| Title of Invention | PYRROLOBENZODIAZEPINES |
|---|---|
| Abstract | Compounds and a method of synthesis of compounds of formula (la) or (Ib): and salts, solvates, and chemically protected forms thereof, wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R<2> and R<3> are independently selected from -H, =O, =CH2, -CN, -R, OR, halo, =CH-R, 0-S02-R, C02R and COR; R<10> is a carbamate-based nitrogen protecting group; and R<11> is an oxygen protecting group. |
| Full Text | PYROLOBENZODIAZEPINES The present, invent ion relates to pyrrolobenzodiazepines (PBDs), and in particular pyrrolobenzodiazepines useful in the synthesis of dirneric compounds. Background to the invention Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first FED antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al . , J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)}. S:i nee then, a number of naturally occurring PBDs have been report-fid, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamyc-in (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al. , --Chem. Brit., . 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758 (1992)), mazethramycin (Kuminoto, et al., J. Antibiotics, 33, 665-667 (1980)), neothramycins A and B (Takeuchi, et al., J. Antibiotics, 29, 93-96 (1976)), porothramycin (Tsunakawa, et al., J. Antibiotics, 41, 1366-1373 (1988)), prothracarcin (Shimizu, et aj, J. Antibiotics, 29, 2492-2503 (1982); Langley and Thurston, J. Org. Chem., 52, 91-97 (1987)), sibanomicin (DC-102) (Hara, et al., J. Antibiotics, 41, 702-704 (1988); Itoh, et al., J. Antibiotics, 41, 1281-1284 (1988)), sibiromycin (Leber, et al., J. Am. Chem. Soc., 110, 2992-2993 (1988)) and tomamycin (Arima, et al., J. Antibiotics, 25, 437-444 (1972)). PBDs are of the general structure: (Figure Remove) They differ in me number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N=0), a carbinolamine(NH-CH(OH)), or a carbinolamine methyl ether (NH-CH(OMe)) at the N10-C11 position which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral Clla position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-.11 (1975); Hurley and Needhair.-VanDevanter, Ace. Chem. Res., 19, 230-237 (1906)). Their ability to form an adduct in the minor groove, enables them to interfere with DNA processing, hence their use as antitumour agents. The present inventors have previously disclosed, in WO 00/12508, dimeric cytotcxic PBD compounds substituted at the C2 position, for example: (Figure Remove) The synthesis of these compounds was achieved by formation of the dimeric backbone comprising the assembled A and C rings linked through the A ring by the diether linking chain. The N10 position was then protected with an Alloc group before a ring closure reaction to form the B ring and subsequent deprotection to give the product. The key stage in this synthesis is described as the ring closure to form the B ring which occurs after the linking of r;he two A rings with the diether chain. Using this route, to synthesise a number of dinners having the same monomer groups but different bridging groups require the synthesis of each compound from scratch, i.e. the synthesis route is not .ible to readJ.ly produce a diverse collection of PBD dimers, where the diversity is in the dirtier bridge. Disclosure of the invention The present Inventors have developed a key intermediate for the production of dinieric PBDs, which has a hydroxyl group at either the Rh and/oi B" position, a carbamate protecting group at the N10 position and a protected hydroxy group at the Cll position. In a first aspect, the present invention comprises a compound with the formula la or Ib: (Figure Remove)wherein: the dotted lines indicate the optional presence of a double bond between Cf and C2 or C2 and C3; R* and RJ are independently selected from -H, =0, =CH2, -CN, -R, OR, halo, =CH-R, 0-S02-R, C02R and COR; R6 and R'J are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR' , nit.ro, Me3Sn and halo; where R and R' are independently selected from optionally substituted aikyl, Co heterocyclyl and Cs-Zo aryl groups; RA is selected from H, R, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn and h a1o; R10 is a carbamate-based nitrogen protecting group; Rn is an oxygen protecting group. Tn a second aspect, the present invention comprises a method of synthesis:) ng a compound of formula la or Ib as defined in the first aspect of the invention from a compound of formula Ila or IIb respe ctive1y: (Figure Remove)wherein RF', R', R3, R6, R9, R10 and R11 are as defined in the first aspect; R14 is an oxygen protecting group which is orthogonal to in a third aspect, the present invention comprises a method of :;ynthesd sing a compound of formula Ilia or Illb: (Figure Remove)or a solvate thereof, from a compound of formula la or Ib as defined in the first aspect, wherein R6, R7, R8, and R9 are as defined in the first aspect; R:2 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NI1R, NRR' , nit.ro, Me3Sn and halo; R10 is as defined in the first aspect and R35 is either 0-R11, wherein R11 is defined in the first aspect, or OH, or R10 and R15 together form a double bond between N10 and Cll; and where R" ie a C3.. alkylene group, which chain may be interrupted by one or more heturoatoms, e.g. 0, S, NH, and/or aromatic rings, e.g. benzene or pyridine, and each X is independently selected from 0, S, or NH; K?', R3', R6', R9', R1"', R12', R13' and R15' are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R1G, R1?, R1-' and R15 respectively. Further aspects of the present invention relate to novel compounds of formula Ilia or Illb (including solvates thereof when R10 and R15 form a double bond between N10 and Cll, and pharmaceutical salts thereof), their use in methods of therapy (particularly in treating proliferative diseases), pharmaceutical compositions comprising these, and their use in the manufacture of a medicament for the treatment of a proliferative disease. Def in i t i_ o n s Carbamate-based nitrogen protecting groups Carbamate-based nitrogen protecting groups are well known in the art, and have the following structure: R'10-CK , 0 wherein R'10 is R as defined above. A large number of suitable groups are described on pages 503 to 549 of Greene, T.W. and Wuts, G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., 1999, which is incorporated herein by reference. Particularly preferred protecting groups include Alloc, Troc, Fmoc, CBz, Teoc, BOG, Doc, Hoc, TcBOC, 1-Adoc and 2-Adoc. Also suitable for use in the present invention are nitrogen protecting group which can be removed in vivo (e.g. enzymatically, using light) as described in WO 00/12507, which is incorporated herein by reference-. Examples of these protecting groups include: (Figure Remove)Oxygen protecting groups are well known in the art. A large number of suitable groups are described on pages 23 to 200 of Greene, T.W. and Wuts, G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., 1999, which is incorporated herein by reference. Classes of particular interest include silyl ethers, methyl ethers, alkyl ethers, benzyl ethers, esters, benzoates, carbonates, and sulfonates. Preferred oxygen protecting groups include TBS, THP for the Cll oxygen atom, and benzyl ether for the C7 or C8 oxygen atom (where present). As mentioned above the oxygen protecting group R14 should be orthogonal to the oxygen protecting group R11. Protecting groups which are orthogonal to one another may each be removed using reagents or conditions which do not remove the other protecting qroup. It may also be preferred that any protecting groups used during i.he synthesis and use of compounds of formula I are orthogonal to one another. However, it is often not necessary, but may be desirable, for the carbamate-based nitrogen protecting group and R11 to be orthogona.l to one another, depending on whether the compound of formula Ilia or Illb is to be used with the nitrogen protecting group in place. Substituents The phrase "optionally substituted" as used herein, pertains to a parent group which may be unsubstituted or which may be substituted. Unless otherwise specified, the term "substituted" as used herein, pertains to a parent group which bears one or more substitutents. The term "substituent" is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known. Examples of substituents are described in more detail below. Ci-i2 alkyl : Tne term alkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 12 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below. Examples of saturated alkyl groups include, but are not limited to, methyl (Co), ethyl (C2) , propyl (C3) , butyl (C4) , pentyl (Cb) , hexyl (C,,) and heptyl (C7) . Examples of saturated linear alkyl groups include, but are not limited to, melhyl (d) , ethyl (C2) , n-propyl (C3) , n-butyl (C4) , n-pentyl (amyl) (C^) , n-hexyl (C6) and n~heptyl Examples of saturated branched alkyl groups include iso-propyl !C'j) , iso-butyi (C4), sec-butyl (C), tert-butyl (C4) , iso-pentyl (C5) , ana neti-pent.yl (C.,) . ex.).? Alkenyl: The term alkenyl" as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2) , 1-propenyl ( -CH=CH-CH3) , 2--propenyl (allyl, -CH-CH=CH2) , jsopropenyl ( 1-methylvinyl, -C (CH:i)=CH2) , butenyl (C4) , pentenyl (C5) , andhexenyl (C6) . Cj-12 alkynyl : The term "C2-i2 alkynyl" as used herein, pertains to an alkyl group) having one or more carbon-carbon triple bonds. Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -CsCH) and 2-propynyl (propargyl, - Cs-ia cycloalkyl: The term "C3_12 cycloalkyl" as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 r.ing atoms. Examples of cycloaDkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C.'j) , cyclobutane (C4) , cyclopentane (C5) , cyclohexane (C6) , eye I oheptane (C-,) , methylcyclopropane (C4) , dimethylcyciopropane (C5) , methylcyclobutane (Cs) , dirnethylcyclobutane (Ce) , methylcyclopentane (C6) , dimethylcyclopentane (C7) and methylcyclohexane (C7) ; unsaturated monocyclic hydrocarbon compounds: cyclopropane (C3) , cyclobutene (C^), cyclopentene (C5) , cyclohexene (C,,) , methylcyclopropene (C4), dimethylcyclopropene SCs) , methylcyclobutene (Cs) , dimethylcyclobutene (C6), methylcyc.l openuene (Ce) , dimethylcyclopentene (C7) and methylcyclohexene (Cv) ; and saturated polycyclic hydrocarbon compounds: norcarane (C/) , norpinane (C7) , norbornane (C7) . C3_2o heterocyclyl: The term WC3_20 heterocyclyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. In this context, the prefixes (e.g. C,2o, C3_7, C5_6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term wC5_6heterocyclyl", as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: Ni: aziridine (C3) , azetidine (C) , pyrrolidine (tetrahydropyrrole) (C5) , pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5) , 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5) , piperidine (C6) , dihydropyridine (C6) , tetrahydropyridine (C6) , azepine (C7); ot : oxirarie (C.-,) , oxetane (€„), oxolane (tetrahydrofuran) (C5) , oxole (dihydrof uran) (Cj) , oxane (tetrahydropyran) (C6) , dihydropyrar (':,,), pyran (C6) , oxepin (C-;); Sj : thiirane {,), thietane (C4), thiolane (tetrahydrothiophene) (C5) , thiiane p.ietrrjhydrothiopyran) (C6) / thiepane (d) ; 02 : dioxolarie (C5) , dioxane (C6) , and dioxepane (C-,) ; 03 : trioxane (C6) ; N;, : imidcizolidine (C5) , pyrazolidine (diazolidine) (C5) , iniidazoline (C;,) , pyrazoline (dihydropyrazole) (C5) , piperazirie (C6); NjOj : tetrahydrooxazole (C5) , dihydrooxazole (C5) , tetrahydroisoxazole (C5) , dihydroisoxazole (C5) , morpholine (C()) tetrahydrooxazine (C6) , dihydrooxazine (C6) , oxazine (C6) ; NjSi: thdazoiine (C5) , thiazolidine (Cs) , thiomorpholine (C6) ; N20! : oxadia/..ine (C6) ; OiS] : oxathiole (Cb) and oxathiane (thioxane) (C6) ; and, NjOjS:: oxathiazinc Examples of substituted monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, f uranoses (C5) , such as arabinof uranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C6) , such as allopyranose, a.ltropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose . C5-2U aryl : The term xsC5_2o aryl", as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms. Preferably, each ring has from 5 to 7 ring atoms . In this context, the prefixes (e.g. C3-20, C5_7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms . For example, the term "C5-6 aryl" as used herein, pertains to an aryl group having 5 or 6 ring atoms . The ring atoms may be all carbon atoms, as in "carboaryl groups". Examples of carboaryl groups include, but are not limited to, those derived irom benzene (i.e. phenyl) (C6) , naphthalene (C10) , azulene iC1Lj), anthracene (C14) , phenanthrene (C14) , naphthacene (C18) / and pyrene (Cu) . Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g. 2,3-dihydro-lH-indene) (C9) , indene (C (1, 2, 3, 4-tet railydronaphthalene (C10) , acenaphthene (CJ2) , fluorene (Ci3) , phenalene (Cu) , acephenanthrene (C15) , and aceanthrene (Ci6) . Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups". Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: Nj: pyrrole (azole) (C5) , pyridine (azine) (Cg) ; qi : furar; (oxole) (C5); Si: thiophene ithiole) (C5) ; NjOj : oxazoj.e (Cs) , isoxazole (C5) , isoxazine (C6) ; NjOj: oxadiazole (furazan) (C5) ; NjO]: oxatriazole (Cs); NjSj: thiazole (C5) , isothiazole (C5) ; N2: imidazole (1,3-diazole) (C5) , pyrazole (1,2-diazole) (C5) , pyridazine (1,2-diazine) (C6) , pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6) ; N3: triazole (C5) , triazine (C6) ; and, no : tetrazole (C5) , Examples of heteroaryl which comprise fused rings, include, but are not limited to: Cs (with 2 fused rings) derived from benzofuran (Oi) , isobenzofuran (Oj) , indole (Nj), isoindole (Ni) , indolizine (Nj), indoline (NJ , isoindoline (Ni) , purine (N4) (e.g., adenine, guanine), benzimidazole (Nj) , indazole (N2) , benzoxazole (NjOi) , benzisoxazole (N-iOji, benzodioxole (02) / benzofurazari (NjOJ , benzotriazole fNj) , benzothiofuran (Si), benzothiazole (NiSj.) , b e n z o t h i a d i a 7. c.'. e (N ,, S} ; C1D (with 2 fused rings) derived from chromene (Oa), isochromene (0-;), chroman (Oj.) , isochroman (Oj.) , benzodioxan (O2) , quinoline (N;), isoquinoline (Ni) , quinolizine (Ni) , benzoxazine (N;0j), benzodiazine (N2) , pyridopyridine (N2)/ guinoxaline (N2), quinazoline (N?) , cinnoline (N2) , phthalazine (N2) , naphthyridine (N2) , pteridinc- (N4) ; Cn (with 2 fused rings) derived from benzodiazepine (N2) ; C13 (with 3 fused rings) derived from carbazole (Nj) , dibenz.ofu.T-an (03), dibenzothiophene (Si), carboline (N2) , perimidine (N2), pyridoindole (N2) ; and, Cn (with 3 fused rings) derived from acridine (Ni) , xanthene (Oi) , thioxanthene (Sj), oxanthrene (02) , phenoxathiin (OiSi) , phenazine (N2) , phenoxazine (NjOi) , phenothiazine (N].Si) , thianthrene (S2), phenanthridine (Ni) , phenanthroline (N2) , phenazine (N2) . The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves and the additional substituents listed below. Halo: -F, -Cl, -Br, and -I. Hydroxy: -OH. Ether: -OR, vJherein R is an ether substituent, for example, a Cj-7 alkyl group (also referred to as a d-7 alkoxy group, discussed below) , a C3..ZD heterocyclyl group (also referred to as a C3_20 heterocyclyloxy group), or a C5_20 aryl group (also referred to as a c5-2o aryloxy group), preferably a Cj--/alkyl group. Alkoxy: -OR, wherein R is an alkyl group, for example, a Ci_7 alkyl group. Examples of C^7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy). Acetal: -CHIOP.') (OR:') , wherein R1 and R2 are independently acetal substituents, for example, a Ci--/ alkyl group, a C3_2o heterocyclyl group, or. a C:0 aryl group, preferably a C-, alkyl group, or, in the case of a "cyclic" acetal group, R1 and R2, taken together with the two oxygen atoms to which they are attached, and the carbon atoms to which they are att.ached, form a heterocyclic ring having from 4 to R ring atoms. Examples of acetal groups include, but are not limited to, -CH(OMe)2, -CH(OEt)2, and -CH(OMe) (OEt) . Hemiacetal: -CH(OH)(OR1), wherein R1 is a hemiacetal substituent, for example, a d--, alkyl group, a C3-2o heterocyclyl group, or a Cr,_2D aryl group, preferably a Ci-7 alkyl group. Examples of hemiacetal groups include, but are not limited to, -CH(OH)(OMe) and -CH(OH) (OEt) . Ketal: -CR(ORa) (OR?) , where R1 and R2 are as defined for acetals, and R is a ketal substituent other than hydrogen, for example, a Cj-7 alkyl group, a C3_20 heterocyclyl group, or a C5-20 aryl group, preferably a CM alkyl group. Examples ketal groups include, but are not limited to, -C(Me) (OMe)2, -C(Me) (OEt)2, -C(Me) (OMe) (OEt), -C(Et) (OMe) 2, -C(F,t) (OEt)2, and -C(Et) (OMe) (OEt) . Hemiketal: -CR(OH) (OR1) , where R1 is as defined for hemiacetals, and R is a hemiketal substituent other than hydrogen, for example, a C,.7 alkyl group, a C3-.20 heterocyclyl group, or a C5-20 aryl group, preferably a C]--, alkyl group. Examples of hemiacetal groups include, but are not limited to, ~C(Me)(OH)(OMe), -C (Et) (OH) (OMe), -C(Me) (OH) (OEt), and -C(Et) (OH) (OEt) . Oxo (keto, -one): =0. Thione (thioketone): =S. Imino (iniine) : =NR, wherein R is an imino substituent, for example, hydrogen, Chalky! group, a C3-20 heterocyciyl group, or a (,'5-20 aryl group, preferably hydrogen or a Cl.1 alkyl group. Examples of ester groups include, but are not limited to, =NH, =NMe, =NEt, and =NPh. Formy] (carbaldehyde, carboxaldehyde): ~C(=0)H. Acyl (keto): -C(~0)R, wherein R is an acyl substituent, for example, a C^-, alkyl group (also referred to as Ci_7 alkylacyl or Ci_7 alkanoyl), a C3.2o heterocyciyl group (also referred to as C3-2o heterocyc] ylacyl) , or a Cs-2o aryl group (also referred to as C5-3o arylacyl), preferably a Cj.7 alkyl group. Examples of acyl groups include, but are not limited to, -C(=0)CH3 (acetyl), -C(=0)CH2CH3 (propionyl), -C(=0) C(CH3) 3 (t-butyryl), and -C(=O)Ph (benzoyl, phenone). Carboxy (carboxylic acid): -C(=0)OH. Thiocarboxy (thiocarboxylic acid): -C(=S)SH. Thiolocarboxy (thiolocarboxylic acid): -C(=0)SH. Thionocarboxy (thi.onocarboxylic acid): -C(=S)OH. Imidic acid: -C(=NH)OH. Hydroxamic acid: -C(=NOH)OH. Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=0)OR, wherein R is an ester substituent, for example, a d-7 alkyl group, a C3_2o heterocyciyl group, or a C5-20 aryl group, preferably a Ci_7 alkyl group. Examples of ester groups include, but are not limited to, -C(=0)OCH3, -C (=0) OCH2CH3, -C (=0) OC (CH3) 3r and -C(=C)OPh. Acyloxy (reverse ester): -OC(=0)R, wherein R is an acyloxy nubstitue.nt, for example, a C^.-, alkyl group, a C3_20 heterocyclyl croup, or a 0.,-.20 aryl group, preferably a Cj-7 alkyl group. Examples c,.f acyloxy groap;-, include, but are not limited to, -OC(=0)CH3 (acetoxy. , -OC (-=0) CH2CH3, -OC (=0) C (CH3) 3, -OC (=0) Ph, and -OC(=0)CH^Ph. Oxycarbcyloxy: -OC(=0)OR, wherein R is an ester substituent, for example, a C[..-; alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group), preferably a Ci_7 alkyl group. Examples of ester groups include, but are not limited to, -OC(=0)OCH3, -OC (=0)OCH2CH3, -OC(=0)OC(CH3)3, and -OC (=0) OPh . Amino: -NR-'R', wherein R1 and R2 are independently amino substituents, for example, hydrogen, a C^ alkyl group (also referred to as d..