PIRROLOBENZODIAZEPIN COMPOUND, ITS PHARMACEUTICAL COMPOSITION AND ITS USE

专利摘要:
abstract "pyrrolobenzodiazepines" the present invention relates to a compound of formula i: (i) or a salt or solvate thereof, wherein: 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; wherein r and r 'are independently selected from optionally substituted c1-7 alkyl, c3-20 heterocyclyl and c5-20 aryl; 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 , em is a pharmaceutically acceptable monovalent cation; a is selected from a1, a2, a3, a4 or a5: (a1) (a2) (a3) (a4) (a5) where x1 and y1 are selected from: ch and nh; ch and nme; n and nme; ch and s; n and s; n and o; and ch and o, respectively; x2 and y2 are selected from: ch and nh; ch and nme; n and nme; ch and s; n and s; n and o; and ch and o, respectively; z1 is selected from o and s; z2 is selected from ch and n; f is selected from a single bond and - (e-f1) m-; each e is independently selected from a single bond, and –c (= o) -nh-; each f1 is independently a c3-20 heteroarylene group; m is 1, 2 or 3; g is selected from hydrogen, c1-4 alkyl group, -c (= o) -o c1-4 alkyl, - (ch2) n-heterocycloalkyl c3-20, and –o- (ch2) n-heterocycloalkyl c3-20 ; each n is 0-4; since a2 is not a2 ': (a2'); wherein x1 and y1 of a2 'are selected from: ch and nme; coh and nme; ch and s; n and nme; n and s, respectively; and provided that a3 is not a3 ’: (a3’) where x2 and y2 of a3 ’are selected from: ch and nme; coh and nme; ch and s; n and nme; n and s, respectively; b is a single bond or: where x and y of b1 are selected from: ch and nme; coh and nme; ch and s; n and nme; n and s, respectively; and r1 is c1-4 alkyl.
公开号:BR112014027190B1
申请号:R112014027190-9
申请日:2013-04-30
公开日:2020-03-03
发明作者:Philip Wilson Howard；David Edwin Thurston；Khondaker Mirazur Rahman；Peter William Taylor
申请人:Medimmune Limited；Ucl Business Plc；
IPC主号:

专利说明:

