WO2017194632A1 - Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer - Google Patents

Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer Download PDF

Info

Publication number
WO2017194632A1
WO2017194632A1 PCT/EP2017/061229 EP2017061229W WO2017194632A1 WO 2017194632 A1 WO2017194632 A1 WO 2017194632A1 EP 2017061229 W EP2017061229 W EP 2017061229W WO 2017194632 A1 WO2017194632 A1 WO 2017194632A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
cancer
Prior art date
Application number
PCT/EP2017/061229
Other languages
English (en)
Inventor
Bernard Christophe Barlaam
Kurt Gordon Pike
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2017194632A1 publication Critical patent/WO2017194632A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This specification relates to substituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof. These compounds and salts selectively modulate ataxia telangiectasia mutated ("ATM") kinase, and the specification therefore also relates to their use to treat or prevent ATM mediated disease, including cancer.
  • ATM telangiectasia mutated
  • the specification further relates to pharmaceutical compositions comprising substituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; and intermediates useful in such manufacture.
  • ATM kinase is a serine threonine kinase originally identified as the product of the gene mutated in ataxia telangiectasia. Ataxia telangiectasia is located on human chromosome 1 lq22-23 and codes for a large protein of about 350 kDa, which is characterized by the presence of a phosphatidylinositol ("PI") 3-kinase- like serine/threonine kinase domain flanked by FRAP-ATM-TRRAP and FATC domains which modulate ATM kinase activity and function. ATM kinase has been identified as a major player of the DNA damage response elicited by double strand breaks.
  • PI phosphatidylinositol
  • ATM kinase signalling can be broadly divided into two categories: a canonical pathway, which signals together with the Mrel l-Rad50-NBS1 complex from double strand breaks and activates the DNA damage checkpoint, and several non-canonical modes of activation, which are activated by other forms of cellular stress (Cremona et al, Oncogene 2013, 3351-3360).
  • ATM kinase is rapidly and robustly activated in response to double strand breaks and is reportedly able to phosphorylate in excess of 800 substrates
  • ATM kinase is present predominantly in the nucleus of the cell in an inactive homodimeric form but autophosphorylates itself on Serl981 upon sensing a DNA double strand break (canonical pathway), leading to dissociation to a monomer with full kinase activity (Bakkenist et al., Nature 2003, 499-506). This is a critical activation event, and ATM phospho-Serl981 is therefore both a direct pharmacodynamic and patient selection biomarker for tumour pathway dependency.
  • ATM kinase responds to direct double strand breaks caused by common anti-cancer treatments such as ionising radiation and topoisomerase-II inhibitors but also to topoisomerase-I inhibitors via single strand break to double strand break conversion during replication.
  • ATM kinase inhibition can potentiate the activity of any these agents, and as a result ATM kinase inhibitors are expected to be of use in the treatment of cancer.
  • CN102372711A reports certain imidazo[4,5-c]quinolin-2-one compounds which are mentioned to be dual inhibitors of PI 3 -kinase a and mammalian target of rapam cin ("mTOR”) kinase, including:
  • CN102399218A reports certain imidazo[4,5-c]quinolin-2-one compounds which are mentioned to be PI 3-kinase a inhibitors.
  • CN102399218A reports certain imidazo[4,5-c]quinolin-2-one compounds which are mentioned to be PI 3-kinase a inhibitors.
  • the compounds reported in CN102399218A are the following:
  • the compounds of the present specification generally possess very potent ATM kinase inhibitory activity, but much less potent activity against other tyrosine kinase enzymes, such as PI 3-kinase a, mTOR kinase, ataxia telangiectasia and Rad3-related protein (“ATR") kinase, and DNA-dependent protein kinase ("DNAPK").
  • PI 3-kinase a mTOR kinase
  • ATR ataxia telangiectasia and Rad3-related protein
  • DNAPK DNA-dependent protein kinase
  • the compounds of the present specification not only inhibit ATM kinase, but can also be considered highly selective inhibitors of ATM kinase.
  • the compounds of the present specification are expected to be particularly useful in the treatment of diseases in which ATM kinase is implicated (for example, in the treatment of cancer), but where it is desirable to minimise off-target effects or toxicity that might arise due to the inhibition of other tyrosine kinase enzymes, such as class PI 3-kinase a, mTOR kinase, ATR kinase and/or DNAPK.
  • other tyrosine kinase enzymes such as class PI 3-kinase a, mTOR kinase, ATR kinase and/or DNAPK.
  • R 1 is 4-fluoropiperidin-l-yl or 3-fluoropyrrolidin-l-yl
  • R 2 is methyl or hydro.
  • composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • This specification also describes, in part, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • This specification also describes, in part, a method for treating cancer in a warm blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Figure 1 X-Ray Powder Diffraction Pattern of Form A of 8-(6-(3-(4- Fluoropiperidin- 1 -yl)propoxy)pyridin-3-yl)- 1 -isopropyl-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-c]quinolin-2-one.
  • Figure 2 DSC Thermogram of Form A of 8-(6-(3-(4-Fluoropiperidin-l- yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5- c]quinolin-2-one.
  • Figure 3 X-Ray Powder Diffraction Pattern of Form C of 8-(6-(3-(4- Fluoropiperidin- 1 -yl)propoxy)pyridin-3-yl)- 1 -isopropyl-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-c]quinolin-2-one.
  • Figure 4 DSC Thermogram of Form C of 8-(6-(3-(4-Fluoropiperidin-l- yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5- c]quinolin-2-one.
  • Figure 5 X-Ray Powder Diffraction Pattern of Form D of 8-(6-(3-(4- Fluoropiperidin- 1 -yl)propoxy)pyridin-3-yl)- 1 -isopropyl-3-methyl- 1 ,3-dihyd] imidazo[4,5-c]quinolin-2-one.
  • Figure 6 DSC Thermogram of Form D of 8-(6-(3-(4-Fluoropiperidin- l- yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5- c]quinolin-2-one.
  • R 1 is 4-fluoropiperidin-l-yl or 3-fluoropyrrolidin- l-yl
  • R 2 is methyl or hydro.
  • hydro group is equivalent to a hydrogen atom. Atoms with a hydro group attached to them can be regarded as unsubstituted.
  • a 3-fluoropyrrolidin-l-yl group can exist in two enantiomeric forms, (S)-3- fluoropyrrolidin-l-yl and (R)-3-fluoropyrrolidin- l-yl, with the structures shown below.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid-addition salt.
  • An acid addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and /?ara-toluenesulfonic acid.
  • an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and /?ara-toluenesulfonic acid.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or /?ara-toluenesulfonic acid salt.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyr
  • a further embodiment provides any of the embodiments defined herein (for example the embodiment of claim 1) with the proviso that one or more specific Examples (for instance one, two or three specific Examples) selected from
  • R 1 is 4-fluoropiperidin-l-yl.
  • R 1 is 3-fluoropyrrolidin- l-yl.
  • R 1 is (S)-3-fluoropyrrolidin- l-yl.
  • R 1 is (R)-3-fluoropyrrolidin-l-yl.
  • R 2 is methyl
  • R 2 is hydro.
  • R 1 is tetrahydropyran-3-yl
  • R 2 is methyl or hydro
  • R 3 is hydro or fluoro
  • R 4 is hydro or fluoro
  • R 5 is methyl
  • any compound of Formula (I), or a pharmaceutically acceptable salt thereof which may be prepared according to the experimental details in the Examples section.
  • 8-(6-(3-(4f uoropiperidin- l- yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5- c]quinolin-2-one there is provided 8-(6-(3-(4f uoropiperidin- l- yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5- c]quinolin-2-one.
  • solvated forms may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof.
  • the invention encompasses all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess ATM kinase inhibitory activity, as for example measured using the tests described herein. Atoms of the compounds and salts described in this specification may exist as their isotopes.
  • the invention encompasses all compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an U C or 13 C carbon isotope, or where one or more hydrogen atoms is a 2 H or 3 H isotope).
  • Tautomers are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.
