(6a7?*,9a5'*,13b / ?*)-example 20]

[0468]

[0469] le 20

[0470] The reaction of IIBc with cyclopentan-1, 3-dione was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 5:5:1). Unifying the product from crystallization and chromatography afforded the compound of Example 20 as yellow powder (41 %), mp decomposes at 210 °C. Rr 0.24 (hexane / chloroform / acetone 5:5:1).

[0471] ¹H-NMR (500 MHz, DMSO-d6) δ 1.74-1.82 (m, 1 H, 12-Hb), 2.14-2.22 (m, 2 H, 11-H), 2.35-2.39 (m, 1 H, 12-Ha), 2.41 (s, 3 H, 2”-H), 3.05 (s, 3 H, 1”-H), 3.31 (d, J= 12.5 Hz, 1 H, 6-Hb), 3.80 (d, J = 12.5 Hz, 1 H, 6-Ha), 4.84 (s, 1 H, 13b-H), 5.25 (d, J = 3.1 Hz, 1 H, 9a-H), 5.61-5.66 (m, 1 H, 9-H), 6.80 (d, J= 9.3 Hz, 1 H, 4-H), 7.17 (d, J= 4.4 Hz, 1 H, 8-H), 7.38 (d, J = 8.3 Hz, 2 H, 3’-H, 5’-H), 7.59 (d, J= 8.3 Hz, 2 H, 2’-H, 6’-H), 7.95 (dd, J= 9.2, 2.6 Hz, 1 H, 3-H), 8.17 (dd, J= 2.6, 1.0 Hz, 1 H, 1-H).

[0472] ¹³C-NMR (125 MHz, DMSO-d6) δ 21.0 (C-2’), 26.2 (C-ll), 28.9 (C-13b), 32.4 (C-12), 38.8 (C-1'), 54.1 (C-6), 65.8 (C-6a), 84.9 (C-9a), 106.4 (C-9), 111.3 (C-4), 114.1 (C-13c), 122.7 (C-13a), 124.0 (C-3), 125.3 (C-l), 126.2 (C-2’, C-6’), 130.1 (C-3’, C-5’), 135.3 (C-8), 136.8 (C-1’), 137.4 (C-2), 143.8 (C-4’), 149.1 (C-4a), 182.2 (C-lOa), 201.9 (C-13a).

[0473] IR(KBr) v: 2922, 2851, 1686, 1627, 1602, 1496, 1300, 1273, 1159, 1130, 1084. HRMS: calcd. for C25H24N3O6S [M+H+] 494.1385, found 494.1381.

[0474] Example 21:

[0475] rac-(6a7?*,9a5'*,16b / ?*)-ll,12,13-trimethoxy-5-methyl-2-nitro-7-tosyl-5,6,9a,16b-tetrahydrochromeno[3',4':5,6]pyrrolo[3',2':2,3]pyrano[3,4-c]quinolin-16(7H)-one \rac-(6a7?*,9a5'*,13b / ?*)-example 21]

[0476]

[0477] rac-(6aR*,9aS*,13bf?*)-Example 21

[0478] The reaction of IIBc with 4-hydroxy-5,6,7-trimethoxy-2 / / -chromen-2-one was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol affording the compound of Example 21 as yellow powder (69 %), mp 231-233 °C. Rr 0.15 (hexane / chloroform / acetone 5:5:1).

[0479] ¹H-NMR (500 MHz, DMSO-d6) δ 2.37 (s, 3 H, 2”-H), 3.11 (s, 3 H, 1”-H), 3.69 (s, 3 H, 5”-H), 3.70 (s, 3 H, 4”-H), 3.90 (s, 3 H, 3”-H), 4.14 (d, J= 12.4 Hz, 1 H, 6Ha-H), 5.22 (s, 1 H, 16b-H), 5.50 - 5.52 (m, 1 H, 9a-H), 5.52 - 5.55 (m, 1 H, 9-H), 6.83 (d, J= 9.4 Hz, 1 H, 4-H), 6.92 (s, 1 H, 14-H), 7.11 (d, J= 4.2 Hz, 1 H, 8-H), 7.29 (d, J= 8.0 Hz, 2 H, 3’-H and 5’-H), 7.61 -7.69 (m, 2 H, 2’-H, 6’-H), 7.97 (dd, J= 9.3, 2.7 Hz, 1 H, 3-H).

[0480] ¹³C NMR (125 MHz, DMSO-d6) δ 21.0 (C-2”), 31.8 (C-16b), 38.9 (C-l”), 53.5 (C-6), 56.6 (C-3”), 60.7 (C-5”), 62.0 (C-4”), 67.8 (C-6a), 84.9 (C-9a), 96.9 (C-14), 102.5 (C-16a), 103.1 (C-10b), 106.6 (C-9), 111.0 (C-4), 121.3 (C-16c), 123.8 (C-l), 124.5 (C-3), 126.4 (C-2’ and C-6’), 129.8 (C-3’, and C-5’), 136.3 (C-8), 136.7 (C-12a), 136.9 (C-2), 139.6 (C-13), 144.1 (C-4’), 149.8 (C-4a), 149.9 (C-12), 157.0 (C-ll), 161.8 (C-lOa), 161.9 (C-16).

[0481] IR: (KBr) v: 2990, 2940, 1697, 1603, 1495, 1451, 1332, 1307, 1291, 1275, 1260, 1157, 1136, 1096, 1036, 997. HRMS: calcd. for C32H29N3O10S [M+Na+] 670.1471, found 670.1475.

[0482] Example 22:

[0483] rac-(3a5'*,6a7?*,12b7?*)-8-methyl-ll-nitro-2-phenyl-6-tosyl-6,7,8,12b-tetrahydro-3aH-pyrrolo[3',2':2,3]pyrano[3,4-c]quinoline-l-carbonitrile [rac-(3a5*,6a7?*,12b7?*)-example 22]

[0484]

[0485] rac-(3aS*,6aR*,12bR*)-Example 22

[0486] The reaction of IIBc with benzoylacetonitrile was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 10:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 22 as yellow powder (85 %), mp 205-207 °C. Rr 0.18 (hexane / chloroform / acetone 10:5:1).

