 pyrrolobenzodiazepines
专利摘要:
abstract "pyrrolobenzodiazepines" a compound of formula i: or a salt or solvate thereof, where: the dotted double bond indicates the presence of a single or double bond between c2 and c3; r2 is selected from -h, -oh, = o, = ch2, -cn, -r, or, halo, di-halo, = chr, = chrr ', -o-so2-r, co2r and color; r7 is 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 c1-7 alkyl, c3-20 heterocyclyl and c5-20 aryl groups; r10 and r11 together form a double bond, or are selected from h and qrq respectively, where q is selected from o, if nh and rq is h or c1-7 alkyl or he soxm, where x is 2 or 3, in is a cation pharmaceutically acceptable monovalent; a is: or, where x and y are selected from: ch and nme; coh and nme; ch and s; n and nme; n and s; b is a single bond or:, where x and y are as defined above; and r1 is c1-4 alkyl. 公开号:BR112014027143B1 申请号:R112014027143 申请日:2013-04-30 公开日:2020-06-09 发明作者:Thurston David；Mirazur Rahman Khondaker；Wilson Howard Philip 申请人:Medimmune Ltd；Spirogen Sarl；Ucl Business Plc； IPC主号:
专利说明:
“PIRROLOBENZODIAZEPIN COMPOUNDS, PHARMACEUTICAL COMPOSITION UNDERSTANDING THESE COMPOUNDS AND THE USE OF THEM FOR THE TREATMENT OF A PROLIFERATIVE DISEASE” [001] The present invention relates to pyrrolobenzodiazepines (PBDs) and in particular to PBD monomers with an amino acid residue based on 4- (1methyl-1H-pyrrol-3-yl) benzyl containing substituent and methods of synthesizing monomers of PBD. Fundamentals of the Invention [002] Some pyrrolobenzodiazepines (PBDs) have the ability to recognize and bind to specific DNA sequences; the preferred sequence is PuGPu. The first anti-tumor antibiotic of PBD, 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)). Since then, several naturally occurring PBDs have been reported, and more than 10 synthetic pathways have been developed for a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433 - 465 (1994)). Family members include abeimicin (Hochlowski, et al., J. Antibiotics, 40, 145 - 148 (1987)), quicamycin (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)), mazetramycin (Kuminoto , et al., J. Antibiotics, 33, 665 - 667 (1980)), neotramicins A and B (Takeuchi, et al., J. Antibiotics, 29, 93 - 96 (1976)), porotramycin (Tsunakawa, et al ., J. Antibiotics, 41, 1366 - 1373 (1988)), protracarcin (Shimizu, et al, J. Antibiotics, 35, 972 - 978 (1982); Langley and Thurston, J. Org. Chem., 52, 91 - 97 (1987)), sibanomycin (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: Petition 870190098905, of 10/03/2019, p. 12/90 2/74 [003] They differ in the number, type and position of the substituents, both in their aromatic A rings and pyrrole C rings, and in the degree of saturation of ring C. In ring B there is an imine (N = C), a carbinolamine ( NH-CH (OH)), or a carbinolamine methyl ether (NH-CH (OMe)) at position N10-C11 which is the electrophilic center responsible for alkylating DNA. All known natural products have a chiral (S) configuration at the C11a position that provides them with a clockwise rotation when viewed from ring C to ring A. This provides them with the appropriate three-dimensional shape for isohelicity with the smallest DNA groove. in form B, leading to a small adjustment at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pages 3 - 11 (1975); Hurley and Needham-VanDevanter, Acc. Chem. Fies., 19, 230 - 237 (1986)). Their ability to form an adduct in the minor groove, allows them to interfere with DNA processing, consequently their use as antitumor agents. The synthesis of the compounds was observed again in Thurston, D.E., et al., Chem. Feb. 1994, 94, 433 - 465 and Thurston, D.E., et al., Chem. Feb. 2011, 111, 2815 - 2864. [004] Several PBD conjugates with pyrroles and imidazoles have been reported, such as: THE where n = 1 to 3 (Damayanthi, Y., et al., Journal of Organic Chemistry, 64 (1), 290 - 292 (1999)); Petition 870190098905, of 10/03/2019, p. 13/90 3/74 THE HN MeO The where n = 1 to 3 and THE MeO The where n = 1 to 2 (Kumar, R. and Lown, J.W. Oncology Research, 13 (4), 221 233 (2003)); Kumar, R., etal., Heterocyclic Communications, 8 (1), 19 - 26 (2002)); N H OM and HN N H MeO The where n = 1 to 4, (Baraldi, P.G., et al., Journal of Medicinal Chemistry, 42 (25), 5131 - 5141 (1999)); where n = 3, (Wells, G., et al., Proc. Am. Assoc. Canc. Res., 2003, 44, 452). [005] In WO 2007/039752 and Wells, G, et al., Journal of Medicinal Chemistry 2006, 49, 5442 - 5461, the following compound (GWL-78) and related structures were disclosed in service by some of the present inventors. This compound showed an increase of up to 50 times in the Petition 870190098905, of 10/03/2019, p. 14/90 4/74 DNA binding affinity compared to its constituent PBD and dipyrrole components. [006] In WO 2005/085177, some of the present inventors have disclosed amino acids comprising a biaryl nucleus which may have properties useful in binding to DNA. [007] The inventors have now discovered that the properties, particularly cytotoxicity and DNA binding, of prior art PBD conjugates can be improved. In particular, the present invention relates to the incorporation of a single amino acid residue based on 4- (1-methyl-1 H-pyrrol-3-yl) benzyl in combination with a single amino acid residue based on heteroaryl in a PBD conjugate results in highly effective compounds. [008] A first aspect of the present invention provides a compound of formula I: or a salt or solvate thereof, where: the dotted double bond indicates the presence of a single or double bond between C2 and C3; R 2 is selected from -H, -OH, = 0, = CH 2 , -CN, -R, OR, halo, dihalo, = CHR, = CHRR ', -O-SO2-R, CO2R and COR; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro, MesSn and halo; where R and R 'are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; Petition 870190098905, of 10/03/2019, p. 15/90 5/74 R 10 and R 11 together form a double bond, or are selected from H and QR Q respectively, where Q is selected from O, S and NH and R Q is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a pharmaceutically acceptable monovalent cation; A is: or (A1) (A2) where X and Y are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S; B is a simple link or: (B1) where X and Y are as defined above; and R 1 is C1-4 alkyl. [009] Thus, B1 can have the following structures: X Y B1 CH NMe THE/ í MH Petition 870190098905, of 10/03/2019, p. 16/90 6/74 COH NMe The H Oh CH s w / o á í MH N NMe --AT THEz ÍHH N s S OH [010] A second aspect of the present invention provides a method of synthesizing a compound of formula I. [011] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the invention and a pharmaceutically acceptable carrier or diluent. [012] A fourth aspect of the present invention provides a compound of the first aspect of the invention for use in a method of therapy. [013] A fifth aspect of the present invention provides the use of a compound of the first aspect of the invention in the manufacture of a medicament for the treatment of a proliferative disease. This aspect also provides a compound of the first aspect for use in a method of treating a proliferative disease. [014] A sixth aspect of the present invention provides a method of treating a patient suffering from a proliferative disease, comprising Petition 870190098905, of 10/03/2019, p. 17/90 7/74 administering to said patient a therapeutically acceptable amount of a compound of the first aspect or a composition of the third aspect. [015] In the fourth to sixth aspects of the invention, the compound of the invention can be administered alone or in combination with other treatments, simultaneously or sequentially depending on the condition to be treated. In the third aspect of the invention, the pharmaceutical composition can comprise one or more (for example, two, three or four) additional active agents. Definitions Substituents [016] The phrase “optionally substituted” as used here, belongs to a parent group that can be unsubstituted or that can be substituted. [017] Unless otherwise specified, the term "substituted" as used here, belongs to a precursor group that carries one or more substituents. The term "substituent" is used here in the conventional sense and refers to a chemical moiety that is covalently attached to, or if appropriate, fused to, a precursor group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of precursor groups are also well known. [018] Examples of substituents are described in more detail below. [019] C1-7alkyl: The term "C1-7alkyl" as used here, belongs to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 atoms of carbon, which can be aliphatic or alicyclic, and which can be saturated or unsaturated (for example, partially unsaturated, completely unsaturated). Thus, the term "alkyl" includes the subclasses alkenyl, alkynyl, cycloalkyl, etc., discussed below. [020] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (Ce) and heptyl Petition 870190098905, of 10/03/2019, p. 18/90 8/74 (C7). [021] Examples of saturated linear alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5) , n-hexyl (Ce) and n-heptyl (C7). [022] Examples of saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl ( C5). [023] C2-7 alkenyl: The term "C2-7 alkenyl" as used here, belongs to an alkyl group having one or more carbon-carbon double bonds. [024] Examples of unsaturated alkenyl groups include, but are not limited to, ethylene (vinyl, -CH = CH2), 1-propenyl (-CH = CH-CH3), 2-propenyl (ally, CH-CH = CH2) , isopropenyl (1-methylvinyl, -C (CH3) = CH2), butenyl (C4), pentenyl (C5), and hexenyl (Ce). [025] C2-7 alkynyl: The term "C2-7 alkynyl" as used here, belongs to an alkyl group having one or more carbon-carbon triple bonds. [026] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethynyl, -C ^ CH) and 2-propynyl (propargyl, -CH2-C ^ CH). [027] C3-7 cycloalkyl: The term "C3-7 cycloalkyl" as used here, belongs to an alkyl group which is also a cyclyl group; that is, a monovalent portion obtained by removing a hydrogen atom from an atom in the alicyclic ring of a cyclic (carbocyclic) hydrocarbon compound, which portion has 3 to 7 carbon atoms, including 3 to 7 ring atoms . [028] Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (Ce), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane Petition 870190098905, of 10/03/2019, p. 19/90 9/74 (Cs), dimethylcyclobutane (Ce), methylcyclopentane (Ce), dimethylcyclopentane (C7) and methylcyclohexane (C7); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C3), cyclobutene (C4), cyclopentene (Cs), cyclohexene (Ce), methylcyclopropene (C4), dimethylcyclopropene (Cs), methylcyclobutene (Cs), dimethylcyclobutene (Ce), methylcyclopentene (Ce) and dimetyl (Ce), dimetyl methylcyclohexene (C7); and saturated polycyclic hydrocarbon compounds: norcaran (C7), norpinan (C7), norbornan (C7). [029] C3-20 heterocyclyl: The term "C3-20 heterocyclyl" as used here, belongs to a monovalent moiety obtained by removing a hydrogen atom from an atom in the ring of a heterocyclic compound, which moiety has 3 to 20 atoms in the ring, of which 1 to 10 are hetero atoms in the ring. Preferably, each ring has 3 to 7 ring atoms, of which 1 to 4 are ring hetero atoms. [030] In this context, prefixes (for example, C3-20, C3-7, Cs-e, etc.) denote the number of atoms in the ring, or range of number of atoms in the ring, whether carbon atoms or heteroatoms . For example, the term "Cs-e heterocyclyl", as used here, belongs to a heterocyclyl group having s or e atoms in the ring. [031] Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (Cs), pyrroline (e.g. 3-pyrroline, 2, s-dihydropyrrol) (Cs), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazol ) (Cs), piperidine (Ce), dihydropyridine (Ce), tetrahydropyridine (Ce), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (Cs), oxol (dihydrofuran) (Cs), oxane (tetrahydropyran) (Ce), dihydropyran (Ce), pyran (Ce), oxepine (C7) ; Petition 870190098905, of 10/03/2019, p. 20/90 10/74 Si: tiirano (C3), tietano (C4), tiolano (tetrahydrothioofeno) (C5), tiano (tetrahydrothiopyano) (Ce), tiepano (C7); O2: dioxolane (C5), dioxane (Ce), and dioxepan (C7); O3: trioxane (Ce); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydroppyrazole) (C5), piperazine (Ce); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (Ce), tetrahydrooxazine (Ce), dihydrooxazine (Ce), oxazine (Ce); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (Ce); N2O1: oxadiazine (Ce); O1S1: oxathiol (C5) and oxatian (thioxane) (Ce); and, N1O1S1: oxatiazine (Ce). [032] Examples of substituted monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lixofuranose, ribofuranose, and xylofuranse, and pyraneses (Ce), such as allopyranosis, altropiranosis, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose. [033] Aryl C5-20: The term "aryl C5-20", as used here, belongs to a monovalent moiety obtained by removing a hydrogen atom from an atom in the aromatic ring of an aromatic compound, which moiety must 3 to 20 atoms in the ring. Preferably, each ring has 5 to 7 ring atoms. [034] In this context, prefixes (for example, C3-20, C5-7, C5-e, etc.) denote the number of atoms in the ring, or range of number of atoms in the ring, whether carbon atoms or heteroatoms . For example, the term "C5-e aryl" as used here, belongs to an aryl group having 5 or e ring atoms. [035] The atoms in the ring can all be carbon atoms, as in Petition 870190098905, of 10/03/2019, p. 21/90 11/74 “carboaryl groups”. [036] Examples of carbohydrate groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthene (C1s) ), and pyrene (C16). [037] Examples of aryl groups comprising 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-1H-indene) (C9 ), indene (C9), isoindene (C9), tetralin (1,2,3,4-tetrahydronaphthalene (C10), acenaphene (C12), fluorene (C13), phenalene (C13), acefenanthrene (C15), and aceantrene ( C16). [038] Alternatively, atoms in the ring can include one or more heteroatoms, as in "heteroaryl groups". Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxol) (C5); S1: thiophene (thiol) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5); N1S1: 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) ( for example, cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: triazole (C5), triazine (C6); and, N4: tetrazole (C5). [039] Examples of heteroaryl that comprise fused rings, include, but are not limited to: C9 (with 2 fused rings) derived from benzofuran (O1), isobenzofuran Petition 870190098905, of 10/03/2019, p. 22/90 12/74 (Oi), indole (Ni), isoindole (Ni), indolizine (Ni), indoline (Ni), isoindoline (Ni), purine (N4) (e.g. adenine, guanine), benzimidazole (N2), indazole (N2), benzoxazole (N1O1), benzisoxazole (N1O1), benzodioxol (O2), benzofurazane (N2O1), benzotriazole (N3), benzothiofuran (Si), benzothiazole (N1S1), benzothiadiazole (N2S); C10 (with 2 fused rings) derived from chromene (Oi), isochromene (Oi), chroman (Oi), isochroman (Oi), benzodioxane (O2), quinoline (Ni), isoquinoline (Ni), quinolizine (Ni), benzoxazine (N1O1), benzodiazine (N2), pyridopyridine (N2), quinoxaline (N2), quinazoline (N2), cinoline (N2), phthalazine (N2), naphthyridine (N2), pteridine (N4); Cii (with 2 fused rings) derived from benzodiazepine (N2); C13 (with 3 fused rings) derived from carbazole (Ni), dibenzofuran (Oi), dibenzothiophene (Si), carboline (N2), perimidine (N2), pyridoindole (N2); and, Ci4 (with 3 fused rings) derived from acridine (Ni), xanthene (Oi), thioxanthene (Si), oxanthrene (O2), phenoxathine (OiSi), phenazine (N2), phenoxazine (NiOi), phenothiazine (N1S1), thianthrene (S2), phenanthridine (Ni), phenanthroline (N2), phenazine (N2). [040] The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves and from the additional substituents listed below. [04i] Halo: -F, -Cl, -Br, and -I. [042] Hydroxy: -OH. [043] Ether: -OR, where R is an ether substituent, for example, a C1-7 alkyl group (also referred to as a C1-7 alkoxy group, discussed below), a C3-20 heterocyclyl group (also referred to as a C3-20 heterocyclyloxy group), or a C5-20 aryl group (also referred to as a C5-20 aryloxy group), preferably a C1-7 alkyl group. [044] Aloxy: -OR, where R is an alkyl group, for example, a C1-7 alkyl group. Examples of C1-7 alkoxy groups include, but are not limited to, -OMe Petition 870190098905, of 10/03/2019, p. 23/90 13/74 (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). [045] Acetal: -CH (OR 1 ) (OR2), where R 1 and R 2 are independently substituents of acetal, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5 aryl group -20, preferably a C1-7 alkyl group, or, in the case of a "cyclic" acetal group, R 1 and R 2 , taken together with the two oxygen atoms to which they are attached, and the carbon atoms to which they are attached. they are linked, form a heterocyclic ring having 4 to 8 ring atoms. Examples of acetal groups include, but are not limited to, -CH (OMe) 2, -CH (OEt) 2, and -CH (OMe) (OEt). [046] Hemiacetal: -CH (OH) (OR 1 ), where R 1 is a hemiacetal substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of hemiacetal groups include, but are not limited to, -CH (OH) (OMe) and -CH (OH) (OEt). [047] Ketal: -CR (OR1) (OR 2 ), where R 1 and R 2 are as defined for acetals, and R is a substituent for ketal except hydrogen, for example, a C1-7 alkyl group, a heterocyclyl group C3-20, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of 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 (Et) (OEt) 2, and C (Et) (OMe) (OEt). [048] Hemicetal: -CR (OH) (OR 1 ), where R 1 is as defined for hemiacetals, and R is a substituent for hemicetal except hydrogen, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group , or a C5-20 aryl group, preferably a C1-7 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). [049] Oxo (keto, -one): = O. [050] Tiona (thiocetone): = S. [051] Imino (imine): = NR, where R is an imino substituent, for example, Petition 870190098905, of 10/03/2019, p. 24/90 14/74 hydrogen, C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group, preferably hydrogen or C1-7 alkyl group. Examples of ester groups include, but are not limited to, = NH, = NMe, = NEt, and = NPh. [052] Formyl (carbaldehyde, carboxaldehyde): -C (= O) H. [053] Acyl (keto): -C (= O) R, where R is an acyl substituent, for example, a C1-7 alkyl group (also referred to as C1-7 alkylacyl or C1-7 alkanoyl), a heterocyclyl C3-20 group (also referred to as C3-20 heterocyclyl) or a C5-20 aryl group (also referred to as C5-20 arylacyl), preferably a C1-7 alkyl group. Examples of acyl groups include, but are not limited to, -C (= O) CH3 (acetyl), -C (= O) CH2CH3 (propionyl), -C (= O) C (CH3) 3 (t-butyryl) , and -C (= O) Ph (benzoyl, phenone). [054] Carboxy (carboxylic acid): -C (= O) OH. [055] Thiocarboxy (thiocarboxylic acid): -C (= S) SH. [056] Thiolocarbonoxy (thiolocarboxylic acid): -C (= O) SH. [057] Thionocarboxy (thionocarboxylic acid): -C (= S) OH. [058] Imidic acid: -C (= NH) OH. [059] Hydroxamic acid: -C (= NOH) OH. [060] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C (= O) OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of ester groups include, but are not limited to, -C (= O) OCH3, C (= O) OCH2CH3, -C (= O) OC (CH3) 3, and -C (= O) OPh. [061] Acyloxy (reverse ester): -OC (= O) R, where R is an acyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group , preferably a C1-7 alkyl group. Examples of acyloxy groups include, but are not limited to, -OC (= O) CH3 (acetoxy), -OC (= O) CH2CH3, OC (= O) C (CH3) 3, -OC (= O) Ph, and -OC (= O) CH2Ph. Petition 870190098905, of 10/03/2019, p. 25/90 15/74 [062] Oxycarboyloxy: -OC (= O) OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a group C1-7 alkyl. Examples of ester groups include, but are not limited to, -OC (= O) OCH3, -OC (= O) OCH2CH3, -OC (= O) OC (CH3) 3, and OC (= O) OPh. [063] Amino: -NR1R 2 , where R 1 and R 2 are independently amino substituents, for example, hydrogen, a C 1-7 alkyl group (also referred to as C 1-7 alkylamino or C1-7 di-alkylamino), a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably H or a C1-7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms. Amino groups can be primary (-NH2), secondary (-NHR 1 ), or tertiary (-NHR1R 2 ), and in the cationic form, they can be quaternary (- + NR1R2R 3 ). Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHC (CH3) 2, -N (CH3) 2, N (CH2CH3) 2, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholino, and thiomorpholino. [064] Starch (carbamoyl, carbamyl, aminocarbonyl, carboxamide): C (= O) NR 1 R 2 , where R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of starch groups include, but are not limited to, -C (= O) NH2, -C (= O) NHCH3, -C (= O) N (CH3) 2, -C (= O) NHCH2CH3, and C (= O) N (CH2CH3) 2, as well as starch groups in which R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. [065] Thioamido (thiocarbamyl): -C (= S) NR1R 2 , where R 1 and R 2 are independently amino substituents, as defined for amino groups. Petition 870190098905, of 10/03/2019, p. 26/90 16/74 Examples of starch groups include, but are not limited to, -C (= S) NH2, C (= S) NHCH3, -C (= S) N (CH3) 2, and -C (= S) NHCH2CH3. [066] Acylamido (acylamino): -NR1C (= O) R 2 , where R 1 is an amide substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or an aryl group C5-20, preferably hydrogen or a C1-7 alkyl group, and R 2 is an acyl substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC (= O) CH3, NHC (= O) CH2CH3, and -NHC (= O) Ph. R 1 and R 2 can together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl: succinimidyl maleimidila phthalimidyl [067] Aminocarbonyloxy: -OC (= O) NR1R 2 , where R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of aminocarbonyloxy groups include, but are not limited to, OC (= O) NH2, -OC (= O) NHMe, -OC (= O) NMe2, and -OC (= O) NEt2. [068] Ureido: -N (R1) CONR 2 R 3 where R 2 and R 3 are independently amino substituents, as defined for amino groups, and R 1 is a ureido substituent, for example, hydrogen, an alkyl group C1-7, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, -NMeCONH2, NMeCONHMe, -NMeCONHEt, -NMeCONMe2, and -NMeCONEt2. [069] Guanidino: -NH-C (= NH) NH2. [070] Tetrazolyl: a five-membered aromatic ring having four nitrogen atoms and one carbon atom, Petition 870190098905, of 10/03/2019, p. 27/90 17/74 [071] Imino: = NR, where R is an imino substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C520 aryl group, preferably H or a C1- alkyl group 7. Examples of imino groups include, but are not limited to, = NH, = NMe, and = NEt. [072] Amidine (amidino): -C (= NR) NR2, where each R is an amidine substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5 aryl group -20, preferably H or a C1-7 alkyl group. Examples of amidine groups include, but are not limited to, -C (= NH) NH2, -C (= NH) NMe2, and C (= NMe) NMe2. [073] Nitro: -NO2. [074] Nitrous: -NO. [075] Azido: -N3. [076] Cyan (nitrile, carbonitrile): -CN. [077] Isocian: -NC. [078] Cyanate: -OCN. [079] Isocyanate: -NCO. [080] Thiocyanate (thiocyanate): -SCN. [081] Isothiocyanate (isothiocyanate): -NCS. [082] Sulfidrila (thiol, mercapto): -SH. [083] Thioether (sulfide): -SR, where R is a thioether substituent, for example, a C1-7 alkyl group (also referred to as a C1-7 alkylthio group), a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of C1-7 alkylthio groups include, but are not limited to, -SCH3 and SCH2CH3. [084] Disulfide: -SS-R, where R is a disulfide substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, Petition 870190098905, of 10/03/2019, p. 28/90 18/74 is preferably a C 1-7 alkyl group (also referred to herein as C 1-7 alkyldisulfide). Examples of C1-7 alkyldisulfide groups include, but are not limited to, SSCH3 and -SSCH2CH3. [085] Sulfino (sulfinyl, sulfoxide): -S (= O) R, where R is a sulfine substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5- aryl group 20, preferably a C1-7 alkyl group. Examples of sulfine groups include, but are not limited to, -S (= O) CH3 and -S (= O) CH2CH3. [086] Sulfone (sulfonyl): -S (= O) 2R, where R is a sulfone substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group, including, for example, a fluorinated or perfluorinated C1-7 alkyl group. Examples of sulfone groups include, but are not limited to, -S (= O) 2CH3 (methanesulfonyl, mesyl), -S (= O) 2CF3 (triflyl), S (= O) 2CH2CH3 (esila), -S (= O) 2C4F9 (nonaflyl), -S (= O) 2CH2CF3 (tresyl), S (= O) 2CH2CH2NH2 (tauryl), -S (= O) 2Ph (phenylsulfonyl, besila), 4-methylphenylsulfonyl (tosyl), 4- chlorophenylsulfonyl (closila), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosila), 2-naphthalenesulfonate (napsila), and 5-dimethylamino-naphthalen-1-ylsulfonate (dansila). [087] Sulfinic acid (sulfine): -S (= O) OH, -SO2H. [088] Sulfonic acid (sulfo): -S (= O) 2OH, -SO3H. [089] Sulfinate (sulfinic acid ester): -S (= O) OR; wherein R is a sulfinate substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S (= O) OCH3 (methoxysulfinyl; methyl sulfinate) and -S (= O) OCH2CH3 (ethoxysulfinyl; ethyl sulfinate). [090] Sulphonate (sulfonic acid ester): -S (= O) 2OR, where R is a sulfonate substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5 aryl group -20, preferably a C1-7 alkyl group. Examples of Petition 870190098905, of 10/03/2019, p. 29/90 19/74 sulfonate groups include, but are not limited to, -S (= O) 2OCH3 (methoxysulfonyl; methyl sulfonate) and -S (= O) 2OCH2CH3 (ethoxysulfonyl; ethyl sulfonate). [091] Sulfinyloxy: -OS (= O) R, where R is a sulfinyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a group C1-7 alkyl. Examples of sulfinyloxy groups include, but are not limited to, -OS (= O) CH3 and -OS (= O) CH2CH3. [092] Sulphonyloxy: -OS (= O) 2R, where R is a sulfonyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a group C1-7 alkyl. Examples of sulfonyloxy groups include, but are not limited to, -OS (= O) 2CH3 (mesylate) and -OS (= O) 2CH2CH3 (esylate). [093] Sulphate: -OS (= O) 2OR; wherein R is a sulfate substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulfate groups include, but are not limited to, -OS (= O) 2OCH3 and -SO (= O) 2OCH2CH3. [094] Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): S (= O) NR1R 2 , where R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S (= O) NH2, -S (= O) NH (CH3), -S (= O) N (CH3) 2, -S (= O) NH (CH2CH3), S (= O) N (CH2CH3) 2, and -S (= O) NHPh. [095] Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): S (= O) 2NR1R 2 , where R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of sulfonamido groups include, but are not limited to, -S (= O) 2NH2, -S (= O) 2NH (CH3), -S (= O) 2N (CH3) 2, -S (= O) 2NH (CH2CH3), S (= O) 2N (CH2CH3) 2, and -S (= O) 2NHPh. [096] Sulfamino: -NR1S (= O) 2OH, where R 1 is an amino substituent, as defined for amino groups. Examples of sulfamino groups include, but are not limited to, -NHS (= O) 2OH and -N (CH3) S (= O) 2OH. Petition 870190098905, of 10/03/2019, p. 30/90 20/74 [097] Sulfonamino: -NR1S (= O) 2R, where R 1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a C1-7 alkyl group, a heterocyclyl group C3-20, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS (= O) 2CH and -N (CH3) S (= O) 2C6H5. [098] Sulfinamino: -NR1S (= O) R, where R 1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a C1-7 alkyl group, a heterocyclyl group C3-20, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS (= O) CH and -N (CH3) S (= O) C6H5. [099] Phosphine (phosphine): -PR2, where R is a phosphine substituent, for example, -H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably - H, a C1-7 alkyl group, or a C5-20 aryl group. Examples of phosphine groups include, but are not limited to, -PH2, -P (CH3) 2, -P (CH2CH3) 2, -P (tBu) 2, and -P (Ph) 2. [0100] Phospho: -P (= O) 2. [0101] Phosphinyl (phosphine oxide): -P (= O) R2, where R is a phosphinyl substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5- aryl group 20, preferably a C1-7 alkyl group or a C5-20 aryl group. Examples of phosphinyl groups include, but are not limited to, -P (= O) (CH3) 2, P (= O) (CH2CH3) 2, -P (= O) (t-Bu) 2, and -P ( = O) (Ph) 2. [0102] Phosphonic acid (phosphono): -P (= O) (OH) 2. [0103] Phosphonate (phosphono ester): -P (= O) (OR) 2, where R is a phosphonate substituent, for example, -H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group, or a C520 aryl