  • the invention includes all tautomers of compounds of Formula (I) particularly to the extent that such tautomers possess ATM kinase inhibitory activity.
  • optically active or racemic forms by virtue of an aymmetric carbon atom.
  • the invention includes any optically active or racemic form of a compound of Formula (I) which possesses ATM kinase inhibitory activity, as for example measured using the tests described herein.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis using optically active materials or by resolution of a racemic form.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof which is a single optical isomer being in an enantiomeric excess (%ee) of > 95%, > 98% or > 99%.
  • the single optical isomer is present in an enantiomeric excess (%ee) of > 99%.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof which is an ( ⁇ -optical isomer being in an enantiomeric excess (%ee) of > 95%, > 98% or > 99%.
  • the (S)- optical isomer is present in an enantiomeric excess (%ee) of > 99%.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof which is an (R)-optical isomer being in an enantiomeric excess (%ee) of > 95%, > 98% or > 99%.
  • the (R)- optical isomer is present in an enantiomeric excess (%ee) of > 99%.
  • Compounds and salts described in this specification may be crystalline, and may exhibit one or more crystalline forms.
  • the invention encompasses any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses ATM kinase inhibitory activity.
  • crystalline materials may be characterised using conventional techniques such as X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
  • XRPD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermal Gravimetric Analysis
  • DRIFT Diffuse Reflectance Infrared Fourier Transform
  • NIR Near Infrared
  • solution and/or solid state nuclear magnetic resonance spectroscopy solution and/or solid state nuclear magnetic resonance spectroscopy.
  • the water content of crystalline materials may be determined by Karl Fischer analysis.
  • the crystalline forms described herein provide XRPD patterns substantially the same as the XRPD patterns shown in the Figures, and have the various 2-theta values as shown in the Tables included herein.
  • an XRPD pattern or diffractogram may be obtained which has one or more measurement errors depending on the recording conditions, such as the equipment or machine used.
  • intensities in an XRPD pattern may fluctuate depending on measurement conditions or sample preparation as a result of preferred orientation.
  • the relative intensity of peaks can also be affected by, for example, grains above 30 ⁇ in size and non-unitary aspect ratios.
  • the skilled person understands that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer, and also the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • solid forms are not limited to the crystals that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures, and any crystals providing XRPD patterns substantially the same as those shown in the Figures fall within the scope of the invention.
  • a person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns.
  • a crystals that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures
  • measurement error of a diffraction angle in an XRPD is approximately plus or minus 0.2° 2-theta, and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction pattern in the Figures and when reading data contained in the Tables included herein.
  • Example 1 exhibits crystalline properties, and three crystalline form are characterised herein.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 10.9°.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 20.6°.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta 10.9 and 20.6°.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta 3.6, 10.9, 12.6, 14.4, 17.3, 18.0, 19.6, 20.3, 20.6 and 23.5°.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 10.9° plus or minus 0.2° 2-theta.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 20.6° plus or minus 0.2° 2-theta.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta 7.0 and 9.2° where both 2-theta values are plus or minus 0.2° 2-theta.
  • a crystalline form, Form A of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at 2-theta 3.6, 10.9, 12.6, 14.4, 17.3, 18.0, 19.6, 20.3, 20.6 and 23.5° where all 2-theta values are plus or minus 0.2° 2-theta.
  • Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 6.8°.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 13.5°.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta 6.8 and 13.5°.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta 6.8, 11.2, 13.3, 13.5, 16.5, 17.6, 18.5, 21.7, 25.0 and 25.8°.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 6.8° plus or minus 0.2° 2-theta.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 13.5° plus or minus 0.2° 2-theta.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta 6.8 and 13.5° where both 2-theta values are plus or minus 0.2° 2-theta.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one which has a DSC endotherm with an onset of melting at about 141.1°C and a peak at about 142.0°C, an exothermic event at about 143.0°C, and an endotherm with an onset of melting at about 158.1°C and a peak at about 159.1°C.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one which has a DSC endotherm with an onset of melting at 141.1°C plus or minus 5°C and a peak at 142.0°C plus or minus 5°C, and an exothermic event at 143.0°C plus or minus 5°C.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one which has a DSC endotherm with an onset of melting at 141.1°C plus or minus 5°C and a peak at 142.0°C plus or minus 5°C, an exothermic event at 143.0°C plus or minus 5°C, and an endotherm with an onset of melting at 158.1°C plus or minus 5°C and a peak at 159.1°C plus or minus 5°C.
  • a crystalline form, Form C of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one which has a DSC endotherm with an onset of melting at 141.1°C and a peak at 142.0°C, an exothermic event at 143.0°C and an endotherm with an onset of melting at 158.1°C and a peak at 159.1°C.
  • Form D 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 10.2°.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta 19.2°.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta 10.2 and 19.2°.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta 3.6, 10.2, 14.3, 14.6, 18.3, 19.2 and 19.6°.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 10.2° plus or minus 0.2° 2-theta.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta 19.2° plus or minus 0.2° 2-theta.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta 7.0 and 9.2° where both 2-theta values are plus or minus 0.2° 2-theta.
  • a crystalline form, Form D of 8-(6-(3- (4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl-l,3-dihydro- 2H-imidazo[4,5-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at 2-theta 3.6, 10.2, 14.3, 14.6, 18.3, 19.2 and 19° where all 2- theta values are plus or minus 0.2° 2-theta.
  • the degree of crystallinity may be greater than about 60%. In some embodiments the degree of crystallinity is greater than about 80%. In some embodiments the degree of crystallinity is greater than about 90%. In some embodiments the degree of crystallinity is greater than about 95%. In some embodiments the degree of crystallinity is greater than about 98%.
  • “Degree of crystallinity” may refer to the percentage of a single crystalline form compared to all other crystalline or amorphous forms present; or the percentage of all crystalline forms compared to amorphous forms present.
  • reaction is conveniently performed in a suitable solvent (for example DMF, DMA or THF) and in the presence of a base (for example sodium hydride) at a suitable temperature (for example a temperature in the range of about 20-50°C).
  • a suitable solvent for example DMF, DMA or THF
  • a base for example sodium hydride
  • R 2 is methyl or hydro
  • X is a leaving group.
  • X is a halogen atom or a triflate group.
  • X is a fluorine atom.
  • R 2 is methyl
  • X is a leaving group.
  • X is a halogen atom or a triflate group.
  • X is a fluorine atom.
  • a suitable salt of a compound of Formula (II) is, for example, an acid-addition salt.
  • An acid addition salt of a compound of Formula (II) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para- toluenesulfonic acid.
  • an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para- toluenesulfonic acid.
  • a compound of Formula (II) or a salt thereof where the salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para- toluenesulfonic acid salt.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by ATM kinase, including cancer.