[0487] 'H-NMR (500 MHz, DMSO-d6) 82.40 (s, 3 H, 3”’-H), 3.04 (s, 3 H, 2”’-H), 3.18 (d, J = 12.2 Hz, 1 H, 7-Hb), 4.13 (d, J= 12.2 Hz, 1 H, 7-Ha), 4.82 (s, 1 H, 12b-H), 5.53 (d, J= 2.4 Hz, 1 H, 3a-H), 5.57-5.66 (m, 1 H, 4-H), 6.83 (d, J= 9.3 Hz, 1 H, 9-H), 7.21 (d, J= 4.3 Hz, 1 H, 5-H), 7.45 (d, J= 8.1 Hz, 2 H, 3”-H, 5”-H), 7.48-7.57 (m, 3 H, 3’-H, 4’-H, 5’-H), 7.66 (d, = 7.0 Hz, 2 H, 2’-H, 6’-H), 7.88 (d, J= 8.1 Hz, 2 H, 2”-H, 6”-H), 8.01 (dd, J= 9.3, 2.3 Hz, 1 H, 10-H), 8.06 (bs, 1 H, 12-H).

[0488] °C-NMR (90 MHz, DMSO-d6) 621.1 (C-3’”), 38.4 (C-12b), 39.1 (C-2’”), 52.7 (C-7), 69.5 (C-6a), 87.2 (C-3a), 89.5 (C-l), 106.4 (C-4), 111.0 (C-9), 119.6 (C-l”’), 121.6 (C-12a), 122.9 (C-12), 124.7 (C-10), 126.8 (C-2”, C-6”), 127.9 (C-3’, C-5’), 128.8 (C-2’, C-6’), 130.3 (C-3”, C-5”), 131.8 (C-l’), 131.8 (C-4’), 136.8 (C-5), 136.8 (C-l”), 136.9 (C-3), 144.6 (C-4”), 150.2 (C-8a), 166.6 (C-2).

[0489] IR (KBr) v: 3120, 2893, 2199, 1626, 1614, 1601, 1581, 1519, 1496, 1291, 1252, 1165, 1077. HRMS: calcd. for C29H25N4O5S [M+H+] 541.1545, found 541.1541.

[0490] Example 23:

[0491] rac-(3aS*,6aR*, 12b / ?*)-methyl 2,8-dimethyl-l l-nitro-6-tosyl-6,7,8, 12b-tetrahydro-3aH-pyrrolo[3', 2':2,3]pyrano[3,4-c]quinoline-l -carboxylate [rac-(3a5'*,6a / ?*,12b / ?*)-example 23]

[0492]

[0493] e 23

[0494] The reaction of IIBc with methyl acetoacetate was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 10:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 23 as yellow powder (63 %), mp 168-170 °C. Rr 0.23 (hexane / chloroform / acetone 10:5:1).

[0495] 'H-NMR (500 MHz, DMSO-d6) 82.03 (s, 3 H, 3’-H), 2.42 (s, 3 H, 5’-H), 3.05 (s, 3 H, 4’-H), 3.21 (d, J= 12.2 Hz, 1 H, 7-Hb), 3.65 (s, 3 H, 2’-H), 4.12 (d, J= 12.2 Hz, 1 H, 7-Ha), 4.88 (s, 1 H, 12b-H), 5.19 (d, J = 2.7 Hz, 1 H, 3a-H), 5.29-5.36 (m, 1 H, 4-H), 6.77 (d, J = 9.4 Hz, 1 H, 9-H), 7.06 (d, J= 4.4 Hz, 1 H, 5-H), 7.43 (d, J = 8.1 Hz, 2 H, 3”-H, 5”-H), 7.68-7.73 (m, 3 H, 2”-H, 6”-H, 12-H), 7.95 (dd, J= 9.4, 2.5 Hz, 1 H, 10-H).

[0496] °C-NMR (125 MHz, DMSO-d6) 620.8 (C-3’), 21.0 (C-5’), 35.1 (C-12b), 39.0 (C-4’), 51.5 (C-2’), 53.4 (C-7), 69.6 (C-6a), 84.6 (C-3a), 106.8 (C-4), 109.1 (C-l), 110.4 (C-9), 123.2 (C-12a), 123.6 (C-12), 124.1 (C-10), 126.5 (C-3”, C-5”), 130.0 (C-2”, C-6”), 135.9 (C-5), 136.8 (C-ll), 137.1 (C-l”), 144.0 (C-4”), 150.2 (C-8a), 167.0 (C-l’), 167.1 (C-2).

[0497] IR (KBr) v: 2949, 1705, 1625, 1600, 1579,1519, 1491, 1299, 1255, 1232, 1184, 1159, 1129, 1093, 1062, 1007. HRMS: calcd. for C25H26N3O7S [M+H+] 512.1491, found 512.1489.

[0498] Example 24:

[0499] rac-(3a5*,6a7?*,12b / ?*)-N-(4-chlorophenyl)-2,8-dimethyl-ll-nitro-6-tosyl-6,7,8,12b-tetrahydro-3aH-pyrrolo[3',2':2,3]pyrano[3,4-c]quinoline-l-carboxamide \rac-(3a5'*,6a7?*,12b / ?*)-example 24]

[0500]

[0501] rac-(3aS*,6a / ?*,12b / ?*)-Example 24

[0502] The reaction of IIBc with 7V-(4-chlorophenyl)-3-oxobutanamide was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 10:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 24 as yellow powder (55 %), mp 95-96 °C. Rr 0.02 (hexane / chloroform / acetone 10:5:1).

[0503] 'H-NMR (500 MHz, DMSO-d6) 8 1.92 (s, 3 H, 3’-H), 2.03 (s, 3 H, 5’-H), 3.07 (s, 3 H, 4’-H), 3.25 (d, J= 12.2 Hz, 1 H, 7-Hb), 4.18 (d, J= 12.2 Hz, 1 H, 7-Ha), 4.63 (s, 1 H, 12b-H), 5.20 (d, J= 2.5 Hz, 1 H, 3a-H), 5.27-5.33 (m, 1 H, 4-H), 6.76 (d, J= 9.4 Hz, 1 H, 9-H), 7.06 (d, J= 4.3 Hz, 1 H, 5-H), 7.17 (d, J = 8.2 Hz, 2 H, 3”’-H, 5”’-H), 7.40 (d, J= 8.9 Hz, 2 H, 3”-H, 5”-H), 7.67-7.78 (m, 4 H, 2”’-H, 6”’-H, 2”-H, 6”-H), 7.95 (dd, J= 9.4, 2.6 Hz, 1 H, 10-H), 8.26-8.37 (m, 1 H, 12-H), 9.34 (s, 1 H, 2’-H).

