WO2018046933A1 - Inhibiteurs de tankyrase - Google Patents

Inhibiteurs de tankyrase Download PDF

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Publication number
WO2018046933A1
WO2018046933A1 PCT/GB2017/052624 GB2017052624W WO2018046933A1 WO 2018046933 A1 WO2018046933 A1 WO 2018046933A1 GB 2017052624 W GB2017052624 W GB 2017052624W WO 2018046933 A1 WO2018046933 A1 WO 2018046933A1
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cancer
compound
formula
solvates
salts
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PCT/GB2017/052624
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English (en)
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Michael David THREADGILL
Amit NATHUBHAI
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University Of Bath
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to compounds of formula (I) and salts and solvates thereof, and pharmaceutical compositions containing them, and the use of such compounds as inhibitors of tankyrase and in the treatment of disorders related to signalling by Tankyrase 1 and tankyrase 2, and to treat diseases or conditions modulated by tankyrase 1 and/ or 2 for example proliferative diseases and autoimmune diseases such as cancer and diabetes respectively.
  • TNKSs Tankyrases
  • TRF1 telomere repeating binding factor- 1
  • NuMA nuclear mitotic apparatus protein
  • TNKSs Inhibition of TNKSs is reported to lead to stabilization of axin and decreased nuclear ⁇ - catenin-driven proliferation of cancer cells. 11
  • the axin-TNKS-KIF3 A complex is required for insulin-stimulated GLUT4 translocation. 12 Additionally, insulin-regulated amino-peptidase (IRAP) is also a binding partner of TNKSs. 13 Together, IRAP and TNKSs can enhance insulin-stimulated exocytosis of GLUT4 which could result in increased uptake of glucose. 13 TNKS-knockout mice display increased sensitivity to insulin and reduced adiposity and pan-PARP inhibitors have been used to investigate the role of TNKSs in studies on the translocation of GLUT4. 14
  • XAV939 1 (shown below) has been extensively used as an inhibitor of TNKSs and of Wnt signalling. 6 Like 1, compounds that bind to TNKSs include flavones, 15 2- arylquinazolin-4-ones 2 , 1 21 isoquinolin- l-ones 17 and aryltetrahydronaphthyridinones which maintain a classic binding mode in the nicotinamide-binding site. 18 IWR- 1 3 (shown below) is an inhibitor of the Wnt signalling cascade through inhibiting TNKSs and binds exclusively to the adenosine-binding site.
  • novel inhibitors including 2-aryl-8 -methylquinazolin-4-ones with 4 '-large or electron-withdrawing substituents (e.g. 2 ) and 3 -arylisoquinoline- l-ones have been reported to provide potent and selective inhibition of TNKS and Wnt signalling.
  • Some compounds have been evaluated as TNKS inhibitors that bind to both the nicotinamide-binding site and the adenosine-binding domain , 22 23 although the increase in potency over 1 were modest. In addition , such compounds showed a similar selectivity for TNKS- 1 over PARP2 as 3 .
  • TNKSs inhibitors have been reported such as WO 20 14/ 023390 and WO 20 14/ 036022.
  • the present invention seeks to overcome problem(s) associated with the prior art.
  • the present invention provides a a compound of formula (I) :
  • X 1 is selected from C-R or N;
  • R 1 , R 2 and R 3 are each independently selected from -H, -Ci-Ce alkyl, -Ci-Ce haloalkyl, - C(0)NR b R c , -C0 2 R b , -CN, -OR b , -NR b R c and -halo;
  • L is selected from -C1-C5 alkylene-, -S-(Ci-C4 alkylene) z - and phenylene; wherein the phenylene is optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and -halo;
  • z is 0 or 1;
  • Yi is selected from - C(0)NH -, -NHC(O)- and -C(O)- ;
  • Ar is selected from a heteroarylene with 5 or 6 ring members; and phenylene wherein the heteroarylene and the phenylene are optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl and -halo;
  • Y 2 is selected from -C(0)NH-, -NHC(O)- and -C(O)-;
  • Ar 2 is a 9- or 10 -membered heteroaryl group or a napthalyl group optionally substituted with up to seven optional substituents independently selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl, -OR d , -NR d R e and -halo; and
  • R , R b , R c , R d and R e are each independently selected from -H and -Ci-Ce alkyl.
  • the present invention provides a compound of formula (I), wherein the compound is a com
  • X 1 is selected from C-R or N;
  • R 1 , R 2 and R 3 are each independently selected from -H , -Ci-Ce alkyl, -Ci-Ce haloalkyl, C(0)NR b R c , -C0 2 R b , -CN, -OR b , -NR b R c and -halo;
  • L is selected from -C1-C5 alkylene- , -S-(Ci-C4 alkylene) z - and phenylene; wherein the phenylene is optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and -halo;
  • z is 0 or 1;
  • Yi is selected from -C(0)NH-, -NHC(O)- and -C(O)-;
  • Ar is selected from a heteroarylene with 5 or 6 ring members ; and phenylene wherein the heteroarylene and the phenylene are optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl , -Ci-Ce haloalkyl and -halo;
  • Y 2 is selected from - C(0)NH-, -NHC(O)- and -C(O)- ;
  • X 2 is selected from N and C-R 4 ;
  • X 3 is selected from N and C-R 5 ;
  • X 4 is selected from N and C-R 6 ;
  • X 5 is selected from N and C-R 7 ;
  • X 6 is selected from N and C-R 8 ;
  • X 7 is selected from N and C-R 9 ;
  • X 8 is selected from N and C-R 10 ;
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from -H , -G-C 6 alkyl, -G- C 6 haloalkyl, -OR d , -NR d R e and -halo; and
  • R , R b , R c , R d and R e are each independently selected from -H and -Ci-Ce alkyl.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the present invention provides a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof, for u se in therapy.
