WO2020030925A1 - Urées substituées hétérocycliques, destinées à être utilisées contre le cancer - Google Patents

Urées substituées hétérocycliques, destinées à être utilisées contre le cancer Download PDF

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WO2020030925A1
WO2020030925A1 PCT/GB2019/052244 GB2019052244W WO2020030925A1 WO 2020030925 A1 WO2020030925 A1 WO 2020030925A1 GB 2019052244 W GB2019052244 W GB 2019052244W WO 2020030925 A1 WO2020030925 A1 WO 2020030925A1
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methyl
compound
alkyl
mmol
phenyl
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Peter BLENCOWE
Mark Charles
Andrew Cridland
Tennyson Ekwuru
Robert Heald
Ellen Macdonald
Hollie MCCARRON
Laurent Rigoreau
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Artios Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention relates to heterocyclic urea derivatives and their use in the treatment and prophylaxis of cancer, and to compositions containing said derivatives and processes for their preparation.
  • DSBs DNA double-strand breaks
  • HR homologous recombination
  • NHEJ non-homologous end-joining
  • alt-NHEJ alternative NHEJ
  • MMEJ Microhomology-mediated end-joining
  • HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability.
  • NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair. MMEJ can function parallel to both HR and NHEJ pathways (Truong et al.
  • DDR DNA damage response
  • An aberrant DDR can also sensitise cancer cells to specific types of DNA damage, thus, defective DDR can be exploited to develop targeted cancer therapies.
  • cancer cells with impairment or inactivation of HR and NHEJ become hyper-dependent on MMEJ-mediated DNA repair.
  • Polq UniProtKB - O75417 (DPOLQ_HUMAN) as the key protein in MMEJ (Kent et al. Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257).
  • Polq is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D.00é DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ.
  • the helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing.
  • the polymerase domain extends the ssDNA ends and fills the remaining gaps.
  • Therapeutic inactivation of Polq would thus disable the ability of cells to perform MMEJ and provide a novel targeted strategy in an array of defined tumour contexts.
  • HRD HR-defective
  • R 1 represents C 1-6 alkoxy, C 2-6 alkenoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CO-C 2-6 alkenyl, - N(R w )-CO-C 2-6 alkenyl, -Z-C 3-8 cycloalkyl, -Z-heterocyclyl, wherein said C 1-6 alkoxy group may be substituted by one or more cyano, hydroxy, -SO2-R w , -CONR x R y groups, and wherein said C2-6 alkenoxy group may be optionally substituted by one or more -COOC1-6 alkyl groups, and wherein said heterocyclyl groups may be optionally substituted by one or more C 1-6 alkyl, C 1-6 alkanol, halogen, hydroxy, C 1-6 alkoxy, oxo, cyano, -COC 1-6 alkyl, -COC 2- 6 alkenyl, -COOC 1-6
  • R w , R x and R y independently represent hydrogen or C1-6 alkyl
  • Z represents a bond, -CH2-O-, -O-CH2-, -O-(CH2)2-, -OC(H)(Me)- or -N(R w )-CH2-;
  • n an integer selected from 0 to 2;
  • R 2 represents hydrogen, C 1-6 alkyl, C 1-6 alkanol, C 1-6 alkoxy, halogen, haloC 1-6 alkyl, cyano or amino;
  • R 3 represents heterocyclyl or heteroaryl optionally substituted by one or more R 5 groups;
  • R 4 represents hydrogen, halogen or C 1-6 alkyl;
  • R 5 represents C 1-6 alkyl, C 1-6 alkanol, C 1-6 alkylamino, cyano, -CO-C 1-6 alkyl, -NHCO-C 1-6 alkyl, -CH 2 CONR x R y or -CH 2 NHCOO-C 1-6 alkyl.
  • halo or‘halogen’ as used herein refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to a group where a carbon atom is triple bonded to a nitrogen atom.
  • C1-6 alkyl as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and the like.
  • C1-6 alkoxy refers to a C1-6 alkyl group which contains an oxygen atom wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy or propoxy.
  • C1-6 alkanol as used herein as a group or part of a group refers to a C1-6 alkyl group which contains a hydroxyl group wherein C1-6 alkyl is as defined herein.
  • C2-6 alkenyl as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond.
  • C2-6 alkenoxy as used herein as a group or part of a group refers to a C2-6 alkenyl group which contains an oxygen atom wherein C 2-6 alkenyl is as defined herein.
  • haloC 1-6 alkyl as used herein as a group or part of a group refers to a C 1-6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • haloC 1-6 alkyl therefore includes monohaloC 1-6 alkyl and also polyhaloC 1-6 alkyl.
  • haloC 1-6 alkyl may have one, two, three or more halogens.
  • groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
  • haloC 1-6 alkoxy as used herein as a group or part of a group refers to a–O-C 1-6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • haloC 1-6 alkoxy therefore includes monohaloC 1-6 alkoxy, and also polyhaloC 1-6 alkoxy.
  • haloC 1-6 alkoxy may have one, two, three or more halogens.
  • examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • amino refers to the group -NR’R’’, wherein R’ and R’’
  • C3-8 cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • heteroaryl refers to a monocyclic or bicyclic aromatic, unsaturated ring system containing for example 3 to 12 ring members. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
  • n a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1- b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).
  • imidazothiazole e.g. imidazo[2,1- b]thiazole
  • imidazoimidazole e.g. imidazo[1,2-a]imidazole
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene,
  • benzimidazole benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole,
  • benzisothiazole isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g. [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.
  • purine e.g., adenine, guanine
  • indazole pyrazolopyrimidine
  • triazolopyrimidine e.g. [1,2,4]triazolo[1,5-a]pyrimidine
  • benzodioxole imidazopyridine and pyrazolopyridine (
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, quinolizine, benzoxazine, pyridopyridine,
  • quinoxaline quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene,
  • heterocyclyl refers to a monocyclic or bicyclic non-aromatic, partially saturated or fully saturated ring system containing for example 3 to 12 ring members. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • Particular examples of‘heterocyclyl’ include morpholine, piperidine (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinone, pyrrolidine (e.g.
  • pyrrolidin-1-yl pyrrolidin-2-yl and pyrrolidin-3-yl
  • pyrrolidone azetidine
  • pyran (2H-pyran or 4H-pyran) dihydrothiophene
  • dihydropyran dihydrofuran
  • dihydrothiazole tetrahydrofuran
  • heterocyclyl includes reference to spiro and bridged heterocyclic derivatives.
  • spiro and bridged heterocyclic derivatives include: hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa- azaspiro[3.3]heptyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazospiro[5.5]undecanyl and oxabicyclo[2.2.1]heptanyl.
  • the term‘optionally substituted’ as used herein refers to a group
  • the compound of formula (I) is a compound of formula (I) a :
  • the compound of formula (I) is a compound of formula (I) b :
  • R 1 represents:
  • C1-6 alkoxy such as propoxy, -O-CH2-CH(Me)2 or -OC(H)(Me)-Et
  • one or more cyano such as -O-CH 2 -C(Me)(Me)(CN)), hydroxy (such as -O- CH2-C(Me)(Me)(OH)), -SO2-R w (such as -O-CH2-C(Me)(Me)(SO2Me) or -CONR x R y (such as - O-CH2-C(Me)(Me)(CONH2)) groups
  • cyano such as -O-CH 2 -C(Me)(Me)(CN)
  • hydroxy such as -O- CH2-C(Me)(Me)(OH)
  • -SO2-R w such as -O-CH2-C(Me)(Me)(SO2Me) or -CONR x R y (such as -
  • haloC1-6 alkyl such as trifluoromethyl
  • haloC 1-6 alkoxy such as trifluoromethoxy
  • -Z-C 3-8 cycloalkyl such as -cyclohexyl or -O-CH 2 -cyclobutyl
  • -Z-heterocyclyl such as -azetidinyl, -pyrrolidinyl, -piperidinyl, -morpholinyl, - tetrahydropyranyl, -pyranyl, -hexahydropyrrolo[2,3-c]pyrrolidinyl, -diazaspiro[3.4]octanyl, - diazaspiro[4.4]nonyl, -oxa-azaspiro[3.4]octanyl, -oxa-azaspiro[4.4]nonyl, -tetrahydrofuro[3,4- c]pyrrolidinyl, -oxa-azaspiro[3.3]heptyl, -diazaspiro[4.5]decanyl, -diazaspiro[3.4]octanyl, - octahydro-naphthyridinyl, -t
  • R 1 represents:
  • Z represents a bond, -CH2-O-, -O-CH2-, -O-(CH2)2-, -OC(H)(Me)-, -N(H)- CH2- or -N(Me)-CH2-.
  • Z represents a bond or -O-CH2-.
  • n represents an integer selected from 1 or 2.
  • R 2 represents hydrogen, C 1-6 alkyl (such as methyl or ethyl), C 1-6 alkanol (such as -CH 2 OH), C 1-6 alkoxy (such as methoxy), halogen (such as fluorine or chlorine), haloC 1-6 alkyl (such as -CH 2 -F) or amino.
  • R 2 represents C 1-6 alkyl (such as methyl or ethyl), C 1-6 alkoxy (such as methoxy) or halogen (such as fluorine or chlorine).
  • R 2 represents C 1-6 alkyl (such as methyl), C 1-6 alkoxy (such as methoxy) or halogen (such as chlorine).
  • R 2 represents methyl, methoxy or chlorine.
  • R 4 represents hydrogen, fluorine or methyl. In a further embodiment:
  • R 3 represents monocyclic heterocyclyl or monocyclic heteroaryl.
  • R 3 represents heterocyclyl (such as piperidinyl or azepanyl) or heteroaryl (such as pyridyl, pyrazolyl, pyrazinyl or pyrimidinyl) optionally substituted by one or more R 5 groups.
  • R 5 represents C1-6 alkyl (such as methyl or ethyl), C1-6 alkanol (such as –(CH2)2-OH), C1-6 alkylamino (such as–CH2-NH2,–(CH2)2-NH2 or -CH2-N(Me)2), cyano, -CO- C1-6 alkyl (such as -COMe), -NHCO-C1-6 alkyl (such as -NHCOMe), -CH2CONR x R y (such as - CH 2 CON(Me) 2 ), or -CH 2 NHCOO-C 1-6 alkyl (such as -CH 2 NHCOO-t-butyl).
  • R 5 represents C 1-6 alkyl (such as methyl).