  • cancer includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.
  • ATM kinase inhibitory activity refers to a decrease in the activity of ATM kinase as a direct or indirect response to the presence of a compound of Formula (I), or pharmaceutically acceptable salt thereof, relative to the activity of ATM kinase in the absence of compound of Formula (I), or pharmaceutically acceptable salt thereof.
  • Such a decrease in activity may be due to the direct interaction of the compound of Formula (I), or pharmaceutically acceptable salt thereof with ATM kinase, or due to the interaction of the compound of Formula (I), or pharmaceutically acceptable salt thereof with one or more other factors that in turn affect ATM kinase activity.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof may decrease ATM kinase by directly binding to the ATM kinase, by causing (directly or indirectly) another factor to decrease ATM kinase activity, or by (directly or indirectly) decreasing the amount of ATM kinase present in the cell or organism.
  • the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by ATM kinase.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by ATM kinase, where the disease mediated by ATM kinase is cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by ATM kinase, where the disease mediated by ATM kinase is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by ATM kinase, where the disease mediated by ATM kinase is colorectal cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of colorectal cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of Huntingdon's disease.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a neuroprotective agent for use as a neuroprotective agent.
  • a “neuroprotective agent” is an agent that preserves neuronal structure and/or function.
  • the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by ATM kinase where the disease mediated by ATM kinase is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer.
  • a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a
  • therapeutically effective amount refers to an amount of a compound of Formula (I) as described in any of the embodiments herein which is effective to provide "therapy” in a subject, or to “treat” a disease or disorder in a subject.
  • the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of "therapy", “treatment” and “prophylaxis” above.
  • the effective amount can reduce the number of cancer or tumour cells; reduce the overall tumour size; inhibit or stop tumour cell infiltration into peripheral organs including, for example, the soft tissue and bone; inhibit and stop tumour metastasis; inhibit and stop tumour growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects.
  • An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of ATM kinase activity.
  • efficacy in-vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
  • effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder in the animal patient.
  • the combined amounts are in a "therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of a disease responsive to inhibition of ATM activity as described above.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of formula (I) or pharmaceutically acceptable salt thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • Warm-blooded animals include, for example, humans.
  • a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a
  • a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a
  • the disease in which inhibition of ATM kinase is beneficial is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer.
  • a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a
  • a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a
  • a method for treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating colorectal cancer in a warm-blooded animal in need of such treatment which comprises
  • a method for treating Huntingdon's disease in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for effecting neuroprotection in a warm-blooded animal in need of such treatment which comprises
  • a method for treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer.
  • said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer.
  • said cancer is colorectal cancer.
  • said cancer may be selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is glioblastoma.
  • the cancer is gastric cancer.
  • the cancer is oesophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is endometrial cancer.
  • the cancer is cervical cancer.
  • the cancer is diffuse large B-cell lymphoma.
  • the cancer is chronic lymphocytic leukaemia.
  • the cancer is acute myeloid leukaemia.
  • the cancer is head and neck squamous cell carcinoma.
  • the cancer is breast cancer. In one embodiment the cancer is triple negative breast cancer.
  • Triple negative breast cancer is any breast cancer that does not test positive for the oestrogen receptor, progesterone receptor and Her2/neu. Test methods to determine a positive test with respect to each of these receptors are well known in the art.
  • the cancer is hepatocellular carcinoma.
  • the cancer is lung cancer. In one embodiment the lung cancer is small cell lung cancer. In one embodiment the lung cancer is non- small cell lung cancer.
  • the cancer is metastatic cancer.
  • the metastatic cancer comprises metastases of the central nervous system.
  • the metastases of the central nervous system comprise brain metastases.
  • the metastases of the central nervous system comprise leptomeningeal metastases.
  • “Leptomeningeal metastases” occur when cancer spreads to the meninges, the layers of tissue that cover the brain and the spinal cord. Metastases can spread to the meninges through the blood or they can travel from brain metastases, carried by the cerebrospinal fluid (CSF) that flows through the meninges.
  • CSF cerebrospinal fluid
  • the cancer is non-metastatic cancer.
  • the anti-cancer treatment described in this specification may be useful as a sole therapy, or may involve, in addition to administration of the compound of Formula (I), conventional surgery, radiotherapy or chemotherapy; or a combination of such additional therapies.
  • Such conventional surgery, radiotherapy or chemotherapy may be administered simultaneously, sequentially or separately to treatment with the compound of Formula (I).
  • Radiotherapy may include one or more of the following categories of therapy:
  • iii Systemic radiation therapy, including but not limited to iodine 131 and strontium 89.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with radiotherapy.
  • radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of glioblastoma, lung cancer (for example small cell lung cancer or non-small cell lung cancer), breast cancer (for example triple negative breast cancer), head and neck squamous cell carcinoma, oesophageal cancer, cervical cancer or endometrial cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy.
  • lung cancer for example small cell lung cancer or non-small cell lung cancer
  • breast cancer for example triple negative breast cancer
  • head and neck squamous cell carcinoma for example oesophageal cancer
  • cervical cancer for example triple negative breast cancer
  • endometrial cancer for use in the treatment of glioblastoma
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with radiotherapy.
  • radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of glioblastoma, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of metastatic cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of metastases of the central nervous system, where the compound of Formula (I), or a
  • radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of leptomeningeal metastases, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with radiotherapy.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a method of treating cancer in a warmblooded animal who is in need of such treatment which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and radiotherapy, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy are jointly effective in producing an anti-cancer effect.
  • the cancer is selected from glioblastoma, lung cancer (for example small cell lung cancer or non-small cell lung cancer), breast cancer (for example triple negative breast cancer), head and neck squamous cell carcinoma, oesophageal cancer, cervical cancer and
  • the cancer is glioblastoma.
  • the cancer is metastatic cancer.
  • the metastatic cancer comprises metastases of the central nervous system.
  • the metastases of the central nervous system comprise brain metastases.