  • the present invention provides a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof, for u se as a medicament.
  • the present invention provides a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof, for u se in the treatment of a disease or condition selected from a proliferative disease (such as cancer) , diabetes and fibrosis.
  • a proliferative disease such as cancer
  • the present invention provides the u se of a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof, in the manufacture of a medicament for treating a disease or condition selected from a proliferative disease (such as cancer), diabetes and fibrosis.
  • the present invention provides a method of treating a disease or condition selected from a proliferative disease, diabetes and fibrosis in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof or a pharmaceutical composition comprising a compound of formula (I) and salts, solvates, tautomers and stereoisomers thereof.
  • the compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof may be used for the isolation and investigation of the activity or expression of TNKSs.
  • they are suitable for use in diagnostic methods for diseases in connection with TNKSs activity, in particular, diseases in connection with unregulated or disturbed TNKSs activity.
  • the present invention provides the use of the compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof, as molecular probes; in particular, as molecular probes for a disease or conditions selected from a proliferative disease (such as cancer), diabetes and fibrosis.
  • a proliferative disease such as cancer
  • diabetes such as diabetes
  • fibrosis a proliferative disease
  • compositions of the present invention may further comprise one or more (e.g. two, three or four) further active agents (such as further tankyrase inhibitors and/ or further active agents for the treatment of a proliferative disease (such as cancer) and/ or diabetes and/ or fibrosis).
  • further active agents such as further tankyrase inhibitors and/ or further active agents for the treatment of a proliferative disease (such as cancer) and/ or diabetes and/ or fibrosis).
  • Ci-Ce alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having from 1 to 6 carbon atoms; more suitably C 1 - C5 alkyl; more suitably Ci- C4 alkyl, more suitably C 1 - C3 alkyl.
  • alkyl groups include methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent- l-yl, pent-2-yl, pent-3-yl, 3- methylbut- l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth- l-yl, n-hexyl, and the like.
  • Alkylene refers to a divalent radical derived from an alkane which may be a straight chain or branched, as exemplified by -Ct -, - CH2CH2-, -CH(CH3)CH2- and -
  • Anticancer agent refers to any agent which is administered to a patient with cancer for the purposes of treating the cancer.
  • Drug drug
  • drug substance drug substance
  • active pharmaceutical ingredient refers to a compound (e.g., compounds of Formula 1 and compounds specifically named above) that may be used for treating a subject in need of treatment.
  • Excipient refers to any substance that may influence the bioavailability of a drug, but is otherwise pharmacologically inactive.
  • Halo refers to -F, -CI, -Br, and -I.
  • Haloalkyl refers to an alkyl as defined herein, which is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloaikyl, dihaloalkyl or polyhaloalkyi including perhaloalkyl.
  • a monohaloaikyl can have one iodo, bromo, chloro or fiuoro within the alkyl group.
  • Dihaloalkyl and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyi contains up to 12, or 10 , or 8 , or 6, or 4, or 3, or 2 halo groups.
  • Non-limiting examples of haloalkyl include fluoromethyl, difiuoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhalo-alkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
  • Heteroaryl with 5 or 6 ring members refers to unsaturated monocyclic aromatic groups comprising from 5 or 6 ring atoms, whether carbon or heteroatoms, of which from 1 to 4 are ring heteroatoms.
  • each ring has from 1, 2 or 3 ring
  • each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • monocyclic heteroaryl groups include, but are not limited to, those derived from:
  • NiOi oxazole, isoxazole, isoxazine
  • N 2 O 1 oxadiazole (e.g. l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, 1-oxa- 3,4-diazolyl) ;
  • oxadiazole e.g. l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, 1-oxa- 3,4-diazolyl
  • N3O1 oxatriazole
  • N 1 S 1 thiazole, isothiazole
  • N 2 imidazole, pyrazole, pyridazine, pyrimidine (e.g., cytosine, thymine, uracil), pyrazine;
  • N3 triazole, triazine
  • a 9- or 10-membered heteroaryl group refers to unsaturated bicyclic aromatic groups comprising from 9 to 10 ring atoms, whether carbon or heteroatoms, of which from 1 to 10 are ring heteroatoms.
  • each ring has from 5 to 6 ring atoms and from 0 to 4 ring heteroatoms.
  • each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group is attached to the parent group at a hetero ring atom.
  • the heteroaryl group is attached to a parent group or to a substrate at a carbon ring atom.
  • Heteroaryl groups may include one or more optional non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • Suitable optional substituents includes one or more optional substituents independently selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl, -OR d , - NR d R e and -halo.