“PYRROLOBENZODIAZEPIN COMPOUND, ITS PHARMACEUTICAL COMPOSITION AND ITS USE” [001] The present invention relates to pyrrolobenzodiazepines (PBDs) and, in particular, to PBD monomers and methods of synthesizing PBD monomers.
BACKGROUND OF THE INVENTION [002] Some pyrrolobenzodiazepines (PBDs) have the ability to recognize making connections to specific DNA sequences; the preferred sequence is PuGPu. The first antitumor PBD antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc., 87, 5,793 to 5,795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5,791 to 5,793 (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 to 465 (1994)). Family members include abeimicin (Hochlowski, et al., J. Antibiotics, 40, 145 to 148 (1987)), quicamycin (Konishi, et al., J. Antibiotics, 37, 200 to 206 (1984)), DC- 81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit., 26, 767 to 772 (1990); Bose, et al., Tetrahedron, 48, 751 to 758 (1992)), mazetramycin (Kuminoto , et al., J. Antibiotics, 33, 665 to 667 (1980)), neotramicins A and B (Takeuchi, et al., J. Antibiotics, 29, 93 to 96 (1976)), porotramycin (Tsunakawa, et al ., J. Antibiotics, 41, 1366 to 1373 (1988)), protracarcin (Shimizu, et al, J. Antibiotics, 35, 972 to 978 (1982); Langley and Thurston, J. Org. Chem., 52, 91 97 (1987)), sibanomycin (DC-102) (Hara, et al., J. Antibiotics, 41, 702 to 704 (1988); Itoh, et al., J. Antibiotics, 41, 1281-1284 (1988 )), sibiromycin (Leber, et al., J. Am. Chem. Soc., 110, 2992 to 2993 (1988)) and tomamycin (Arima, et al., J. Antibiotics, 25, 437 to 444 (1972) ). PBDs are of the general structure:
[003] They differ in the number, type and position of substituents,
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2/75 in both its aromatic A-rings and pyrrole C-rings, and the degree of ring C saturation. In ring B there is either an imine (N = C), a carbinolamine (NH-CH (OH)), or a methyl ether carbinolamine (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 position C11a that provides them with a right twist when viewed from ring C in the direction of ring A. This provides them with the appropriate three-dimensional shape for this helical with the groove smaller form B DNA, leading to a tight fit at the binding site (Kohn, in Antibiotics III. Springer-Verlag, New York, pages 3 to 11 (1975); Hurley and NeedhamVanDevanter, Acc. Chem. Res., 19 , 230 to 237 (1986)). Their ability to form an adduct in the minor groove allows them to interfere with DNA processing, therefore their use as anti-tumor agents. The synthesis of the compounds was reviewed in Thurston, D.E., et al., Chem. Rev., 1994, 94, 433 to 465 and Thurston, D.E., et al., Chem. Rev., 2011, 111, 2,815 to 2,864.
[004] The vast majority of antibiotics in current clinical use are derived from derivatives of bactericidal or bacteriostatic molecules produced as secondary metabolites by microbes, predominantly those belonging to molds and actinobacteria. The screening identified molecules such as tomamycin, anthramycin and DC-81 pyrrolobenzodiazepines (PBDs) that exerted potent antibacterial activity against human pathogens through an ability to bind to DNA; some of these compounds have potential as cancer chemotherapeutics, but a high degree of cytotoxicity has made them unattractive as antibacterial antibiotics compared to other classes of the compound.
[005] However, the evolution of multidrug-resistant pathogens with the ability to quickly and efficiently transmit antibiotic resistance determinants of gene encoding has facilitated the erosion of a relatively short period of time from much of the therapeutic value of agents
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3/75 frontline antibacterial chemotherapeutics. Increasing resistance to multiple drugs in Gram-negative pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii forced the reassessment of colistin for systemic use; this polymyxin antibiotic, observed more than fifty years ago and until recently considered too toxic for non-topical use, is now widely used systematically due to the limited therapeutic options for these infections.
[006] Several PBD conjugates with pyrroles and imidazoles have been reported, such as:
^The Me [007] where n = 1-3 (Damayanthi, Y., et al., Journal of Organic Chemistry,
64 (1), 290 to 292 (1999));
Me [008] where n = 1-3 and
Me
Me [009] where n = 1-2 (Kumar, R. and Lown, J.W. Oncology Research, 13 (4), 221 to 233 (2003)); Kumar, R., et al., Heterocyclic Communications, 8 (1), 19 to 26 (2002));
the M ^and [010] where n = 1-4, (Baraldi, PG, et al., Journal of Medicinal Chemistry,
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4/75
452).
42 (25), 5,131 to 5,141 (1999));
[011] where n = 3, (Wells, G., et al., Proc. Am. Assoc.
Canc. Res., 2003, 44, [012] In WO 2005/085177, some of the present inventors have disclosed amino acids that comprise a number of biaryl which may have useful properties in DNA binding.
[013] The inventors have now observed that prior art PBD conjugates can be modified in order to achieve improved properties, particularly antibacterial properties. In particular, the present invention relates to the incorporation of an amino acid residue that contains a 5-membered heterocyclic group in combination with an arylene based amino acid residue in a PBD conjugate that results in highly effective compounds.
[014] A first aspect of the present invention provides a compound of formula I:
[015] or a salt or solvate thereof, where:
(I) [016] the dotted double bond indicates the presence of a single or double bond between C2 and C3;
[017] R ² is selected from -H, -OH, = O, = CH2, -CN, -R, OR, halo, dihalo, = CHR, = CHRR ', -O-SO2-R, CO2R and COLOR;
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5/75 [018] R ⁷ is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro,
MeaSn and halo;
[019] where R and R 'are independently selected from alkyl groups
Optionally substituted C1-7, C3-20 heterocyclyl and C5-20 aryl;
[020] 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;
(TO 1)
G (A3)
G [021] A is selected from A1, A2, A3, A4 or A5:
G — F
N (A4) (A5)
N H
N H
G — F
G — F (A2) [022] Where [023] X ¹ and Y ¹ are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N
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6/75 and S; N and O; and CH and O, respectively;
[024] X2 and Y ² are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively;
[025] Z ¹ is selected from O and S;
[026] Z ² is selected from CH and N;
[027] F is selected from a single bond and - (EF ¹ ) m-;
[028] each E is independently selected from a single bond, and C (= O) -NH-;
[029] each F ¹ is independently a C3-20 heteroarylene group;
[030] m is 1,2 or 3;
[031] G is selected from hydrogen, C1-4 alkyl group, -C (= O) -O-C1-4 alkyl, - (CH2) n-C3-20 heterocycloalkyl, and -O- (CH2) n-C3 -20 heterocycloalkyl, and each n is 0-4;
[032] as long as A2 is not A2 ':
[033] where X ¹ and Y ¹ of A2 'are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and [034] provided that A3 is not A3 ':
(A3 ') [035] where X ² and Y ² of A3' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively;
[036] B in A2 'and A3' is a single link or:
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7/75
Η (B1);
[037] where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and [038] R ¹ is C1-4 alkyl.
[039] A second aspect of the present invention provides a method of synthesizing a compound of formula I.
[040] A third aspect of the present invention provides a pharmaceutical composition that comprises a compound of the first aspect of the invention and a pharmaceutically acceptable diluent or carrier.
[041] A fourth aspect of the present invention provides a compound of the first aspect of the invention for use in a method of therapy.
[042] 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 bacterial infection. This aspect also provides a compound of the first aspect for use in a method of treating a bacterial infection.
[043] A sixth aspect of the present invention provides a method of treating a patient suffering from a bacterial infection which comprises administering to said patient a therapeutically acceptable amount of a compound of the first aspect or a composition of the third aspect.
[044] In the fourth to sixth aspects of the invention, the compound of the invention can be administered alone or in combination with other treatments, either 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
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8/75 [045] The term “optionally substituted”, as used in this document, belongs to a parent group that can be unsubstituted or that can be substituted.
[046] Unless otherwise specified, the term “substituted”, as used in this document, belongs to a parent group that has one or more substituents. The term "substituent" is used in this document in the conventional sense and refers to a chemical moiety that is covalently linked, or, if appropriate, fused, to a parent group. A wide variety of substituents is well known, and methods for their formation and introduction into a variety of parent groups are also known.
[047] Examples of substituents are described in more detail below.
[048] C1-7alkyl: The term “C1-7alkyl”, as used herein, belongs to a monovalent chemical moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound that has to 1 to 7 carbon atoms, which can be aliphatic or acyclic, and which can be saturated or unsaturated (for example, partially unsaturated, completely unsaturated). Therefore, the term "alkyl" includes the subclasses alkenyl, alkynyl, cycloalkyl, etc., discussed below.
[049] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6) and heptyl (C7).
[050] 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), nhexyl (C6) and n-heptyl (C7).
[051] Examples of saturated branched alkyl groups include iso-propyl (C3), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl (C5) .
[052] C2-7 alkenyl: The term "C2-7 alkenyl", as used herein, belongs to an alkyl group that has one or more double bonds of
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9/75 carbon-carbon.
[053] 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 (Cs).
[054] C2-7 alkynyl: The term "C2-7 alkynyl", as used herein, belongs to an alkyl group that has one or more carbon-carbon triple bonds.
[055] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethynyl, -C ^ CH) and 2-propynyl (propargyl, -CH2-C ^ CH).
[056] C3-7 cycloalkyl: The term "C3-7 cycloalkyl", as used herein, belongs to an alkyl group which is also a cyclyl group; that is, a monovalent chemical moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic (carbocyclic) hydrocarbon compound, whose chemical moiety has 3 to 7 carbon atoms, including 3 to 7 carbon atoms. ring.
[057] Examples of cycloalkyl groups include, but are not limited to, those derived from:
[058] saturated monocyclic hydrocarbon compounds:
[059] cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (Cs), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (Cs) Cs), dimethylcyclopentane (C7) and methylcyclohexane (C7);
[060] unsaturated monocyclic hydrocarbon compounds:
[061] cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (Cs), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (Cs), methylcyclopent (dimethylcyclopent) C7) and
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10/75 methylcyclohexene (C7); and [062] saturated polycyclic hydrocarbon compounds:
[063] norcaran (C7), norpinan (C7), norbornan (C7).
[064] C3-20 heterocyclyl: The term "C3-20 heterocyclyl", as used herein, belongs to a monovalent chemical moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, the chemical moiety of which 3 to 20 ring atoms, 1 to 10 of which are ring heteroatoms. Preferably, each ring has 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms.
[065] In this context, prefixes (for example, C3-20, C3-7, C5-6, etc.) denote the number of ring atoms, or range of ring atoms, whether carbon atoms or hetero atoms. For example, the term "C5-6 heterocyclyl", as used herein, belongs to a heterocyclyl group that has 5 or 6 ring atoms.
[066] Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:
[067] N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g. 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole ( isopyrrole, isoazole) (C5), piperidine (Ce), dihydropyridine (Ce), tetrahydropyridine (Ce), azepine (C7);
[068] O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxol (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepine (C7);
[069] S1: thyrane (C3), tiethane (C4), thiolane (tetrahydrothiophene) (C5), thiano (tetrahydrothiopyran) (C6), tiepane (C7);
[070] O2: dioxolane (C5), dioxane (C6), and dioxepan (C7);
[071] O3: trioxane (C6);
[072] N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5),
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11/75 pyrazoline (dihydropyrazole) (C5), piperazine (Ce);
[073] NiOi: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (Ce), tetrahydrooxazine (Ce), dihydrooxazine (Ce), oxazine (Ce);
[074] NiSi: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6);
[075] N2Oi: oxadiazine (C6);
[076] OiSi: oxathiol (C5) and oxatian (thioxane) (C6); and, [077] NiOiSi: oxatiazine (Ce).
[078] 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 alopiranosis, altropirosis, glucopiranose , mannopyranose, gulopyranose, idopyranose, galactopyranose and talopyranose.
[079] Arila C5-20: The term “arila C5-20”, as used in this document, belongs to a monovalent chemical moiety obtained by removing from an aromatic ring atom of an aromatic compound, whose chemical moiety has 3 to 20 ring atoms. Preferably, each ring has 5 to 7 ring atoms.
[080] In this context, prefixes (for example, C3-20, C5-7, C5-e, etc.) denote the number of ring atoms, or the range of number of ring atoms, whether carbon or heteroatoms. For example, the term "C5-e aryl", as used herein, belongs to an aryl group that has 5 or 6 ring atoms.
[081] Ring atoms can all be carbon atoms, like "carboaryl groups".
[082] Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (Ce), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthaene (C18) ), and pyrene (C1e).
[083] Examples of aryl groups comprising fused rings, at least
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12/75 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), acephenanthrene (C15), and aceanthrene (C16).
[084] Alternatively, ring atoms can include one or more heteroatoms, such as "heteroaryl groups". Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:
[085] Ni: pyrrole (azole) (C5), pyridine (azine) (C6);
[086] Hi: furan (oxol) (C5);
[087] Si: thiophene (thiol) (C5);
[088] NiOi: oxazole (C5), isoxazole (C5), isoxazine (C6);
[089] N2Oi: oxadiazole (furazan) (C5);
[090] N3Oi: oxatriazole (C5);
[091] NiSi: thiazole (C5), isothiazole (C5);
[092] 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);
[093] N3: triazole (C5), triazine (C6); and, [094] N4: tetrazole (C5).
[095] Examples of heteroaryl comprising fused rings include, but are not limited to:
[096] C9 (with 2 fused rings) derived from benzofuran (Oi), isobenzofuran (Oi), indole (Ni), isoindol (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);
[097] Ci0 (with 2 fused rings) derived from chromene (Oi), isochromene (Oi),
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13/75 cromano (Oi), isochroman (Oi), benzodioxane (O2), quinoline (Ni), isoquinoline (Ni), quinolizine (N1), benzoxazine (N1O1), benzodiazine (N2), pyridopyridine (N2), quinoxaline ( N2), quinazoline (N2), cinoline (N2), phthalazine (N2), naphthyridine (N2), pteridine (N4);
[098] C11 (with 2 fused rings) derived from benzodiazepine (N2);
[099] C13 (with 3 fused rings) derived from carbazole (N1), dibenzofuran (O1), dibenzothiophene (S1), carboline (N2), perimidine (N2), pyridoindole (N2); and, [0100] C14 (with 3 fused rings) derived from acridine (N1), xanthene (O1), thioxanthene (S1), oxanthrene (O2), phenoxathine (O1S1), phenazine (N2), phenoxazine (N1O1), phenothiazine (N1S1), thianthrene (S2), phenanthridine (N1), phenanthroline (N2), phenazine (N2).
[0101] The terms "arylene", "carboarylene", "heteroarylene", as used herein, belong to a divalent chemical moiety obtained by removing one hydrogen atom from each of two ring atoms of an aromatic compound as described above with reference to aryl, carboaryl and heteroaryl.
[0102] The above groups, whether alone or as part of another substituent, may themselves be optionally substituted with one or more groups selected from among them and the additional substituents listed below.
[0103] Halo: -F, -Cl, -Br, and -I.
[0104] Hydroxy: -OH.
[0105] 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.
[0106] 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
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14/75 (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).
[0107] Acetal: -CH (OR ¹ ) (OR ² ), where R ¹ and R ² are independently substituents of acetal, for example, a C1-7 alkyl group, a C320 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 , together with the two oxygen atoms to which they are attached, and the carbon atoms to which the they are linked, form a heterocyclic ring that has 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).
[0108] Hemiacetal: -CH (OH) (OR1), where R ¹ is a hemiacetal substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C520 aryl group, preferably a group C1-7 alkyl. Examples of hemiacetal groups include, but are not limited to, -CH (OH) (OMe) and -CH (OH) (OEt).
[0109] Ketal: -CR (OR1) (OR ² ), where R ¹ and R ² are as defined for acetals, and R is a non-hydrogen ketal 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 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).
[0110] Hemicetal: -CR (OH) (OR1), where R ¹ is as defined for hemiacetals, and R is a non-hydrogen hemicetal substituent, for example, a C1-7 alkyl group, a C3- heterocyclyl group 20, 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).
[0111] Oxide (keto, -one): = O.
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15/75 [0112] Tiona (thiocetone): = S.
[0113] Imino (imine): = NR, where R is an imino substituent, for example, hydrogen, 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 ester groups include, but are not limited to, = NH, = NMe, = NEt, and = NPh.
[0114] Formyl (carbaldehyde, carboxaldehyde): -C (= O) H.
[0115] 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 C3-20 heterocyclyl 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).
[0116] Carboxy (carboxylic acid): -C (= O) OH.
[0117] Thiocarboxy (thiocarboxylic acid): -C (= S) SH.
[0118] Thiolocarbonoxy (thiolocarboxylic acid): -C (= O) SH.
[0119] Thionocarboxy (thionocarboxylic acid): -C (= S) OH.
[0120] Imidic acid: -C (= NH) OH.
[0121] Hydroxamic acid: -C (= NOH) OH.