  • the metastases of the central nervous system comprise leptomeningeal metastases.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • a method of treating cancer in a warmblooded animal who is in need of such treatment which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and simultaneously, separately or sequentially administering radiotherapy, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy are jointly effective in producing an anticancer effect.
  • the cancer is glioblastoma.
  • the cancer is metastatic cancer.
  • the metastatic cancer comprises metastases of the central nervous system.
  • the metastases of the central nervous system comprise brain metastases.
  • the metastases of the central nervous system comprise leptomeningeal metastases.
  • the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.
  • Chemotherapy may include one or more of the following categories of anti- tumour substance:
  • Antineoplastic agents and combinations thereof such as DNA alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustards like ifosfamide, bendamustine, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas like carmustine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin
  • Antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor
  • endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), sorafenib, vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and cediranib (AZD2171); compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO
  • linomide inhibitors of integrin ⁇ 3 function and angiostatin
  • angiopoietins and their receptors Tie-1 and Tie-2
  • inhibitors of PLGF inhibitors of delta-like ligand (DLL-4); iii.
  • 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 or regulatory T-cell function; approaches that enhance T-cell responses to tumours, such as blocking antibodies to CTLA4 (for example ipilimumab and tremelimumab), B7H1, PD-1 (for example BMS-936558 or AMP-514), PD-L1 (for example MEDI4736) and agonist antibodies to
  • CD 137 approaches using transfected immune cells such as
  • cytokine-transfected dendritic cells approaches using cytokine-transfected tumour cell lines, approaches using antibodies to tumour associated antigens, and antibodies that deplete target cell types (e.g., unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campath); approaches using anti-idiotypic antibodies; approaches that enhance Natural Killer cell function; and approaches that utilize antibody-toxin conjugates (e.g. anti- CD33 antibody Mylotarg); immunotoxins such as moxetumumab pasudotox; agonists of toll-like receptor 7 or toll-like receptor 9;
  • unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campath
  • approaches using anti-idiotypic antibodies approaches that enhance Natural Killer cell function
  • approaches that utilize antibody-toxin conjugates e.g
  • Efficacy enhancers such as leucovorin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with at least one additional anti-tumour substance.
  • the additional anti- tumour substance is selected from one or more of the anti-tumour substances listed under points (i) - (iv) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance.
  • the additional anti-tumour substance is selected from one or more of the anti-tumour substances listed under points (i) - (iv) above.
  • a method of treating cancer in a warmblooded animal who is in need of such treatment which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
  • the additional anti-tumour substance is selected from one or more of the anti-tumour substances listed under points (i) - (iv) above.
  • a method of treating cancer in a warmblooded animal who is in need of such treatment which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said warm-blooded animal, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
  • the additional anti-tumour substance is selected from one or more of the anti-tumour substances listed under points (i) - (iv) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent for use in the treatment of cancer In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with at least one anti-neoplastic agent. In one embodiment the anti-neoplastic agent is selected from the list of
  • antineoplastic agents in point (i) above In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent for use in the simultaneous, separate or sequential treatment of cancer. In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one anti-neoplastic agent. In one embodiment the antineoplastic agent is selected from the list of antineoplastic agents in point (i) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738.
  • additional anti-tumour substance selected from cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cisplatin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738.
  • additional anti-tumour substance selected from cisplatin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etopo
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib.
  • additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.
  • additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, pirarubicin, amrubicin and epirubicin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of acute myeloid leukaemia, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, pirarubicin, amrubicin and epirubicin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, pirarubicin, amrubicin and epirubicin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of triple negative breast cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, pirarubicin, amrubicin and epirubicin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of hepatocellular carcinoma, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, pirarubicin, amrubicin and epirubicin.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with irinotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of colorectal cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with irinotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of colorectal cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with FOLFIRI.
  • FOLFIRI is a dosage regime involving a combination of leucovorin, 5- fluorouracil and irinotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with olaparib.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of gastric cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with olaparib.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with topotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of lung cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with topotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of small cell lung cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with topotecan.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with immunotherapy.
  • the immunotherapy is one or more of the agents listed under point (iii) above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with an anti-PD-Ll antibody (for example MEDI4736).
  • an anti-PD-Ll antibody for example MEDI4736
  • a further additional anti-tumour substance in a further unit dosage form b) A further additional anti-tumour substance in a further unit dosage form; c) Container means for containing said first and further unit dosage forms; and optionally
  • the anti-tumour substance comprises an anti-neoplastic agent.
  • the antineoplastic agent is one or more of the agents listed under point (i) above.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients. Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain
  • pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing), or as a suppository for rectal dosing.
  • the compositions may be obtained by conventional procedures well known in the art.
  • Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the compound of Formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 2.5-5000 mg/m 2 body area of the animal, or approximately 0.05-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 0.1-250 mg of active ingredient.
  • the overall dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated. Accordingly the practitioner who is treating any particular patient may determine the optimum dosage, with reference to the approved label of the drug.
  • compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.
  • a pharmaceutical composition for use in therapy comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for use in the treatment of a disease in which inhibition of ATM kinase is beneficial comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • compositions for use in the treatment of cancer comprising a compound of Formula (I), or a