group. Examples of phosphonate groups include, but are not limited to, -P (= O) (OCH3) 2, -P (= O) (OCH2CH3) 2, -P (= O) (Ot-Bu) 2, and -P (= O) (OPh) 2. Petition 870190098905, of 10/03/2019, p. 31/90 21/74 [0104] Phosphoric acid (phosphonooxy): -OP (= O) (OH) 2. [0105] Phosphate (phosphonooxy ester): -OP (= O) (OR) 2, where R is a phosphate substituent, for example, -H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group, or a C520 aryl group. Examples of phosphate groups include, but are not limited to, -OP (= O) (OCH3) 2, OP (= O) (OCH2CH3) 2, -OP (= O) (Ot-Bu) 2, and -OP ( = O) (OPh) 2. [0106] Phosphorous acid: -OP (OH) 2. [0107] Phosphite: -OP (OR) 2, where R is a phosphite substituent, for example, H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably -H , a C1-7 alkyl group, or a C5-20 aryl group. Examples of phosphite groups include, but are not limited to, -OP (OCH3) 2, -OP (OCH2CH3) 2, OP (O-t-Bu) 2, and -OP (OPh) 2. [0108] Phosphoramidite: -OP (OR1) -NR 2 2, where R 1 and R 2 are substituents of phosphoramidite, for example, -H, a C1-7 alkyl group (optionally substituted), a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group, or a C5-20 aryl group. Examples of phosphoramidite groups include, but are not limited to, -OP (OCH2CH3) -N (CH3) 2, -OP (OCH2CH3) -N (i-Pr) 2, and OP (OCH2CH2CN) -N (i-Pr) 2. [0109] Phosphoramidate: -OP (= O) (OR 1 ) -NR 2 2, where R 1 and R 2 are substituents of phosphoramidate, for example, -H, a C1-7 alkyl group (optionally substituted), a group C3-20 heterocyclyl, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group, or a C5-20 aryl group. Examples of phosphoramidate groups include, but are not limited to, -OP (= O) (OCH2CH3) -N (CH3) 2, -OP (= O) (OCH2CH3) -N (i-Pr) 2, and OP (= O) (OCH2CH2CN) -N (i-Pr) 2. Nitrogen Protection Groups [0110] Nitrogen protecting groups are well known in the art. Preferred nitrogen protection groups are carbamate protection groups Petition 870190098905, of 10/03/2019, p. 32/90 22/74 that have the general formula: * [0111] A large number of possible nitrogen carbamate protecting groups are listed on pages 706-771 of Wuts, PGM and Greene, TW, Protective Groups in Orgnic Synthesis, 4th Edition, Wiley-Interscience, 2007 which is incorporated herein by reference. [0112] Particularly preferred protecting groups include Alloc, Troc, Teoc, BOC, Doc, Hoc, TcBOC, Fmoc, 1-Adoc and 2-Adoc. Hydroxyl Protection Groups [0113] Hydroxyl protecting groups are well known in the art. A large number of suitable groups are described on pages 16 to 366 of Wuts, PGM and Greene, TW, Protective Groups in Orgnic Synthesis, 4th Edition, Wiley-Interscience, 2007 which is incorporated herein by reference. [0114] Classes of particular interest include silyl esters, methyl ethers, alkyl ethers, benzyl ethers, esters, benzoates, carbonates and sulfonates. [0115] Particularly preferred protecting groups include THP. Proliferative Diseases [0116] A person of ordinary skill in the art is easily able to determine whether or not a candidate compound treats a proliferative condition for any particular cell type. For example, assays that can be conveniently used to assess the activity offered by a particular compound are described in the examples below. [0117] The term "proliferative disease" belongs to an unwanted or uncontrolled cell proliferation of excessive or abnormal cells that is undesired, such as neoplastic or hyperplastic growth, whether in vitro or in vivo. [0118] Examples of proliferative conditions include, but are not limited to Petition 870190098905, of 10/03/2019, p. 33/90 23/74 a, benign, premalignant, and malignant cell proliferation, including but not limited to, neoplasms and tumors (eg, histocytoma, glioma, astrocytoma, osteoma), cancers (eg, lung cancer, lung cancer small cell, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, bowel cancer, colon cancer, hepatoma, breast cancer, glioblastoma, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, cancer rectum, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, head and neck cancer, head cancer bladder, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (for example, connective tissue disorders), and atherosclerosis if. Cancers of particular interest include, but are not limited to, leukemias and ovarian cancers. [0119] Any cell type can be treated, including but not limited to, lung, gastrointestinal (including, for example, intestine, colon), breast (mammary), ovary, prostate, liver (liver), kidney (kidney) , bladder, pancreas, brain, and skin. [0120] Cancers of particular interest include, but are not limited to, breast cancer (both ER positive and ER negative), pancreatic cancer, lung cancer and leukemia. Treatment Methods [0121] As described above, the present invention provides the use of a compound of the first aspect of the invention in a method of therapy. [0122] The term "therapeutically effective amount" is an amount sufficient to show benefit to a patient. Such a benefit can be at least the improvement of at least one symptom. The actual amount administered, and rate and Petition 870190098905, of 10/03/2019, p. 34/90 24/74 administration time, will depend on the nature and severity of what is being treated. Prescribing treatment, for example, dosage decisions, is within the responsibility of general practitioners and other doctors. [0123] A compound can be administered alone or in combination with other treatments, simultaneously or sequentially depending on the condition being treated. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, for example, drugs); surgery; and radiation therapy. [0124] Examples of chemotherapeutic agents include: erlotinib (TARCEVA ® Genentech / OSI Pharm.), Docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8) , gemcitabine (GEMZAR®, Lilly), PD0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum (II), CAS No. 15663-27-1), carboplatin (CAS No. 41575 -94-4), paclitaxel (TAXOL®, Bristol - Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTIN ®, Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabiciclo [ 4.3.0] nona-2,7,9-triene-9carboxamida, CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plow), tamoxifen ((2) -2- (4- (1,2 -diphenylbut-1 -enyl) phenoxy] -M, M-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin. [0125] Further examples of chemotherapeutic agents include: oxaliplatin (ELOXATIN ® , Sanofi), bortezomib (VELCADE ® , Millennium Pharm.), Sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate ( GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ -235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Petition 870190098905, of 10/03/2019, p. 35/90 25/74 Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), telafarnib (SARASAR ™, SCH 66336, Schering Plow), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinot CAMPTOSAR®, CPT11, Pfizer), tipifarnib (ZARNESTRA ™, Johnson & Johnson), ABRAXANE ™ (Cremofor free), nanoparticle formulations engendered in paclitaxel albumin (American Pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL ®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamida (TELCYTA ®, Telik), thiotepa and cyclophosphamide (CYTOXAN ®, Neosar ®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenomelamine, triethylenophosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bulatacin and bulatacinone); a camptothecin (including the synthetic analogue topotecan); briostatin; calistatin; CC-1065 (including their synthetic analogues adozelesin, carzelesin and bizelesin); cryptoficina (particularly cryptoficina 1 and criptoficina 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleuterobin; pancratistatin; a sarcodictiina; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mecloretamine, meclorethamine oxide hydrochloride, melphalan, novembiquine, phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, photemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enedinin antibiotics (eg, calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183 - 186); speramycin; as well as neocarzinostatin chromophore and related chromophoric enediin antibiotic chromophores), Petition 870190098905, of 10/03/2019, p. 36/90 26/74 aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophylline, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholine-doxorin-oxide, morpholine-doxorin-oxide, morpholine-doxorin-oxide; -pyrroline-doxorubicin and deoxidoxorubicin), epirubicin, esorubicin, idarrubicin, nemorubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, estromycin, streptococcal, streptococcin, streptococcin, streptococcin, streptococcal, , zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, tiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, didesoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutetimide, mitotane, trilostane; replenishing folic acid such as frolinic acid; aceglatone; glycoside aldophosphamide; aminolevulinic acid; eniluracil; ansacrine; bestrabucila; bisanthrene; edatraxate; defofamine; demecolcine; diaziquone; elfornitine; ellipinium acetate; an epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainin; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; fenamet; pirarrubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2.2 ', 2 "trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesina; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and Petition 870190098905, of 10/03/2019, p. 37/90 27/74 carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); new chair; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ® , Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. [0126] Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit the action of the hormone in tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including , for example, tamoxifen (including NOLVADEX ® ; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene, ceoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the aromatase enzyme, which regulates the production of estrogen in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutetimide, MEGASE ® (megestrol acetate), AROMASIN ® (exemestane; Pfizer), formestanie, fadrozol, RIVISOR ® (vorozol), FEMARA ® (letrozol; Novartis), and ARIMIDEX ® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a nucleoside 1,3-dioxolane cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersene (GENASENSE ® , Genta Inc.); (vii) ribozymes such as inhibitors of VEGF expression (for example, ANGIOZYME ® ) and inhibitors of HER2 expression; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN ® , LEUVECTIN ® , and VAXID ® ; PROLEUKIN ® rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN ® ; Petition 870190098905, of 10/03/2019, p. 38/90 28/74 ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above. [0127] Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX ® , Amgen), rituximab (RITUXAN ® , Genentech / Biogen Idec), pertuzumab (OMNITARG ™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the conjugate of febrile antibody, gentuzumab ozogamycin (MYLOTARG ® , Wyeth). [0128] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansina, cantuzumab mertansine, cedelizumab, cibernumab, ducumab, dumont, cumbuma eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gentuzumab ozogamycin, inotuzumab ozogamycin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxethane, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleucine, tucusituzumab, umavizumab, urtoxazumab, and visilizumab. [0129] Pharmaceutical compositions in accordance with the present invention, and for use in accordance with the present invention, may comprise, in addition to the Petition 870190098905, of 10/03/2019, p. 39/90 29/74 active ingredient, i.e. a compound of formula I, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials must be non-toxic and must not interfere with the effectiveness of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which can be oral, or by injection, for example, cutaneous, subcutaneous or intravenous. [0130] Pharmaceutical compositions for oral administration can be in the form of a tablet, capsule, powder or liquid. A tablet can 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, dextrose or other solution of saccharide or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule can comprise a solid carrier such as gelatin. [0131] For intravenous, cutaneous or subcutaneous injection, or injection at the affliction site, the active ingredient will be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has adequate 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 chloride injection, Ringer injection, lactated Ringer injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included as needed. Dosage [0132] It will be assessed by a person of skill in the art that appropriate dosages of the compound may vary from patient to patient. Determining the ideal dosage will usually involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The dosage level Petition 870190098905, of 10/03/2019, p. 40/90 30/74 selected will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and the patient's previous medical history. The amount of compound and route of administration will basically be at the discretion of the doctor, veterinarian, or clinician, although generally the dosage will be selected to obtain local concentrations at the site of action that achieve the desired effect without causing any harmful side effects or substantial deleterious effects. [0133] Administration can be carried out in one dose, continuously or intermittently (for example, in doses divided at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of therapy, the target cell (s) being treated , and the patient being treated. Single or multiple administrations can be performed with the dose level and standard being selected by the doctor, veterinarian, or treatment clinician. [0134] In general, a suitable dose of the active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram of the patient's body weight per day. Where the active compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the precursor compound and so that the actual weight to be used is increased