  • Examples of heteroaryl groups which comprise two fused rings include, but are not limited to, those derived from :
  • Ni indole, isoindole, quinoline, isoquinoline;
  • NiOi benzoxazole, benzisoxazole
  • NiSi benzothiazole
  • N 2 benzimidazole, indazole, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine;
  • N2O1 benzofurazan
  • N4 purine (e.g., adenine, guanine), pteridine.
  • Heteroarylene refers to a divalent radical derived from a heteroaryl group, as exemplified by pyridinylene - (C5H3N)-.
  • methyl may be selected as an example of a Ci-6 alkyl for the first instance of R in the compound and -H may be selected for the next instance of R in the compound.
  • Optionally substituted refers to a parent group which may be unsubstituted or which may be substituted with one or more substituents.
  • the optional substituted parent group comprises from one to three optional substituents, i.e. one, two, or three optional substituents.
  • “Pharmaceutically acceptable” substances refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like,
  • “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipient, carrier or diluent.
  • Phenylene refers to a divalent radical derived from a phenyl group, i.e. - (CeEU)- .
  • subject refers to a human or non-human mammal.
  • non -human mammals examples include livestock animals such as sheep, horses, cows, pigs, goats, rabbits and deer; and companion animals such as cats, dogs, rodents, and horses.
  • Substituted when used in connection with a chemical substituent or moiety (e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
  • a chemical substituent or moiety e.g., an alkyl group
  • “Therapeutically effective amount” of a drug refers to the quantity of the drug or composition that is effective in treating a subject and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the therapeutically effective amount may depend on the weight and age of the subject and the route of administration, among other things.
  • Treating refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder, disease or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disorder, disease or condition.
  • Tankyrase inhibitor means a compound or that can inhibit tankyrase activity such as to reduce and/ or eliminate and/ or prevent the detrimental action of tankyrase.
  • tankyrase is selectively inhibited, that is tankyrase is preferentially inhibited compared to another enzyme. The inhibition of tankyrase can be assessed using the assay provided in the Examples.
  • the compound of formula (I) is a compound of formula (IV) :
  • the compound of formula (I) is a compound of formula (V):
  • the compound of formula (I) is a compound of formula (VI):
  • R 1 , R 2 and R 3 are each independently selected from -H, -methyl, -ethyl, - propyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, - dichloromethyl, -trichloromethyl, -pentafluoroethyl, -difluoroethyl, -dichloroethyl, - C(0)NH 2 , -C(0)NH(CH 3 ), -C(0)NH(CH 2 CH 3 ), -C(0)N(CH 3 ) 2 , -C(0)N(CH 2 CH 3 ) 2 , - C0 2 H, -C0 2 CH 3 , -C0 2 CH 2 CH 3 , -C0 2 CH 2 CH 3 , -C0 2 CH 2 CH 3 , -CN, -OH, -0-CH 3 , -
  • R 1 , R 2 and R 3 are each independently selected from -H, -methyl, -ethyl, - fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, -dichloromethyl, - trichloromethyl, , -C(0)NH 2 , -C(0)NH(CH 3 ), -C(0)N(CH 3 ) 2 , -C0 2 H, -C0 2 CH 3 , -CN, - OH, -0-CH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -F, -CI, -Br and -I.
  • R 1 , R 2 and R 3 are each independently selected from -H, -methyl, -ethyl, - fluoromethyl, -difluoromethyl, -trifluoromethyl, -OH , -0-CH 3 , -NH 2 , -NH(CH 3 ), -F and -CI.
  • R 1 , R 2 and R 3 are -H.
  • at least two of R 1 , R 2 and R 3 are -H.
  • L is selected from -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, - CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, - CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH 2 CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH
  • L is selected from -CH 2 -, - CH 2 CH 2 - ,- CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 CH 2 -, -S-,— S-CH 2 -,— S-CH 2 CH 2 -,— S-CH 2 CH 2 CH 2 -, -S- CH 2 CH 2 CH 2 CH 2 - and phenylene; wherein the phenylene is optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and - halo.
  • suitably L is selected from - CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 - and - CH 2 CH 2 CH 2- .
  • suitably L is phenylene optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and -halo.
  • L is phenylene optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -propyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, -dichloromethyl, -trichloromethyl, -pentafluoroethyl, -difluoroethyl, - dichloroethyl, -F, -CI, -Br and -I.
  • L is phenylene optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -fluoromethyl, -difluoromethyl, - trifluoromethyl, -chloromethyl, -dichloromethyl, -trichloromethyl, -F, -CI, -Br and -I
  • L is phenylene optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -fluoromethyl, - difluoromethyl, -trifluoromethyl, -F and -CI.
  • L is-S-, - S-CH 2 -, - S-CH 2 CH 2 -, - S-CH 2 CH 2 CH 2 - and -S- CH 2 CH 2 CH 2 CH 2- .
  • Yi is selected from - C(0)NH -, -NHC(O)- and -C(O)-.
  • Yi is -C(0)NH - it is attached to the adjacent L and Ar as -L-C(0)-NH-Ar-.
  • Yi is - NHC(O)- it is attached to the adjacent L and Ar as -L-NH -C(0)-Ar-.
  • Yi may be an amide group attached to the adjacent L and Ar groups in either direction .
  • Yi is selected from - C(0)NH - and - NHC(O)- .
  • Yi is - C(0)NH- .