  • R 3 represents:
  • heterocyclyl such as piperidinyl or azepanyl
  • R 5 groups selected from C 1-6 alkyl (such as methyl), C 1-6 alkanol (such as–(CH 2 ) 2 -OH), -CO- C 1-6 alkyl (such as -COMe) or -CH 2 CONR x R y (such as -CH 2 CON(Me) 2 ); or
  • R 5 groups selected from C 1-6 alkyl (such as methyl or ethyl), C 1-6 alkanol (such as -CH 2 -OH), C 1-6 alkylamino (such as–CH 2 -NH 2 ,–(CH 2 ) 2 -NH 2 or -CH 2 -N(Me) 2 ), cyano, -NHCO-C 1-6 alkyl (such as -NHCOMe) or -CH 2 NHCOO-C 1-6 alkyl (such as - CH 2 NHCOO-t-butyl).
  • R 3 represents:
  • piperidinyl optionally substituted by one or more C 1-6 alkyl (such as methyl), C 1-6 alkanol (such as–(CH 2 ) 2 -OH), -CO-C 1-6 alkyl (such as -COMe) or -CH 2 CONR x R y (such as - CH2CON(Me)2);
  • C 1-6 alkyl such as methyl
  • C 1-6 alkanol such as–(CH 2 ) 2 -OH
  • -CO-C 1-6 alkyl such as -COMe
  • -CH 2 CONR x R y such as - CH2CON(Me)2
  • azepanyl optionally substituted by one or more C1-6 alkyl (such as methyl);
  • pyridyl optionally substituted by one or more C1-6 alkyl (such as methyl or ethyl), C1-6 alkanol (such as -CH2-OH), C1-6 alkylamino (such as–CH2-NH2,–(CH2)2-NH2 or -CH2- N(Me)2), cyano, -NHCO-C1-6 alkyl (such as -NHCOMe) or -CH2NHCOO-C1-6 alkyl (such as - CH2NHCOO-t-butyl);
  • C1-6 alkyl such as methyl or ethyl
  • C1-6 alkanol such as -CH2-OH
  • C1-6 alkylamino such as–CH2-NH2,–(CH2)2-NH2 or -CH2- N(Me)2
  • cyano cyano
  • -NHCO-C1-6 alkyl such as -NHCOMe
  • -CH2NHCOO-C1-6 alkyl such as - CH2NHCOO-t-
  • R 3 represents:
  • R 3 represents piperidinyl optionally substituted by a methyl group (such as piperidin-3-yl or 1-methyl-piperidin-3-yl) or pyridyl substituted by a methyl group (such as 6-methyl-pyrid-3-yl).
  • R w , R x and R y independently represent hydrogen or methyl.
  • R x and R y both represent hydrogen, both represent methyl or one represents hydrogen and the other represents methyl.
  • the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-215 or a pharmaceutically acceptable salt or solvate thereof.
  • a reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof.
  • Certain compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • a-oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • salts consist of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic,
  • salts of the compounds of formula (I) may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci.1977, 66, pp.1-19.
  • Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Other salts e.g.
  • oxalates or formates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
  • salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts.
  • non-pharmaceutically acceptable salts forms which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as“solvates”.
  • a complex with water is known as a“hydrate”.
  • Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention.
  • the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.
  • said crystalline form of the compounds of formula (I) is a cocrystal or coformer.
  • Such a cocrystal or coformer may be prepared using water-soluble molecules such as saccharin, caffeine, nicotinamide or carboxylic acids.
  • Coformers may be prepared as described in Emami S et al (2016) BioImpacts 8(4), 305-320, the techniques of which are herein incorporated by reference. It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention. As used herein "pharmaceutically acceptable derivative” includes any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon
  • N-oxides may also form N-oxides.
  • a reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Commun.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • the compounds of formula (I) may be achiral or R or S enantiomers. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the invention also extends to any tautomeric forms or mixtures thereof.
  • the subject invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I, 125 I and 131 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labelled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc.
  • labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H (D)
  • Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed. Purity
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the
  • a process for the preparation of compounds of formula (I) and derivatives thereof comprising: (a) reacting a compound of formula (II):
  • L 1 represents a suitable leaving group such as a halogen atom (e.g. bromine), with a compound of formula (III) a and (III) b :
  • R 2 , U, V, W, X, Y and R 3 are as defined above and L 2 represents a suitable leaving group, such as a halogen atom (e.g. bromine), with a compound of formula R 1 -H, wherein R 1 is as defined above; (d) reacting a compound of formula (VI):
  • R 2 , U, V, W, X, Y and R 3 are as defined above, with a compound of formula R 1 -L 3 , wherein R 1 is as defined above and L 3 represents a suitable leaving group, such as a halogen atom (e.g. chlorine, bromine or iodine); (e) reacting a compound of formula (V):
  • a halogen atom e.g. chlorine, bromine or iodine
  • R 2 , U, V, W, X, Y and R 3 are as defined above and L 2 represents a suitable leaving group, such as a halogen atom (e.g. bromine), with a compound of formula (VII):
  • a halogen atom e.g. bromine
  • Process (a) typically comprises reacting a compound of formula (II) with compounds of formulae (III) a and (III) b in the presence of suitable reagents such as Pd(PPh 3 ) 4 , K 3 PO 4 and suitable solvents such as 1,4-dioxane and water under suitable conditions, such as by heating.
  • suitable reagents such as Pd(PPh 3 ) 4 , K 3 PO 4 and suitable solvents such as 1,4-dioxane and water under suitable conditions, such as by heating.
  • Process (b) typically comprises reacting a compound of formula (IV) with the compound of formula R 3 -NH 2 in the presence of a suitable reagent, such as DPPA, in the presence of suitable solvents, such as toluene and DMF, in the presence of a suitable base, such as TEA under suitable conditions, such as by heating.
  • Process (c) typically comprises reacting a compound of formula (V) with the compound of formula R 1 -H in the presence of suitable reagents, such as Pd2(dba)3, BINAP and in the presence of suitable solvents such as t-BuONa and 1,4-dioxane, under suitable conditions, such as by heating.
  • Process (d) typically comprises reacting a compound of formula (VI) with the compound of formula R 1 -L 3 in the presence of suitable reagents, such as K2CO3 and NMP, under suitable conditions, such as by heating.
  • Process (e) typically comprises reacting a compound of formula (V) with a compound of formula (VII) in the presence of suitable reagents, such as Pd(PPh3)2Cl2 and K2CO3, in the presence of suitable solvents, such as 1,4-dioxane and water, under suitable conditions, such as by heating.
  • suitable reagents such as Pd(PPh3)2Cl2 and K2CO3
  • suitable solvents such as 1,4-dioxane and water
  • Step (a) typically comprises reacting a compound of formula (VIII) with a compound of formula H 2 N-R 3 in the presence of a suitable reagent, such as DPPA, in the presence of suitable solvents, such as toluene and DMF, in the presence of a suitable base, such as TEA under suitable conditions, such as by heating.
  • a suitable reagent such as DPPA
  • suitable solvents such as toluene and DMF
  • a suitable base such as TEA
  • Step (a) typically comprises reacting a compound of formula (IX) with the compounds of formulae (III) a and (III) b in the presence of suitable reagents such as Pd(PPh 3 ) 4 , K 3 PO 4 and suitable solvents such as 1,4-dioxane and water under suitable conditions, such as by heating.
  • Step (b) typically comprises reacting a compound of formula (X) with a suitable reagent, such as LiOH in the presence of suitable solvents, such as water and THF.
  • Step (a) typically comprises reacting a compound of formula (XI) with a compound of formula R’R’’N-H in the presence of suitable reagents, such as Pd(OAc) 2 , K 3 PO 4 and RuPhos, in the presence of a suitable solvent such as toluene, under suitable conditions, such as by heating.
  • Step (b) typically comprises reacting a compound of formula (IV) a with a suitable reagent, such as DPPA, in the presence of suitable solvents, such as toluene and TFA, under suitable conditions, such as by heating.
  • Step (a) typically comprises reacting a compound of formula (XII) with a compound of formula R 3 -NH2 in the presence of a suitable reagent, such as DPPA, in the presence of suitable solvents, such as toluene and DMF, the presence of a suitable base, such as TEA under suitable conditions, such as by heating.
  • a suitable reagent such as DPPA
  • suitable solvents such as toluene and DMF
  • a suitable base such as TEA
  • Step (b) typically comprises reacting a compound of formula (V) with a compound of formula R’R’’NH in the presence of suitable reagents, such as Pd 2 (dba) 3 , BINAP and t-BuONa, in the presence of a suitable solvent, such as 1,4-dioxane, under suitable conditions, such as by heating.
  • suitable reagents such as Pd 2 (dba) 3 , BINAP and t-BuONa
  • a suitable solvent such as 1,4-dioxane
  • Step (a) typically comprises reacting a compound of formula (V) with a compound of formula R 1a -OH in the presence of suitable reagents such as Pd(OAc)2 and BINAP, in the presence of a suitable solvent, such as toluene, under suitable conditions, such as by heating.
  • suitable reagents such as Pd(OAc)2 and BINAP
  • Step (a) typically comprises reacting a compound of formula (XIII) with a compound of formula R 1a -L 6 in the presence of suitable reagents such as K2CO3 and NMP, under suitable conditions, such as by heating.
  • suitable reagents such as K2CO3 and NMP
  • Step (a) typically comprises reacting a compound of formula (V) with a compound of formula (XIV) in the presence of suitable reagents, such as Pd(PPh 3 ) 2 Cl 2 and K 2 CO 3 , in the presence of suitable solvents, such as 1,4-dioxane and water, under suitable conditions, such as by heating.
  • suitable reagents such as Pd(PPh 3 ) 2 Cl 2 and K 2 CO 3
  • suitable solvents such as 1,4-dioxane and water
  • An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO- OCH2C6H5, -NH-Cbz or NH-Z); as a tert-butyl carbamate (-NHCOOC(CH3)3, NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6H5, NH-Boc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carba
  • a carboxylic acid group may be protected as an ester for example, as: an C1-7 alkyl ester (e.g. a methyl ester; a tert-butyl ester); a C1-7 haloalkyl ester (e.g.
  • a C1-7 trihaloalkyl ester a triC1-7 alkylsilyl-C1-7 alkyl ester; or a C5-20 aryl-C1-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester.
  • a benzyl ester a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester.
  • Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the compounds of the invention, subgroups and examples thereof, are inhibitors of Polq polymerase activity, and which may be useful in preventing or treating disease states or conditions described herein.
  • the compounds of the invention, and subgroups thereof, will be useful in preventing or treating diseases or condition mediated by Polq.
  • references to the preventing or prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence of cancer.
  • the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.
  • the compounds of the present invention may be useful for the treatment of the adult population.
  • the compounds of the present invention may be useful for the treatment of the pediatric population.
