WO2010136778A1 - Dérivés de dibenzothiophène en tant qu'inhibiteurs d'adn-pk - Google Patents

Dérivés de dibenzothiophène en tant qu'inhibiteurs d'adn-pk Download PDF

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WO2010136778A1
WO2010136778A1 PCT/GB2010/001075 GB2010001075W WO2010136778A1 WO 2010136778 A1 WO2010136778 A1 WO 2010136778A1 GB 2010001075 W GB2010001075 W GB 2010001075W WO 2010136778 A1 WO2010136778 A1 WO 2010136778A1
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mmol
compound according
group
optionally substituted
evaporated
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Mark Frigerio
Marc Geoffrey Hummersone
Keith Allan Menear
Maurice Raymond Verschoyle Finlay
Edward Jolyon Griffen
Linette Lys Ruston
Jeffrey James Morris
Attila Kuan Tsuei Ting
Bernard Thomas Golding
Roger John Griffin
Ian Robert Hardcastle
Sonsoles Rodriguez-Aristegui
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Kudos Pharmaceuticals Limited
Cancer Research Technology Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to compounds which act as DNA-PK inhibitors, their use and synthesis.
  • DNA-PK The DNA-dependent protein kinase
  • DNA-PKcs a large catalytic subunit
  • Ku a regulatory component of DNA-PK
  • DNA DSBs are regarded as the most lethal lesion a cell can encounter.
  • eukaryotic cells have evolved several mechanisms to mediate their repair. In higher eukaryotes, the predominant of these mechanisms is DNA non-homologous end-joining (NHEJ), also known as illegitimate recombination.
  • NHEJ DNA non-homologous end-joining
  • DNA-PK plays a key role in this pathway. Increased DNA-PK activity has been demonstrated both in vitro and in vivo and correlates with the resistance of tumour cells to IR and bifunctional alkylating agents (Muller C, et al., Blood, 92, 2213-2219 (1998), Sirzen F., et al., Eur. J.
  • DNA-PK activity has been proposed as a cellular and tumour resistance mechanism.
  • inhibition of DNA-PK with a small molecule inhibitor may prove efficacious in tumours where over-expression is regarded as a resistance mechanism.
  • LY294002 is able to inhibit DNA-PK function in vitro (Izzard, R.A., et a/., Cancer Res., 59, 2581-2586 (1999)).
  • the IC 50 concentration at which 50% of enzyme activity is lost
  • LY294002 is also able to weakly sensitise cells to the effects of IR (Rosenzweig, K.E., et al., CHn. Cancer Res., 3, 1149-1156 (1999)).
  • WO 03/024949 describes a number of classes of compounds useful as DNA-PK inhibitors, including 2-amino-chromen-4-ones of the general structure:
  • This compound exhibited an IC 50 of 10-12 nM and an DMR of 1.3 (see below for methods).
  • WO 2006/032869 describes compounds useful as DNA-PK inhibitors, including 2-amino- chromen-4-ones of the general structure:
  • Y is an optionally substituted C 1 .5 alkylene group and X is selected from H, or a thioether or amino group.
  • WO 2006/109081 describes compounds useful as DNA-PK inhibitors, including 2-amino- pyridopyrimidines of the general structure:
  • Y is an optionally substituted Ci -5 alkylene group and X is selected from H, or a thioether or amino group.
  • DNA-PK inhibitors may also prove useful in the treatment of retroviral mediated diseases. For example it has been demonstrated that loss of DNA-PK activity severely represses the process of retroviral integration (Daniel R, et al., Science, 284, 644-7 (1999)).
  • the present inventors have now discovered further compounds which exhibit similar or improved levels of DNA-PK inhibition to exsiting compounds, whilst generally exhibiting lower levels of Pl 3-kinase inhibition.
  • the compounds may also possess other useful properties for use as active pharmaceuticals, in particular improved solubility and cellular efficacy.
  • Some of the compounds of the present invention also show good solubility in both aqueous media and phosphate buffer solution - enhanced solubility may be of use in formulation the compounds for administration by an IV route, or for oral formulations (e.g. liquid and small tablet forms) for paediatric use.
  • the oral bioavailablity of the compounds of the present invention may be enhanced.
  • the first aspect of the invention provides a compound of formula I: wherein:
  • X 1 and X 2 may be either (a) C and O, (b) N and N, or (c) C and NH, where the dotted bonds represents a double bond in the appropriate location;
  • R 1 and R 2 are independently selected from hydrogen, an optionally substituted Ci -7 alkyl group, an optionally substituted C 3-2O heterocyclyl group, or an optionally substituted C 5-2 O aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
  • R N1 is selected from hydrogen and an optionally substituted C 1-4 alkyl group
  • R C1 is selected from an optionally substituted C 1-7 alkyl group, an optionally substituted C 3-2 O heterocyclyl group, or an optionally substituted C 5-20 aryl group; or R N1 and R C1 may together form an optionally substituted C 2-4 alkylene group.
  • a second aspect of the invention provides a composition comprising a compound of the first aspect and a pharmaceutically acceptable carrier or diluent.
  • a third aspect of the invention provides a compound of the first aspect for use in a method of therapy.
  • a fourth aspect of the invention provides for the use of a compound of the first aspect in the preparation of a medicament for treating a disease ameliorated by the inhibition of DNA-PK.
  • the fourth aspect of the invention also provides a compound of the first aspect for use in the method of treatment of a disease ameliorated by the inhibition of DNA-PK.
  • the compounds of the first aspect selectivity inhibit the activity of DNA-PK compared to Pl 3-kinase.
  • the compounds may be: (a) used as, or in the preparation of a medicament for use as an adjunct in cancer therapy or for potentiating tumour cells for treatment with ionising radiation or chemotherapeutic agents; or (b) used to treat, or in the preparation of a mediacament for the treatment of, retroviral mediated diseases.
  • a further aspect of the invention provides an active compound as described herein for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical composition.
  • Another aspect of the invention provides a method of inhibiting DNA-PK in vitro or in vivo, comprising contacting a cell with an effective amount of an active compound as described herein.
  • Ci -7 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a Ci -7 hydrocarbon compound having from 1 to 7 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
  • saturated linear C 1-7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, and n-pentyl (amyl).
  • saturated branched C 1-7 alkyl groups include, but are not limited to, iso-propyl, iso-butyl, sec-butyl, tert-butyl, and neo-pentyl.
  • saturated alicyclic Ci -7 alkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as substituted groups (e.g., groups which comprise such groups), such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl and cyclohexylmethyl.
  • substituted groups e.g., groups which comprise such groups
  • Examples of unsaturated C 1-7 alkyl groups which have one or more carbon-carbon triple bonds include, but are not limited to, ethynyl (ethinyl) and 2-propynyl (propargyl).
  • Examples of unsaturated alicyclic (carbocyclic) Ci -7 alkyl groups which have one or more carbon-carbon double bonds include, but are not limited to, unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as substituted groups (e.g., groups which comprise such groups) such as cyclopropenylmethyl and cyclohexenylmethyl.
  • C 3-20 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a C 3-20 heterocyclic compound, said compound having one ring, or two or more rings (e.g., spiro, fused, bridged), and having from 3 to 20 ring atoms, atoms, of which from 1 to 10 are ring heteroatoms, and wherein at least one of said ring(s) is a heterocyclic ring.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • Ring heteroatoms may preferably be selected from the group consisting of O, N, S and P.
  • C 3-20 denotes ring atoms, whether carbon atoms or heteroatoms.