[0504] °C-NMR (125 MHz, DMSO-d6) 620.4 (C-5’), 20.7 (C-3’), 36.3 (C-12b), 39.0 (C-4’), 54.0 (C-7), 70.8 (C-6a), 84.7 (C-3a), 106.5 (C-4), 110.2 (C-9), 115.0 (C-l), 121.1 (C-2”, C-6”), 124.0 (C-10), 124.3 (C-12a), 125.3 (C-l”), 126.6 (C-12), 126.7 (C-2’”, C-6’”), 128.4 (C-3”, C-5”), 129.9 (C-3’”, C-5’”), 136.0 (C-5), 136.8 (C-l”’), 137.1 (C-ll), 138.5 (C-4”), 143.8 (C-4’”), 150.6 (C-8a), 160.4 (C-2), 166.5 (C-l”).

[0505] IR (KBr) v: 2921, 1648, 1598, 1515, 1490, 1295, 1160. HRMS: calcd. for C30H28ClN4O6S [M+H+] 607.1418, found 607.1412.

[0506] Example 25:

[0507] rac-(3a5'*,6a7?*,12b5'*)-2,8-dimethyl-ll-nitro-l-(phenylsulfonyl)-6-tosyl-6,7,8,12b-tetrahydro-3aH-pyrrolo[3',2':2,3]pyrano[3,4-c]quinoline [rac-(3a5'*,6a / ?*,12b5'*)-example 25]

[0508]

[0509] rac-(3aS*,6aR*,12bS*)-Example 25

[0510] The reaction of IIBc with 1 -(phenyl sulfonyl)propan-2-one was carried out according to method D, and the product precipitated upon cooling to room temperature. The precipitate was filtered and washed with 5 ml of cold ethanol. The filtrate was concentrated in vacuo, and it was then purified by column chromatography (hexane / chloroform / acetone 10:5:1). Unifying the products from crystallization and chromatography afforded the compound of Example 25 as yellow powder (81 %), mp 200-203 °C. Rr 0.06 (hexane / chloroform / acetone 10:5:1).

[0511] 'H-NMR (400 MHz, DMSO-d6) 8 1.98 (s, 3 H, 1”), 2.40 (s, 3 H, 3”-H), 2.62 (d, J= 11.7 Hz, 1 H, 7-Hb), 2.89 (s, 3 H, 2”-H), 4.06 (d, J= 11.7 Hz, 1 H, 7-Ha), 5.19 (s, 1 H, 12b-H), 5.21 (d, J = 4.4 Hz, 1 H, 4-H), 5.24 (d, J= 4.4 Hz, 1 H, 3a-H), 6.77 (d, J= 9.4 Hz, 1 H, 9-H), 6.94 (d, J = 4.4 Hz, 1 H, 5-H), 7.43 (d, J= 8.2 Hz, 2 H, 3”’-H, 5”’-H), 7.63 (t, J= 7.7 Hz, 2 H, 3’-H, 5’-H), 7.73 (t, J= 7.7 Hz, 1 H, 4’-H), 7.83 (d, J= 8.2 Hz, 2 H, 2”’-H, 6”’-H), 7.98 (dd, J= 9.4, 2.5 Hz, 1 H, 10-H), 8.05 (d, J= 7.7 Hz, 2 H, 2’-H, 6’-H), 8.19 (s, 1 H, 12-H).

[0512] ¹³C-NMR (100 MHz, DMSO-d6) δ 20.0 (C-l”), 21.0 (C-3”), 39.2 (C-2”), 39.3 (C-12b), 52.3 (C-7), 70.2 (C-6a), 86.8 (C-3a), 108.0 (C-4), 110.9 (C-9), 122.3 (C-l), 123.1 (C-12a), 124.3 (C-12), 124.5 (C-10), 126.9 (C-2’”, C-6’”), 127.2 (C-2’, C-6’), 129.4 (C-3’, C-5’), 130.1 (C-3’”, C-5’”), 133.5 (C-4’), 136.4 (C-5), 137.3 (C-ll, C-l’”), 141.9 (C-l’), 144.4 (C-4’”), 150.5 (C-8a), 166.3 (C-2).

[0513] IR (KBr) v: 2920, 1625, 1602, 1582, 1498, 1287, 1150. HRMS: calcd. for C29H28N3O7S2 [M+H+] 594.1368, found 594.1366.

[0514] Example 26:

[0515] rac-(3a5'*,6a7?*,12b / ?*)-2-amino-8-methyl-ll-nitro-6-tosyl-6,7,8,12b-tetrahydro-3aH-pyrrolo[3', 2':2,3]thiopyrano[3,4-c]quinoline-l -carbonitrile [rac-(3a5'*,6a / ?*,12b / ?*)-example 26]

[0516]

[0517] mple 26

[0518] To a standard 10 mL volume cylindrical Pyrex® reaction vessel IIBc, 2-cyanothioacetamide and 2 ml of absolute ethanol were added. The vessel was sealed with PEEK snap cap and standard PTFE-coated silicone septum and warmed up to 120 °C and stirred for 15 minutes. The solvent was removed in vacuo, and the crude was triturated with 3 ml of cold ethanol, and the crystals were filtered and washed with 2 ml of cold ethanol, affording the compound of Example 26 as orange powder (76 %), mp 244-247 °C. Rr 0.43 (chloroform / acetone 20:1).

[0519] 'H-NMR (500 MHz, DMSO-d6) 82.41 (s, 3 H, 3’-H), 2.96 (s, 3 H, 4’-H), 3.06 (d, J= 11.8 Hz, 1 H, 7-Hb), 4.10 (d, J= 11.8 Hz, 1 H, 7-Ha), 4.45 (s, 1 H, 3a-H), 4.66 (s, 1 H, 12b-H), 5.09 (dd, J= 4.1, 2.5 Hz, 1 H, 4-H), 6.72 (d, J= 9.3 Hz, 1 H, 9-H), 6.78 (dd, J= 4.3, 1.4 Hz, 1 H, 5-H), 7.05 (s, 2 H, 2’-H), 7.44 (d, J= 8.1 Hz, 2 H, 3”-H, 5”-H), 7.84 (d, J = 8.1 Hz, 2 H, 2”-H, 6”-H), 7.89 (dd, J= 2.6, 1.3 Hz, 1 H, 12-H), 7.95 (dd, J= 9.2, 2.6 Hz, 1 H, 10-H).