  • the compounds will be useful in providing a means of disabling the ability of cells to perform MMEJ. It is therefore anticipated that the compounds may prove useful in treating or preventing proliferative disorders such as cancers.
  • the compounds of the invention may be useful in the treatment of diseases in which there is a disorder associated with cell accumulation.
  • the Polq inhibitors of the present invention will demonstrate certain properties for them to be of particular utility in the therapeutic treatment of certain cancers.
  • the Polq inhibitors of the present invention are suitably lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumours, including breast, ovarian, prostate and pancreas.
  • the Polq inhibitors of the present invention are suitably lethal in a variety of primary and secondary solid tumours which are HRD by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation.
  • the Polqi may be given along with another DDR modulator such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a wee1 inhibitor or a CHK1 inhibitor.
  • a PARP inhibitor such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a wee1 inhibitor or a CHK1 inhibitor.
  • the Polq inhibitors of the present invention are suitably lethal in primary and secondary breast, ovarian, prostate and pancreatic tumours retaining BRCA1 deficiency but which, following or not following exposure to PARPi medication, are resistant to PARPi treatment.
  • the Polq inhibitors of the present invention suitably increase the ORR including CRR, will delay the onset of PARPi resistance, will increase the time to relapse and DFS, and will increase the OS of HRD (BRCA1/2 deficient and other HRD mechanisms) primary and secondary tumours (breast, ovarian, prostate and pancreas) when given with PARPi treatment programmes.
  • the Polq inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in a variety of tumours with loss of ATM activity (ATM -/- ) particularly in the context of WT p53. Tumour types will include around 10% of all solid tumours including gastric, lung, breast, and CRC, along with CLL.
  • Co-medicating with another DDR modifier such as a DNA-PK inhibitor, PARP inhibitor or ATR inhibitor, may further enhance such activity.
  • Polq inhibitors will resensitise CLL to classical chemotherapy and chemo-immunotherapy where drug resistance has emerged.
  • the pharmaceutical composition of the present invention additionally comprises a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor.
  • the Polq inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in a variety of tumours deficient in the DNA double strand break repair process of non-homologous end-joining (NHEJ-D).
  • Tumour types will include approximately 2-10% of all solid tumours including prostate, pancreatic, cervical, breast, lung, bladder and oesophageal. Co-medicating with another DDR modifier, such as a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor, may further enhance such activity. Polq inhibitors will further sensitise NHEJD cancer cells to DNA DSB inducing chemotherapies and to ionising radiation based therapies.
  • the pharmaceutical composition of the present invention additionally comprises a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor.
  • the Polq inhibitors of the present invention suitably reduce the DNA replication stress response during the chemotherapy of HR proficient tumours such as ovarian, NSCL and breast tumours over expressing Polq. This will increase the ORR to treatment and increase OS. Such effects are particularly likely with cytarabine (Ara-C) and hydroxyurea used in a wide variety of leukemias including CML, and the management of squamous cell carcinomas.
  • the Polq inhibitors of the present invention suitably selectively sensitise solid tumours to radiotherapy, including EBRT and brachytherapy, with little or no sensitisation of normal tissues. In a fractionated curative-intent setting this will increase loco- regional control driving increased survival.
  • the Polq inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in PTEN deleted tumours such as CaP, with or without comedication with a PARPi. Furthermore, such tumours will exhibit extraordinarily sensitivity to radiotherapy both by dint of the PTEN deletion as well as the Polq inhibitor induced radiosensitivity.
  • the Polq inhibitors of the present invention suitably suppress TLS polymerase activity, sensitising primary and secondary solid tumours (e.g. breast, lung, ovarian, CRC) to drugs (e.g.
  • the Polq inhibitors of the present invention suitably resensitise BCR- ABL-positive CML which is has developed imatinib resistance, as well as other solid tumours with elevated ligase IIIa levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.
  • the Polq inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in aromatase inhibitor resistant ER- primary and secondary breast cancers, again showing elevated ligase IIIa levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.
  • HRD homologous recombination
  • references herein to“deficiency in homologous recombination (HRD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV),
  • said homologous recombination genes are selected from any of: ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1 and PTEN.
  • references herein to“non-homologous end-joining deficiency (NHEJD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene.
  • examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV),
  • said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.
  • a compound of formula (I) as defined herein for use in the treatment of tumours which have elevated ligase IIIa levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.
  • cancers and their benign counterparts which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian
  • lymphoid lineage for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma
  • lymphomas hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic
  • CMML myelomonocytic leukemia
  • hypereosinophilic syndrome myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia
  • myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia
  • tumours of mesenchymal origin for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas,
  • tumours of the central or peripheral nervous system for example astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas
  • endocrine tumours for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid
  • ocular and adnexal tumours for example retinoblastoma
  • germ cell and trophoblastic tumours for example teratomas, seminomas, dysger
  • cancers which can be treated by the compounds of the invention include primary tumours (i.e.
  • cancer cells at the originating site include local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours ie. tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body.
  • cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.
  • a further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer.
  • the compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti- metastatic agent.
  • the potency of the compounds of the invention as inhibitors of Polq can be measured using the biological and biophysical assays set forth in the examples herein and the level of affinity exhibited by a given compound can be defined in terms of the IC50 value.
  • Particular compounds of the present invention are compounds having an IC50 value of less than 1mM, more particularly less than 0.1 mM.
  • Polq inhibitory compounds are likely to be useful in enhancing the efficiency of CRISPR based editing methodologies and/or CRISPR based editing therapeutics.
  • compound mediated Polq inhibition is likely to reduce the frequency of random integration events and thus provide a route to ameliorate any safety concerns of CRISPR mediated technology.
  • a compound of formula (I) as defined herein in a CRISPR based editing methodology and/or CRISPR based editing therapeutics such as the enhancement of efficiency of CRISPR based editing methodology and/or CRISPR based editing therapeutics.
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). In one embodiment this is a sterile pharmaceutical composition.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents, as described herein.
  • the pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g.
  • a solid, liquid or semi-solid carrier a solid, liquid or semi-solid carrier
  • adjuvants diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.
  • excipients for various types of pharmaceutical compositions are set out in more detail below.
  • pharmaceutically acceptable as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g.
  • compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical
  • compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.
  • compositions adapted for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient.
  • aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable poly
  • compositions for parenteral administration may also take the form of aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p 201-230).
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried
  • the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent.
  • the pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub-groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate.
  • compositions of the present invention may also contain adjuvants such as
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
  • the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.
  • a pharmaceutically acceptable excipient such as 0.9% saline or 5% dextrose
  • the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
  • Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms eg; tablets, capsules etc.
  • Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes.
  • the coating e.g. a EudragitTM type polymer
  • the coating can be designed to release the active component at a desired location within the gastro-intestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon.
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract.
  • the drug can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • the coating can be designed to disintegrate under microbial action in the gut.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.
  • the compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption.
  • nanoparticles offer the possibility of direct penetration into the cell.
  • Nanoparticle drug delivery systems are described in“Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13 th March 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.
  • the pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95% (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a
  • compositions comprise from approximately 20% (w/w) to approximately 90%,% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95%, particularly from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragées, tablets or capsules.
  • the pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co- solvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.
  • diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co- solvents
  • disintegrants e.g solid diluents such as fillers or bulking agents
  • lubricants such as solvents and co- solvents
  • flow aids e.g. release retard
  • tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition contain 0-99% (w/w) release-controlling (e.g. delaying) polymers (depending on dose).
  • the film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.
  • Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried).
  • Formulations for intramuscular depots may also contain 0-99% (w/w) oils.
  • Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.
  • the compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids.
  • Solid solutions are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281- 1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.
  • This invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form.
  • a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant.
  • a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose.
  • a tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant.
  • a chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours.
  • Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non-pareils’). These beads can subsequently be filled into capsules or compressed into tablets.
  • compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.
  • Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g.50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g.0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g.100 miligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • the compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by Polq.
  • a method of treating a disease state or condition mediated by Polq e.g. cancer
  • a disease state or condition mediated by Polq e.g. cancer
  • the compounds are generally administered to a subject in need of such administration, for example a human or animal patient, particularly a human.
  • the compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic.
  • the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
  • the compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).
  • a typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g.10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required.
  • the compound of the formula (I) can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.
  • the compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g.2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg.
  • the compound may be administered once or more than once each day.
  • the compound can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen).
  • the compound can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen).
  • treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g.2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.
  • a patient will be given an infusion of a compound of the formula (I) for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.
  • a patient may be given an infusion of a compound of the formula (I) for periods of one hour daily for 5 days and the treatment repeated every three weeks.
  • a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g.3 hours.
  • a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.
  • a patient is given the compound orally once a week.
  • a patient is given the compound orally once-daily for between 7 and 28 days such as 7, 14 or 28 days.
  • a patient is given the compound orally once-daily for 1 day, 2 days, 3 days, 5 days or 1 week followed by the required amount of days off to complete a one or two week cycle.
  • a patient is given the compound orally once-daily for 2 weeks followed by 2 weeks off.
  • a patient is given the compound orally once-daily for 2 weeks followed by 1 week off.
  • a patient is given the compound orally once-daily for 1 week followed by 1 week off.
  • the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
  • Polq inhibitors can be used as a single agent or in combination with other anticancer agents. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27– 55.
  • the compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined.
  • the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy.