  • C 3-20 heterocyclyl groups having one nitrogen ring atom include, but are not limited to, those derived from aziridine, azetidine, pyrrolidines (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole), piperidine, dihydropyridine, tetrahydropyridine, and azepine.
  • pyrrolidines tetrahydropyrrole
  • pyrroline e.g., 3-pyrroline, 2,5-dihydropyrrole
  • 2H-pyrrole or 3H-pyrrole isopyrrole, isoazole
  • piperidine dihydropyridine, tetrahydropyridine, and azepine.
  • C 3-20 heterocyclyl groups having one oxygen ring atom include, but are not limited to, those derived from oxirane, oxetane, oxolane (tetrahydrofuran), oxole (dihydrofuran), oxane (tetrahydropyran), dihydropyran, pyran (C 6 ), and oxepin.
  • substituted C 3-20 heterocyclyl groups include sugars, in cyclic form, for example, furanoses and pyranoses, including, for example, ribose, lyxose, xylose, galactose, sucrose, fructose, and arabinose.
  • Examples of C 3-20 heterocyclyl groups having one sulphur ring atom include, but are not limited to, those derived from thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), and thiepane.
  • Examples of C 3-2O heterocyclyl groups having two oxygen ring atoms include, but are not limited to, those derived from dioxolane, dioxane, and dioxepane.
  • C 3-2 O heterocyclyl groups having two nitrogen ring atoms include, but are not limited to, those derived from imidazolidine, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole), and piperazine.
  • C 3-2 O heterocyclyl groups having one nitrogen ring atom and one oxygen ring atom include, but are not limited to, those derived from tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine.
  • C 3-2 O heterocyclyl groups having one oxygen ring atom and one sulphur ring atom include, but are not limited to, those derived from oxathiolane and oxathiane (thioxane).
  • C 3-20 heterocyclyl groups having one nitrogen ring atom and one sulphur ring atom include, but are not limited to, those derived from thiazoline, thiazolidine, and thiomorpholine.
  • C 3-20 heterocyclyl groups include, but are not limited to, oxadiazine and oxathiazine.
  • C 5 heterocyclics such as furanone, pyrone, pyrrolidone (pyrrolidinone), pyrazolone
  • C 5-20 aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C 5-2 O aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
  • each ring has from 5 to 7 ring atoms.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups", in which case the group may conveniently be referred to as a "C 5-20 carboaryl” group.
  • C 5-20 aryl groups which do not have ring heteroatoms include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ), naphthalene (Cio), anthracene (Ci 4 ), phenanthrene (Ci 4 ), naphthacene (Ci 6 ), and pyrene (C 16 ).
  • aryl groups which comprise fused rings include, but are not limited to, groups derived from indene and fluorene.
  • the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulphur, as in “heteroaryl groups".
  • the group may conveniently be referred to as a "C 5-20 heteroaryl” group, wherein “C 5-20 " denotes ring atoms, whether carbon atoms or heteroatoms.
  • each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.
  • C 5-2 O heteroaryl groups include, but are not limited to, C 5 heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1 ,3-diazole), pyrazole (1 ,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, oxadiazole (furazan) and oxatriazole; and C 6 heteroaryl groups derived from isoxazine, pyridine (azine), pyridazine (1 ,2-diazine), pyrimidine (1 ,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) and triazine.
  • C 5 heteroaryl groups derived from furan (o
  • C 5-2 O heterocyclic groups (some of which are C 5-20 heteroaryl groups) which comprise fused rings, include, but are not limited to, C 9 heterocyclic groups derived from benzofuran, isobenzofuran, indole, isoindole, purine (e.g., adenine, guanine), benzothiophene, benzimidazole; Ci 0 heterocyclic groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine, quinoxaline; C 13 heterocyclic groups derived from carbazole, dibenzothiophene, dibenzofuran; Ci 4 heterocyclic groups derived from acridine, xanthene, phenoxathiin, phenazine, phenoxazine, phenothiazine.
  • Halo -F, -Cl, -Br, and -I.
  • Ether -OR, wherein R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group, discussed below), a C 3-20 heterocyclyl group (also referred to as a C 3-20 heterocyclyloxy group), or a C 5-20 aryl group (also referred to as a C 5-20 aryloxy group), preferably a C 1-7 alkyl group.
  • R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group, discussed below), a C 3-20 heterocyclyl group (also referred to as a C 3-20 heterocyclyloxy group), or a C 5-20 aryl group (also referred to as a C 5-20 aryloxy group), preferably a C 1-7 alkyl group.
  • C 1-7 alkoxy -OR, wherein R is a C 1-7 alkyl group.
  • Examples of C 1-7 alkoxy groups include, but are not limited to, -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy) and -OC(CH 3 ) 3 (tert-butoxy).
  • Oxo (keto, -one): 0.
  • lmino (imine): NR, wherein R is an imino substituent, for example, hydrogen, C 1-7 alkyl group, a C 3 . 2 oheterocyclyl group, or a C 5-20 aryl group, preferably hydrogen or a C 1-7 alkyl group.
  • R is an acyl substituent, for example, a group (also referred to as C 1-7 alkylacyl or Ci -7 alkanoyl), a C 3-20 heterocyclyl group (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a Ci-7 alkyl group.
  • R is an acyl substituent, for example, a group (also referred to as C 1-7 alkylacyl or Ci -7 alkanoyl), a C 3-20 heterocyclyl group (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a Ci-7 alkyl group.
  • Acyloxy (reverse ester): -OC( O)R, wherein R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C( O)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl and phthalimidyl:
  • R 1 and R 2 are independently ureido substituents, for example, hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably hydrogen or a C 1-7 alkyl group.
  • R 3 is an acyl group as defined for acyl groups.
  • acylureido groups include, but are not limited to, -NHCONHC(O)H, - NHCONMeC(O)H, -NHCONEtC(O)H, -NHCONMeC(O)Me, -NHCONEtC(O)Et, - NMeCONHC(O)Et, -NMeCONHC(O)Me, -NMeCONHC(O)Et, -NMeCONMeC(O)Me, - NMeCONEtC(O)Et, and -NMeCONHC(O)Ph.
  • Carbamate -NR 1 -C(O)-OR 2 wherein R 1 is an amino substituent as defined for amino groups and R 2 is an ester group as defined for ester groups.
  • carbamate groups include, but are not limited to, -NH-C(O)-O-Me, -NMe-C(O)-O-Me, -NH-C(O)-O-Et, -NMe- C(O)-O-t-butyl, and -NH-C(O)-O-Ph.
  • Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a Ci -7 alkyl group (also referred to as Ci -7 alkylamino or di-d -7 alkylamino), a C 3-2 O heterocyclyl group, or a C 5-2 O aryl group, preferably H or a Ci -7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • a Ci -7 alkyl group also referred to as Ci -7 alkylamino or di-d -7 alkylamino
  • C 3-2 O heterocyclyl group or a C 5-2 O aryl group, preferably H or a Ci -7 alkyl group
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -NHC(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
  • cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
  • Imino: NR, wherein R is an imino substituent, for example, for example, hydrogen, a Ci. 7 alkyl group, a C 3-20 heterocyclyl group, or a Cs -20 aryl group, preferably H or a Ci -7 alkyl group.
  • R is an imino substituent, for example, for example, hydrogen, a Ci. 7 alkyl group, a C 3-20 heterocyclyl group, or a Cs -20 aryl group, preferably H or a Ci -7 alkyl group.