[0122] 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.
[0123] 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, Petition 870190100538, of 10/07/2019, p. 31/96
16/75
OC (= O) C (CH3) 3, -OC (= O) Ph, and -OC (= O) CH2Ph.
[0124] 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.
[0125] 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 di-C1-7 alkylamino), a heterocyclyl C3-20 group, or a C520 group, preferably H or a C1-7 alkyl group, or, in the case of a "cyclic" amino group, R ¹ and R ² , together with the nitrogen atom to which they are linked, form a heterocyclic ring that has 4 to 8 ring atoms. The amino groups can be primary (-NH2), secondary (-NHR ¹ ) or tertiary (-NHR1R ² ) and, in the cationic form, 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.
[0126] Starch (carbamoyl, carbamyl, aminocarbonyl, carboxamide): C (= O) NR1R 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 such as, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl and piperazinocarbonyl.
[0127] Thioamido (thiocarbamyl): -C (= S) NR1R ² , where R ¹ and R ² are independently amino substituents, as defined for amino groups.
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Examples of starch groups include, but are not limited to, -C (= S) NH2, -C (= S) NHCH3, -C (= S) N (CH ₃ ) 2, and -C (= S) NHCH ₂ CH3.
[0128] Acylamido (acylamino): -NR ¹ C (= O) R ² , where R ¹ is a starch substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, 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, such as succinimidyl, maleimidyl and phthalimidyl:
succinimidyl maleimidile talimidila [0129] Aminocarbonyloxy: -OC (= O) NR ¹ R 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) NMe ₂ , and -OC (= O) NEt ₂ .
[0130] Ureido: -N (R ¹ ) 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, a group C1-7 alkyl, a C320 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, -NHCONMe ₂ , -NHCONEt ₂ , -NMeCONH ₂ , -NMeCONHMe, NMeCONHEt, -NMeCONMe ₂ , and -NMeCONEt ₂ .
[0131] Guanidine: -NH-C (= NH) NH ₂ .
[0132] Tetrazolyl: a five-membered aromatic ring that has four hydrogen atoms and one carbon atom,
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[0133] Imino: = NR, where R is an imino substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably H or a C1-7 alkyl group. Examples of imino groups include, but are not limited to, = NH, = NMe, and = NEt.
[0134] 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.
[0135] Nitro: -NO2.
[0136] Nitrous: -NO.
[0137] Azido: -N3.
[0138] Cyan (nitrile, carbonitrile): -CN.
[0139] Isocian: -NC.
[0140] Cyanate: -OCN.
[0141] Isocyanate: -NCO.
[0142] Thiocyanate (thiocyanate): -SCN.
[0143] Isothiocyanate (isothiocyanate): -NCS.
[0144] Sulfidrila (thiol, mercapto): -SH.
[0145] 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, preferably a C1-7 alkyl group. Examples of C1-7 alkylthio groups include, but are not limited to, -SCH3 and SCH2CH3.
[0146] 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,
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19/75 preferably a C1-7 alkyl group (also referred to herein as C1-7 alkyl disulfide). Examples of C1-7 alkyl disulfide groups include, but are not limited to, -SSCH3 and -SSCH2CH3.
[0147] Sulphine (sulfinyl, sulfoxide): -S (= O) R, where R is a sulfin 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 sulfin groups include, but are not limited to, -S (= O) CH3 and -S (= O) CH2CH3.
[0148] 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 C520 aryl group, preferably one C1-7 alkyl group, which includes, 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).
[0149] Sulfinic acid (sulfine): -S (= O) OH, -SO2H.
[0150] Sulfonic acid (sulfo): -S (= O) 2OH, -SO3H.
[0151] Sulfinate (sulfinic acid ester): -S (= O) OR; wherein R is a sulfinate substituent, for example, a C1-7 alkyl group, a C320 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).
[0152] 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 sulfonate groups include, but are not limited to, -S (= O) 2OCH3 (methoxysulfonyl;
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20/75 methyl sulfonate) and -S (= O) 2OCH2CH3 (ethoxysulfonyl; ethyl sulfonate).
[0153] 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.
[0154] 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).
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] Sulfonamino: -NR1S (= O) 2R, where R ¹ is an amino substituent,
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21/75 as defined for amino groups, and R is a sulfonamino 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 sulfonamino groups include, but are not limited to, -NHS (= O) 2CH3 and -N (CH3) S (= O) 2C6H5.
[0160] 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) CH3 and -N (CH3) S (= O) C6H5.
[0161] Phosphine (phosphine): -PR2, where R is a phosphine substituent, for example, -H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C520 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, -F2, -P (CH3) 2, -P (CH2CH3) 2, -P (t-Bu) 2, and -P (F) 2.
[0162] Phospho: -P (= O) 2.
[0163] 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 ) (F) 2.
[0164] Phosphonic acid (phosphono): -P (= O) (OH) 2.
[0165] 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 ) (OF) 2.
[0166] Phosphoric acid (phosphonooxy): -OP (= O) (OH) 2.
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22/75 [0167] Phosphate (phosphonooxy ester): -OP (= O) (OR) 2, where R is a phosphate substituent, for example, -H, a C1-7 alkyl group, a C3 heterocyclyl group -20, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group or a C5-20 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 ) (OF) 2.
[0168] Phosphorous acid: -OP (OH) 2.
[0169] 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-tBu) 2, and -OP (OF) 2.
[0170] 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.
[0171] Phosphoramidate: -OP (= O) (OR1) -NR ² 2, where R ¹ and R ² are substituents of phosphoramidate, for example, -H, a Cw alkyl group (optionally substituted), a C3 heterocyclyl group -20, 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 [0172] Nitrogen protection groups are well known in the art. Preferred nitrogen protection groups are carbamate protection groups that have the general formula:
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R ¹ —O. , O [0173] A large number of nitrogen carbamate protection groups are listed on pages 706 to 771 of Wuts, PGM and Greene, TW, Protective Groups in
Organic Synthesis, 4th Edition, Wiley-Interscience, 2007 which is incorporated herein by reference.
[0174] Particularly preferred protection groups include Alloc, Troc,
Teoc, BOC, Doc, Hoc, TcBOC, Fmoc, 1-Adoc and 2-Adoc.
Hydroxyl protecting groups [0175] 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 Organic Synthesis, 4th Edition, Wiley-Interscience, 2007 which is incorporated herein by reference.
[0176] Classes of particular interest include silyl ethers, methyl ethers, alkyl ethers, benzyl ethers, esters, benzoates, carbonates and sulfonates.
[0177] Particularly preferred protection groups include THP.
Bacterial infections and contagious diseases [0178] A person of ordinary skill in the art is readily able to determine whether a candidate compound treats a bacterial infection or contagious bacterial disease. For example, assays that can be conveniently used to assess the activity offered by a particular compound are described in the examples below.
[0179] The term "bacterial infection" belongs to an invasion of body tissues by bacteria, their multiplication and the reaction of body tissues to bacteria and the toxins they produce. The term "bacterial contagious disease" belongs to a disease caused by bacteria.
[0180] Examples of bacterial infection and contagious bacterial diseases include, but are not limited to, infections acquired in hospital and community due to
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24/75 to Gram-positive bacteria such as Staphylococcus aureus, including multidrug-resistant forms such as methicillin-resistant S. aureus (MRSA), and streptococci, including drug-resistant forms such as vancomycin-resistant enterococci (VRE). Other infections that can be treated include those due to Clostridium difficile, Listeria monocytogenes and skin infections due to Gram-positive bacteria.
[0181] Preferably, the compounds of the present invention are useful in the treatment of contagious bacterial diseases caused by bacterial infections involving drug-resistant bacterial strains. Particularly preferred bacterial strains are Staphylococcus aureus.
[0182] Preferably, treatment is for a contagious bacterial disease or bacterial infection involving MRSA, vancomycin-resistant S. aureus (VISA), vancomycin-resistant S. aureus (VRSA) and other infections due to Gram-positive bacteria resistant to drugs.
Treatment Methods [0183] As described above, the present invention provides the use of a compound of the first aspect of the invention in a method of therapy.
[0184] The term "therapeutically effective amount" is an amount sufficient to show benefits to a patient. Such a benefit can be at least an improvement of at least one symptom. The actual amount administered, and the rate and course of administration 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.
[0185] A compound can be administered alone or in combination with other treatments, either simultaneously or sequentially, depending on the condition being treated. Examples of treatments and therapies include, but are not limited to, β-lactam drugs such as penicillins and cephalosporins, aminoglycosides,
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25/75 fluoroquinolones, oxazolidinones and streptogramins.
[0186] Pharmaceutical compositions according to the present invention, and for use according to the present invention, may comprise, in addition to the active ingredient, that is, a compound of formula I, a pharmaceutically acceptable stabilizer, buffer, vehicle or excipient or other materials well known to those skilled in the art. Such materials must be non-toxic and must not interfere with the active ingredient. The precise nature of the vehicle or other material will depend on the route of administration, which can be oral, or by injection, for example, cutaneous, subcutaneous or intravenous.
[0187] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can comprise a solid vehicle 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.
[0188] For intravenous, cutaneous or subcutaneous 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 will be well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer Injection, Lactated Ringer Injection. Condoms, stabilizers, buffers, antioxidants and / or other additives can be included as needed.
Dosage [0189] It will be observed by an individual skilled in the art that dosages
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Appropriate 26/75 of the compound may vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or harmful side effects. The dosage level selected will depend on a variety of factors, which include, but are 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, others 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 ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage is selected to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or harmful side effects.
[0190] Administration can be carried out in one dose, continuously or intermittently (for example, in divided doses at appropriate intervals) over the course of treatment. Methods for determining the means and dosage of administration are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of therapy, the target cell (s) to be treated, and the individual who should to be treated. Single or multiple administrations can be conducted at the dose level and standard selected by the doctor, veterinarian, or treatment clinician.
[0191] 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 individual's body weight per day. When the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound, and then the actual weight to be used is increased proportionally.
[0192] In one embodiment, the active compound is administered to a patient
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27/75 human according to the following dosage regimen: about 100 mg, 3 times a day.
[0193] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 150 mg, twice a day.
[0194] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 200 mg, twice a day.
[0195] For disease prevention or treatment, 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, regardless of whether the molecule is administered for preventive or therapeutic purposes. , prior to therapy, the patient's medical history and antibody response, and the attending physician's discretion. The molecule is properly administered to the patient in an hour or by a series of treatments. Depending on the type and severity of the disease, about 1 pg / kg to 15 mg / kg (eg 0.1 to 20 mg / kg) of molecule is an initial candidate dosage for administration to the patient, if, for example, through one or more separate administrations, or by continuous infusion. A typical daily dosage can range from about 1 pg / kg to 100 mg / kg or more, depending on the factors mentioned above. An exemplary dosage of 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 for several days or more, depending on the condition, treatment is continued until a desired suppression of 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 every week, two weeks, or three weeks of a compound. Other dosage regimens may be useful. The progress of this
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28/75 therapy is easily monitored through tests and conventional techniques.
Includes Other Forms [0196] Unless otherwise specified, the protected forms of the following substituents are included above: ionic, salt and solvate. 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 [0197] Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereomeric, tautomeric, conformational, or anomeric forms, which include, but are not limited to, cis and trans; 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; sin and antiform forms; syncline and anticline forms; α and β forms; axial and equatorial forms; boat, chair, twist, envelope-, and half-chair shapes; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
[0198] Preferably, the compounds of the present invention have the following stereochemistry at the C11 position:
The [0199] Note that, except as discussed below for forms
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29/75 tautomeric, specifically excluded from the term "isomers" as used herein, are structural (or constitutional) isomers (that is, isomers that differ in the connections between atoms rather than merely in the position of atoms in space). For example, 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 also include structurally isomeric forms that fall into that class (for example, C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n, iso, see, and tert-butyl; methoxyphenyl includes ortho, meta, and para-methoxyphenyl).
[0200] The above exclusion does not belong to tautomeric forms, for example, keto-, enol-, and enolate forms, such as, for example, in the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide alcohol / imino, amidine / amidine, nitrous / oxime, thiocetone / enethiol, N-nitrous / hydroxy, and nitro / aci-nitro.
1, 0 , Oh H ⁴ ° ’= / ^{= C} c = c ^{z -} I ^C Ceto Enol H ⁴ Enolato [0201] Note that specifically They are included in the term “isomer ^:
compounds with one or more isotopic substitutions. For example, H can be in any isotopic form, which includes ¹ H, ² H (D), and ³ H (T); C can be in any isotopic form, which includes ¹² C, ¹³ C, and ¹⁴ C; O can be in any isotopic form, which includes ¹⁶ O and ¹⁸ O; and the like.
[0202] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, which include (completely or partially) racemic and other mixtures thereof. Methods for preparation (eg asymmetric synthesis) and separation (eg
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30/75 (fractional crystallization and chromatographic media) of such isomeric forms are either known in the art or readily obtained by adapting the methods taught in the present document, or known methods, in a known manner.
[0203] Unless otherwise specified, a reference to a particular compound also includes ions, salt, solvate, and protected forms thereof, for example, as discussed below.
[0204] 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 to 19 (1977).
[0205] 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 like Na + and K ⁺ , alkaline earth cations like Ca ²⁺ and Mg ²⁺ , and other cations like 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, ethylenediamine, 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 ⁺ .
[0206] 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,
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31/75 iodide, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
[0207] Examples of suitable organic anions include, but are not limited to, the derivatives of the following organic acids: 2-acetoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, gluceptonic, gluconic, glutamic, glycolic, hydroximaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, malealic, malic, methanesulfonic, musclic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenyl sulfonic, propionic, salty, pyruvic, salicylic, pyronic, salicylic, pyronic, salicylic, pyronic, salic, pyronic, salicylic, propionic, salic, pyronic, salic, pyronic, salic, pyridic, salic, pyridic, salicylic, pyridic, salicyl, propionic, salicyl. succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, derivatives of the following polymeric acids: tannic acid, carboxymethylcellulose.
[0208] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the active compound. The term "solvate" is used in this document in the conventional sense to refer to a solute complex (eg, 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.
[0209] The compounds of formula I include compounds in which a nucleophilic solvent (H2O, RAOH, R ^A NH2, R ^A SH) is added along the imine bond of the chemical portion of PBD, 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):
h ₂ o
R
O
R ^A OH
[0210] These forms can be called forms of the PBD carbinolamine and carbinolamine ether. The balance of this balance depends on the conditions in which the compounds are found, as well as the nature of the chemical portion itself.
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32/75 [0211] These compounds can be isolated in solid form, for example, by lyophilization.
General Synthetic Pathways [0212] 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:

(2) [0213] R ^'10 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, in the document Wuts, PGM and Greene TW, Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, 2007. If both nitrogen protecting groups and hydroxyls are present, they are preferably selected to be removable under the same conditions.
[0214] If this deprotection is carried out 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 conducted.
[0215] The conversion of 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. Additional methods are described in GB 2 053 894, which is incorporated by reference in this document.
[0216] The compounds of formula 2 can be made by coupling compounds of Formula 3 and Formula 4:
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(3) [0217] under standard conditions of amide bond formation, for example, in the presence of HOBt or DMAP and EDCl.
[0218] The compounds of formula 3 can be synthesized from the compounds of formula 5:
(5) [0219] where R ' ⁸ is a C1-4 alkyl group, for example, methyl. This deprotection of the carboxyl group can be carried out using standard means, for example, treatment based.
[0220] 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 by reference in this document. 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 coupling a protected or precursor form to a hydroxy group on the benzene ring using, for example, Mitsunobo coupling.
[0221] Compounds of formula 4 can be synthesized using the methods disclosed in document No WO 2005/085177, which are incorporated
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Dna binding [0222] 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 assessed using a thermal DNA denaturation assay calf thymus, 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.
Additional Preferences
C2 [0223] It can be preferred in any of the modalities that C2 carbon has 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 [0224] there is a double bond between C2 and C3.
[0225] When R ² is selected from any of the following groups:
= O, = CH2, = CHR, = CHRR '[0226] there cannot be a double bond between C2 and C3.
_R 2 [0227] R ² is selected from -H, -OH, = O, = CH2, -CN, -R, OR, halo, dihalo, = CHR, = CHRR ', -O-SO2-R, CO2R and COR.
[0228] In some modalities, R ² can be selected from -H, -OH, = O, = CH2, -CN, -R, -OR, = CHR, = CRR ', -O-SO2-R, -CO2R and -COR.
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35/75 [0229] In some modalities, R ² can be selected from -H, = CH2, R, = CHR, and = CRR '.
[0230] In one mode, R ² is H.
[0231] In one mode, R ² is = O.
[0232] In one embodiment, R ² is = CH2.
[0233] In one embodiment, R ² is = CHR. In the PBD compound, the = CHR group can have any configuration shown below:
H (C1)
(C2) [0234] In one mode, the configuration is the configuration (C1).
[0235] In one mode, R ² is = CRR '.
[0236] In one mode, R ² is = CF2.
[0237] In one modality, R ² is R.
[0238] In one embodiment, R ² is optionally substituted C5-20 aryl.
[0239] When R ² is optionally substituted C5-20 aryl, substituted C5-7 aryl or C ^8-10 aryl may be optionally preferred. R ² can 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.
[0240] When R ² is optionally substituted C5-20 aryl, it may be preferable to have one to three substituting groups, with 1 and 2 being more preferred, and substituted groups being only most preferred. Substituents can be in any position.
[0241] Where R ² is a C5-7 aryl group, a single substituent is
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36/75 preferably on a ring atom that is not adjacent to the bond to the rest of the compound, that is, β or γ is preferred to the bond to the rest of the compound. Therefore, where the aryl group C5-7 is phenyl, the substituent is preferably in the meta or para positions, and most preferably it is in the para position.
[0242] In one mode, R ² is selected from:
[0243] where the asterisk indicates the attachment point.
[0244] Where R ² is a C8-10 aryl group, for example, quinolinyl or isoquinolinyl, it can carry any amount of substituents in any position of the quinoline or isoquinoline rings. In some embodiments, it supports one, two or three substituents, and these can be either in the proximal or distal ring or both (if more than one substituent).
[0245] When R ² is optionally substituted C5-20 aryl, the substituents can be selected from: halo, hydroxyl, ether, formyl, acyl, carboxy, ester, acyloxy, amino, amide, acylamido, aminocarbonyloxy, ureido, nitro, cyano and thioether.
[0246] 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'.
[0247] If a substituent on R ² is halo, it is preferably F or Cl, more preferably Cl.
[0248] If a substituent in 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 be, in some embodiments, a C5-7 aryloxy group (e.g., phenoxy, pyridyloxy, furanyloxy).
[0249] If a substituent on R ² is C1-7 alkyl, it may be preferable to be a C1-4 alkyl group (for example, methyl, ethyl, propyl, butyl).
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37/75 [0250] If a substituent in R ² is C3-7 heterocyclyl, it may, in some embodiments, be C6 nitrogen that contains a heterocyclyl group, for example, morpholino, thiomorpholino, piperidinyl, piperazinyl. These groups can be linked to the rest of the chemical portion of PBD through the nitrogen atom. These groups can be further substituted, for example, by C1-4 alkyl groups.
[0251] If a substituent in R ² is bis-oxy-C1-3 alkylene, it is preferably bis-oxy-methylene or bis-oxy-ethylene.
[0252] Particularly preferred substituents for R ² include methoxy, ethoxy, fluorine, chlorine, cyano, bis-oxymethylene, methyl-piperazinyl, morpholino and methyl-thienyl.
[0253] Particularly preferred substituted R ² groups include, but are not limited to, 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-ile and quinolin-6-ile, isoquinolin-3-ile and isoquinolin-6-ile, 2-thienyl,
2-furanyl, methoxynaphthyl, and naphthyl.
[0254] In one embodiment, R ² is optionally substituted C1-12 alkyl.
[0255] 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;
, 22, 23 (c) where each of R ²¹ , R ²² and R ²³ are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the number total carbon atoms in group R ¹² is not greater than 5;
R ^25b (d), where one of R ^25a and R ^25b is H and the other is selected from: phenyl, whose phenyl is optionally substituted by a group selected from
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38/75 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, whose phenyl is optionally substituted by a group selected from halo methyl, methoxy; pyridyl; and thiophenyl.
[0256] When R ¹² is C1-5 saturated aliphatic alkyl, it can be methyl, ethyl, propyl, butyl or pentyl. In some modalities, it can be methyl, ethyl or propyl (n-pentyl or isopropyl). In some of these modalities, the same can be methyl. In other embodiments, it can be butyl or pentyl, which can be linear or branched.
[0257] When R ¹² is C3-6 saturated cycloalkyl, it can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, it may be cyclopropyl.
, 22, 23 [0258] When R ¹² is ^R , each of R ²¹ , R ²² and R ²³ is independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, wherein the total number of carbon atoms in the R ¹² group is not greater than 5. In some embodiments, the total number of carbon atoms in the R ¹² group is not greater than 4 or no more than 3.
[0259] In some embodiments, one of R ²¹ , R ²² and R ²³ is H, with the other two groups selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl.
[0260] In other modalities, two of R ²¹ , R ²² and R ²³ are H, where the other group is selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl.
[0261] In some modalities, groups that are not H are selected from methyl and ethyl. In some of these modalities, groups that are not H are
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39/75 methyl.
[0262] In some modalities, R ²¹ is H.
[0263] In some modalities, R ²² is H.
[0264] In some modalities, R ²³ is H.
[0265] In some modalities, R ²¹ and R ²² are H.
[0266] In some modalities, R ²¹ and R ²³ are H.
[0267] In some modalities, R ²² and R ²³ are H.
R ^25b *
[0268] When R ¹² is _25a ^R , one of R ^25a and R ^25b is
H and the other is selected from: phenyl, whose phenyl is optionally substituted selected from halo, methyl, methoxy; pyridyl; and thiophenyl.
by a group
In some embodiments, the group that is not H is optionally substituted phenyl. If the optional phenyl substituent is halo, it is preferably fluorine. In some modality, the phenyl group is not substituted.
* [0269] When R ¹² is ^R , R ²⁴ is selected from: H; saturated C1-3 alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, whose phenyl is optionally substituted by a group selected from halo methyl, methoxy;
pyridyl; and thiophenyl. If the optional phenyl substituent is halo, it is preferably fluorine. In some modality, the phenyl group is not substituted.
[0270] In some modalities, R ²⁴ is selected from H, methyl, ethyl, ethylene and ethynyl. In some of these modalities, R ²⁴ is selected from H and methyl.
[0271] In one embodiment, R ² is halo or di-halo. In one embodiment, R ² is F or -F2, whose substituents are illustrated below as (C3) and (C4) respectively:
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F
O
F
F
(C3) (C4) [0272] R2 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 most preferably a group optionally substituted aryl C5-20. Particularly preferred groups for R ² include = CH2, = CH-Me, and an optionally substituted phenyl group.
R ⁷ [0273] R ⁷ is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro, Me3Sn and halo;
[0274] R ⁷ can preferably be selected from H, OR, SH, SR, NH2, NHR, NRR ', and halo.
[0275] R ⁷ can be selected more preferably from H and OR.
[0276] In some embodiments, R ⁷ is OR, and more particularly OR ^7A , where R ^7A is independently optionally substituted C1-7 alkyl.
[0277] R ^7A can be selected from optionally substituted C1-7 saturated alkyl and optionally substituted C2-4 alkenyl.
[0278] R ^7A can preferably be selected from Me, CH2Ph and alila. [0279] R ¹⁰ / R ¹¹ [0280] 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;
[0281] In some modalities, R ¹⁰ and R ¹¹ form a double bond together.
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41/75 [0282] In some embodiments, R ¹⁰ is H and R ¹¹ is OR ^Q. In these modalities, R ^Q can preferably be selected from H or Me.
[0283] In some modalities, R ¹⁰ is H and R ¹¹ is SOxM. x may preferably be 3, and M may preferably be Na +.
R ¹ [0284] R1 is C1-4 alkyl.
[0285] R1 can preferably be C1-2 alkyl, and more preferably methyl.
[0286] A is selected from A1, A2, A3, A4 or A5.
X ¹ and Y ¹ [0287] For each of A1, A2, A3, A4 and A5, X ¹ and Y ¹ are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively.
[0288] Preferably, X ¹ and Y ¹ are selected from: CH and NMe; N and NMe; CH and S; and CH and O, respectively. Most preferably, X ¹ and Y ¹ are selected from N and NMe and CH and NMe, respectively.
F [0289] F is selected from a single connection and - (EF ¹ ) m-.
[0290] When F is - (EF ¹ ) m-, each E is independently selected from a single bond, and -C (= O) -NH-; each F ¹ is independently a C3-20 heteroarylene group; in is 1,2 or 3.
[0291] Preferably, F ¹ is a C5-6 heteroarylene group, more preferably a C5 heteroarylene group. More preferably, F ¹ is represented by the F11 structure:
(F11)
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42/75 [0292] where X ³ and Y ³ are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively. Preferably X ³ and Y ³ are selected from: CH and O; and CH and NMe, respectively.
[0293] Thus, the preferred structures of F11 are:
X ³ Y ³ F11 CH NMeCH O
[0294] Each E is selected independently from a single bond and -C (= O) -NH-. In some embodiments, each E is -C (= O) -NH-.
[0295] m is 1,2 or 3. Preferably m is 1. In other modalities, m is 3.
[0296] In some modalities F is a simple link.
[0297] G is selected from hydrogen, C1-4 alkyl, -C (= O) -O-C1-4 alkyl, - (CH2) n-C3-20 heterocycloalkyl, and -O- (CH2) n-C3 group -20 heterocycloalkyl; and each n is 0 to 4.
[0298] Preferably, the C3-20 heterocycloalkyl group is a morpholine group. Preferably, G is selected from the group consisting of -H, -Me, -C (= O) -O-Me, - (CH2) n-N (CH2CH2OCH2CH2), and -O- (CH2) n-N (CH2CH2OCH2CH2).
[0299] n is 0 to 4. Thus, n can be 0, 1, 2, 3 or 4.
Preferential combinations of F and G [0300] In some embodiments, G and at least one of the units (-EF ¹ ) of F are provided by structures FG1 and FG2:
OMe
(FG1),
(FG2).
[0301] FG1 and FG2 can be combined with other units - (EF ¹ ) - of F
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A1 [0302] A1 is represented by the structure:
(A1) [0303] Z1 is O or S. Preferably X ¹ and Y ¹ are selected from CH and
NMe, and N and NMe.
[0304] Thus, the preferred structures of A1 are A11, A12, A13 and A14:
_X 1 _Y 1 _Z 1 TO 1 CH NMe O i oV / Z ^ N ^^ X //(A11) N NMe O ^G ^ = I O Η N— ⁷ (A12) CH NMe s G- ^F / V o ΧΪ Η N— ^J (A13)
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[0305] A2 is represented by the structure:
(A2) [0306] Preferably X ¹ and Y ¹ are selected from CH and NMe, and N and
NMe. Thus, the preferred structures of A2 are A21, A22, A23 and A24:
X ¹ Y ¹ Z ² A2 CH NMe CH Η N— ^J / (A21) N NMe N Χ ^ λ Λ N__i(A22) N NMe CH G ^ r. OΗ N—(A23) CH NMe N (A24)
[0307] Preferably, -F-G is arranged in the position for the phenylene or pyridinyl group of A2.
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45/75 [0308] When A2 is represented by structures A21 or A23, A may not be A2 ':
[0309] where X ¹ and Y ¹ of A2 'are selected from: CH and NMe and N and NMe, respectively;
[0310] B is a simple link or:
[0311] where X and Y from (B1) are selected from: CH and NMe; COH and NMe;
CH and S; N and NMe; N and S, respectively; and [0312] R ¹ is C1-4 alkyl.
A3 [0313] A3 is represented by the structure:
(A3) [0314] Preferably, X ¹ and Y ¹ are selected from CH and NMe, N and
NMe, and CH and O.
[0315] Preferably X ² and Y ² are selected from CH and NMe, and N and
NMe.
[0316] Thus, the preferred structures of A3 are A31, A32, A33, A34, A35 and A36:
X ¹ Y ¹ X ² Y ² A3
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CH NMe CH NMe Η N— ^J (A31) CH NMe N NMe ^{G F} ' > ÍT ^ i> = n Λ .. JI —j— | 11 ^ Η / N —- <(A32) N NMe CH NMe g ^ ^f __ o Η N— ^J (A33) N NMe N NMe g ^ ^f 9> = N Λ N II 11 ^ Η N— ^J (A34) CH O CH NMe ^G > H (A35) CH O N NMe g ^ ^f ° = N Λ .. II HO — V (A36)
[0317] Preferably, the PBD portion of the compound is arranged in the para position of the phenylene group of A3.
[0318] When A3 is represented by structures A31 or A32, A may not be A3 ':
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(A3 ') [0319] where X ² and Y ² of A3' are selected from: CH and NMe; COH and
NMe; CH and S; N and NMe; N and S, respectively;
[0320] B is a simple link or:
[0321] where X and Y of B1 are selected from: CH and NMe; COH and NMe;
CH and S; N and NMe; N and S, respectively; and [0322] R1 is C1-4 alkyl.
A4 [0323] A4 is represented by the structure:
[0324] Preferably, X ¹ (A4) and Y ¹ are CH and O and Z ¹ is NMe. Thus, a preferred structure of A4 is A41:
(A41)
A5 [0325] A5 is represented by the structure
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[0326] Preferably X ¹ and Y ¹ are selected from CH and NMe, and CH and
O. So, the preferred structures of A5 are given as A51, A52, A53 and A54:
_X 1 _Y 1 _Z 2 A5 CH NMe CH G — F θ V // Η N— ^J / (A51) CH O CH 'λ ^{H 0} (A52) CH NMe N 'j Q _N / (A53) CH O N p __- FO 1 / -v // ^{H 0} (A54)
[0327] When Z ² of A5 is CH, F is preferred for a single bond.
[0328] The preferred compounds of the present invention are as follows:
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40 H 'Meo ⁰ 49 H LN / ^ _y N— / LI Z ⁵ yZl ° <. / MeO N ^ Z = / / 51 H ^{NS! RS} ^ ^XX > -zs. Ο. c> JL II __! y — r O ° y— / MeO = J / 52 <n _k jrV ^ - ^{n =} x £ - —'o— JT ^N / = (i> J Od V ^ hUZ ^οΐί > - θ / - ^J / —7lí ^ O ~ ON ^Me ° ° 53 t Η / Ά N- 'n _x JL o — g λ— < ₀ yv 0 J, __,' 4 — f MeO ⁰ rY / V ^N N ^ Z = J 54 och ₃ 0 ^ / ³ H A NtfSXXx ^ —nj / = (N ^ y J ^N o oA ^. ΖΓΠΧ Y- ¹ MeO 56 _OCH3 ⁰ 5SZ -Ν] H ^ s = L ^ Ti, ° - J i J ~ \ / - / ^ ⁰ The XssSk / "Ά / - ^Me0 1> - (/ 7-N ^ Z _ / 59 ^H / - 0 --Xk / _χ XOCH, _N * N ^N -5 - ^^ Ο Ύ O ° γ ^Ν ° οΜθ o4 7 N 0 Z ^ V -Ο-n ⁰ or
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51/75 [0329] Compounds 26, 27, 28, 35, 54, and 56 are preferred. Compounds 26, 27, and 35 are more preferred, and compound 35 is particularly preferred.
Example
General Methods [0330] Optical rotations were measured on an ADP 220 polarimeter (Bellingham Stanley Ltd) and concentrations (c) are given in g / 100 ml. Melting points were measured using a digital melting point device (Electrothermal). The IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT IR spectrometer. The 1H and ¹³ C NMR spectra were acquired at 300 K using a Bruker Advance NMR spectrometer at 400 and 100 MHz, respectively. Chemical shifts are reported in relation to TMS (δ = 0.0 ppm) and signals are designated as s (singlet), d (doublet), t (triplet), dt (double triplet), dd (doublet of doublets) , ddd (double doublet of doublets) or m (multiplet), with the coupling constants provided in Hertz (Hz). A pro-PBD numbering system is used for proton and carbon assignments to synthetic intermediates (that is, based on the final tricyclic PBD ring system). Mass spectrometry data were collected using a Waters Micromass ZQ instrument coupled to a Waters 2695 HPLC with a Waters 2996 PDA. The ZQ parameters of 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 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 instrument . Thin Layer Chromatography (TLC) was performed on silica gel aluminum plates (Merck 60, F254) and flash chromatography used silica gel (Merck 60, 230 to 400 mesh ASTM). The reactions
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52/75 parallel were conducted using a RadleysTM Green House Synthesizer (Greenhouse Synthesizer) and parallel purifications were conducted using an IST VacmasterTM. For reactions conducted in parallel, the solvents were evaporated using a Genevac VC 2000D (Genevac Technologies, UK). The purified compounds were freeze-dried using a Heto-Lyolab 3000 freeze dryer. The hydrogenation reactions were conducted using a UHP-60H hydrogen generator attached to a Parr hydrogenation apparatus. Synthetic building blocks were purchased from Maybridge Chemicals (UK), Bachem Chemicals (USA) and Sigma-Aldrich (UK). Reagents and solvents were purchased from Sigma-Aldrich (UK).
Synthesis of Intermediates (a) 4- (4- (tert-butoxycarbonylamino) phenyl) -1-methyl-1 H-pyrrol-2-carboxylate (5) (i) 2- (trichloroacetyl) -1-methyl pyrrole ( 2) [0331] A solution of N-methyl pyrrole (1) (113.06 g, 1.39 mol, 1.0 eq.) In dry ether (350 ml) was added in drops 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 2 L, 3 flask with neck. The HCl gas produced in the reaction was removed by purging with nitrogen. The reaction mixture could be stirred for 1.5 hours and the progress of the reaction was monitored regularly using TLC and LCMS. After 1.5 hours the reaction was quenched with the use of a 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 in vacuo. The yield - 281.18 g, 79.5%, NMR compared to the IR literature, (FTIR, vmax / cm-1) 3299, 3121, 3008, 2954, 1789, 1674, 1521, 1406, 1206, 1100, 980, 881, 757; 1H-NMR (CDCl3, 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 =
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4.4, 2.4 Hz) 3.97 (3H, s); 13C NMR (CDCI3, 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) [0332] NBS (N-Bromosuccinimide, 2.36 g, 13, 24 mmol, 1.0 equiv.) Was 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 left to reach room temperature (approximately 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, ymax / cm-1): 3148, 2956, 1669 (C = O), 1458, 1215, 1189, 1062, 923, 842, 823, 748, 678; 1HRMN (CDCl3, 400 MHz) δ 7.46 (1H, d, J = 2.0 Hz), 6.95 (1H, d, J = 1.6 Hz) 3.95 (3H, s); 13C NMR (CDCl3, 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) [0333] 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
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54/75 combined, dried (MgSO4), filtered and concentrated in vacuo to provide the product as a pale white solid. (2.28 g, 97%). IR (FTIR, νmax / cm-1): 3138, 2948, 1692, 1472, 1334, 1245, 1115, 1082, 921, 823, 753; 1H-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 (s, 3H); 13C-NMR (100 MHz, CDCl3): 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 methyl 219.26 (M + H) + (iv) 4- (4- (tert-butoxycarbonylamino) phenyl) -1-methyl-1 H-pyrrol-2-carboxylate ( 5) [0334] A catalytic amount of tetracis (triphenylphosphine) paladin, Pd (PPh3) 4 (0.477g, 0.413, 0.06 eq.) Was added to a solution of 4 (1.5 g, 6.88 mmol, 1 eq.) And (4 - ((tert-butoxycarbonyl) amino) phenyl) boronic acid (1.57 g, 6.88 mmol, 1.20 eq.) In a 9: 3: 1 combination (13.5 ml ) of EtOH, toluene and water in the presence of K2CO3 (2.856 g, 3 eq ..) in a 10 to 20 ml microwave container containing a magnetic stirrer. The reaction vessel was purged with nitrogen during each addition. The reaction mixture was sealed in an N2 inert atmosphere and heated with microwave radiation in an EMRYS ™ (Optimizer Microwave Station) microwave optimizer station (Personal Chemistry) at 100 ° C for 12 minutes. After the LCMS and TLC analyzes 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, νmax / cm-1): 3353, 2975, 1696, 1521, 1441, 1366, 1264, 1235, 1209, 1058, 822, 799, 657; 1H-NMR (400 MHz, CDCl3): 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); 13C-NMR (100 MHz, CDCl3): 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
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330.46 (M + H) + (b) 4- (4- (tert-butoxycarbonylamino) phenyl) -1-methyl-1H-pyrrole-2-carboxylic acid (6)
6 [0335] A 0.5 M solution of NaOH (2.0 eq) was added to a solution of 5 (1.0 g, 3.027 mmol) in dioxane (40 ml). The reaction mixture was allowed to stir at room temperature for 6 hours at which point the TLC revealed completion of the reaction. 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 the 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) calculated for C17H20N2O4 (M) ⁺ 316.35 obtained 315.16 (M + H) ⁺ (c)
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(i) Methyl 4- (4-aminophenyl) -1-methyl-1H-pyrrole-2-carboxylate (7) [0336] 5 (1g, 3.027 mmol) was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 ml) was added slowly to the solution while being stirred. The reaction mixture was stirred for 6 hours when TLC showed completion of the reaction. Excess solvent was evaporated in vacuo to obtain a brown solid 7. The solid product was subjected to flash chromatography (n-hexane / EtOAc 9: 1) to generate pure 7 (065 g, 94.2%). IR (FTIR, y ^max / cm ^-1 ): 3,366, 2,987,1,688, 1,629, 1,566, 1,422, 1,372, 1,262, 1,181, 1,103, 1,067, 951, 821, 784, 756; ¹ H NMR (400 MHz, CDCla): 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, CDCla): δ 161.7, 144.7, 126.2, 125.4,125.2, 115.5, 114.4, 51.0, 36.8; EIMS m / z (+ EI) calculated for C13H14N2O2 (M) ⁺ 230.26 obtained 231.1 (M + H) ⁺