  • Ar is selected from a heteroarylene with 5 or 6 ring members and 1 Or 2 heteroatoms ; and phenylene wherein the heteroarylene and the phenylene are optionally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and -halo
  • Ar is selected from pyrrolylene, pyridinylene, furanylene, thiophenylene, oxazolylene, imidazolylene and phenylene; wherein these groups are option ally substituted with one to three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and-halo.
  • Ar is selected from pyrrolylene, pyridinylene, imidazolylene and phenylene; wherein these groups are optionally substituted with one, two or three optional substituents selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl and-halo.
  • the Ar group is optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -propyl, -fluoromethyl, -difluoromethyl, - trifluoromethyl, -chloromethyl, -dichloromethyl, -trichloromethyl, -pentafluoroethyl, - difluoroethyl, -dichloroethyl, -F, -CI, -Br and -I.
  • substituents selected from -methyl, -ethyl, -propyl, -fluoromethyl, -difluoromethyl, - trifluoromethyl, -chloromethyl, -dichloromethyl, -trichloromethyl, -pentafluoroethyl, - difluoroethyl, -dichloroethyl, -F, -CI, -Br
  • the Ar group is optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -fluoromethyl, -difluoromethyl, - trifluoromethyl, -chloromethyl, -dichloromethyl, -trichloromethyl, -F, -CI, -Br and -I More suitably, the Ar group is optionally substituted with one, two or three optional substituents selected from -methyl, -ethyl, -fluoromethyl, -difluoromethyl, - trifluoromethyl, -F and - CI.
  • Y 2 is selected from - C(0)NH-, -NHC(O)- and -C(O)-.
  • Y 2 is - C(0)NH - it is attached to the adjacent Ar and bicyclic ring groups as - Ar-C(0)-NH-bicyclic ring.
  • Y 2 is - NHC(O)- it is attached to the adjacent Ar and bicyclic ring groups as -Ar-NH -C(0)-bicyclic ring.
  • Y 2 may be an amide group attached to the adjacent Ar and bicyclic ring groups in either direction .
  • Y 2 is selected from - C(0)NH- and -NHC(O)-. More suitably, Y 2 is -C(0)NH-
  • Ar 2 is a 9- or 10 -membered heteroaryl group or a napthalyl group selected from benzofuranyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, indazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, benzofurazanyl,
  • benzothiadiazolyl benzotriazolyl, purinyl, pteridinyl and napthalyl optionally substituted with up to seven optional substituents independently selected from -Ci-Ce alkyl, -G-C 6 haloalkyl, -OR d , -NR d R e and -halo.
  • Ar 2 is a 9- or 10 -membered nitrogen -containing heteroaryl group or a napthalyl group optionally substituted with up to seven optional substituents independently selected from -Ci-Ce alkyl, -Ci-Ce haloalkyl, -OR d , -NR d R e and -halo.
  • Ar 2 is a 9- or 10 -membered heteroaryl group or a napthalyl group selected from indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl and napthalyl optionally substituted with up to seven optional substituents
  • Ar 2 is a 9- or 10 -membered heteroaryl group or a napthalyl group optionally substituted with 0 , 1, 2, 3 , 4, 5 , 6 or 7 optional substituents independently selected from -Ci-Ce alkyl, -G-C 6 haloalkyl, -OR d , -NR d R e and -halo.
  • 2 is selected from groups (VII), (VIII) and (IX) :
  • X 4 is selected from N and C-R 6 ;
  • X s is selected from N and C-R 7 ;
  • X 6 is selected from N and C-R 8 ;
  • X 7 is selected from N and C-R 9 ;
  • X 8 is selected from N and C-R 10 ;
  • X 9 is N-R d ;
  • one of X 10 and X n is N-R d ; whilst the other is selected from C-R 7 and N.
  • zig-zag line indicates the point of attachment of the shown group (e.g. the options for A 2 shown for groups (VII), (VIII) and (IX) above) to the rest of the compound of formula (I).
  • 2 is selected from groups (X), (XI) and (XII) :
  • X 2 is selected from N and C-R 4 ;
  • X 3 is selected from N and C-R 5 ;
  • X 4 is selected from N and C-R 6 ;
  • X 5 is selected from N and C-R 7 ;
  • X 6 is selected from N and C-R 8 ;
  • X 7 is selected from N and C-R 9 ;
  • X 8 is selected from N and C-R 10 ;
  • X 9 is N-R d ;
  • one of X 10 and X 11 is N-R d ; whilst the other of X 10 and X 11 is selected from C-R 7 and N.
  • Ar 2 is a group (X).
  • Ar 2 is:
  • suitably X 2 is N.
  • X 2 is C-R 4 .
  • suitably X 3 is N.
  • X 3 is C-R 5 .
  • suitably X 4 is N.
  • X 4 is C-R 6 .
  • suitably X s is N.
  • X s is C-R 7 .
  • suitably X 6 is N.
  • X 6 is C-R 8 .
  • suitably X 7 is N.
  • X 7 is C-R 9 . x_.
  • suitably X 8 is C-R 10 .
  • X 8 is N.
  • X 9 is selected from N-H, N-CH 3 and N-CH 2 CH 3 .
  • X 10 and X" are selected from N-H, N-CH 3 and N-CH 2 CH 3 .
  • one X 10 and X" is selected from N-H, N-CH 3 and N-CH 2 CH 3 ; whilst the other of X 10 and X» is selected from C-R 7 and N.