[0520] °C-NMR(125 MHz, DMSO-d6) 621.1 (C-3’), 39.3 (C-4’), 44.3 (C-12a), 54.9 (C-3a), 55.1 (C-7), 69.7 (C-l), 70.9 (C-6a), 110.3 (C-4, C-9), 110.4 (C-l’), 120.8 (C-12), 122.1 (C-10), 124.0 (C-12a), 124.3 (C-2”, C-6”), 126.8 (C-3”, C-5”), 130.1 (C-5), 131.5 (C-ll), 137.1 (C-l”), 137.4 (C-7”), 144.1 (C-4”), 151.5 (C-8a), 158.5 (C-2).

[0521] IR (KBr) v: 3418, 3318, 3210, 3099, 2320, 2175, 1623, 1602, 1579, 1561, 1517, 1488, 1467, 1314, 1291, 1157. HRMS: calcd. for C23H22N5O4S2 [M+H+] 496.1113, found 496.1109.

[0522] Example 27:

[0523] rac-(6aR*,9aS*, 14b7?*)-l 1, 12,13, 14b-tetrahy dro-6H-chromeno[3,4-c]furo[3,2-b]chromen- 14(9aH)-one [rac-(6a7?*,9a5*,14b7?*)-example 27]

[0524]

[0525] rac-(6aR*,9aS*,14bR*)-Example 27

[0526] The reaction of IIBa with cyclohexan-l,3-dione was carried out according to method E, and the crude product was triturated with 3 ml of cold ether. The precipitate was filtered and washed with 2 ml of cold ether affording the compound of Example 27 as white powder (82 %), mp 75-78 °C. Rf: 0.16 (hexane / ethyl acetate 5:1).

[0527] 'H-NMR (400 MHz, CDCh) 8 1.79-1.93 (m, 1 H, 12-Hb), 1.94-2.04 (m, 1 H, 12-Ha), 2.28-2.36 (m, 2 H, 11-H), 2.37-2.48 (m, 1 H, 13-Hb), 2.51-2.61 (m, 1 H, 13-Ha), 3.98 (d, J= 10.7 Hz, 1 H, 6-Hb), 4.04 (d, J= 10.7 Hz, 1 H, 6-Ha), 4.57 (s, 1 H, 14b-H), 5.20 (t, J= 2.5 Hz, 1 H, 9-H), 5.38 (d, J = 2.5 Hz, 1 H, 9a-H), 6.56 (d, J= 2.5 Hz, 1 H, 8-H), 6.81-6.90 (m, 2 H, 2-H, 4-H), 6.98 (d, J= 7.7 Hz, 1 H, 1-H), 7.10 (t, J= 7.7 Hz, 1 H, 3-H).

[0528] °C-NMR (100 MHz, CDCh) 620.1 (C-12), 29.7 (C-ll), 31.0 (C-14b), 36.7 (C-13), 67.2 (C-6), 82.1 (C-9a), 82.9 (C-6a), 101.9 (C-9), 114.9 (C-14a), 116.3 (C-4), 122.0 (C-2), 123.8 (C-14c), 127.9 (C-3), 129.5 (C-l), 151.1 (C-8), 153.1 (C-4a), 172.6 (C-lOa), 198.0 (C-14a).

[0529] IR(KBr) v: 2925, 2873, 2373, 2319, 1649, 1620, 1579, 1486, 1390, 1223, 1050. HRMS: calcd. for C18H17O4 [M+H+] 297.1126, found 297.1122.

[0530] Example 28:

[0531] rac-(6a7?*,9a5*,14b7?*)-12-methyl-9a,14b-dihydrofuro[3',2':2,3]pyrano[3',4':5,6]pyrano[3,4-c]chromen-14(6H)-one [rac-(6a7?*,9a5*,14b7?*)-example 28]

[0532]

[0533] rac-(6aR*,9aS*,14bR*)-Example 28 The reaction of IIBd with 4-hydroxy-2 / / -pyran-2-one was carried out according to method E, and the reaction mixture was concentrated in in vacuo. The crude product was purified with column chromatography (hexane / ethyl acetate 3:1) affording the compound of Example 28 as pale yellow oil (97 %). Rr 0.34 (hexane / ethyl acetate 3:1).

[0534] 'H-NMR (400 MHz, CDCh) 82.17-2.24 (m, 3 H, l’-H), 4.01 (d, J= 10.8 Hz, 1 H, 6-Hb), 4.06 (d, J= 10.8 Hz, 1 H, 6-Ha), 4.61 (s, 1 H, 14b-H), 5.20-5.25 (m, 1 H, 9-H), 5.48 (d, J= 2.7 Hz, 1 H, 9a-H), 5.74 (s, 1 H, 11-H), 6.57 (dd, J= 2.7, 0.6 Hz, 1 H, 8-H), 6.83-6.93 (m, 2 H, 2-H, 4-H), 7.10-7.17 (m, 1 H, 3-H), 7.23-7.29 (m, 1 H, 1-H).

[0535] °C-NMR (100 MHz, CDCh) δ 20.0 (C-1'), 32.7 (C-14b), 67.0 (C-6), 82.3 (C-6a), 82.6 (C-9a), 101.4 (C-ll), 101.5 (C-14a), 101.8 (C-9), 116.5 (C-4), 122.2 (C-2), 122.6 (C-14c), 128.4 (C-3), 129.3 (C-l), 151.4 (C-8), 153.0 (C-4a), 161.4 (C-12), 165.5 (C-lOa), 165.8 (C-14).

[0536] IR(KBr)v: 2923, 2350, 2319, 1688, 1577, 1487, 1451, 1274, 1260. HRMS: calcd. for C18H15O5[M+H+] 311.0919, found 311.0915.

[0537] Example 29:

[0538] rac-(6a7?*,9a5'*,16b / ?*)-ll,12,13-trimethoxy-9a,16b-dihydrofuro[2',3':5,6]pyrano[3,2-c:5,4-c']dichromen-16(6H)-one [rac-(6a / ?*,9a5'*,16b / ?*)-example 29]

[0539]

[0540] rac-(6aR*,9aS*,16bR*)-Example 29

[0541] The reaction of IIBd with 4-hydroxy-5,6,7-trimethoxycumarine was carried out according to method E, and the reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (hexane / ethyl acetate 3:1), affording the compound of Example 29 as colourless oil (35 %) Rr 0.16 (hexane / ethyl acetate 3:1).