-/ alkylamino or di-Ci_7 alkylamino) , a cb-so heterocyclyl group, or a C5.?o aryl group, preferably H or a Ci--, alkyl group, cr, in the case of a "cyclic" aniino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (-NHj) , secondary (-NHR1), or tertiary (-NH^R2) , and in cationic form, may be quaternary (-+NR1R2R3) . Examples of aniino groups include, but are not limited to, -NH2, --NHCH;,, -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, and -NHPh. Examples of cyclic amj.no groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholinc. Amido (carbamoyl, carbarayl, aminocarbonyl, carboxamide): -C(=O)NRjR2, wherein R1 and R2 are independently amino substituents, as defined for aniino groups. Examples of amido groups include, but are not limited to, -C(=0)NH2, -C(-0)NHCH3, -C (=0) N (CH3) 2, -C (=0)NHCH2CH3, and -C (=0) N (CH2CH3) 2, as well as amido groups in which R! and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbony.i , morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarhonyl. Thioamido (thiocarbamyl): ~C(=S)NR1R2, wherein R1 and R2 are •independently arrdnc substituents, as defined for ami no groups. Examples of am:: do croups include, but are not limited tor --C (=-S}NH?, -C(=S)NHCH3, -C (=S) N (CH3) 2, and -C ( = S) NHCHZCH3 . Acylamido (ac:y.l amino) : -NRIC(=0)R2, wherein R1 is an amide substi tuent, for example, hydrogen, a Cj-7 alkyl group, a C3_zc heterocyc.i yl group, or a Cj,-2o aryl group, preferably hydrogen or a Cj--; alkyi group, and R' is an acyl substituent, for example, a Ci-7 alkyl group, a C:,..2(J heterocyclyl group, or a Cs-zoaryl group, preferabjy hydrogen or a ci-t alkyl group. Examples of acylamide groups include, but are not. limited to, -NHC(=0)CH3 , -NHC(=0)CH2CH3, and -NHC (=0) Ph. R1 and R2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phtha 1 irnidyl: (Figure Remove)Aminocarbonyloxy: -OC(=0)NR:R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of aminocarbonyloxy groups include, but are not limited to, -OC(=0)NH2, -OC(=0)NHMe, -OC (=0)NMe2, and -OC(=0)NEt2. Ureido: -N (R1) CONR2R3 wherein R2 and R3 are independently amino substituentc, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a Ca_7 alkyl group, a C3-20 heterocyclyl group, or a C5-2o aryl group, preferably hydrogen or a ci-t alkyl group. Examples of ureido groups include, but are not limited to, -NT!CONhi; -NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, NMeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, and -NMeCONEt2. Guanidino: -NH-C f=NH)NB2. Tetra/.olyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom, (Figure Remove)J.rnino: ~NR, wherein R is an imino substituent, for example, for example, hydrogen, a Ci_7 alkyl group, a C3-2o heterocyclyl group, or a C5-2o aryl group, preferably H or a Chalky! group. Examples of imino groups include, but are not limited to, =NH, =NMe, and =NEt. Amidine (amtdino): -C(=NR)NR2, wherein each R is an amidine substituent, for example, hydrogen, a ci-t alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group, preferably H or a C1.1 aJkyi group. Examples of amidine groups include, but are not limited to, -C(-NH)NH2, -C(=NH)NMe2, and -C (=NMe) NMe2. Nitro: -NO,. Ndtroso: -NO. Azido: -N-). Cyano (nitrile, carbonitrile): -CN. Isocyano: -NC. Cyanato: -OCN. Isocyanato: -NCO. fsothiocyano (isothxocyanato): -NCS. '•ulfhydryl (Lhiol, mercapto) : -SH. Thioet.her (su.lf.ide) : -SR, wherein R is a thioether substituent, '.or example, a C;-/ alkyl group (also referred to as a Ci^alkylthio qroup) , a C3....;,0 heterocyclyl group, or a C5_20 aryl group, preferably a Cj-7 alkyl group. Examples of C]_-; alkylthio groups include, but are not Limited l.o, ~SCH3 and -SCH2CH3. Disulfide: -S8-R, wherein R is a disulfide substituent, for example, a C-,.-) alkyl group, a C3-2o heterocyclyl group, or a Cr,-2o aryl group, preferably a Cj._i alkyl group (also referred to herein as Ci-v alkyl disulfj.de) . Examples of gi--j alkyl disulfide groups include, but. are not limited to, -SSCH3 and -SSCH2CH3. Sulfine (su.'ltinyl, sulfoxide) : -S(=0)R, wherein R is a sulfine substituent, for example, a C^ alkyl group, a C3-2o heterocyclyl group, or a Cb.2o aryl group, preferably a gi.-j alkyl group. Examples of sulfine groups include, but are not limited to, -S(=0)CH3 and -S (-0) CH2CH3. Sulfone (sulfonyl) : ~S(=0) 2R, wherein R is a sulfone substituent, for example, a C,._7 alkyl group, a C3-20 heterocyclyl group, or a C5.2o aryl group, preferably a C1-1 alkyl group, including, for example, a fluorinated 01 perfluorinated C^ alkyl group. Examples of sulfone groups include, but are not limited to, -S (=0)zCRi (methanesullonyl, mesyl), -S(=0)2CF3 (triflyl), -S(-0) 2CH2CH3 (esyl), -S(=0)2C4FS (nonaflyl), -S (=0) 2CH2CF3 (tresyl) , -S (=0) jCH?CH-,NH2 (tauryl) , -S (=O) 2Ph (phenylsulf onyl, besyl) , 4-methylpheny.1 sulfonyl (tosyl), 4-chlorophenylsulf onyl (closyl), 4-bromophenylculfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and 5-dimethylamino-naphthalen-l-ylsulfonate (dansyl). Sulfinic acid (aulfino): -f (=0)OH, -S02H. Sulfonic acid (sulfo): -S(=0)2OH, -S03H. Sulfinate (sulfinic acid ester): -S(=0)OR; wherein R is a .sulfinate substituent, for example, a Cj-7 alkyl group, a Ca-jo heterocyclyl group, or a C5_20 aryl group, preferably a Ci_7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S(-0)OCH^ (methoxysulfinyl; methyl sulfinate) and -S(=0)OCH2CH, •etho.xysulfinyl; ethyl sulfinate). Sulfonate (su'Jfonic acid ester): -S(=O)2OR, wherein R is a sulfonafe substj tuent, for example, a Ci-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a Cj-? alkyl group. Examples of sulfonate groups include, but are not limited to, -S(K))2OCH3 (methoxysulfonyl; methyl sulfonate) and -S (=0) sOCH?CHi (ethoxysulfonyl; ethyl sulfonate). Sulfinyloxy: -OS(=0)R, wherein R is a sulfinyloxy substituent, for example, a c,..-, alkyl group, a C3..2o heterocyclyl group, or a C5_20 aryl group, preferably a C^ alkyl group. Examples of sulfinyloxy groups include, taut are not limited to, -OS(=0)CH3 and -OS(=0)CH2CH3. Sulfonyloxy: -OS(--0)2R, wherein R is a sulfonyloxy substituent, for example, a C^, alkyl group, a C3.20 heterocyclyl group, or a C5_2o aryl group, preferably a cj-t alkyl group. Examples of sulfonyloxy groups include, but are not limited to, -OS(=0)2CH3 (mesylate) and -OS(=0)2CH2CH3 (esylate) . Sulfate: -OS(-0)2OR; wherein R is a sulfate substituent, for example, a C^7 alkyl group, a C3_20 heterocyclyl group, or a C5.-20 aryl group, preferably a Chalky! group. Examples of sulfate groups include, but are not limited to, -OS(=O)2OCH3 and -SO(=0)2OCH:.CH3. Sulfamyl (sulfamoy.'l ; sulfinic acid amide; sulfinamide) : -E (=0) nr'r' , wherein R1 and R2 are independently ami no substituents, as defined for amino groups. Examples of sulfamyl groups include, out are not limited to, -S(=0)NH2, -S (=0) NH (CH3) , -S (=0) N (CH3) 2, -S (=0) Nl-i iCHvf'H3) , -S (=0)N (CH2CH3)2, and -S(=0)NHPh. Kulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): - S (=O) 2NRaR?, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of culfonamido groups include, but are not limited to, ~S(=Q)2NH2, -S (=O)2NH(CH3) , -S (--0)2N(CH3)2, -S (=0) 2NH (CH2CH3) , -S (=0) 2N (CH2CH3) 2, and -S (=0)2NHPh. Sulf amino: --NR^ (=0) 2OH, wherein R1 is an amino substituent, as defined for amino groups. Examples of sulfamino groups include, but are not limited to, -NHS(=0)2OH and -N(CH3) S(=0)2OH. Sulf onaird no: -NR1S(=0)2R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, d C. -, alkyl group, a C3-20 heterocyclyl group, or a Cs^20 aryl group, preferably a Cj_v alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS(=0)2CH3 and -N(CH3)S(=0)2Cr)H.,. Sulfinamino: ~NR1S(=0)R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a Ci_, alkyl group, a C3_20 heterocyclyl group, or a 05-20 aryl group, preferably a Cj-7 alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS(=0)CH3 and -N (CH3) S(=0)C6H5. Phosphirio (phosphine) : -PR2, wherein R is a phosphino substituent, for example, -H, a Cj.-/ alkyl group, a C3.20 heterocyclyl group, or a C5_2Q aryi group, preferably -H, a Ci_7 alkyl group, or a C5-2o aryl group. Examples of phosphino groups include, but are not limited to, -PH2, -P(CH.,)2, P(CH2CH3)2, -P(t-Bu)2, and-P(Ph)2. Phospho: -P(=-0)2. Phosphiny.l (phosphine oxide) : -P(=0)R2, wherein R is a phosphinyl substituent, for example, a alkyl group, a C3..20 heterocyclyl group, or a (V,,0 aryl group, preferably a alkyl group or a C5.2D aryl group. Examples of phosphinyl groups include, but are not limited to, -P (-0) (CH3) 2, -P (=0) (CH2CH3) 2, -P (=0) (t-Bu) 2, and -P(=0) (Ph);,. Phosphonic acid (phosphono): -P(=0)(OH)2. Phosphonate (phosphono ester): -P(=0)(OR)2, where R is a phosphorate substituent, for example, -H, a Ci-7 alkyl group, a C3-20 heterocyclyl group, or a Cs-2o aryl group, preferably -H, a cj-t alkyl group, or a C5-2c aryl group. Examples of phosphonate. groups .include, bat are not limited to, -P (=0) (OCH3)2, -P (=0) (OCH2CH3)2, -P(=0) (0-t-Bu),, and -P(=0) (OPh)2. Phosphoric acid (phosphonooxy): -OP(=0) (OH)2. Phosphate {phosphonooxy ester): -OP(=0)(OR)2, where R is a phosphate substituent, for example, -H, a alkyl group, a CV20 heterocyclyl group, or a C5.2o aryl group, preferably -H, a C3--) alkyl group, or a Cb.,20 aryl group. Examples of phosphate groups include, but are not limited to, -OP(=0) (OCH3)2, -OP(=0) (OCH2CH3)2, -OP(=0) (0-t-Bu)?, and ~OP(=0)(OPh)2. Phosphorous acid: -OP(OH)2. Phosphite: -OP(OR)2, where R is a phosphite substituent, for example, -H, a C,--, alkyl group, a C3_20 heterocyclyl group, or a C5_20 aryl group, preferably -H, a alkyl group, or a C5-20 aryl group. Examples o£ phosphite groups include, but are not limited to, -OP(OCH3)2, -OP(OCil2CIi3)2, ~OP(0-t-Bu)2, and -OP (OPh) 2. Phosphoramidite: -OP (OR1) -NR22, where R1 and R2 are phosphoramidite .substituents, i or example, -H, a (optionally substituted) Ci_7 alkyl qroup, a r:r,_:,B hete.rocyc.lyl group, or a C5-20 aryl group, preferably -H, a Cj-7 aikyl qroup, or a C5,20 aryl group. Examples of phosphorainiditfc groups include, but are not limited to, -OP(OCH2CHj) -N (CH3) j, -OP (OCH2CH3)-N(i-Pr)2, and -OP(OCH2CH2CN)-N(i- Phosphoramidat: -OP (=0), where R1 and R2 are phosphoramidate substituents, for example, -H, a (optionally substituted) alkyl group, a C3-20 heterocyclyl group, or a C5_20 aryl group, preferably -H, a ci-t alkyl group, or a CV2o aryl group. Examples of phosphoramidate groups include, but are not limited to, -OP(=0) (OCH2CH3) -N(CH3)?, -OP (=0) (OCH2CH3) -N (i-Pr) 2, and -OP(=0) (OCH2CHiCN)-N(i-Pr)2 . Alkylene C3_i2 alkyj.enti: The term "C3-i2 alkylene", as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound having from 3 to 12 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below. Examples of linear saturated C3_12 alkylene groups include, but are not limited to, -(CH2)n- where n is an integer from 3 to 12, for example, -CH2CH2CH?- (propylene) , -CH2CH2CH2CH2- (butylene), -CH?CH2CH2CH2CH2- (pentylene) and -CH2CH2CH2CH2CH2CH2CH2- (heptylene) . Examples of branched saturated C3-i2 alkylene groups include, but are not Jimiued to, -CH (CH3) CH2-, -CH (CH3) CH2CH2-, -CH (CH3) CH2CH2CH2-, -CHjCH (CH3}CH,-, -CHjCH(CH3)CH2CH2-, -CH (CH2CH3)-, -CH (CH2CH3) CH2-, and CH2CU (CH:,CH:i.CH2~. Examples of .Linear partially unsaturated C3-i2 alkylene groups (C3-i2 alkenylene, and alkynylene groups) include, but are not limited to, -CH=CH-CHj-, -CH2-CH=CH2-, -CH=CH-CH2-CH2-, -CH=CH-CH2-CH2-CH2-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH2-, -CH=CH-CH=CH-CH2-CH2-, -CH=CH-CH2-CH=CH- , -CH=CH-CH2-CH2~CH=CH-, and -CH2-CsC-CH2-. Examples of branched partially unsaturated C3_lz alkylene groups (C3_ 12 alkenylene and alkynylene groups) include, but are not limited to, -C (CH:J) =0rl-, -C(CH3)=CH-CH2-, -CH=CH-CH (CH3) - and -C=C-CH(CH3) - . Examples of alicyclic saturated C3_i2 alkylene groups (C3.12 cycloalky.1 enes) include, but are not limited to, cyclopentylene (e.g. cyciopent-1,3-ylene), and cyclohexylene (e.g. cyclohex-1,4-ylene). Examples of alicyclic partially unsaturated C3_12 alkylene groups (C3-i2 cycloalky] enes) include, but are not limited to, cyclopenteny]ene (e.g. 4-cyclopenten-l,3-ylene), cyclohexenylene (e.g. 2-cyclohexen-l,4-ylene; 3-cyclohexen-l,2-ylene; 2,5-cyclohexadien-l,4-ylene). Proliferat1ve Dlseases One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a proliferative condition for any particular cell type. For example, assays which may conveniently he used to assess the activity offered by a particular rompound are described in the examples below. The term "proliferative disease" pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of prolifcrative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not -Limited lo, neoplasms and tumours (e.g. hjstocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, .small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, Lest: icular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproilferative disorders (e.g. of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancieas, brain, and skin. Methods of. Treatment As described above, the present invention provide the use of a compound of formula Ilia or Illb in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of formula Ilia or Illb, preferably in the form of a pharmaceutical composition, which is the third aspect of the present invention. The term "therapeutically effective amount" is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the respons.ibi.lity of general practitioners and other medical doctors. A compound may be administered alone or in combination with other treatmentk, wither simultaneously or sequentially dependent upon the condition:o be treated. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs; surgery; and radiation therapy. If tne compound of formula Ilia or Illb bears a carbamate-based nitrogen protecting group which may be removed in vivo, then tne methods of treatment described in WO 00/12507 (ADEPT, GDEPT and PDT) may be used. Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in add:it:Jon to the active ingredient, i.e. a compound of formula Ilia or: Illb, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous. Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin. For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parente.rally acceptable aqueous solution which is pyrogeri-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloridf; injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required. Tneludes _0t.]ie_£ Forms Unless otherwise; specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituer.ts . For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COCT) , a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-N1HR1Fa), a salt or solvate of the amino group, for example, a hydrochlo.ride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0") , a salt or solvate thereof, as well as conventional protected forms. Isomers, Salts _and Solvates Certain compounds may exist in one or more particular geometric, optical, enaritiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forrns; c-, t-, and r- forms; endo- and exo-forms; R~, S-, and rneso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal-and anticlinal-forms; a- and (3-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "dsomeric forms"). Preferably compounds of the present invention have the following stereochemistry at the Cll position: (Figure Remove)Note t.hat, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structura] (or constitutional) isomers (i.e. isomers which differ in the; connections between atoms rather than merely by the position of atoms in space) . For example, a reference to a methoxy group, -OCI-U, is not to be construed as a reference to its structural i.'jomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. C^ alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxypheriyl ) . The above exclusion does not pertain to tautomeric forms, for example, keto--, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitio. (Figure Remove)Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D) , and 3H (T) ; C may be in any isotopic form, including 12C, 13C, and 14C; 0 may be in any isotopic form, including 160 and 1B0; and the like. Unless otherwise specified, a reference to a particular compound includes all such :i someric forms, including (wholly or partiaJly) racern.ic end other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms cire either known in the art or are readily obtained by adapting the methods '.aught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al, , J. Pharm. Sci., 66, 1-19 (1977). For example, if the compound is anionic, or has a functional group which may be anionic (e.g. -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Alt3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH/} and substituted ammonium ions (e.g. NH3R+, NH2R2*, NHR3+, NR4+) . Examples of some suitable substituted ammonium ions are those derived from: ethylamine, djethylamine, dicyclohexylamine, triethylamine, butylarnine, et.hylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamjne, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)/. If the compound is cationic, or has a functional group which may be cationic (e.g. ~NH2 may be -NH3+) , then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acrid.--,: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutaraic, glycolic, hydroxymaJeic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesu.! fonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluener.ulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. A particular salt form of interest can be formed from compounds of formula Ilia and Illb, where R10 and R15 form an imine bond, by reacting said compound with a bisulphite salt to form a bisulphite derivative of the PBD. These compounds can be represented as: (Figure Remove)M arid M' are independently monovalent pharmaceutically acceptable cations, or together form a divalent pharmaceutically acceptable cation, and the other groups are as previously defined. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute- (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a rii-hydrate, a tri-hydrate, etc. Solvates of particular relevance to the present invention are those where the solvent adds across the imine bond of the PBD moiety, which is illustrated below where the solvent is water or an alcohol (RhOH, where RB is an ether substituent as described above) : (Figure Remove)These forms can be called the carbinolamine and carbinolamine ether forms 01 the PBD. The balance of these equilibria depend on the conditions in which the compounds are found, as well as the nature of the moiety itself. In general any nucleophilic solvent is capable of forming such solvat.es as illustrated above for hydroxylic solvents. Other nucleophilic solvents include thiols and amines. These soivates may be isolated in solid form, for example, by lyophilisation . Gen e ra ] The syrithes: r- of PBD compounds is extensively discussed in WO 00/12508, which discussion is incorporated herein by reference. As discussed in that patent application, a key step in a preferred route to PBDs is a cyclisation to produce the B-ring, involving generation of an aldehyde (or functional equivalent thereof) at what will be the ]l-position, and attack thereon by the Pro-NlO-nitrogen: (Figure Remove)wherein the substituents are as defined in the second aspect of the invention and R12 and R13 are either OR" and RA respectively or RA and OR1" repectively i.e. the protected hydroxyl group may be at either the C7 or C8 position with the other position being RA. The "masked aldehyde" -CPQ may be an acetal or thioacetal, in which case the cyclisation involves unmasking. Alternatively, it may be an alcohol -CHOH, in which case the reaction involves oxidation, e.g. by means of TPAP, TEMPO or DMSO (Swern oxidation). The masked aldehyde compound can be produced by condensing a corresponding 2,4-substituted pyrrolidine with a 2-nitrobenzoic acid: (Figure Remove) The n.itro group can then be reduced to -NH2 and protected by reaction with a suitable agent, e.g. a chloroformate, which provides the removable nitrogen protecting group in the compound of formula IV. A process Involving the oxidation-cyclization procedure is illustrated in scheme 1 (an alternative type of cyclisation will be described later with reference to scheme 2). (Figure Remove)Exposure of the alcohol (B) (in which the Pro-NlO-nitrogen is generally protected as carbamate) to tetrapropylammonium perruthenate (TFAP) /N-methylrnorpholine N-oxide (NMO) over A4 sieves results in oxidation accompanied by spontaneous B-ring closure to afford the desired product IV. The TPAP/NMO oxidation procedure .is found to be particularly convenient for small scale reactions while the use of DMSO-based oxidation methods, particularly Swern oxidation, proves superior for larger scale work (e.g. > 1 g) . A particularly preferred oxidising agent is (diacetoxyiodoibenzene (1.1 eq) and TEMPO (0.1 eq) dissolved in CH2C12. The uncyclized alcohol (B) may be prepared by the reaction of a nitrogen protection reagent of formula D, which is preferably a chlorofurinate or acid chloride, to a solution of the amino alcohol C, generally in solution, generally in the presence of a base such as pyridine (preferably 2 equivalents) at a moderate temperature (e.g. at. 0°C). Under these conditions little or no 0-acylation is usually observed. The key amino alcohol C may be prepared by reduction of the corresponding nitro compound E, by choosing a method which will leave the rest: of the molecule intact. Treatment of E with tin (II) chloride in a suitable solvent, e.g. refluxing methanol, generally affords, after the removal of the tin salts, the desired product in high yield. Exposure of E to hydrazine/Raney nickel avoids the production of tin salts and may result in a higher yield of C, although this method is less compatible with the range of possible C and A-ring substituents. For instance, if there is C-ring unsaturation (either in the ring itself, or in R2 or R3), this technique may be unsuitable. The nit.ro compound ot formula E may be prepared by coupling the appropriate o- ru trohenzoyl chloride to a compound of formula F, e.g. in the presence of K.2CG3 at -25 °C under a N2 atmosphere. Compounds of formula F can be readily prepared, for example by o!l efination of the ketone derived from L-trans-hydroxy proline. The ketone intermediate can also be exploited by conversion to the enol triflate for use in palladium mediated coupling reactions. The o-nitrobenzoyl chloride is synthesised from the o-nitrobenzoic acid (or alky.I. ester after hydrolysis) of formula G, which itself is prepared from the vanillic acid (or alkyl ester) derivative H. Many of these are commercially available and some are disclosed in Althuls, T.H. and Hess, H.J., J. Medicinal Chem., 20(1), 146-266 (1977). (Figure Remove) the final or penultimate step was an oxidative cyclisation. An alternative, using thioacetal coupling, is shown in scheme 2. Mercury-mediated unmasking causes cyclisation to the protected PBD compound IV. The thioacetal compound may be prepared as shown in scheme 2: the thioacetal protected C-ring [prepared via a literature method: Langley, D.R. & Thurston, D.E., J. Organic Chemistry, 52, 91-97 (1987)] is coupled to the o-nitrobenzoic acid (or alkyl ester after hydrolysis) (G) using a literature procedure. The resulting nitro compound cannot be reduced by hydrogenation, because of the thioaceta] group,, so the tin (II) chloride method is used to afford the amine. Thir, as then N-protected, e.g., by reaction with a r:hloroiormate or acid chloride, such as 2,2,2-Lr:i chl or oe thy .Lchlor ;.; formate . Acetal-containing C-rings can be used as an alternative in this type of route with deprotection involving other methods, including the use of acidic conditions. Alternative routes to PBDs Alternative methods of synthesising N10 protected PBDs are disclosed jn co-pending application PCT/GB2004/003873 (filed 10 September 2004) which claims priority from GB0321295.8 (filed 11 September 2003), which describes the use of isocyanate i intermediates, Formation of compounds Ilia and Illb (Scheme 3} (Figure Remove)Formation of the protected compound Illb dimer from compound Ib is illustrated, however, protected compound Ilia is formed in an analogous manner with compound la as the starting material. The PBD dimer compound Ilia or Illb may be synthesized by dimerisation of compounds of formula la or Ib respectively following deprotection of the OH group at either the C7 or C8 position. The synthesis route illustrated in scheme 3 shows compounds when the dimer linkage is of the formula -0-(CH2) n~0-. The protected dimer Ilia or Illb may be formed from compounds of formula la or Ib respectively through reaction with a disubscitut.eti linking chain. The linking chain is preferably of the genera.1. form Y-R"-Y' where R" is as previously defined and Y and Y' are gioupt which can be reacted with an alcohol to form an ether linkage;. Y and Y' are preferably independently selected from 1, Br, 01, OH, mesylate or tosylate. In a preferred aspect, Y and Y' are the same. In a preferred aspect Y and Y' are both i.odo- groups Where Y and/or Y' j.s 1, Br, Cl, mesylate or tosylate, the Y-R"-Y' reactant is coupled to the compound of formula la or Ib by a simple elimination reaction with Y and Y' as leaving groups. For example where che linking chain is -O-CHj-CHg-CHj-O-, the compound of formula la or Ib is reacted with 1,3-diiodopropane in the presence of K2C03. Generally, where the linking chain is a straight chain alkyl ether of the form -0-(CH2) n-0-, the compound of formula la or Ib is preferably reacted with the corresponding I, n-diiodoalkane. Where Y and/or Y' is OH, the Y-R"-Y' reactant is coupled to the compound of formula la or Ib under Mitsunobu conditions. It .is important that the OH protecting group at Cll in formula la or Ib is orthogonal to the OH protecting group at C7 and/or C8. This allows the 07 and/or C8 protection to be removed to give the free alcohol to allow dimerisation whilst the Cll OH group remains protected arid therefore unreactive under the dimerisation conditions. Following dimerisation, the inline bond in the compound of formula Illb-prot can be deprotected by standard methods to yield the unprotected compound Illb (which may be in its carbinolamine or carboinolamine ether form , depending on the solvents used). For example if R10 is Alloc, then the deprotection is carried using palladium to remove the N10 protecting group, followed by the elimination of water. If R10 is Troc, then the deprotection is carried out a Cd/Pb couple to yield the compound of formula Illb. Compound Ilia may be formed in an analogous manner via deprotection ol t:he protected inline. If the nitrogen protecting group (R10) is such that the desired end product still contains it, e.g. if it is removable in vivo, then the Cll deprotected forms of compounds of formula Ilia or Illb may he synthesised by removal of the oxygen protecting groups under suitable cond.ii.donr, to leave the R10 group in unaffected. The above de.seribed methods are suited to the synthesis of dimers where both the PBD monomers have the same substituent pattern. One method of synthesising a dimer where the substituent pattern of the two PBO monomers is not the same involves protecting one end of the compound Y-R"-Y' (or using an already protected compound) , coupling a PBD monomer to the unprotected end, deprotect: ing the other end and coupling a different PBD monomer to the free end. This route is shown in scheme 4. (Figure Remove)Where YProt, is a protected version, or precursor to If Y' is protected then the protecting group used should be orthogonal to those on the rest of the molecule, in particular, R10 and R11. One example of this route, would be to have Y as -OH and YProt as -0-benzyl. The first monomer could be joined by Mitsunobu coupling, the benzyl hydroxy deprotected, and then the free hydroxy coupled :o the second monomer by a further Mitsunobu reaction. Compound of formula Ja or Ib (Figure Remove)Following cyclisatJon to form the B-ring, the Cll-alcohol IV is then preferably protected, by conventional means to provide II. For example, if P.11 .is THP, the protection can take place by reacting IV with dihydropyran (DHP) and catalytic p-toluene sulfonic acid. Cleavage of the C7 or CB-protecting group from II then provider, the corresponding C7 or C8 alcohol. For example, where the C7 or C8 protecting group (R12 or R13) is a benzyl ether, th.i s deprotection may be performed by reaction with H2 catalysed by palladium on carbon. This protection at the Cll position and deprotection of the C7 or C8 alcohol allows subsequent reaction of selectively the C7 or C8 alcohol position, for example to form the dimer compound Ilia or Illb leaving the Cll position unaffected. Further Pr e_f e re nee s The following preferences may apply to all aspects of the invention as described above, or may relate to a single aspect. The preferences may be combined together in any combination. Rs is preferably H. R2 is preferably R, and is more preferably an optionally substituted C5-20 aryl group. Most preferred is an optionally substituted phe.ny.1 group. K6 is preferably selected from H, OH, OR, SH, NH2, nitro and halo, and is more preferably H or halo, and most preferably is H. RA is preferably independently selected from H, OR, SH, SR, NH2, NHR, NRR', and halo, and more preferably independently selected from H and OR, where R is preferably selected from optionally substituted CV', alkyl, C3_10 heterocyclyl and C5-10 aryl groups. In the first aspect of the invention, R10 is preferably BOC or Troc. R11 is preferably THP or a silyl oxygen protecting group (for example TBS) and RR is preferably selected from OMe and H. In a most preferred first aspect of the invention, R10 is BOC, R11 is THP and RA is OMe. In the second aspect of the invention, at least one of R1" is preferably a benzyl ether and RA is preferably OMe or H. R11 is preferably THP or a. silyl oxygen protecting group (for example TBS). Accordingly, in a particularly preferred embodiment of the second aspect of the invention R;' is OMe and R11 is THP or TBS. Furthermore, R10 is preferably BOC. In some embodiments of the third aspect of the invention, R10 is preferably BOC and R15 is 0-R11, wherein R11 is preferably THP or a silyl oxygen protecting group (for example TBS). In other embodiments of the third aspect of the invention, R10 and R15 together form a double bond between N10 and Oil. In some aspects of the third embodiment of the invention, the two PBD monomer units are linked at the C7 and C7' positions. In other aspects of the third embodiment of the invention, the two PBD monomer units are linked at the C8 and C8' positions. 1- (3-dimethylam:nopropyl)-3-ethylcarbodiimide (EDCI) (6.33 g, 33.0 mmo.'l , 1.1) equiv) was added to a stirred solution of the acid 1 (10 g, 33.0 mol, 1.0 equiv) in anhydrous DCM (300 mL) under a nitrogen atmosphere a;: OC. After stirring for 10 minutes the mixture was treated with HOBt (4.46 g, 33.0 mmol, 1.0 equiv) and few drops of DMF and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was again cooled down to 0°C and treated with dropwise with a solution of pyrrclidinemethanol (5 g, 49.50 mmol, 1.5 equiv) in anhydrous DCM (100 mL). When the reaction mixture was complete, as indicated by TLC (EtOAc), the reaction mixture was diluted with DCM, washed with IN HC.l (100 mL) , saturated NaHC03 (100 mL) , brine (100 mL) , dried (MgSO.,) , filtered and evaporated in vacuo. The title compound was isolated by flash column chromatography (SiOz, 50% EtOAc-hexane) to afford the coupled compound 2 (10 g, 25.7 mol, 78%) as a brown oil: [a]2DD = -77" (c = 0.22, CHC13) ; lti NMR (CDC13, '•100 MHz): o 1.65-1,92 (m, 3H, 1-H, 2-H), 2.10-2.22 (m, 1H, 1-H), 2.96-3.08 (Hi, 2H, 3-H) , 3.62-3.90 (m, 2H, 11-H) , 3.98 (s, 3H, 7-OMe), 4.29-4.43 (m, 2H, lla-H, OH), 5.24 (s, 2H, OBn), 6.81 (s, 1H, 6-H) , ".31- 7.47 (m, 5H, Ph), 7.72 (s, 1H, 9H) ; 13C NMR (CDC13, •100 MHz): 6 24.3, 28.4, 49.4, 56.5, 61.4, 66.0, 71.4, 101.4, 110.9, 12V.0, ]27.j, 127.4, 128.3, 128.5, 128.81, 128.87, 135.0, 137.3, 149.6, 153.4; IK (neat): 3391, 2971, 2888, 1620, 1576, 1523, 144], 1336, 1277, 1222, 1061 cm"1; MS (FAB) m/z (relative intensity) 409 ([M+Na]+-, 58), 387 (M *', 100), 285 (13). (b) (2-Amino~5~benzyloxy-4-methoxybenzoyl) -pyrrolidine-2~methanol (3) (Figure Remove)A solution of the nitro compound 2 (15.49 g, 40.12 mmol, 1.0 equiv) and tin (II) chloride (45.27 g, 200.64 mol, 5.0 equiv) in methanol (300 mL) was heated at reflux for 4 h. Excess solvent was removed by rotary evaporation under reduced pressure. The preferred aspect;:, of the third embodiment of the invention, the ;-;ubst3 tuent groups on C7, C8, N10 and Cll are the same on each monomer unit. thai, makes up the dinners of the third aspect of the .invention. in is 1 urther preferred that the substituent groups on all positions of each mononmer unit that make up the dimer are the same . Novel compounds of the present invention preferably have R1D and R15 forming a double bond between N10 and Cll. Preferably, the novel compounds of: the invention are dimers through C7 or C8, i.e. the R1 or RE groups of each monomer form together a dimer bridge having the formula -X-R"-X- linking the monomers. More preferably, the dimer bridge is of formula -0-(CH2) n-O-, where n is 3 to 12, more preferably for the dimers linked at the C8 position, n is 7 to 12, more preferably n is 7 to 11 and even more preferably n is 1, 9 or 11; for the dimer Jinked at the C7 position, n is preferably 3 to 1.2, more preferably 3, 5, or 7. The preferences for R6, R7 and R9 are as expressed above. Preferably, R12 and R13 are independently selected from ft, OH, OR, SH, NH2, nitro and halo. More preferably R12 and R1J are independently selected from H, OH and OR. Most preferred is R12 and R13 as OMe. If R is optionally substituted C.i_12 alkyl, it is preferred that it is optionally substituted cj-t alkyl. Example 1 - Synthesis of PBD monomer - (US, llaS) -10- (tert-Butyloxycarbonyl)-7-hydroxy-8-methoxy-ll-(tetrahydroxy-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro~5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (7) (a) (5-Benzyloxy-4~methoxy~2-nitrobenzoyl) -pyrrolidine-2-methanol (Figure Remove)was treated carefully with a saturated aqueous sodium bicarbonate sc.lut.ion to basify the mixture to pH 9. The resulting suspension was allowed to stir ove:rnight with ethyl acetate (100 mL), and iiitrated through Celite to remove precipitated tin •salts. The aqueous phase was extracted with EtOAc (2x50 mL) , and the combined organic phase washed with brine (50 mL), dried (MgSOj , and evaporated in vavuo to provide 3 as a pink oil, which was used in the subsequent reaction without further purification: ia]20n = -971-' (c = 0.18, CHC13) ; 3H NMR (CDC13, 400 MHz): 5 1.50-1.81 (m, 3H, ]-H, 2-H), 2.05-2.15 (m, 1H, 1-H), 3.03-3.16 (m, 1H, 3-H), 3.23-3.36 (m, 1H, 3-H), 3.56-3.78 (m, 2H, 11-H), 3.88 (s, 3H, 7-OMe) , 4.21-4.36 (m, 1H, lla-H), 4.47-4.75 (m, 1H, 3-H), 5.03 (d, :.1H, J= 12.4 Hz, OBn), 5.10 (d, 1H, J = 12.4 Hz, OBn), 6.26 (s, 1H, 9-H), 6.6G (s, 1H, 6-H), 7.28- 7.41 (m, 5H, Ph); 13C NMR (CDClj, 400 MHz): 5 24.8, 28.5, 51.1, 55.7, 61.1, 67.5, 72.5, 100.8, 116.9, .127.5, 127.7, 128.4, 137.4, 138.8, 142.6, 153.0, 171.1, 171.7; IP. (neat): 3436, 33.52, 29.67, 28.73, 1621, 1589, 1513, 1448, 1402, 1264, 1216, 1172, 1110, 1025cm"1; MS (FAB) m/z (relative intensity) 379 ([M+Na]+', 5), 357 (M +', 100), 255 (58). (c) N- [5--Benzyloxy-2- (tert-butyloxycarbonylamino) -4-methoxybenzoyl/-pyrrolidine-2~methanol (4) (Figure Remove)A solution of amine 3 (8 g, 22.47 mmol, 1.0 equiv) and Di-tert-butyl dicarbonate (7.35 g, 33.70 mmol, 1.5 equiv) in THF (150 mL) was heated at reflux overnight. The reaction mixture was allowed to cool to RT and excess THF was removed under reduced pressure to give the crude product. The residue was subjected to flash column chromatography (Si02, 30% EtOAc-hexane) to afford the product 4 (6.2 g, 13.59 mmol, 60%) as yellow oil: [a]20D = -106° (c = 0.198, CHC13); Ml NMR (CDC13, 400 MHz): 5 1.47 (s, 9H, Boc) , 1 .50-1 .77 (m, 3H, ]-H, 2--H), 2.03-2.15 (m, 1H, 1-H), 2.83-3.00 (m, 1H, 3-H), 3.09-3.24 (m, l.H, 3-H), 3.56-3.84 (m, 2H, 11-H), 3.90 (s, 3H, 7-OMe), 4.21-4.43 (m, 2H, lla-H, OH), 5.07 (d, 1H, J = 13 Hz, OBn), 5.19 (d, 1H, J= 13 Hz, OBn), 6.68 (s, 1H, 6-H), 7.26- 7.38 (m, 5H, Ph), 7.R5 (s, 1H, 9-H), 8.60 (s, 1H, NH) ; 13C NMR (CDClj, 400 MHz): 5 21.0, 20.33, 28.36, 51.1, 56.0, 61.1, 66.8, 71.6, 80.3, 104.4, 127.2, 1?7.8, 128.5, 133.5, 137.1, 141.4, 152.1, 153.1, 171.6; TH meat;: 1350, 2975, 1721, 1596, 1520, 1453, 1395, 1240, 1158, 11J 3, JO/19 cm"1; MS (FAB) m/z (relative intensity) 479 ( (M -t-NaT', 40), 4.c-7 (M '•, 100), 357 (51). id) (llS,llaSi-7-Benzyloxy-10-(tert-butyloxycarbonyl) ~ll-hydroxy-8-methoxy-'i ,2,3,10,11,1 la-hexahydro-5H~pyrrolo [2,1-c][1, 4]benzodlazepine-5-one (5) (Figure Remove)To a solution of Boc protected amine alcohol 4 (6.2 g, 13.59 nunol, 1.0 equiv) in DCM (50 mL), BAIB (4.82 g, 14.95 mmol, 1.1 equiv) and TEMPO (0.21 g, 1.35 mmol, 0.1 equiv) were added and the mixture was stirred overnight. When the reaction was complete as indicated by TLC (Si02, 50% EtOAc-hexane), the reaction mixture was diluted with DCM (100 mL) and washed with saturated Na2S203 (60 mL) . The aqueous layer was extracted with DCM (2x50 mL) and the combined organic layer was washed with brine (50 mL) and dried (MgSOo). Removal of excess solvent under reduced pressure afforded a crude solid which was washed with cold EtOAc to give cyclized PBD 5 (4.9 g, 10.8 mmol, 79%) as white solid: [a]20D = +146° (c = 0.178, CHC1:I); nH NMR (CDC13, 400 MHz): 5 1.40 (S, 9H, Boc),1.93-2.18 (m, 28.7, 16.3, 5t-..l, b9.6, 70.9, 7 f , . 7 , 77.0, 77.3, 81.7, 85.7, 112.3, 112.9, .125.'!, l."7.5, 128.0, 128.5, 129.6, 136.4, 147.2, 151.0, 159.0, Hif>.9; JR. meat): 3372, 2977, 2879, 1698, 1622, 1514, 1450, ]393, 1368, 1326, 1279, 1215, 1162, 1135, 1103, 1052, 1025cm"1; MS (FAB) m/z (re.lat.ive intensity) 477 ( [M + Na]"", 35), 455 (M +' , 100) , 399 (85) , 337 (20) . (e) (1 IS, } laS) - 7-Benzyloxy-10- (tert-butyloxycarbonyl) -8-methoxy-1 1- (tetrahydroxy-pyran-2-yloxy) -1,2,3,10,11, lla~hexahydro-5H~ pyrrolo ! 2 , l~-c] [1 , 4 ]benzodiazepine-5-one (6) (Figure Remove)A catalytic amount, of PTSA was added to a solution of DHP (2.87 g, 34.14 mrnol, 5.0 equiv) in EtOAc (10 mL) at 0°C. After stirring 10 minutes, the cyclized compound 5 (3.1 g, 6.8 mmol, 1.0 equiv) was added portion-wise to the mixture and the resulting mixture was stirred untJl starting material disappearance by TLC (Si02, 50% EtOAc-hexane) . The mixture was diluted with EtOAc (100 mL) , washed with saturated NaHC03 (30mL), brine (30 mL) and dried (MgS04). Removal of excess solvent afforded the protected compound 6 (3.5 g, 6.5 mmol, 95% yield, mixture of diastereomers from THP protecting group) , which was used in the subsequent reaction without further purification: [a]20D = +33° (c = 0.21, CHC13) ; lli NMR (CDC13, 400 MHz): 6 1.36 (s, 18H, Hoc) , 1 . 47-1 . 