  • other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) include but are not limited to:
  • anti-cancer agents or adjuvants include but are not limited to any of the agents selected from groups (i)-(xlvi), and optionally group (xlvii), below: (i) Platinum compounds, for example cisplatin (optionally combined with amifostine),
  • Taxane compounds for example paclitaxel, paclitaxel protein bound particles
  • Topoisomerase I inhibitors for example camptothecin compounds, for example
  • camptothecin irinotecan(CPT11), SN-38, or topotecan;
  • Topoisomerase II inhibitors for example anti-tumour epipodophyllotoxins or
  • podophyllotoxin derivatives for example etoposide, or teniposide
  • Vinca alkaloids for example vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or vinvesir;
  • Nucleoside derivatives for example 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;
  • Antimetabolites for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide);
  • Alkylating agents such as nitrogen mustards or nitrosourea, for example
  • cyclophosphamide chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU);
  • doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. CaelyxTM, MyocetTM, DoxilTM), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;
  • Epothilones for example ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS- 862), aza-epothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;
  • DNA methyl transferase inhibitors for example temozolomide, azacytidine or
  • Antifolates for example methotrexate, pemetrexed disodium, or raltitrexed
  • Cytotoxic antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin
  • Tubulin-binding agents for example combrestatin, colchicines or nocodazole
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • MTKI multi target kinase inhibitors
  • Raf inhibitors mTOR inhibitors for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032/RG7204), dabrafenib, encorafenib or an IkB kinase inhibitor such as SAR- 113945, bar
  • CDK inhibitors for example AT7519, roscovitine, seliciclib, alvocidib (flavopiridol),
  • AKT inhibitors such as KRX-0401 (perifosine/ NSC 639966), ipatasertib (GDC-0068; RG-7440), afuresertib (GSK-2110183; 2110183), MK-2206, MK-8156, AT13148, AZD-5363, triciribine phosphate (VQD-002; triciribine phosphate monohydrate (API-2; TCN-P; TCN-PM; VD- 0002), RX-0201, NL-71-101, SR-13668, PX-316, AT13148, AZ-5363, Semaphore, SF1126, or Enzastaurin HCl (LY317615) or MTOR inhibitors such as rapamycin analogues such as RAD 001 (everolimus), CCI 779 (temsirolemus), AP
  • CBP-501 forkhead translocation inhibitors
  • enzastaurin HCl LY317615
  • PI3K Inhibitors such as dactolisib (BEZ235), buparlisib (BKM-120; NVP- BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC- 0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206, M
  • Hsp90 inhibitors for example AT13387, herbimycin, geldanamycin (GA), 17-allylamino- 17-desmethoxygeldanamycin (17-AAG) e.g. NSC-330507, Kos-953 and CNF-1010, 17- dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) e.g.
  • Monoclonal Antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti- HER2, anti-CTLA4, anti-PD-1 or anti-EGFR antibodies, for example rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzum
  • tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);
  • Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;
  • Aromatase inhibitors and related drugs such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane or vorozole;
  • Antiandrogens i.e. androgen receptor antagonists
  • related agents for example bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;
  • Hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (a.k.a. diethylstilboestrol) or octreotide;
  • CYP17 Steroidal cytochrome P45017alpha-hydroxylase-17,20-lyase inhibitor
  • Glucocorticoids for example prednisone, prednisolone, dexamethasone
  • Differentiating agents such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin
  • RAMBA retinoic acid metabolism blocking agents
  • Chromatin targeted therapies such as histone deacetylase (HDAC) inhibitors for example panobinostat, resminostat, abexinostat, vorinostat, romidepsin, belinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, CUDC-907, CUDC-101, ACY-1215, MGCD-290, EVP-0334, RG-2833, 4SC-202, romidepsin, AR-42 (Ohio State University), CG-200745, valproic acid, CKD-581, sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP- LAQ824), R306465/ JNJ-16241199, JNJ-26481585, trichostatin A, chlamydocin
  • HDAC
  • Proteasome Inhibitors for example bortezomib, carfilzomib, delanzomib (CEP- 18770), ixazomib (MLN-9708), oprozomib (ONX-0912) or marizomib;
  • Radiolabelled drugs for radioimmunotherapy for example with a beta particle-emitting isotope (e.g. , Iodine -131, Yittrium -90) or an alpha particle-emitting isotope (e.g., Bismuth-213 or Actinium-225) for example ibritumomab or Iodine tositumomab;
  • a beta particle-emitting isotope e.g. , Iodine -131, Yittrium -90
  • an alpha particle-emitting isotope e.g., Bismuth-213 or Actinium-225
  • interleukins e.g. interleukin 2
  • interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b;
  • Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or
  • (xliv)Enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase;
  • DNA repair inhibitors such as PARP inhibitors for example, olaparib, velaparib, iniparib, rucaparib (AG-014699 or PF-01367338), talazoparib or AG-014699;
  • Agonists of Death receptor e.g. TNF-related apoptosis inducing ligand (TRAIL) receptor
  • TRAIL TNF-related apoptosis inducing ligand
  • mapatumumab previously HGS-ETR1
  • conatumumab previously AMG 655
  • PRO95780 lexatumumab
  • dulanermin CS-1008
  • apomab recombinant TRAIL ligands
  • recombinant Human TRAIL/Apo2 Ligand recombinant Human TRAIL/Apo2 Ligand
  • Prophylactic agents i.e. agents that reduce or alleviate some of the side effects associated with chemotherapy agents, for example
  • neutropenia and prevent complications that arise from reduced levels of platelets, red blood cells or white blood cells, for example interleukin-11 (e.g. oprelvekin), erythropoietin (EPO) and analogues thereof (e.g. darbepoetin alfa), colony- stimulating factor analogs such as granulocyte macrophage-colony stimulating factor (GM-CSF) (e.g. sargramostim), and granulocyte-colony stimulating factor (G-CSF) and analogues thereof (e.g. filgrastim, pegfilgrastim),
  • interleukin-11 e.g. oprelvekin
  • EPO erythropoietin
  • analogues thereof e.g. darbepoetin alfa
  • colony- stimulating factor analogs such as granulocyte macrophage-colony stimulating factor (GM-CSF) (e.g. sargramostim), and gran
  • agents that inhibit bone resorption such as denosumab or bisphosphonates e.g. zoledronate, zoledronic acid, pamidronate and ibandronate,
  • agents that suppress inflammatory responses such as dexamethasone, prednisone, and prednisolone
  • agents used to reduce blood levels of growth hormone and IGF-I and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other agents used to reduce blood levels of growth hormone and IGF-I (and other
  • hormones in patients with acromegaly or other rare hormone-producing tumours, such as synthetic forms of the hormone somatostatin e.g. octreotide acetate, – antidote to drugs that decrease levels of folic acid such as leucovorin, or folinic acid, – agents for pain e.g. opiates such as morphine, diamorphine and fentanyl, – non-steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors for example celecoxib, etoricoxib and lumiracoxib,
  • NSAID non-steroidal anti-inflammatory drugs
  • agents for mucositis e.g. palifermin
  • the anticancer is selected from recombinant interferons (such as interferon-g and interferon a) and interleukins (e.g. interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b; interferon-a2 (500 ⁇ /ml) in particular interferon-b; and signal transduction inhibitors such as kinase inhibitors (e.g.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • MTKI multi target kinase inhibitors
  • Raf inhibitors mTOR inhibitors for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032/RG7204), dabrafenib, encorafenib or an IkB kinase inhibitor such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354,
  • GSK121120212 in particular Raf inhibitors (e.g. vemurafenib) or MEK inhibitors (e.g.
  • Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ: each may be administered at the same time or at different times.
  • a person skilled in the art would know through his or her common general knowledge the dosing regimes and combination therapies to use.
  • the compound of the invention may be using in combination with one or more other agents which are administered according to their existing combination regimen. Examples of standard combination regimens are provided below.
  • the taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 75 to 250 mg/m 2 , particularly for paclitaxel in a dosage of about 175 to 250 mg/m 2 and for docetaxel in about 75 to 150 mg/m 2 per course of treatment.
  • the camptothecin compound is advantageously administered in a dosage of 0.1 to
  • the anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 250mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m 2 per course of treatment.
  • the anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to
  • the anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 to
  • the alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 120 to 200 mg/m 2 , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m 2 , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m 2 , and for lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • the anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m 2 ) of body surface area, for example 15 to
  • the antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated.
  • Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, particularly 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Anastrozole is advantageously administered orally in a dosage of about 1mg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20-100mg once a day.
  • Raloxifene is advantageously administered orally in a dosage of about 60mg once a day.
  • Exemestane is advantageously administered orally in a dosage of about 25mg once a day.
  • Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m 2 ) of body surface area, or as known in the art, if different.
  • Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m 2 ) of body surface area, particularly 2 to 4mg/m 2 per course of treatment.
  • the compound of the formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one)
  • the compounds can be administered simultaneously or sequentially.
  • the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • a compound of formula (I) for the manufacture of a medicament for use in therapy wherein said compound is used in combination with one, two, three, or four other therapeutic agents.
  • a medicament for treating cancer which comprises a compound of formula (I) wherein said medicament is used in combination with one, two, three, or four other therapeutic agents.
  • the invention further provides use of a compound of formula (I) for the manufacture of a medicament for enhancing or potentiating the response rate in a patient suffering from a cancer where the patient is being treated with one, two, three, or four other therapeutic agents.
  • a compound of formula (I) for the manufacture of a medicament for enhancing or potentiating the response rate in a patient suffering from a cancer where the patient is being treated with one, two, three, or four other therapeutic agents.
  • the weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • a particular weight ratio for the present compound of formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
  • the compounds of the invention may also be administered in conjunction with non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.
  • the compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.
  • the compounds of the present invention can be used as "radiosensitizer” and/or“chemosensitizer” or can be given in combination with another "radiosensitizer” and/or“chemosensitizer”.
  • the compound of the invention is for use as chemosensitiser.
  • the term "radiosensitizer” is defined as a molecule administered to patients in
  • therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
  • chemosensitizer is defined as a molecule administered to patients in
  • the compound of the invention is administered with a "radiosensitizer” and/or“chemosensitizer”. In one embodiment the compound of the invention is
  • immunosensitizer is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to a Polq inhibitor.
  • Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays.
  • x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5- bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of radiosensitizers to the target cells;
  • Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.
  • Calcium antagonists for example verapamil
  • antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.
  • immune sensitizers include the following, but are not limited to:
  • immunomodulating agents for example monoclonal antibodies such as immune checkpoint antibodies [e.g. CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD-L2 for example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti- PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4)]; or Signal Transduction inhibitors; or cytokines (such as recombinant interferons); or oncolytic viruses; or immune adjuvants (e.g.
  • immune checkpoint antibodies e.g. CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD-L2
  • Immune sensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of immune sensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; therapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.
  • the compound of the formula (I) and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents i.e. in a unitary pharmaceutical composition containing all agents.
  • the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • a PI3K/AKT pathway inhibitor selected from: apitolisib, buparlisib, Copanlisib, pictilisib, ZSTK- 474, CUDC-907, GSK-2636771, LY-3023414, ipatasertib, afuresertib, MK-22
  • a compound of formula (I) in combination with one or more (e.g.1 or 2) other therapeutic agents (e.g. anticancer agents) for use in therapy, such as in the prophylaxis or treatment of cancer.
  • the pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s).
  • the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.
  • the invention relates to a product containing a compound of formula (I) and one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • THF Tetrahydrofuran Typical Preparative LCMS method For purification of samples by High Performance LCMS the following conditions were used: The pumps used were Waters 2545, the mixer was a Waters SFO, the UV detector was a Waters 2998. The detection was done at 254nm and an array between 210-600nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700g/mol. A SunFire, 5 ⁇ m pore size, C18 column of dimensions 50x19 mm was used. The injection volume was up to 500 ⁇ L of the solution (max 50mg/mL). The flow rate was 25 mL/min and the mobile phases of water and MeCN contained 0.1% formic acid.