[0542] 'H-NMR (500 MHz, CDCh) 63.81

[0543]

[0544] 3.85 (s, 3 H, 2’-H), 3.91 (s, 3 H, 3’-H), 4.08 (d, J= 10.9 Hz, 1 H, 6-Hb), 4.14 (d, J = 10.9 Hz, 1 H, 6-Ha), 4.77 (s, 1 H, 16b-H), 5.28-5.33 (m, 1 H, 9-H), 5.74 (d, J= 2.6 Hz, 1 H, 9a-H), 6.57-6.62 (m, 1 H, 8-H), 6.69 (s, 1 H, 14-H), 6.80-6.90 (m, 2 H, 2-H, 4-H), 7.08-7.14 (m, 1 H, 3-H), 7.16 (d, J= 7.7 Hz, 1 H, 1-H).

[0545] °C-NMR (125 MHz, CDCh) 633.4 (C-16b), 56.4 (C-3’), 61.3 (C-l’), 62.3 (C-2’), 67.1 (C-6), 82.7 (C-6a), 83.5 (C-9a), 96.6 (C-14), 101.6 (C-9), 102.8 (C-16c), 104.8 (C-14a), 116.6 (C-2), 122.2 (C-4), 122.5 (C-16a), 128.4 (C-3), 129.2 (C-l), 140.2 (C-12), 150.6 (C-ll), 151.8 (C-8), 153.3 (C-4a), 156.9 (C-13), 162.5 (C-lOa), 163.8 (C-16).

[0546] IR (KBr) v: 2989, 2349, 2310, 1704, 1608, 1396, 1276, 1260.

[0547] HRMS: calcd. for C24H21O8 [M+H+] 437.1236, found 437.1234.

[0548] Example 30:

[0549] rac-(4a7?*,7a5'*,12b / ?*)-3-acetyl-l,3,4,7a,9,10,ll,12b-octahydrofuro[3',2':2,3]chromeno[3,4-c]pyridin-12(2H)-one [rac-(4a7?*,7 aS*,12b / ?*)-example 30]

[0550] rac-

[0551]

[0552] Example 30

[0553] The reaction of IIBe with cyclohexan-1, 3-dione was carried out according to method F, and the crude product was purified by column chromatography (hexane / acetone 1:1) affording the compound of Example 30 as a pale yellow oil (82 %). Rf = 0.44 (hexane / acetone 1:1).

[0554] 'H NMR (400 MHz, acetone r,) 8 1.26 - 1.40 (m, 2 H, 1-Ha), 1.71 - 1.85 (m, 5 H, 10-H, 1-Hb), 1.90 - 1.99 (m, 2 H, 10-H), 2.11 (s, 6 H, 2x2’-H), 2.25 (dd, J= 8.3, 5.1 Hz, 4 H, 11-H), 2.28 -2.37 (m, 4 H, 9-H), 2.66 (d, J= 13.0 Hz, 2 H, 4-Hb), 3.16 (dd, J= 12.4, 5.2 Hz, 2 H, 12b-H), 3.21 - 3.32 (m, 2 H, 2-Hb), 3.92 - 4.02 (m, 2 H, 2-Ha), 4.56 (dd, J= 13.0, 1.8 Hz, 2 H, 4-Ha), 5.01 (d, J= 2.6 Hz, 1 H, 7a-H), 5.15 - 5.20 (m, 1 H, 7-H), 6.68 (d, J= 2.5 Hz, 1 H, 6-H). °C NMR (100 MHz, acetone r,) 521.3 (C- 10), 21.3 and 21.4 (C-2’), 31.7 (C-l), 31.8 (C-l 2b), 37.1 (C-ll), 41.4 and 46.1 (C-4), 46.6 and 51.2 (C-2), 83.1 (C-7a), 86.8 (C-4a), 102.3 (C-7), 115.5 (C-12a), 152.0 and 152.2 (C-6), 169.7 (C-l’), 172.4 (C-8a), 195.7 (C-12).

[0555] IR: (KBr) v: 2945, 1623, 1425, 1390, 1367, 1276, 1261, 1185, 1160, 1060. HRMS: calcd. for C16H20NO4[M+H+] 290.1392, found 290.1388.

[0556] Example 31:

[0557] rac-( R*,7 a5*, 1 lb / ?*)-3-acetyl-3,4,7a,9, 10, 1 Ib-hexahydro-lH-cyclopenta[5,6]furo[3',2':2,3]pyrano[3,4-c]pyridin-ll(2H)-one [rac-(4a7?*,7a5'*,llb / ?*)-example 31]

[0558] rac-

[0559]

[0560] Example 31

[0561] The reaction of IIBe with cyclopentan- 1,3 -di one was carried out according to method F, and the crude product was purified by column chromatography (hexane / acetone 1:1) affording the compound of Example 31 as a pale yellow oil (32 %) Rf = 0.25 (hexane / acetone 1:1).

[0562] 'H NMR (400 MHz, acetone r,) 8 1.33 - 1.54 (m, 2 H, 1-H), 1.81 - 1.95 (m, 2 H, 1-H), 2.04 -2.07 (m, 6 H, 2x2’-H), 2.29 - 2.35 (m, 2 H, 10-H), 2.39 - 2.45 (m, 1 H, 9-Ha), 2.46 - 2.51 (m, 1 H, 9-Hb), 2.51 - 2.59 (m, 1 H, 2-Hb), 2.85 - 2.96 (m, 1 H, llb-H), 3.02 (d, J= 13.9 Hz, 1 H, 4-Hb), 3.07 - 3.18 (m, 1 H, 2-Hb), 3.66 (d, J= 14.4 Hz, 1 H, 4-Hb), 3.86 (d, J= 14.4 Hz, 1 H, 4-Ha), 3.89 - 4.01 (m, 1 H, 2-Ha), 4.52 - 4.65 (m, 2 H, 4-Ha and 2-Ha), 5.96 - 6.06 (m, 1 H, 7-H), 6.44 (s, 1 H, 7a-H), 6.49 - 6.58 (m, 3 H, 7a-H, 2x 6-H).

[0563] °C NMR (100 MHz, acetone-t / 6) 621.4 and 21.6 (C-2’), 28.1 and 28.2 (C-9), 28.8 (C-l), 33.9 (C-10), 41.3 (C-2), 44.3 (C-l lb), 45.9 (C-2), 47.1 and 52.6 (C-4), 90.8 and 91.2 (C-4a), 107.6 and 107.9 (C-7a), 119.6 and 119.8 (C-l la), 125.3 and 125.5 (C-7), 139.7 and 140.0 (C-6), 169.1 and 169.4 (C-l’), 177.9 and 178.1 (C-8a), 205.1 and 205.1 (C-ll).