92 (m, 12H, THP), 1.93-2.20 (m, 8H, 1-H, 2-H) , 3.41-3.75 (m, 8H, 3-H, lla-H, THP), 3.84-4.09 (m, 8H, 7-OMe, THP), 4.82-5.28 (m, 6H, OBn, THP), 5.69-5.79 (d, 1H, 11-H), 5.80-5.91 (d, 1H, 11-H), 6.54 (s, 1H, 9-H), 6.91 (s, 1H, 9-H), 7.27- 7.47 (m, 12H, 6-H, Ph) ; 13CNMR (CDC13, 400 MHz): 5 19.8, 23.2, 25.31, 25.34, 25.4, 28.1, 28.2, 28.8, 29.1, 30.7, 30.9, 46.2, 55.9, 56.2, 60.0, 60.1, 63.3, 63.4, 70.94, 70.98, 81.0, 01.3, 88.2, 91.2, 98.4, 100.3, 112.0, 112.1, 113.6, 114.2, 126.4, 127. 50, 127.54, 127.9, 128.0, 128.56, 128.58, 130.2, 136.5, 136.6, 147. -1, 147.7, 151,0, 151.4, 159.0, 159.5, 167.2, 167.4; TR (neat:): ;- (f) (US, 1 laS) -.7 0- ('tert-ButyloxycarbonyJ j -7-hydroxy-8-methoxy-ll-\\.ettahydrQxy-py xan-2-yloxy) -1,2, 3,10,11, lla-hexahydro-5H-pyrrol o "{?., 1-c] ,4]benzodiazepine-5-one (7) (Figure Remove)A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 6 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3h at 35 Psi . When the reaction was complete as indicated by TLC (SiOs, 50%Et:OAc-hexane) the reaction mixture was filtered through Celir.e, and removal of excess solvent under reduced pressure afforded the phenol 7 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [ai2'J,, = +52° (c = 0.183, CHC13) ; JH NMR (CDC13, 400 MHz): 6 1.35 (s, 18H, Hoc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, lla-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13CNMR (CDC13, 400 MHz): 6 19.8, 20.5, 23.1, 23.2, 25.2, 25.3, 28.1, 28.2, 28.8, 29.1, 30.8, 31.2, 46.2, 55.9, 56.1, 59.9, 60.1, 63.3, 64.6, 80.9, 88.1, 91.1, 95.2, 100.4, 112.6, 113.3, 113.6, 114.2, 127.1, 129.0, 145.0, 145.3, 148.1, 148.5, 155.1, 167.1, 167.3; IR (neat): 3306, 2946, 1703, 1632, 1511, 1453, 1394, 1368, 1334, 1274, 1212, 1163, 1116, 1023cm"1; MS (FAB) m/z (relative intensity) 471 ( [M + Na]+', 5), 449 (M + , 100), 246 (50), 393 (22). 136.5, 136.6, 147.-'1, 147.7. 151.0, 151.4, 159.0, 159.5, 167.2, 167.4; IR (nea;:): 3410, 2944, 2B'3, 1103, 1645, 1604, 1513, 1448, 1393, 1326, 1271, 12.16, 1163, 1022cm"1; MS (FAB) m/z (relative -intensity) 56.1 (\M-\- Na]+', 5), 539 (M +', 100), 337 (82), 483 (24) if) (IIS,1 JaS)-1 0-(tert-Butyloxycarbonyl)-7-hydroxy-8-methoxy-ll-(t.etrahydroxy-pyran-2-yloxy) -1, 2, 3,10,11, lla-hexahydro-5H~ pyrrolo(2,1~cj [1,4]benzodiazepine-5-one (7) (Figure Remove)A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 6 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3h at 35 Ps:i.. When the reaction was complete as indicated by TLC (SiOt, 50%EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 7 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [a]K'i.; = +52° (c = 0.1B3, CHC13); !H NMR (CDC13, 400 MHz): 6 1.35 (s, 18H, Hoc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, BH, 3-H, lla-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (in, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13CNMR (CDC13, 400 MHz): 6 19.8, 20.5, 23.1, 23.2, 25.2, 25.3, 28.1, 28.2, 28.8, 29.1, 30.8, 31.2, 46.2, 55.9, 56.1, 59.9, 60.1, 63.3, 64.6, 80.9, 88.1, 91.1, 95.2, 100.4, 112.6, 113.3, 113.6, 114.2, 127.1, 129.0, 145.0, 145.3, 148.1, 148.5, 155.1, 167.1, 167.3; IR (neat): 3306, 2946, 1703, 1632, 1511, 1453, 1394, 1368, 1334, 1274, 1212, 1163, 1116, 1023cm'"1; MS (FAB) m/z (relative intensity) 471 ( [M + Na]+', 5), 449 (M *', 100), 246 (50), 393 (22). Examples 2-11 position (9) - Formation of PBD dimmers linked at the C-7 (Figure Remove)n = 3,4,5,6,7,8,9,10,11,12 Example 2 (n-3) i'a; !,!'-•[ (Propane-l,3-diyl)dioxy]bis[ (US, llaS)-10- ftert-L>utyloj 147.3, 147.8, :';55.'-'r 167.4, 167.6; IR (neat): 3306, 2945, 1704, 1643, 1605, ]5;3, ';450, 1393, 1327, 1217, 1164, 1022cm-"1; MS (FAB) m/z (relative intensity) 937 (MH', 100), 735 (25), 954 (14). (b) 1,1' - { (Propane-1,3-diyJ.) dioxyjbis [ (llaS) -8-methoxy~l ,2,3,lla-tetrahydro-511-pyrrulo [2,1-c] [ 1, 4 jbenzodiazepine-5-one] (9a) 95% TFA i3 ml,', was added drop-wise to dimer compound 8a (80 mg, 0.08 mmol) at C°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 ml>) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 inL) . The organic layer was then washed water (20 mL) , brine (20 vnL) then dried (MgSOj and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiOa, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9a (31 mg, 0.06 mmol, 75%) as a solid: [«]20D = +515° (c = 0.10, CHC13) j^H NMR (CDC13, 400 MHz): 5 2.01-2.31 (m, 4H, 2-H, 2'-H), 2.28-2.36 (m, 4H, 1-H, I'll), 2.38-2.45 (m, 2H, 13-H), 3.52-3.61 (m, 2H, 3-H, 3'-H), 3.67-3.75 (m, 2H, Ha-H, lla'-H), 3.77-3.85 (m, 2H, 3-H, 3'-H), 3.90 (s, 6H, 7-OMe, 7'-OMe), 4.23-4.30 (m, 4H, 12-H, 12'-H), 6.79 (s, ?H, 9-H, 9'-!l), 7.53 (s, 211, 6-H, 6'-H), 7.65 (d, 2H, J= 4, 11-H, U'-H); 13C NMR (CDC13, 400 MHz): 6 24.1, 29.0, 29.6, 46.6, 53.7, 56.0, 65.6, 109.6, 112.9, 120.2, 140.7, 146.9, 151.8, 162.3, 164.6; Ik (neat): 3350, 2956, 1599, 1506, 1447, 1385, 1262, 1216, 1091cm"1; MS (FAB) m/z (relative intensity) 597 ( [M + 2 x MeOH]+1, 22), 565 ([M+MeOH]+'f 25), 533 (M +', 100). Example 3 (n=4) (a) !,!'-[(Butane-1,4-diyl)dioxy]bis[(IIS, llaS)-10-(tert-butyloxycarbonyl) -8-methoxy-ll- (r.etrahydro-pyran-2-yloxy) -1,2,3,10,11, lla~hexahydro~5H-pyrrolo 12,1-c] [1, 4] berizodiazepine-5~ one] (8b) 1,4-Diiodobutane (G9.1 mg, was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90"C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, ^hich was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 8b (134 mg, 0.14 mmol, 63% yieJd, mixture of diastereomers from THP protecting group as a solid: [cxj^u = +36° (c = 0.19, CHC13); JH NMR (CDC13, 400 MHz): 5 1.35 (s, 36H, Hoc), 1.45-1.67 (m, 16H, THP), 1.68-1.86 (m, 8H, 1'HP) , 1.90-2.21 (m, 24H, 1-H, 2-H, 13-H) , 3.44-3.78 (m, 16H, 3-H, lla-H, THP), 3.84-4.02 (m, 16H, 7-OMe, THP), 4.04-4.25 (m, 8H, 12-H), 5.02-5.10 (m, 2H, THP), 5.11-5.20 (m, 2H, THP), 5.69-5.77 (d, ?.K, 11-H), 5.79-5.89 (d, 2H, 11-H) , 6.51 (s, 2H, 9-H) , 6.88 (s, 2H, 9-H), 7.19 (s, 2H, 6-H) , 7.28 (s, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 5 19.8, 20.5, 23.1, 23.2, 25.3, 25.9, 28.1, 28.2, 28.9, 30.9, 31.2, 46.2, 55.9, 56.2, 60.1, 63.3, 63.6, 68.6, 80.9, 91.2, 96.2, 100.2, 111.1, 111.4, 113.4, 114.1, 118.5, 126.4, 129.8, 143.1, 14V.9, 148.2, 151.5, 151.6, 155.8, 167.4, 167.6; IR (neat): 2945, 1704, 1644, 1604, 1513, 1449, 1392, 1327, 1217, 1163, 1022cm"1; MS (FAB) m/z (relative intensity) 973 ( [M + Na]+', 11) , 951 (M '* , 100) , 749 (36) . Ib) 1,I'-{ (Butane-l,4-diyl)dioxy]bis[(llaS)-8-methoxy-l,2,3,lla-Letrahydro~5H-pyrrc.lo [2,1-c] [1, 4]benzodiazepine~5-one] (9b) 95% TFA (3 mL) was added drop-wise to dimer compound Bb (134 mg, 0.14 mmol) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO/j) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-ohloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9b (60 mg, 0.11 mmol, 78%) as a solid: fa]20D = +477° (c = 0.09, CHC13) ; *H NMR (CDC13, 400 MHz): 5 1.88-2.06 (m, 8H, 2-H, 2'-H, 13-H, 13'-H), 2.16-2.36 (m, 4H, 1-H, I'-H), 3.4G-3.57 (m, 2H, 3-H, 3'-H), 3.63-3.69 (m, 2H, lla-H, lla'-H), 3.60-3.69 (m, 2H, 3-H, 3r-H), 3.82 (s, 6H, 7-OMe, ""-OMei, 3.98-4.!',- (m, 4H, !2-H, 12'-H), 6.72 (s, 2H, 9-H, 9'-H), •'.14 (s, 2H, 6-11, 6'-H), 7.59 (d, 2H, J= 4, 11-H, ll'-H); "C NMR (CDCli, 400 Mil/;. : 5 24.1, 25.8, 29.65, 46.6, 53.7, 56.0, 68.6, iOS.6, 112,6, 120.2, 140.6, 147.0, 151.7, 162.8, 164.6; IR (neat): 3351, 2950, 1622, 1600, 1506, 1447, 1387, 1262, 1216, 1092, 1026cm" •;MS (FAB; m/v. (relative intensity) 611 ( [M 4 2 x MeOH]+', 9), 579 ;IM4 MeOH]'-, 19), 547 (M '•, 100). Example 4 (n=5) fa; 1,1'-I (Per.tane-l,5-diyl)dioxy]bis [ (HS,llaS) -10- ftert-i>utyJoxycarr>OT))/J.,) -6-methoxy-ll- (tetra.hydro-pyra.n-2-yloxyJ -1,2,3,10,11,1 la~hexahydro-5H~pyrrolo[2,1-c][1, 4]benzodiazepine-5-onej (Be) i,5-Diiodopentane 172.2 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.9B mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 hours. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column ohromntography (SiO?, 50%EtOAc-hexane) to afford the dimerized compound 8c (160 mg, 0.1 6mmol, 74% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +40° (c = 0.16, CHC13) ; 'H NMR (CDC13, 400 MHz): 5 1.35 (s, 36H, Boc) , .1.45-1.86 (m, 28K, 14-H, THP), 1.88-2.22 (m, 24H, 1-H, 2-H, 13-H) , 3.44-3.77 (m, 16H, 3-H, lla-H, THP), 3.82-4.02 (m, 16H, 7-OMe, THP), 4.03-4.19 (m, 8H, 12-H), 5.02-5.10 (m, 2H, THP), 5.11-5.20 (m, 2H, THP), 5.69-5.77 (d, 2H, 11-H), 5.79-5.89 (d, 2H, 11-H), 6.51 (s, 2H, 9-H), 6.88 (s, 2H, 9-H), 7.19 (s, 2H, 6-H) , 7.22 (s, 2H, 6-H); "C NMR (CDC13, 400 MHz): 6 19.8, 20.4, 22.5, 23.1, 23.2, 25.3, 28.1, 28.2, 28.8, 29.1, 30.9, 31.2, 46.3, 55.9, 56.2, 60.0, 60.1, 63.3, 64.4, 68.8, 80.9, 81.2, 88.3, 91.4, 96.0, 100.4, 111.2, 113.5, l]4.j, 126.5, 129.8, 135.8, 147.4, 148.0, 150.9, 154.4, 167.4, 167.6; IR (neat): 2945, 1704, 1643, 1604, 1513, 1449, 1392, ]327, 1217, 1163, 1022cm"1; MS (FAB) m/z (relative intensity) 987 ([M-i-Na]4', 14), 965 (M+', 100), 863 (9). (h) 1,1' -I (Pencanr- ! , 5-diyl) dloxylbls [ (llaS) ~8-methoxy-l ,2,3,lla-retrahyd.ro-5ft-py.rroJ o[2 ,1 -c] [1 , 4]benzodiazepine-5-one] (9c) 95% TFA (3 rnli! wa,c- ridded drop-wise to dimer compound Be (160 mg , 0.16 mrnol; at 0UC . '"his was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL) . The organic layer was then washed water (20 mL) , brine (20 ml.) then dried (MgS0.5) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to Hash column chromatography (Si02, 2%methanol-chloroform) . Removal of excess eluent under reduced pressure without heating afforded the final product 9c (72 mg, 0.13 mmol, 81 %) as a solid: [u]2ut) =-- +416° (c = 0.12, CHC13) ; XH NMR (CDC13, '100 MHz): 5 1,62-1.71 (m, 2H, 14-H), 1.88-1.99 (m, 4H, 13-H, 13'-H) , 2.0]-2.n (m, 4H, 2-H, 2'-H), 2.26-2.36 (m, 4H, 1-H, I'-H), 3. 53-3. 62 (m, 2H, 3-H, 3'-H), 3.69-3.75 (m, 2H, lla-H, lla'-H), 3.76-3.85 (m, 2H, 3-H, 3'-H), 3.90 (s, 6H, 7-OMe, 7'-OMe), 4.02-4.21 (m, 4H, 12-13, 12'-H), 6.79 (s, 2H, 9-H, 9'-H), 7.50 (s, 2H, 6-H, 6'-H), 7.65 (d, 2H, J = 4, 11-H, ll'-H); 13C NMR (CDC13, 400 MHz): 6 22.5, 24.1, 28.8, 29.6, 46.6, 53.7, 56.0, 68.9, 109.6, 112.6, 120.2, 140.5, 147.0, 151.7, 162.3, 164.6; IR (neat): 332.5, 3946, 1600, 1505, 1448, 1386, 1262, 1217, 1091, 1023cm"1; MS (FAB) m/z (relative intensity) 625 ( [M + 2 x MeOH]'K, 19), 593 ( [M + , 25) , 561 (M +', 100) . Example 5 (n=6) (a) 1, l'~[ (Hexane-1, 6-diyl) dioxylbis [ (HS,llaS) -10- (tert-outyloxycarbonyl) --B-methoxy-11- (tetrahydro-pyran~2-yloxy) - 1,2,3,10,11, lla~hexahydro-5H-pyrrolo [2,1-c] [l,4]benzodiazepine-5-one] (8d) 1 , 6-Diiodohexane (75.3 mg, 0.00 mmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 eguiv) in dry DMF (30 mL) , and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 hours. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (EiCs, 50%Et:OAc-hexane) to afford the dimerized compound 8d (174 mg, 0.17 mmol, 79% yield, mixture of diastereomcrs from THP protecting group) as a solid: [a]2DD = +44° ic = 0.16, CHC13) ; 'H NMR (CDC13, 400 MHz): 5 1.25-1.67 (m, 60H, .M-H, Boc:, THP), .1.70-2.24 (m, 32H, 1-H, 2-H, 13-H, THP), 3.44-3.77 (m, 16H, 2-H, lla-H, THP), 3.84-4.18 (m, 24H, 12-H, 7~OMe, THP), 5.02-5.jG (m, 2H, THP), 5.11-5.20 (m, 2H, THP), 5.69-5.77 (d, 2H, 1J-H), 5. -'&- 5. 89 (d, 2H, 11-H), 6.51 (s, 2H, 9-H) , 6.87 (s, 2K, 9-H), 7.18 (s, 2H, 6-H), 7.22 (s, 2H, 6-H)/ 13CNMR (CDC13, •100 MHz): £ 19.8, /0.3, 23.1, 23.2, 25.3, 25.8, 28.1, 28.2, 28.9, 29.0, 29.], 30.9, 31.2, 46.3, 55.9, 56.2, 60.0, 60.1, 63.3, 64.1, 68.9, 80.9, 6J.2, 88.2, 91.1, 95.0, 100.5, 111.2, 111.7, 113.5, 114.1, 118.2, 127.1, 134.8, 147.7, 148.0, 155.2, 162.3, 163.0, 167.4, ]67.6; IR (neat): 2943, 1703, 1644, 1604, 1513, 1449, 1392, 1327, 1217, H63, 1022cm"1; MS (FAB) m/z (relative intensity) 1001 ! [M + Na]+', 10), 979 (M "', 100), 777 (24), 877 (12). i'-bj 1,1' - [ (Hfxane-2 , 6-diyl) djoxyjbis [ (llaS) -B~methoxy-l,2, 3,lla-t:et:rahyd.ro~51;- pyrrolo [2,1 -c] [1, 4]benzodiazepine~5-one] (9d) 05% TFA (3 mL) was added drop-wise to dimer compound 8d (174 mg, 0.17 mmol) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 rnL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO/j) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-ehloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9d (86 mg, 0.15 mmol, 88%) as a solid: [a]2DD = +500° (c = 0.09, CHC13) ; XH NMR (CDC1-,, 400 MHz): 5 1.39-1.55 (m, 4H, 14-H, 14'-H), 1.72-1.89 (m, 4H, 13-H, il-J'-H), 1.91-2.05 (m, 4H, 2-H, 2'-H), 2.17-2.31 (m, 4H, 1-H, I'll), 3.45-3.56 (m, 2H, 3-H, 3'-H), 3.62-3.69 (m, 2H, lla-H, lla'-!!) , 3.70-3.79 (m, 2H, 3-H, 3'-H), 3.83 (s, 6H, 7-OMe, 7'-OMe), 3.95-1.13 (m, 4H, 12-H, 12'-H), 6.73 (s, 2H, 9-H, 9'-H), 7.43 (s, 2H, 6-H, 6'-H), 7.58 (d, 2H, J= 4, 11-H, ll'-H); 13C NMR (CDCl3r '!00 MHz): 5 24.1, 2!,.7, 29.0, 29.6, 46.5, 53.7, 56.0, 69.0, 109.6, •12.5, 120.2, 140.5, 147.1, 151.7, 162.8, 164.6; IR (neat): 3385, 2945, 1622, 1:>99, 1506, 144".-', 1387, 1261, 1217, 1093cnTl; MS (FAB) m/z (relative intensity) 639 ( [M -I- 2 x MeOH]4"', 4), 607 ( [M + MeOH] K , 12; , 571) (« ' •, 100) . Example 6 (n=7) (a) "1,1'-/ (Heptane-I, 7-dlylj dioxy'Jbis[ (113,llaS) -10- (tert-butyloxycarbonyl! -8~methoxy-ll-(tetrahydro-pyran-2~yloxy)-1,2,3, LO,11,lla-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-:>ne] (Be) 1,7-Dibromohept.an« (57.5 mg, 0.22 mmol, 0.5 eguiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMF (30 mL) , and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 8e (190 mg, 0.19 mmol, 38% yield, mixture of diastereomers from THP protecting group) as a solid: [a]2t)c = -159° (c = 0.16, CHC13) ; ltt NMR (CDC13, 400 MHz): 5 1.25-1.67 (m, 64H, 14-H, 15-H, Boc, THP), 1.68-1.92 (16H, 13-H, THP), 1.93-2.21 (m, 16H, 1-H, 2-H), 3.44-3.75 (m, 16H, 3-H, lla-H, THP), 3.84-4.17 (m, 2.4H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 2H, THP), 5.11-5.20 (m, 2H, THP), 5.69-5.77 (d, 2H, 11-H), 5.79-5.89 (d, 2H, 11-H), 6.5] (s, 2H, 9-H), 6.87 (s, 2H, 9-H), 7.19 (s, 2H, 6-H), 7.22 (p, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 6 19.8, 20.4, 23.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, 30.9, 31.2, •16.3, 55.9, 56.2, 60.0, 60.1, 63.3, 64.4, 69.0, 80.6, 80.9, 88.2, 96.4, IOC.2, 111.3, 111.9, 113.4, 114.0, 115.5, 116.1, 126.3, 129.7, 149.6, 149.9, 151.1, 155.5, 167.4, 167.6; IR (neat): 2942, 1704, 1643, 1604, 1514, 1450, 1392, 1327, 1218, 1164, 1022cm" \- MS (FAB) m/z (relative intensity) 1015 ( [M + Na]1', 12), 993 (M '-, 100) , 791 (23) , 891 (9) . (b) 1,1' ~ ! (Heptane-1, 7-diyl) dioxyjbis [ (HaS)-8-methoxy-l ,2, 3 ,1 la-tetrahydro-5H-pyrrolo[2,1-cj /1, 4]benzodiazepine~5~one] (9e) 95% TFA (3 mL) was added drop-wise to dimer compound 8e (195 mg, 0.19 rnmo] ) rat P°c:. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture, '"lie mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO,,) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected Lc flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heat.ino afforded the final product 9e (76 mg, 0.12 mmol, t.B %) as a solid: [«J20D = +473° (c = 0.14, CHC13); XH NMR (CDC13, 100 MHz): 5 3.41-1.55 (m, 6H, 14-H, 14'-H, 15-H), 1.85-1.94 (m, 4H, 13-H, 13'-fc), 2.04-2.10 (m, 4H, 2-H, 2'-H), 2.28-2.38 (m, 4H, 1-H, I'-H), 3.56-3.63 (m, 2H, 3-H, 3'-H), 3.72-3.76 (m, 2H, lla-H, lla'-H), 3.79-3.85 (m, 2H, 3-H, 3'-H), 3.92 (s, 6H, 7-OMe, 7'-OMe) , 4.01-4.19 (in, 4H, 12-H, 12'-H), 6.79 (s, 2H, 9-H, 9'-H) , 7.49 (s, 2H, 6-H, 6'-H), 7.64 (d, 2H, J= 4, 11-H, ll'-H); 13C NMR (CDC13, 400 MHz): 6 24.1, 25.9, 29.0, 29.2, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2935, 1600, 1506, 1448, 1388, 1261, 1217, 1022cm"1; MS (FAB) m/z (relative intensity) 653 ([M + 2 x MeOH]+", 14), 621 ([M + MeOH]+', 20), 589 (M *', 100). Example 7 (n=8) (a) 1,1'-I (Octane-1,8-diyl) dioxy]bis [ (US, llaS) -10-(tert~ hutyloxycarbonyl) -8-ntethoxy-ll- (tetrahydro-pyran-2-yloxy) -1,2,3,10,11,lle-hexahydro-5H-pyrrolo[2,l-c][I, 4]benzodiazepine-5-one] (8f) 1,8-Diiodooctane (El. 6 mg, 0.22 mmol, 0.5 equiv) was added to the mixture ot monomer 1 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2,2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (SiOj, 50%EtOAc~hexane) to afford the dimerized compound 8f (191 ing, 0.18 mmo.i , 85% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +50° (c = 0.15, CHC13) ; 3H NMR ICDC13, 400 MHz): f 1.27-1.66 (m, 68H, 14-H, 15-H, Hoc, THP), 1.68-1.91 (16H, 3--H, THP), 1.93-2.20 (m, 1 6H, 1-H, 2-H), 3.45-3.75 (m, I6H, 3--11, lla-H, THP), 3.83-4.14 (m, 24H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 211, THP), 5.11-5.20 (m, 2H, THP), 5.69-5.77 (d, 2H, 11-II), 5.79-5.89 id, 2H, 11-H), 6.51 (s, 2H, 9-H) , 6.87 (&, 2H, 9-H), 7.19 (s, 2H, 6-H), 7.22 (s, 2H, 6-H); 13CNMR (CDC13, 400 MHz): 5 1.9.8, 20.4, 23.1, 23.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, ."9.3, 30.,9, 31.2, 46.3, 55.9, 56.2, 60.0, 60.1, 63.3, 64.4, 69.0, 30.9, 81.2, Sfi.2, 91.2, 95.8, 100.2, 111.1, 111.7, 113.4, 114.0, 122.0, 126.4, 129.7, 138.0, 147.8, 148.1, 150.1, 150.5, 155.7, ;67.4, 167.6; 1R (neat): 2941, 1704, 1643, 1604, 1514, '1450, 1392, 1327, 1218, 1164, 1022cm"1; MS (FAB) m/z (relative intensity) 1029 (!W+ Na]4', 30), 1007 (M +-, 100), 905 (15). (b) !,!'-[ 'Octane- 1,8-diyl)dioxyjhis[ (llaS)-8-methoxy-l,2,3,1la-ietrahydro-5H-py::rolo [2,1 -c] [1, 4 Jbenzodiazepine-5-one] (9f) 95% TFA (3 mli) was added drop-wise to dimer compound 8f (191 mg, 0.18 mmol) at 3nC. This was then stirred for Ihr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL) . The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9f (106 mg, 0.17 mmol, 97%) as a solJd: [a]20n = +467° (c = 0.14, CHC13) ; XH NMR (CDC13, 400 MHz): 5 1.34-1.53 (m, 8H, 14-H, 14' -H, 15-H, 15'-H), 1.78-1.91 (m, 411, 13-H, 13'-H), .1.96-2.10 (m, 4H, 2-H, 2'-H), 2.25-2.38 (m, 4H, 1-H, l'-H), 3.54-3.63 (m, 2H, 3-H, 3'-H), 3.70-3.76 (m, 2H, lla-H, na'-H), 3.77-3.88 (m, 2H, 3-H, 3'-H), 3.90 (s, 6H, 7-OMe, 7'-OMe), 4.04-4.37 (m, 1H, 12-H, 12'-H), 6.81 (s, 2H, 9-H, 9'-H), 6'-H), 7.67 (d, 2H, J= 4, 11-H, 11'-H); 13C NMR (CDC1-,, 100 MHz): f 24.1, 25.8, 29.0, 29.1, 29.6, 46.6, 53.7, 56.0, t,9.0, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.3, 164.6; IR (neat) : 3326, 2937, 1599, 1506, 1448, 1387, 1262, 1217, 1092, 1923crrf:; ME (FAB) m/z (relative intensity) 667 ((M+ 2 x MeOH]+-, /), 635 ! \M t- MeOHj* , 15), 603 (M *', 100). Example 8 (n=9) (a) 1, I'-/ (Nnnane-!, 9-diyl)dioxy]bis[ (HS,llaS) -10- (tert-butyloxycarbonyi) -l!-methoxy-ll- (tetrahydro-pyran~2-yloxy) -1,2,3,10, 11,1.1 a-hexahydro-5H-pyrrolo[2,1-c] [ 1, 4]benzodiazepine-5-onej (8g) 1,9-Dibromononanc (63.7 mg, 0.22 tnmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmcl, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMK (30rnL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 8g (181 mg, 0.17 mmol, "'9% y.ield, mix Lure of diastereomers from THP protecting group) as d solid: [a]20D =-- +56° (c - 0.16, CHC1-,) ; XH NMR (CDC13, 400 MHz): 5 1.27-1.66 (m, n2H, 14-H, 15-H, 16-H, Hoc, THP), 1.68-1.92 (16H, 13-H, THP), 1.93-2.20 (m, 16H, 1-H, 2-H), 3.45-3.75 (m, 16H, 3-H, Lla-H, THP), 3.83-4.14 (m, 24H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 2H, THP), 5.32-5.19 (m, 2H, THP), 5.69-5.77 (d, 2H, 11-H), 5.79-5.89 (d, 2H, 11-H), 6.51 (s, 2H, 9-H) , 6.87 (s, 2H, 9-H), 7.19 (s, 2H, 6-H) , 7,22 (s, 2H, 6-H) ; 13C NMR (CDC13, 400 MHz): 5 19.8, 20.4, 23.1, 23.2, 25.