  • spectrometer used was an Acquity SQD which detected masses between 100 and 700g/mol.
  • a Waters Cortecs, 2.7 ⁇ m particle size, C18 column of dimensions 50x4.60 mm was used at a temperature of 45 °C.
  • the injection volume was 10mL.
  • the flow rate was 2.2 mL/min and the mobile phases of water and acetonitrile contained 0.1% formic acid. Starting at 95% water:5% MeCN decreasingly polar ratios of water and MeCN containing 0.1% formic acid were used as a mobile phase over 2.2 min.
  • For analysis of samples by NMR the following conditions were used:
  • 6-Bromopyrazine-2-carboxylic acid (18.2 mmol, 1 eq) was added to TEA (27.3 mmol, 1.5 eq) in dry toluene (150 mL), followed by DPPA (21.9 mmol, 1.2 eq) and 5-amino-2-methyl- pyridine (18.2 mmol, 1 eq).
  • the reaction was refluxed for 1.5 h, with monitoring by LCMS.
  • the mixture was filtered to remove black precipitate, and the filtrate was diluted with EtOAc (100 mL) and washed with water (2 x 100 mL), then brine (100 mL).
  • the organic extracts were dried and evaporated in vacuo to give a dark red oily solid.
  • Step a A mixture of 5-bromo-2-iodoanisole (0.5 g, 1.6 mmol), morpholine (0.14 mL, 1.6 mmol), Pd 2 (dba) 3 (0.04 g, 0.048 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.08 g, 0.144 mmol) and sodium tert-butoxide (0.46 g, 4.79 mmol) in toluene (10 mL) was heated to 70 °C for 20 h. The reaction was diluted with water, extracted with EtOAc, dried and evaporated.
  • Step b A mixture of 4-(4-bromo-2-methoxy-phenyl)morpholine (0.24 g, 0.90 mmol), bis(pinacolato)-diboron (0.46 g, 1.81 mmol), Pd(dppf)Cl 2 .DCM (0.03 g, 0.045 mmol), and KOAc (0.18 g, 1.81 mmol) in 1,4-dioxane (6 mL) was degassed for 20 min, then stirred at 100 °C for 1 h. The solvent was evaporated and re-dissolved in EtOAc (10 mL), filtered through celite and washed through with more EtOAc.
  • Step a A mixture of 4-(bromomethyl)pyrrolidin-2-one (CAS Number 945671-51-2; 476 mg, 2.67 mmol), 4-bromo-2-methylphenol (1.0 g, 5.35 mmol) and potassium carbonate (3.69 g, 16.0 mmol) in DMA (1.5 mL) was heated to 85 °C for 3 h. Further 4-(bromomethyl)pyrrolidin- 2-one was added at 30 min intervals over a 7 h period and then the mixture stirred overnight. The mixture was diluted with MeOH, filtered through celite and evaporated under reduced pressure to give a brown oil. The crude oil was purified by flash column chromatography (0– 5% MeOH in DCM). Fractions were combined and evaporated under reduced pressure to give 4-[(4-bromo-2-methyl-phenoxy)methyl]pyrrolidin-2-one, (1.11 g, 73%) as a colourless solid.
  • Step b Bis(pinacolato)diboron (1.2 g, 4.73 mmol), KOAc (1.16 g, 11.8 mmol) and 4-[(4- bromo-2-methyl-phenoxy)methyl]pyrrolidin-2-one (1.12 g, 3.94 mmol) in 1,4-dioxane (39 mL) subjected to vacuum then backfilled with nitrogen 3 times to degas the mixture.
  • Step a Sodium hydride (16 mg, 0.417 mmol) was added to 4-hydroxy-1-methylpyrrolidin-2- one (52 mg, 0.45 mmol) in THF (4 mL) at 0 °C and stirred for 20 min.4-Bromo-2- methylbenzyl bromide (100 mg, 0.38 mmol) was then added and the mixture was stirred at rt for 18 h. The reaction was quenched with water (25 mL) and extracted with DCM (3 x 25 mL). The organics were dried and evaporated to give 4-[(4-bromo-2-methyl- phenyl)methoxy]-1-methyl-pyrrolidin-2-one (0.098 g, 87%) as a yellow oil.
  • Step b A suspension of 4-[(4-bromo-2-methyl-phenyl)methoxy]-1-methyl-pyrrolidin-2-one (0.1 g, 0.32 mmol), bis(pinacolato)diboron (0.1 g, 0.38 mmol) and KOAc (0.09 g, 0.96 mmol) in 1,4-dioxane (1 mL) was degassed. Pd(dppf)Cl 2 .DCM (0.01 g, 0.016 mmol) was added and the reaction was heated at 100°C for 1 h. The reaction mixture was filtered through celite, eluting with MeOH and concentrated under reduced pressure.
  • pinacol ester (CAS Number 508223-54-9; 0.25 g, 0.75 mmol) in DMF (4 mL) was slowly added sodium hydride (0.05 g, 1.12 mmol) at 0 °C, under nitrogen. The mixture was stirred at rt for 20 min, then cooled to 0 °C. Iodomethane (0.09 mL, 1.5 mmol) was slowly added. After completion of the addition, the reaction mixture was stirred at rt overnight. The reaction was quenched with H2O, and extracted with EtOAc.
  • 4-(bromomethyl)-1- methyl-pyrrolidin-2-one 160 mg, 0.84 mmol was added and the mixture heated to reflux for 4 h. The mixture was cooled to rt and evaporated under reduced pressure.
  • Step b To 4-[[4-bromo-2-(hydroxymethyl)phenoxy]methyl]-1-methyl-pyrrolidin-2-one (134 mg, 0.42 mmol) in DCM (2 mL) at -78 °C was added Deoxo-Fluor 50% in THF (0.18 mL, 0.42 mmol) and the mixture stirred for 3 h. The mixture was warmed to rt and stirred for 1 h then quenched by addition of water and partitioned between DCM and saturated NaHCO3. The layers were separated, aqueous reextracted with DCM and the combined organics washed with brine, dried and evaporated under reduced pressure to give a brown oil.
  • Step a A solution of 4-(hydroxymethyl)-4-methylpyrrolidin-2-one (292 mg, 2.26 mmol) and imidazole (0.38 g, 5.65 mmol) in DMF (2 mL) was treated with tert-butyl-dimethylsilyl chloride (0.41 g, 2.71 mmol) and stirred for 4 h. The reaction was diluted with sat. aq. ammonium chloride, water and extracted into EtOAc. The aqueous was further extracted with EtOAc and the combined organics were washed with brine, dried and evaporated.
  • Step b A mixture of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-pyrrolidin-2-one (364 mg, 1.49 mmol) in toluene (7.4 mL) was treated with sodium hydride (72 mg, 1.79 mmol) at 0 °C and the mixture stirred for 15 min at rt and then iodomethane (0.11 mL, 1.79 mmol) was added and the mixture stirred at rt. The mixture was quenched at 0 °C by the addition of water and sat. aq. NaHCO 3 and extracted into EtOAc (x3). The combined organics were washed with brine, dried and evaporated under reduced pressure.
  • Step b A suspension of Intermediate 1 (0.15 g, 0.487 mmol), 3-methyl-4-(trifluoromethyl)- phenylboronic acid (0.07 mL, 0.535 mmol), potassium carbonate (0.2 g, 1.46 mmol) and Pd(PPh3)4 (0.03 g, 0.024 mmol) in 1,4-dioxane (60 mL) and water (20 mL) was heated to 100°C for 30 min. The reaction mixture was cooled, diluted with EtOAc (250 mL), washed with water (2 x 150 mL) then brine (100 mL), dried and evaporated.
  • Example 14 A suspension of Example 14 (46 mg, 0.108 mmol) in THF (1 mL) and MeOH (0.50 mL) was treated with formaldehyde (37% aqueous solution; 0.16 mL, 2.17 mmol) followed by sodium triacetoxyborohydride (0.11 g, 0.54 mmol).
  • Example 17 1-[(3S)-1-(2-Hydroxyethyl)-3-piperidyl]-3-[6-[3-methyl-4-[(5-oxopyrrolidin- 3-yl)methoxy]-phenyl]pyrazin-2-yl]urea
  • Example 18 1-[(3S)-1-Acetyl-3-piperidyl]-3-[6-[3-methyl-4-[(5-oxopyrrolidin-3- yl)methoxy]phenyl]-pyrazin-2-yl]urea
  • Acetyl chloride (0.01 mL, 0.124 mmol) was added to a mixture of Example 14 (44 mg, 0.104 mmol) and potassium carbonate (0.04 g, 0.311 mmol) in DCM (2 mL) and stirred for 90 min. Further acetyl chloride (0.01 mL, 0.124 mmol) was added and stirred for 4 h total. The mixture was loaded onto an SCX-2 cartridge in MeOH and eluted with MeOH followed by 2M methanolic ammonia and the basic fractions were evaporated under reduced pressure.
  • Step a A mixture of potassium carbonate (0.36 g, 2.60 mmol), Pd(PPh 3 ) 4 (0.05 g, 0.044 mmol), Intermediate 1 (0.27 g, 0.87 mmol) and Intermediate 14 (0.31 g, 0.87 mmol) in 1,4- dioxane (6mL) / water (2mL) was heated at 90 °C in the microwave for 30 min. The reaction mixture was diluted with EtOAc (100mL), washed with water (2x100mL), dried (MgSO 4 ) and concentrated in vacuo.
  • Step b To a clear solution of dichlorotin (0.66 g, 3.46 mmol) in EtOH (25mL) was added 1- [6-[4-(2,6-dimethylmorpholin-4-yl)-3-nitro-phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea (321 mg, 0.69 mmol) and the mixture was stirred at reflux (80 °C) for 1 h.
  • Example 19 A mixture of Example 19 (74 mg, 0.17 mmol) and conc hydrochloric acid (2.5 mL, 0.17 mmol) was cooled to 0 °C. Sodium nitrite (0.02 mL, 0.341 mmol) was added and the mixture was left to stir at 0 °C for 20 min. Meanwhile, a mixture of cuprous chloride (34 mg, 0.341 mmol) and conc hydrochloric acid (2.5 mL, 0.171 mmol) was heated at 60 °C. To this warm mixture was added the diazonium solution and the mixture was left to stir. The mixture was evaporated and purified by flash column chromatography, eluting with DCM/MeOH using a 0 -10% gradient.