(i)
Methyl 4- (4- (4-aminophenyl) -1-methyl-1H-pyrrole-2-carboxamido) -1-methyl-1H-pyrrole-2carboxylate (9) [0337] 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 be stirred
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57/75 for 30 minutes after the same 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 when TLC showed completion of the reaction. The reaction was cooled by pouring it 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), saturated aqueous NaHCO3 (100 ml), water (100 ml), brine (100 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated through rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, yield 90.6%) was used for the bit deprotection step to provide 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 solution being stirred. The reaction mixture was stirred for 6 hours when TLC showed completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown colored solid (9). The solid product was subjected to flash chromatography (9: 1 n-hexane / EtOAc) to generate pure 9. Yield 0.21 gm, 95%.
(ii) 4- (4- (4- (4-aminophenyl) -1-methyl-1 H-pyrrole-2-carboxamido) - 1-methyl-1Hpyrrole-2-carboxamido) -1-methyl-1H-pyrrole- Methyl 2-carboxylate (10) [0338] 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 when TLC showed 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 from 9a as a white solid (yield 0.23 g, 91 , 6%). To a solution being stirred from the white solid (0.23 gm,
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0.52 nmol) in DMF, 2.0 equivalent of EDCI and 2.5 equivalent of DMAP was added. After stirring the mixture for 20 minutes, commercially available methyl 4-amino-1-methyl-1Hpyrrole-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 when TLC showed completion of the reaction. The reaction was cooled by pouring it 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. Excess ethyl acetate was evaporated by the rotary evaporator under reduced pressure and the crude product was used for the bit deprotection step to provide 10. For 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 solution while being stirred. The reaction mixture was stirred for 3 hours when TLC showed completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown colored solid (10). The solid product was subjected to flash chromatography (n-hexane / EtOAc 8: 2) to generate pure 10. Yield 0.20 gm, 83% over 2 stages.
[0339] 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) calculated for C25H26N6O4 (M) ⁺ 474.51 obtained 475.35 ([M + H] ⁺
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Methyl 4- (4- (4-aminophenyl) -1-methyl-1H-pyrrole-2-carboxamido) -1-methyl-1H-imidazole2-carboxylate (11) [0340] 0.3 gm of protected bit 6 ( 0.94 mmol, 1.2 eq) was dissolved in DMF (5 ml) to which 2.0 eq of EDCI and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes, after the same commercially available methyl 4-amino-1-methyl-1Himidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 6 hours when TLC showed completion of the reaction. The reaction was cooled by pouring it 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 NaHCO3 (50 ml), water (50 ml), brine (50 ml) and finally dried over MgSO4. Excess ethyl acetate was evaporated through the rotary evaporator under reduced pressure and the crude product (0.48 gm) was used for the bit deprotection step to provide 11. For the bit deprotection, the raw intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 ml) was added slowly to the solution while being stirred. The reaction mixture was stirred for 2 hours when TLC showed completion of the reaction. The excess solvent was evaporated in vacuo to obtain a brown colored solid (11). The solid product was subjected to flash chromatography (n-hexane / EtOAc 9: 1) to generate pure 11. Yield 0.35 gm, 81% over two stages.
[0341] 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) calculated for C18H19N5O3 (M) ⁺ 353.38 obtained 354.42 ([M + H] ⁺ (f) acid 4- (10- (allyloxycarbonyl) -7-methoxy-5-oxo-11- (tetrahydro-2H-pyran-2-yloxy) 2,3,5, 10,11,11a-hexahydro-1H-pyrrolo [2,1-c] [1,4] benzodiazepine-8-yloxy) butanoic (13)
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[0342] A 0.5 M NaOH solution (made from 1.4135 g NaOH) was added to a solution of 12 (Compound 18, document No WO 2007/039752) in dioxane at room temperature. The reaction mixture was allowed to stir for 4 hours when TLC showed 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 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) calculated for C26H34N2O9 (M) ⁺ 518.56 obtained 519.26 (M + H) ⁺ [0343] Other amine formation blocks Q ¹ and Q ² are commercially available or synthesized in an analogous manner .
Example 1 (Comparative compounds)
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General Experimental Procedure for coupling different formation blocks to THP Aloc protected PBD acid to different formation blocks. Example provided here is for 15a. Similar procedures were followed to obtain other hybrids of C8-bound THP Aloc protected PBD.
7-methoxy-8- (4- (4- (5- (methoxycarbonyl) -1-methyl-1 H-pyrrol-3-yl) phenylamino) -4oxobutoxy) -5-oxo-11- (tetrahydro-2H-pyran -2-yloxy) -2,3,11,11a-hexahydro-1H-pyrrolo [2,1c] [1,4] benzodiazepine-10 (5H) -carboxylate (11aS) -alyl (15a) [0344] One solution of PBD acid protected with THP Aloc 13 (3.72 g, 7.16 mmol, 1.2 equivalent) was dissolved in DMF. EDCI (2.49 g, 13.02 mmol, 2.0 eq) and DMAP (1.989 g, 16.28 mmol, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to mix. was stirred for 30 minutes after which MPB-ester 7 (1.5 g, 6.514 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 2 hours when TLC showed completion of the reaction. The reaction was cooled by pouring it 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 NaHCOa (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 was purified by flash chromatography on silica gel (MeOH: CHCl3, 20:80) to generate a foamy solid.
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62/75 white, 15a. Yield - 4.05 g, 85.5%.
(FTIR, vmax / cm ^-1 ): 2,949, 2,362, 1,704, 1,600, 1,514, 1,436, 1,372, 1,269, 1,203, 1,107, 1,021,964, 765. ( ¹ H NMR, 400 MHz, CDCLb): 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), 1.601.44 (m, 12H); ( ¹³ C NMR, 100 MHz, CDCla): 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) calculated for C39H46N4O10 (M) ⁺ 730.80 obtained 731.67 ([M + H] ⁺
General Experimental Procedure to obtain the final PBD imine by deprotecting the C8-bound THP Aloc protected PBD hybrid. Example provided here is for 16.
[0345] Tetrakis [triphenylphosphine] palladium (5.60 mg, 4.8 pM, 0.05 equiv) was added to a solution of PBD THP Aloc 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 when TLC showed completion of the reaction. Excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue dried in vacuo to remove pyrrolidone. The product was purified by column chromatography (eluted with n-hexane 651-7, EtOAc 35%) to generate the product as a yellowish solid, 3.37 (40 mg, 77%). [o] ²² - ⁷ d + 165 ° (c = 0.046, CHCl3); IR (FTIR, v ^max / cm ¹ ): 3,297, 2,944, 2,358, 1,701, 1,598, 1,567, 1,508, 1,442, 1,374, 1,264, 1,212, 1,181, 1,106, 1,072, 824, 730; ¹ H NMR (500 MHz, CDCla): 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
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63/75 = 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 (side chain ligand CH2, m, 2H), 3.94 (3H, s, NCH3) , 3.88 (3H, s, O-CH3), 3.68-3.71 (1H, m, H-11a), 3.50-3.60 (2H, m, H2-3), 2.582, 62 (2H, m, CH2), 2.26-2.31 (4H, m, CH2), 1.50-1.54 (2H, m, CH2); ¹³ C NMR (125 MHz, CDCIs): 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) calculated for C30H32N4O6 (M + H) ⁺ 545.2400 obtained 545.2422 (M + H) ⁺ , δ 4ppm [0346] Compound 18 was done in an analogous manner.
5- (4- (4- ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8 (S) -methyl (18) -yl) oxy) butanamido) phenyl) thiophene-2-carboxylate (18).
¹ H NMR (500 MHz, CDCl 3): δ 7.75 (1H, s), 7.69 (2H, d, J = 8.4 Hz), 7.58 (1H, s), 7.49 ( 2H, d, J = 8.4), 7.23 (1H, d, J = 4.0 Hz), 7.13 (1H, d, J = 4.0 Hz), 4.24 (chain linker lateral CH2, m, 2H), 3.90 (3H, s, O-CH3), 3.86 (3H, s, O-CH3), 3.71 3.73 (1H, m, H-11 a) , 3.50-3.60 (2H, m, H2-3), 2.55-2.67 (2H, m, CH2), 2.23-2.33 (4H, m, CH2), 1, 56-1.74 (2H, m, CH2); ¹³ C NMR (125 MHz, CDCI3): δ 164.5, 162.5, 161.4, 150.6, 147.7, 140.6, 134.5, 132.9, 132.1, 131, 9, 128.6, 126.8, 120.3, 114.6, 111.8, 111.0, 94.4 (2C), 68.0, 63.7, 56.1, 53.7, 52 , 1,46,6, 36,8, 31,9, 29,6, 25,2, 24,8,
24.1, 20.2; HRMS m / z (+ EI) calculated for C29H29N3O6S (M + H) ⁺ 547.6200 obtained 547.6422 (M + H) ⁺
Example 2 (Compounds of the present invention)