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 30.9, 31.2, 46.2, 55.9, 56.2, 60.0, 60.1, 63.3, 64.4, 69.0, 69.1, 60.9, 81.2, 88.2, 91.2, 95.8, 100.2, 111.1, 111.5, 113.4, 214.0, 120.5, 129.6, 138.2, 147.8, 148.1, 151.2, 151.5, 161.9, 167.4, 167.6; IR (neat): 2938, 1703, 1643, 1604, 1513, 14-19, 1392, 1327, 1217, 1163, 1022cm'1; MS (FAB) m/z {relative intensity) 1043 ( [M -f Na]"', 21), 1021 (M *•, 100), 819 (20), 919 (16). (b) 1,1'- I (Nonane-1,9-diyl) dioxyjbis[(llaS)-8-methoxy-l,2,3rlla~ tetra/iydro-5W-pyrroJo [2, l~c] [ 1, 4)benzodiazepine-5-one] (9g) c)5% TFA (3 ml,) was added drop-wise to dimer compound 8g (170 mg, 7.18 mmoI) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 :nL) then dried (MgSO,,) and filtrated. The excess solvent was removed under teduced pressure to give the crude product, which was subjected to Clash column chromatography (Si02, 2%methanol-'..•hioroform) . Removal of excess eluent under reduced pressure without hearinq afrorded the final product 9g (93 mg, 0.15 mmol, B8yd) as f: .so!.id: [o'j20,, =- +547° (c = 0.13, CHC13); XH NMR (CDC13, 400 MHz): 5 1.31-1.53 im, 10H, 14-H, 14' -H, 15-H, 15'-H, 16-H), 1.83-1.9-5 (m, 4H, ]3-H, 13' -H) , 2.00-2.12 (m, 4H, 2-H, 2'-H), 2.27-2.38 (m, 4H, l-l-l, 1'~H), 3.54-3.64 (m, 2H, 3-H, 3'-H), 3.69-3.78 (in, 211, lla-H, lla'-Il), 3.79-3.87 (m, 2H, 3-H, 3'-H), 3.92 (s, 6H, 7-OMe, 7'-OMe), '1.01-4.19 (m, 4H, 12-H, 12'-H), 6.81 (s, 2H, 9-H, 9'-H), 7.1-2 is, 211, 6-H, 6'-H), 7.67 (df 2H, J= 4, 11-H, ll'-H); i:'C NMR (CDClj, 400 MHz): 5 24.1, 25.9, 29.0, 29.3, 29.4, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2933, 1600, 1507, 1448, 1388, 1261, 1217, 1092, 1024cm"1; MS (FAB) m/z (relative intensity) 617 (M +', 100), 6 3 b (10), 785 (6) . Example 9 (n=10) (a) !,!'-[ (Decane-l,10-diyl)dioxy]bis[ (IIS,llaS)-10- (tert-butyloxycarbonyl)-8-methoxy-ll-(tetrahydro~pyran-2-yloxy) -'1,2,3,10,11,1 la-hexahydro-5H-pyrrolo[2,1-c] [1, 4]benzodiazep±ne-5-one] (8h) 1, 10-Diiododecane (87.8 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere Cor 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc:-hexane) to afford the dimerized compound 8h (191 mg, 0,1 Smmol, 62% yield, mixture of diastereoiners from THP protecting group) as a solid: [a]?0D = +75° (c = 0.10, CHC13); lti NMR (CDC13, 400 MHz): 5 1.25-1.59 (m, 76H, 14~H, 15-H, 16-H, Boc, THP), 1.68-1.92 (16H, 13-H, THP), 1.93-2.20 (m, 36H, 1-H, 2-H), 3.45-3.75 (m, 16H, 3-H, lla-H, THP), 3.83-4.14 (m, 24H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 2H, THP), 5.32-5.19 (m, 2H, THP), 5.69-5.77 (d, 2H, 1.1--H), 5.79-5.89 (d, 2H, 11-H), 6.49 (s, 2H, 9-H) , 6.86 (s, 2H, 9-H), 7.17 [s, 2H, 6-H), 7.21 (s, 2H, 6-H); 13CNMR (CDC13, 400 MHz): 6 19.9, 20.4, 23.1, 23.2, 25.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, 29.2, 29.3, 29.5, 30.9, 31.3, 46.3, 55.9, 56.2, 60.0, 60.1, 63.3, 69.1, 80.9, 81.2, 88.2, 91.2, 95.8, 100.2, 111.1, 111.5, 113.-1, 114.0, 121.6, 126.4, 141,0, 143.1, 148.1, 148.4, 155.4, 167.4, 167.6; IR (neat): 2937, 1703, 1643, 1604, 1513, 1450, 1392, 1327, 1218, 1164, 1022cm"1; MS (FAB) m/z (relative .intensity) 1057 ( [M + Na]+', 34), 1035 (M *•, 100), 833 (26), 933 (25) . (b) 1,1'-I (Decane-1,10-diyl)dioxyjbis[(llaS)-8-methoxy-l,2,3,lla~ tetrahydro-5H~pyrrolo[2,1-c][1, 4]benzodiazepine-5-one] (9h) 95% TFA (3 mL) was added drop-wise to dimer compound 8h (191 mg, 0.18 minol) at: 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiOz, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9h (103 mg, 0.16 mmol, 90%) as a solid: [cx]2Cu = +387° (c = 0.17, CHC13) ; JH NMR (CDC13, 400 MHz): 5 1.25-1.50 (m, 12H, 14-H, 14'-H, 15-H, 15'-H, 16-H, 16'-H), 1.72-1.92 (m, 4H, 13-H, 13'-H), 1.98-2.09 (m, 4H, 2-H, 2'-H), 2.25-2.38 (m, 4H, 1-H, I'-H), 3.52-3.62 (m, 2H, 3-H, 3'-H), 3.68-3.73 (m, 2H, lla-H, lla'-H), 3.76-3.85 (m, 2H, 3-H, 3'-H), 3.90 (s, 6H, 7-OMe, 7'-OMe), 3.95-4.19 (m, 4H, 12-H, 12'-H), 6.79 (s, 2H, 9-H, 9'-f!), 7,50 (s, 2H, 6-H, 6'-H), 7.64 (d, 2H, J= 4, 11-H, ll'-H); UC NMR (CDC.'!,, 400 MHz): 6 24.1, 25.9, 29.0, 29.3, 29.4, 29.6, 46.6, 5";. 7, 56.0, 69.V, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2931, 1600, 1506, 1448, 13HB, 1262, .i.?J7, J092, 1024cm"1; MS (FAB) m/z (relative intensity) i.95) (\M i 2 x MeOHp, 14), 663 (|M+ MeOH]*', 20), 631 (M + , 100). Example 10 (n=ll) (a) 1,1' - i (Undecanv-1,11-diyl)dioxyjbls[ (IIS,llaS)-ID- (tert-butyloxycarbonyl)-8~methoxy~ll-(tetrahydro-pyran-2-yloxy)-] ,2,3,10,1J , j j.cJ-hexahydro~5H-pyrrolo [2,1-c] [1, 4]benzodiazepine~5-one] (8i) 1,11-Dibromoundecane (70.0 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.96 rnmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMF (30 mL) , and the resulting mixture was heated to OO^C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 8i (217 mg, 0.20 mmol, 94% yield, mixture of diastereomers from THP protecting group) as a solid: [«]% -• +52° (c = 0.17, CHC13) ; XH NMR (CDC13, 400 MHz): 5 1.27-1.60 (m, 80H, 14-H, 15-H, 16-H, 17-H, Hoc, THP), 1.71-1.89 (16H, 13-H, THP), 1.93-2.20 (m, 16H, 1-H, 2~H), 3.45-3.75 (m, 16H, 3-H, lla-H, THP), 3.83-4.14 (m, 24H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 211, THP), 5.12-5.19 (m, 2H, THP), 5.69-5.77 (d, 2H, 11-H), 5.79-5.09 (d, 2H, 11-H), 6.51 (s, 2H, 9-H), 6.87 (s, 2H, 9-H), 7.19 (s, 2H, 6-H), 7.22 (s, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 5 19.9, 20.4, 23.1, 23.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, 29.2, 29.3, 29.5, 30.9, 31.2, 46.3, 55.9, 56.2, 60.0, 60.1, 63.3, 64.4, 69.1, 80.9, 81.2, 88.2, 91.2, 95.8, 100.2, 111.1, 111.5, 113.4, 114.0, 126.3, 129.6, 134.1, 138.8, 148.0, 148.4, 155.3, 155.6, 167.4, 167.6; IR (neat): 2935, 1704, 1643, 1604, 1513, 1449, 1392, 1327, 1218, 1164, 1022cm"1; MS (FAB) m/z (relative intensity) 1071 ([M-t Na] ' , 16), 1049 (M+', 100), 947 (15), 847 (13) . (b) 1,1 ' -I (Undecane-1,11-dlyl)dioxyjbis[(llaS)-8-methoxy- .3,2,3, Ha-tKtrahydT o~5H~pyrrolo [2,1-c][1, 4]benzodiazepine-5-one] 95% TFA i,3 ml,) was added drop-wise to dimer compound 8i (217 mg, u.20 mmol} at 0°C. This was then stirred for ]hr and the mixture was poured intc sat urated NaHC03 (30 mL) solution to naturalize the reaction mixture. Tne mixture was extracted with chloroform (3x20 n\L) . The organic layer was then washed water (20 mL) , brine (20 mL) then dried (MgSO.i) and filtrated. The excess solvent was removed under reduced pressure tc give the crude product, which was subjected i.o flash column chromatography (SiC>2, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9i (113 mg, 0.17 mmol, 87%) as a .solid: [a'j20D = +401° (c = 0.19, CHC13) ; XH NMR (CDC13, 400 MHz): 6 1.26-1,5:: (m, 14H, 14-H, 14'-H, 15-H, 15'-H, 16-H, 16'-H, 17-H), 1.84-1,92 (m, 4H, 13-H, 13'-H), 2.01-2.11 (m, 4H, 2-H, 2'-H) , 2.27-2.36 (rn, 4H, 1-H, I'-H), 3.55-3.64 (m, 2H, 3-H, 3'-H), 3.70-3.76 (m, 2H, lla-H, lla'-H), 3.78-3.87 (m, 2H, 3-H, 3'-H), 3.92 (s, 6H, 7-OMe, 7'-OMe), 4.02-4.20 (m, 4H, 12-H, 12'-H), 6.81 (s, 2H, 9~H, 9'-H), 7.52 (s, 2H, 6-H, 6'-H), 7.67 (d, 2H, J= 4, 11-H, ll'-H); 13C NMR (CDC13, 400 MHz): 5 24.1, 25.9, 29.0, 29.3, 29.5, 29,6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2928, 1600, 1507, 1448, 1261, 1217, 1023cm'1; MS (FAB) m/z (relative intensity) 709 ([MH 2 x MeOHr1', 14), 677 ( [M + MeOH]+', 20), 645 (M+', 100). Example 11 (n=12) (a) 1,1'-I (Dodecane-l,12-diyl)dioxy]bis[ (HS,llaS)-10-(t&rt-butyloxycarbonyl!- 8~methoxy-ll-(tetrahydro-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H~pyzrolo[2,1-c][1,4]benzodiazepine-5-one] (8j) 1, 12-Dibrornododecane (73.1 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 7 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMF (30 mL), and the resulting mixture was heated to 90°C undet a nitrogen atmosphere for 5 h. Removal of rixcess solvent jnclei reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%KtOAc-hexane) to afford the dimerized compound 8j (208 mg, 0.19 mmol, 87% yje.ld, mixture of diastereomers from THP protecting group) as ,-. solid: laj2"L -= i50° (c = 0.20, CHC13) ; JH NMR (CDC13, 400 MHz): 5 1.26-1.60 (m, 84H, 14-H, 15-H, 16-H, 17-H, Boc, THP), 1.69-1.89 (16H, :i3~H, THP), 1.93-2.20 (m, 16H, 1-H, 2-H) , 3.44-3.75 (m, 16H, 3-H, lla-H, THP), 3.83-4.14 (m, 24H, 12-H, 7-OMe, THP), 5.02-5.10 (m, 2H, THP), 5.12-5.IB (m, 2H, THP), 5.69-5.77 (d, 2H, 11-H), 5.79-5.89 (d, 2H, ]1-H), 6.50 (s, 2H, 9-H), 6.87 (s, 2H, 9-H), 7.19 (s, 2.H, 6-R), 7.22 (s, 2H, 6-H) ; 13C NMR (CDC13, 400 MHz): 6 19.9, 20.4, 23.1, 23.2, 25.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.0, 29.1, 29.2, 29.3, 29.56, 29.58, 30.9, 31.2, 46.2, 55.9, 56.2, 60.0, 60.1, €3.3, M.4, 69.12, 69.15, 80.9, 81.2, 88.2, 91.2, 95.8, 100.2, 111.1, 111.5, 113-.4, 114.0, 126.3, 129.6, 134.1, 138.8, 147.3, 148.1, 151.5, 155.3, 167.4, 167.6; IR (neat): 2932, 1703, 1643, 1604, 1513, 1450, 1392, 1327, 1218, 1164, 1022cm"1; MS (FAB) m/y. (relative intensity) 1085 ( [M + Na]+', 28), 1063 (M+', 100), 961 (17), 861 (13). (b) 1,1' - I (Uodt'cane-1 f 12-dd.yl) dioxyjbis [ (llaS) -8-methoxy- 1,2,3,lib -tetrahydro-5H-pyrrolo[2,1-c] [1, 4]benzodiazepine-5-one] 95% TFA (3 mil) was added drop-wise to dimer compound 8j (208 mg, 0.19 mmoJ ) at 0DC. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL) . The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04) and filtrated. The excess solvent was removed under reduced pressure to give the crude-product, which was subjected to flash column chromatography (SiOj/ 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9j (107 mg, 0.16 mmol, 85%) as a solid; [a]20D = +506° (c = 0.15, CHC13) ; ^ NMR (CDC13, 400 MHz): 5 1.26-1.52 (m, 16H, 14-H, 14'-H, 15-H, 15'-B, 16-H, 16'-H, 17-H, 17'-H), 1.83-1.92 (m,. 4H, 13-H, 13'-H), 2.01-2.12 (m, 4H, 2-H, 2'~H), 2.28-2. 3 / (m, 4H, 1-H, I'-H), 3.55-3.64 (m, 2H, 3-H, 3'-H) , 3.70-3.77 (m, 2H, lla-H, lla'-H) , 3.78-3.87 (m, 2H, 3-H, 3'-11), 3.92 us, 6H, 7-OMe, V'-OMe), 4.03-4.19 (m, 4H, 12-H, 12'-H), 6.8: (s, 211, 9-H, 9'-H), 7.52 (s,, 2H, 6-H, 6'-H), 7.67 (d, 2H, J = 4, 11-H, 1]'-H); l';C NMR (CDC13, 400 MHz): 5 24.1, 25.9, 29.0, 29.3, 29.b4, 29.S"?, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, ]40,CJ, 1-17.1, 151.6, 162.2, 164.6, ; IR (neat): 3338, 2926, 1600, lb()7, 1448, 1261, 1217, 1021cm"1; MS (FAB) m/z (relative intensity) 723 ( [N -I- 2 x MeOH]*', 14), 691 ([M + MeOH]+', 20), 659 (M "', 100} . Example 12 - Synthesis of PBD monomer - (IIS,llaS)-8-Hydroxy-10-(tert-butyloxycarbonyl)-7-methoxy-ll-(tetrahydroxy-pyran-2-yloxy)-1,2 ,3 ,10 ,11,lla-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (14) (a) N-[4 -Benzyloxy-5-methoxy-2-(tert- buty.l oxyc3 rbojiylamino) benzoyl] -pyrrolidine-2-methanol (11) (Figure Remove)A solution of amine 10 (B g, 22.47 iranol, 1.0 equiv) and Di-tert-butyl dicarbonate (7.35 g, 33.70 mmol, 1.5 equiv) in THF (150 mL) was heated at reflux overnight. The reaction mixture was allowed to cool to RT and excess THF was removed under reduced pressure to give the crude product. The residue was subjected to flash column chromatography (S.t02, 30% BtOAc-hexane) to afford the product 11 (6.2 g, 13.59 mmol, 60%) as yellow oil: [a]20D = -95° (c = 0.17, CHC1;,); Hi NMR (CDC13, 400 MHz): 5 1.50 (s, 9H, Boc), 1.64-1.80 (m, 2H, 1-H, 2-H), 1.86-1.95 (m, 1H, 2-H), 2.14-2.23 (m, 1H, 1-H), 3.46-3.54 (m, 111, 3-H), 3.56-3.64 (m, 1H, 3-H), 3.67-3.77 (m, 1H, 11-H), 3.81-3.89 (m, 4H, 11-H, 7-OMe), 4.29-4.48 (m, 2H, lla-H, OH), 5.14 (m, 2H, OBn), 6.82 (s, 1H, 6-H), 7.29- 7.33 (m, 1H, Ph), 7.34-7.39 (m, 2H, Ph), 7.46-7.49 (m, 2H, Ph) , 7.89 (s, 1H, 9-H) , 8.38 (br s, 111, NH) ; 13C NMR (CDC13, 400 MHz): 6 21.8, 28.3, 28.4, 52.4, 57.5, 61.6, 67.5, 71.5, 81.1, 107.0, 112.6, 128.3, 128.6, 128.8, 129.2, 133.2, 137.1, 144.7, 151.3, 153.9, 171.9; IR (neat): cm'1; MS (FAB) m/z (relative intensity) 479 ( [M + Na]+', 20), 457 (M ' , 100), 357 (25), 255 (23), 401 (21). lb) (118,1188)-8-Benzyloxy-10-(tert-butyloxycarbonyl)-ll~hydroxy-7-methoxy-l ,2, 3,10,11, lla~-hexahydro-5H-pyrrolo [2,1-c][1, 4]benzodiazepine-5-one (12) (Figure Remove)To a solution of Boc protected amine alcohol 11 (6.2 g, 13.59 mmol, 1.0 equiv) in DCM (50 mL), BA1B (4.82 g, 14.95 mmol, 1.0 equiv) and TEMPO (0.21 g, 1.35 mmol, 0.1 equiv) were added and the mixture was stirred overnight. When the reaction was complete as indicated by TLC (Si02, 50% EtOAc-hexane), the reaction mixture was diluted with DCM (100 mL) and washed with saturated Na2S2O3 (60 mL) . The aqueous layer was extracted with DCM (2x50 mL) and the combined organic layer was washed with brine (50 mL) and dried (MgSO,)) . Removal of excess solvent under reduced pressure afforded a crude solid which was washed with cold EtOAc to give cyclized PBD 12 (4.9 g, 10.8 mmol, 79%) as white solid: [a]2DD = +136° (c = 0.190, CHC13) ; JH NMR (CDC13, 400 MHz): 5 1.28 (s, 9H, Boc),1.95-2.18 (m, 4H, 1-H, 2-H), 3.43-3.50 (m, 1H, lla-H), 3.53-3.66 (m, 2H, 3-H, OH), 3.67-3.78 (m, 1H, 3-H), 3.95 (s, 3H, 7-OMe), 5.10 (d, 1H, J= 12 Hz, OBn), 5.22 (d, 1H, J = 12 Hz, OBn), 5.51-5.59 (m, 1H, 11-H), 6.66 (s, 1H, 9-H), 7.26 (s, 1H, 6-H), 7.33- 7.34 (m, 1H, Ph), 7.38-7.41 (m, 2H, Ph), 7.41-7.45 (m, 2H, Ph); 13C NMR (CDC13, 400 MHz): 5 23.0, 28.1, 28.7, 46.3, 56.1, 59.7, 71.1, 81.6, 85.6, 110.7, 114.6, 126.0, 127.0, 128.1, 128.7, 129.1, 130.2, 136.4, 148.5, 149.8, 155.4, 167.0; IR (neat): 3374, 2974, 1699, 1623, 1602, 1511, 1454, 1433, 1324, 1161, 1050cm'1; MS (FAB) m/z (relative intensity) 477 ([M+ Na]+', 25), 455 (M+', 100), 399 (94), 337 (60), 437 (45). (c) (US, llaS) -8-Benzyloxy-10- (tert-butyloxycarbonyl) -7-methoxy~ 11-(tetrahydroxy-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H-Iyrro2o[2,1 ~r:j 11, 4jbenzodiazepine-5-one (13) (Figure Remove)A. catalytic amount of PTSA was added to a solution of DHP (2.87 g, 34.14 mmol, 5 equiv) in EtOAc (10 mL) at 0°C. After stirring 10 minutes, the cyclized compound 12 (3.1 g, 6.8 mmol, 1.0 equiv) was added portion-wise to the mixture and the resulting mixture was stirred until starting material disappearance by TLC (SiO2, 50% EtOAc-hexane) . The mixture was diluted with BtOAc (100 mL), washed with saturated NaHC03 (30 mL) , brine (30 mL) and dried (MgS04) . Removal of excess solvent afforded the protected compound 13 (3.5 g, 6.5 mmol, 95% yield, mixture of diastereomers from THP protecting group), which was used in the subsequent reaction without further purification: [a]20D = +64° (c = 0.58, CHC13) ; 1H NMR (CDC13, 400 MHz): 6 1.12-1.80 (m, 30H, Boc, THP), 1.90-2.14 (m, 8H, i-H, 2-H), 3.39-3.70 (m, 8H, 3-H, lla-H, THP), 3.81-3.99 (m, 8H, 7-OMe, THP), 4.89-4.94 (m, 1H, THP), 5.05-5.26 (m, 5H, OBn, THP), 5.65-5.70 (d, 1H, 11-H), 5.74-5.81 (d, 1H, 11-H), 6.49 (s, 1H, 9-H) , 6.08 (s, 1H, 9-H), 7.20- 7.36 (m, 12H, 6-H, Ph) ; 13C NMR (CDC13, 400 MHz): 5 18.8, 19.6, 22.0, 22.2, 24.21, 24.25, 26.9, 27.0, 27.8, 28.0, 29.7, 30.2, 45.2, 55.06, 55.09, 58.95, 59.1, 62.2, 63.5, 69.9, 70.3, 79.8, 87.0, 90.2, 94.5, 99.5, 109.1, 109.6, 3:14.5, 114.7, 125.8, 126.93, 126.99, 127.65, 127.69, 128.7, 135.6, 135.7, 147.6, 147.9, 149.0, 149.1, 153.8, 166.3, 166.5; IR (neat): 3410, 2945, 2873, 1704, 1643, 1604, 1511, 1454, 1431, 1402, 1326, 1272, 1202, 1163, 1116, 1022cm"1; MS (FAB) m/z (re.lat.ive intensity) 561 (\M + Na]1', 51), 539 (M+', 78), 337 (100), 540 127), 338 (24) . Id) (1 IS,i LaS) ~8-Hydroxy~10-(tert-butyloxycarbonyl)-7-methoxy~ll~ : t etxahydroxy-py-aj-i -2 -yl oxy) -1,2,3,1 0,11 ,lla -hexahydro~5H-pyrrcio/2, J -cj ;'j / 4 J jbenzodiazepine-5-one (14,) (Figure Remove) (380 mg) was added to a solution of TUP protected compound 13 (3.8 g, 7 mmol) in absolute alcohoj (30 mL). The reaction mixture was hydrogenated for 3h a! 35 P.si. When the reaction was complete as indicated by TLC (Si02, 50%Et,OAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 14 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: |aJ20n = +84'" (c = 0.48, CHC13JH NMR (CDC13, 400 MHz): 5 1.35 is, 18H, Boc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.16 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, lla-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H) , 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H) / 13C NMR (CDC13, 400 MHz): 5 19.9, 20.7, 23.1, 23.2, 25.1, 25.3, 28.0, 28.1, 28.9, 29.1, 30.8, 31.2, 46.3, 56.13, 56.19, 60.0, 60.2, 63.4, 64.5, 81.0, 81.1, 87.9, 91.1, 95.8, 100.7, 109.6, 110.0, 116.4, 117.0, 125.5, 125.9, 130.2, 130.5, 145.7, 145.8, 147.4, 147.5, 154.9, 155.3, 167.4, 167.6; IR (neat): 3266, 2947, 1703, 1631, 1612, 1514, 1468, 1411, 1368, 1331, 1275, 1201, 1163, 1116, 1023cm"1; MS (FAB) m/z (relative intensity) 471 ([M+Na]*', 15), 449 (M+', 99), 246(100),347(25). (Figure Remove) butyloxycarbonyl) ~'!-methoxy~ll- (tetrahydro-pyran-2-yloxy) -1,2,3,10,11,1la~hexahydro-5H-pyrrolo[2,1-c][1, 4]benzodiazepine-5-one] (15a) 1,3-Diiodopropane (66 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (S1O2, 50%EtOAc-hexane) to afford the dimerized compound 15a (90 mg, 0.09 mmol, 43% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +57° (c = 0.14, CHC13) ; XH NMR (CDC13, 400 MHz): 5 1.20-1.84 (m, 60H, Boc, THP), 1.91-2.20 (m, 16H, 1-H, 2-H), 2.34-2.46 (m, 4H, 13-H) , 3.40-3.74 (m, 16H, 3-H, lla-H, THP), 3.79-3.99 (m, 16H, 7-OMe, THP), 4.12-4.30 (m, 8H, 12-H), 4.97-5.15 (m, 4H, THP), 5.66-5.75 (d, 2H, 11-H), 5.77-5.89 (d, 2H, 11-H), 6.55 (s, 2H, 9-11), 6.89 (s, 2H, 9-H), 7.16 (s, 2H, 6-H) , 7.20 (s, 2H, 6-H) ; 13C NMR (CDC13, 400 MHz): 5 19.9, 20.5, 23.3, 23.2, 25.2, 25.3, 28.1, 28.2, 28.9, 29.0, 29.1, 30.9, 31.3, 46.3, 56.0, 56.1, 60.0, 60.2, 63.4, 64.5, 65.3, 65.7, 81.0, 81.1, 88.1, 91.2, 95.7, 100.3, 110.1, 110.8, 114.7, 115.2, 127.5, 129.8, 148.5, 148.8, 150.0, 155.1, 167.4, 167.6; IR (neat): 3426, 2943, 1703, 1643, 1604, 1.513, 1454, 1432, 1326, 1270, 1201, 1163, 10 2-3 cm" J; MS (FAB) m/z (relative intensity) 959 ([M + Na]+', 100),937 (M "-, 62) , 835 (67), 735 (60) . (b) 1,1' ~ I(Propane-!, 3-diyl)dioxyjhis [ (llaS)-l~methoxy-lf2,3,lla-!:etrahydro~5H-pyrrolo [2,1-c] {1, 4]benzodiazepine~5-one] (16a) 'J5% TFA (3 mL) was added drop-wise to dimer compound 15a (75 mg, 0.08 inmol) at 0"C. This was then stirred for Ih and the mixture was poured into saturated NaHC03 (30 mL) solution to naturaliEe the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO/j) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiC>2, 2%methanol~ chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16a (30 mg, 0.05 mmol, 70%) as a solid: [a]20D = +477° (c = 0.11, CHC13) ; :E NMR (CDC13, 400 MHz): 5 2.01-2.06 (m, 4H, 2-H, 2'-H), 2.28-2.31 (m, 4H, 1-H, 1'-H), 2.39-2.42 (m, 2H, 13-H), 3.55-3.60 (m, 2H, 3-H, 3'-H), 3.67-3.73 (m, 2H, lla-H, lla'-H), 3.77-3.87 (m, 2H, 3-H, 3'-H), 3.91 (s, 6H, 7-OMe, 7'~OMe), 4.23-4.3] (m, 4H, 12-H, 12'-H), 6.84 (s, 2H, 9-H, 9'-H», 7.'iO (s, 2H, 6-H, 6'-H), 7.64 (d, 2H, J- 4, 11~H, ll'-H); "C NMR (CDC13, 400 MHz): 6 24.1, 28.4, 29.6, 46.6, 53.6, 56.1, 58.4, 65.4, 110.8, 111.6, 120.4, 140.6, 147.8, 150.6, 162.3, 164.6; IR (neat): 3350, 2951, 1600, 1505, 1434, 1262, 1217, 1021cm" :; MS (FAB) m/z (relative intensity) 597 ([M + 2 x MeOH]+', 16), 565 ([M+MeOH]+', 5), 533 (M +', 100). Example 14 (n=4) (a) 1,1'-I (Butane-1, 4-diyl) dioxy]bis [ (HS,llaS)-10- (tert-butyloxycarbonyl)-7-methoxy-ll- (tetrahydro-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one] (15b) 1,4-Diiodobutane (69.1 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 15b (210 mg, 0.22 miiiol, 99% yield, mixture of diastereomers from THP protecting group) as a solid: [Qfj20D = -11° (c = 0.18, CHC13) ; 1H NMR «CDC13, 400 MHz): 6 1.21-1.87 (m, 60H, Boc, THP), 1.94-2.21 (m, 24H, 1-H, 2-H, 1.3-H) , 3.43-3.77 (m, 16H, 3-H, lla-H, THP), 3.86-4.01 (m, 161-1, 7-OMe, THP), 4.02-4.19 (m, 8H, 12-H) , 4.97-5.15 (m, 4H, THP), 5.66-5.75 (d, 2H, 11-H), 5.77-5.89 (d, 2H, 11-H), 6.53 is, 2H, 9-H), 6.88 (s, 2H, 9-H), 7.20 (s, 2H, 6-H) , 7.24 (s, 2H, 6-H); "C NMR (CDC13/ 400 MHz): 5 19.9, 20.6, 23.1, 23.2, 25.3, 25.9, 26.1, 28.2, 28.8, 29.1, 29.2, 30.9, 31.3, 46.3, 56.0, 56.1, 60.0, 60.i, 63.4, 64.6, 68.4, 68.8, 80.9, 81.2, 88.3, 91.2, 95.7, 100.4, riO.l, 110.7, 114.6, 115.1, 127.5, 129.8, 148.5, 148.8, 150.0, 155.0, 167.3, 167.6; IR (neat): 3472, 2945, 