proportionally. [0135] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 100 mg, 3 times a day. [0136] In one embodiment, the active compound is administered to a Petition 870190098905, of 10/03/2019, p. 41/90 31/74 human patient according to the following dosage regimen: about 150 mg, twice a day. [0137] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 200 mg, twice a day. [0138] For the prevention or treatment of the disease, the appropriate dosage of the compound of the invention will depend on the type of disease to be treated, as defined above, on the severity and course of the disease, whether the molecule is administered for preventive or therapeutic purposes, therapy the patient's clinical history and antibody response, and the attending physician's discretion. The molecule is properly administered to the patient at once or in a series of treatments. Depending on the type and severity of the disease, about 1 ug / kg to 15 mg / kg (eg 0.1 to 20 mg / kg) of the molecule is an initial candidate dosage for administration to the patient, if, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage could range from about 1 µg / kg to 100 mg / kg or more, depending on the factors mentioned above. An exemplary dosage of the compound to be administered to a patient is in the range of about 0.1 to about 10 mg / kg of the patient's weight. For repeated administrations over several days or more, depending on the condition, treatment is continued until a desired suppression of the symptoms of the disease occurs. An exemplary dosage regimen comprises a course of administration of an initial loading dose of about 4 mg / kg, followed by additional doses each week, two weeks, or three weeks of a compound. Other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and trials. Includes Other Shapes [0139] Unless otherwise specified, included in the above are the Petition 870190098905, of 10/03/2019, p. 42/90 32/74 well-known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO - ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-N + HR1R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (O - ), a salt or solvate thereof, as well as conventional protected forms. Isomers, Salts and Solvates [0140] Certain compounds may exist in one or more geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or particular anomeric forms, including but not limited to, cis and trans forms; E and Z forms; forms c, t, and r; endo- and exo-forms; R, S-, and meso-forms; forms D and L; d and l forms; (+) and (-) forms; keto, enol, and enolate forms; syn- and anti-forms; syncline and anticline forms; α and β forms; axial and equatorial forms; boat, chair, spiral, envelope, and half chair shapes; and combinations of these, hereinafter collectively referred to as "isomers" (or "isomeric forms"). [0141] Preferably the compounds of the present invention have the following stereochemistry at the C11 position: THE [0142] Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used here, they are structural (or constitutional) isomers (that is, isomers that differ in connections between atoms rather than merely by position atoms in space). For example, Petition 870190098905, of 10/03/2019, p. 43/90 33/74 a reference to a methoxy group, -OCH3, should not be interpreted as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl should not be interpreted as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms that fall within this class (for example, C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert -butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). [0143] The above exclusion does not belong to tautomeric forms, for example, keto, enol, and enolate forms, as, for example, in the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol , amidine / amidine, nitrous / oxime, thiocetone / enethiol, N-nitrous / hypoxia, and nitro / acid nitro. H / 0 Z OH H + χ O - H + / keto enol enolate [0144] Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C can be in any isotopic form, including 12 C, 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; and the like. [0145] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic mixtures and the like. Methods for the preparation (for example, asymmetric synthesis) and separation (for example, partial crystallization and chromatographic medium) of such isomeric forms are known in the art or are easily obtained by adapting the methods shown here, or known methods, in a manner known. [0146] Unless otherwise specified, a reference to a Petition 870190098905, of 10/03/2019, p. 44/90 34/74 particular compound also includes ionic, salt, solvate, and protected forms of it, for example, as discussed below. [0147] 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). [0148] For example, if the compound is anionic, or has a functional group that can be anionic (for example, -COOH can be -COO - ), then a salt can 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 Ca 2+ and Mg 2+ , and other cations such as Al 3+ . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4 + ) and substituted ammonium ions (for example, NH3R + , NH2R2 + , NHR3 + , NR4 + ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylene diamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine . An example of a common quaternary ammonium ion is N (CH3) 4 + . [0149] If the compound is cationic, or has a functional group that can be cationic (for example, -NH2 can be -NH3 + ), then a salt can be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric and phosphorous. [0150] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, Petition 870190098905, of 10/03/2019, p. 45/90 35/74 ethanedisulfonic, ethanesulfonic, fumaric, gluqueptonic, glyconic, glutamic, glycolic, hydroxylenic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, musico, oleic, oxalic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phalic, phalic, phalic, phalic, phaenic, phallic, phaenic, oxalic, phallic, oxalic, phallic, phaenic, oxalic, phallic, phallic, oxalic, phallic, oxalic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, phallic, peach's phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, 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. [0151] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the active compound. The term "solvate" is used here in the conventional sense to refer to a solute complex (for example, active compound, active compound salt) and solvent. If the solvent is water, the solvate can conveniently be referred to as a hydrate, for example, a monohydrate, a dihydrate, a trihydrate, etc. [0152] The compounds of formula I include compounds where a nucleophilic solvent (H2O, RAOH, RANH2, RASH) joins via the imine bond of the PBD portion, which is illustrated below where the solvent is water or an alcohol (R A OH, where R A is an ether substituent as described above): [0153] These forms can be called the carbinolamine and carbinolamine ether forms of PBD. The balance of these equilibria depends on the conditions in which the compounds are found, as well as on the nature of the portion itself. [0154] These compounds can be isolated in solid form, for example, by lyophilization. General Synthetic Pathways Petition 870190098905, of 10/03/2019, p. 46/90 36/74 [0155] The compounds of formula I where R 10 and R 11 together form a double bond can be synthesized from the compounds of formula 2: [0156] R ' 1 ° is a nitrogen protecting group and R' 11 is OR 12 , where R 12 is H or a hydroxyl protecting group. Such techniques are well known in the art and are described, for example, Wuts, PGM and Greene TW, Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, 2007. If both nitrogen protecting groups as hydroxyl are present, they are preferably selected as being removable under the same conditions. [0157] If this deprotection is performed in a solvent of the formula HQR Q , then R 10 and R 11 will be H and QR Q respectively. Alternatively, these groups can be introduced by adding the compound to a solvent other than that in which deprotection is carried out. [0158] The conversion of the compounds of formula I as discussed above to those having R 11 as SOxM can be achieved by adding the appropriate bisulfite or sulfinate salt, followed by a purification step. Other methods are described in GB 2,053,894, which is incorporated herein by reference. [0159] The compounds of formula 2 can be manufactured by linking the compounds of formula 3 and formula 4: L d OR Formula 4 Petition 870190098905, of 10/03/2019, p. 47/90 37/74 under standard amide bonding conditions, for example, in the presence of HOBt or DMAP and EDCI. [0160] The compounds of formula 3 can be synthesized from the compounds of formula 5: where R ' 8 is a C1-4 alkyl group, for example, methyl. This deprotection of the carboxyl group can be accomplished using standard means, for example, treatment based. [0161] The compounds of the formula 5 can be synthesized in general following the methods described in WO 00/12506 and WO 2007/039752, which are incorporated herein by reference. In particular, the butanoic acid side chain can be introduced at any stage in the synthesis, usually with appropriate protecting groups in place. For example, the side chain can be formed by bonding in a protected or precursor manner to a hydroxy group on the bezene ring using, for example, Mitsunobo bond. [0162] The compounds of formula 4 can be synthesized using the methods disclosed in WO 2005/085177, which are incorporated herein by reference. Reference is also made to the disclosure of WO 2007/039752. DNA binding [0163] The ability of compounds to bind to DNA, and in particular oligonucleotides, can be measured using an ion pair reverse phase HPLC assay, as described in Rahman, KM, et al., Journal of the American Chemical Society 2009 , 131, 13756 and Narayanaswamy, M., et al., Analytical Biochemistry 2008, 374, 173. DNA binding affinity can also be Petition 870190098905, of 10/03/2019, p. 48/90 38/74 assessed using a calf thymus DNA thermal denaturation assay, as described in Wells, G., et al., Journal of Medicinal Chemistry 2006, 49, 5442; Jenkins, T. C., et al., Journal of Medicinal Chemistry 1994, 37, 4529; and Gregson, S. J., et al., Journal of Medicinal Chemistry 2001, 44, 737. Other Preferences C2 [0164] It may be preferred in any of the embodiments that C2 carbon is a sp 2 center, so that when R 2 is selected from any of the following groups: -H, -OH, -CN, -R, -OR, halo, -O-SO2-R, -CO2R and -COR there is a double bond between C2 and C3. [0165] When R 2 is selected from any of the following groups: = O, = CH2, = CHR, = CHRR 'there cannot be a double bond between C2 and C3. [0166] In other embodiments, there is no double bond between C2 and C3, and R 2 is H. R 2 [0167] R 2 is selected from -H, -OH, = O, = CH2, -CN, -R, OR, halo, dihalo, = CHR, = CHRR ', -O-SO2-R, CO2R and COR. [0168] In some embodiments, R 2 can be selected from -H, OH, = O, = CH2, -CN, -R, -OR, = CHR, = CRR ', -O-SO2-R, - CO2R and -COR. [0169] In some embodiments, R 2 can be selected from -H, = CH2, -R, = CHR, and = CRR '. [0170] In one embodiment, R 2 is H. [0171] In one embodiment, R 2 is = O. [0172] In one embodiment, R 2 is = CH2. [0173] In one embodiment, R 2 is = CHR. Within the compound of Petition 870190098905, of 10/03/2019, p. 49/90 39/74 PBD, the group = CHR can have any configuration shown below: (C1) (C2) [0174] In one embodiment, the configuration is the configuration (C1). [0175] In one embodiment, R 2 is = CRR '. [0176] In one embodiment, R 2 is = CF2. [0177] In one embodiment, R 2 is R. [0178] In one embodiment, R 2 is optionally substituted C5-20 aryl. [0179] When R 2 is optionally substituted C5-20 aryl, it can preferably be optionally substituted C5-7 aryl or C8-10 aryl. R 2 may further preferably be optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted quinolinyl or isoquinolinyl. Of these groups, optionally substituted phenyl is most preferred. [0180] When R 2 is optionally substituted C5-20 aryl, it can preferably carry one to three substituent groups, with 1 and 2 being more preferred, and individually substituted groups being most preferred. Substituents can be of any position. [0181] Where R 2 is a C5-7 aryl group, a single substituent is preferably on an atom in the ring that is not adjacent to the bond to the rest of the compound, i.e. it is preferably β or γ to the bond to the rest of the compound. Therefore, where the C5-7 aryl group is phenyl, the substituent is preferably in the meta or para positions, and most preferably it is in the para position. [0182] In one embodiment, R 2 is selected from: Petition 870190098905, of 10/03/2019, p. 50/90 40/74 where the asterisk indicates the connection point. [0183] Where R 2 is a Cs-io aryl group, for example quinolinyl or isoquinolinyl, it can carry any number of substituents in any position of the quinoline or isoquinoline rings. In some embodiments, it carries one, two or three substituents, and these can be on the proximal and distal rings or both (if more than one substituent). [0184] When R 2 is optionally substituted C5-20 aryl, the substituents can be selected from: halo, hydroxyl, ether, formyl, acyl, carboxy, ester, acyloxy, amino, starch, acylamido, aminocarbonyloxy, ureido, nitro, cyano and thioether. [0185] When R 2 is optionally substituted C5-20 aryl, the substituents can be selected from the group consisting of R, OR, SR, NRR ', NO2, halo, CO2R, COR, CONH2, CONHR and CONRR'. [0186] If a substituent on R 2 is halo, it is preferably F or Cl, more preferably Cl. [0187] If a substituent on R 2 is ether, it may in some embodiments be an alkoxy group, for example, a C1-7 alkoxy group (for example, methoxy, ethoxy) or it may in some embodiments be a C5-7 aryloxy group (e.g., phenoxy, pyridyloxy, furanyloxy). [0188] If a substituent on R 2 is C1-7 alkyl, it may preferably be a C1-4 alkyl group (for example, methyl, ethyl, propyl, butyl). [0189] If a substituent on R 2 is C3-7 heterocyclyl, it may in some embodiments be a heterocyclyl group containing C6 nitrogen, for example, morpholino, thiomorpholino, piperidinyl, piperazinyl. These groups can be