ex. 26a ex. 26
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[0347] General Experimental Procedure to couple different (Q1) formation blocks to 13 PBD acid protected by THP Aloc to different formation blocks. Example provided here is for 14a. Similar procedures were followed to obtain other PBD hybrid intermediates protected with C8-bound THP Aloc.
(4 - ((((11S, 11aS) -10 - (((allyloxy) carbonyl) -7-methoxy-5-oxo-11 - (((tetrahydro2H-pyran-2-yl) oxy) -2,3,5, 10,11,11a-hexahydro-1H-benzo [e] pyrrolo [1,2-a] [1,4] diazepin-8yl) oxy) butanamido) -1-methyl-1 H-pyrrole-2-carboxylic (14a ).
[0348] A solution of THP Aloc 13 protected PBD acid (1.85 g, 3.57 mmol, 1.2 equivalent) was dissolved in DMF. EDCI (1.24 g, 6.48 mmol, 2.0 eq) and DMAP (0.99 g, 8.1 mmol, 2.5 eq) were added to the stirred solution of 13 at room temperature and allowed to the mixture was stirred for 30 minutes after which commercially available methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.5 g, 3.243 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for an additional 6 hours when TLC showed completion of the reaction. The reaction was cooled by pouring it over a mixture mixture
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65/75 ice / water 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 through a rotary evaporator under reduced pressure and the crude product (1.88 gm) was used for hydrolysis reaction to provide 14a. For hydrolysis, lithium hydroxide (0.24 g, 5.71 mmol, 3 eq) was added to the crude product (1.88 g, 2.87 mmol) in aqueous dioxane (75 ml dioxane, 11.5 ml water ) at room temperature. The reaction mixture was stirred for 3 hours when TLC showed 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 combined organic layer 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 two-step).
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- side chain 1, pyran H6), 3.87 (3H, s, O / NCH3), 3.87 (3H, s, O / NCH3), 3.86 (3H, s), 3.53-3.44 (3H , m), 2.552.45 (2H, m), 2.13-1.88 (6H, m), 1.70-1.39 (6H). m / z (+ EI) calculated for C32H40N4O10 (M) ⁺ 640.68 obtained 641.57 ([M + H] ⁺
General experimental procedure to obtain 26a of 14a by coupling blocks of formation of Q2 to blocks of formation Q1 containing intermediates (for example, 14a).
[0349] 7-methoxy-8- (4 - ((5 - ((4- (5- (methoxycarbonyl) -1-methyl-1 H-pyrrol-3yl) phenyl) carbamoyl) -1-methyl-1H-pyrrole -3-yl) amino) -4-oxobutoxy) -5-oxo-11 - (((tetrahydro-2Hyran-2-yl) oxy) -2,3,11,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2-a] [1,4] diazepine-10 (5H) (11S, 11aS) -alyl (26a) carboxylate.
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66/75 [0350] A Pyd acid solution of PBD protected with THP Aloc 14a (150 mg, 0.23 mmol, 1.0 equivalent) was dissolved in DMF. EDCI (0.46 mmol, 2.0 eq) and DMAP (0.58 mmol, 2.5 eq) were added to the stirred solution of 14a at room temperature and the mixture was allowed to stir for 30 minutes after which benzofuran-5-amine (38.3 mg, 0.29 mmol, 1.25 eq) was added. The reaction mixture was allowed to stir for an additional 3 hours when TLC showed completion of the reaction. The reaction was cooled by pouring it 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 NaHCOa (50 ml), water (50 ml), brine (50 ml) and finally dried over MgSO4. The excess ethyl acetate was evaporated through a rotary evaporator under reduced pressure and the crude product was used directly in the next step without further purification.
m / z (+ EI) calculated for C40H45N5O10 (M) ⁺ 755.91 obtained 756.76 ([M + H] ⁺ .
[0351] Compounds 26a, 27a, 28a, 30a, 31a, 35a, 37a, 39a, 40a, 49a, 51a, 52a, 53a, 54a and 56a were obtained in an analogous manner .__________
Q ² h ₃ co s — C jç/ (/ N - ά \ --- / n-- '£
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General experimental procedure to obtain 26 of 26a through simultaneous THP Aloc deprotection.
(i) (S) -N- (benzofuran-5-yl) -4- (4 - (((7-methoxy-5-oxo-2,3,5 _! 11a-tetrahydro-1Hbenzo [e] pyrrole [1, 2-a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-1H-pyrrole-2carboxamide (26) [0352] Tetrakis [triphenylphosphine] palladium (12.17 mg, 10.5 μΜ , 0.05 equiv) was added to a solution of PBD THP Aloc 26a conjugate (154 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 hours when TLC showed completion of the reaction. Excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue dried in vacuo to remove pyrrolidone. The product was purified by high performance liquid chromatography (eluted with acetone: water gradient with 1% TFA) to generate the product as a light yellow solid, 26 (38 mg, 36% after HPLC purification).
¹ H NMR (500 MHz, CDCl3): 7.98 (1H, s), 7.94 (1H, d, J = 2.0 Hz), 7.83 (1H, s), 7.65 (1H , d, J = 4.4 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.52 (1H, s), 7.42 (1H, d, J = 9.0
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Hz), 7.33 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.10 (1H, s), 6.82 (1H, s, H-9), 6.71 ( 1H, s) 4,064.14 (2H, m, CH2), 3.90 (3H, s, N-CH3), 3.88 (3H, s, O-CH3), 3.66-3.72 (1H , m, H-11a), 3.50-3.59 (2H, m, H2-3), 2.47-2.54 (2H, m, CH2), 2.18-2.31 (4H, m, CH2), 1.95-2.08 (2H, m); ¹³ C NMR (125 MHz, CDCla): δ 169.9, 164.6, 162.7,159.9, 151.9, 150.6,
147.7, 145.7, 140.6, 133.2, 132.1, 128.5, 127.8, 123.4 (2C), 121.5, 120.5, 119.6, 118.0 ,
113.2, 111.8, 111.3, 111.0, 106.8 (2C), 103.9, 68.1, 56.2 (2C), 53.7, 46.7 (2C), 36 , 7 (2C), 33.1, 29.8, 24.5, 24.1; HRMS m / z (+ EI) calculated for C31H31N5O6 (M) ⁺ 569.6900 obtained 569.6981 ([M + H] ⁺ ) [0353] Compounds 27, 28, 30, 31.35, 37, 39, 40, 49, 51, 52, 53, 54 and 56 were obtained in an analogous manner.
ii) (S) -N- (benzo [b] thiophen-5-yl) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 Hbenzo [e ] pyrrole [1,2-a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-1 H-pyrrole-2carboxamide (27)
¹ H NMR (500 MHz, CDCla): δ 8.23 (1H, d, J = 4.5 Hz), 8.21 (1H, d, J = 2.0 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 4.0 Hz), 7.61 (1H, d, J = 1.6 Hz), 7.53 (1H, d, J = 3.6 Hz), 7.48 (1H, s), 7.45 (2H, dd, J = 8.0 Hz, 2.0 Hz), 7.39 (1H, s), 7.09 (1H, d, J = 1.6 Hz), 6.80 (1H, s, H-9), 4.03-4.08 (2H, m, CH2), 3.85 (3H, s, N -CH3), 3.82 (3H, s, O-CH3), 3.63-3.69 (1H, m, H-11a), 3.49-3.57 (2H, m, H2-3) , 2.44-2.49 (2H, m, CH2), 2.15-2.29 (4H, m, CH2), 1.95-2.04 (2H, m); ¹³ C NMR (125 MHz, CDCla): δ 169.9,
164.6, 162.7,160.0, 150.7, 147.7, 140.7, 140.1, 135.1, 132.8, 131.9, 128.6, 127.3,
123.9, 123.2, 122.5, 121.6, 120.4, 119.8, 118.1, 114.8, 111.8, 110.9, 104.2, 68.1.56, 1 (2C), 53.7, 46.7 (2C), 36.7 (2C), 32.9, 29.5, 24.9, 24.2;
iii) 5- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8 -yl) oxy) butanamido) -1-methyl-1H-pyrrole-2carboxamido) (S) -methyl (28) thiophene-2-carboxylate (28)
¹ H NMR (500 MHz, CDCla): δ 8.29 (1H, d, J = 2.0 Hz), 8.10 (1H, s), 7.97 (1H, s), 7.76 ( 1H, d, J = 8.0 Hz), 7.73 (1H, s), 7.66 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.64 (1H,
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69/75 d, J = 1.6 Hz), 7.55 (2H, dd, J = 8.0 Hz, 2.0 Hz), 7.47 (2H, d, J = 3.0 Hz), 7.11 (1H, s), 6.83 (1H, s, H-9), 4.09-4.15 (2H, m, CH2), 3.93 (3H, s, N-CH3), 3.90 (3H, s, O-CH3), 3.87 (3H, s, O-CH3), 3.68-3.73 (1H, m, H-11 a), 3.51 -3, 60 (2H, m, H2-3), 2.49-2.57 (2H, m, CH2), 2.19-2.34 (4H, m, CH2), 1.94-2.09 (2H , m); ¹³ C NMR (125 MHz, CDCla): δ
169.9, 164.6, 163,2,150.6, 147.7, 139.3, 137.66, 135.7, 134.3, 132.8, 132.1, 132.0,
131.9, 130.5, 128.6, 123.1, 122.5, 121.5, 120.9, 120.0, 116.1, 111.8, 104.2, 101.1,
68.1, 56.2 (2C), 53.7, 52.5, 46.7 (2C), 36.7 (2C), 33.1.29.6, 25.0, 24.2;
iv) (S) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-N- (4-morpholinophenyl) -1 H-pyrrole-2carboxamide (30)
¹ H NMR (500 MHz, CDCla): δ 7.71 (1H, s), 7.65 (1H, d, J = 4.6 Hz), 7.52 (1H, s), 7.46 ( 2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 2.0 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.82 (1H, s), 6.55 (1H, d, J = 1.6 Hz), 4.05-4.19 (2H, m, CH2), 3.88 (3H, s, N-CH3), 3.85 (3H, s, OCH3), 3.73-3.82 (4H, m), 3.66-3.72 (1H, m, H-11a), 3.52-3.60 (2H, m, H2-3), 3.03-3.13 (4H, m), 2.50-2.56 (2H, m, CH2), 2.19-2.33 (4H, m, CH2), 1, 97-2.07 (2H, m); ¹³ C NMR (125 MHz, CDCl3): δ 169.9, 164.6, 162.7, 159.6, 150.6, 148.1, 147.7, 130.8, 123.5,
121.5, 120.6, 119.5, 116.4, 111.8, 111.1, 103.8, 68.1, 66.9 (2C), 56.2 (2C), 53.7, 49.8, 46.7 (2C), 36.7 (2C), 33.1.29.6, 25.0, 24.2;
v) (S) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo [e] pyrrole [1,2a] [1,4] diazepin- 8-yl) oxy) butanamido) -1-methyl-N- (6-morpholinopyridin-3-yl) -1 H-pyrrole-2carboxamide (31)
¹ H NMR (400 MHz, CDCla): δ 8.23 (1H, s), 7.92 (1H, s), 7.89 (1H, d, J = 8.4 Hz), 7.83 ( 1H, s), 7.65 (1H, d, J = 3.6 Hz), 7.51 (1H, s), 7.08 (1H, s), 6.82 (1H, s), 6, 63 (1H, d, J = 8.4 Hz), 6.56 (1H, s), 4.05-4.16 (2H, m, CH2), 3.91 (3H, s, N-CH3) , 3.85 (3H, s, O-CH3), 3.74-3.82 (4H, m), 3.67-3.71 (1H, m, H-11a), 3.51-3, 61 (2H, m, H2-3), 3,413.48 (4H, m), 2.49-2.57 (2H, m, CH2), 2.17-2.26 (2H, m, CH2), 1.99-2.09 (2H, m); ¹³ C NMR (100 MHz, CDCla): δ 169.9, 164.5, 162.7, 159.9, 156.8, 150.6, 147.7, 140.6,
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131.5, 126.3, 123.0, 121.5, 120.6, 119.7, 111.9, 111.1, 106.8, 104.2, 68.1, 66.7 (2C), 56 , 2 (2C), 53.7, 46.7, 46.1 (2C), 41.0, 36.7 (2C), 33.1.29.6, 25.0, 24.2;
vi) 5- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8 -yl) oxy) butanamido) -1-methyl-1H-imidazole-2carboxamido) (S) -methyl (35) thiophene-2-carboxylate (35)
¹ H NMR (500 MHz, CDCla): δ 9.04 (1H, s), 8.35 (1H, s), 8.04 (1H, s), 7.74 (1H, d, J = 8 , 4 Hz), 7.66 (1H, d, J = 4.0 Hz), 7.61 (1H, d, J = 1.6 Hz), 7.53 (1H, d, J = 3.6 Hz), 7.48 (1H, s), 7.45 (2H, dd, J = 8.0 Hz, 2.0 Hz), 7.39 (1H, s), 7.09 (1H, d, J = 1.6 Hz), 4.10-4.22 (2H, m, CH2), 3.96 (3H, s, N-CH3), 3.94 (3H, s, O-CH3), 3 , 80 (3H, s, O-CH3), 3.66-3.71 (1H, m, H-11a), 3.50-3.57 (2H, m, H2-3), 2.49- 2.57 (2H, m, CH2), 2.21-2.34 (4H, m, CH2), 1.95-2.08 (2H, m); ¹³ C NMR (125 MHz, CDCla): δ 169.9, 164.6,
163,2,150,6, 147,7, 139,3, 137,66, 135,7, 134,3, 132,9, 132,1, 132,0, 131,9, 130,5,