  • At least one of X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 is N.
  • at least X 8 is N.
  • At least two of X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are N.
  • at least three of X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are N.
  • X s , X 6 and X 7 are N R 4 .
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from -H , - methyl, -ethyl, -propyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, - chloromethyl, -dichloromethyl, -trichloromethyl, -pentafluoroethyl, -difluoroethyl, - dichloroethyl, -OH , -0-CH 3 , -0-CH 2 CH 3 , -Nth, -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -F, -CI, -Br, and -I.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from -H , - methyl, -ethyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, - dichloromethyl, -trichloromethyl, -OH, -0-CH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -F, -CI, - Br, and -I.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from -H , - methyl, -ethyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, -OH, -0-CH 3 , -NH 2 , - NH(CH 3 ), -F and -CI.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is -H.
  • at least two of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are -H.
  • at least three, at least four, at least five, at least six of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are -H.
  • R , R b , R c , R d and R e are each independently selected from -H, -methyl, -ethyl, -n-propyl, -i-propyl, -n-butyl, -s-butyl, -i-butyl and -t-butyl.
  • R , R b , R c , R d and R e are each independently selected from -H , -methyl, -ethyl, -n-propyl and -i-propyl.
  • R , R b , R c , R d and R e are each independently selected from -H and - methyl,
  • R n , R 12 and R 13 are independently selected from -H , -Ci-Ce alkyl, -Ci-Ce haloalkyl and - halo.
  • R n , R 12 and R 13 are independently selected from -H , -Ci-Ce alkyl, -Ci-Ce haloalkyl and - halo.
  • the compound of formula (I) is a compound is selected from :
  • R n , R 12 and R 13 are each independently selected from -H, -methyl, -ethyl, - propyl, -fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, - dichloromethyl, -trichloromethyl, -pentafluoroethyl, -difluoroethyl, -dichloroethyl, -F, - CI, -Br and -I.
  • R n , R 12 and R 13 are each independently selected from -H, -methyl, -ethyl, - fluoromethyl, -difluoromethyl, -trifluoromethyl, -chloromethyl, -dichloromethyl, - trichloromethyl, -F, -CI, -Br and -I
  • R n , R 12 and R 13 are each independently selected from -H, -methyl, -ethyl, - fluoromethyl, -difluoromethyl, -trifluoromethyl, -F and -CI.
  • the invention finds application in the treatment of diseases or conditions selected from proliferative diseases, diabetes and fibrosis.
  • proliferative disease refers to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g.
  • lung cancer small cell lung cancer, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, bowel cancer, colon cancer, hepatoma, breast cancer, glioblastoma, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, head and neck cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukaemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis.
  • Cancers of particular interest include, but are not limited to, breast cancer (both ER positive and ER negative), pancreatic cancer, lung cancer and leukaemia.
  • Compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof, are useful for treating proliferative diseases in any type of cell, including but not limited to, the head, neck, eye, mouth, throat, oesophagus, bronchus, larynx, pharynx, chest, bone, lung, bowel, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumours and blood-borne tumours.
  • compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof are used in the treatment of a proliferative disease selected from bladder cancer, bone cancer, bowel cancer, brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, head and neck cancer, leukaemia, liver cancer, lung cancer, lymphoma, melanoma, oesophageal cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, retinoblastoma, sarcoma, skin cancer, testicular cancer, thyroid cancer and uterine cancer.
  • a proliferative disease selected from bladder cancer, bone cancer, bowel cancer, brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, head and neck cancer, leukaemia, liver cancer, lung cancer, lymphoma, melanoma, oesophageal cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, retin
  • compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof are useful in the treatment of a proliferative disease wherein the proliferative disease is a diabetes-related cancer.
  • Suitable diabetes-related cancers include colon cancer, gastric cancer, prostate cancer and rectal cancer.
  • stereoisomers thereof are useful in the treatment of a proliferative disease wherein the proliferative disease is colon cancer.
  • the disease is prostate cancer.
  • the prostate cancer is androgen-independent prostate cancer.
  • compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof are used in the treatment of diabetes; in particular, in the treatment of type II diabetes.
  • compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof are used in the treatment of fibrosis.
  • subjects are human, livestock animals and companion animals.
  • the compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof may be used for the isolation and investigation of the activity or expression of TNKSs.
  • they are suitable for use in diagnostic methods for diseases in connection with TNKSs activity, in particular, diseases in connection with unregulated or disturbed TNKSs activity.
  • the compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof may be used as molecular probes; in particular, as molecular probes for disease or conditions selected from a proliferative disease (such as cancer), diabetes and fibrosis.
  • a proliferative disease such as cancer
  • Compounds of formula (I) and salts, solvates, tautomers and stereoisomers thereof have been found to be highly potent and specific TNKS inhibitors, and they can effectively inhibit Wnt signalling, increase glucose uptake into adipocytes and reduce colon cancer growth in vitro using functional cellular assays.
  • Compounds of formula (I) may be administered alone or in combination with one or another or with one or more pharmacologically active compounds which are different from the compounds of formula (I).
  • the compounds of formula (I) may be administered simultaneously, sequentially or in alternation with administration of at least one or more pharmacologically active compounds.