  • a pharmaceutical composition for use in the treatment of a cancer in which inhibition of ATM kinase is beneficial comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Armen Glider Flash Spot II Ultimate (Armen Instrument, Saint- Ave, France) or automated Presearch combiflash companions using prepacked Merck normal phase Si60 silica cartridges (granulometry: 15-40 or 40- 63 ⁇ ) obtained from Merck, Darmstad, Germany, silicycle silica cartridges or graceresolv silica cartridges;
  • NMR magnetic resonance
  • LCMS mass spectroscopy following liquid chromatography
  • the collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 5.89mm antiscatter slit and a 9.55mm detector slit.
  • the sample was exposed for 0.03 seconds per 0.00570° 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode.
  • the running time was 3 minutes and 36 seconds.
  • the instrument was equipped with a Position sensitive detector (Lynxeye). Control and data capture was by means of a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+ software; Differential Scanning Calorimetry was performed on a TA Instruments Q2000 DSC.
  • the reaction mixture was diluted with ethyl acetate (400 ml), and washed three times with water (3 x 200 ml). The organic layer was dried over MgS0 4 , filtered and evaporated to afford crude product.
  • the crude product was purified by FCC, elution gradient 0 to 4% 2N NH 3 /MeOH in DCM and pure fractions were evaporated to dryness then stirred overnight with diethyl ether (20 ml).
  • Example 1 Form A is characterised in providing an X-ray powder diffraction pattern substantially as shown in Figure 1.
  • Ten X-Ray powder diffraction peaks are shown in Table 1.
  • Example 1 Form A displays the following thermal parameters: a melting endotherm with an onset of 157.8°C and a peak at 158.9°C, preceded by a small endotherm at 59°C as determined by DSC at a scanning rate of 10°C/mins ( Figure 2).
  • a different crystalline form of 8-(6-(3-(4-fluoropiperidin-l-yl)propoxy)pyridin-3- yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one , Form C was produced by slurrying the Form A material described above in ethyl acetate at ambient temperature. Approximately 20mg of the Form A material was placed in a vial with a magnetic stirrer bar, and approximately 2ml of ethyl acetate added. The vial was then sealed tightly with a cap and left to stir on a magnetic stirrer plate. After approximately 4 days, the sample was removed from the plate, the cap taken off and the slurry left to dry under ambient conditions before it was analysed by XRPD and DSC.
  • Example 1 Form C is characterised in providing an X-ray powder diffraction pattern substantially as shown in Figure 3. Ten X-Ray powder diffraction peaks are shown in Table 2.
  • Example 1 Form C displays the following thermal parameters: a melting endo therm with an onset of 141.1°C and a peak at 142.0°C, followed by an exothermic event ar 143.0°C and a subsequent endotherm with an onset of 158.1°C and a peak at 159.1°C as determined by DSC at a scanning rate of 10°C/mins ( Figure 4).
  • a different crystalline form of 8-(6-(3-(4-fluoropiperidin-l-yl)propoxy)pyridin-3- yl)-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one , Form D was produced by slurrying the Form A material described above in water at ambient temperature. Approximately 20mg of the Form A material was placed in a vial with a magnetic stirrer bar, and approximately 2ml of water added. The vial was then sealed tightly with a cap and left to stir on a magnetic stirrer plate. After approximately 4 days, the sample was removed from the plate, the cap taken off and the slurry left to dry under ambient conditions before it was analysed by XRPD and DSC.
  • Example 1 Form D is characterised in providing an X-ray powder diffraction pattern substantially as shown in Figure 5. Characteristic X-Ray powder diffraction peaks are shown in Table 3.
  • Example 1 Form C displays the following thermal parameters: a melting endo therm with an onset of 141.1°C and a peak at 142.0°C, followed by an exothermic event ar 143.0°C and a subsequent endotherm with an onset of 158.1°C and a peak at 159.1°C as determined by DSC at a scanning rate of 10°C/mins ( Figure 6).
  • Example 1 8-(6-(3-(4-fluoropiperidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3- methyl-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one can also be isolated as the methanesulfonic acid salt by dissolving the free base in a small quantity of DCM and treating with an equivalent of methanesulfonic acid dissolved in a small quantity of DCM, removing the solvent and then stirring the residue in diethyl ether followed by filtration.
  • (R)-8-(6-(3-(3-Fluoropyrrolidin-l-yl)propoxy)pyridin-3-yl)-l-isopropyl-3-methyl- l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one can also be isolated as the methanesulfonic acid salt by dissolving the free base in a small quantity of DCM and treating with an equivalent of methanesulfonic acid dissolved in a small quantity of DCM, removing the solvent and then stirring the residue in Et 2 0 followed by filtration.
  • the reaction was stirred at room temperature for between 2 to 28 h.
  • N,N-Dimethylformamide dimethyl acetal (54.2 mL, 408.29 mmol) was added to a solution of 8-bromo-l-isopropyl-3H-imidazo[4,5-c]quinolin-2-one (25.00 g, 81.66 mmol) in DMF (375 mL). The mixture was heated to 80°C for 3 h then allowed to cool to ambient temperature and stirred for 16 h. The precipitate was collected by filtration, washed with water (4 x 300 mL) and dried under vacuum at 50°C to afford the desired material as a white solid (23.82 g, 91 %).
  • Triethylamine (45.3 mL, 332.06 mmol) was added to 6-bromo-4- (isopropylamino)quinoline-3-carboxylic acid (34.22 g, 110.69 mmol) in DMF (342 mL) at ambient temperature. After stirring at ambient temperature for 30 minutes, diphenyl phosphorazidate (26.2 mL, 121.76 mmol) was added and the resulting mixture stirred at 60 °C for 2 h.
  • reaction mixture was poured into water (1500 mL); the precipitate collected by filtration, washed with water (2 x 700 mL) and dried under vacuum at 50°C to afford the desired material as a beige solid (29.6 g, 87 ), which was used without further purification.
  • Ethyl 6-bromo-4-(isopropylamino)quinoline-3-carboxylate (38.0 g, 112.69 mmol) was suspended in methanol (800 mL) and water (200 mL). 10M sodium hydroxide solution (33.8 mL, 338.07 mmol) was added and the mixture stirred at ambient temperature for 1 h. THF (200 mL) was added and the resultant mixture stirred for 16 h. Water (400 mL) was added and the organics removed under reduced pressure.
  • Propan-2-amine (11.00 ml, 128.02 mmol) was added to a suspension of ethyl 6- bromo-4-chloroquinoline-3-carboxylate (36.61 g, 116.38 mmol) and potassium carbonate (32.2 g, 232.77 mmol) in acetonitrile (250 mL) at 0°C. The mixture was stirred at 54 °C under reflux for 3 h. Further potassium carbonate (10.7 g, 77.6 mmol) and propan-2-amine (3.6 ml, 42.7 mmol) were added and stirring continued at 48 °C for a further 16 h.
  • the following assays were used to measure the effects of the compounds of the present invention: a) ATM cellular potency assay; b) PI3K cellular potency assay; c) mTOR cellular potency assay; d) ATR cellular potency assay; e): DNAPK cellular potency assay.
  • 4NQO 4-Nitroquinoline N- oxide
  • Ab Antibody
  • BSA Bovine Serum Albumin
  • C0 2 Carbon Dioxide
  • DMEM Dulbecco's Modified Eagle Medium
  • DMSO Dimethyl Sulphoxide
  • EDTA Ethylenediaminetetraacetic Acid
  • EGTA Ethylene Glycol Tetraacetic Acid
  • ELISA Enzyme-linked Immunosorbent Assay
  • EMEM Eagle's Minimal Essential Medium
  • FBS Foetal Bovine Serum
  • h hour(s)
  • HRP Horseradish Peroxidase; i.p.
  • TRIS Tris(Hydroxymethyl)aminomethane
  • MTS reagent [3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt, and an electron coupling reagent (phenazine methosulfate) PMS; s.c. sub-cutaneously.
  • IC50 values were calculated using a smart fitting model in Genedata. The IC50 value was the concentration of test compound that inhibited 50% of biological activity.
  • pATM assay The rationale of the pATM assay is to identify inhibitors of ATM in cells.
  • HT29 cells are incubated with test compounds for lhr prior to X-ray-irradiation, lh later the cells are fixed and stained for pATM (Serl981). The fluorescence is read on the arrayscan imaging platform.
  • HT29 cells (ECACC #85061109) were seeded into 384 well assay plates (Costar #3712) at a density of 3500 cells / well in 40 ⁇ 1 EMEM medium containing 1% L glutamine and 10% FBS and allowed to adhere overnight.
  • the following morning compounds of Formula (I) in 100% DMSO were added to assay plates by acoustic dispensing. After lh incubation at 37°C and 5% C0 2 , plates (up to 6 at a time) were irradiated using the X-RAD 320 instrument (PXi) with equivalent to ⁇ 600cGy. Plates were returned to the incubator for a further lh.