[0564] IR: (KBr) v: 2926, 1682, 1641, 1608, 1467, 1448, 1394, 1358, 1307, 1270, 1256, 1197, 1124, 1070.

[0565] HRMS: calcd. for C15H18NO4[M+H+] 276.1235, found 276.1231. Example 32:

[0566] rac-(4a7?*,7a5'*,12b / ?*)-3-acetyl-10-methyl-3,4,7a,12b-tetrahydro-lH-furo[3',2':2,3]pyrano[3',4':5,6]pyrano[3,4-c]pyridin-12(2H)-one [rac-(4a7?*,7a5*,12b / ?*)-example 32]

[0567]

[0568] rac-(4aR*,7aS*,12bR*)-Example 32

[0569] The reaction of IIBe with 4-hydroxy-27 / -pyran-2-one was carried out according to method F, and the crude product was purified by column chromatography (hexane / acetone 2:1) affording the compound of Example 32 as a pale yellow oil (52 %) Rf = 0.11 (hexane / acetone 1:1). 'H NMR (400 MHz, aceton e-t / r,) 8 1.40 - 1.52 (m, 2 H, 1-Hb), 1.91 - 1.99 (m, 2 H, 1-Ha), 2.13 (s, 6 H, 2x2’-H), 2.15 (s, 6 H, 2x3’-H), 2.74 (d, J = 13.1 Hz, 2 H, 4-Hb), 3.12 - 3.23 (m, 2 H, 12b-H), 3.27 - 3.40 (m, 2 H, 2-Hb), 3.98 - 4.09 (m, 2 H, 2-Ha), 4.56 - 4.67 (m, 2 H, 4-Ha), 5.14 (d, J= 2.7 Hz, 1 H, 7a-H), 5.20 - 5.25 (m, 1 H, 7-H), 5.90 (s, 1 H, 9-H), 6.73 (d, J= 2.6 Hz, 1 H, 6-H).

[0570] °C NMR (100 MHz, acetone-t / 6) 6 19.68 (C-3’), 21.33 (C-2’), 30.99 (C-l), 33.45 (C-12b), 41.17 (C-4), 45.90 (C-4), 46.36 (C-2), 50.94 (C-2), 83.30 (C-7a), 83.58 (C-7a), 86.15 (C-4a), 101.36 (C-9), 102.06 (C-12a), 102.30 (C-7), 152.41 (C-6), 152.62 (C-6), 161.84 (C-10), 163.63 (C-12), 165.98 (C-8a), 169.86 (C-F).

[0571] IR: (KBr) v: 2922, 2853, 1707, 1645, 1611, 1587, 1448, 1408, 1275, 1051, 1030.

[0572] HRMS: calcd. for C16H18NO5[M+H+] 304.1184, found 304.1183.

[0573] Example 33:

[0574] rac-(3a5'*,6a7?*,12b / ?*)-2-phenyl-7,12b-dihydro-3aH-furo[3',2':2,3]pyrano[3,4-c]chromene-l-carbonitrile [rac-(3a5*,6a7?*,12b / ?*)-example 33]

[0575] ra

[0576]

[0577] Example 33

[0578] The reaction of IIBd with benzoyl acetonitrile was carried out according to method E, and the reaction mixture was concentrated in in vacuo. The crude product was purified by column chromatography (hexane / ethyl acetate 3:1), affording Example 33 as yellow oil (21 %). Rf: 0.39 (hexane / ethyl acetate 3:1).

[0579] ¹H-NMR (400 MHz, CDCl₃) δ 4.10 (d, J= 11.0 Hz, 1 H, 7-Hb), 4.16 (d, J= 11.0 Hz, 1 H, 7-Ha), 4.19 (s, 1 H, 12b-H), 5.37 (t, J = 2.2 Hz, 1 H, 4-H), 5.62 (d, J = 1.9 Hz, 1 H, 3a-H), 6.70 (dd, J = 2.6, 0.9 Hz, 1 H, 5-H), 6.91-6.98 (m, 1 H, 9-H), 7.01-7.10 (m, 1 H, 11-H), 7.19-7.28 (m, 1 H, 10-H), 7.39-7.50 (m, 3 H, 3”-H, 4”-H, 5”-H), 7.55 (d, J= 7.8 Hz, 1 H, 12-H), 7.75-7.82 (m, 2 H, 2”-H, 6”-H).

[0580] ¹³C-NMR (100 MHz, CDCl₃) δ 39.2 (C-12b), 67.0 (C-7), 83.6 (C-6a), 84.4 (C-3a), 87.8 (C-l), 101.14 (C-4), 116.9 (C-9), 121.0 (C-l’), 122.0 (C-lOa), 122.4 (C-ll), 128.3 (C-2”, C-6”), 128.5 (C-3”, C-5”), 128.6 (C-12), 129.0 (C-10), 131.4 (C-4”), 132.8 (C-l”), 151.9 (C-5), 153.3 (C-8a), 166.6 (C-2).

[0581] IR (KBr) v: 2961, 2922, 2206, 1628, 1600, 1525, 1499, 1484, 1296, 1263, 1257.

[0582] HRMS: calcd. for C21H16NO3 [M+H+] 330.1130, found 330.1126.

[0583] In vitro cytostatic activity of the compounds

[0584] Cell culturing and media

[0585] For the in vitro studies, the following cell culture was used: U87 human glioblastoma (ATCC HTB-14; (a) J. A. Schulz, L. T. Rodgers, R. J. Kryscio, A. M. S. Hartz, B. Bauer, BMC Cancer 2022, 22, 844; (b) J. Ponten, E. H. Macintyre, Acta Pathol Microbiol Scand 1968, 74, 465-486.). For maintaining U87 cell culture, DMEM (Lonza, Basel, Switzerland)) supplemented with 10% FBS (Biosera, Nuaille, France), 2 mM L-glutamine, 100 pg / ml penicillin / streptomycin (50 lU / mL and 50 pg / mL, respectively, Gibco (Thermo Fisher Scientific, Waltham, MA, USA), 1 mM pyruvate, and 1% non-essential amino acids (CM DMEM) were used. The culture was maintained at 37 °C in a humidified atmosphere with 5% CO2.