  • azino groups include, but are not limited to, -C(O)-NN-H, - C(O)-NN-Me, -C(O)-NN-Et, -C(O)-NN-Ph, and -C(O)-NN-CH 2 -Ph.
  • R is a thioether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkylthio group), a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Examples of Ci -7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • Disulfide -SS-R 1 wherein R is a disulfide substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group (also referred to herein as C 1-7 alkyl disulfide).
  • C 1-7 alkyl disulfide groups include, but are not limited to, -SSCH 3 and -SSCH 2 CH 3 .
  • Sulfone (sulfonyl): -S( O) 2 R, wherein R is a sulfone substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Sulfine (sulfinyl, sulfoxide): -S( O)R, wherein R is a sulfine substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R is a sulfinyloxy substituent, for example, a Ci -7 alkyl group, a C3- 2 0 heterocyclyl group, or a Cs -2O aryl group, preferably a Ci -7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a Ci -7 alkyl group, a C 3-2 O heterocyclyl group, or a Cs -20 aryl group, preferably a C 1-7 alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a Ci -7 alkyl group, a C 3-2 O heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • a special class of sulfonamino groups are those derived from sultams - in these groups one of R 1 and R is a C 5-20 aryl group, preferably phenyl, whilst the other of R 1 and R is a bidentate group which links to the C 5-20 aryl group, such as a bidentate group derived from a Ci -7 alkyl group.
  • examples of such groups include, but are not limited to:
  • Examples of phosphoramidite groups include, but are not limited to, -OP(OCH 2 CH 3 )-N(CH3)2, -OP(OCH 2 CH 3 )-N(i-Pr) 2 , and -OP(OCH 2 CH 2 CN)-N(J-Pr) 2 .
  • a C 1-7 alkoxy group may be substituted with, for example, a C 1-7 alkyl (also referred to as a C 1-7 alkyl- C 1-7 alkoxy group), for example, cyclohexylmethoxy, a C 3-20 heterocyclyl group (also referred to as a C 5-20 aryl-C 1-7 alkoxy group), for example phthalimidoethoxy, or a C 5-20 aryl group (also referred to as a C 5-20 aryl-C 1-7 alkoxy group), for example, benzyloxy.
  • a C 1-7 alkyl also referred to as a C 1-7 alkyl- C 1-7 alkoxy group
  • cyclohexylmethoxy for example, cyclohexylmethoxy, a C 3-20 heterocyclyl group (also referred to as a C 5-20 aryl-C 1-7 alkoxy group), for example phthalimidoethoxy
  • a reference to carboxylic acid also includes the anionic (carboxylate) form (-COO ' ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ - forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomers" (or "isomers" (or "isomers" (or "
  • isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxy phenyl).
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. ScL, 66, 1-19 (1977).
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • 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(CH 3 J 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulphuric, sulphurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric, phenylsulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, pantothenic, isethionic, valeric, lactobionic, and gluconic.
  • suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH- Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (- NHCO-OC(CHa) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6- nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-NH-
  • a carboxylic acid group may be protected as an ester for example, as: an Ci -7 alkyl ester (e.g. a methyl ester; a t-butyl ester); a Ci -7 haloalkyl ester (e.g., a Ci -7 trihaloalkyl ester); a triCi -7 alkylsilyl-Ci -7 alkyl ester; or a C 5-2 O aryl-Ci -7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an Ci -7 alkyl ester e.g. a methyl ester; a t-butyl ester
  • a Ci -7 haloalkyl ester e.g., a Ci -7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • some prodrugs are esters of the active compound (e.g. a physiologically acceptable metabolically labile ester).
  • Examples of such metabolically labile esters include those wherein R is C 1-7 alkyl (e.g. -Me, -Et); Ci -7 aminoalkyl (e.g.
  • acyloxy-C 1-7 alkyl e.g. acyloxymethyl; acyloxyethyl; e.g.
  • pivaloyloxymethyl acetoxy methyl; 1-acetoxyethyl; 1-(1-methoxy-1- methyl)ethyl-carbonxyloxyethyl; 1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1 -cyclohexyl- carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4- tetrahydropyranyloxy) carbonyloxymethyl; 1 -(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • 'Selective inhibition means the inhibition of one enzyme to a greater extent than the inhibition of one or more other enzymes. This selectivity is measurable by comparing the concentration of a compound required to inhibit 50% of the activity (IC 50 ) of one enzyme against the concentration of the same compound required to inhibit 50% of the activity (IC 50 ) of the other enzyme (see below). The result is expressed as a ratio. If the ratio is greater than 1 , then the compound tested exhibits some selectivity in its inhibitory action.
  • the compounds of the present invention preferably exhibit a selectivity of greater than 3, 10, 20, 50 or 100 against DNA-PK over Pl 3-kinase.
  • IC 50 values used to assess selectivity are determined using the methods described in the examples below.
  • R 1 and R 2 when R 1 and R 2 form, along with the nitrogen atom to which they are attached, a heterocyclic ring having from 4 to 8 atoms, this may form part of a C4-20 heterocyclyl group defined above (except with a minimum of 4 ring atoms), which must contain at least one nitrogen ring atom. It is preferred that R 1 and R 2 form, along with the nitrogen atom to which they are attached, a heterocyclic ring having 5, 6 or 7 atoms, more preferably 6 ring atoms.
  • Single rings having one nitrogen atom include azetidine, azetidine, pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole), piperidine, dihydropyridine, tetrahydropyridine, and azepine;
  • two nitrogen atoms include imidazolidine, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole), and piperazine;
  • one nitrogen and one oxygen include tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine;
  • one nitrogen and one sulphur include
  • Preferred rings are those containing one heteroatom in addition to the nitrogen, and in particular, the preferred heteroatoms are oxygen and sulphur.
  • preferred groups include morpholino, thiomorpholino, thiazolinyl.
  • Preferred groups without a further heteroatom include pyrrolidino.
  • the most preferred groups are morpholino and thiomorpholino. As mentioned above, these heterocyclic groups may themselves be substituted; a preferred class of substituent is a C 1-7 alkyl group.
  • the substituent group or groups are preferably methyl or ethyl, and more preferably methyl. A sole methyl substituent may be in the 2 or 3 position. If the morpholino group does bear a sole methyl substituent, the morpholino group has a chiral centre; thus, a racemic or enantiomeric group may be present.
  • rings with bridges or cross-links are also envisaged.
  • Examples of these types of ring where the group contains a nitrogen and an oxygen atom are:
  • R N1 is selected from hydrogen and an optionally substituted C 1-4 alkyl group.
  • R N1 is hydrogen
  • R N1 is an optionally substituted C 1-4 alkyl group.
  • the optional substituents may be selected from halo, hydroxy, nitro, cyano, -NH 2 and thiol.
  • the substituents may be selected from halo and hydroxy.
  • the C 1-4 alkyl group is unsubstituted.
  • the C 1-4 alkyl group may be methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopropylmethyl. In some embodiments, the group may be methyl, or cyclopropylmethyl.
  • Particular groups of interest are hydrogen, unsubstituted methyl and unsubstituted cyclopropylmethyl.
  • R C1 is an optionally substituted C 1 .7 alkyl group.
  • R C1 is an optionally susbstituted C 1-4 alkyl group, e.g. methyl, ethyl, propyl, cyclopropyl, butyl, cyclobutyl.