  • Step a A mixture of Intermediate 6 (0.26 g, 0.74 mmol), Intermediate 1 (0.18 g, 0.57 mmol), Pd(PPh 3 ) 4 (0.03 g, 0.028 mmol) and sodium carbonate (0.24 g, 2.27 mmol) in 1,4- dioxane (6 mL) and water (2 mL) was stirred at 70 °C for 6 h. The mixture was diluted with EtOAc and washed with water, dried and evaporated. The crude product was purified by column chromatography, eluting with a gradient of 0-10% MeOH/DCM. Clean fractions were combined and concentrated in vacuo to give 130 mg of clean material.
  • the title compound was prepared in a similar manner to Example 215, using 6-[4- (trifluoromethyl)phenyl]pyridin-2-amine (CAS Number 1159815-87-8) in step a.
  • Example 26 1-[6-[3-Methyl-4-[[(2S)-2-methyl-1-[2-(methylamino)acetyl]pyrrolidin-2- yl]methoxy]phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 109 A mixture of Example 109 (30 mg, 0.069 mmol), Boc-N-methylglycine (0.01 g, 0.076 mmol) and pyridine (0.02 mL, 0.208 mmol) in DMF (0.50 mL) was treated with HATU (0.04 g, 0.097 mmol) and stirred for 18 h. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3 and brine, dried and evaporated under reduced pressure to give an orange oil. The oil was dissolved in DCM (5 mL), treated with TFA (0.2 mL, 2.60 mmol) and stirred for 1 h.
  • Step a A mixture of 6-bromopyrazine-2-carboxylic acid (0.15 g, 0.746 mmol), 6-(2-trimethyl- silylethynyl)pyridin-3-amine (0.14 g, 0.746 mmol), DPPA (0.16 mL, 0.746 mmol) and TEA (0.16 mL, 1.12 mmol) in toluene (10 mL) were heated at reflux for 2 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 (x2), dried and evaporated.
  • Step b A mixture of 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- morpholine (CAS Number; 1361110-63-5; 0.06 g, 0.2 mmol), 1-(6-bromopyrazin-2-yl)-3-[6- (2-trimethyl-silylethynyl)-3-pyridyl]urea (0.06 g, 0.154 mmol), Pd(PPh 3 ) 4 (0.01 g, 0.008 mmol) and potassium carbonate (0.11 g, 0.769 mmol) in 1,4-dioxane (3 mL) and water (1 mL) were heated at reflux for 2 h.
  • Step a A mixture of methyl 6-bromopyrazine-2-carboxylate (0.17 g, 0.81 mmol), 3-methyl-4- trifluoromethoxyphenylboronic acid (0.2 g, 0.89 mmol), Pd(PPh 3 ) 4 (0.05 g, 0.04 mmol) and potassium carbonate (0.33 g, 2.42 mmol) in 1,4-dioxane (3 mL) / water (1 mL) was heated at 90 °C in the microwave for 30 min. The reaction mixture was taken up in EtOAc (100 mL), washed with water (2x100 mL), brine (100 mL) then dried (MgSO 4 ), filtered and concentrated to give the crude product.
  • the aqueous layer was acidified with 2M HCl (100mL) and extracted with EtOAc (100mL) once more before the organic layer was dried (MgSO 4 ), filtered and concentrated. This was combined with the previously extracted product to give crude product as a mixture of the ester and the acid, methyl 6-[3-methyl-4- (trifluoromethoxy)phenyl]pyrazine-2-carboxylate and 6-[3-methyl-4-(trifluoromethoxy)- phenyl]pyrazine-2-carboxylic acid, (345 mg). This was used in the next step of the synthesis where the remaining ester was hydrolysed to the acid.
  • Step b Lithium hydroxide monohydrate (55 mg, 1.33 mmol) was slowly added to the intermediate described above (345 mg) in THF (3.1 mL) / water (0.78 mL) and cooled to 0 °C. The reaction was stirred at 0-5°C for 45 min. Solvent was removed under reduced pressure to give crude product which was diluted with water (100 mL) and washed with EtOAc (100 mL). The aqueous phase was acidified with 2M (100 mL) HCl and extracted into EtOAc (100 mL). The organic layer was dried and evaporated in vacuo to give 6-[3-methyl-4- (trifluoromethoxy)-phenyl]pyrazine-2-carboxylic acid, (235 mg, 66%).
  • Step c To 6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrazine-2-carboxylic acid (235 mg, 0.79 mmol) in dry toluene (9 mL) was added TEA (0.16 mL, 1.18 mmol) DPPA (0.2 mL, 0.95 mmol) and 5-amino-2-methylpyridine (0.09 g, 0.79 mmol) and refluxed for a 1.5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2 x 100 mL) and brine (100 mL), dried and evaporated to give an orange solid.
  • the title compound was prepared in a similar manner to Example 29, using 4-(2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (CAS Number 1361110-63- 5) in step a and 3-amino-4-methylpyridine (CAS Number 3430-27-1) in step c.
  • Step a Potassium phosphate tribasic (0.35 g, 1.63 mmol), 4 ⁇ molecular sieves (beads, 2.5 g) and a stirrer bar were heated with a heat gun for 5 min under vacuum until the base appeared dry then allowed to cool under nitrogen.
  • Intermediate 8 250 mg, 0.81 mmol
  • (S)- 3-acetamidopyrrolidine CAS Number 114636-31-6; 0.14 g, 1.06 mmol
  • RuPhos (0.06 g, 0.13 mmol
  • toluene 8 mL
  • Step b Lithium hydroxide monohydrate (0.01 g, 0.30 mmol) in water (0.67 mL) was added to methyl 6-[4-[(3S)-3-acetamidopyrrolidin-1-yl]-3-methyl-phenyl]pyrazine-2-carboxylate (96 mg, 0.27 mmol) in THF (2 mL) and the mixture stirred for 90 min. The mixture was evaporated to give lithium 6-[4-[(3S)-3-acetamidopyrrolidin-1-yl]-3-methyl-phenyl]pyrazine-2- carboxylate, (100 mg, quantitative yield) as a yellow solid.
  • Step c To lithium 6-[4-[(3S)-3-acetamidopyrrolidin-1-yl]-3-methyl-phenyl]pyrazine-2- carboxylate (100 mg, 0.29 mmol) in toluene (5 mL) was added 2M HCl in ether (0.43 mL, 0.86 mmol) followed by TEA (0.24 mL, 1.73 mmol).5-Amino-2-methylpyridine (0.04 g, 0.35 mmol) and DPPA (0.08 mL, 0.37 mmol) were added. The mixture heated to reflux for 2 h. MeOH was added to homogenise the solution and then evaporated under reduced pressure.
  • Example 41 1-[6-[4-(2,3,3a,4,6,6a-Hexahydro-1H-pyrrolo[2,3-c]pyrrol-5-yl)-3-methyl- phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 40 A solution of Example 40 (100 mg, 0.189 mmol) in DCM (5 mL) was treated with 4M HCl in dioxane (0.47 mL, 1.89 mmol) and the mixture stirred for 2 h. The mixture was evaporated to give an orange solid that was dissolved in MeOH/DCM and loaded onto SCX-2 cartridge then eluted with MeOH followed by 2M methanolic ammonia.
  • Example 42 1-[6-[4-(1-Acetyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl)-3- methyl-phenyl]-pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 41 A solution of Example 41 (80 mg, 0.19 mmol) in DCM (5 mL) was treated with acetic anhydride (0.05 mL, 0.56 mmol) and the mixture stirred for 2 h. The mixture was partitioned between NaHCO3 (sat. aq.) and DCM. The organics were washed with further sat. aq.
  • Example 43 1-[6-[4-(1,7-Diazaspiro[3.4]octan-7-yl)-3-methyl-phenyl]pyrazin-2-yl]-3-(6- methyl-3-pyridyl)urea
  • Example 47 N-[[4-[2-Methyl-4-[6-[(6-methyl-3-pyridyl)carbamoylamino]pyrazin-2- yl]phenyl]-morpholin-2-yl]methyl]acetamide Isomer 1
  • Example 49 1-[6-[3-Methyl-4-[methyl-[(1-methyl-5-oxo-pyrrolidin-3-yl)methyl]amino]- phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea Isomer 1
  • Step a Potassium phosphate tribasic (310 mg, 1.46 mmol) was heated to 130 °C for 5 min under vacuum then cooled to rt under a stream of nitrogen.
  • Intermediate 8 225 mg, 0.733 mmol
  • RuPhos 0.05 g, 0.117 mmol
  • tert-butyl-dimethyl-(morpholin-3-ylmethoxy)silane 220 mg, 0.952 mmol
  • Palladium acetate (10 mg, 0.059 mmol) was added and the mixture evacuated then backfilled with nitrogen once more. The mixture was heated at reflux over the weekend and then allowed to cool to rt.
  • EtOAc was added and the mixture stirred for 1 h to make homogenous. This was then filtered through celite, washing with more EtOAc and the obtained filtrate evaporated. The mixture was evaporated, then suspended in THF (5 mL) and lithium hydroxide monohydrate (0.05 g, 1.10 mmol) in water (1 mL) was added and the mixture stirred for 2 h at rt. The organics were evaporated and then the mixture partitioned between EtOAc and 2M NaOH. The organics were removed and washed with brine, dried and evaporated.
  • Step b A mixture of 6-[4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]morpholin-4-yl]-3-methyl- phenyl]pyrazine-2-carboxylic acid (173 mg, 0.39 mmol), TEA (0.16 mL, 1.17 mmol), DPPA (0.13 mL, 0.585 mmol) and 5-amino-2-methylpyridine (55 mg, 0.51 mmol) in toluene (5 mL) were heated to reflux for 2 h.
  • Step c To a solution of 1-[6-[4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]morpholin-4-yl]-3- methyl-phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea (70 mg, 0.13 mmol) in MeOH (4 mL) and DCM (1 mL) was added 4M HCl in dioxane (0.5 mL, 2.0 mmol) and the mixture stirred for 1 h. The mixture was evaporated under reduced pressure and the crude product was purified by preparatory LCMS.
  • Step a Sodium hydrogencarbonate (358 mg, 4.27 mmol) was added to (morpholin-2- yl)methanol (250 mg, 2.13 mmol) in THF (3 mL) and water (3 mL) and the mixture stirred for 5 min. Benzyl chloroformate (0.3 mL, 2.13 mmol) was added and the mixture stirred for 3 h. The mixture was diluted with EtOAc and washed with water. The aqueous was reextracted with EtOAc and the combined organics were dried and evaporated to give a colourless oil (485 mg).
  • Step b A solution of benzyl 2-(hydroxymethyl)morpholine-4-carboxylate (376 mg, 1.50 mmol) and imidazole (0.25 g, 3.74 mmol) in DMF (1.5 mL) was treated with tert-butyl- dimethylsilyl chloride (0.27 g, 1.80 mmol) and the mixture stirred for 18 h. The mixture was partitioned between EtOAc and saturated ammonium chloride. The layers were separated and the aqueous reextracted with EtOAc. The combined organics were washed with brine (x2), dried and evaporated to give a colourless oil (670 mg).