1704, 1643, 1604, 1513, 1454, 1432, 1327, 1271, 1202, 1163, 1023cm"1; MS (FAB) m/z (relative intensity) 973 ( [M + Na]*', 46), 951 (M *', 100), 968 (86), 849 (82), ",'49 (34). (b) 1f 1'-[(Butane-1, 4-diyl)dioxy]bis[(llaS)~7-methoxy-l,2,3,11a-tretra.hydro-5H~pyr.roJ o [2,1 ~c] [1, 4]benzodiazepine~5-one] (16b) 95% TFA (3 mL) was added drop-wise to dimer compound 15b (170 mg, 0,17 mmol) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16b (58 mg, 0.1 mmol, 62%) as a solid: [a]20D = +517° (c = 0.18, CHC13) ; 1E NMR (CDC13, 400 MHz): 5 2.04-2.09 (m, BH, 2-H, 2'-H, 13-H, 13'-H), 2.30-2.36 (m, 4H, 1-H, 3'-H), 3,57-3.62 (m, 2H, 3-H, 3'-H), 3.71-3.74 (m, 2H, lla-H, ]la'-H), 3.79-3.85 (m, 2H, 3-H, 3'-H), 3.93 (s, 6H, 7-OMe, 7'-OMe), 4.11-4.21 (m, 4H, 12-H, 12'-H), 6.82 (s, 2H, 9-H, 9'-H), 7.52 (s, 2H, 6-H, 6'-H), 7.66 (d, 2H, J= 4, 11-H, ll'-H); 13C NMR (CDClj, 400 MHz): 6 24.1, 25.7, 29.4, 46.6, 53.7, 56.1, 68.5, 110.5, 111.5, 120.2, 140.6, 147.8, 150.7, 162.3, 164.6; IR (neat): 3316, 2972, 1601, ]505, 1433, 1381, 1262, 1217, 1091cm'1; MS (FAB) m/z (relative intensity) 611 ( [M + 2 x MeOH]"1', 32), 579 ( [M + MeOHl1', ]1) , 547 (M +', 100;, . Example 15 (n=5) (a) 1,2'-[ (Pentane~l,5-diyl)dioxy]bis[ (US, llaS) -10- (tert-butyloxycarbonyl)-7-methoxy-ll-(tetrahydro-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H-pyrrolo[2,1-c][1, 4]benzodiazepine-5-one] (15c) 1,5-Diiodopentane (72.2 mg, 0.22 mmol, 0.5 equiv) was added to the mixture oi monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal ot excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 15c (212 mg, 0.21 mmol, 98% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +40° (c = 0.22, CHC13) ; :H NMR (CDC.1,, 400 MHz): 5 1.21-1.83 (m, 64H, 14-H, Boo, THP), 1.88-2.18 (m, 24H, 1-H, 2-H, 13-H), 3.41-3.73 (m, 16H, 3-H, lla-H, THP), 3.84-4.10 (m, 24H, 12-H, 7-OMe, THP), 4.97-5.15 (m, 4H, THP), 5.66-5.75 (d, 2H, 11-H), 5.77-5.89 (d, 2H, 11-H), 6.50(s, 2H, 9-H), 6.84 (s, 2H, 9-H), 7.17 (s, 2H, 6-H), 7.21 (s, 2H, 6-H); 13C NMR (CDCJ.3, 400 MHz): 5 19.9, 20.5, 21.0, 22.7, 23.1, 23.3, 25.3, 28.], 28.2, 28.9, 29.1, 31.0, 31.3, 46.3, 56.0, 56.1, 60.0, 60.1, 63.4, 64.6, 68.7, 69.0, 80.9, 81.3, 88.2, 91.2, 95.7, 100.4, 110.2, 110.7, 114.5, 115.0, 126.3, 129.7, 129.8, 148.5, 148.8, 150.0, 155.1, 167.4, 167.6; IR (neat): 3431, 2945, 1704, 1643, 1604, 1513, 1453, 1432, 1327, 1271, 1202, 1163, 1023cm"1; MS (FAB) m/z (relative intensity) 987 ( [M 4- Na]+', 37), 965 (M +', 100), 763 (92), 863 (75), 982 (49). (b) 1,2'-I (Pentane- l,5-diyl)dioxy]bis[(llaS)-7-methoxy-l, 2, 3, lla-t.Rtrahydxo-5H-pyi-rolo [2,1-c] [1, 4]benzodiazepinc-5-one] (16c) 95% TFA !3 mL) was added drop-wise to dinner compound 15c (180 mg, 0.19 mmoi) at 0"C. This was then stirred for Ihr and the mixture was poured intc saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 ml.) . The orgaruc layer was then washed water (20 mL) , brine (20 mL) then dried (MgSOj and filtrated. The excess solvent was removed undei reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without neating afforded the final product 16c (70 mg, 0.12 mmol, 65%) as a solid: |a]?0n = +626° (c = 0.17, CHC13) ; :H NMR (CDC13, 400 MHz): 5 1.62-1.71 im, 2H, 34-H), 1.89-1.99 (m, 4H, 13-H, 13'-H), 2.0-2.11 (m, 4H, 2-H, 2'-H), 2.25-2.36 (m, 4H, 1-H, I'-H), 3.53-3.62 (m, 2H, 3-H, 3'-H), 3.66-3.V6 (m, 2H, lla-H, lla'-H), 3.77-3.85 (m, 2H, 3-H, 3'-H), 3.92 (s, 6H, 7-OMe, 7'-OMe), 4.01-4.16 (m, 4H, 12-H, 12r-H), 6.78 (s, 2H, 9-H, 9'-H), 7.50 (s, 2H, 6-H, 6'-H), 7.61 (d, 2H, J= 4, 31-H, ll'-H); 13C NMR (CDC13, 400 MHz): 6 22.5, 29.6, 46.6, 53.7, 56.1, 68.7, 110.5, 111.6, 120.1, 140.6, 147.8, 150,8, .162.3, 364.6; IR (neat): 3350, 2946, 1600, 1505, 1455, 1433, 1383, 1262, 1217, 1092, 1020cm"1; MS (FAB) m/z (relative intensity) 625 ( [M + 2 x MeOH]+', 4), 593 ( [M + MeOH]*', 12) , 547 (M +', 100) . Example 16 (n=6) (a) 1,1'~ I (Hexane-1 , 6-diyl)dioxy]bis[(llS,llaS)-10- (tert-butyloxycarbonyl) - '-methoxy-11 - (tetrahydro-pyran-2-yloxy) -1,2,3,10,11,lla-hexahydro-5H~pyrrolo[2,1-c][1, 4]benzodiazepine~5-one] (15d) !1 , 6-Diiodohexane (75.3 mg, 0.22 mg, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 15d (190 rug, 0.19 mmol , 87% yield, mixture of diastereomers from THP protecting group} as a solid: [a]20D = +11° (c = 0.18, CHC13) ; XH NMR (CDC]3, 400 MHz): 6 1.25-1.66 (m, 60H, 14-H, Boc, THP), 1.68-2.85 m\, 8H, THP), 1, 86-1:. 20 (m, 24H, 1-H, 2-H, 13-H) , 3.44-3-73 (m, :6H, 3 -H, lla H, THP), 3.86-4.10 (m, 24H, 12-H, 7-OMe, THP), 5.01- '.-.17 (m, AH, THP;, 5.68-5.76 (d, 2H, 11-H) , 5.78-5.89 (d, 2H, 11-11), 6.50U;, ?.H, 9-H), 6.87 (s, 2H, 9-H), 7.19 (s, 2H, 6-H) , 7.23 is, 2H, 6-H); nC NMR (CDC13; 400 MHz): 5 19.8, 20.5, 23.1, 23.2, 25.3, 25.9, 28.1, 28.2, 28.9, 29.02, 29.06, 29.1, 29.2, 30.9, 31.2, 46.3, 56.1, 56.2, 60.0, 60.1, 63.3, 64.5, 68.8, 69.1, 80.9, rfl.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.5, 115.0, 126.3, 129.8, 148.5, 148.8, 150.0, 155.1, 167.4, 167.6; IR (neat): 2944, 1704, 1643, 1605, 1513, 1454, 1432, 1327, 1272, 1202, 1164, 1023cm" '; MS (FAR) m/z (.relative intensity) 1001 ( [M + Na] + ', 21), 979 (M '•, 100) , 877 (26) , 777 (17) . (b) 1,1'~ ( (Hexane-], 6~diyl)dioxyjbis[(llaS)~7-methoxy-l,2,3,1la~ tetrahydro-5H-pyrrolo(2,1-c][1,4]benzodiazepine-5-one] (16d) 95% TFA (3 ml,) was added drop-wise to dimer compound 15d (190 mg, 0.19 mmol) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL) . The organic layer was then washed water (20 mL) , brine (20 mL) then dried (MgSO,) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16d (99 mg, 0.17 mmol, 90%) as a solid: la]s°D = +474° (c = 0.19, CHC13) ; ^ NMR (CDC13, 400 MHz): 5 1.49-1.65 (m, 4H, 14-H, 14'-H), 1.82-1.97 (m, 4H, 13-H, 13'-H), 1.99-2.13 (m, 4H, 2-H, 2'-H), 2.26-2.41 (m, 4H, 1-H, I'~ H), 3.53-3.65 (m, 2H, 3~H, 3'-H), 3.68-3.76 (m, 2H, lla-H, lla'-H), 3.77-3.89 (m, 2H, 3-H, 3'-H), 3.94 (s, 6H, 7-OMe, 7'-OMe), 4.01-4.17 (m, 4H, 12-H, 12'-H), 6.80 (s, 2H, 9-H, 9'-H), 7.52 (s, 2H, 6-H, (.'-Hi, 7.66 (d, 2H.. J= 4, 11-H, ll'-H); 13CNMR (CDC13, -500MHz): b 24.1, 2b.7, 2B.8, 29.6, 46.6, 53.7, 56.1, 68.8, 110.4, r.13.6, 120.], 140,6, 147.8, 150.8, 162.3, 164.6; IR (neat): 3318, i'943, 1601, 3506, 1454, 1433, 1382, 1262, 1217, 1021cm"1; MS (FAB) m/z (relative intensity) 639 ([M * 2 x MeOH] + ', 6), 607 ( [M -f MeOH]"', 23) , 575 (M *', 100) . Example 17 (n=7) (a) 1,1'-I (Heptane-1, 7-diyl)dioxy]bis[(IIS,1laS)-10- ftert-butyloxycarbony 1) -7-methoxy-.il- (tetrahydro-pyran-2-yloxy) -j,2,3,10,11,1la-hexahydro~5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one] (ISet 1,7-Dibromoheptane (57.5 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv), potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of 'potassium iodide in dry DMF (30 mL) , and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) ro afford the dimerized compound 15e (200 mg, 0.20 mmol, 91% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +34° (c = 0.13, CHC13) ; 1E NMR (CDC13, 400 MHz): 5 1.25-1.64 (m, 64H, 14-H, 15-H, Hoc, THP), 1.67-1.92 (m, 16H, 13-H, THP), 1.93-2.19 (m, 16H, 1-H, 2-H), 3.41-3.73 (m, 16H, 3-H, lla-H, THP), 3.86-4.08 (m, 24H, 12-H, 7-OMe, THP), 5.01-5.17 (m, 4H, THP), 5.68-5.76 (d, 2H, 11-H), 5.78-5.89 (d, 2H, 11-H), 6.49(s, 2H, 9-H) , 6.85 (s, 2H, 9-H) , 7.18 (s, 2H, 6-H), 7.22 (s, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 5 19.8, 20.5, 23.1, 23.3, 25.3, 25.9, 28.1, 28.2, 28.9, 29.1, 29.2, 29.3, 30.9, 31.2, 46.3, 56.1, 56.2, 60.0, 60.2, 63.3, 64.5, 68.9, 69.1, 80.9, 81.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.4, 115.0, 121.0, 129.8, 133.4, 148.4, 148.8, 155.1, 167.4, 167.6; IR (neat): 2942, 1704, 1643, 1605, 1513, 1454, 1432, 1327, 1272, 1202, 1164, 1023cm"1; MS (FAB) m/z (relative intensity) 1015 ([M+Na]*-, 23), 993 (M*', 100), 891 (34), 791 (25). (b) 1,1 '-••! (Heptane-1, '/-diyl) dioxyjbis [ (llaS) -7-methoxy-l, 2,3,1 la-tetrahydru-BH-pyrzoLo[2,1-cj11, 4]benzodiazepine~5-one] (16e) 95% TFA (3 mL) was added drop-wise to dimer compound 15e (200 mg, ().2 mrnol) at 0DC. This was then stirred for Ihr and the mixture was poured into saturated NaHCOj (30 mL) solution to naturalize the -reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04> and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to Hash column chromatography (SiC>2, 2%methanol-chlorofonn). Removal of excess eluent under reduced pressure without heating afforded the final product 16e (100 mg, 0.17 rranol, 85%) as a solid: iajz°D = +484° (c = 0.15, CHC13) ; :H NMR (CDC13, 400 MHz): 5 1.39-1.56 (m, 6H, 14-H, 14'-H, 15-H), 1.83-1.94 (m, 4H, 13-H, 13'-H), 2.00-2.10 (m, 4H, 2-H, 2'-H), 2.26-2.38 (m, 4H, 1-H, :i'-H), 3.54-3.63 (m, 2H, 3-H, 3'-H), 3.70-3.77 (mr 2H, lla-H, :ila'-H), 3.79-3.91 (m, 2H, 3-H, 3'-H), 3.93 (s, 6H, 7-OMe, 7'-OMe), 4.00-4.16 (m, 4H, 12-H, 12'-H), 6.79 (s, 2H, 9-H, 9'-H), V.51 (s, 2H, 6-K, 6'-H), 7.65 (d, 2H, J= 4, 11-H, ll'-H); 13C NMR (CDC13, 400 MHz): 5 24.1, 25.8, 28.8, 29.0, 46.6, 53.7, 56.1, 68.9, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 33]7, 2936, 1620, 1599, 1505, 1453, 1430, 1381, 1261, 1216, 1092, 1020cm"1; MS (FAB) m/z (relative intensity) 653 ([M + 2 x MeOH]+', 4), 621 i [M + MeOH'jS 3), 589 (M *', 100). Example 18 (n=8) (a) 1,1'-I (Octane-1 r8~diyl) dioxyjbis [ (HS,llaS)-10-(tert-butyloxycarbonyl)-7-methoxy-ll-(tetrahydro-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H-pyrrolo[2,l-c][1,4]benzodiazepine-5-one] (15f) 1,8~Diiodooctane (81.6 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc--hexane) to afford the dimerized compound 15f (190 Tig, 0.18 mmol, 851 yield, mixture of diastereomers from THP protecting group) an a solid: [a]20D = + 28° (c = 0.16, CHC13) ; 1H NMR ,'CDC13, 400 MHz.: 5 1.22-1.64 (m, 68H, 14-H, 15-H, Hoc, THP), 1.67-;.91 (m, 16K, 13-11, THP), 1.93-2.19 (m, 16H, 1-H, 2-H) , 3.41-3.72 .rn, J6H, 3-H, lla-H, THP), 3.85-4.08 (m, 24H, 12-H, 7-OMe, THP), 5. 01-5.17 (m, 4H, THP), 5.68-5.76 (d, 2H, 11-H) , 5.78-5.89 (d, 2H, 11-H), 6.49(a, 2H, 9-H), 6.85 (s, 2H, 9-H), 7.18 (s, 2H, 6-H), 7.22 (s, 2H, 6-H); UC NMR NMR (CDCl:j, 400 MHz!: 5 24.1, 25.8, 28.8, 29.2, 29.6, 46.6, 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.2, 164.67; IP. (neat) : 3326, 2934, 1599, 1505, 1455, 1431, 1382, 1261, 1216, 1092, ]019cnf"; MS (FAB) m/2 (relative intensity) 667 ([M + 2 y. MeOH]4', 3), f.3[, ([M+ MeOH]1"', 8), 603 (M+', 100). Example 19 (n=9) faj 1,1'- I (Nonane-:,9-diyl)dioxyjbis[(IIS,llaS)-10-(tert-butyJ oxyca rbonyj) -7-mekhoxy-ll- (tetrahydro-pyran-2-yloxy) - 1,2,3,10,1j,lla-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-onc) (15g) 1,9-Dibromononane (63.7 mg, 0.22 minol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMF (30 ir.L) , and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent: under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02f 50%EtOAc-hexane) to afford the dimerized compound 15g (200 mg, 0.19 mmol, 89% yield, mixture of diastereomers from THP protecting group) as -a solid: |a]2ur, = +43° (c = 0.16, CHC13) ; JH NMR (CDC13, 400 MHz): 5 1.22-1.6'/ (m, 72H, 14-H, 15-H, 16-H, Boc, THP), 1.68-1.91 (m, 16H, 13-H, THP), 1.92-2.19 (m, 16H, 1-H, 2-H) , 3.41-3.74 (m, 16H, 3-H, lla-H, THP), 3.85-4.09 (m, 24H, 12-H, 7-OMe, THP), 5.01-5.17 (m, 4H, THP), 5.68-5.76 (d, 2H, 11-H), 5.78-5.89 (d, 2H, 11-H), 6.49(s, 2H, 9-H), 6.85 (s, 2H, 9-H), 7.18 (s, 2H, 6-H), 7.22 (s, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 5 19.8, 20.5, 23.2, 23.3, 25.3, 25.9, 28.1, 28.2/28.9, 29.01, 29.06, 29.1, 29.4, 30.9, 31.3, 46.3, 56.1, 56.2, 60.0, 60.2, 63.3, 64.5, 69.0, 69.2, 80.9, 81.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.5, 115.0, 126.4, 129.8, 133.4, 148.5, 148.8, 155.1, 167.4, 167.6; IR (neat): 2939, 1703, 3642, 1604, 1513, 1454, 1432, 1327, 1271, 1202, 1163, 1023cm"1; MS (FAB) m/7. (relative intensity) 1043 ([M+ Na]+', 45), 1021 (M4', 100), 919 (28), 819 (19). (b) 1,1'-I (Nonane-j,9-diyl) dioxyjbisI(llaS)-7-methoxy-l,2,3flla-tetrahydro~5H-pyrrolo[2,l~c][1, 4]benzodiazepine-5-one] (16g) 95% TFA (3 mL) was added drop-wise to dimer compound 15g (200 mg, 0.19 mmol) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 ml). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16g (98 mg, 0.15 mmol, 83%) as 5 solid: [a]20D = +864° (c = 0.14, CHC13) ; 1R NMR (CDC1-,, 400 MHz): 5 I.32-1.52 (m, 10H, 14-H, 14'-H, 15-H, 15'-H, 16-H), 1.83-1.90 (m, 4H, 13-H, 13'-H), 2.02-2.09 (m, 4H, 2-H, 2'-H), 2.27-2.36 (m, 4H, 1-H, I'-H), 3.54-3.64 (m, 2H, 3-H, 3'-H), 3.70-3.77 (m, 2H, lla-H, lla'-U), 3.78-3.88 (m, 2H, 3-H, 3'-H), 3.93 (s, 6H, 7-OMe, 7'-OMe), 3.99-4.15 (m, 4H, 12-H, 12'-H), 6.80 (s, 2H, 9-H, 9'-H), 7.51 (s, 2H, 6-H, 6'-H), 7.65 (d, 2H, J= 4.4, 11-H, 11'-11); 13C NMR (CDC13, 400 MHz): 5 24.1, 25.8, 28.8, 29.2, 29.3, 29.6, 46.6, 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.8, 164.6; IR (neat): 2934, 1622, 1599, 1557, 1505, 1455, 1429, ]382, 1339, 1260, 1216, 1092, 1020cm"1; MS (FAB) m/z (relative intensity) 681 ( [M + 2. x MeOH]+', 6), 649 ( [M + MeOH]+', 12), 617 (M "•, 100) . Example 20 (n=10) (a) 1,1' •-[ (Decane-J ,10-diyl) dioxyjbis [ (HS,llaS) -10- ftert-butyloxycarbonyl)- 7-methoxy-ll-(tetrahydro-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro~5H-pyrrolo[2,1-c][1, 4]benzodiazepine-5-one] (15h) 1,10-Diiododecane (87.8 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) and potassium carbonate (0.98 mmol, 2.2 equiv) in dry DMF (30 mL), and the resulting mixture was heated to 90°C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid,- which was subjected to flash column chromatography (SiO^, 50%Et;OAc-hexune) to afford the dimerized compound 15h (180 ing, 0.17 mmol, 79% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20D = +59° (c = 0.16, CHC13) ; 1H NMR (CDC13, 400 MHz): 5 1.22-1.67 (m, 76H, 14-H, 15-H, 16-H, Hoc, THP), I. 68-1. 91 (m, 16H, 13-H, THP), 1.92-2.19 (m, 16H, 1-H, 2-H), 3.41-3.72 (m, 16H, 3-H, lla-H, THP), 3.85-4.09 (m, 24H, 12-H, 7-OMe, TFIP) , 5.01-5.17 (m, 4H, THP), 5.68-5.76 (d, 2H, 11-H), 5.78-5.89 (d, 211, 11-H), 6.50 (s, 2H, 9-H) , 6.85 (s, 2E, 9-H), 7.18 (s, 2H, 6-H) , 7.23 (s, 2H, 6-H) ; 13C NMR (CDC13, 400 MHz): 6 19.8, 20.5, 23.2, 23.3, 25.3, 26.0, 28.1, 28.2, 28.9, 29.00, 29.04, 29.1, 29.4, 29.5, 30.9, 31.3, 46.3, 56.1, 56.2, 60.0, 60.2, 63.3, 64.5, 69.0, 69.2, 80.9, 81.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.5, 115.0, 126.4, 129.8, 133.4, 148.5, 148.8, 155.1, 167.4, 167.6; IP. (neat): 2938, 1703, 1642, 1605, 1513, 1454, 1432, 1327, 1271, 1202, 1163, 1023cm'1; MS (FAB) m/z (relative intensity) 1057 l[M+Na]4', 48), 1035 (M+', 100), 933 (26), 833 (20). (b) 1,1'-! (Dccane-1,10-diyl)dioxy]bisf(llaS)-7-methoxy-l,2,3,11a-j.etrahyctro-5H-pyrrolo [2,1-c] [ 1, 4]benzodiazepine-5-one] (16h) 95% 'ITA (3 ml.) was added drop-wise to dimer compound 15h (180 mg, 0.17 mmol) at. 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHCOs (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgS04) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiOa, 2%methanol~ chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16h (103 mg, 0.16 mmol, 96%) as a solid: [a]20D = +500° (c = 0.11, CHC13) ; :H NMR (CDC13, 400 MHz): 5 1.26-1.50 (m, 12H, 14-H, 14/-H, 15-H, 15'-H, 16-H, 16'-H), 1.82-1.91 (m, 4H, J3-H, 13'-H), 1.98-2.09 (m, 4H, 2-H, 2'-H), 2.25-2.35 (m, 4H, 1-H, l'-H), 3.54-3.61 (m, 2H, 3-H, 3'-H), 3.69-3.73 (m, 2H, lla-H, lla'-H), 3.78-3.83 (m, 2H, 3-H, 3'-H), 3.93 (s, 6H, 7-OMe, 7'-OMe), 3.98-4.14 (m, 4H, 12-H, 12'-H), 6.79 (s, 2H, 9-H, 9'-H.', 7.50 (s, 2H, 6-H, 6'-H), 7.65 (d, 2H, J= 4.4, 11-H, ll'-H); 1:>C NMR (CDC13, 400 MHz): 5 24.1, 25.8, 28.8, 29.3, 29.4, 29.G, 4h.6, 53/7, 56.1, 69.0. 110.4, 111.6, 120.0, 140.6, .147.8, 150.9, 152.3, 164.6; IR (neat): 2928, 1599, 1557, 1505, i455, 1430, 1382, 1261, 1216, 1092, 1019cm"1; MS (FAB) m/z (relative intensity) 695 ([M + 2 x MeOH] + ', 8), 663 ( [M + MeOH]4', J G) , 631 (M "', 100) . Example 21 (n=ll) (a) 1,1'-[ (Undecane-1,11-diyl)dioxy]bis[(]IS,llaS)-10- (tert-butyloxycarbonyl)-7-methoxy-ll-(tetrahydro-pyran-2-yloxy)- 1,2,3,10,11,1]a-hexahydro-5H-pyrrolo[2,1-c][1, 4]benzodiazepine~5-one] (15±) 1,11-Dibromounclecanc (70.0 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium iodide in dry DMF (30 mL) , and the resulting mixture was heated to 90DC under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-hexane) to afford the dimerized compound 15i (210 mg, 0.20 mmol, 91% yield, mixture of diastereomers from THP protecting group) as a solid: (a]20D = +33" (c = 0.18, CHC13) ; AH NMR (CDC13, 400 MHz): 5 1.22-1.66 (m, BOH, 14-H, 15-H, 16-H, 17-H, Boc, THP), 1.67-1.91 (m, 16H, 13-H, THP), 1.92-2.18 (m, 16H, 1-H, 2-H), 3.41-3.72 (m, 16H, 3-H, lla-H, THP), 3.85-4.08 (m, 24H, 12-H, 7-OMe, THP), 4.99-5.15 (m, 4H, THP), 5.67-5.75 (d, 2H, 11-H), 5.77-5.88 (d, 2H, 11-H) , 6.49 (s, 2H, 9-H), 6.85 (s, 2.H, 9-H), 7.18 (s, 2H, 6-H), 7.21 (s, 2H, 6-H); 13C NMR (CDC13, 400 MHz): 5 19.8, 20.5, 23.2, 23.3, 25.3, 26.0, 2B.1, 28.2, 28.9, 29.0, 29.1, 29.4, 29.5, 30.9, 31.3, 46.3, 56.1, 56.2, 60.0, 60.2, 63.3, 64.5, 69.0, 69.2, 80.9, 81.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.5, 115.0, 126.4, 129.8, 133.4, 148.5, 148.8, 155.1, 167.4, 167.7; IR (neat): 2936, 1704, 1642, 1605, 1513, 1454, 1432, 1327, 1272, 1202, 1164, 1023cm"1; MS (FAB) m/z (relative intensity) 1071 ( [M + Na]S 76), 1049 (M +~, 100), 947 (24), 847 (19), (b) 1,1'-I(Undecanc-1,11-diyl)dioxy]bis[(llaS)-7-methoxy-1,2,3,2la~tetrahydro-5H-pyrrolo[2,2-c][1,4]benzodiazepine~5-one] (16±) 95% TFA (3 mLj was added drop-wise to dimer compound 15i (210 mg, 0.20 mmoJ) at C°C. This was then stirred for Ihr and the mixture was poured intc saturated NaHCQ3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL). The organic layer was then washed water (20 mL), brine (20 ml,) then dried (MgSO/j) and filtrated. The excess solvent was removed undea: reduced pressure to give the crude product, which was subjected to fj.ash column chroma tography (Si02, 2%methanol~ chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16i (105 mg, 0.16 mmol, 81%) as a solid: [«)20D = +623° (c = 0.13, CHC13) ; 1K NMR (CDC13, 400 MHz): 6 1.26-1.52 (m, 14H, 14-H, 14'-H, 15~H, 15'-H, 16-H, 16'-H, 17-H), 1.62-1.92 (m, 4H, 13-H, 13'-H), 1.99-2.12 (m, 4H, 2-H, 2'-H), 2.26-2.38 (m, 4H, 1-H, I'-H), 3.55-3.64 (m, 2H, 3-H, 3'-H), 3.69-3.77 (m, 2H, lla-H, lla'-H), 3.78-3.91 (m, 2H, 3-H, 3'-H), 3.94 (s, 6H, 7-OMe, 7'-OMe), 4.99-4.24 (m, 4H, 12-H, 12'-H), 6.80 (s, 2H, 9-H, 9'-H), 7.51 (s, 2H, 6-H, 6'-H), 7.65 (d, 2H, J= 4.4, 11-H, ll'-H); 13C NMR (CDC13, 400 MHz): 5 24.1, 25.9, 28.9, 29.3, 29.4, 29.6, 46.6, 53.7, 56.1, 69.1, 110.4, 111.5, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3321, 2927, 1599, 1505, 1455, 1431, 1382, 1261, 1216, 1092, 1022cm"1; MS (FAB) m/z (relative intensity) 709 ([M + 2 x MeOH]+', 4), 677 ( [M + MeOH]+', 11) , 645 (M * , IOC) . Example 22 (n=12) (a) 1,1'-I (Dodecane-1,12-diyl) dioxyjbis [ (HS,llaS) -10- (tert-butyloxycarbonyl)-7-methoxy~ll-(tetrahydro-pyran-2-yloxy) -1,2,3,10,llflla-hexahydro~5H-pyrrolo[2,l-c][1, 4]benzodiazepine~5-one] (15j) 1,12-Dibromododecane (73.1 mg, 0.22 mmol, 0.5 equiv) was added to the mixture of monomer 14 (0.2 g, 0.44 mmol, 1.0 equiv) potassium carbonate (0.98 mmol, 2.2 equiv) and a catalytic amount of potassium :iodide in dry DMF (30 m'L) , and the resulting mixture was heated to 90°C uride.r a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, 50%EtOAc-nexane) to afford the dimerized compound 15j (210 mg, 0.19 mmol, H9% yield, mixture of diastereomers from THP protecting group) as a solid: [a]20,., =• +50° (c = 0.19, CHC13) ; 1E NMR (CDC13, 400 MHz): 5 1.22-1.66 (m, B4H, 14-H, 15-H, 16-H, 17-H, Boc, THP), 1.67-1.91 (m, 16H, 13-K, THP), 1.92-2.19 (m, 16H, 1-H, 2-H) , 3.41-3.72 (m, 16H, 3-H, lla-H, THP), 3.88-4.08 (m, 24H, 12-H, 7-OMe, THP), 5.00-5.15 (m, 4H, THP), 5.67-5.74 (d, 2H, 11-H) , 5.78-5.87 (d, 2H, 11-H), 6.49 (s, 2fi, 9- H) , 6.85 (s, 2H, 9-H), 7.18 (s, 2H, 6-H), 7.21 (s, 2H, h-K) ; "C NMR (CDC13, 400 MHz): 6 19.8, 20.5, 23.1, 23.3, 25.3, 26.0, ?8.1, 28.2, 28.91, 28.98, 29.0, 29.1, 29.4, 29.5, 29.6, 30.9, 31.3, '16.3, 56.1, 56.2, 60.0, 60.2, 63.3, 64.5, 69.0, 69.2, 80.9, 81.3, 88.2, 91.2, 95.7, 100.3, 110.1, 110.6, 114.5, 115.0, 126.4, 129.8, 133.4, 148.5, 148.8, 155.1, 167.4, 167.7; 1R (neat): 2932, 1702, 1644, 1604, 1512, 1454, 1431, 1326, 1271, 1202, 1163, 1023cm"1; MS (FAB) m/z (relative intensity) 1085 ( [M + Na]+', 43), 1063 (M " ' , 100), 961 (31), 861 (17). (b) !,]'-[ (Dodecane-1 ,12-diyl) dioxy] bis [ (llaS) -7-methoxy-.1,2,3, lla-tetrahydro-5H-pyrrolo [2,1-c] [1 , 4]benzodiazepine-5-one] 95% TFA (3 mL) was added drop-wise to dimer compound 15j (210 mg, 0.19 mmol ) at 0°C. This was then stirred for Ihr and the mixture was poured into saturated NaHC03 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3x20 mL) . The organic layer was then washed water (20 mL) , brine (20 mL) then dried (MgSO^) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2%methanol-chloroform) . Removal of excess eluent under reduced pressure without heating afforded the final product 16j (112 mg, 0.17 mmol, 89%) as a solid: fa]20^ = +637° (c = 0.13, CHC13) ; XH NMR (CDC13, 400 MHz): 5 1.24-1.51 (m, 16H, 14-H, 14'-H, 15-H, 15'-H, 16-H, 16'-H, 17-H,. 