  • R C1 is an optionally substituted C 1-7 alkyl, or C 1-4 alkyl, group
  • R C1 is an optionally substituted C 1-7 alkyl, or C 1-4 alkyl, group
  • group may be selected from: C 5 . 2 o aryl, C 3-2O heterocyclyl, halo, hydroxy, ether, oxo, imino, formyl, acyl, carboxy, ester, acyloxy, amido, acylamido, acylureido, carbamate, thioamido, tetrazolyl, amino, imino, amidine, carbazoyl, nitro, nitroso, azido, cyano, isocyano, cyanato, thiocyanato, isothiocyano, thiol, thioether, disulfide, sulfone, sulfine, sulfonyloxy, sulfinyloxy, s
  • the optional substituents when R C1 is an optionally substituted C 1-7 alkyl, or C 1-4 alkyl, group may be selected from: C 5-2O aryl, C 3-20 heterocyclyl, halo, hydroxy, ether, carboxy, ester, acyloxy, amido, acylamido, amino, nitro, cyano, thiol and thioether.
  • the optional substituents when R C1 is an optionally substituted C 1-7 alkyl, or C 1-4 alkyl, group may be selected from: amino, C 5-20 aryl (e.g. C 6 aryl), cyano, carboxy and acylamido.
  • the C 6 aryl substituent may be phenyl or pyridyl.
  • the optional substituents when R C1 is an optionally substituted C 1-7 alkyl, or C 1-4 alkyl, group may be selected from: C 5-20 aryl (e.g. C 6 aryl), hydroxy, carboxy, ester, acylamido, amino, cyano and sulfone.
  • R C1 group When the substituent on R C1 is amino, the R C1 group may be of formula III:
  • R N2 and R N3 are independently selected from hydrogen, an optionally substituted C 1-7 alkyl group, an optionally substituted C 3-20 heterocyclyl group, or an optionally substituted C 5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms.
  • R N2 and R N3 are independently selected from hydrogen and an optionally substituted C 1 .7 or C 1-4 alkyl group.
  • the C 1-7 or C 1-4 alkyl group may be unsubstituted, and may be, for example, methyl or ethyl.
  • the heterocyclic ring may have 5, 6 or 7 atoms, and in particular embodiments 6 ring atoms.
  • Single rings having one nitrogen atom include azetidine, azetidine, pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole), piperidine, dihydropyridine, tetrahydropyridine, and azepine;
  • two nitrogen atoms include imidazolidine, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole), and piperazine;
  • one nitrogen and one oxygen include tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine;
  • one nitrogen and one sulphur include
  • Rings of particular interest are those containing one heteroatom in addition to the nitrogen, and in particular, oxygen, sulphur and nitrogen.
  • groups of particular interest include morpholino, thiomorpholino and piperazinyl, with morpholino being of most interest.
  • piperazinyl is of interest.
  • these heterocyclic groups may themselves be substituted; a class of substituent that may be present is a Ci -7 , or C 1-4 , alkyl group, e.g. methyl, ethyl.
  • a morpholino group this may be unsubstituted or substituted with one or two methyl groups (i.e. methylmorpholino, dimethylmorpholino), or one or two ethyl groups (i.e. ethylmorpholino, diethylmorpholino).
  • the R C1 group may be of formula HIa: where R N4 is an optionally substituted C 1-7 or C 1-4 alkyl group, and Q is as defined above.
  • the optional substituents for R N4 may be selected from hydroxy, halo, cyano, and in some embodiments may be hydroxy.
  • R N4 may be methyl, hydroxymethyl, ethyl and hydroxyethyl.
  • C 1-7 alkyl groups of particular interest are those of formula III where R N2 and R N3 together form, along with the nitrogen atom to which they are attached, an optionally substituted morpholino group, where the optional substituents are C 1-4 alkyl (e.g. methyl, ethyl). In these groups, it may be that Q is methylene or ethylene.
  • C 1-7 alkyl groups of particular interest are pyridyl substituted methyl or ethyl.
  • the pridyl groups may themselves be unsubsituted.
  • R C1 is an optionally substituted C 5-20 aryl group.
  • R C1 is an optionally substituted C 5-6 aryl group.
  • the C5-6 aryl group may be a C 5 or C 6 aryl group.
  • the C 5 aryl group may be selected from furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and oxatriazolyl.
  • the C 5 aryl group may be selected from furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl and isothiazolyl.
  • a C 5 aryl group of particular interest is oxazolyl.
  • the C 6 aryl group may be selected from phenyl, isoxazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. In some embodiments is may be selected from phenyl and pyridinyl. In other embodiments, the C 6 aryl group may also be pyrimidinyl.
  • the C 5-6 aryl group may be selected from phenyl, pyrrolyl, oxazolyl and pyridyl. In some of these embodiments, the C 5-6 aryl group may be selected from oxazolyl and pyridyl.
  • R C1 is an optionally substituted C 9- -I 0 aryl group.
  • the C 9-I0 aryl group may be a C 9 aryl group or a C 10 aryl group.
  • the Cg aryl groups may be derived from benzofuran, isobenzofuran, indole, isoindole, purine (e.g., adenine, guanine), benzothiophene and benzimidazole.
  • the C 10 aryl groups may be derived from quinoline, isoquinoline, benzodiazine, pyridopyridine, quinoxaline and naphthalene.
  • the C 9-10 aryl group may be indolyl.
  • the optional substituents on the C 5-2 O aryl group may be selected from: hydroxy, C 1-4 alkoxy, carboxy, C 1-4 alkyl ester, cyano, nitro and halo.
  • the optional substituents on the C 5-2O aryl group may also be selected from: C 1-4 alkyl (e.g. methyl).
  • these substituents may be hydroxy, cyano or carboxy, or the group may be unsubstituted.
  • C 5-20 aryl groups of particular interest are oxazolyl and pyridyl, which may be unsubstituted.
  • Other C 5-20 aryl groups of particular interest are phenyl (optionally substituted by carboxy or methyl ester, pyrimidinyl (optionally substituted by methyl) and pyrrolyl (optionally substituted by cyano).
  • R C1 is an optionally substituted C 3-20 heterocyclyl group.
  • R C1 may be a C 4-6 heterocyclic group.
  • R C1 may be a C 4 , C 5 or C 6 heterocyclic group.
  • the C 4 heterocyclic groups may be derived from azetidine, oxetane, thietane, dioxetane and dithiethane.
  • the C 5 heterocyclic groups may be derived from pyrrolidine, oxolane, thiolane, imidazoline, oxazolidine, thiazolidine, dioxolane and dithiolane.
  • the C 6 heterocyclic groups may be derived from piperidine, tetrahydropyran, thiane, piperazine, oxazine, dithiane, dioxane and trioxane.
  • R C1 may be selected from azetidinyl and piperidinyl (bound via a carbon atom). In some of these embodiments, R C1 may be piperidinyl (bound via a carbon atom).
  • R C1 is an optionally substituted C 3-2 O heterocyclyl, or C 4-6 heterocyclyl, group
  • Ci -20 alkyl e.g. C 1-4 alkyl
  • C 5-20 aryl halo, hydroxy, ether, oxo, imino, formyl, acyl, carboxy, ester, acyloxy, amido, acylamido, acylureido, carbamate, thioamido, tetrazolyl, amino, imino, amidine, carbazoyl, nitro, nitroso, azido, cyano, isocyano, cyanato, thiocyanato, isothiocyano, thiol, thioether, disulfide, sulfone, sulfine, sulfonyloxy, sulfinyloxy, sulfamino, sulfonamino, s
  • the optional substituents when R C1 is an optionally substituted C 3-20 heterocyclyl, or C 4-6 heterocyclyl, group may be selected from: C L20 alkyl (e.g. C 1-4 alkyl), C 5- 20 aryl, halo, hydroxy, ether, carboxy, ester, acyloxy, amido, acylamido, amino, nitro, cyano, thiol and thioether
  • the optional substituents when R C1 is an optionally substituted C 3-20 heterocyclyl, or C 4-6 heterocyclyl, group may be Ci -4 alkyl (e.g. methyl).