  • Step c A mixture of benzyl 2-[[tert-butyl(dimethyl)silyl]oxymethyl]morpholine-4-carboxylate (380.0 mg, 1.04 mmol) and palladium on carbon (40 mg, 0.104 mmol) in EtOAc (5 mL) was stirred at rt under an atmosphere of H 2 for 3 h. The mixture was filtered through celite (x3) and then evaporated under reduced pressure to give tert-butyl-dimethyl-(morpholin-2- ylmethoxy)silane, (194 mg, 81%) as an oil.
  • Step b A mixture of Intermediate 10 (80 mg, 0.2 mmol), morpholine (2 equiv, 0.4 mmol), Pd 2 (dba) 3 (10 - 15 mol%, 0.02– 0.03 mmol), BINAP (12 - 18 mol%, 0.024– 0.036 mmol) and NaOtBu (4 equiv for free amine substrates; 6 equiv for amine ⁇ HX salts) in 1,4-dioxane (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 6 - 16 hr.
  • Example 74 1-[6-(3-Chloro-4-morpholino-phenyl)pyrazin-2-yl]-3-(6-ethyl-3-pyridyl)urea
  • Step a To a stirred mixture of Example 75 (0.07 g, 0.15 mmol), di-tert-butyl dicarbonate (0.07 g, 0.31 mmol) and sodium borohydride (0.04 g, 1.09 mmol) in MeOH was added, under a nitrogen atmosphere, 1-[6-(3-chloro-4-morpholino-phenyl)pyrazin-2-yl]-3-[6- (cyanomethyl)-3-pyridyl]urea (0.07 g, 0.156 mmol) portionwise and the resultant black solution was stirred at rt overnight. The mixture was diluted with EtOAc (50ml) and filtered through celite.
  • EtOAc 50ml
  • Step a A mixture of TEA (0.1 mL, 0.75 mmol), DPPA (0.11 mL, 0.5 mmol), Intermediate 11 (0.16 g, 0.5 mmol) and tert-butyl N-[(5-amino-2-pyridyl)methyl]carbamate (0.04 mL, 0.5 mmol) in toluene (10 mL) was heated at reflux for 3 h. The solvent was removed by evaporation in vacuo and the resultant gum was purified by flash chromatography, using cyclohexane/EtOAc as eluent. The isolated yellow powder was further purified by preparatory LCMS.
  • Step b To a stirred mixture of tert-butyl N-[[5-[[6-(3-chloro-4-morpholino-phenyl)pyrazin-2- yl]carbamoylamino]-2-pyridyl]methyl]carbamate (0.09 g, 0.17 mmol) in DCM (10 mL) at rt was added TFA (0.5 mL, 6.5 mmol) and the mixture was stirred at rt for 4 h. The mixture was passed through an ISOLUTE SCX-2 cartridge followed by 60 ml of MeOH. The product was released from the cartridge by passing 2M ammonia in MeOH solution.
  • the title compound was prepared in a similar manner to Example 29, using 4-(2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (CAS Number 1361110-63- 5) in step a and 5-amino-2-(hydroxymethyl)pyridine (CAS Number 873651-92-4) in step c.
  • Example 80 A solution of Example 80 (83 mg, 0.19 mmol) in THF (4.0 mL) and MeOH (2 mL) was treated with paraformaldehyde aqueous solution (0.07 mL, 0.96 mmol) and the mixture stirred for 10 min.
  • Sodium triacetoxyborohydride (68 mg, 0.96 mmol) was added and the mixture stirred for 90 min.
  • the mixture was diluted with water and was partitioned between EtOAc and sat. aq. NaHCO3, the layers were separated and the aqueous re-extracted with EtOAc. The combined organics were washed with brine, dried and evaporated.
  • the title compound was prepared in a similar manner to Example 80 using tert-butyl 4- aminoazepane-1-carboxylate.
  • Example 84 (S)-1-(6-(3-Chloro-4-morpholinophenyl)pyrazin-2-yl)-3-(piperidin-3-yl)urea
  • Step a A mixture of tert-butyl (2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (CAS Number 1339022-10-4; 230 mg, 1.07 mmol), Intermediate 8 (229 mg, 0.536 mmol), racemic-2-di-t-butylphosphino-1,1'-binaphthyl (0.02 g, 0.054 mmol) and caesium carbonate (0.52 g, 1.61 mmol) in toluene (2 mL) was degassed for 30 min. Palladium acetate (0.01 g, 0.043 mmol) was then added and the reaction mixture was heated to 90 °C for 4 h.
  • the reaction mixture was diluted with THF (6 mL) and water (2 mL) and lithium hydroxide monohydrate (0.16 g, 3.91 mmol) was added. The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and 1.5M HCl (100 mL) and EtOAc (100 mL) were added. The layers were separated and the organic extract was dried and evaporated. The crude product was purified using reverse phase column chromatography, eluting with a gradient of 10 - 100% MeCN/H 2 O with 0.1% formic acid.
  • Step b A solution of 6-[4-[[(2S)-1-tert-butoxycarbonyl-2-methyl-pyrrolidin-2-yl]methoxy]-3- methyl-phenyl]pyrazine-2-carboxylic acid (0.27 g, 0.609 mmol) in toluene (10 mL) was treated with TEA (0.13 mL, 0.913 mmol) followed by 5-amino-2-methylpyridine (0.04 mL, 0.791 mmol) and DPPA (0.03 mL, 0.122 mmol). The reaction mixture was heated at 90 °C for 2 h and then allowed to cool to rt.
  • Example 100 To a solution of Example 100 (40 mg, 0.096 mmol) in isopropanol (1 mL) was added potassium hydroxide (48 mg, 0.086 mmol) and hydrogen peroxide (98 mg, 0.086 mmol, 30% purity), the mixture was stirred at rt for 18 h. Upon completion, the reaction mixture was treated with saturated aqueous sodium sulfite. The resulting mixture was evaporated under reduced pressure.
  • potassium hydroxide 48 mg, 0.086 mmol
  • hydrogen peroxide 98 mg, 0.086 mmol, 30% purity
  • Example 109 1-[6-[3-Methyl-4-[[(2S)-2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazin- 2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 86 A solution of Example 86 (0.25 g, 0.469 mmol) in DCM (15 mL) was treated with TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure and the residue was loaded onto an SCX ion exchange cartridge which was washed with DCM then MeOH and then the product was eluted with 2M ammonia in MeOH. The solvent was removed under reduced pressure to yield 1-[6-[3-methyl-4-[[(2S)- 2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea, (0.15g, 73%).
  • Example 110 1-[6-[3-Methyl-4-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazin- 2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 111 1-[6-[3-Methyl-4-[[(2S)-2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazin- 2-yl]-3-(5-methyl-2-pyridyl)urea
  • Example 113 1-[6-[4-[[(2S)-1-Acetyl-2-methyl-pyrrolidin-2-yl]methoxy]-3-methyl- phenyl]pyrazin-2-yl]-3-[6-(hydroxymethyl)-3-pyridyl]urea
  • Step a A mixture of tert-butyl (2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (CAS Number 1339022-10-4; 850 mg, 3.95 mmol), Intermediate 8 (606 mg, 1.97 mmol), racemic-2-di-t-butylphosphino-1,1'-binaphthyl (79 mg, 0.197 mmol) and potassium phosphate tribasic (1.26 g, 5.92 mmol) in toluene (7.5 mL) was degassed for 30 min.
  • Step b A suspension of methyl 6-[4-[[(2S)-1-tert-butoxycarbonyl-2-methyl-pyrrolidin-2- yl]methoxy]-3-methyl-phenyl]pyrazine-2-carboxylate (0.62 g, 1.413 mmol) in DCM (20 mL) was treated with TFA (1.1 mL) and stirred at rt for 20 h. Further TFA (1.1 mL) was added and stirring continued for 4h.
  • reaction mixture was absorbed onto an SCX-2 cartridge washed with MeOH, eluted with 2M methanolic ammonia and solvent was removed under a flow of nitrogen and further dried in the vacuum oven overnight to give methyl 6-[3-methyl-4- [[(2S)-2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazine-2-carboxylate, (0.422 g, 87%).
  • Step c Acetic anhydride (0.58 mL, 6.18 mmol) was added to TEA (0.86 mL, 6.18 mmol) and methyl 6-[3-methyl-4-[[(2S)-2-methylpyrrolidin-2-yl]methoxy]phenyl]pyrazine-2-carboxylate (0.42 g, 1.236 mmol) in DCM (20 mL) and stirred for 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with sat. aq. NaHCO 3 , (50 mL), dried and evaporated. The crude product was purified using column chromatography, eluting with a gradient of 0-5% MeOH/DCM.
  • Step d A solution of methyl 6-[4-[[(2S)-1-acetyl-2-methyl-pyrrolidin-2-yl]methoxy]-3-methyl- phenyl]pyrazine-2-carboxylate (0.27 g, 0.696 mmol) in THF (4.5 mL) and water (1.5 mL) was treated with lithium hydroxide monohydrate (0.03 g, 0.77 mmol) and the reaction was stirred for 1 h. The reaction mixture was diluted with 2M HCl (40 mL) and extracted with EtOAc (3 x 40 mL).
  • Step e A mixture of Intermediate 18 (126 mg, 0.528 mmol), 6-[4-[[(2S)-1-acetyl-2-methyl- pyrrolidin-2-yl]methoxy]-3-methyl-phenyl]pyrazine-2-carboxylic acid (150 mg, 0.406 mmol), DPPA (0.11 mL, 0.49 mmol) TEA (0.08 mL, 0.61 mmol) in toluene (5 mL) was heated at reflux for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc, washed with water (x2) and brine, dried and evaporated.
  • the crude material was purified by flash column chromatography, eluting with 0-100% EtOAc/c-Hex.
  • the material was dissolved in THF (5 mL), 1.0 M TBAF in THF (2.0 mL, 2.0 mmol) was added and the reaction was heated at reflux for 1 h.
  • the reaction was cooled to rt, diluted with DCM (20 mL), washed with sat.
  • Example 116 1-[6-[4-[[(2S)-1-Acetyl-2-methyl-pyrrolidin-2-yl]methoxy]-3-methyl- phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Acetic anhydride (0.04 mL, 0.462 mmol) was added to a solution of TEA (0.06 mL, 0.46 mmol) and Example 109 (0.04 g, 0.092 mmol) in DCM (2 mL) and stirred for 3 h. The mixture was diluted with DCM (5 mL) and washed with sat. aq.