linked to the rest of the PBD portion via the nitrogen atom. These groups can be replaced, for example, by C1-4 alkyl groups. Petition 870190098905, of 10/03/2019, p. 51/90 41/74 [0190] If a substituent on R 2 is bis-oxy-C1-3 alkylene, it is preferably bis-oxy-methylene or bis-oxy-ethylene. [0191] Particularly preferred substituents for R 2 include methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thienyl. [0192] Particularly preferred substituted R 2 groups include, but are not limited to, 4-methoxy-phenyl, 3-methoxyphenyl, 4-ethoxy-phenyl, 3-ethoxy-phenyl, 4-fluorophenyl, 4-chloro-phenyl, 3 , 4-bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4-phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl, 2-furanyl, methoxylamine and naphthyl . [0193] In one embodiment, R 2 is optionally substituted C1-12 alkyl. [0194] When R 2 is optionally substituted C1-12 alkyl, it can be selected from: (a) C1-5 saturated aliphatic alkyl; (b) C3-6 saturated cycloalkyl; R 22 * R 23 I (c) R , where each of R 21 , R 22 and R 23 are independently selected from H, saturated C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of atoms of carbon in group R 12 is not more than 5; R 25b *. (d) D 25a R , where one of R 25a and R 25b is H and the other is selected from: phenyl, which is optionally substituted by a group selected from halo methyl, methoxy; pyridyl; and thiophenyl; and * (e) R , where R 24 is selected from: H; saturated C1-3 alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which is optionally substituted by a group selected from halo methyl, methoxy; pyridyl; and thiophenyl. Petition 870190098905, of 10/03/2019, p. 52/90 42/74 [0195] When R 2 is C1-5 saturated aliphatic alkyl, it can be methyl, ethyl, propyl, butyl or pentyl. In some embodiments, it can be methyl, ethyl or propyl (n-pentyl or isopropyl). In some of these embodiments, it can be methyl. In other embodiments, it can be butyl or pentyl, which can be linear or branched. [0196] When R 2 is C3-6 saturated cycloalkyl, it can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, it can be cyclopropyl. R 22 Á21 [0197] When R 2 is R , each of R 21 , R 22 and R 23 is independently selected from H, saturated C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of atoms of carbon in group R 2 is not more than 5. In some embodiments, the total number of carbon atoms in group R 2 is not more than 4 or not more than 3. [0198] In some embodiments, one of R 21 , R 22 and R 23 is H, with the other two groups being selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl. [0199] In other embodiments, two of R 21 , R 22 and R 23 are H, with the other group being selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl. [0200] In some embodiments, groups that are not H are selected from methyl and ethyl. In some of these embodiments, groups that are not H are methyl. [0201] In some embodiments, R 21 is H. [0202] In some embodiments, R 22 is H. [0203] In some embodiments, R 23 is H. [0204] In some embodiments, R 21 and R 22 are H. Petition 870190098905, of 10/03/2019, p. 53/90 43/74 [0205] In some embodiments, R 21 and R 23 are H. [0206] In some embodiments, R 22 and R 23 are H. R 25b [0207] When R 2 is r-x25a R , one of R 25a and R 25b is H and the other is selected from: phenyl, which is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl. In some embodiments, the group that is not H is optionally substituted phenyl. If the optional phenyl substituent is halo, it is preferably fluoro. In some embodiments, the phenyl group is not substituted. * [0208] When R 2 is q24 R , R 24 is selected from: H; saturated alkyl C1-3; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which is optionally substituted by a group selected from halo methyl, methoxy; pyridyl; and thiophenyl. If the optional phenyl substituent is halo, it is preferably fluoro. In some embodiments, the phenyl group is not substituted. [0209] In some embodiments, R 24 is selected from H, methyl, ethyl, ethylene and ethynyl. In some of these embodiments, R 24 is selected from H and methyl. [0210] In one embodiment, R 2 is halo or di-halo. In one embodiment, R 2 is -F or -F2, the substituents of which are illustrated below as (C3) and (C4) respectively: O (C3) O (C4) F R 2 can preferably be selected from = CH2, = CH-R, where R is more preferably an optionally substituted C1-4 alkyl group, and -R, where R is Petition 870190098905, of 10/03/2019, p. 54/90 44/74 more preferably an optionally substituted C5-20 aryl group. Particularly preferred groups for R 2 include = CH2, = CH-Me, and an optionally substituted phenyl group. R 7 [0211] R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro, Me3Sn and halo; R 7 can preferably be selected from H, OR, SH, SR, NH2, NHR, NRR ', and halo. [0212] R 7 can more preferably be selected from H and OR. [0213] In some embodiments, R 7 is OR, and more particularly OR 7A , where R 7A is independently optionally substituted C 1-7 alkyl. [0214] R 7A can be selected from optionally substituted saturated C1-7 alkyl and optionally substituted C2-4 alkenyl. [0215] R 7A can preferably be selected from Me, CH2Ph and allyl. R 10 / R 11 [0216] R 10 and R 11 together form a double bond, or are selected from H and QR Q respectively, where Q is selected from O, S and NH and R Q is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a pharmaceutically acceptable monovalent cation; [0217] In some embodiments, R 10 and R 11 together form a double bond. [0218] In some embodiments, R 10 is H and R 11 is OR Q. In these embodiments, R Q can preferably be selected from H or Me. [0219] In some embodiments, R 10 is H and R 11 is SOxM. x may preferably be 3, and M may preferably be Na + . R 1 [0220] R 1 is C1-4 alkyl. Petition 870190098905, of 10/03/2019, p. 55/90 45/74 [0221] R 1 may preferably be C 1-2 alkyl, and more preferably methyl. THE [0222] A is: or (A1) (A2) where X and Y are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S. [0223] In some embodiments, A is A1. [0224] In some embodiments, A is A2. [0225] In any of these embodiments, X and Y can preferably be selected from CH and NMe; CH and S; N and NMe; and N and S. X and Y can more preferably be selected from CH and NMe; and N and NMe. [0226] In some embodiments X and Y are CH and NMe. [0227] In some embodiments X and Y are N and NMe. B [0228] B is a simple link or: where X and Y are as defined selected. (B1) , above, but regardless Petition 870190098905, of 10/03/2019, p. 56/90 46/74 [0229] In some embodiments, B is a simple link. [0230] In some embodiments, B is B1. [0231] In any of these embodiments, X and Y can preferably be selected from CH and NMe; CH and S; N and NMe; and N and S. X and Y can more preferably be selected from CH and NMe; and N and NMe. [0232] In some embodiments X and Y are CH and NMe. [0233] In some embodiments X and Y are N and NMe. Figures [0234] Figures 1A and 1B show the results of an assay to determine the maximum tolerated dose of two compounds of the invention; [0235] Figure 2 shows the result of an assay to determine the in vivo activity of a compound of the invention; and [0236] Figure 3 shows the result of another test to determine the in vivo activity of the same compound as in Figure 2. Examples General Methods [0237] Optical rotations were measured in an ADP 220 polarimeter (Bellingham Stanley Ltd) and concentrations (c) are given in g / 100mL. Melting points were measured using a digital melting point apparatus (Electrothermal). IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT IR Spectrometer. 1 H and 13 C NMR spectra were acquired at 300 K using a Bruker Advance NMR spectrometer at 400 and 100 MHz, respectively. Chemical substitutions are reported in relation to TMS (δ = 0.0 ppm), and signals are designated as s (singlet), d (doublet), t (triplet), dt (triplet doublet), dd (doublet of doublets) , ddd (double doublet of doublets) or m (multiplet), with the coupling constants given in Hertz (Hz). A pro-PBD numbering system is used for carbon and proton assignments to synthetic intermediates (ie, Petition 870190098905, of 10/03/2019, p. 57/90 47/74 based on the final tricyclic PBD ring system). Mass spectrometry data was collected using a ZQ Waters Micromass instrument coupled to a 2695 Waters HPLC with a 2996 Waters PDA. The parameters of ZQ Waters Micromass used were: Capillary (kV), 3.38; Cone (V), 35; Extractor (V), 3.0; Source temperature (° C), 100; Desolvation Temperature (° C), 200; Cone Flow Rate (L / h), 50; Desolvation Flow Rate (L / h), 250. High resolution mass spectrometry data was recorded on a Waters Micromass QTOF Global in positive W mode using metal-coated borosilicate glass tips to introduce samples into the instruments. Thin Layer Chromatography (TLC) was performed on silica gel aluminum plates (Merck 60, F254), and instant chromatography used silica gel (Merck 60, 230 400 mesh ASTM). Parallel reactions were performed using a Green House Radleys TM Synthesizer and parallel purifications were performed using an IST Vacmaster TM . For reactions carried out in parallel, the solvents were evaporated using a Genevac VC 2000D (Genevac Technologies, UK). The purified compounds were lyophilized using a 3000 Heto-Lyolab lyophilizer. The hydrogenation reactions were loaded using a UHP-60H hydrogen generator connected to a Parr hydrogenation device. The synthetic building blocks were purchased from Maybridge Chemicals (UK), Bachem Chemicals (USA) and SigmaAldrich (UK). The reagents and solvents were purchased from Sigma-Aldrich (UK). Synthesis of Key Intermediates (a) Methyl 4- (4- (tert-Butoxycarbonylamino) phenyl) -1-methyl-1H-pyrrole-2-carboxylate (5) Petition 870190098905, of 10/03/2019, p. 58/90 48/74 H 3 CO THE Br 2- (Trichloroacetyl) -1-methyl pyrrole (2) [0238] A solution of N-methyl pyrrole (1) (113.06 g, 1.39 mol, 1.0 eq) in dry ether (350 mL) was added dropwise over a period of 1 hour and 10 minutes to a stirred solution of trichloroacetyl chloride (254 g, 1.39 mol, 1.0 eq) in dry ether (350 mL) in a 3-neck 2 L flask. The HCl gas produced in the reaction was removed through the nitrogen flow. The reaction mixture was allowed to stir for 1.5 hours and the progress of the reaction was monitored regularly by TLC and LCMS. After 1.5 h, the reaction was quenched quickly using 1 M K2CO3 solution. The reaction mixture was extracted with ethyl acetate (3x) and the organic layers were combined and concentrated in vacuo. The crystalline residue was washed with n-hexane and finally dried under vacuum. Yield 281.18 g, 79.5%, NMR compared to the literature. IR, (FTIR, Vmax / cm -1 ) 3299, 3121, 3008, 2954, 1789, 1674, 1521, 1406, 1206, 1100, 980, 881,757; 1 H NMR (CDCh, 400 MHz) δ 7.42 (1H, dd, J = 4.4, 1.6 Hz), 6.97 (1H, t, J = 1.6 Hz), 6.22 (1H, dd, J = 4.4, 2.4 Hz) 3.97 (3H, s); 13 C NMR (CDCh, 400 MHz): δ 133.6, 124.0, 122.4, 108.9, 38.5. (ii) 1 - (4-Bromo-1-methyl-1 H-pyrrol-2-yl) -2,2,2-trichloroethanone (3) [0239] NBS (N-Bromosuccinimide, 2.36 g, 13.24 mmol, 1.0 equiv.) Was Petition 870190098905, of 10/03/2019, p. 59/90 49/74 added to a stirred solution of 2- (trichloroacetyl) -1-methylpyrrole (2) (3 g, 13.24 mmol, 1.0 equiv.) In anhydrous THF (35 mL) at -10 ° C. The reaction mixture was kept at -10 ° C for 2 hours and then allowed to reach room temperature (ca. 4 hours). The excess THF was evaporated in vacuo and the solid was redissolved in an EtOAc / n-hexane (1: 9) mixture. The resulting mixture was filtered through a plug of silica, and the filtrate was evaporated in vacuo. The resulting solid was recrystallized from n-hexane to provide 3 (3.55 g, 88%). IR (FTIR, Vmax / cm 1 ): 3148, 2956, 1669 (C = O), 1458, 1215, 1189, 1062, 923, 842, 823, 748, 678; 1 H NMR (CDCl3, 400 MHz) δ 7.46 (1H, d, J = 2.0 Hz), 6.95 (1H, d, J = 1.6 Hz) 3.95 (3H, s) ; 13 C NMR (CDCh, 100 MHz): δ 172.4, 132.8, 124.6, 132.2, 96.1, 38.7; EIMS m / z (+ EI) calc. for C7H5BrCl3NO (M) + 305.38, LCMS Analysis found 306.86 (M + H) + (iii) methyl 4-Bromo-1-methyl-1H-pyrrole-2-carboxylate (4) [0240] To a stirred solution of 1- (4-bromo-1-methyl-1H-pyrrol-2-yl) -2,2,2trichloroethanone (3) (3.28 g, 10.74 mmol, 1 eq.) in dry MeOH (30 ml), a solution of sodium methoxide (0.5 ml) was added by syringe. The sodium methoxide solution was prepared from 60% NaH in mineral oil (43 mg, 1.07 mmol, 0.1 eq.), Which was previously washed with n-hexane. The solution was heated to reflux over a period of 30 minutes, when the TLC analysis showed complete consumption of the starting material. A few drops of concentrated H2SO4 were added to the solution to neutralize the base (pH 2). The excess MeOH was evaporated in vacuo and the resulting oil was redissolved in EtOAc (50 ml) and washed with water (40 ml). The aqueous layer was extracted with EtOAc (3 x 40 ml), and the organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the product as a pale white solid. (2.28 g, 97%). IR (FTIR, Vmax / cm -1 ): 3138, 2948, 1692, 1472, 1334, 1245, 1115, 1082, 921, 823, 753; 1 H NMR (400 MHz, CDCl3): δ 6.89 (d, 1H, J = 2.0 Hz), 6.76 (d, 1H, J = 2.0 Hz), 3.89 (s, 3H), 3.81 Petition 870190098905, of 10/03/2019, p. 60/90 50/74 (s, 3H); 13 C NMR (100 MHz, CDCl 3): δ 160.8, 128.7, 122.9, 119.2, 95.1, 51.2, 36.9; EIMS m / z (+ EI) calc. for C7H8BrNO2 (M) + 218.05 found 219.26 (M + H) + (iv) 4- (4- (tert-Butoxycarbonylamino) phenyl) -1-methyl-1H-pyrrol-2-carboxylate (5 ) [0241] A catalytic amount of tetracis (triphenylphosphino) palladium, Pd (PPh3) 4 (0.477g, 0.413, 0.06 eq) was added to a solution of 4 (1.5 g, 6.88 mmols, 1 eq) and (4 - ((tert-butoxycarbonyl) amino) phenyl) boronic acid (1.57 g, 6.88 mmols, 1.20 eq) in a 9: 3: 1 (13.5 ml) combination of EtOH, toluene and water in the presence of K2CO3 (2.856 g, 3 eq.) in a 10 to 20 mL microwave vial containing a magnetic stirrer. The reaction vessel was flushed with nitrogen during each addition. The reaction mixture was sealed in an inert N2 atmosphere and heated with microwave radiation in an EMRYS ™ Microwave Optimizer Station (Personal Chemistry) at 100 ° C for 12 minutes. After the LCMS and TLC analysis revealed the completion of the reaction, the cooled reaction mixture