  • C 3-20 heterocyclyl groups of particular interest are piperidinyls (bound via a carbon atom) and in particular, N-methyl piperidinyls.
  • R N1 and R C1 together form an optionally substituted C 2-4 alkylene group.
  • the group is
  • the C 2 - 4 alkylene group may be unsubstituted. If the group is substituted, the substituents may be selected from: halo, hydroxy, nitro and cyano.
  • the compounds are of formula Ix:
  • X 1 and X 2 may be either (a) C and O 1 or (b) N and N, and NR 1 R 2 is selected from:
  • Formula 2 either by activating the compound of Formula 2 or with the assistance of an amide coupling reagent, e.g. HBTU, HATU, HOBt, or by activation of the acid of formula 2.
  • an amide coupling reagent e.g. HBTU, HATU, HOBt
  • the compound coupled to the compound of formula 1 may only form part of the compound of formula 2, and a further derivitisation may be required to achieve the desired compound.
  • R N1 is hydrogen by treatment with a stong base, e.g sodium hydride, followed by reaction with R N1 - X, where X is a halogen, e.g. I.
  • a stong base e.g sodium hydride
  • the present invention provides active compounds, specifically, active substituted dibeznothiophenyl, amino-chromen-4-ones, aminopyridopyrimidines or aminoquinolinones.
  • active pertains to compounds which are capable of inhibiting DNA-PK activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • the present invention further provides a method of inhibiting DNA-PK inhibition in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practised in vitro or in vivo.
  • a sample of cells e.g. from a tumour
  • an active compound brought into contact with said cells in conjunction with agents that have a known curative effect, and the enhancement of the curative effect of the compound on those cells observed.
  • the present invention further provides active compounds which inhibit DNA-PK activity as well as methods of methods of inhibiting DNA-PK activity comprising contacting a cell with an effective amount of an active compound, whether in vitro or in vivo.
  • Active compounds may also be used as cell culture additives to inhibit DNA-PK, for example, in order to sensitize cells to known chemotherapeutic agents or ionising radiation treatments in vitro.
  • Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the invention further provides active compounds for use in a method of treatment of the human or animal body. Such a method may comprise administering to such a subject a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. prophylaxis is also included.
  • terapéuticaally-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
  • adjunct anti-cancer agents that could be combined with compounds from the invention include, but are not limited to, the following: alkylating agents: nitrogen mustards, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil: Nitrosoureas: carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), ethylenimine/methylmelamine, thriethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): Alkyl sufonates; busulfan; Triazines, dacarbazine (DTIC): Antimetabolites; folic acid analogs, methotrex
  • the present invention provides active compounds which are anticancer agents or adjuncts for treating cancer.
  • active compounds which are anticancer agents or adjuncts for treating cancer.
  • One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.
  • cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma and leukemias.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • gastrointestinal including, e.g., bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • anti-tumour agents may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinT], the anti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (AvastinT) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2- fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and
  • immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
  • vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • a pharmaceutical composition e.g. formulation
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxy propylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
  • Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
  • the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • DRX400 operating at 400 MHz 1 a Bruker DRX500 operating at 500 MHz or a Bruker AV700 operating at 700 MHz.
  • NMR spectra were obtained at 400 MHz in c ⁇ -dimethylsulfoxide. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; (vi) Unless stated otherwise compounds containing an asymmetric carbon and/or sulphur atom were not resolved;
  • 2-chloro-5-methoxyphenylboronic acid (1.25 g, 6.71 mmol), 2,6-dibromoaniline (1.851 g, 7.38 mmol), sodium carbonate (6.71 mL, 13.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.465 g, 0.40 mmol) were dissolved in dioxane (10 mL), degassed and sealed into a microwave tube. The reaction was heated to 150 0 C for 1 hour in the microwave reactor and cooled to room temperature.
  • the reaction mixture was poured into saturated aqueous NH 4 CI solution (100 mL), extracted with EtOAc (100 mL), and the organic layer was washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO 4 , filtered and evaporated to afford an orange oil.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane.
  • the reaction was cooled to room temperature, filtered and the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with 2N NaOH (20 mL), water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over MgSO 4 , filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • N-(6-bromodibenzo[b,d]thiophen-2-yl)-2-hydroxy-2-methylpropanamide (A6, 221 mg, 0.61 mmol) was suspended in ethanol (5 mL) and 6N hydrochloric acid (2.5 ml_). The reaction was then heated at reflux for 36 hours. The reaction was then cooled and diluted with water (20 mL) and neutralised with 2N aqueous NaOH solution. The aqueous phase was then extracted with DCM (3 x 10 mL). The combined organic extracts were then purified by ion exchange chromatography, using an SCX column.
  • the reaction was heated to 150 0 C for 1 hour in the microwave reactor and cooled to room temperature. The reaction was then quenched with saturated aqueous ammonium chloride solution (6 mL). The crude product was purified by ion exchange chromatography, using an SCX column.
  • the resulting solution was stirred under nitrogen at 100°C for 4 hours.
  • the cooled reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (500 mL).
  • the aqueous was further extracted with EtOAc (2 x 200 mL) and the combined organics concentrated under reduced pressure.
  • the residue was dissolved in THF (62 mL) and treated with 2M aqueous HCI solution (63 mL, 126 mmol).
  • the resulting solution was stirred at ambient temperature for 15 minutes.
  • the reaction mixture was then poured onto saturated aqueous NaHCO 3 solution (500 mL) and extracted with DCM (3 x 300 mL).
  • the combined organics were dried over MgSO 4 and concentrated under reduced pressure.
  • 1,1 ,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (541 mg, 1.51 mmol) was added to 9-(8-hydroxydiben2o[b,d]thiophen-4-yl)-2-morpholino-4H-pyrido[1 ,2- a]pyrimidin-4-one (B1 , 500 mg, 1.16 mmol) and potassium carbonate (161 mg, 1.16 mmol) in DMF (18 ml). The resulting solution was stirred under nitrogen at ambient temperature for 2 hours.
  • the desired product was eluted from the column using 1 :1 DCM/7M NH3/MeOH and evaporated to dryness to afford a second batch of 9-(8-aminodibenzo[b,d]thiophen-4-yl)-2- morpholino-4H-pyrido[1 ,2-a]pyrimidin-4-one (0.68 g, 18 %) as a yellow solid, which was used without further purification.
  • the reaction mixture was diluted with DCM (50ml), and washed sequentially with water (50 ml_), and saturated brine (50 ml_).
  • the organic layer was dried over Na2SO4, filtered and evaporated to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in DCM.
  • the reaction mixture was stirred at room temperature temperature for 90 minutes.
  • the reaction mixture was diluted with DCM (10ml), and washed sequentially with water (50 ml_), and saturated brine (50 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product.
  • the crude product was purified by crystallisation from Et 2 CVMeOH to afford 2-chloro-N-methyl-N-(6-(2- morpholino-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)acetamide (157 mg, 72.7 %) as a cream solid.
  • Ozone gas was passed into a mixture of 2,5-dihydrofuran (1.402 g, 20.00 mmol), methanol (8 ml_),DCM (32.0 ml_) at -60°C,(containing a trace of sudan red), until the red colour disappeared leaving a greyish solution.