  • Phospho-ATM Serl981 antibody (Millipore #MAB3806) was diluted 10000 fold in PBS containing 0.05% polysorbate/Tween and 3% BSA and 20 ⁇ 1 was added to each well and incubated over night at r.t. The next morning plates were washed three times with 50 ⁇ 1 / well PBS, using a Biotek EL405 plate washer, and then 20 ⁇ 1 of secondary Ab solution, containing 500 fold diluted Alexa Fluor® 488 Goat anti- rabbit IgG (Life Technologies, A11001) and 0.002mg/ml Hoeschst dye (Life technologies #H-3570), in PBS containing 0.05% polysorbate/Tween and 3% BSA, was added.
  • ATR is a PI 3-kinase-related kinase which phosphorylates multiple substrates on serine or threonine residues in response to DNA damage during or replication blocks.
  • Chkl a downstream protein kinase of ATR, plays a key role in DNA damage checkpoint control. Activation of Chkl involves phosphorylation of Ser317 and Ser345 (the latter regarded as the preferential target for
  • HT29 cells (ECACC #85061109) were seeded into 384 well assay plates (Costar #3712) at a density of 6000 cells / well in 40 ⁇ 1 EMEM medium containing 1% L glutamine and 10% FBS and allowed to adhere overnight.
  • the following morning compound of Formula (I) in 100% DMSO were added to assay plates by acoustic dispensing.
  • 40nl of 3mM 4NQO in 100% DMSO was added to all wells by acoustic dispensing, except minimum control wells which were left untreated with 4NQO to generate a null response control. Plates were returned to the incubator for a further lh.
  • Phospho-Chkl Ser 345 antibody (Cell Signalling Technology #2348) was diluted 150 fold in PBS containing 0.05% polysorbate/Tween and 15 ⁇ 1 was added to each well and incubated over night at r.t. The next morning plates were washed three times with 50 ⁇ 1 / well PBS, using a Biotek EL405 plate washer, and then 20 ⁇ 1 of secondary Ab solution, containing 500 fold diluted Alexa Fluor 488 Goat anti- rabbit IgG (Molecular Probes #A- 11008) and 0.002mg/ml Hoeschst dye (Molecular Probes #H-3570), in PBST, was added.
  • PDKl was identified as the upstream activation loop kinase of protein kinase B (Aktl), which is essential for the activation of PKB. Activation of the lipid kinase
  • PI3K phosphoinositide 3 kinase
  • PI3K is activated, which converts PIP2 to PIP3, which is bound by the PH domain of PDKl resulting in recruitment of PDKl to the plasma membrane where it phosphorylates AKT at Thr308 in the activation loop.
  • the aim of this cell-based mode of action assay is to identify compounds that inhibit PDK activity or recruitment of PDKl to membrane by inhibiting PI3K activity.
  • Phosphorylation of phospho-Akt (T308) in BT474c cells following treatment with compounds for 2h is a direct measure of PDKl and indirect measure of PDK activity.
  • BT474 cells human breast ductal carcinoma, ATCC HTB-20
  • black 384 well plates Costar, #3712
  • 5600 cells / well in DMEM containing 10% FBS and 1% glutamine were seeded into black 384 well plates (Costar, #3712) at a density of 5600 cells / well in DMEM containing 10% FBS and 1% glutamine and allowed to adhere overnight.
  • the cell lysates were transferred into ELISA plates (Greiner # 781077) which had been pre-coated with an anti total- AKT antibody in PBS buffer and non-specific binding was blocked with 1% BSA in PBS containing 0.05% Tween 20. Plates were incubated over night at 4°C. The next day the plates were washed with PBS buffer containing 0.05% Tween 20 and further incubated with a mouse monoclonal anti-phospho AKT T308 for 2h. Plates were washed again as above before addition of a horse anti-mouse-HRP conjugated secondary antibody.
  • the phospho-AKTser473 cell assay was performed in the MDA-MB-468 cell line, a PTEN null breast adenocarcinoma human cell line. As a consequence of the lack of PTEN, pAKT is constitutively activated which eliminates the requirement for stimulation to induce phosphorylation.
  • MDA-MB-468 cells were cultured in cell media composed of DMEM (Dulbecco's modified Eagle's medium #D6546)), 10% (v/v) Foetal Calf Serum and 1% (v/v) L-Glutamine. After harvesting, cells were dispensed into black, 384- well Costar plates (#3712, Corning) to give 1500 cells per well in a total volume of 40 ⁇ 1 cell media, and were incubated overnight at 37°C, 90% relative humidity and 5% C02 in a rotating incubator. Compounds were then tested by one of two assay protocols A or B:
  • the cell plates were then incubated for 2 h at 37 °C before being fixed by the addition of 20 ⁇ 1 3.7% formaldehyde in PBS/A (1.2% final concentration), followed by a 40 minute room temperature incubation, and then a 2x wash with 150 ⁇ 1 PBS/A (phosphate buffered saline) using a BioTek ELx406 platewasher.
  • Cells were permeabilised and blocked with 20 ⁇ 1 of assay buffer (0.5% Tween 20 in PBS/A + 1% milk powder) for lh at room temperature, and then washed lx with 50 ⁇ 1 PBS/A.
  • DMSO dimethyl sulphoxide
  • All compounds or DMSO (dimethyl sulphoxide) for the DNAPK cell ELISA assay were dispensed from source plates containing compounds at lOmM in 100% (v/v) DMSO or 100% DMSO, directly into assay plates using an Echo 555 Acoustic dispenser (Labcyte IncTM).
  • lOmM compound stocks were diluted 1 : 100 using a fixed-tip 96-head Agilent VPrep liquid handler (Agilent Technologies, Santa Clara, CA) to give four intermediate dilutions (lOmM, ⁇ , ⁇ , ⁇ ).
  • This intermediate plate was used by the Echo to dispense compounds and DMSO directly into the cell plates with a 12 point dose range (30, 10, 3.125, 1.25, 0.3, 0.1, 0.03125, 0.0125, 0.003, 0.001, 0.0003125, 0.00003 ⁇ ) in order to calculate compound IC50, with a total DMSO concentration in the assay of 0.3%.
  • the DNA-PK cell ELISA assay was performed in the HT29 colorectal carcinoma cell line.
  • HT29 cells were cultured in cell media composed of MEM (Minimum Essential Medium Eagle Sigma #M2279), 10% (v/v) Foetal Calf Serum and 1% (v/v) 200 mM L-Glutamine. After harvesting, cells were dispensed into black, 384-well Costar plates (#3712, Corning) to give 15,000 cells per well in a total volume of 40 ul cell media, and were incubated overnight at 37°C, 90% relative humidity and 5% CO2 in a rotating incubator.
  • Greiner 781077 all-black high-bind 384-well ELISA plates were coated with 0.5 ⁇ / ⁇ 1 DNA-PK antibody (Abeam #abl832) in PBS overnight at 4°C. The following day the Greiner ELISA plates were washed 3x with PBS-T and blocked with 3% BSA/PBS for ⁇ 2h, before a further 3x wash with PBS-T. Test compounds and reference controls were dosed directly into the cell plates using a Labcyte Echo 555 acoustic dispenser. The cell plates were then incubated for 1 h at 37°C before receiving a radiation dose of 8 Gy (XRAD 320, table height 65). The cells were incubated for a further 1 h before removal of cell media.
  • Lysis buffer in-house preparation with addition of protease inhibitor cocktail tablets, Roche # 04 693 116 001 was dispensed at 25 ⁇ 1 ⁇ 11 and plates were incubated at 4°C for 15-20 min. Cell lysates (20 ⁇ 1 ⁇ 11) were transferred to the DNA-PK antibody-coated ELISA plates using a CyBio Felix liquid handling platform, and ELISA plates were incubated at 4°C overnight. The following day, ELISA plates were washed 3x with PBS-T and dispensed with in- house pS2056-DNA-PK antibody (O ⁇ g/ml in 3% BSA/PBS) at 20 ⁇ 1 ⁇ 11.
  • Table 5 shows comparative data for certain Compounds of CN102399218A and CN102372711A in Assays a) to e).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne d'une manière générale des composés de formule (I) et des sels correspondants pharmaceutiquement acceptables, R1 étant du 4-fluoropipéridin-1-yle ou du 3-fluoropyrrolidin-1-yle; et R2 étant méthyle ou hydro; l'utilisation des composés de formule (I) ou de ses sels pharmaceutiquement acceptables pour traiter ou prévenir une maladie conditionnée par l'ATM (ataxie télangiectasie muté), y compris le cancer; des compositions pharmaceutiques comprenant des composés imidazo [4,5-c]quinolin-2-one substitués ou de ses sels pharmaceutiquement acceptables; des kits comprenant les composés de formule (I) ou ses sels pharmaceutiquement acceptables; des procédés de fabrication des composés de formule (I) ou de ses sels pharmaceutiquement acceptables; et des intermédiaires utiles dans cette fabrication.
PCT/EP2017/061229 2016-05-11 2017-05-10 Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer WO2017194632A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1608227.3 2016-05-11
GBGB1608227.3A GB201608227D0 (en) 2016-05-11 2016-05-11 Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer

Publications (1)

Publication Number Publication Date
WO2017194632A1 true WO2017194632A1 (fr) 2017-11-16

Family

ID=56297492

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/061229 WO2017194632A1 (fr) 2016-05-11 2017-05-10 Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer

Country Status (4)

Country Link
AR (1) AR108461A1 (fr)
GB (1) GB201608227D0 (fr)
TW (1) TW201805284A (fr)
WO (1) WO2017194632A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019201283A1 (fr) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Inhibiteurs doubles d'atm et d'adn-pk pour une utilisation en thérapie antitumorale
WO2020063855A1 (fr) * 2018-09-30 2020-04-02 南京明德新药研发有限公司 Dérivé de quinolino-pyrrolidin-2-one et application associée
CN112469720A (zh) * 2018-04-20 2021-03-09 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
WO2021098734A1 (fr) * 2019-11-19 2021-05-27 南京明德新药研发有限公司 Composé de quinolinopyrrolidone substitué utilisé en tant qu'inhibiteur d'atm et son application
WO2021139814A1 (fr) * 2020-01-09 2021-07-15 南京明德新药研发有限公司 Composé d'imidazole quinoléine et son utilisation
WO2021197339A1 (fr) * 2020-03-30 2021-10-07 南京明德新药研发有限公司 Forme cristalline de composé de quinopyrrolidine-2-one servant d'inhibiteur d'atm et son utilisation
WO2021260580A1 (fr) 2020-06-24 2021-12-30 Astrazeneca Uk Limited Combinaison d'un conjugué anticorps-médicament et d'un inhibiteur de l'atm
JP2022500428A (ja) * 2018-09-14 2022-01-04 スゾウ、ザンロン、ファーマ、リミテッドSuzhou Zanrong Pharma Limited 毛細血管拡張性運動失調症変異（ＡＴＭ）キナーゼの選択的調節物質としての１−イソプロピル−３−メチル−８−（ピリジン−３−イル）−１，３−ジヒドロ−２Ｈ−イミダゾ［４，５−ｃ］シンノリン−２−オンおよびその使用
EP3992191A1 (fr) 2020-11-03 2022-05-04 Deutsches Krebsforschungszentrum Dérivés d'imidazo[4,5-c]quinoline et leur utilisation en tant qu'inhibiteurs de kinase atm
CN115778962A (zh) * 2022-11-28 2023-03-14 中国医学科学院肿瘤医院 治疗男性食管癌患者的药物及其相关应用
WO2023143282A1 (fr) * 2022-01-26 2023-08-03 正大天晴药业集团股份有限公司 Composé contenant un groupe hydrazino

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
CN102372711A (zh) 2010-08-18 2012-03-14 山东轩竹医药科技有限公司 咪唑并喹啉类PI3K和mTOR双重抑制剂
CN102399218A (zh) 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 一类并合三杂环及其作为pi3k抑制剂的用途
WO2015170081A1 (fr) * 2014-05-08 2015-11-12 Astrazeneca Ab Composés imidazo[4,5c]quinoline-2-one et leur utilisation dans le traitement du cancer
WO2017046216A1 (fr) * 2015-09-17 2017-03-23 Astrazeneca Ab Dérivés 8-[6-[3-(amino)propoxy]-3-pyridyl]-1-isopropyl-imidazo[4,5-c]quinoléin-2-one utilisés en tant que modulateurs sélectifs de l'ataxie télangiectasie mutée (atm) kinase pour le traitement du cancer

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
CN102372711A (zh) 2010-08-18 2012-03-14 山东轩竹医药科技有限公司 咪唑并喹啉类PI3K和mTOR双重抑制剂
CN102399218A (zh) 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 一类并合三杂环及其作为pi3k抑制剂的用途
WO2015170081A1 (fr) * 2014-05-08 2015-11-12 Astrazeneca Ab Composés imidazo[4,5c]quinoline-2-one et leur utilisation dans le traitement du cancer
WO2017046216A1 (fr) * 2015-09-17 2017-03-23 Astrazeneca Ab Dérivés 8-[6-[3-(amino)propoxy]-3-pyridyl]-1-isopropyl-imidazo[4,5-c]quinoléin-2-one utilisés en tant que modulateurs sélectifs de l'ataxie télangiectasie mutée (atm) kinase pour le traitement du cancer