was diluted with water (50 ml), extracted with EtOAc (3 x 40 ml), the combined filtrates, dried over MgSO4 and concentrated in vacuo. The resulting oil was subjected to flash chromatography (n-hexane / EtOAc 9: 1) to provide 5 (Yield - 2.2 g, 97%). IR (FTIR, v max / cm -1 ): 3353, 2975, 1696, 1521, 1441, 1366, 1264, 1235, 1209, 1058, 822, 799, 657; 1 H NMR (400 MHz, CDCh): δ 7.40 (d, 2H, J = 8.8 Hz), 7.33 (d, 2 H, J = 8.8 Hz), 7.16 (d, 1H, J = 2.0 Hz,), 7.02 (d, 1H, J = 2.0), 6.45 (br s, 1H), 3, 95 (s, 3H), 3.83 (s, 3H), 1.52 (s, 9H); 13 C NMR (100 MHz, CDCh): δ 161.7, 152.8, 136.5, 129.5, 125.9, 125.6, 123.7, 123.0, 119.0, 114, 6, 80.5, 51.1, 36.9, 28.4; EIMS m / z (+ EI) calc. for C18H22N2O4 (M) + 330.38 found 330.46 (M + H) + (b) 4- (4- (tert-butoxycarbonylamino) phenyl) -1-methyl-1H-pyrrole-2-carboxylic acid (6) Petition 870190098905, of 10/03/2019, p. 61/90 51/74 6 [0242] A 0.5 M solution of NaOH (2.0 eq) was added to a solution of 5 (1.0 g, 3.027 mmols) in dioxane (40 ml). The reaction mixture was allowed to stir at room temperature for 6 hours at which point TLC revealed the completion of the reaction. The excess 1,4-dioxane was evaporated in vacuo and the residue was diluted with water. The resulting solution was acidified with 0.5 M HCl. The product was extracted from water with 2 x ethyl acetate (100 ml x 2) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. . The product was purified using flash chromatography (ethyl acetate / n-hexane 2: 8). Yield - 0.92 g, 96.8%. IR (FTIR, v max / cm -1 ): 3371, 2979, 1698, 1671, 1522, 1445, 1367, 1285, 1161, 1112, 1047, 823, 803, 762, 714, 631; 1 H NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 7.55 (d, 2H, J = 8.8 Hz), 7.50 (d, 2 H, J = 8, 8 Hz), 7.36 (d, 1H, J = 2.0 Hz), 7.22 (d, 1H, J = 2.0), 3.97 (s, 3H), 1.50 (s , 9H); 13 C NMR (100 MHz, CDCl3): δ 162.3, 153.7, 138.6, 123.0, 127.1, 126.0, 124.4, 124.0, 119.5, 115, 1, 79.9, 36.9, 28.6; EIMS m / z (+ EI) calc. for C17H20N2O4 (M) + 316.35 found 315.16 (M + H) + Methyl 4- (4-Aminophenyl) -1-methyl-1H-pyrrole-2-carboxylate (7) [0243] 5 (1 g, 3.027 mmols) was dissolved in a small volume of MeOH Petition 870190098905, of 10/03/2019, p. 62/90 52/74 and 4M HCl in dioxane (15 ml) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed the completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown solid 7. The solid product was subjected to flash chromatography (nhexane / EtOAc 9: 1) to provide pure 7 (065 g, 94.2%). IR (FTIR, v max / cm -1 ): 3366, 2987, 1688, 1629, 1566, 1422, 1372, 1262, 1181, 1103, 1067, 951, 821, 784, 756; 1 H NMR (400 MHz, CDCL): δ 7.28 (2H, d, J = 8.4 Hz), 7.11 (1H, d, J = 2.0 Hz), 6.96 (1H, d, J = 2.0 Hz), 6.68 (d, 2 H, J = 8.0 Hz), 3.94 (s, 3H), 3.83 (s, 3H); 13 C NMR (100 MHz, CDCl 3): δ 161.7, 144.7, 126.2, 125.4, 125.2, 115.5, 114.4, 51.0, 36.8; EIMS m / z (+ EI) calc. for C13H14N2O2 (M) + 230.26 found 231.1 (M + H) + (ii) 4- (4- (4- (4-Aminophenyl) -1-methyl-1 H-pyrrole-2-carboxamido) phenyl ) Methyl -1-methyl-1Hpirrol-2-carboxylate (8) [0244] 0.2 g of 6 protected per mouth (0.63 mmol, 1.2 eq) was dissolved in DMF (5 ml), where 2.0 eq of EDCI and 2.5 eq of DMAP were added and the mixture was allowed to stir for 30 minutes. At this point, methyl 4-amino-1-methyl-1H-pyrrole-2carboxylate (80.9 mg, 0.52 mmol, 1.0 eq) was added and the reaction mixture was allowed to stir for an additional 3 hours at which point TLC showed the completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts were sequentially washed with saturated aqueous NaHCO3 (50 ml), water (50 ml), brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product was used for the deprotection step to obtain 8 without further purification. For the deprotection of boc, the crude product was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 ml) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed the completion of the reaction. THE Petition 870190098905, of 10/03/2019, p. 63/90 53/74 excess solvent was evaporated in vacuo to obtain a brown solid (8). The solid product was subjected to flash chromatography (n-hexane / EtOAc 9: 1) to provide pure 8. Yield - 0.21 gm, 77%. 1 H NMR (400 MHz, CDCl3): δ 7.72 (1H, s), 7.69 (1H, s), 7.57 (2H, d, J = 8.0 Hz), 7.46 ( 4H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.06 (1H, d, J = 2.0 Hz, 7.02 (1H, d, J = 1.6 Hz), 6.92 (1H, s). m / z (+ EI) calc. for C25H24N4O3 (M) + 428 , 48 found 429.26 ([M + H] + (d) NHBoc 9a 9 P CH 3 nh 2 ° H f 0 ϊγ / 0 I (i) 4- (4- (4-Aminophenyl) -1-methyl-1H-pyrrol-2-carboxamido) -1-methyl-1H-pyrrole-2carboxylate methyl (9) [0245] Two eq of EDCI and 2.5 eq of DMAP were added to a stirred solution of 6 (0.45 gm, 1.2 eq) in DMF (8 ml) and the mixture was allowed to stir for 30 minutes after that methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.18 g, 1.18 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 6 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined extracts were sequentially washed with citric acid (100 mL), aqueous NaHCO3 Petition 870190098905, of 10/03/2019, p. 64/90 54/74 saturated (100 ml), water (100 ml), brine (100 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, 90.6% yield) was used for the deprotection step to obtain 9 without further purification. For boc deprotection, 0.29 gm of 9a was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 ml) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed the completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown solid (9). The solid product was subjected to flash chromatography (nhexane / EtOAc 9: 1) to provide pure 9. Yield - 0.21 gm, 95%. (ii) 4- (4- (4- (4-Aminophenyl) -1-methyl-1 H-pyrrole-2-carboxamido) -1-methyl-1 H-pyrrole2-carboxamido) -1-methyl-1H-pyrrole -2-methyl carboxylate (10) [0246] Lithium hydroxide (68 mg, 1.65 mmol, 3 eq) was added to 9a (0.25 g, 0.55 mmol) in aqueous dioxane (8 ml dioxane, 4 ml water) at room temperature . The reaction mixture was stirred for 3 hours at which point TLC showed the completion of the reaction. Dioxane was evaporated under high vacuum and the residue was diluted with water. The resulting solution was acidified with 1 M citric acid followed by extraction with ethyl acetate (2 x 50 ml). The combined organic layer and washed with brine (50 ml), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure to obtain the hydrolyzed acid form 9a as a white solid (yield 0.23 g, 91, 6%). To a stirring solution of the white solid (0.23 gm, 0.52 nmol) in DMF, 2.0 equivalents of EDCI and 2.5 equivalents of DMAP was added. After stirring the mixture for 20 minutes, commercially available methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (80.1 mg, 0.52 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 3 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into a Petition 870190098905, of 10/03/2019, p. 65/90 55/74 ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 50 ml). The combined extracts were sequentially washed with saturated aqueous NaHCO3 (50 ml) and brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product was used for the bit deprotection step to obtain 10. For the bit deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 ml) was added slowly to the stirring solution. The reaction mixture was stirred for 3 hours at which point TLC showed the completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown solid (10). The solid product was subjected to flash chromatography (n-hexane / EtOAc 8: 2) to provide pure 10. Yield - 0.20 gm, 83% in 2 steps. 1 H NMR (DMSO, 400 MHz): δ 9.72 (1H, s), 8.09 (1H, t, J = 5.6 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.27 (1H, d, J = 2.0), 7.19 (1H, d, J = 2.0), 7.03 (1H, dd, J = 4.0, 1.6 Hz), 7.00 (1H, t, J = 2.0 Hz) , 6.84 (1H, d, J = 2.0 Hz), 6.10 (1H, m), 3.89 (3H, s). m / z (+ EI) calc. for C25H26N6O4 (M) + 474.51 found 475.35 ([M + H] + (e) NHBoc / / 11a 11 Methyl 4- (4- (4-Aminophenyl) -1-methyl-1 H-pyrrol-2-carboxamido) -1-methyl-1 H-imidazole-2carboxylate (11) [0247] 0.3 gm of boc protected 6 (0.94 mmol, 1.2 eq) was dissolved in DMF (5 ml), in which 2.0 eq of EDCI and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The mixture of Petition 870190098905, of 10/03/2019, p. 66/90 The reaction was allowed to stir for an additional 6 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined extracts were sequentially washed with saturated aqueous NaHCOs (50 ml), water (50 ml), brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 11a (0.48 gm) was used for the bit deprotection step to obtain 11. For the bit deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed the completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown solid (11). The solid product was subjected to flash chromatography (n-hexane / EtOAc 9: 1) to provide pure 11. Yield - 0.35 gm, 81% in two stages. 1 H NMR (DMSO, 400 MHz): 9.75 (1H, s), 8.03 (1H, s), 7.71 (2H, d, J = 8.8 Hz, 7.53 (1H, s), 7.52 (1H, s), 7.48 (2H, d, J = 8.8 Hz), 7.42 (1H, s), 7.19 (1H, d, J = 2.0 ), 3.94 (3H, s), 3.91 (3H, s), 3.89 (3H, s). M / z (+ EI) calc. For C18H19N5O3 (M) + 353.38 found 354, 42 ([M + H] + (f) Acid 4- (10- (allyloxycarbonyl) -7-methoxy-5-oxo-11 - (tetrahydro-2H-pyran-2yl0xi) -2,3,5,10 , 11,11a-hexahydro-1H-pyrrolo [2,1-c] [1,4] -benzodiazepine-8yloxy) butanoic (13) [0248] A 0.5 M solution of NaOH (made of 1.4135 g of NaOH) was added to a solution of 12 (Compound 18, WO 2007/039752) in dioxane at room temperature. The reaction mixture was allowed to stir for 4 hours in which Petition 870190098905, of 10/03/2019, p. 67/90 57/74 TLC point showed completion of the reaction. Dioxane was evaporated under high vacuum and the residue was diluted with water. The resulting solution was acidified with citric acid M followed by extraction with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure. Yield - 8.7 g, (94%), 1 H NMR (400 MHz, CDCl3): δ 7.2 (2H, s), 6.90 (1H, s), 6.58 (1H, s), 5.85 (2H, d, J = 9.2 Hz), 5.73 (2H, d, J = 9.2 Hz), 5.03 - 5, 13 (m, 6H), 4.68 - 4.35 (m, 4H), 4.09 - 4.01 (m, 4H), 3.91 - 3.82 (m, 8H), 3.69 - 3.46 (m, 8H ), 2.60 - 2.55 (m, 4H), 2.18 - 2.00 (m, 10H), 1.76 - 1.55 (m, 4H), 1.53 - 1.43 (m, 8H); 13 C NMR (100 MHz, CDCl3): δ 177.6, 167.6, 149.8, 132.1, 131.9, 126.7, 117.3, 114.9, 110.8, 100.7, 96.0, 91.7, 88.5, 67.9, 66.6, 63.6, 60.1, 56.1, 46.5, 31.1, 30, 3, 28.8, 25.2, 24.1, 23.2, 20.0; EIMS m / z (+ EI) calc. for C26H34N2O9 (M) + 518.56 found 519.26 (M + H) + (g) 4 - [[4 - [[4- (4-Aminophenyl) -1-methyl-pyrrole-2-carbonyl] amino] Methyl -1-methyl-imidazole-2-carbonyl] amino] -1-methyl-pyrrole-2-carboxylate (19) OH NHBoc [0249] Lithium hydroxide (40 mg, 1.65 mmol, 3 eq) was added to 11a (0.25 g, 0.55 mmol) in aqueous dioxane (8 ml dioxane, 4 ml water) at room temperature . The reaction mixture was stirred for 3 hours at which point TLC showed the completion of the reaction. Dioxane was evaporated under high vacuum and the residue was diluted Petition 870190098905, of 10/03/2019, p. 68/90 58/74 with water. The resulting solution was acidified with 1 M citric acid followed by extraction with ethyl acetate (2 x 50 ml). The combined organic layer and washed with brine (50 ml), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure to obtain the hydrolyzed acid form 17 as a white solid (0.235 g, 97% yield) which was used for the next reaction without any further purification. To a stirring solution 17 (0.235 gm, 0.54 nmol) in DMF, 2.0 equivalents of EDCI and 2.5 equivalents of DMAP was added. After stirring the mixture for 20 minutes, commercially available methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (100.00 mg, 0.54 mmol, 1.2 eq) was added. The reaction mixture was allowed to stir for an additional 3 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts were sequentially washed with saturated aqueous NaHCO3 (50 ml) and brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product was used for the bit deprotection step to obtain 18 which was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 ml). added slowly to the stirring solution. The reaction mixture was stirred for 3 hours at which point TLC showed the completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown solid (19). The solid product was subjected to flash chromatography (n-hexane / EtOAc 8: 2) to provide 19 pure. Yield 0.22 gm, 85% over 2 stages. 