  • Example 117 1-[6-[4-[[(2R)-1-Acetyl-2-methyl-pyrrolidin-2-yl]methoxy]-3-methyl- phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Example 109 0.05 g, 0.12 mmol
  • MeOH MeOH
  • THF THF
  • paraformaldehyde aqueous solution 0.02 g, 0.58 mmol
  • sodium triacetoxyborohydride 0.38 mL, 0.58 mmol
  • the resultant solution was stirred at rt under nitrogen for 3 h.
  • the solvent was removed under reduced pressure and the residue was dissolved in MeOH and absorbed onto an SCX-2 cartridge. The cartridge was washed with MeOH and then eluted with 2M ammonia in MeOH.
  • Example 119 1-[6-[3-Methyl-4-[[(2S)-2-methyl-1-methylsulfonyl-pyrrolidin-2- yl]methoxy]phenyl]-pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Methane sulfonic anhydride (0.03 g, 0.15 mmol) was added to Example 109 (54 mg, 0.125 mmol) and TEA (0.03 mL, 0.19 mmol) in DCM (5 mL) and the reaction stirred for 18 h. The mixture was diluted with DCM, washed with sat. aq. NaHCO3 (x2) and brine, dried and evaporated to give a light pink solid.
  • Example 120 1-[6-[3-Methyl-4-[(3-methyltetrahydrofuran-3-yl)methoxy]phenyl]pyrazin- 2-yl]-3-[(3S)-3-piperidyl]urea Isomer 1
  • Step a A mixture of Intermediate 8 (2.48 g, 8.07 mmol), (3-methyloxolan-3-yl)methanol (1.64 g, 14.1 mmol), racemic-2-di-tert-butylphosphino-1,1'-binaphthyl (0.32 g, 0.81 mmol) and potassium phosphate tribasic (5.14 g, 24.2 mmol) in toluene (50 mL) was degassed for 30 min. Palladium acetate (0.15 g, 0.646 mmol) was added and the mixture was heated to 70 °C for 3 h under nitrogen.
  • Step b To a suspension of 6-[3-methyl-4-[(3-methyltetrahydrofuran-3-yl)methoxy]phenyl]- pyrazine-2-carboxylic acid (0.19 g, 0.417 mmol) in toluene (6 mL) was added TEA (0.09 mL, 0.625 mmol). DPPA (0.14 mL, 0.667 mmol) was added and the mixture stirred for 1 h.
  • Step c.6-[3-Methyl-4-[(3-methyltetrahydrofuran-3-yl)methoxy]phenyl]pyrazine-2-carbonyl azide (94 mg, 0.27 mmol) was refluxed in toluene (4 mL) for 10 min until nitrogen evolution had ceased.
  • a solution of (S)-(+)-3-amino-1-Boc-piperidine (0.07 g, 0.372 mmol) in toluene (1 mL) was then added and stirring continued at reflux for 45 min. The reaction mixture was evaporated in vacuo. Crude product was dissolved in DCM and loaded onto silica. It was then purified using column chromatography, eluting with a gradient of 50-100%
  • Step d Each isomer was dissolved in DCM (1 mL) and TFA (0.12 mL, 1.56 mmol) was added. The mixture was stirred for 2 h at rt. They were each absorbed onto an SCX-2 cartridge washed with MeOH and eluted with 7M methanolic ammonia. The solutions were evaporated to give:
  • Example 122 1-[6-[4-[(1-Acetyl-3-methyl-3-piperidyl)methoxy]-3-methyl- phenyl]pyrazin-2-yl]-3-[(3S)-3-piperidyl]urea
  • Example 124 1-[6-[4-[(4-Ethyltetrahydropyran-4-yl)methoxy]-3-methyl-phenyl]pyrazin- 2-yl]-3-(1-methyl-3-piperidyl)urea
  • Example 125 1-[6-(Hydroxymethyl)-3-pyridyl]-3-[6-[3-methyl-4-[(5-oxopyrrolidin-3- yl)methoxy]-phenyl]pyrazin-2-yl]urea Isomer 1 hydrochloride
  • Step a A mixture of methyl 6-bromopyrazine-2-carboxylate (1.05 g, 4.83 mmol),
  • Step b A solution of Intermediate 18 (72 mg, 0.302 mmol), 6-[3-methyl-4-[(5-oxopyrrolidin- 3-yl)-methoxy]phenyl]pyrazine-2-carboxylic acid (90 mg, 0.275 mmol), DPPA (0.07 mL, 0.33 mmol), TEA (0.06 mL, 0.412 mmol) in toluene (5 mL) was heated at reflux for 2 h. The reaction mixture was cooled to rt diluted with EtOAc, washed with water (x2) and brine, dried over MgSO 4 and evaporated.
  • Step c The first eluting isomer from the previous step (0.03 g, 0.047 mmol) was dissolved in MeOH (1 mL), HCl in dioxane (0.01 mL, 0.047 mmol) was added and the reaction was stirred at rt for 1 h. Solvent was removed in vacuo to give 1-[6-(hydroxymethyl)-3-pyridyl]-3- [6-[3-methyl-4-[(5-oxopyrrolidin-3-yl)methoxy]phenyl]pyrazin-2-yl]urea isomer 1
  • Example 127 1-[6-[3-Methyl-4-[(3-methyl-5-oxo-pyrrolidin-3-yl)methoxy]phenyl]- pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea Isomer 1
  • Example 128 1-[6-[3-Methyl-4-[(3-methyl-5-oxo-pyrrolidin-3-yl)methoxy]phenyl]- pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea Isomer 1
  • Step a A mixture of Intermediate 13 (1.33 g, 5.35 mmol), Intermediate 8 (0.82 g, 2.67 mmol), racemic-2-di-t-butylphosphino-1,1'-binaphthyl (107 mg, 0.268 mmol) and potassium phosphate tribasic (1.7 g, 8.02 mmol) in toluene (10 mL) was degassed for 30 min.
  • Step b A solution of ammonium cerium(IV) nitrate (2.89 g, 5.30 mmol) in water (4.5 mL) was added to a solution of methyl 6-[4-[[1-[(4-methoxyphenyl)methyl]-3-methyl-5-oxo- pyrrolidin-3-yl]methoxy]-3-methyl-phenyl]pyrazine-2-carboxylate (0.5 g, 1.06 mmol) in MeCN (12 mL). The reaction was stirred at rt for 4 days. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO 3 solution (100 mL). The aqueous layer was further extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried and evaporated. The crude product was purified using column
  • Step c A solution of methyl 6-[3-methyl-4-[(3-methyl-5-oxo-pyrrolidin-3- yl)methoxy]phenyl]pyrazine-2-carboxylate (0.11 g, 0.315 mmol) in THF (2 mL) and water (0.7 mL), lithium hydroxide monohydrate (0.03 g, 0.63 mmol) was added and the reaction was stirred for 20 h.
  • reaction mixture was diluted with 2M HCl (20 mL) and extracted into EtOAc (3 x 20 mL), dried and evaporated to give 6-[3-methyl-4-[(3-methyl-5-oxo- pyrrolidin-3-yl)methoxy]phenyl]pyrazine-2-carboxylic acid, (0.098 g, 91%) as yellow solid.
  • Step d The title compound was prepared in a similar manner to Example 86, using the Intermediate described above.
  • the enantiomers were separated by chiral SFC using the following conditions: Lux A1 (21.2mm x 250mm, 5um) column, eluting with 50:50 MeOH:CO2 (0.1% v/v NH3) to provide: 1-[6-[3-Methyl-4-[(3-methyl-5-oxo-pyrrolidin-3-yl)methoxy]phenyl]pyrazin-2-yl]-3-(6-methyl-3- pyridyl)urea isomer 1
  • Example 130 1-[6-[4-[[1-[3-(Dimethylamino)propanoyl]pyrrolidin-3-yl]methoxy]-3- methyl-phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridyl)urea
  • Step a A suspension of Example 129 (0.17 g, 0.33 mmol) in DCM (2 mL) was treated with TFA (0.16 mL, 0.33 mmol) and stirred for 1 h. The reaction mixture was absorbed onto an SCX-2 cartridge washed with MeOH, eluted with 7M methanolic ammonia. The solvent was removed in vacuo to give 1-(6-methyl-3-pyridyl)-3-[6-[3-methyl-4-(pyrrolidin-3- ylmethoxy)phenyl]pyrazin-2-yl]urea, (50 mg, 36%) as a yellow solid.
  • Step b N,N-Diisopropylethylamine (0.02 mL, 0.12 mmol) was added to 3-(dimethylamino)- propionic acid hydrochloride (0.01 g, 0.12 mmol) and 1-(6-methyl-3-pyridyl)-3-[6-[3-methyl-4- (pyrrolidin-3-ylmethoxy)phenyl]pyrazin-2-yl]urea (0.05 g, 0.12 mmol) in NMP (2 mL). HATU (0.05 g, 0.12 mmol) was added to the solution and the reaction mixture was stirred at rt under nitrogen for 2 h.

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Abstract

L'invention concerne des dérivés hétérocycliques d'urée et leur utilisation dans le traitement et la prophylaxie du cancer, et des compositions contenant lesdits dérivés et des procédés pour leur préparation.
PCT/GB2019/052244 2018-08-10 2019-08-09 Urées substituées hétérocycliques, destinées à être utilisées contre le cancer WO2020030925A1 (fr)

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WO2021219750A1 (fr) 2020-04-28 2021-11-04 The Institute Of Cancer Research: Royal Cancer Hospital Vaccins anticancéreux et traitement associé
WO2023052508A2 (fr) 2021-09-30 2023-04-06 Astrazeneca Ab Utilisation d'inhibiteurs pour augmenter l'efficacité d'insertions de crispr/cas
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WO2021219750A1 (fr) 2020-04-28 2021-11-04 The Institute Of Cancer Research: Royal Cancer Hospital Vaccins anticancéreux et traitement associé
CN112210553A (zh) * 2020-09-14 2021-01-12 菁良基因科技(深圳)有限公司 一种同源重组修复检测参考品的制备及应用
WO2023052508A2 (fr) 2021-09-30 2023-04-06 Astrazeneca Ab Utilisation d'inhibiteurs pour augmenter l'efficacité d'insertions de crispr/cas
WO2023052508A3 (fr) * 2021-09-30 2023-05-11 Astrazeneca Ab Utilisation d'inhibiteurs pour augmenter l'efficacité d'insertions de crispr/cas
WO2024073587A1 (fr) * 2022-09-29 2024-04-04 Vividion Therapeutics, Inc. Dérivés de n-acryloylmorpholine utilisés en tant que modulateurs de keap1 et utilisations associées

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