128.5, 123.2, 122.5, 121.5, 120.1, 120.0, 115.4, 114.8, 11.6, 111.0, 100.0, 67.7, 56.1 ( 2C), 53.7, 52.5, 46.7 (2C), 35.8 (2C), 33.0, 29.6, 24.7, 24.1;
vii) (S) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-N- (4-morpholinophenyl) -1 H-imidazole-2carboxamide (37)
¹ H NMR (400 MHz, CDCla): δ 8.80 (1H, s), 7.98 (1H, s), 7.83 (1H, s), 7.64 (1H, d, J = 4 , 0 Hz), 7.54 (1H, s), 7.51 (2H, d, J = 8.4 Hz), 7.40 (1H, s), 6.90 (2H, d, J = 8 , 4 Hz), 6.82 (1H, s), 4.05-4.18 (2H, m, CH2), 4.01 (3H, s, N-CH3), 3.95 (3H, s, O-CH3), 3.74-3.82 (4H, m), 3.67-3.71 (1H, m, H-11a), 3.52-3.57 (2H, m, H2-3 ), 3.11 - 3.14 (4H, m), 2.61 - 2.63 (2H, m, CH2), 2.17-2.23 (2H, m, CH2), 2.02-2 , 09 (2H, m); ¹³ C NMR (125 MHz, CDCla): δ 169.9, 164.5, 162.5, 156.4, 150.5, 148.3, 147.8, 140.7, 135.7,
133.9, 130.2, 120.9, 120.6, 116.3, 114.5 (2C), 111.6, 110.9, 67.8, 66.9 (2C), 56.1 ( 2C),
53.7, 49.7 (2C), 46.7, 35.8 (2C), 29.6, 24.8, 24.1;
viii) (S) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-N- (4- (2-morpholinoethoxy) phenyl) -1 H-
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¹ H NMR (400 MHz, CDCla): δ 8.80 (1H, s), 7.96 (1H, s), 7.83 (1H, s), 7.65 (1H, d, J = 4 , 0 Hz), 7.54 (1H, s), 7.51 (2H, d, J = 8.8 Hz), 7.41 (1H, s), 6.90 (2H, d, J =
8.8 Hz), 6.83 (1H, s), 4.17-4.22 (2H, m, CH2), 4.06-4.12 (4H, m), 4.06 (3H, s , N-CH3), 3.95 (3H, s, O-CH3), 3.72-3.79 (4H, m), 3.67-3.71 (1H, m, H-11a), 3 , 52-3.57 (2H, m, H2-3), 2.79-2.81 (4H, m), 2.53-2.66 (6H, m, CH2), 2.31-2, 29 (2H, m, CH2), 2.01-2.07 (2H, m); ¹³ C NMR (100 MHz, CDCla): δ 174.7, 169.5, 167.0, 162.5, 155.6, 149.4, 147.8, 147.8, 140.7, 135, 7, 131.8, 130.9, 121.3, 120.6, 115.1, 111.6, 110.9, 67.8, 66.9 (2C), 66.0, 57.6, 56 , 1 (2C), 54.0, 53.7, 48.2 (2C), 46.7, 35.8 (2C), 33.0, 29.6, 24.8,
24.2, 24.1;
ix) (S) -4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) -1-methyl-N- (6-morpholinopyridin-3-yl) -1 H-imidazole-2carboxamide (40)
¹ H NMR (400 MHz, CDCla): δ 8.73 (1H, s), 8.27 (1H, s), 7.98 (2H, m), 7.64 (1H, d, J = 3 , 6 Hz), 7.53 (1H, s), 7.42 (1H, s), 6.82 (1H, s), 6.64 (1H, d, J = 7.2 Hz), 4.074, 22 (2H, m, CH2), 4.04 (3H, s, N-CH3), 3.93 (3H, s, O-CH3), 3.78-3.85 (4H, m), 3.673, 72 (1H, m, H-11a), 3.52-3.59 (2H, m, H2-3), 3.44-3.5 (4H, m), 2.58-2.65 (2H , m, CH2), 2.23-2.34 (2H, m, CH2), 2.00-2.08 (2H, m); ¹³ C NMR (100 MHz, CDCla): δ
169.6, 164.5, 162.7, 159.9, 150.4, 147.8, 140.6, 139.9, 135.8, 133.6, 130.4, 125.7,
120.7, 114.6, 111.7, 110.9, 106.8, 67.8, 66.7 (3C), 56.1 (2C), 53.7, 46.7, 46.1 (2C) , 35.7 (2C), 32.9, 29.6, 24.7, 24.2;
x) (S) -4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1, 4] diazepin-8-yl) oxy) butanamido) phenyl) -1-methyl-N- (4-morpholinophenyl) -1H-pyrrole-2carboxamide (49)
¹ H NMR (400 MHz, CDCla): δ 7.75 (1H, s), 7.9 (1H, s), 7.64 (1H, d, J = 4.0 Hz), 7.52 ( 1H, s), 7.46 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.00 (1H, s), 6.91 ( 1H, s), 6.90 (2H, d, J = 8.0 Hz), 6.82 (1H, s), 4.08-4.14 (2H, m, CH2), 3.98 (3H , s, N
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CH3), 3.87 (3H, s, O-CH3), 3.74-3.82 (4H, m), 3.69-3.74 (1H, m, H-11a), 3.55- 3.4 (2H, m, H2-3), 3.11-3.13 (4H, m), 2.58-2.60 (2H, m, CH2), 2.25-2.31 (4H , m, CH2), 2.03-2.06 (2H, m); ¹³ C NMR (100 MHz, CDCI3): δ 175.4, 169.9, 162.5, 162.7, 150.4, 148.1,
147.7, 140.7, 130.8, 125.4, 124.9, 123.2, 121.6, 120.4, 116.4, 111.7, 110.9, 109.3,
67.9, 66.9 (2C), 56.1 (2C), 53.7, 49.8, 46.7 (2C), 36.9 (2C), 34.1.29.6, 24, 8, 24.2;
xi) (S) -4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1, 4] diazepin-8-yl) oxy) butanamido) phenyl) -1-methyl-N- (4- (2-morpholinoethoxy) phenyl) -1 Hpirrola-2-carboxamide (51)
¹ H NMR (400 MHz, CDCla): δ 7.77 (1H, s), 7.73 (1H, s), 7.65 (1H, d, J = 4.4 Hz), 7.52 ( 1H, s), 7.8 (2H, d, J = 8.0 Hz), 7.45 (1H, s), 7.38 (2H, d, J = 8.0 Hz), 7.00 ( 1H, s), 6.91 (2H, d, J = 8.8 Hz), 6.83 (1H, s), 4.14-4.18 (2H, m, CH2), 4.09-4 , 14 (4H, m), 3.98 (3H, s, N-CH3), 3.87 (3H, s, O-CH3), 3.77-3.83 (1H, m, H-11 a ), 3.71-3.75 (4H, m), 3.52-3.57 (2H, m, H2-3), 2.79-2.82 (2H, m), 2.53-2 , 64 (6H, m, CH2), 2.25-2.31 (4H, m, CH2), 2.01-2.07 (2H, m); ¹³ C NMR (100 MHz, CDCla): δ 174.7, 164.6, 162.2,
159.8, 155.4, 150.5, 147.7, 140.7, 135.7, 131.8, 126.6, 125.4, 125.0, 122.0, 120.4, 115.0, 111.7, 110.9, 67.9, 66.8 (2C), 66.0, 57.6, 56.1 (2C), 54.1 (2C), 53.7, 46.7, 35 , 9, 33.0, 29.6, 24.8, 24.2, xii) (S) -4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11 α-tetrahydro-1 H-benzo [e] pyrrolo [1,2a] [1,4] diazepin-8-yl) oxy) butanamido) phenyl) -1-methyl-N- (4- (2-morpholinoethoxy) benzyl ) -1 Hpirrola-2-carboxamide (52)
¹ H NMR (500 MHz, CDCla): δ 7.77 (1H, s), 7.68 (1H, s), 7.65 (1H, d, J = 4.0 Hz), 7.51 ( 1H, s), 7.44 (2H, d, J = 8.0 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.27 (1H, s), 6.96 ( 1H, d, J = 2.0 Hz), 6.88 (2H, dd, J = 7.0, 2.0 Hz), 6.82 (1H, s), 6.73 (1H, s), 4.50 (2H, d, J = 5.5 Hz), 4.10-4.20 (4H, m, CH2), 3.98 (3H, s, N-CH3), 3.87 (3H, s, O-CH3), 3.78-3.83 (1H, m, H-11a), 3.68-3.71 (4H, m), 3.52-3.59 (2H, m, H2 -3), 2.80-2.82 (2H, m), 2.53-2.64 (6H, m, CH2), 2.24-2.33 (4H, m, CH2), 2.01 -2.07 (2H, m); ¹³ C NMR (125 MHz, CDCl3): δ 174.7, 164.6, 161.6, 158.1, 150.4, 147.7, 140.7, 137.5, 135.7, 131, 8, 129.2,
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126.6, 125.4, 124.5, 120.4, 114.9 (2C), 111.7, 110.9, 108.7, 67.9, 66.8 (2C), 66.0, 57, 6, 56.1 (2C), 54.1 (2C), 53.7, 46.7, 35.9, 33.0, 29.6, 24.8, 24.2, xiii) (S) - 4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo [e] pyrrole [1,2a] [1,4] diazepin-8-yl ) oxy) butanamido) phenyl) -1-methyl-N- (6-morpholinopyridin-3-yl) -1 H-pyrrole2-carboxamide (53).
¹ H NMR (500 MHz, CDCla): δ 8.25 (1H, s), 7.96 (1H, d, J = 6.5 Hz), 7.90 (1H, s), 7.85 ( 1H, s), 7.65 (1H, d, J = 4.0 Hz), 7.51 (1H, s), 7.44 (2H, d, J = 8.0 Hz), 7.35 ( 2H, d, J = 8.0 Hz), 7.00 (1H, s), 6.95 (1H, s), 6.82 (1H, s), 6.65 (1H, d, J = 9 , 0 Hz), 4,084.15 (2H, m, CH2), 3.97 (3H, s, N-CH3), 3.84 (3H, s, O-CH3), 3.78-3.82 ( 4H, m), 3,673.70 (2H, m, H2-3), 3.53-3.59 (1H, m, H-11a), 3.42-3.46 (4H, m), 2, 55-2.58 (2H, m, CH2), 2.23-2.30 (4H, m, CH2), 1.99-2.05 (2H, m); ¹³ C NMR (125 MHz, CDCla): δ
174.7, 164.6, 162.7, 159.9, 156.8, 150.4, 147.7, 140.7, 131.6, 126.2, 125.4, 125.1, 120.4, 111.7, 110.8, 109.6, 106.9, 67.9, 66.7 (3C), 56.1, 53.7, 46.7, 46.1 (2C), 41.0, 36.9 (2C), 34.0, 29.6, 24.8, 24.2;
xiv) 4- (4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1,2a] [1, 4] (S) -methyl diazepin-8-yl) oxy) butanamido) phenyl) furan-2-carboxamido) -1-methyl-1 H-pyrrole-2carboxylate (54)
¹ H NMR (500 MHz, CDCla): δ 7.98 (1H, s, NH), 7.88 (1H, s, NH), 7.68 (1H, s, H-6), 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-CH3), 3.84 (3H, s, O-CH3), 3.79 (3H, s, OCH3), 3.66-3.70 (1H, m, H-11a), 3.55-3.60 (2H, m, H2-3), 2.56-2.61 ( 2H, m, CH2), 2,232.32 (4H, m, CH2), 2.00-2.05 (2H, m); ¹³ C NMR (125 MHz, CDCla): 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;
Petition 870190100538, of 10/07/2019, p. 89/96
74/75 xv) 4- (4- (4- (4- (4 - ((7-methoxy-5-oxo-2,3,5,11 a-tetrahydro-1 H-benzo [e] pyrrole [1 , (S) -methyl (56), 2-a] [1,4] diazepin-8-yl) oxy) butanamido) phenyl) furan-2carboxamido) phenyl) -1-methyl-1H-pyrrole-2-carboxylate (56).
¹ H NMR (500 MHz, CDCla): 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 (side chain linker CH2, m, 2H), 4.00 (3H, s, N-CH3), 3.96 (3H , s, N-CH3), 3.88 (3H, s, O-CH3), 3.84 (3H, s, O-CH3), 3.70-3.73 (1H, m, H-11a) , 3,553.61 (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, CDCla): 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, 24.1,20.2 .
Example 3 - Antibacterial Evaluation [0354] The antibacterial properties of the compounds of the invention 26, 27, 28, 30, 31, 33, 35, 37, 39, 40, 49, 51, 52, 53, 54, 56 and 59 were compared with comparative compounds 16 and 18 against a number of bacterial strains using the CLSI broth microplate assay, as described below.
[0355] Methicillin-resistant Staphylococcus aureus (MRSA) strains EMRSA15 and EMRSA-16 were isolated from clinical material at the Royal Free Hospital, London; the MRSA BB568 strain was a gift from Brigitte Berger-Bãchi, Institute of Medical Microbiology, University of Zürich, Switzerland. The USA300 associated community MRSA isolate was purchased by the American Type Culture Collection as BAA1556. The VISA S. aureus Mu50 strain is an MRSA clinical isolate with intermediate resistance to vancomycin and was isolated and supplied by Keiichi Hiramatsu, Juntendo University, Tokyo. ATCC 29213 is a reference strain of S. aureus susceptible to antibiotics. Vancomycin-resistant enterococcus isolates E. faecalis VRE1
Petition 870190100538, of 10/07/2019, p. 90/96
75/75 and E. faecium VRE10 were isolated at the Royal Free Hospital. Bacteria were grown in Mueller-Hinton broth (MH) (Oxoid) or on MH agar plates at 37 ° C.
[0356] MICs of antibacterial agents were determined by the CLSI broth microplate assay as previously described (Hadjivassileva T, Stapleton PD, Thurston DE et al. Interactions of pyrrolobenzodiazepine dimers and duplex DNA from methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 2007; 290: 672 to 678); agents were dissolved in DMSO before dilution in broth. At the concentrations used, the solvent had no effect on bacterial growth. Three MIC determinations per strain were performed in duplicate for each compound tested ._____________________________________________________
PBD No. Minimum inhibitory concentration (MIC mg / l) EMRSA -15 EMRSA -16 BB568 USA300 Mu50 VRE1 VRE10 16 * > 32 32 > 32 > 32 32 > 32 16 18 * > 32 > 32 > 32 32 > 32 > 32 16 26 0.06 0.125 0.125 0.125 0.06 0.06-0.125 0.06 27 0.03 0.125 0.125 0.06-0.125 <0.03 0.125 0.03 28 0.06 0.125 0.125 0.060.06 0.06 30 0.5 2 2 0.51 0.5 31 0.5 4 4 11 0.5 35 0.06 0.06 0.06 0.060.06 0.06 37 0.125 0.5 0.5 0.1250.25 0.125 39 0.25 0.25 0.25-0.5 0.5 0.125 0.125 0.5 40 0.125 0.5 0.5 0.125 - 0.25 0.125 49 2 2 2 2 1 0.5 0.5-1 51 2 2 2 2 1 0.5 1 52 4 1-2 4 4 2 2 1 53 1 2-4 4 4 2 1 0.5 54 <0.03 0.06 0.125 0.06 0.03 0.06 <0.03 56 0.25 0.5 0.5 1 0.5 0.5 0.25 59 2 16 16 16 to 32 4 32 4
* Comparative Examples