1 H NMR (DMSO, 400 MHz): 10.09 (1H, s), δ 9.89 (1H, s), 7.78 (2H, d, J = 8.8), 7.68 (1H , s), 7.49 (2H, d, J = 8.64), 7.35 (1H, d, J = 1.6), 7.21 (1H, d, J = 2.0 Hz), 7.15 (1H, d, J = 2.0 Hz), 3.97 (6H, s), 3.90 (3H, s), 3.84 (3H, s) m / z (+ EI) calc . for C23H23N7O4 (M) + 461.47 found 462.17 ([M + H] + Petition 870190098905, of 10/03/2019, p. 69/90 59/74 Example 1 15a-d, g 16a-d, THEQ 2 15 / 16a * 5 MPB / ___N OMe Í / H 0 15 / 16b * 8 MPB-MPB The v/ ^ OMepAn 15 / 16c 9 MPB-Py 0 / ~~ OMe / Η / == / r N v / N ^ V ^ ill ° 15 / 16d 11 MPB-Im 0 / HN ^ / ^ 0Me r / N v x Petition 870190098905, of 10/03/2019, p. 70/90 60/74 15 / 16g 10 MPB-Py-Py 0 0 OMe \ z— N / H Ãq H 0 15 / 16h 19 MPB-Py-Im 0 0 \ / OMe \ z— N r N / n ^ vL * comparative examples (a) 4- (4- (4- (7-Metoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo [2,1-c] [1,4] benzodiazepine-8-yloxy) butanamido) phenyl) -1 (methyl) -1-methyl-1H-pyrrole-2-carboxylate (16a) (i) 7-methoxy-8- (4- (4- (5- ( methoxycarbonyl) -1-methyl-1H-pyrrol-3-yl) phenylamino) -4oxobutoxy) -5-oxo-11- (tetrahydro-2H-pyran-2-yloxy) -2,3,11,11a-hexa -hydro-1Hpirrolo [2,1-c] [1,4] -benzodiazepine-10 (5H) -carboxylate (11aS) -alyl (15a) [0250] A solution of PBD acid protected by Alloc-THP 13 (3.72 g, 7.16 mmols, 1.2 equivalent) was dissolved in DMF. EDCI (2.49 g, 13.02 mmols, 2.0 eq) and DMAP (1.989 g, 16.28 mmols, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to stir for 30 minutes after the MPB-ester 7 (1.5 g, 6.514 mmols, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 2 hours at which point TLC showed the completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined extracts were sequentially washed with citric acid (200 ml), saturated aqueous NaHCO3 (250 ml), water (250 ml), brine (250 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by Petition 870190098905, of 10/03/2019, p. 71/90 61/74 rotary evaporator under reduced pressure and the crude product was purified by flash silica gel chromatography (MeOH: CHCl3, 20:80) to provide a white foamy solid, 15a. Yield - 4.05 g, 85.5%. (FTIR, Vmax / cm -1 ): 2949, 2362, 1704, 1600, 1514, 1436, 1372, 1269, 1203, 1107, 1021, 964, 765. ( 1 H NMR, 400 MHz, CDCL): δ 7 , 82 (1H, s), 7.48 (2H, m), 7.41 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 2.4 Hz), 7 , 23 (2H, d, J = 8.4 Hz), 7.17 (1H, d, J = 2.0 Hz), 7.04 (1H, d, J = 2.0 Hz), 5.93 - 5.65 (2H, m), 5.09 - 5.4.97 (m, 4H), 4.68 - 4.32 (m, 4H), 4.15 - 4.10 (m, 4H) , 3.94 - 3.82 (m, 12H), 3.68 (m, 2H), 3.59 - 3.49 (m, 6H), 2.60 - 2.57 (m, 3H), 2 , 15 - 2.00 (m, 8H), 1.88 - 1.80 (m, 2H), 1.79 - 1.70 (6H), 1.60 - 1.44 (m, 12H); ( 13 C NMR, 100 MHz, CDCl3): δ 177.1, 170.5, 167.3, 161.6, 149.1, 136.3, 132.1, 131.9, 130.4, 128.9, 127.1, 125.9, 125.4, 123.5, 123.1, 120.3, 117.3, 114.6, 110.8, 91.5, 88.6, 68.2, 66.5, 64.3, 63.6, 60.3, 56.0, 51.1.46.4, 36.8, 31.1,30,9, 29, 1, 25,1,24,6, 23.2, 21.0, 20.1; m / z (+ EI) calc. for C39H46N4O10 (M) + 730.80 found 731.67 ([M + H] + (ii) 4- (4- (4- (7-Metoxy-5-oxo-2,3,5,11a-tetra- (S) -methyl hydroxy-1H-pyrrolo [2,1-c] [1,4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1H-pyrrole-2-carboxylate (16a) [0251] Palladium tetracis [triphenylphosphine] (5.60 mg, 4.8 pM, 0.05 equiv) was added to a solution of Alloc-THP-PBD 15a conjugate (70 mg, 0.097 mmol), pyrrolidine (8 , 36 mg, 0.117 mmol, 1.2 eq) and triphenylphosphine (8.62 mg, 0.25 equiv) in DCM (5 ml). The reaction mixture was stirred at room temperature for 2 hours at which point TLC showed the completion of the reaction. The excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue vacuum dried to remove pyrrolidone. The product was purified by column chromatography (eluted with 65% n-hexane, 35% EtOAc) to provide the product as a yellowish solid, 3.37 (40 mg, 77%). [a] 22.7 D + 165 ° (c = 0.046, CHCl3); IR (FTIR, v max / cm -1 ): 3297, 2944, 2358, 1701, 1598, 1567, 1508, 1442, 1374, 1264, 1212, Petition 870190098905, of 10/03/2019, p. 72/90 62/74 1181, 1106, 1072, 824, 730; 1 H NMR (500 MHz, CDCl 3): δ 7.68 (1H, s), 7.65 (1H, d, J = 4.5 Hz, H-11), 7.52 (1H, s, H -6), 7.46 (2H, dd, J = 8.4, 2.0 Hz, 2Ar-H), 7.40 (2H, dd, J = 8.4, 2.0 Hz, 2Ar-H ), 7.16 (1H, d, J = 2.0 Hz, Py-H), 7.03 (1H, d, J = 1.6 Hz, Py-H), 6.82 (1H, s, H-9), 4.12 - 4.20 (2H, m, CH2 side chain linker), 3.94 (3H, s, N-CH3), 3.88 (3H, s, O-CH3), 3.68 - 3.71 (1H, m, H-11a), 3.50 - 3.60 (2H, m, H2 - 3), 2.58 - 2.62 (2H, m, CH2), 2 , 26 - 2.31 (4H, m, CH2), 1.50 - 1.54 (2H, m, CH2); 13 C NMR (125 MHz, CDCh): δ 164.5, 162.4, 161.6, 150.5, 147.8, 140.7, 125.9, 125.5 (2C), 123.6 , 123.1, 120.3, 114.6, 111.8, 111.0, 94.4 (2C), 68.0, 63.7, 56.1, 53.7, 51.0, 46, 6, 36.8, 31.9, 29.6, 25.2, 24.8, 24.1, 20.2; HRMS m / z (+ EI) calc. for C30H32N4O6 (M + H) + 545.2400 found 545.2422 (M + H) + , δ 4ppm [0252] Compounds 15b-d, g, h and 16b-d, g, h were made in an analogous manner, with compound A reacting with 13, followed by deprotection. (b) 4- (4- (4- (4- (4- (7-Metoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo [2,1-c] [1 , 4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1H-pyrrole-2-carboxamido) phenyl) -1 (S) -methyl (16b) methyl-1H-pyrrole-2-carboxylate (16b) [0253] [a] 22 ' 7 D + 134 ° (c = 0.038, CHCl3); IR (FTIR, Vmax / cm -1 ): 3850.89, 3732, 3619, 2443, 2354, 2228, 2169, 2091, 1971, 1859, 1729, 1679, 1521, 1265, 734, 629; 1 H NMR (500 MHz, CDCh): δ 7.72 (1H, s, NH), 7.69 (1H, s, NH), 7.66 (1H, d, J = 4.0 Hz, H -11), 7.57 (2H, d, J = 8.0 Hz, 2Ar-H), 7.53 (1H, s, H-6), 7.46 (4H, d, J = 8.0 Hz, 4Ar-H), 7.41 (2H, d, J = 8.0 Hz, 2Ar-H), 7.20 (1H, d, J = 2.0 Hz, Py-H), 7.06 (1H, d, J = 2.0 Hz, Py-H), 7.02 (1H, d, J = 1.6 Hz, Py-H), 6.92 (1H, s, Py-H), 6.84 (1H, s, H-9), 4.12 - 4.20 (2H, m, CH2 side chain linker), 4.00 (3H, s, W-CH3), 3.96 (3H , s, N-CHs), 3.88 (3H, s, O-CH-3), 3.84 (3H, s, O-CH3), 3.70 - 3.73 (1H, m, H- 11 a), 3.55 - 3.61 (2H, m, H2-3), 2.58 - 2.62 (2H, m, CH2), 2.29 - 2.31 (2H, m, CH2) , 1.93 2.06 (4H, m, CH2); 13 C NMR (125 MHz, CDCh): δ 164.5, 162.4, 161.7, 150.7, 147.3, 139.2, 126.0, 125.6, 125.4 (2C), 125.2 (2C), 123.0, 120.4 (2C), 114.6 (2C), 111.4, 94.6 (2C), 68.3, 63.7, 56.1, 51.6 (2C), 41.0, 36.9, 31.9, 29.6, 25.2, 24, 2, 24.1, Petition 870190098905, of 10/03/2019, p. 73/90 63/74 20.2; HRMS m / z (+ EI) calc. for C42H42N6O7 (M + H) + 743.3193 found 743.3193 ([M + H] + , δ 0.3 ppm) (c) 4- (4- (4- (4- (7-Met0xi-5- oxo-2,3,5,11 a-tetrahydro-1H-pyrrolo [2,1-c] [1,4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1 H-pyrrole- (S) -methyl (16c) 2-carboxamido) -1-methyl1H-pyrrole-2-carboxylate (16c) [0254] [o] 22 ' 7 d + 128 ° (c = 0.037, CHCb); IR (FTIR, Vmax / cm -1 ): 3321, 2237, 2107, 2041, 1967, 1860, 1685, 1517, 1435, 1254, 1180, 1118, 749, 722, 696, 667; 1 H NMR (500 MHz, CDCb): δ 7.98 (1H, s, NH), 7.88 (1H, s, NH), 7.68 (1H, s, H6), 7.65 (1H , d, J = 4.0 Hz, H-11), 7.64 (2H, d, J = 8.0 Hz, 2Ar-H), 7.54 (1H, d, J = 1.6 Hz, Py-H), 7.52 (1H, d, J = 1.6 Hz, Py-H), 7.45 (1H, d, J = 2.0 Hz, Py-H), 7.33 (2H , d, J = 8.0 Hz, 2Ar-H), 6.97 (1H, s, Py-H), 6.89 (1H, s, H-9), 4.08 - 4.18 (2H , m, CH2), 3.97 (3H, s, N-CH3), 3.89 (3H, s, N-CH-3), 3.84 (3H, s, O-CH3), 3.79 (3H, s, O-CH3), 3.66 - 3.70 (1H, m, H-11 a), 3.55 - 3.60 (2H, m, H2-3), 2.56 - 2 , 61 (2H, m, CH2), 2.23 2.32 (4H, m, CH2), 2.00 - 2.05 (2H, m); 13 C NMR (125 MHz, CDCI3): δ 162.5, 161.6, 159.1, 150.4, 147.7, 138.4, 132.8, 132.1 131.9 (2C), 128.6, 128.4 (2C), 125.4 (2C), 124.8, 123.0, 121.0, 120.4 (2C), 116.2, 114.6 (2C), 109.9, 94.2, 67.4, 63.6, 57.1, 53.7, 51.1, 46.7, 36.9, 36.7, 34.0, 29.6, 24.2; HRMS m / z (+ EI) calc. for C36H38N6O7 (M) + 667.2880 found 667.2881 ([M + H] + , δ 0.1 ppm) (d) 4- (4- (4- (4- (7-Methoxy-5-oxo- 2,3,5 ! 11 α-tetrahydro-1H-pyrrolo [2,1-c] [1,4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1 H-pyrrole-2- (S) -ethyl (16d) -1-methyl1H-imidazole-2-carboxylate (16d) [0255] [o] 22 ' 7 d + 122 ° (c = 0.028, CHCh), IR (FTIR, Vmax / cm -1 ): 3324, 2355, 2157, 2109, 2032, 1913, 1600, 1533, 1465, 1262 , 1179, 1109, 751; 1 H NMR (500 MHz, CDCl3): δ 8.47 (1H, s, NH), 7.72 (1H, s, NH), 7.66 (1H, d, J = 4.0 Hz, H -11), 7.55 (1H, s, H-6), 7.52 (1H, d, J = 2.0, Py-H), 7.49 (2H, d, J = 8.0 Hz , 2Ar-H), 7.37 (2H, d, J = 8.0 Hz, 2Ar-H), 7.16 (1H, d, J = 1.6 Hz, Py-H), 7.03 ( 1H, s, Im-H), 6.91 (1H, s, H-9), 4.39 - 4.43 (2H, m, O-CH2) 4.13 - 4.22 (2H, m, CH2), 4.01 (3H, s, N Petition 870190098905, of 10/03/2019, p. 74/90 64/74 CH3), 3.99 (3H, s, N-CH-3), 3.83 (3H, s, O-CH3), 3.68 - 3.72 (1H, m, H-11a), 3, 55 3.60 (2H, m, H2-3), 2.58 - 2.63 (2H, m, CH2), 2.24 - 2.32 (4H, m, CH2), 2.00 - 2, 07 (2H, m, H2-1), 141 - 1.45 (3H, m, CH3); 13 C NMR (125 MHz, CDCI3): δ 163.1, 162.5, 158.7, 150.4, 147.7, 140.7, 137.2, 131.5, 125.6 (2C), 125.4 (2C), 123.8, 123.0, 120.4 (2C), 114.5, 111.6, 110.8, 109.9, 100.0, 67.4, 61.5, 56.1, 53.7, 51.1, 46.7, 37.0, 36.0, 34.0, 29.6, 24.8, 24.2, 14.4; HRMS m / z (+ EI) calc. for C36H39N7O7 (M) + 682.2989 found 682.2986 ([M + H] + , δ - 0.4 ppm). (e) 4- (4- (4- (4- (4- (7-Metoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo [2,1-c] [1 , 4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1 H-pyrrole-2-carboxamido) -1-methyl1H-pyrrole-2-carboxamido) -1-methyl-1H-pyrrole-2-carboxylate of (S) -methyl (16g) [0256] [a] 22 ' 7 D + 149 ° (c = 0.054, CHCU); IR (FTIR, Vmax / cm -1 ): 3310, 2947, 2358, 2168, 2153, 2132, 2070, 2011, 1989, 1651, 1538, 1434, 1402, 1257, 1107, 753; 1 H NMR (400 MHz, CDCl3): δ 8.02 (1H, s, NH), 7.88 (1H, d, J = 5.2 Hz, H11), 7.68 (1H, s, H -6), 7.67 (1H, d, J = 1.6 Hz, Py-H), 7.64 (1H, d, J = 1.6 Hz, Py-H), 7.53 (2H, d, J = 8.0 Hz, 2Ar-H), 7.45 (1H, d, J = 1.6 Hz, Py-H), 7.31 (2H, d, J = 8.0 Hz, 2Ar -H), 7.20 (1H, s, Py-H), 6.96 (1H, s, Py-H), 6.89 (1H, bs, NH), 6.81 (1H, s, H9 ), 6.78 (1H, d, J = 1.6 Hz, Py-H), 6.71 (1H, bs, NH), 4.11 - 4.16 (2H, m, CH2), 3, 97 (3H, s, N-CH3), 3.92 (3H, s, N-CH-3), 3.88 (3H, s, N-CH-3), 3.84 (3H, s, N -CH-3), 3.79 (3H, s, O-CH3), 3.68 - 3.71 (1H, m, H-11a), 3.55 - 3.60 (2H, m, H2- 3), 2.56 - 2.61 (2H, m, CH2), 2.22 - 2.28 (4H, m, CH2), 1.99 - 2.04 (2H, m); HRMS m / z (+ EI) calc. for C41H43N9O8 (M) + 790.3313 found 790.3314 [M + H] + , δ 0.1 ppm. (f) 4- (4- (4- (4- (4- (7-Methoxy-5-oxo-2,3,5 ! 11a-tetrahydro-1H-pyrrolo [2,1-c] [1 , 4] benzodiazepine-8-yloxy) butanamido) phenyl) -1-methyl-1 H-pyrrole-2-carboxamido) -1-methyl1H-imidazole-2-carboxamido) -1-methyl-1H-pyrrole-2-carboxylate (S) -methyl (16h) [0257] [«] 22 ' 7 d + 142 ° (c = 0.043, CHCl3); IR (Vmax cm -1 ): 3408, 2358, 2168, 2148, 2019, 1978, 1938, 1718, 1534, 1260, 1118, 757; 1 H NMR (500 MHz, CDCl3): δ 8.72 (1H, s, NH), 8.12 (1H, s, NH), 7.71 (1H, s), 7.65 (1H, d , J = 4.4 Hz), Petition 870190098905, of 10/03/2019, p. 75/90 65/74 7.53 (1H, s), 7.48 (2H, d, J = 8.0 Hz), 7.47 (1H, s), 7.42 (2H, d, J = 1.6 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.03 (1H, d, J = 1.6 Hz), 6.95 (1H, s), 6.82 (1H, s), 6.81 (1H, d, J = 1.6 Hz,), 4.12 - 4.21 (2H, m), 4.07 (3H, s), 4.00 (3H, s), 3.91 (3H, s), 3.89 (3H, s), 3.81 (3H, s), 3.69 - 3.72 (1H, m), 3.55 - 3.61 (2H, m), 2.58 - 2.63 (2H, m) , 2.26 - 2.32 (4H, m, CH2), 2.02 - 2.07 (2H, m,); HRMS (EI, m / z): Calc. for C41H43N9O8 (MH +): 790.3313. Found, 790.3314. Example 2 HO 14a, b 15e, f Q 1 14a N OHThe 14b OH Q 2 15/16 Py-MPB N OMe fi 0 Petition 870190098905, of 10/03/2019, p. 76/90 66/74 (a) (i) 4- (4 - (((11S, 11aS) -10 - (((allyloxy) carbonyl) -7-methoxy-5-oxo-11 - acid ((tetrahydro-2H-pyran-2-yl ) oxy) -2 ! 3 ! 5,10 ! 11,11a-hexahydro-1H-benzo [e] pyrrolo [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) -1- methyl-1H-pyrrole-2-carboxylic (14a) [0258] A solution of Alloc-THP 13 protected PBD acid (1.85 g, 3.57 mmols, 1.2 equivalent) was dissolved in DMF. EDCI (1.24 g, 6.48 mmols, 2.0 eq) and DMAP (0.99 g, 8.1 mmols, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was left stir for 30 minutes after which 4 methyl amino-1- methyl-1H- pyrrole-2- carboxylate (0.5 g, 3.243 mmols, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 6 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined extracts were sequentially washed with citric acid (200 ml), saturated aqueous NaHCO3 (250 ml), water (250 ml), brine (250 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product (1.88 gm) was used by hydrolysis reaction to obtain 14a. For hydrolysis, lithium hydroxide (0.24 g, 5.71 mmols, 3 eq) was added to the crude product (1.88 g, 2.87 mmols) in aqueous dioxane (75 ml of dioxane, 11.5 ml water) at room temperature. The reaction mixture was stirred for 3 hours at which point TLC showed the completion of the reaction. Dioxane was evaporated under high vacuum and the residue was diluted with water. The resulting solution was acidified with 1 M citric acid followed by extraction with ethyl acetate (2 x 100 ml). The layer Petition 870190098905, of 10/03/2019, p. 77/90 67/74 combined organic and washed with brine (100 mL), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure to obtain 14a as a white solid (yield, 1.68 gm, 74.0% over 2 steps ). 1 H NMR δ 9.09 (1H, s, NH), 7.39 (1H, d, J = 2.0 Hz), 7.14 (1H, s, H-6), 7.12 (1H , s, H-6), 6.96 (1H, s, H-9), 6.76 (1H, d, J = 2.0 Hz, Py-H), 5.86 - 5.75 (2H , m, H-11), 5.13 - 4.84 (3H, m), 4.61 - 4.21 (2H, m), 4.06 - 3.88 (3H, m, H-1 of side chain, H-6 pyran), 3.87 (3H, s, O / NCH3), 3.87 (3H, s, O / NCH3), 3.86 (3H, s), 3.53 - 3, 44 (3H, m), 2.55 - 2.45 (2H, m), 2.13 - 1.88 (6H, m), 1.70 - 1.39 (6H). m / z (+ EI) calc. for C32H40N4O10 (M) + 640.68 found 641.57 ([M + H] + (ii) 7-Methoxy-8- (4 - ((5 - ((4- (5- (methoxycarbonyl) -1-methyl -1 H-pyrrol-3-yl) phenyl) carbamoyl) -1-methyl-1 H-pyrrol-3-yl) amino) -4-oxobutoxy) -5-oxo-11 - ((tetrahydro-2H- pyran2-yl) oxy) -2,3,11,11a-tetrahydro-1H-benzo [e] pyrrolo [1,2-a] [1,4] diazepine-10 (5H) (11S, 11aS) carboxylate ) -alyl (15e) [0259] A solution of PBD-Py acid protected by Alloc-THP 14a (150 mg, 0.23 mmol, 1.0 equivalent) was dissolved in DMF. EDCI (2.49 g, 13.02 mmols, 2.0 eq) and DMAP (1.989 g, 16.28 mmols, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to stir for 30 minutes after the MPB-ester 7 (67.83 mg, 0.29 mmol, 1.25 eq) was added. The reaction mixture was allowed to stir for an additional 3 hours at which point TLC showed completion of the reaction. The reaction was cooled quickly by pouring into an ice / water mixture and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined extracts were sequentially washed with citric acid (50 ml), saturated aqueous NaHCO3 (50 ml), water (50 ml), brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product was used directly in the next step without further purification. m / z (+ EI) calc. for C45H52N6O11 (M) + 852.93 found 854.87 ([M + H] + Petition 870190098905, of 10/03/2019, p. 78/90 68/74 (iii) 4- (4- (4- (4- (7-Methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo [2,1-c] [1 , 4] - (S) -methyl (16e) - benzodiazepine-8-yloxy) butanamido) -1-methyl-1 H-pyrrol-2-carboxamido) phenyl) -1-methyl1H-pyrrole-2-carboxylate (16e) [0260] Palladium tetracis [triphenylphosphine] (12.17 mg, 10.5 μΜ, 0.05 equiv) was added to a solution of Alloc-THP-PBD 15e conjugate (179 mg, 0.21 mmol), pyrrolidine (17.91 mg, 0.25 mmol, 1.2 eq) and triphenylphosphine (13.81 mg, 0.25 equiv) in DCM (5 ml). The reaction mixture was stirred at room temperature for 2 h at which point TLC showed the completion of the reaction. The excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue vacuum dried to remove pyrrolidone. The product was purified by high performance liquid chromatography (eluted with gradient of acetone: water with 1% TFA) to provide the product as a light yellowish solid, 16e (48 mg, 34% after purification by HPLC). [0261] [o] 22 ' 7 d + 197 ° (c = 0.052, CHCh), IR (FTIR, Vmax / cm -1 ): 3330, 2360, 2214, 2180, 2041, 2020, 1999, 1967, 1698, 1517, 1438, 1265, 1180, 1119, 756, 722, 696, 667, 630; 1 H NMR (500 MHz, CDCh): δ 7.77 (1H, s, NH), 7.68 (1H, s, H-6), 7.67 (2H, d, J = 8.0 Hz , 2Ar-H), 7.64 (1H, d, J = 5.0 Hz, H-11), 7.55 (2H, d, J = 8.0 Hz, 2Ar-H), 7.47 ( 1H, d, J = 2.0 Hz, Py-H), 