  • sodium cyanotrihydroborate 0.80 g, 14 mmol was added to the solution and the mixture stirred at -5O 0 C for 10mins.
  • Ozone gas was passed into a mixture of 2,5-dihydrofuran (1.994 g, 28.46 mmol), methanol (24 ml_),DCM (100 mL) at -60°C,(containing a trace of sudan red), until the red colour disappeared leaving a greyish solution.
  • sodium cyanotrihydroborate 1.252 g, 19.92 mmol was added to the solution and the mixture stirred at -50 0 C for 10mins.
  • Morpholine (68.7 mg, 0.79 mmol) was added to 3-bromo-2,2-dimethylpropanoic acid (119 mg, 0.66 mmol), and potassium carbonate (109 mg, 0.79 mmol) in acetonitrile (2 ml_). The resulting suspension was stirred at room temperature for 18 hours. The white solid was filtered off and washed with diethyl ether to give potassium 2,2-dimethyl-3- morpholinopropanoate (165 mg, 111 %); 1 H NMR (400 MHz, DMSO) ⁇ 0.95 (6H, s), 2.32 (2H, s), 2.38 (4H, t), 3.50 (4H, t).
  • the reaction mixture was filtered to remove inorganics and washed with acetonitrile.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane.
  • Methyl i-morpholin-4-ylcyclopropane-i -carboxylate (M1 , 80 mg, 0.43 mmol) was added to water (1 mL) and hydrochloric acid, 37% (1 mL) and the reaction heated at 100 0 C for 48 hours. The reaction was concentrated under vacuum and toluene was added twice to azeotrope any water off to give 1-morpholin-4-ylcyclopropane-1-carboxylic acid hydrochloride (85 mg, 95 %); 1 H NMR (400 MHz, D 2 O) ⁇ 1.36 - 1.39 (2H, m), 1.41 - 1.43 (2H, m), 3.43 (4H, s), 3.84 (4H, s).
  • Morpholine (216 mg, 2.47 mmol) was added ethyl 1-(methylsulfonyloxymethyl)cyclopropane- 1-carboxylate (NI 1 500 mg, 2.25 mmol), and potassium carbonate (342 mg, 2.47 mmol) in acetonitrile (10 mL). The resulting suspension was stirred at 80 0 C for 4 hours and then at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL), and saturated brine (25 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product.
  • Lithium hydroxide (129 mg, 5.39 mmol) was added to ethyl 1-(morpholin-4- ylmethyl)cyclopropane-1-carboxylate (N2, 230 mg, 1.08 mmol) in MeOH (5 mL), THF (5.00 mL) and a few drops of water. The resulting solution was stirred at 60°C for 18 hours. The reaction was then allowed to stand at room temp for the weekend. The reaction was evaporated to dryness and then water (5mL) was added and aqueous HCI (2molar) was added dropwise to neutral pH. The remaining gum was dissolved in water and purified by ion exchange chromatography, using an SCX column.
  • the reaction mixture was diluted with Et 2 O (200 ml_), and washed sequentially with saturated NH 4 CI (200 ml_), and saturated brine (150 ml_).
  • the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product as an orange oil.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product as an orange oil.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
  • the combined liquids were further diluted with methanol (10 mL) and purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 ZMeOH in DCM. Pure fractions were evaporated to dryness to afford (8-aminodibenzothiophen-4-yl) trifluoromethanesulfonate
  • the reaction mixture was diluted with EtOAc (200 ml_), filtered through celite and washed with water (100 ml_). The organic layer was dried over MgSO 4 , filtered and evaporated onto silica gel (5 g). The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
  • 2-bromo-2-methylpropanoyl bromide (13.44 ml_, 108.74 mmol) was added dropwise from a pressure equalising dropping funnel to a stirred solution of ammonium hydroxide (17.85 ml_, 128.35 mmol) in water (22 ml.) cooled to below 5°C. The internal temperature was not allowed to rise above 15°C. The resulting solution was stirred at between 0 and 5°C for 1 hour until the reaction was complete.
  • the reaction mixture was diltued with EtOAc (100 mL) and washed with water (200 mL). The aqueous was further extracted with EtOAc (2 x 100 mL) and the combined organics washed with saturated brine, dried over MgSO 4 and concentrated under reduced pressure.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM. Pure fractions were evaporated to dryness and then slurried in methanol.
  • the resulting suspension was stirred at 11O 0 C for 3 days.
  • the reaction mixture was evaporated to dryness and redissolved in EtOAc (250 ml_), and washed with water (250 mL).
  • the organic layer was dried over MgSO 4 , filtered and evaporated on to silica gel (10 g).
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • the reaction was heated to 150 0 C for 2 hours in the microwave reactor and cooled to room temperature.
  • the reaction was incomplete and further (R)-3-methylmorpholine (283 mg, 2.80 mmol) was added and the solution was stirred at 15O 0 C for a further 1 hour.
  • the reaction mixture was filtered, then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • reaction mixture was filtered, and then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • the reaction was heated to 150 0 C for 2 hours in the microwave reactor and cooled to room temperature.
  • the reaction mixture was filtered then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • reaction mixture was filtered then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • Trifluoromethanesulfonic anhydride (1.541 mL, 9.12 mmol) was added dropwise to ([2- hydroxy-3-[3-[(3R)-3-methylmorpholin-4-yl]-3-oxopropanoyl]phenyl] trifluoromethanesulfonate (Z2, 1316 mg, 3.2 mmol) in dichloromethane (100 mL) at O 0 C over a period of 5 minutes under nitrogen. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated onto silica gel (10 g) then purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM.
  • Acetic anhydride (0.628 mL, 6.68 mmol) was added to 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1 g, 6.68 mmol), MP-carbonate (8.88 g, 20.05 mmol) and diisopropylamine (0.043 mL, 0.33 mmol) in THF (70 mL) under nitrogen. The resulting suspension was stirred very slowly at room temperature for 18 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX column.
  • Trifluoromethanesulfonic anhydride (3.22 mL, 19.04 mmol) was added dropwise to [2- hydroxy-3-[3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-oxopropanoyl]phenyl] trifluoromethanesulfonate (AA2, 2.83 g, 6.68 mmol) in dichloromethane (100 mL) at 0 0 C over a period of 5 minutes under nitrogen. The resulting solution was stirred at room temperature for 18 hours. Silica gel (10 g) was added and the mixture evaporated to dryness.
  • Acetyl chloride (2.109 ml_, 29.66 mmol) was added to zinc(ll) oxide (1.207 g, 14.83 mmol) in DCM (70 mL) at 0 0 C over a period of 2 minutes under nitrogen.
  • (3S)-3-methylmorpholine (3 g, 29.66 mmol) was added dropwise to the reaction mixture and the resulting suspension was allowed to warm to room temperature and stirred for 2 hours.
  • the reaction mixture was washed with saturated NaHCO3 (75 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • Chloracetyl chloride (42.2 mL, 529.53 mmol) was added dropwise to a suspension of Potassium carbonate (95 g, 688.38 mmol) and (2R)-2-aminobutan-1-ol (50 mL, 529.53 mmol) in water (0.143 mL, 7.94 mmol) and dichloromethane (472 mL) at 0 0 C, adjusting the addition rate to keep the reaction temperature kept below 1O 0 C during addition.
  • the reaction mixture was stirred at 0 0 C for 1.5 hours, filtered through a celite pad and the filter cake washed with dichloromethane (472 mL) and tetrahydrofuran (500 mL).