权利要求:
Claims (11)
[1]
1. Compound, CHARACTERIZED by the fact that it has formula I:

[2]
2/4

[3]
3/4 each F ¹ is independently a C3-20 heteroarylene group;
m is 1,2 or 3;
G is selected from hydrogen, C1-4 alkyl group, -C (= O) -O-C1-4 alkyl, (CH2) n-C3-20 heterocycloalkyl and -O- (CH2) n-C3-20 heterocycloalkyl;
each n is 0-4;
provided that A2 is not A2 ':

[4]
4/4
3. Compound according to claim 1 or 2, CHARACTERIZED by the fact that there is no double bond between C2 and C3 and R ² is H.
A compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that X ¹ and Y ¹ are selected from: N and NMe and CH and NMe, respectively.
[5]
A compound according to any one of claims 1 to 4, CHARACTERIZED by the fact that F is - (EF ¹ ) m-, and F ¹ is a C5 heteroarylene group.
[6]
6. Compound, according to claim 5, CHARACTERIZED by the fact that F ¹ is represented by the structure F11:

[7]
7. Compound according to claim 5 or 6, CHARACTERIZED by the fact that E is a single bond.
[8]
8. A compound according to claim 5 or 6, CHARACTERIZED by the fact that E is -C (= O) -NH-.
[9]
Compound according to any one of claims 1 to 8,
CHARACTERIZED by the fact that G is selected from the group consisting of -H, Me, -C (= O) -O-Me, - (CH2) n-N (CH2CH2OCH2CH2) and -O- (CH2) n-N (CH2CH2OCH2CH2).
[10]
10. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 9.
[11]
11. Use of a compound, as defined in any of claims 1 to 9, CHARACTERIZED by the fact that it is in the manufacture of a drug to treat bacterial infection.

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JP2020517652A|2017-04-20|2020-06-18|アーデーセー セラピューティクス ソシエテ アノニム|Combination therapy|

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GB201900929D0|2019-01-23|2019-03-13|King S College London|Nf-kappa b inhibitors|

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WO2021137646A1|2019-12-31|2021-07-08|주식회사 레고켐바이오사이언스|Pyrrolobenzodiazepine derivative and ligand-linker conjugate thereof|

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GB2597532A|2020-07-28|2022-02-02|Femtogenix Ltd|Cytotoxic compounds|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-20| B25C| Requirement related to requested transfer of rights|Owner name: UCL BUSINESS PLC (GB) , SPIROGEN SARL (CH) Free format text: A FIM DE ATENDER A TRANSFERENCIA, REQUERIDA ATRAVES DA PETICAO NO 860160061528 DE 18/03/2016, E NECESSARIO APRESENTAR A TRADUCAO JURAMENTADA DO DOCUMENTO, ALEM DA GUIA DE CUMPRIMENTO DE EXIGENCIA. Owner name: UCL BUSINESS PLC (GB) , SPIROGEN SARL (CH) |

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-06-26| B25A| Requested transfer of rights approved|Owner name: MEDIMMUNE LIMITED (GB) ; UCL BUSINESS PLC (UK) |

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2019-01-29| 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 |

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2019-07-09| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-02-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-03-03| 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. |

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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. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261640316P| true| 2012-04-30|2012-04-30|

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US61/640.316|2012-04-30|

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PCT/GB2013/051097|WO2013164592A1|2012-04-30|2013-04-30|Pyrrolobenzodiazepines|

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