7.43 (1H, s, NH), 7.18 (1H, d, J = 2.0 Hz, Py-H), 7.09 (1H, d, J = 2.0 Hz, Py-H), 7.05, (1H, d, J = 2.0 Hz, Py-H), 6.83 (1H, s, H9), 4 , 09 - 4.16 (2H, m, CH2), 3.95 (3H, s, N-CH3), 3.90 (6H, s, A / -CH-3, O-CH3), 3.84 (3H, s, O-CH3), 3.67 - 3.71 (1H, m, H-11a), 3.54 - 3.57 (2H, m, H2-3), 2.53 - 2, 56 (2H, m, CH2), 2.23 - 2.30 (4H, m, CH2), 2.00 - 2.05 (2H, m); 13 C NMR (125 MHz, CDCl3): δ 169.8, 164.5, 162.6, 161.6, 159.5, 150.7, 147.9, 140.8, 133.1, 132, 2, 132.1, 131.9, 131.7, 128.5, 128.4, 125.9, 125.5, 123.7, 123.1, 121.5, 120.7, 120.4, 119.7, 114.7, 112.0, 111.4, 103.9, 68.1.56.2, 53.7, 51.0, 46.7, 36.8, 33.2, 29, 6, 25.1, 24.1; HRMS m / z (+ EI) calc. for C36H38N6O7 (M) + 667.2880 found 667.2882 ([M + H] + , δ 0.3 ppm). Petition 870190098905, of 10/03/2019, p. 79/90 69/74 [0262] Compounds 14b, 15f and 16f, were made in an analogous manner, reacting compound 13 with the imidazolyl building block, followed by reaction with the MPB building block and finally by deprotection. (b) 4- (4- (4- (4- (7-Metoxy-5-oxo-2,3,5,11 a-tetrahydro-1H-pyrrolo [2,1-c] [1,4 ] benzodiazepine-8-yloxy) butanamido) -1-methyl-1 H-imidazol-2-carboxamido) phenyl) -1 (S) -methyl (16f) methyl-1H-pyrrole-2-carboxylate (16f) [0263] [o] 22 ' 7 d + 188 ° (c = 0.052, CHCh), IR (FTIR, Vmax / cm -1 ): 3301, 2169, 2136, 2018, 1978, 1937,1680, 1564, 1518, 1439, 1265, 1181, 1108, 750, 722; 1 H NMR (500 MHz, CDCh): δ 8.90 (1H, s, NH), 7.98 (1H, s, NH), 7.67 (1H, s, H-6), 7.63 (1H, d, J = 4.4 Hz, H-11), 7.59 (2H, d, J = 8.4 Hz, 2Ar-H), 7.46 (2H, d, J = 8.4 Hz, 2Ar-H), 7.42 (1H, s, Im-H), 7.19 (1H, d, J = 2.0 Hz, Py-H), 7.06 (1H, d, J = 1.6 Hz, PyH), 6.83 (1H, s, H-9), 4.10 - 4.22 (2H, m, CH2), 4.07 (3H, s, N-CH3), 3 , 96 (6H, s, NCH-3, O-CH3), 3.84 (3H, s, O-CH3), 3.67 - 3.70 (1H, m, H-11a), 3.54 - 3.58 (2H, m, H2-3), 2.57 - 2.67 (2H, m, CH2), 2.26 - 2.31 (4H, m, CH2), 1.98 - 2.05 (2H, m); 13 C NMR (125 MHz, CDCh): δ 169.5, 164.5, 162.5, 161.6, 156.4, 150.4, 147.8, 135.6, 132.1, 131, 9 (2C), 128.5, 128.4, 126.0, 125.6, 123.5, 123.1, 121.5, 119.7, 114.6 (2C), 111.6, 111, 0, 67.7, 56.1, 53.7, 51.1, 46.6, 36.9, 35.8, 33.9, 29.6, 24.7, 24.1; HRMS m / z (+ EI) calc. for C35H37N7O7 (M) + 668.2833 found 668.2838 [M + H] + , δ 0.5 ppm. Example 3 [0264] The potential cytotoxicity of the compounds of the invention 16c-h was compared with the comparative compounds 16a, 16b and GWL-78 in various tumor cell lines and the non-cancer cell line WI38 after 96 hours of exposure using the colorimetric assay of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide), as described below. [0265] A panel of several types of human cancer cell lines including epidermoid (A431), lung (A549), ovary (A2780) and breast (MCF7 and Petition 870190098905, of 10/03/2019, p. 80/90 70/74 MDAMB-231), as well as WI38 non-tumor cell lines, were used to determine the cytotoxicity of the compounds. The cells were grown under normal conditions at 37 ° C under a humidified atmosphere of 5% CO2, in Dulbecco's Modified Eagle's Medium or Modified Eagle's Medium (depending on cell line), supplemented with 10% fetal bovine serum (Biosera, UK ), 1% L-glutamine, 1% non-essential amino acids and 0.05% hydrocortisone (Gibco, Invitrogen, USA). The cells were then seeded in 96-well plates in a total volume of 160 pl, and allowed to reach a degree of 30 to 40% confluence before starting the experiment. The binders were dissolved in sterile ultrapure water at a maximum concentration of 100 pM, and serial serial dilutions were prepared. These were added to the cells in a volume of 40 pl. After 96 hours of continuous exposure to each binder, cytotoxicity was determined by the colorimetric assay of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (Lancaster Synthesis Ltd, UK) ( Skehan P, SR, et al., Journal of the National Cancer Institute 1990, 82, 1107). The absorbance was quantified by spectrophotometry at λ = 570 nm (ELx808, Bio-Tek Instruments, Inc., USA). IC50 values were calculated by dose-response analysis using Origin 6.0 TM software. IC50 (nM) Compound A431 A549 A2780 MCF7 MDAMB-231 Mia Paca 2 WI38 16th * 2.31 7.50 1.87 1.91 2.11 1.2 159.9 16b * 2.91 0.54 0.56 0.90 0.46 0.35 158.7 16c 4.60 0.019 0.96 1.70 2.70 0.34 425.9 16d 0.19 0.47 0.15 0.37 0.45 0.11 1240 16e 0.0056 0.056 0.013 0.00002 0.000065 0.0013 473.8 16f 0.018 0.034 0.021 0.00002 0.00018 0.0021 129.2 16g 0.86 2.3 0.24 0.31 0.59 0.31 41.3 4 PM 03064 0.45 ND 0.075 0.015 0.25 65.6 GWL-78 * 0.55 6.1 0.57 0.32 0.12 2.4 41.3 * comparative compounds [0266] The potential for cytotoxicity of compounds of the invention 16c-h Petition 870190098905, of 10/03/2019, p. 81/90 71/74 was also compared with comparative compounds 16a, 16b and GWL-78 in a primary CLL cell line using the Annexin V assay (van Engeland, M, et al., Cytometry 1998, 31, 1 - 9), as described below. [0267] Freshly isolated peripheral blood CLL cells (1 χ 10 6 mL -1 ) were cultured in RPMI medium (Invitrogen, Paisley, UK) supplemented with penicillin (100 U / mL), streptomycin (100 mg / mL ), and 10% fetal calf serum. The cells were incubated at 37 ° C in a 5% humidified CO2 atmosphere in the presence of each compound. All compounds were dissolved in DMSO and were evaluated in serial dilutions against primary CLL cells. In addition, control cultures were performed so that no drugs were added. The cytotoxic effects of the compounds were quantified using an annexin V / propidium iodide flow cytometry assay (Bender Medsystems, Vienna, Austria). All assays were performed in duplicate, and LD50 values were calculated from sigmoidal dose response curves using the Prism 6.0 software (Graphpad Software Inc., San Diego, CA). The sigmoidal dose-response curves were derived by plotting log [compound concentration] against the percentage of apoptosis induced by this concentration. A wide range of concentrations was used to establish the biologically active range for each individual compound. Compound IC50 (nM) 16th * 6.2 16b * 4.7 16c 2.1 16d 3.0 16e 0.098 16f 0.17 16g 0.96 4 PM 0.037 GWL-78 * 1.3 Petition 870190098905, of 10/03/2019, p. 82/90 72/74 Example 4 [0268] 16e and 16f were tested in in vivo xenograft studies in mouse models of breast and pancreatic cancer. [0269] Initially a small-scale study was carried out to determine the BAT (maximum tolerated dose) in Swiss-Webster mice using intraperitoneal (IP) dosing. The compounds were generally well tolerated without any signs of toxicity. However, less weight loss was observed at a dose level of 400 pg / kg / day for 16e (Figure 1A). Some negligible weight loss to 16f was also seen at the same dose level. A repeated BAT experiment using only 16f at 350 pg / kg / day showed no weight loss or other signs of toxicity (Figure 1B). As 16f provided a marginally better toxicity profile in the BAT study, it was decided to conduct more extensive tumor xenograft studies in vivo on this molecule. MB 231 ER-Negative MDA Breast Cancer Xenograft Study [0270] In vivo studies of 16f activity were performed on an MDA MB 231 ER-negative breast cancer xenograft in a mouse model. The human breast cancer cell line MDA-MB-231 (5 x 10 6 cells) was used to establish xenografts on the flanks of female nude MF1 mice, 2 to 3 months old and weighing 20 to 25 g. The subsequent passage was by subcutaneous implantation of small tumor pieces (approximately 1 mm 3 ) in the flank. When the tumors reached approximately 0.06 cm 3 (three weeks after implantation) they were divided into 3 groups of 4 mice. The drug-treated groups were administered an IV dose (in DMSO) of 250 pg / Kg / day or 300 pg / Kg / day for 5 consecutive days followed by two drug-free days for 3 weeks, followed by 2 consecutive days in week 4 at which point dosing was stopped. As shown in Figure 2, 16f produced Petition 870190098905, of 10/03/2019, p. 83/90 73/74 prominent anti-tumor activity in vivo compared to control mice (A) at dose levels of 250 μg / kg (♦) and 300 μg / kg () without any signs of toxicity (Figure 2, where the arrow shows the last injected dose). The tumor did not grow again until 3 weeks after the last IV dose was administered in the case of the dose level of 300 μg / kg. Pancreatic Cancer Xenograft of Mia Paca 2 in Mouse Model [0271] An in vivo 16f study was performed on a mouse model with pancreatic cancer xenograft, in a similar manner as above. The drug-treated group (16f) was administered an IV dose of 300 μg / kg / day for 5 consecutive days followed by 2 drug-free days, and the cycle was continued for 3 weeks. 16f produced prominent anti-tumor activity compared to control mice at the dose level of 300 μg / kg without any signs of toxicity (Figure 3: ♦ 300 μg / kg 16f; control). The inability of the tumor to grow back immediately after drug withdrawal was notable and no growth was observed until 21 days after the last dose administered. The cross sections of tumor and control tissues were subjected to immunohistochemical staining, and the results were compatible with the inhibition of NFkB in experimental animals compared to controls. Example 5 [0272] 16f was evaluated in a commercial Assay TM Transcription Factor Activation Array (Signosis) using the HeLa cell line. In this assay, the activities of 48 transcription factors can be monitored simultaneously using a collection of biotin-labeled DNA probes based on the consensus sequences of individual transcription factor DNA binding sites. The top five transcription factors, whose activities were at least 30% down regulated by 7 am in a Petition 870190098905, of 10/03/2019, p. 84/90 74/74 concentration of 10 nM for 4 hours were: NFAT, EGR, NF-κΒ, SMAD and OCT-4. NF-kB activity was reduced by almost 50%. [0273] Based on the hypothesis that 16f can down-regulate the expression of NF-kB-dependent genes (eg IkB, BCL2, BCLXl) by binding to the NF-kB cognate DNA sequence, thereby blocking the interaction of the transcription factor protein and inhibiting the transcription of several genes, it was decided to explore this possibility in CLL cells, in which NF-kB signaling is known to be active and closely correlates with the initiation and progression of malignancy. Using levels of IkB and phosphorylated p65 as a substitute for NF-kB activity compared to Actin protein as a control, Western Blotting indicated that after 24 hours of incubation, 16f caused a significant suppression of phosphorylated ΙκΒα in concentrations up to 0.1 nM, with only a marginal effect on phosphorylated p65.
权利要求:
Claims (16) [1] 1. Compound CHARACTERIZED by the fact that it presents formula I: [2] 2/4 [3] 3. Composed, according to claim 2, CHARACTERIZED by the fact that groups A, X and Y are selected from CH and NMe; and N and NMe. [4] Compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that B is a single bond. [5] A compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that B is B1, and X and Y in B1 are selected from CH and NMe; and N and NMe. [6] A compound according to any one of claims 1 to 5, CHARACTERIZED by the fact that R7 is OR 7A , wherein R 7A is selected from Me, CH2Ph and allyl. [7] A compound according to any one of claims 1 to 6, CHARACTERIZED by the fact that R 10 and R 11 together form a double bond. [8] 8. Composed, according to claim 1, CHARACTERIZED by the fact Petition 870190098905, of 10/03/2019, p. 87/90 3/4 of which R 1 is methyl. [9] A compound according to any one of claims 1 to 8, CHARACTERIZED by the fact that R2 is selected from -H, = CH2, -R, = CHR e = CRR '. [10] A compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that R 2 is optionally substituted C5-20 aryl. [11] 11. Compound according to claim 10, CHARACTERIZED by the fact that R 2 is selected from 4-methoxy-phenyl, 3-methoxy-phenyl, 4-ethoxy-phenyl, 3-ethoxy-phenyl, 4-fluorophenyl, 4 -chloro-phenyl, 3,4-bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4-phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl , 2-furanyl, methoxynaphthyl and naphthyl. [12] 12. A compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that R 2 is selected from: (a) C1-5 saturated aliphatic alkyl; (b) C3-6 saturated cycloalkyl; (ç) [13] 13. A compound according to any one of claims 1 to 8, CHARACTERIZED by the fact that if R2 is selected from = O, = CH2, = CHR, = CHRR ', there is a simple link between C2 and C3. [14] 14. A compound according to any one of claims 1 to 8, CHARACTERIZED by the fact that there is no double bond between C2 and C3 and R 2 is H. [15] 15. Pharmaceutical composition CHARACTERIZED by the fact that it comprises a compound as defined in any one of claims 1 to 14, and a pharmaceutically acceptable carrier or diluent. [16] 16. Use of a compound as defined in any one of claims 1 to 14, CHARACTERIZED by the fact that it is in the manufacture of a medicament for the treatment of a proliferative disease.
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引用文献:
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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-03-20| B25C| Requirement related to requested transfer of rights|Owner name: SPIROGEN SARL (CH) , UCL BUSINESS PLC (GB) Free format text: A FIM DE ATENDER A TRANSFERENCIA, REQUERIDA ATRAVES DA PETICAO NO 860160061523 DE 18/03/2016, E NECESSARIO APRESENTAR A TRADUCAO JURAMENTADA DO DOCUMENTO, ALEM DA GUIA DE CUMPRIMENTO DE EXIGENCIA. Owner name: SPIROGEN SARL (CH) , UCL BUSINESS PLC (GB) | 2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2018-06-26| B25A| Requested transfer of rights approved|Owner name: UCL BUSINESS PLC (GB) ; MEDIMMUNE LIMITED (GB) | 2019-04-24| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI | 2019-07-09| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]| 2020-03-10| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2020-06-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/04/2013, OBSERVADAS AS CONDICOES LEGAIS. | 2022-02-22| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 9A ANUIDADE. |
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申请号 | 申请日 | 专利标题 US201261640310P| true| 2012-04-30|2012-04-30| PCT/GB2013/051098|WO2013164593A1|2012-04-30|2013-04-30|Pyrrolobenzodiazepines| 相关专利
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