  • reaction was cooled to 15 0 C and further sodium tert- butoxide (25.96 g, 270.03 mmol) added portionwise as a solid (slight exotherm).
  • the reaction mixture was filtered through celite pad, washing the filter cake well with tetrahydrofuran (3 x 430 mL). The combined organics were concentrated to dryness to give a pale oil.
  • reaction mixture was stirred for a further five hours, diluted with addition of tetrahydrofuran (89 mL) and cooled to 5°C.
  • the resulting suspension was filtered, washing the solid residue with tetrahydrofuran (2 x 89 mL).
  • the reaction mixture was quenched with saturated NH 4 CI (2 L), extracted with CH 2 CI 2 (2 x 1 L), the organic layer was dried over MgSO 4 , filtered and evaporated to afford crude pruduct.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane.
  • N-[(2R)-2-hydroxypropyl]-4-methylbenzenesulfonamide (FFI) 4-methylbenzene-1-sulfonyl chloride (49.9 g, 261.88 mmol) was added portionwise to a stirred solution of triethylamine (110 mL, 785.65 mmol) and (2R)-1-aminopropan-2-ol (19.67 g, 261.88 mmol) in CH 2 CI 2 (1569 mL) at 0 0 C, over a period of 1 hour under air. The resulting solution was stirred at room temperature for 4 hours.
  • the cooling bath was removed and the reaction mixture allowed to warm to room temperature and stirred for 5 hours.
  • the reaction mixture was quenched with saturated NH 4 CI (2 L) 1 extracted with CH 2 CI 2 (2 x 1 L), the organic layer was dried over MgSO 4 , filtered and evaporated to afford crude pruduct.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • the resulting solution was stirred at ambient temperature for 3 days.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the impure material was then purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • reaction mixture was diluted with methanol to a total volume of 4 mL, filtered and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents.
  • preparative HPLC Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length
  • Chloracetyl chloride (0.020 ml_, 0.26 mmol) was added to 9-(8-aminodibenzo[b,d]thiophen-4- yl)-2-morpholino-4H-pyrido[1 ,2-a]pyrimidin-4-one (B3, 100 mg, 0.23 mmol) and triethylamine (0.098 mL, 0.70 mmol) in anhydrous DMA (2.88 ml_) at ambient temperature. The resulting solution was stirred under nitrogen at ambient temperature for 1 hour.
  • the solution was diluted with methanol to a total volume of 4 mL, filtered and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • preparative HPLC Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1 % NH3) and MeCN as eluents.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • the resulting solution was stirred under nitrogen at ambient temperature for 3 hours and then 1-(2-hydroxyethyl)piperazine (456 mg, 3.50 mmol) added and the reaction mixture stirred at ambient temperature for a further 1 hour.
  • the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • Example 12 The procedure described above in Example 1 was repeated using the appropriate amine and 2-chloroacetyl chloride with 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino-4H- chromen-4-one (A8'). The compounds described below were thus obtained:
  • the reaction mixture was diluted with methanol (10ml).
  • the crude reaction mixture was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 ZMeOH and fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% 7M NH 3 /MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 10% 7M NH 3 ZMeOH in DCM.
  • reaction mixture was quenched with methanol (10 mL) and purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • the reaction mixture was diluted with methanol (20 ml.) and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the impure product was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 /MeOH in DCM. Fractions containing the desired product were evaporated to dryness to afford impure material.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added in one portion to 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino- 4H-chromen-4-one (A8 ⁇ 100 mg, 0.23 mmol), 1 H-indole-6-carboxylic acid (39.5 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.102 ml_, 0.58 mmol) in DMA (1.5 mL) at ambient temperature.
  • the resulting solution was stirred at ambient temperature for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • O- ⁇ -Azabenzotriazol-i-yO-N.N.N'.N'-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added in one portion to 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino- 4H-chromen-4-one (A8 ⁇ 100 mg, 0.23 mmol), I H-indole-5-carboxylic acid (39.5 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.102 ml_, 0.58 mmol) in DMA (1.5 ml_) at ambient temperature.
  • the resulting solution was stirred at ambient temperature for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added in one portion to 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino- 4H-chromen-4-one (A8 ⁇ 100 mg, 0.23 mmol), 2-(1H-indol-3-yl)acetic acid (42.9 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.102 ml_, 0.58 mmol) in DMA (1.5 ml.) at ambient temperature.
  • the resulting solution was stirred at ambient temperature for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /Me0H in DCM.
  • the resulting solution was stirred at ambient temperature for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • the resulting solution was stirred at ambient temperature for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 ZMeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 ZMeOH in DCM.
  • reaction mixture was treated with morpholine (61.0 mg, 0.70 mmol) and stirred at room temperature for a further 4 hours. After a further 4 hours at room temperature the reaction was heated to 5O 0 C overnight.
  • the crude reaction mixture was purified by ion exchange chromatography, using an SCX column. The product was eluted from the column using 7M NH 3 /MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
  • the reaction mixture was evaporated to dryness and re-dissolved in DCM (20 mL) and washed with water (10 mL). The organic layer was separated and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
  • the crude product was absorbed onto an SCX ion exchange column then left for 3 hours.
  • the product was eluted using 7M NH 3 /MeOH and the solvent removed in vacuo.
  • Trifluoroacetic acid (2 mL, 25.96 mmol) and DCM (25.00 mL) were added and the mixture stirred at room temperature for 1 hour.
  • the reaction mixture was evaporated to dryness and redissolved in MeOH (10 mL).
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and product-containing fractions were evaporated onto silica gel (5 g).
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Product containing fractions were evaporated to dryness to afford semi-pure 1-amino-N-(6-(2-morpholino-4-oxo-4H-chromen- ⁇ -ylJdibenzotb.dlthiophen ⁇ -yOcyclopropanecarboxamide (230 mg, 101 %) as a white solid. 110 mg of this material was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents.
  • O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (81 mg, 0.21 mmol) was added to sodium 2-methyl-2-morpholinopropanoate (E1 , 207 mg, 0.53 mmol), 8- (8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (A8, 101 mg, 0.21 mmol) and N,N-Diisopropylethylamine (0.111 mL, 0.64 mmol) in DMA (4 ml_). The resulting solution was stirred at room temperature for 18 hours.
  • reaction mixture was evaporated to dryness and redissolved in EtOAc (50 mL), and washed with water (50 mL). The organic layer was dried over MgSO 4 , filtered and evaporated onto silica gel (5 g). The resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • reaction mixture was acidified with 2M HCI then filtered and the filtrate was purified by preparative HPLC (Waters SunFire column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • reaction mixture was acidified with 2M HCI then filtered and the filtrate was purified by preparative HPLC (Waters SunFire column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • 2-Bromopropionic acid (0.020 ml_, 0.26 mmol) was added to 8-(8- aminodibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (A8, 100 mg, 0.23 mmol) and N,N-Diisopropylethylamine (0.041 ml_, 0.23 mmol) in DCM (3 ml_). The resulting suspension was stirred at room temperature for 1 hour.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-((3S,5R)-3,5- dimethylmorpholino)-N-(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2- yl)acetamide (86 mg, 65.1 %) as a brown solid.
  • the crude product was purified by preparative HPLC (Waters SunFire column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.
  • the reaction mixture was diluted with EtOAc (25 ml_), and washed sequentially with water (25 mL) and saturated brine (5 mL). The organic layer was dried over MgSO 4 , filtered and evaporated onto silica gel (2 g). The resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and product containing fractions were evaporated onto silica gel (5 g).