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WEINHEIM/ZIIRICHIWILEY-VCH/VHCA
BAKKENIST ET AL., NATURE, 2003, pages 499 - 506
BUNN, C.W.: "Chemical Crystallography", 1948, CLARENDON PRESS
CREMONA ET AL., ONCOGENE, 2013, pages 3351 - 3360
JENKINS, R; SNYDER, R.L: "Introduction to X-Ray Powder Diffractometry", 1996, JOHN WILEY & SONS
KLUG, H. P.; ALEXANDER, L. E., X-RAY DIFFRACTION PROCEDURES, 1974
KURZ; LEES MILLER, DNA REPAIR, 2004, pages 889 - 900
LAVIN, M. F., REV. MOL. CELL BIOL., 2008, pages 759 - 769
MATSUOKA ET AL., SCIENCE, 2007, pages 1160 - 1166

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019201283A1 (fr) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Inhibiteurs doubles d'atm et d'adn-pk pour une utilisation en thérapie antitumorale
CN112469720A (zh) * 2018-04-20 2021-03-09 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
CN112469720B (zh) * 2018-04-20 2024-03-29 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
JP2022500428A (ja) * 2018-09-14 2022-01-04 スゾウ、ザンロン、ファーマ、リミテッドSuzhou Zanrong Pharma Limited 毛細血管拡張性運動失調症変異（ＡＴＭ）キナーゼの選択的調節物質としての１−イソプロピル−３−メチル−８−（ピリジン−３−イル）−１，３−ジヒドロ−２Ｈ−イミダゾ［４，５−ｃ］シンノリン−２−オンおよびその使用
JP7436465B2 (ja) 2018-09-14 2024-02-21 スゾウ、ザンロン、ファーマ、リミテッド 毛細血管拡張性運動失調症変異（ＡＴＭ）キナーゼの選択的調節物質としての１－イソプロピル－３－メチル－８－（ピリジン－３－イル）－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｃ］シンノリン－２－オンおよびその使用
JP2021529214A (ja) * 2018-09-30 2021-10-28 メッドシャイン ディスカバリー インコーポレイテッド キノリノピロリジン−２−オン系誘導化合物及びその使用
KR20210060613A (ko) * 2018-09-30 2021-05-26 메드샤인 디스커버리 아이엔씨. 퀴놀리노-피롤리딘-2-온 유도체 및 이의 응용
KR102345208B1 (ko) 2018-09-30 2021-12-30 메드샤인 디스커버리 아이엔씨. 퀴놀리노-피롤리딘-2-온 유도체 및 이의 응용
CN112771045A (zh) * 2018-09-30 2021-05-07 南京明德新药研发有限公司 喹啉并吡咯烷-2-酮类衍生物及其应用
WO2020063855A1 (fr) * 2018-09-30 2020-04-02 南京明德新药研发有限公司 Dérivé de quinolino-pyrrolidin-2-one et application associée
JP6997358B2 (ja) 2018-09-30 2022-01-17 メッドシャイン ディスカバリー インコーポレイテッド キノリノピロリジン－２－オン系誘導化合物及びその使用
US11230549B2 (en) 2018-09-30 2022-01-25 Medshine Discovery Inc. Quinolino-pyrrolidin-2-one derivative and application thereof
AU2019348132B2 (en) * 2018-09-30 2022-03-31 Medshine Discovery Inc. Quinolino-pyrrolidin-2-one derivative and application thereof
CN112771045B (zh) * 2018-09-30 2022-04-19 南京明德新药研发有限公司 喹啉并吡咯烷-2-酮类衍生物及其应用
RU2771314C1 (ru) * 2018-09-30 2022-04-29 Медшайн Дискавери Инк. Производные хинолинпирролидин-2-она и их применение
WO2021098734A1 (fr) * 2019-11-19 2021-05-27 南京明德新药研发有限公司 Composé de quinolinopyrrolidone substitué utilisé en tant qu'inhibiteur d'atm et son application
CN114746421A (zh) * 2019-11-19 2022-07-12 南京明德新药研发有限公司 作为atm抑制剂的有取代的喹啉吡咯酮类合物及其应用
WO2021139814A1 (fr) * 2020-01-09 2021-07-15 南京明德新药研发有限公司 Composé d'imidazole quinoléine et son utilisation
CN115003672A (zh) * 2020-01-09 2022-09-02 南京明德新药研发有限公司 喹啉并咪唑类化合物及其应用
CN115380031A (zh) * 2020-03-30 2022-11-22 南京明德新药研发有限公司 作为atm抑制剂的喹啉并吡咯烷-2-酮类化合物的晶型及其应用
WO2021197339A1 (fr) * 2020-03-30 2021-10-07 南京明德新药研发有限公司 Forme cristalline de composé de quinopyrrolidine-2-one servant d'inhibiteur d'atm et son utilisation
WO2021260580A1 (fr) 2020-06-24 2021-12-30 Astrazeneca Uk Limited Combinaison d'un conjugué anticorps-médicament et d'un inhibiteur de l'atm
WO2022096361A1 (fr) 2020-11-03 2022-05-12 Deutsches Krebsforschungszentrum Composés imidazo[4,5-c]quinoléine et leur utilisation en tant qu'inhibiteurs de kinase atm
EP3992191A1 (fr) 2020-11-03 2022-05-04 Deutsches Krebsforschungszentrum Dérivés d'imidazo[4,5-c]quinoline et leur utilisation en tant qu'inhibiteurs de kinase atm
WO2023143282A1 (fr) * 2022-01-26 2023-08-03 正大天晴药业集团股份有限公司 Composé contenant un groupe hydrazino
CN115778962A (zh) * 2022-11-28 2023-03-14 中国医学科学院肿瘤医院 治疗男性食管癌患者的药物及其相关应用

Also Published As

Publication number Publication date
GB201608227D0 (en) 2016-06-22
AR108461A1 (es) 2018-08-22
TW201805284A (zh) 2018-02-16

Similar Documents

Publication Publication Date Title
WO2017194632A1 (fr) Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer
US10882858B2 (en) Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
EP3371183A1 (fr) Composés imidazo[4,5-c]quinoléine-2-one et leur utilisation dans le traitement du cancer
AU2018234985B2 (en) Deuterated imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
JP2018531226A6 (ja) 癌の治療のための血管拡張性失調症変異（ａｔｍ）キナーゼの選択的モジュレーターとしての８−［６−［３−（アミノ）プロポキシ］−３−ピリジル］−１−イソプロピル−イミダゾ［４，５−ｃ］キノリン−２−オン誘導体
WO2017153578A1 (fr) Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer
US20190099421A1 (en) Cinnolin-4-amine compounds and their use in treating cancer
WO2019057757A1 (fr) Composés 1,3-dihydroimidazo[4,5-c]cinnolin-2-one et leur utilisation dans le traitement du cancer
AU2017247558A1 (en) N,N-dimethyl-3-[[5-(3-methyl-2-oxo-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-8-yl)-2-pyridyl]oxy]propan-1-amine oxide as ATM (ataxia telangiectasia mutated) kinase modulator for treating cancer

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17722777

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17722777

Country of ref document: EP

Kind code of ref document: A1