  • the one or more pharmacologically active compounds are anticancer agents.
  • compositions of the invention may suitably be combined with various components to produce compositions of the invention.
  • compositions are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical
  • composition (which may be for human or animal use).
  • Suitable carriers and diluents include isotonic saline solutions, for example phosphate-buffered saline.
  • Useful pharmaceutical compositions and methods for their preparation may be found in standard pharmaceutical texts. See, for example, Handbook for Pharm aceutical Additives, 3rd Edition (eds. M. Ash and I. Ash), 2007 (Synapse Information Resources, Inc., Endicott, New York, USA) and Rem ington: The Science and Practice of
  • the compounds of the invention may be administered by any suitable route.
  • the compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • the compounds of the invention can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the invention or and salts, solvates, tautomers and stereoisomers thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or
  • compositions which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, controlled-release or pulsatile delivery applications.
  • the compounds of the invention may also be administered via fast dispersing or fast dissolving dosages forms.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate,
  • croscarmellose sodium and certain complex silicates such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/ or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and
  • Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/ or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients maybe present both within the dosage form i.e. within the matrix, and/ or on the dosage form i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin,
  • hydroxypropylmethyl cellulose magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • the compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, or they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • Suitably formulation of the invention is optimised for the route of administration e.g. oral, intravenously, etc.
  • Administration may be in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) during the course of treatment.
  • Methods of determining the most effective means and dosage are well known to a skilled person and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated.
  • Single or multiple administrations can be carried out with the dose level and the dose regimen being selected by the treating physician, veterinarian, or clinician.
  • the compositions may be administered at varying doses.
  • a typical dosage for an adult human may be 100 ng to 25 mg (suitably about 1 micro g to about 10 mg) per kg body weight of the subject per day.
  • guidance may be taken from studies in test animals when estimating an initial dose for human subjects.
  • an initial test dose for humans may be approx. 0.5x to 2x the mg/ Kg value given to mice.
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR'R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 ), a salt or solvate thereof, as well as conventional protected forms.
  • Certain compounds may exist in one or more particular geometric, optical,
  • enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1- forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; alpha- and beta-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, - CH 2 OH .
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. C 1 -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1 -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl.
  • tautomeric forms for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/ enol, imine/ enamine, amide/ imino alcohol, amidine/ amidine, nitroso/ oxime,
  • H may be in any isotopic form, including ⁇ , 2 H (D), and 3 H (T) ; C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 1 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
  • Compounds of formula (I), which include compounds specifically named above, may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include nontoxic acid addition salts (including di-acids) and base salts. If the compound is cationic, or has a functional group which may be cationic (e.g. -NH 2 may be -Nth "1" ), then an acid addition salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids hydrochloric acid, nitric acid, nitrous acid, phosphoric acid, sulfuric acid, sulphurous acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid and phosphorous acids.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
  • a base salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, metal cations, such as an alkali or alkaline earth metal cation, ammonium and substituted ammonium cations, as well as amines.
  • suitable metal cations include sodium (Na + ) potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), zinc (Zn 2+ ), and aluminum (Al 3+ ).
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4 + ) and substituted ammonium ions (e.g. Nt R*, NH2 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine,
  • phenylbenzylamine, choline, meglumine, and tromethamine as well as amino acids, such as lysine and arginine.
  • amino acids such as lysine and arginine.
  • An example of a common quaternary ammonium ion is ⁇ ( ⁇ 3)4 + .
  • suitable amines include arginine, ⁇ , ⁇ '- dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2- amino-2-hydroxymethyl-propane- l,3-diol, and procaine.
  • Pharmaceutically acceptable salts may be prepared using various methods. For example, one may react a compound of formula (I) with an appropriate acid or base to give the desired salt. One may also react a precursor of the compound of formula (I) with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, one may convert a salt of the compound of formula (I) to another salt through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, one may then isolate the salt by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.
  • solvate describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., EtOH).
  • solvent molecules e.g., EtOH
  • hydrate is a solvate in which the solvent is water.
  • Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D 2 O, acetone-d6, DMSO-d6).
  • a currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H . G. Brittain ed.)
  • Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound.
  • the solvent molecules lie in lattice channels where they are next to other solvent molecules.
  • metal-ion coordinated solvates the solvent molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non- stoichiometry will typically be observed. These compounds may be isolated in solid form, for example, by lyophilisation.
  • Figure 1 shows a model of docking of compound ( 13 ) into the structure of TNKS- 1.
  • the protein is shown in pink and ( 13) in cyan.
  • Key hydrogen bonds shown as gray dashed lines.
  • Figure 2 show an example image of DLD- 1 colony forming assay (1000 cells/ well) with ⁇ ⁇ (control with 1% DMSO v/ v only), ⁇ and ⁇ of nicotinamide-site binder 1, adenosine-site binder 3 , compound ( 13) and (14 ) .
  • Figure 4 shows the effect of 1, ( 13) and ( 14 ) on percentage insulin-stimulated glucose uptake in 3T3-L1 adipocytes.
  • Basel levels (B) with or without compound contain no insulin (I).
  • Figure 5 shows IC5 0 graphs obtained from the Tankyrase-2 assay for compounds 1, 3 , (6 ) , ( 11) , ( 12) , ( 13 ) and ( 14 ) .