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 20% methanolic ammonia in DCM.
  • the resulting solution was stirred at room temperature for 24 hours.
  • the reaction mixture was diluted with EtOAc (150 ml_), and washed sequentially with water (50 mL) and saturated brine (10 mL).
  • the organic layer was dried over MgSO 4 , filtered and evaporated onto silica gel (5 g).
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM.
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Product containing fractions were evaporated to dryness.
  • the crude product was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and 3:1 MeOH: MeCN as eluents.
  • the reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • the reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM. Pure fractions were evaporated to dryness to afford N-methyl-N-[6-(2-morpholin-4- yM-oxochromen- ⁇ -ylJdibenzothiophen ⁇ -yllpyridine-S-carboxamide (101 mg, 67%) as a yellow solid.
  • Sodium hydride, 60% dispersion in mineral oil (11.25 mg, 0.28 mmol) was added in one portion to N-[6-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-2-yl]-2-pyridin-3- ylacetamide (45, 140 mg, 0.26 mmol) in anhydrous DMF (2.5 ml.) cooled to 0 0 C.
  • the resulting mixture was stirred under nitrogen at 0 0 C for 20 minutes then methyl iodide (10% solution in anydrous DMF, 0.17 ml_, 0.27 mmol) was added and the reaction mixture allowed to warm to ambient temperature and stirred for a further 1 hour.
  • the reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • N-methyl-2-[(2S)-2-methylmo ⁇ holin-4-yl]-N-[6-(2-mo ⁇ holin-4-yl-4-oxopyrido[1,2-a]pyrimidin- 9-yl)dibenzothiophen-2-yl]acetamide (77) N-ethyl-N-isopropylpropan-2-amine (0.413 mL, 2.37 mmol) was added to a suspension of 2- chloro-N-methyl-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9-yl)dibenzothiophen-2- yl]acetamide (D2, 410 mg, 0.79 mmol) and (2S)-2-methylmorpholine hydrobromide (EE3, 216 mg, 1.18 mmol) in anhydrous DMA (7 mL).
  • the resulting suspension was stirred under nitrogen at ambient temperature for 3 days.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 ZMeOH in DCM.
  • N-methyl-2-[(2R)-2-methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxopyrido[1,2- a]pyrimidin-9-yl)dibenzothiophen-2-yl]acetamide (78) N-ethyl-N-isopropylpropan-2-amine (0.393 ml_, 2.25 mmol) was added to a suspension of 2- chloro-N-methyl-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9-yl)dibenzothiophen-2- yl]acetamide (D2, 390 mg, 0.75 mmol) and (2R)-2-methylmorpholine hydrobromide (FF3, 205 mg, 1.13 mmol) in anhydrous DMA (7 ml_).
  • the resulting suspension was stirred under nitrogen at 6O 0 C for 18 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 ZMeOH in DCM.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM. Pure fractions were evaporated to dryness to afford still slightly impure product.
  • the crude product was repurified by flash silica chromatography, elution gradient 0 to 4% 7M NH 3 /MeOH in DCM.
  • the second eluted isomer was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM. Pure fractions were evaporated to dryness to afford 2- morpholin-4-yl-N-[6-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-2-yl]propanamide (87 mg) as a white solid.
  • the reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 8% 7M NH 3 /MeOH in DCM. Pure fractions were evaporated to dryness to afford a white solid.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing [AP-HPLC Buffer]) and MeCN as eluents.
  • the resulting solution was stirred at 60 0 C for 1.5 hours.
  • the crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 /MeOH in DCM. Fractions were evaporated to dryness to afford a liquid.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents.
  • the resulting solution was stirred at 60 0 C for 1.5 hours.
  • the crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH 3 /MeOH in DCM.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents.
  • the reaction was stirred at ambient temperature for 1 hour. A further 25mg acid and 50mg HATU were added and the reaction left heating at 50 0 C for a further hour.
  • the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford a gum. The resulting gum was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 MeOH in DCM. Fractions were evaporated to dryness to afford a yellow gum. The gum was sonicated in ether until solid formed. Hexane was then added and the resulting solid filtered.
  • the resulting mixture was stirred under nitrogen at 0 0 C for 20 minutes then Methyl iodide (42.5 mg) was added and the reaction mixture allowed to warm to ambient temperature and stirred for a further 1 hour.
  • the reaction mixture was diluted with methanol and a few drops water and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 ZMeOH in DCM.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford a gum.
  • the resulting gum was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 MeOH in DCM. Fractions were evaporated to dryness to afford a yellow gummy solid. The gum was sonicated in ether until solid formed. Hexane added and the resulting solid filtered.
  • the reaction mixture was diluted with methanol and water and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 8% 7M NH 3 /MeOH in DCM.
  • the reaction was stirred at ambient temperature for 2 hours.
  • the reaction mixture was diluted with EtOAc (150 mL), and washed with water (50 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered and evaporated onto silica.
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 7% MeOH in DCM. Fractions were evaporated to dryness to afford a yellow gum, and LCMS showed 5% starting material remaining.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
  • the reaction was then stirred at 60 0 C for 2 hours.
  • the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford a gum
  • the gum was diluted with EtOAc (150 ml_), and washed sequentially with 2M NaOH (50 ml_), water (50 ml_), The organic layer was dried over Na 2 SO 4 , filtered and evaporated onto silica.
  • the resulting powder was purified by flash silica chromatography, elution gradient 0 to 7% MeOH in DCM. Fractions were evaporated to dryness to afford a yellow solid.
  • the reaction was then quenched with methanol and left to stand at room temperature for 48 hours.
  • the reaction mixture was diluted with methanol and water and the crude product was purified by ion exchange chromatography, using an SCX column.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and evaporated to dryness to afford impure material.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 7% 7M NH 3 ZMeOH in DCM.
  • the resulting suspension was stirred at room temperature for 2 hours and heated to 50 0 C for 1 hour.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford product as a yellow oil. This was purified by crystallisation from Et20 to afford product as a cream solid. The solid was dissolved in DCM and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford product.
  • the product was diluted with DCM (50 ml_), and washed sequentially with water (50 ml_), and saturated brine (20 ml_). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford desired product.
  • the crude product was purified by flash silica chromatography, eluting with ethyl acetate and then elution gradient 5 to 100% MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in DCM.
  • the desired product was eluted from the column using 7M NH 3 /MeOH and pure fractions were evaporated to dryness to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in DCM.

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Abstract

La présente invention concerne un composé de formule I : dans laquelle : X1 et X2 peuvent être soit (a) C et O, soit (b) N et N, soit (c) C et NH, où les liaisons en pointillé représentent une double liaison à l'emplacement approprié; R1 et R2 sont indépendamment choisis parmi l'hydrogène, un groupe alkyle en C1-7 éventuellement substitué, un groupe hétérocyclyle en C3-20 éventuellement substitué, ou un groupe aryle en C5-20 éventuellement substitué, ou peuvent former ensemble, conjointement avec l'atome d'azote auquel ils sont attachés, un cycle hétérocyclique éventuellement substitué comportant 4 à 8 atomes de cycle; RN1 est choisi parmi un hydrogène et un groupe alkyle en C1-4 éventuellement substitué; RC1 est choisi parmi un groupe alkyle en C1-7 éventuellement substitué, un groupe hétérocyclyle en C3-20 éventuellement substitué, ou un groupe aryle en C5-20 éventuellement substitué; ou RN1 et RC1 peuvent former ensemble un groupe alkylène en C2-4 éventuellement substitué.
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