[0586] For the end-point type tetrazolium (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, MTT) assay ((a) Y. Liu, D. A. Peterson, H. Kimura, D. Schubert, J. Neurochem. 1997, 69, 581-593; (b) T. F. Slater, B. Sawyer, U. Strauli, Biochim. Biophys. Acta 1963, 77, 383-393; (c) T. Mosmann, J. Immunol. Methods 1983, 65, 55-63). cells were seeded during the exponential growth phase, one day before the experiment. In the case of cytostasis 5 * 103cells / 100 pL / well, for were seeded on a 96-well cell culture plate (Sarstedt, Numbrecht, Germany) in CM DMEM. Cells were treated with the compounds using DMSO stock solutions (c = 20mM) diluted in DMEM incomplete medium (ICM) (final c = 1% (v / v) for DMSO content) in the concentration range 2.56 × 10⁻3- 100 pM. Cells were treated with the compounds for 24 h. As control, ICM and ICM containing 1% (v / v) DMSO were used. After incubation, cells were washed with ICM three times, and in the last step, CM was added. After culturing the cells for 72 h, 45 pL sterile-filtered MTT (Mill ex 0.22 pm filter, Millipore, Cork, Ireland) was added (2 mg / mL in ICM) to the cells. Mitochondrial enzymes reduce MTT to a formazan derivative (purple crystals). As positive control etoposide was employed.

[0587] After 3.5 h incubation, plates were centrifuged (2000 rpm, 5 min), the supernatant was removed, and formazan crystals were dissolved in DMSO. Absorbance was determined with an ELISA plate reader (Labsystems iEMS reader, Helsinki, Finland) at λ = 540 and 620 nm. A620values were subtracted from A540values, and cytostatic activity was calculated with the formula: cytostasis% = 100 × (1-Atreated cells / Acontrol cells), where Atreated cellsand Acontrol cellsare the average absorbance of treated and control cells. The 50% inhibitory concentration (IC50) values were determined from the dose-response curves. The curves were calculated with Microcal OriginPro (version: 2018) software (OriginLab, Northampton, MA, USA).

[0588] In vitro antiploriferative studies on U87 human glioblastoma cell line showed that some of the compounds had remarquable activity (Table 1). Table 1

[0589]

[0590] Conclusions:

[0591] Condensed chiral tetra-, penta- or hexacyclic compounds, containing a bridged or spirocyclic dihydrofuran, dihydrothiophene or dihydropyrrole moiety, were prepared in domino Knoevenagel-cyclization reactions. The bridged dihydrofuran derivatives, containing a condensed tetrahydroquinoline subunit, were synthesized in domino Knoevenagel-cyclization reactions, whereinhe cyclization step took place with a 1,4-addition to the furan subunit involving either a DA reaction or a formal [4+4] cycloaddition. The compounds, containing a spirocyclic moiety, were prepared in domino Knoevenagel-cyclization reactions performed between substrates containing a 2-formylarylamine residue and a furan, thiophene or pyrrole subunit and active methylene reagents, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate reacted in an intramolecular cyclization step of a domino Knoevenagel-cyclization sequence as a dienophile.

[0592] Some of the products showed remarkable in vitro antiproliferative activity against the U87 human glioblastoma.

Claims

CLAIMS1. Process for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged or spirocyclic dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted in an intramolecular cyclization step of a domino Knoevenagel-cyclization sequence.

2. Process according to claim 1 for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted in [4+2] or [4+4] cycloaddition with the double bond of the Knoevenagel intermediate to form the oxygen-, sulphur- or nitrogen-bridged scaffold.

3. Process according to claim 2 for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a bridged dihydrofuran moiety, wherein the furan subunit of the corresponding substrate is reacted with the double bond of the Knoevenagel intermediate in [4+2] or [4+4] cycloaddition to produce an oxygen-bridged scaffold.

4. Process according to any of claims 1 or 2 for the preparation of a compound of formula (V)whereinX is O, S or NR6wherein R6is Ts or other electron-withdrawing group;Y is NR7or O, wherein R7is alkyl or C(O)-alkyl;R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group;R11is CN, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group; R1is NO2, halogen, alkyl or CF3and n is an integer selected from 0, 1, 2; by reacting a compound of formula (IIB)wherein X, Y, R1and n are as defined above,with a compound of formula (VI)wherein R10and R11are as defined above.

5. Process according to claim 4 wherein X is O.

6. Process according to claim 4 or 5, wherein Y is NR7, wherein R7is alkyl, preferably methyl.

7. Process according to any of claims 1-3 for the preparation of a compound of formula (VII)whereinX is OY is O or NR7, wherein R7is alkyl or C(O)-alkyl;B is a 5-membered monocyclic carbocycle or a 9-membered bicyclic carbocycle; R1is NO2, halogen, alkyl, CF3; and n is an integer selected from 0, 1, 2; by reacting a compound of formula (IIB)wherein X, Y, R1and n are as defined above;with a compound of formula (VIII),wherein B is as defined above, in the presence of a Lewis-acid.

8. Process according to claim 1 for the preparation of a condensed tetra-, penta- or hexacyclic compound containing a spirocyclic dihydrofuran, dihydrothiophene or dihydropyrrole moiety, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with a carbonyl, thiocarbonyl or vinyl-N-heterocycle subunit in an intramolecular hetero-Diels-Alder reaction to form the spirocyclic scaffold.

9. Process according to claim 8 wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with an a, P-unsaturated carbonyl subunit in an intramolecular oxa-Diels-Alder reaction.

10. Process according to claim 8, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with an a, P-unsaturated thiocarbonyl subunit in an intramolecular thia-Diels-Alder reaction.

11. Process according to claim 8, wherein the furan, thiophene or pyrrole subunit of the corresponding substrate is reacted with a vinyl-N-heterocyclic subunit, such as a vinyl-2-pyridyl subunit, in an intramolecular aza-Diels-Alder reaction.