  • the x-axis shows the % inhibition and the y-axis shows the amount of the inhibitor compound ( ⁇ ).
  • Figure 6 shows IC5 0 graphs obtained from the Takyrase-1 assay for compounds 1, 3, (6), (11), (12), (13) and (14).
  • the x-axis shows the % inhibition and the y-axis shows the amount of the inhibitor compound ( ⁇ ).
  • Figure 7 shows IC5 0 graphs obtained from the PARP-1 assay for compounds 1, 3, (6), (11), (12), (13) and (14).
  • the x-axis shows the % inhibition and the y- axis shows the amount of the inhibitor compound ( ⁇ ).
  • Figure 8 shows IC5 0 graphs obtained from the PARP-2 assay for compounds 1, 3, (11), (13) and (14).
  • the x-axis shows the % inhibition and the y-axis shows the amount of the inhibitor compound ( ⁇ ).
  • Figure 9 shows Wnt signalling graphs obtained from the Wnt signalling cellular assay for compounds (13), (14) and 1.
  • Figure 10 shows exemplary images of prostate cancer PC3 cell colony forming assays for control (C) and for samples treated with XAV939 (1), IWR-1 (3), compound (13) and compound (14).
  • Figure 11 shows camera images using an inverted light microscope of colonies for control (C) and for samples treated with XAV939 (1), IWR-1 (3), compound (13) and compound (14).
  • Modelling was performed with the SYBYL software suite with UCSF Chimera for visualisation. Ligands were constructed and charged within SYBYL using the TNKS-2 structure 4I9I. 23 The original ligand was removed from the 4i9i structure. Once docking experiments in SYBYL was complete using the surflexTM docking suite, the complete ligand-receptor complex was minimized in SYBYL (without restraints) to give the final structures. Modelling. Structural alignment of the co-crystal structures of 2 (PDB 4UFU) and 3 (PDB 3UA9) with TNKS2 20 21 provided initial insights towards the design of 13 and 14.
  • the quinazolinone of 2 binds into the nicotinamide-binding site, making hydrogen bonds with Ser 1068 and Gly 1032 and ⁇ -stacks with Tyr 1071 (TNKS2 numbering).
  • the quinolone of 3 is located in the adenosine-binding site, making a ⁇ -stack with His 1048 (TNKS2 numbering).
  • Features binding at each site were linked to create chimeric compounds 13 and 14 combining important hydrogen bonds and stacking interactions at both binding sites. Modelling of 13 and 14 into the active site of TNKS1 (PDB 4I9I) 23 predicted that the designed compounds could bind to the pocket in the intended way and that the linker length was appropriate.
  • the quinazolin-4-one core could bind to the nicotinamide-binding site to create conserved H-bond and ⁇ -stacking interactions.
  • Compounds 1 and 2 contain a 2-aryl ring, which is shown to occupy a hydrophobic pocket. Modelling of 13 into TNKS1 suggests that the chosen linker could allow Tyr 1203 to move towards the nicotinamide-binding site and decrease the size of the
  • Tankyrase- 1 assays were performed using a commercial kit (Amsbio Europe Ltd.
  • a solution of 20X 1- PAR assay buffer (catalogue # 4684-096-07) was diluted to IX (1:20) with dH 2 0.
  • the IX 1-PAR assay buffer solution (was used to rehydrate the histone-coated wells (50 ⁇ L ⁇ per well at room temperature for 30 min.).
  • the lX-PAR assay buffer was removed by aspiration.
  • a suspension of Tankyrase-1 protein was prepared (5 mU in 25 ⁇ L ⁇ IX 1-PAR assay buffer solution) and added to appropriate wells (25 ⁇ ) containing the appropriate volume of IX 1-PAR assay buffer solution.
  • the anti-PAR monoclonal antibody (catalogue # 4684-096-04) was diluted 1000 fold with IX antibody diluent and 50 ⁇ . was used per well. The reaction was left at room temperature for 30 min. The wells were washed with 2 x PBS-T and 2 x PBS.
  • a solution of goat anti-mouse IgG-HRP congugate was prepared by dilution of 5X antibody diluent (catalogue # 4684-096-03) to IX ( 1:5) using dH 2 0.
  • the goat anti- mouse IgG-HRP conjugate (catalogue # 4684-096-05) was diluted 1000 fold with IX antibody diluent and 50 ⁇ . was used per well. The reaction was left at room
  • PARP- 1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 4676-096-K) using pre-coated histone well plates.
  • a solution of 20X PARP assay buffer (catalogue # 4671-096-02) was diluted to IX (1:20) with dH 2 0.
  • the IX PARP assay buffer solution was used to rehydrate the histone-coated wells (50 ⁇ L ⁇ per well) at room temperature for 30 min.
  • the IX PARP assay buffer was removed by aspiration.
  • a suspension of PARP- 1 protein was prepared (0.5 mU in 25 ⁇ L ⁇ IX PARP assay buffer solution) and added to appropriate wells (25 ⁇ .) containing the appropriate volume of IX PARP assay buffer solution.
  • Varying concentrations of inhibitor containing a final concentration of 0.1% DMSO were prepared in IX PARP assay buffer solution and added to appropriate wells (5 ⁇ 3 ⁇ 4.