17'-H), 1.76-1.93 (m, 4H, 13-H, 13'-H), 1.98-2.11 (m, 4H, 2-H, 2'-H), 2.25-2.38 (m, 4H, 1-H, I'-H), 3.54-3.64 (m, 2H, 3-H, 3'-11), 3.68-3.76 (m, 211, lla-H, lla'-H), 3.77-3.89 (m, 2H, 3-H, 3'-H), 3.93 (s, 6H, 7-OMe, 7'-OMe), 3.98-4.14 (m, 4H, 12-H, 12'-H), 6.79 (s, 2H, 9~H, 9'-H), 7.50 (s, 2H, 6-H, 6'-H), 7.64 (d, 2H, J= 4.4, 11-H, 11'-H); i:JC NMR (CDC13, 400 MHz): 5 24.1, 25.9, 28.9, 29.3, 29.5, 29.5, 29.6, 46.6, 53.7, 56.1, 69.1, 110.4, 111.5, 120.0, I4C.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3338, 2926, 1599, 1506, 1456, 1431, 1381, 1261, 1216, 1092, 1023cm"1; MS (FAB) m/z (relative intensity) 723 ([M + 2 x MeOH]4', 9), 691 ( [M + MeOH]'"', 35) , 659 (M "', 100) . Example 23: Synthesis of PBD monomer - (HS,llaS) -10- (tert-Butyloxycarbonyl)-8-hydroxy-7-methoxy-2-methylidene-ll-(te trahydroxy-pyran-2-yloxy)~1,2,3,10,11,11a-hexahydro-5 H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (27) (a) A'- [4-Benzyloxy-5-methoxy-2-nitro-benzoyl]- (2S,4R) - [4- hydroxypyrrolLdine-2-carboxylate] (19) (Figure Remove)A catalytic amount of dry DMF (2 drops) was added to a solution of acid 17 (5 g, 16.4 mmol, 1.0 equiv.) in dry DCM (70 mL) and oxalyl chloride (1.6 mL, 2.3 g, 18.1 mmol, 1.1 equiv.) and then the reaction mixture was stirred overnight under nitrogen. The resulting solution was added dropwise to a solution of the salt 18 (5.74 g, 18.1 mmol, 1.1 equiv.; J. Org. Chem., 59, 13, 1994, 3621) and TEA (6.84 mL, 4.96 g, 49.2 mmol, 3.0 equiv.) in dry DCM (100 mL) at -20 °C (ethylene glycol/dry-ice). The reaction mixture was allowed to warm to room temperature and stirred overnight at which point TLC (Si02, EtOAc) revealed reaction completion. The mixture was washed with 1N-HC1 (50 mL) , water (50 mL) , saturated aqueous NaHC03 (50 mL) , brine (50 mL) and dried over MgSOa. The solvents were removed under vacuum to leave a yellow solid which was triturated with cold EtOAc to yield pure ester compound 19 (4.84 ]2BD - -57° (c = 0.20, CHC13) ; 1H NMR (CDC13, 400 MHz) (Kotamers): 5 1.22-1.38 (m, 1-H rotamers), 2.10-2.45 (m, i-H), 3.10-3.18 (in, 3-H), 3.47 (s, CO2Me rotamers), 3.49-3.53 (m, ';-H) , 3.71-3.75 (m, 3-H rotamers), 3.80 (s, C02Me) , 3.93 (s, 7-OMe rotamers), 3.9' (f., 7-OMe) , 4.09-4.20 (m, 3-H rotamers, lla-H rotamers), 4,42-4,49 (m, 2-H), 4.52-4.59 (m, 2-H rotamers), 4.83 it, lla-H, J =-• 8.0 Hz), 5.20 (s, 2H, OCH2Ph) , 6.80 (s, 6-H rotamers), 6.85 (s, 6-H), 7.32-7.46 (m, 5H, Ph) , 7.69 (s, 1H, 9-H); 13C NMP. (CDC1-,, 100 MHz) (Rotamers): 6 38.0, 39.4, 52.3, 52.5, 54.6, 56.3, 56.6, 56.8, 57.2, 59.0, 69.2, 70.0, 71.4, 109.1, 109.7, 126.5, 127.3, 127.6, 128.5, 128.8, 135.2, 135.3, 137.3, 148.2, 148.3, 154.5, 154.9, 166.7, 167.0, 172.4, 172.5; IR (neat): 3433, 2950, 1742, a626, 1577, 1521, 1454, 1432, 1336, 1277, 1213, 1073, 750 cnfj; MS (ES*) m/z (relative intensity) 431 ( [M 4 H]"1', 100) , 432 ( [M -i 2HJ"', 25) . (b) N- [4-Benzy.loxy-5-methoxy~2-nitro-benzoyl] - (2S, 4R) - [4-hydraxy-2 - (hydroxymer.nyl!pyrrolidine] (20) (Figure Remove)A solution of the ester 19 (3.8 g, 8.83 mmol, 1.0 equiv.) in THF (100 mL) was cooled to 0 °C and treated with LiBH4 (0.29 g, 13.25 mmol, 1.5 equiv.) in portions. After stirring for 30 min at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 4 h at which time TLC (Si02, EtOAc) revealed complete consumption of ester 19. The mixture was cooled to 0 °C again and water (100 mL) was carefully added followed by IN HCl (250 mL) which provoked vigorous effervescence. After evaporation of the THF in vacuo, the mixture was neutralised to pH 7 with IN NaOH. The aqueous solution was then extracted with EtOAc (4 x 70mL), the combined organic layers washed with brine (50 mL), dried (MgSO«) , filtered and evaporated in vacuo to furnished the pure diol 20 (3.2 q, 7.96 mmol, 90%), which was used in the subsequent reaction without further purification: ia]29,, = -96° (c = 0.15, CHC13) ; aH NMR (CDC13, 400 MHz): 5 ]. 85-1. 99 (rn, 1H, 1-H) , 2.09-2.28 (m, 1H, 1-H), 3.11-3.20 (m, 1H, 11--H), 3.2.4-3.39 (m, 1H, 11--H) , 3.70- 3.82 (m, 1H, 3-H) , 3.85-4.04 (m, 5H, 3-H, 7-OMe, OH), 4. 30-4. 38 (m, 1H, lla-H), 4.46-4.61 (m, 2H, 2-H), 5.20 (m, 2H, OCH?Ph) , 6.86 (s, 1H, 6-H), 7.29-7.50 (m, 5H, Ph), 7.74 (s, 1H, 9-H) ; 13C NMR (CDC13, 100 MHz): 5 37.1, 56.8, 56. B, 59.9, 65.0, 69.4, 71.4, 109.1, 109.3, 127.6, 127.7, 128.5, 128.8, 135.2, 137.2, 148.2, 155; IR (neat): 3357, 2938, 1614, 1576, 1520, 1454, 1434, 1333, 1276, 1220, 1069, 1048, 1006, 730, 698, 647 cm"'; MS (ES+) m/z (relative intensity) 426 ({M t Na]+', 5), 403 |[M+ H]+', 100), 404 ( [M + 2H]+', 40). (c) N- l2-Amino-4-benzyloxy-5-methoxy-benzoyl] - (25 , 4R) - [4-hydroxy-2- IhydroxymethyDpyrrolidine] (21) (Figure Remove)A mixture of diol 20 (26 g, 64.6 mmol, 1.0 equiv.) and SnCl2.2H2O (72.9 g, 323 mmol, 5.0 equiv.) in MeOH (300 mL) , was heated at reflux and the progress of the reaction monitored by TLC (EtOAc) . After 3 h, the MeOH was evaporated in vacua and the resulting residue was cooled and treated carefully with saturated NaHC03 (400 mL) . The mixture was diluted with EtOAc (800 mL) , and after 12 h stirring al room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL) , dried (MgSO«) , filtered and evaporated in vacua to give a brown solid 21 which was used in the next reaction without further purification: [a]29D = -69° (c = 0.13, CHC13) ; :H NMR (CDC13, 400 MHz): 5 1.70-1.82 (m, 1H, 1-H), 2.06-2.19 (m, 1H, 1-H), 3.52-3.85 (m, 9H, 3-H, 11~H, 7-OMe, 2 x OH), 4.26-4.72 (m, 1H, lla-H), 4.47-4.60 (m, 1H, 2-H), 5.10 (s, 2H, OCH2Ph) , 6.26 (s, 1H, 9-H), 6.78 (s, 1H, 6-H), 7.29-7.36 (m, 7H, Ph, NH2) ; nC NMR (CDC13, 100 MHz): 5 37.0, 57.1, 58.5, 59.0, 66.2, 69.4, 70.7, 103.4, 112.4, 112.9, 127.1, 128.0, 128.6, 136.5, 140.0, 141.9, 151.0, 172.6; IR (neat):, 3358, 2939, 1619, 1589, 1512, 1455, 1432, 1408, 1263, 1231, 1171, 1113, 1012, 787, 735, 698, 644 cm"1; MS fES') m/z (relative intensity) 395 ( [M + Na]+1, 4), 373 ( [W -t HI1', 70), r/4 ([M + 2H]+-, 40), 256 (100), 257 (45). (d) N-[4-Benzy}oxy-5-methoxy-2- (tert- butyloxycarbonylamjno) benzoyl] - (25, 4R) - [ 4-hydroxy-2-(hydroxyme thyl ) pyrrol idine] (22) (Figure Remove)A solution of amine 21 (24 g, 64.6 mmol, 1.0 eguiv.) and Di-tert-hutyl dicarbonate (14.12 g, 64.6 mmol, 1.0 equiv.) in THF (300 mL) was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and excess THF was removed under reduced pressure to give the crude product. The residue was subjected to flash, column chromatography (Si02, 30% EtOAc-hexane) to afford the product 22 (18.29 g, 38.75 mmol, 60%) as a yellow oil: [a]z5D =- -46" (c = 0.15, CHC13) ; ^ NMR (CDC13, 400 MHz): 6 1.46 (s, 9H, Hoc), 1.71-1.84 (m, 1H, 1-H) , 2.15-2.24 (m, 1H, 1-H) , 2.78 (bs, 1H, OH), 3.54-3.76 (m, 3H, 3-H, 11-H) , 3.77-3.94 (m, 4H, 3-H, 7-OMe), 4.26-4.43 (m, 1H, lla-H), 5.15 (d, 2H, J = 4.54 Hz, OCH2Ph) , 6.79 (s, 1H, 6-H) , 7.26-7.49 (m, 6H, 9-H, Ph) , 7.72 (s, 1H, NH); "C NMR (CDC13, 100 MHz): 6 28.3, 37.2, 56.7, 59.4, 69.7, 70.8, 80.8, 108.1, 111.5, 118.8, 127.6, 128.1, 128.6, 130.4, 136.2, 145.1, 150.1, 153.6; IR (neat): 3358, 2971, 1717, 1597, 1519, 1454, 1432, 1404, 1367, 1241, 1157, 1118, 1016, 773, 698 cm" '; MS (ESH) m/z (relative intensity) 473 (M *', 100), 474 ([M + 2H]+", 30), 256 (74), 373 (57), 416 (38). (e) (IIS, llaS) -8-Benzyloxy-10- (tert-butyloxycarbonyl) -11-hydroxy-7 -methoxy- 2-oxo-l ,2 ,3,10,11 , lla-hexahydro-5H~pyrrolo [2 , 1-c] [1, 4]benzodiazepine-5~one (23) (Figure Remove)BAJB (11 g, 52.96 mmol, 5.0 equiv.) and TEMPO (0.17 g, 1.05 mmol, 0.1 equiv.) were added to a solution of Boc protected amine alcohol 22 (5.0 g, 10.59 mmol, 1.0 equiv.) in DCM (50 m'L) and the mixture was allowed to stir overnight. When the reaction was complete as indicated by TLC (Si02, 50% EtOAc-hexane), the reaction mixture was diluted with DCM (100 mL) and washed with saturated NajSjOj (60 mL) - The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO,) . Removal of excess solvent under reduced pressure afforded a crude solid which was washed with cold EtOAc to give cyclized compound 23 (2.3 g, 4.9 mmol, 46%) as a white solid: ia]2'D = +117" (c = 0.14, CHC13) ; aH NMR (CDC13, 400 MHz): 6 1.28 (s, 9H, Boc), 2.68-2.73 (rn, 1H, 1-H), 2.90-3.02 (m, 1H, 1-H) , 3.75-1.01 (m, 6H, 3-H, ila-H, OH, 7-OMe), -1.22-4.46 (m, 1H, 3-H), 5.03-5.26 (m, 2H, OCH?Ph) , 5.55-5.69 (m, 1H, 11-H) , 6.68 (s, 1H, 9-H) , 7.23 (s, 1H, 6-H), 7.33-7.45 (m, 5H, Ph) ; 13C NMR (CDC13, 100 MHz): 6 28.0, 40.3, 52.6, 56.2, 56.6, 71.1, 86.0, 110.7, 114.6, 123.9, 127.0, 128.2, 128.6, 128.8, 129.1, 130.3, 136.2, 149.0, 150.5, 167.7, 207.9; IR (neat): 3389, 2978, 1762, 1700, 1637, 1603, 1511, 3456, 1431, 1368, 1329, 1256, 1221, 1157, 1118, 1059, 767 cm"1; MS (ES+) m/z (relative intensity) 469 (M *', 27), 413 (100), 351 (61) , 256 (30) . (f) (llS,llaS) ~10-(tert-Butyloxycarbonyl)-8,ll-dihydroxy-7-methoxy-2-oxo-1,2,3,10,11,lla-hexahydro-5H~pyrrolo[2,1-c] [1, 4]benzodiazepine-5-one (24) (Figure Remove)catalytic amount of 10% palladium on carbon (0.23 g) was added i:o a solution of cyclized compound 23 (2.3 g, 4.9 nvrnol) in absolute alcohol (50 mL) . The reaction mixture was hydrogenated for 4 h at 30 Psi . When the reaction was complete as indicated by TLC (SiCb, 50% EtOAc-hexane) the reaction mixture was filtered through CelJte, and removal of excess solvent under reduced pressure afforded the phenol 24 (4.7 g, 2.64 ramol, 53%) as a white solid: [Qj'br, = -CHS0 (c = 0.10, MeOH) ; :H NMR (CDC13, 400 MHz): b "1.39 (s, 9K, Boc), 2.68-2.80 (m, 1H, 1-H) , 2.87-3.02 (m, 1H, 1-H) , 3.84-4.06 (m, 6H, 3~H, lla-H, OH, 7-OMe) , 4.22-4.35 (m, 1H, 3-H) , 5.53-5.71 (m, 1H, !1-H), 6.02 (s, 1H, OH), 6.73 (s, 1H, 9-H), 7.2.0 (s, 1H, 6-H) ; nC NMR (CDC13/ 100 MHz): 6 28.1, 40.4, 52.6, 56.2, 56.7, 85.9, 110.1, 115.9, 123.1, 129.9, 145.9, 148.2, 167.8, 208.1; IR (neat): 3355, 2977, 1760, 1685, 1606, 1515, 1469, 1415, 1369, 1332, 1297, 1212, 1162, 1132, 1042, 767 cm'1; MS (ES+) m/z (relative intensity) 379 (M +' , 93), 380 ([M + 2H]+', 25), 364 (100) , 396 (75! , 47.0 (45) . (g) (IIS, llaS) -10- (tert-Butyloxycarbonyl) -7-methoxy~2-oxo-8 ,11-di (tetrahydroxy~pyran-2-yloxy) -1,2,3,10,11 ,lla-hexahydro-5H-pyrrolo [2, 1 -c] [1 , 4] benzodiazepine-5-one (25) (Figure Remove)A catalytic amount of PTSA was added to a solution of DHP (4.8 mL, 52.8 mmol, 10.0 equiv.) in EtOAc (10 mL) at 0 °C . After stirring for 10 minutes, the phenolic compound 24 (2.0 g, 5.28 mmol, 1.0 equiv.) was added portionwise to the mixture and stirred until the disappearance of starting material was observed by TLC (Si02, 50% EtOAc-hexane) . The mixture was diluted with EtOAc (100 mL) , washed with saturated NaHC03 (30 mL) , brine (30 mL) and dried (MgSO4) . Removal of excess solvent under reduced pressure afforded a crude solid which was subjected to flash column chromatography (SiO2, 30% EtOAc-hexane) to give the protected compound 25 (1.8 g, 3.4 mmol 65% yield, mixture of diastereomers from THP protecting group): la]24[, = -ijlO0 (c = i.i.10, CHC13) ; aH NMR (CDC13, 400 MHz): 6 1.34 (s, ifiH, Hoc), l.li-l.Bl (m, 18H, THP), 1.83-2.14 (m, 6H, THP), 2.55-,:.65 (m, 1H, 1-H), 2.82-3.00 (m, 3H, 1-H), 3.51-3.66 (m, 4H, THP), .:>.82-4 .05 (m, 14H, ?.~H, lla-H, 7-OMe, THP), 4.23-4.44 (m, 2H, 3-H), •1.96-5.Of) im, 1H, THP), 5.12-5.20 (m, 1H, THP), 5.26-5.41 (in, 1H, THP), 5.43-5.5C (m, 1H, THP), 5.77-5.86 (d, 1H,,11-H), 5.90-6.01 id, Hi, 31-Hj, 6.80-6.90 (2 x s, 1H, 9-H) , 7.15-7.22 (3 x s, 3H, G-H, 9-H); :'JC NMR (CDC13, 100 MHz): 6 18.2, 18.6, 18.8, 20.0, 20.2, 20.6, 25.1, 25.2 (x 2), 27.9, 28.0, 28.1, 28.2, 30.0, 30.1, 30.6, 30.9, 31.1, 31.2, 40.4, 40.8, 52.7, 52.8, 56.2, 56.9, 57.0, 61.6, 62.0, 62.1, 63.6, 63.9, 64.7, 81.5, 88.3, 91.2, 96.6, 100.4, 110.5, 110.9, 118.2, 125.9, 129.5, 129.6, 148.6, 148.7, 168.1, 168.2, 208.3, 208,5; IR (neat): 2941, 1762, 1702, 1649, 1604, 1508, 1454, 1429, 1393, 1367, 1324, 1256, 1197, 1162, 1115, 1072, 1021, 960, 904, 870, 731 cm"1; MS (ES+) m/z (relative intensity) 547 (M '", 56), 548 {[M-f 2H]+', 20), 261 (100), 345 (94). (h) (IIS,llaS)-10-(tert-Butyloxycarbonyl)-7-methoxy-2-methylidene-8,11-di (tetrahydroxy-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro-5H-pyrrolo[2,1-c] [1,4]benzodiazepine-5-one (26) (Figure Remove)Potassium tert-butoxide (4.1 g, 36 mmol, 10.0 equiv.) was added portionwise to a suspension of methyltriphenylphosphonium bromide (12.8 g, 36 mmol, 10.0 equiv.) in THF (50 mL) at 0 °C, under nitrogen. After stirring for 2 h at 0 °C, a solution of the ketone 25 (2.0 g, 3.6 mmol, 1.0 equiv.) was added dropwise and the mixture allowed to warm to room temperature. After stirring overnight, the reaction mixture was diluted with EtOAc (250 mL) and water (250 mL) and the organic layer separated, washed with brine, dried (MgSCu) , filtered and evaporated in vacua to give a dark red oil, wrn eh was shown to contain a mixture of several components by TLC (Si02, 50% EtOAc-hexane). Purification by flash chromatography (S.iOa, 30% EtOAc-hexane) isolated the pure olefin 26 ds a white solid (1.4 g, 2.59 ramol, 72% yield, mixture of di astereomers from THP protecting group: [a]22D = +105° (c = 0.20, CHClj) ; Hi NMR (CDC13, 400 MHz): 5 1.32 (s, 18H, Hoc), 1.40-1.81 (m, 18H, THP), 1.B3-2.14 (m, 6H, THP), 2.50-2.59 (m, 1H, 1-H) , :J.69-2.95 (m, 31-1, 1-H), 3.51-3.72 (m, 6H, lla-H, THP), 3.82-4.03(m, 10H, 7-OMe, THP), 4.04-4.18 (m, 2H, 3-H), 4.23-4.38 (m, 211, 3-H), 4.96-5.19 (in, 6H, 2a-H, THP), 5.22-5. 48 (m, 2H, THP), 5.62-5.7] (d, 1H, 11-H), 5.75-5.87 (d, 1H, 11-H), 6.77-6.90 (2 x s, 1H, 9-H), 7.10-7.20 (3 x s, 3H, 6-H, 9-H); 13C NMR (CDC13, 100 MHz): 5 18.3, 18.7, 18.8, 19.9, 20.0, 20.6, 25.1, 25.2, 25.3, 27.9, 28.0, 28.2, 30.1, 30.2, 30.4, 30.7, 31.0, 31.2, 31.3, 35.1, 35.5, 50.7, 56.2, 59.8, 60.0, 61.6, 62.0, 62.1, 63.4, 63.6, 64.5, 81.1, 81.2, 88.0, 90.9, 96.0, 96.3, 96.5, 96.7, 98.4, 99.6, 100.3, 109.4, 109.5, 110.3, 110.7, 118.1, 120.3, 127.3, 129.6, 129.7, 129.8, 142.3, 147.9, 148.1, 148.8, 149.4, 155.2, 168.1, 168.2; IR (neat) : 2940, 2866, 1702, 1639, 1604, 1506, 1453, 1431, 1393, 1367, 1324, 1198, 1162, 1114, 1072, 1019, 960, 906, 870, 727, 644cm""1; MS (ES + ) m/z (relative intensity) 545 (M *', 38), 546 ( [M + 2H]f', 15), 343 (100), 259 (95), 344 (23). (i) (HS,.llaS) -10- (tert-Butyloxycarbonyl) -8-hydroxy~7-methoxy-2-methylidene-11- (tetrahydroxy-pyran-2-yloxy)-1,2,3,10,11,lla-hexahydro~5H~pyrrolo[2,1-c][1, 4]benzodiazepine-5-one (27) (Figure Remove)A solution of THF/AcOH/H20 (2: 1: 1, 5 mL) was added to the olefin 26 (1.8 g, 3.3 mmol) and the resulting mixture was stirred for 3 h at which point TLC (Si02, 50% EtOAc-hexane) revealed complete reaction. The mixture was then neutralized with saturated NaHCOa and extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgS04) . Removal of excess solvent under reduced pressure gave the crude product. The residue was subjected to flash chromatography (Si02, 50% EtOAc-hexane) to afford the product 27 (1.34 g, 2.9 mmol, 87 % yield, mixture of diastcreomers from THP protecting group): [a]2/D = +81° (c =- 0.16, CHCi;,); JH NMR (CDC13, 400 MHz): 5 1.32 (s, 18H, Boc) , J.45-1.64 (m, 8H, THP), 1.66-1.84 (m, 4H, THP), 2.50-2.58 (m, 1H, 1-H) , 2.68-2.80 (rr», 1H, 1-H), 2.84-2.96 (m, 2H, 1-H), 3.51-3.67 (m, 4H, lla-H, THP), 3.87-4.00 (m, 8H, 7-OMe, THP), 4.04-4.18 (m, 2H, 3~H), 4.23-4.3B (m, 2H, 3-H), 4.96-5.19 (m, 6H, 2a-H, THP), 5.65-5.72 (d, 1H, 11-H), 5.75-5.38 (d, 1H, 11-H), 5.97 (s, 1H, 8-OH), 6.00 (s, 1H, 8-OH), 6.63 (s, 1H, 9-H), 6.92 (s, 1H, 9-H), 7.17 (s, 1H, 6-11), '/.21 (s, 1H, 6-H); 13C NMR (CDC13, 100 MHz): 5 20.0, 20.7, 25.1, 25.2, 28.0, 28.1, 29.7, 30.8, 31.3, 35.1, 35.4, 50.7, 56.1, 56.2, 59.8, 60.0, 63.6, 64.6, 88.0, 91.0, 96.1, 100.7, 109.8, 116.4, 117.0, 130.3, 130.5, 142.0, 145.8, 146.0, 147.7, 167.3, 167.5; IR (neat): 2940, 2851, 1703, 1630, 1512, 1467, 1440, 1407, 1391, 1367, 1326, 1200, 1161, 1118, 1072, 1019, 910, 730 ciif1; MS (ES + ) m/z (relative intensity) 461 (M +', 75), 462 ([M+ 2H]1 , 20), 259 (100), 260 (30), 359 (21). Examples 24-: Synthesis of C-2 unsatured PBD dimmers linked at the C-B position (Figure Remove)hutyloxycarbonyj j -7-~methoxy-.il- (tetrahydro-pyran-2-yloxy) -2-methylidene-1,2, 3,10,11,11 a-hexahydro-5H-pyrrolo[2,1-c][1, 4]benzodiazepine-5-one] (28a) 1,8-Diiodooctane (53 ing, 0.14 mmol, 0.5 equiv.) was added to the mixture of monomer 27 (134 mg, 0.29 mmol, 1.0 equiv.) and potassium carbonate (60 mg, 0.58 mmol, 2.0 equiv.) in dry DMF (30 mL), and the resulting mixture was heated to 90 °C under a nitrogen atmosphere for 4 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected to flash column chromatography (Si02, "75% EtOAc-hexane) to afford the dimerized compound 28a (77 mg, 0.074 mmol, 51% yield, mixture of diastereomers from THP protecting group) as a solid: [cc]26D = +63° (c = O.i:i, CHC13); *H NMR (CDC13, 400 MHz): 5 1.30-1.64 (m, 68H, 14-H, 15-H, Boc, THP), 1.71-1.94 (m, 16H, 13-H, THP), 2.51-2.62 (m, 2H, J-H), 2.72-2.83 (m, 2H, 3-H), 2.87-2.98 (m, 4H, 1-H), 3.53-3.72 (m, 8H, lla-H, THP) , 3.85-4.19 (m, 28H, 3-H, 12-H, 7-OMe, THP), -1.27-1.38 (m, All, 3-H), 5.01-5.20 (m, 12H, 2a-H, THP), 5.68-5.76 (a, 211, 11-H), 5.78-5.89 (d, 2H, 11-H), 6.51(s, 2H, 9-H) , f).07 (s, 2H, 9-H) , 7,18 (s, 2H, 6-H) , 7.22 (s, 2H, 6-H); 13C 64.4, 68. 