12. Process according to claim 1 or 8 for the preparation of a compound of formula (I)whereina)X is O, S or NR6, wherein R6is Ts or another electron-withdrawing group;Y is NR7, or O, wherein R7is alkyl, preferably methyl, or -C(O)-alkyl;Z is O or S;R2is CN, -SO2-aryl, C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group; andR3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; orR2and R3form together a carbocyclic or heterocyclic ring, which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensationto form a compound of formula (IA)wherein A is a 5-6 membered carbocycle or heterocycle, or a 9-10 membered bicyclic carbocycle or heterocycle, each of which can be optionally substituted by one or more substituent independently selected from the following: alkyl, alkoxy, and aryl;R4and R5are H, or form together with the carbon atoms, to which they are attached an optionally substituted arene moiety;with the proviso that when R4and R5mean both H, R2and R3form together with the carbon atoms to which they are linked group (A); orb)Z is NR9, wherein R9forms together with R3and N an optionally substituted N- heterocycle such as pyridine, andR2is CN, -SO2-aryl, -C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group, andX, Y, R4, R5are as defined above,wherein the process comprisesfor the preparation of a compound of formula (I) as defined under a) above, reacting a compound of formula (II)wherein X, Y and R4and R5are as defined above under point a),with a compound of formula (III)wherein Z, R2and R3are as defined above under point a); orfor the preparation of a compound of formula (I) as defined under point b) above; reacting a compound of formula (II)wherein X, Y and R4and R5are as defined under point b) above,with a compound of formula (IV)R2-CH2-Hetwherein R2is as defined under point (b) above, andHet is an optionally substituted N-heterocycle, such as pyridine.

13. Process according to claim 12 for the preparation of a compound of formula (IB)whereinX is O, S or NR6, wherein R6is Ts or an electron-withdrawing group;Y is NR7or O, wherein R7is alkyl, preferably methyl;Z is O or S;R2is CN, -SO2-aryl, C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group; andR3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; orR2and R3form together a carbocyclic or heterocyclic ring, which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensationto form a compound of formula (IBA)wherein A is a 5-6 membered carbocycle or heterocycle or a 9-10 membered bicyclic carbocycle or heterocycle, which can be optionally substituted by one or more substituents independently selected from the following alkyl, alkoxy, and aryl; andR1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2; by reacting a compound of formula (II)wherein X, Y, R1and n and are as defined above;with a compound of formula (III)wherein Z is O or S, and R2and R3are as defined above.

14. Process according to any of claims 12 or 13 wherein X is O.

15. Process according to any of claims 1, 8, 11 or 12 for the preparation of a compound of formula (IC)whereinX is O,Y is NR7or O, wherein R7is alkyl, preferably methyl;R2is CN, -SO2-aryl, C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group, preferably CN;R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2;by reacting a compound of formula (IIB),wherein X, Y, R1and n are as defined above,with a compound of formula (IV’)wherein R2is as defined above.

16. Compound of formula (V)R11? R'«ni j-iRiin(V)whereinX is O, S or NR6wherein R6is Ts or other electron-withdrawing group;Y is NR7or O, wherein R7is alkyl or C(O)-alkyl;R10is CN, SO2-Ph, C(O)-NH2, C(O)-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group;R11is CN, C(O)-O-alkyl, C(O)-alkyl or other electron-withdrawing group R1is NO2, halogen, alkyl or CF3, and n is an integer selected from 0, 1, 2.

17. Compound according to claim 16, whereinX is O; and / orY is NR7, wherein R7is C1-4alkyl; and / orR10is CN, SO2-Ph, CO-NH2, CO-N(alkyl)2, C(O)-O-alkyl, C(O)-alkyl; and / or R11is CN, C(O)-alkyl, C(O)-O-alkyl, and / orR1is NO2, F, C1-4alkyl or CF3; and n is an integer selected from 0, 1, 2, preferably n is 1.

18. Compound according to any of claims 16 or 17, whereinX is O; and / orY is N-Me; and / orR10is CN, SO2-Ph, C(O)-NH2, C(O)-N(Me)2. C(O)-OEt, C(O)OMe, C(O)-Me; and / orR11is CN, C(O)-OMe, C(O)-Me;R1is NO2and n is 1.Compound according to any of claims 16 to 18, which is selected from the following:

20. Compound of formula (VII)whereinX is OY is O or NR7, wherein R7is alkyl or C(O)-alkyl;B is a 5-membered monocyclic carbocycle or a 9-membered bicyclic carbocycle; R1is NO2, halogen, alkyl, CF3; and n is an integer selected from 0, 1, 2.

21. Compound of claim 20, whereinX is O and / orY is O or N-ME; and / orB is selected fromwherein dashed line indicates the place of condensation; and / orR1is NO2, and n is 0 or 1.

22. A compound of claim 20 or 21. wherein the compound is selected from23. Compound of formula (IB)whereinX is O, S or NR6, wherein R6is Ts or other electron-withdrawing group;Y is NR7or O, wherein R7is alkyl, preferably methyl;Z is O or S;R2is CN, -SO2-aryl, C(O)-NH-aryl, -C(O)-O-alkyl, -C(O)-alkyl, -C(O)-NH2, -C(O)- N(alkyl)2, -C(O)-H, or another electron- withdrawing group; andR3is alkyl, aryl, alkoxy, -NH2, -N(alkyl)2; orR2and R3form together a carbocyclic or heterocyclic ring which can be benzene- condensed as represented by formula A, wherein dashed line indicates the place of condensationto form a compound of formula (IBA)wherein A is a 5-6 membered carbocycle or heterocycle or a 9-10 membered bicyclic carbocycle or heterocycle, which can be optionally substituted by one or more substituent independently selected from the following alkyl, alkoxy, and aryl; andR1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2.

24. Compound according to claim 23, whereinZ is O or S; and / orX is O, S or NTs; and / orY is NMe or O; and / orR1is NO2 or CF3, and n is 0 or 1; and / orR2is CN, -COOMe, methyl, NH-Ph-4-Cl, or SO2Ph; andR3is amino, -N(Me)2, -N(Ci-4alkyl)2, methyl, phenyl, -OMe, or -OEt; orR2and R3form together with the carbon atoms to which they are linked group A selected from the following, wherein dashed line indicates the place of condensation:

25. Compound according to any of claims 23 to 24, wherein X is O.

26. Compound according to any of claims 23 to 25, wherein Y is O.

27. Compound according to any of claims 23 to 24, wherein the compound is selected from the following:

28. Compound according to claim 27, which is selected from the following29. Compound of formula (IC)whereinX is O;Y is NR7or O, wherein R7is alkyl, preferably methyl;R2is CN, ester, -SO2-aryl, -CONH-aryl, or another electron-withdrawing group, preferably CN;R1is NO2, halogen, alkyl or CF3; and n is an integer selected from 0, 1, 2;30. Compound according to any of claims 16 to 19, 20 to 22 or 23 to 29 for use in the treatment of cancer.

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