4, 59.2, 91.1, 96.4, 100.3, 109.4, 110.0, 110.5, 114.4, 114.9, 129.6, 142.8, 148.6, 148.9, 167.2, 167.4; IR (neat): 2938, 2857, 1702, 1643, 1604, 1511, 1454, 1430, 1400, 1367, 1325, 1273, 1254, 1211, 1163, 1118, 1072, 1019, 911, 869, 729 cm"1; MS (ES4) m/z (relative intensity) 1054 ( [M + Na]4', 9), 1031 ( [M + H]4', 100), 1032 ([M + 2H]+', 65), 929 (46), 829 (38), 1048 (34). (b) 1,1' - [ (Octane-1, 8-diyl)dioxyjbis[(llaS)-7-Jnethoxy-2~methylene-1,2,3,1 la~tetrahydro~5H-pyrrolo[2,1-c] [1, 4]benzodiazepine~5-one] (29a) 95% TFA (2 mL) was added dropwise to dimer compound 28a (77 mg, 0.074 mmol) at 0 °C which was stirred for 1 h and then poured into saturated aqueous NaHC03 (30 mL) . The mixture was extracted with chloroform i3 x 20 mL) and the organic layer was then washed with water (20 ml,), brine (20 mL) , dried (MgS04) and filtered. The excess solvent: was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29a (39 mg, 0.062 mmol, 84%) as a solid: [a]29D = +428° (c = 0.07, CHC13) ; lli NMR (CDC13, 400 MHz): 5 1.33-1.54 (m, 8H, 14-H, 15-H), 1.78-1.93 (m, 4H, 13-H) , 2.86-2.97 (m, 2H, 1-H), 3.04-3.17 (m, 2H, 1-H), 3.83-3.89 (m, 2H, lla-H), 3.93 (s, 6H, 7-OMe), 3.99-4.12 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.49 (s, 2H, 6-H), 7.66 (d, 2H, J= 4.42 Hz, 11-H); 13C NMR (CDC13, 100 MHz): 5 25.2, 25.8, 28.8, 29.2, 35.5, 51.3, 53.8, 56.1, 58.4, 69.0, 109.3, 110.4, 111.4, 119.6, 140.7, 141.7, 147.9, 151.0, 162.4, 164.8; IR (neat): 3310, 2932, 2855, 1598, 1503, 1463, 1451, 1429, 1381, 1260, 1216, 1096, 1013, 911, 786, 729 cm"1; MS (ES+) m/z (relative intensity) 627 ( [M + H]+', 100), 628 ([M + 2H]+ , 53) , 332 (9?), 323 (61) . Example 25 (n=9) (a) '! , J '- [ (Nonane-1, 9-diyl) dioxyjbis [ (IIS,llaS) ~10~ (tert- niity.loxycarbonyl) -7-methoxy-ll- (tetrahydro-pyran-2-yloxy) -2-methylidene-1,2,3,10,11,lla-hexahydro-5H~pyrrolo[2,1-c][1,4Jbenzodiazepine-5-one] (23b) I, 9-Dibromononane {35.75 mg, 0.125 mmol, 0.5 equiv.) was added to the mixture of monomer 27 (115 mg, 0.25 mmol, 1.0 equiv.), potassium carbonate (53 mg, 0.5C mmol, 2.0 equiv.) and a catalytic amount ol potassium iodide (1 mg) in dry DMF (30 mL) , and the resulting mixture was heated to 90 °C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded n crude sol .id, which was subjected to flash column chromatography (Si05, 50% EtOAc-hexane) to afford the dimerized compound 28b (89 mg, 0.085 mmol, 68% yield, mixture of diastereomers from THP protecting group, as a solid: [a]29D = +36° (c = 0.11, CHC13); aH NMR (CDC13, 400 MH2> : & 1.25-1.67 (m, 72H, 14-H, 15-H, 16-H, Boc, THP), 1.70-1.91 (in, 16H, 13-H, THP), 2.51-2.58 (m, 2H, 1-H) , 2.72-2.81 (m, 2H, 1-H), 2.R4-2.97 (m, 4H, 1-H), 3.51-3.65 (m, 8H, lla-H, THP), 3.85-4.19 (in, 28H, 3-H, 12-H, 7-OMe, THP), 4.26-4.38 (m, 4H, 3-H) , 5.00-5.18 (m, 12H, 2a-H, THP), 5.65-5.74 (d, 2H, 11-H) , 5.76-5.88 (d, 2.11, 11-H), G.49(s, 2H, 9-H) , 6.85 (s, 2H, 9-H) , 7.16 (s, 2H, 6-H) , 7.1.9 (s, 2H, 6-H) ; 13C NMR (CDC13, 100 MHz): 5 20.2, 25.2, 2i;i.9, 2B.'J, 28.2, 29.0, 29.3, 29.4, 31.0, 31.1, 35.1, 35.4, 50.6, 56.1, 59.9, 60.0, 63.5, 68.9, 69.2, 91.1, 96.2, 100.3, 109.3, 110.4, 110.5, 114.8, 114.9, 129.8, 142.1, 148.6, 148.9, 167.2; 1R (neat): 2935, 2856, 1704, 1645, 1604, 1511, 1454, 1430, 1401, 1367, 1325, 1255, 1210, 1163, 1119, 1020, 907, 729 cm"1; MS (ES+) m/7. (relative intensity) 1068 ([M + Na]+', 13), 1045 ([M + H]+', 100), 1046 ([M+ 2H]"', 65), 943 (42), 843 (26). (b) 1,1' -1 (Nonane-1,9-diyl)dioxy]bis[(llaS)-7-methoxy-2~methylene-1,2,3, llti-teti-ahydro-5H-pyrrolo[2, l~c] [1, 4]benzodiazepine-5-one] (29b) 95% TFA (2 ml.) was added dropwise to dimer compound 28b (69 mg, 0.085 mmol) at 0 r'C which was stirred for 1 h and then poured into saturated aqueous NaHC03 (30 mL) . The mixture was extracted with chloroform (3 x 20 mL) and the organic layer was washed with water (20 mL) , brine (20 mL) , dried (MgS04) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiOz, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29b (30 mg, 0.046 mmoi, 55%) as a solid: [a]27D = +308° (c = 0.24, CHC13); JH NMR (CDCl-j, 100 MHz): S 1.30-1.39 (m, 611, 15-H, 16-H), 1.40-1.50 (m, 4H, 14-H), 1.82-1.91 (m, 4H, 13-H), 2.89-2.97 (m, 2H, 1-H), 3.06-3.16 (m, 2H, 1-H), 3.81-3.90 (m, 2H, lla-H), 3.93 (s, 6H, 7-OMe), 3.98-4.10 (in, 4H, 12-H) , 4.28 (s, 4H, 3-H) , 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.48 (s, 2H, 6-H) , 7.66 (d, 2H, J = 4.44 Hz, 1]-H); 1JC NMR (CDC1;,, 100 MHz): 6 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.3, 111.3, 119.5, 140.6, 141.7, 151.0, J6:>.4, 164.8; IR (neat): 2928, 2854, 1624, 1599, 1506, 1464, 1429, 1381, 1261, 1216, 1096, 729 crrf1; MS (ES+) m/z (relative intensity) 641 ( (M + M]+', 100), 642 ([M+ 2H]+', 52), 339 (97 } . Example 26 (n=10) (a) !,!'-[ (Decane-l,10~diyl)dioxy]bis[(llS,llaS)-10~ (tert-butyloxycarbonyl) -7-methoxy-ll-(tetrahydro-pyran-2-yloxy)-2-methylidene-1,2, 3,10,1.1,lla-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one] (28c) 1,10-Diiododecane (49.26 mg, 0.125 mmol, 0.5 equiv.) was added to the mixture of monomer 27 (115 mg, 0.25 mmol, 1.0 equiv.) and potassium carbonate (53 mg, 0.50 mmol, 2.0 equiv.) in dry DMF (30 mL), and the resulting mixture was heated to 90 °C under a nitrogen atmosphere for 5 h. Removal of excess solvent under reduced pressure afforded a crude solid, which was subjected, to flash column chromatography (Si02, 60% EtOAc-hexane) to afford the dimerized compound 28c (90 mg, 0.084 mmol, 67% yield, mixture of diastereomers from THP protecting group) as a solid: [a]"D = +22° (c = 0.11, CHC1,) ; 'H NMR (CDC13, 400 MHz): 6 1.26-1.65 (m, 76H, 14-H, 15-H, 16-H, Hoc, THP) , 1.72-1.90 (m, 16H, 13-H, THP) , 2.55-2.95 (rn, 8H, 1-H), 3.53-3.69 (m, 8H, lla-H, THP), 3.85-4.15 (m, 28H, 3-H, 1?-H, 7-OMe, THP), 4.25-4.36 (m, 4H, 3-H), 4.97-5.18 (m, 12H, 2a-H, THP), b. 65-5.88 (m, 4H, 11-H), 6.48 (s, 3H, 9-H), 6.85 (s, 1H, 9-H), 7.15-7.19 (2 x s, 4H, 6~H); 13C NMR (CDC13, 100 MHz): 5 20.0, 20.5, 25.2, 25.9, 28.1, 28.2, 29.0, 29.4, 29.5, 31.0, 31.3, 35.1, 35.4, 50.6, 56.1, 60.0, 63.5, 64.4, 68.9, 69.2, 91.1, 96.4, 100.3, 109.4, 110.0, 110.6, 114.3, 114.9, 128.4, 142.1, 148.8, 149.3, 167.3; IR (neat): 2933, 2854, 1703, 1643, 1603, 1512, 1454, .1430, 1402, 1367, 1324, 1254, 1209, 1162, 1118, 1018, 910, 860, 729 cm""1; MS (ES + ) m/z (relative intensity) 1059 ( [M + H] + ', 100), 1060 ( [M + 2H]+', 70), 957 (50). (b) -!,!'-((Decane-1,10-diyl)dioxy]bis[ (llaS)-7-methoxy-2- methylene-1,2,3,lla-tetrahydro-5H-pyrrolo[2,1-c] [ 1, 4]benzod.iazepine-5-one] (29c) 95% TFA (2 mL) was added dropwise to dimer compound 28c (90 mg, 0.084 mmol) at 0 °C which was snirred for 1 h and then poured into saturated aqueous NaHC03 (30 mL) . The mixture was extracted with chloroform (3 x 20 mL) and the organic layer was washed with water (20 mL) , brine (20 mL) , dried (MgS04) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (Si02, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29c (34 mg, 0.052 mmoL, 61%) as a solid: [a]26D = +309° (c = 0.31, CHC13) ; 'H NMR (CDC13, 400 MHz): 5 1.31-1.39 (m, 8H, 15-H, 16-H), 1.40-1.51 (m, 4H, 14-H), 1.80-1.93 (m, 4H, 13-H), 2.89-3.10 (m, 2H, 1-H), 3.06-3.19 (m, 2H, 1-H), 3.81-3.95 (m, 8H, lla-H, 7-OMe), 3.98-4.11 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.18 (m, 4H, 2a-H), 6.80 (s, 2H, 9-H), 7.49 (s, 2H, 6-H) , 7.66 (d, 2H, J = 4.56 Hz, 11-H); 13C NMR (CDC13, 100 MHz): 5 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.4, 111.4, 119.5, 140.7, 141.7, 151.1, 162.4, 164.8; IR (neat): 2933, 1599, 1506, 1464, 1429, 1380, 1262, 1216,. 1096, 729, 628 cm"1; MS (ES+) m/z (relative intensity) 655 ( [M -t H]4', ,100), 656 ([M-t 2H] + ', 50), 346 (97). Example 27 - Determination of DMA Cross-Linking ability and in vitro Cytotoxicity (a) DNA Cross-linking The extent; of DNA cross-linking induced by each PBD dimer was determined using the electrophoretic assay method of Hartley, et al. (Hartley, 0. A., Berardini, M. D., and Souhami, R. L. (1991) Ana] . Diochem. '19j, 131-134) based on the principle that, follow.i ng complete denaturation of linear pBR322 DNA (-4,300 bp) to the sing]e-stranded (SS) form, an interstrand cross-link results in renaturation to double-stranded (DS) in a neutral gel. Closed-circular DMA was linearized with Hindlll, then dephosphoryiated and finally 5'-singly end-labelled using [y32P]-ATP and polynucleotide kinase. Reactions containing 30-40 ng of DNA and the test, compound were carried out in aqueous TEOA (25 rnM triethanolanune, 3 mM EDTA, pH 7.2) buffer at 37°C in a final volume of 50 }d for 2 hours. Reactions were terminated by addition of an equal volume of stop solution (0.6 M NaOAc, 20 mM EDTA, 100 ug/ml tRNA) followed by precipitation with ethanol. Following centrifugation, the supernatant was discarded and the pellet dried by lyophilization. Samples were re-suspended in 10 u.1 of strand separation buffer (30% DMSO, 1 mM EDTA, 0.04% bromophenol blue and 0.04% xylene cylanol) and denatured by heating to 90°C for 2.5 miri, followed by immersion in an ice/water bath. Control non-denatured samples were re-suspended in 10 ul of non-denaturing buffer solution '(0.6% sucrose, 0.04% bromophenol blue in aqueous TAB buffer 140 mM Tris, 20 mM acetic acid, 2 mM EDTA, pH 8.1]) and loaded directly onto the gel for comparison. Electrophoresis was carried out for 14-16 h at 40 V using a 0.8% submerged agarose gel (20 * 25 x 0.5 cm) in TAB buffer. Gels were dried under vacuum for 2 hour at 80°C onto one layer each of Whatman 3MM and DE81 filter papers using a BioRad 583 gel dryer. Ante-radiographs were obtained after exposure of Hyperfilm-MP film (Amersham pic, O.K.) to the dried gel for either 4 hour with a screen (or over night, without a screen, to obtain a sharper image). Film bands were quantitated using a BioRad GS-670 imaging laser densitometer. Percentage cross-linking was calculated by measuring the total DNA in each lane (summed density for the double-stranded [DS] and single-stranded [SS] bands) relative to the amount of cross-linked DNA (density of DS band alone). A dose-response curve was derived by plotting drug concentration against the determined percentage level of cross-linked DNA which was then analysed to determine the concentration of test compound that results in 50% cross-linked plasmid DNA (XL50) . (b) In vitro cytoxicity (i)_K562 cells K562 human chronic myeloid leukaemia cells were maintained in RPM1 1640 medium supplemented with 10% fetal calf serum and 2 mM glutamine at 37°C in a humidified atmosphere containing 5% C02 and were incubated with a specified dose of drug for 1 hour or 96 hours at 37°C in the dark. The incubation was terminated by centrifugation (5 min, 300 g) and the cells were washed once with drug-free medium. Following the appropriate drug treatment, the cells were transferred to 96-well microtiter plates (lO0 cells per well, 8 wells per sample). Plates were then kept in the dark at 37°C in a humidified atmosphere containing 5% C02. The assay is based on the ability of viable cells to reduce a yellow soluble tetrazoliurn salt, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2tf-tetrazolium bromide (MTT, Aldrich-Sigma), to an insoluble purple formaean precipitate, following incubation of the plates for 4 days (to allow control cells to increase in number by approximately 10 fold) , 20 uL of MTT solution (5 mg/raL in phosphate-buffered saline) was added to each well and the plates further incubated for 5 hours. The plates were then centrifuged for 5 minutes at 300 g and the bulk of the medium pipetted from the cell pellet leaving 10-20 uL per well. DMSO (200 uL) was added to each well and the samples agitated to ensure complete mixing. The optica] density was then read at a wavelength of 550 nm on a Titertek Multiscan ELISA plate reader, and a dose-response curve was constructed. For each curve, an IC50 value was read as the dost required to reduce the final optical density to 50% of the control value. (ii) NCI 60 cell screen The National Cancer Institute (NCI), Bethesda, Maryland, USA has available an in vitro cytotoxicity screen which consists of approximately 60 human tumour cell lines against which compounds are tested at a minimum of five concentrations each differing 10-fold. A 48 hour continuous exposure protocol is used, where cell viability or growth is estimated with an SRB protein assay. The test compounds were evaluated against approximately 60 human tumour cell lines. The NCI screening procedures were described in detail by Monks and co-workers (Monks, A et a 1. , Journal of the National Cancer Institute, 1991, 83, 757). Briefly, cell suspensions were diluted according to the particular cell type and the expected target cell density (5000-40,000 cells per well based on cell growth characteristics), and added by pipette (100 uL) into 96-well microtitre plates. The cells were allowed a preincubation period of 24 hours at 37°C for stabilisation. Dilutions at twice the intended test concentration were added at time zero in 100 uL aliquots to the wells. The test compounds were evaluated at five 10-fold dilutions (10"", 10's, 10~6, 10"7 and 10'"8 uM) . The test compounds were incubated for 48 hours in 5% C02 atmosphere and 100% humidity. The cells were then assayed using the sulphorhodamine B assay. A plate reader was used to read the optical densities and a microcomputer processed the readings into GIio values (in Moles), which is the dosage required to limit cell growth to 50%.(Table Remove) WE CLAIM 1. A compound of formula Ia or Ib: (Formula Removed) and salts, and solvates, wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 and R3 are independently selected from -H, =O, =CH2, -CN, -R, OR, halo, =CH-R, O-SO2-R, CO2R and COR; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; R10 is a carbamate-based nitrogen protecting group; and R11 is an oxygen protecting group. 2. A compound as claimed in claim 1, wherein RA is independently selected from H, OR, SH, SR, NH2, NHR, NRR' and halo. 3. A compound as claimed in either claim 1 or claim 2, wherein R11 is THP or a silyl oxygen protecting group. 4. A compound as claimed in any of the preceding claims, wherein R10 is BOC or Troc. 5. A compound as claimed in any one of the preceding claims, wherein R9 is H. 6. A compound as claimed in any one of the preceding claims, wherein R2 is R. 7. A compound as claimed in any one of the preceding claims, wherein R6 is selected from H, OH, OR, SH, NH2, nitro and halo. 8. A compound of formula IIIa or IIIb: (Formula Removed) and salts and thereof, wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 and R3 are independently selected from -H, =O, =CH2, -CN, -R, OR, halo, =CH-R, O-SO2-R, CO2R and COR; R6, R9, R12 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-2C heterocyclyl and C5-2c aryl groups; R10 is a carbamate-based nitrogen protecting group and R15 is either O-R11, wherein R11 is an oxygen protecting group, or OH, or R10 and R15 together form a double bond between N10 and Cll; and where R" is a C2-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. 0, S, NH, and/or aromatic rings, and each X is independently selected from 0, S, or NH; and R2', R3', R6', R9', R10', R12', R13' and R15' are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R10, R12, R13 and R15 respectively; and wherein -X'-R"-X- of formula IIIa or IIIb is -O-(CH2) n-O-, and n is 8 to 12. 9. A compound as claimed in claim 8, wherein the dimers are linked at the C8 position. 10. A compound as claimed in claim 8, wherein the dimers are linked at the C1 position. 11. A compound as claimed in any one of claims 8 to 10, wherein n is 8 to 11. 12 A compound as claimed in claim 11, wherein n is 8 to 10. 13. A compound as claimed in claim 12, wherein n is 8 or 9. 14. A compound as claimed in any one of claims 8 to 13, wherein R15 is O-R11 and R11 is THP or a silyl oxygen protecting group. 15. A compound as claimed in any one of claims 8 to 14, wherein R10 is BOC or Troc. 16. A compound as claimed in any one of claims 8 to 13, wherein R10 and R15 together form a double bond between N10 and Cll. 17. A compound as claimed in any one of claims 8 to 16, wherein R9 is H. 18. A compound as claimed in any one of claims 8 to 17, wherein R2 is R. 19. A compound as claimed in any one of claims 8 to 18, wherein R6 is selected from H, OH, OR, SH, NH2, nitro and halo. 20. A compound as claimed in any one of claims 8 to 19 for use in a method of therapy. 21. A pharmaceutical composition containing a compound of any one of claims 8 to 19, and a pharmaceutically acceptable carrier or diluent. 22. A method of synthesising a compound of formula Ia or Ib: (Formula Removed) from a compound of formula IIa or IIb respectively: (Formula Removed) wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 and R3 are independently selected from -H, =O, =CH2, -CN, -R, OR, halo, =CH-R, O-SO:-R, CO2R and COR; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and hale-where R and R' are independently selected from optionally substituted C1-10 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; R10 is a carbamate-based nitrogen protecting group; R11 is an oxygen protecting group; and R14 is an oxygen protecting group orthogonal to R1l. 23. A method as claimed in claim 22, wherein R14 is benzyl ether and RA is OMe or H. 24. A method as claimed in either claim 22 or claim 23, wherein R11 is THP or a silyl oxygen protecting group. 25. A method of synthesising a compound of formula IIIa or IIIb: (Formula Removed) or a solvate thereof, from a compound of formula Ia or Ib respectively: (Formula Removed) wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 and R3 are independently selected from -H, =O, =CH2, -CN, -R, OR, halo, =CH-R, O-SO2-R, CO2R and COR; R6, R9, R10 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR' , nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; Rl0 is a carbamate-based nitrogen protecting group and RlD is either O-R11, wherein R11 is an oxygen protecting group, or OH, or R10 and R15 together form a double bond between N10 and Cll; and wherein -X'-R"-X- of formula IIIa or IIIb is -O-(CH2) n-O-, and n is 8 to 12; and R2', R3', R6', R9', R10', R12', R13' and R15' are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R10, R12, R13 and R15 respectively. 26. A method as claimed in claim 25, comprising the step of either: (a) reacting a compound of formula Ia or Ib with a compound having the formula Y-R"-Y' to yield a compound of formula IIIa or IIIb; or (b) (i) reacting a compound of formula Ia or Ib with a compound having the formula Y-R"-YProt, and (ii) converting YProt in the reaction product from (i) to Y', and (iii) reacting the product from (ii) with a compound of formula Ia or Ib to yield a compound of formula IIIa or IIIb; wherein: Y, Y' are independently selected from OH, I, Br, C1, mesylate or tosylate; YProt is a precursor to Y' or a chemically protected form of Y' having a protecting group that is orthogonal to R10 and R11. 27. A method as claimed in claim 26, wherein Y and Y' are I. 28. A method as claimed in claim 26, wherein Y is OH and YProt is O-benzyl. |
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4922-delnp-2006-Assignment-(17-09-2013).pdf
4922-delnp-2006-Claims-(05-12-2012).pdf
4922-DELNP-2006-Claims-(19-06-2012).pdf
4922-DELNP-2006-Correspondence Others-(03-02-2012).pdf
4922-delnp-2006-Correspondence Others-(05-12-2012).pdf
4922-delnp-2006-Correspondence Others-(17-09-2013).pdf
4922-DELNP-2006-Correspondence Others-(19-06-2012).pdf
4922-delnp-2006-correspondence-others.pdf
4922-delnp-2006-description (complete).pdf
4922-delnp-2006-Form-1-(17-09-2013).pdf
4922-delnp-2006-Form-2-(17-09-2013).pdf
4922-DELNP-2006-Form-3-(19-06-2012).pdf
4922-delnp-2006-GPA-(17-09-2013).pdf
| Patent Number | 260688 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 4922/DELNP/2006 | |||||||||
| PG Journal Number | 21/2014 | |||||||||
| Publication Date | 23-May-2014 | |||||||||
| Grant Date | 16-May-2014 | |||||||||
| Date of Filing | 25-Aug-2006 | |||||||||
| Name of Patentee | SPIROGEN Sarl | |||||||||
| Applicant Address | 79 GEORGE STREET, RYDE, ISLE OF WIGHT PO33 2JF, U.K. | |||||||||
Inventors:
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| PCT International Classification Number | C07D 519/00 | |||||||||
| PCT International Application Number | PCT/GB2005/000770 | |||||||||
| PCT International Filing date | 2005-03-01 | |||||||||
PCT Conventions:
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