  • a solution of substrate consisting of 10X PARP cocktail (2.5 ⁇ . per well, catalogue # 4671-096-03), 10X activated DNA (2.5 ⁇ . per well, catalogue # 4671-096-06) and IX PARP assay buffer ( 15 ⁇ L ⁇ per well) was added to appropriate wells (20 ⁇ , ⁇ well). The reaction was left at room temperature for 1 hour. The wells were washed with 2 x PBS-T and 2 x PBS.
  • PARP- 1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 80552).
  • a solution of 5X histone mixture solution (catalogue # 52029) was diluted to IX (1:5) with PBS.
  • Each well was treated with histone solution (50 ⁇ per well) at 4°C for 16 hours.
  • the wells were washed with 3 x PBS-T (200 ⁇ per well).
  • the blocking buffer solution provided was added to the wells (200 ⁇ per well) and the plate was incubated at room temperature for 90 minutes.
  • the wells were washed with 3 x PBS-T (200 ⁇ per well).
  • a solution of 10X PARP assay buffer (catalogue # 80602) was diluted to IX (1: 10) with dF O.
  • Varying concentrations of inhibitor containing a final concentration of 0.1% DMSO were prepared in IX PARP assay buffer solution and added to appropriate wells (5 ⁇ ).
  • Substrate solution mixture for the ribosylation reaction was prepared by preparing a solution of 10X PARP assay buffer (2.5 ⁇ per well), 10X PARP assay mixture (2.5 ⁇ per well, catalogue # 40305), Activated DNA (5.0 ⁇ ⁇ well, catalogue # 80605) and dt O (15 ⁇ ⁇ well). The substrate solution was added to all wells (25 ⁇ ⁇ well).
  • PARP-2 enzyme solution (catalogue # 80502) was diluted with IX PARP assay buffer to 2.0 ng/ mL final concentration.
  • the diluted PARP-2 solution was added to appropriate wells (20 ⁇ per well). The reaction was left at room temperature for 1 hour. The wells were washed with 3 x PBS-T (200 ⁇ per well). A solution of Strep-HRP (catalogue # 130708) was diluted 50 fold with blocking buffer and added to each well (50 ⁇ ) and left for 30 minutes at room temperature. The wells were washed with 3 x PBS-T (200 ⁇ per well). The wells were treated with a 1: 1 mixture of HRP chemiluminescent solution A and HRP chemiluminescent solution B ( 100 ⁇ ⁇ well, catalogue # 140613) and the luminescence was recorded immediately using a chemiluminescence plate reader.
  • IC5 0 data was calculated using a four parameter logistic curve and SigmaPlot 12.0 software.
  • IC5 0 graphs obtained for compounds 1, 3 , ( 11) , ( 12) , ( 13) and ( 14 ) from this assay are shown in Figure 8.
  • Exam ple 14 Wnt signalling cellular assay experim ental
  • rHEK293 The Wnt Signalling Pathway TCF/ LEF Reporter-HEK293 Cell Line (rHEK293) containing stably integrated Wnt reporter assay was bought from BPS Bioscience, catalog #60501. rHEK293 cells were grown at 37° C with 5% CO 2 using Dulbecco's Modified Eagle's Medium (DMEM, Sigma), supplemented with 10 % of fetal bovine serum (Lonza), 1% non-essential amino acid (Sigma), IX of penicillin and streptomycin (Sigma), and 400 ⁇ g/ ml of Geneticin (Roche).
  • DMEM Dulbecco's Modified Eagle's Medium
  • Wnt-3a and L cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10 % fetal bovine serum, penicillin and streptomycin at 37° C in a 5% CO 2 atmosphere.
  • Wnt3a and control conditioned medium were prepared as described previously. 31
  • rHEK293 cells/ well in 40 ⁇ 1 of serum-free DMEM were plated on 96 well plate (white wells, clear bottom, Perkin Elmer). 10 ⁇ of 50 mM LiCl in serum-free DMEM with 5x concentration of tankyrase inhibitors was added and cells were incubated for 16 hours. Next, 25 ⁇ 1 of Wnt3a or control conditioned medium supplemented with DMSO or tankyrase inhibitors was added on cells and cells were incubated for 20 hours. After the second incubation, the plates were allowed to settle in room temperature for 30 minutes before luciferase measurements.
  • Wnt3a induced luciferase activity was determined using ONE-Glo Luciferase Assay System (Promega) according to manufacturer's protocol. Wnt signalling graphs obtained from the Wnt signalling cellular assay for compounds ( 13) , ( 14 ) and 1 are shown in Figure 9. Inhibition of Wnt signalling in TCF/ LEF reporter-HEK293 cells
  • a TCF/ LEF Reporter-HEK293 Cell line (BPS Bioscience, catalog #60501) was utilized to evaluate the cellular potency of the compounds. 27 Upon extracellular Wnt signals, ⁇ - catenin is stabilized and associates with TCF/ LEF transcription factors activating transcription. 6 27 Tankyrases control the stability of the ⁇ -catenin destruction complex and TNKS inhibition is expected to stabilize the destruction complex and subsequently lower the levels of ⁇ -catenin. 6 The TCF/ LEF Reporter-HEK293 cell line is used to measure this interference with this pathway.
  • Known compounds 1 and 3 were used as control inhibitors against TNKS1, TNKS2, PARPl and PARP2 to compare their potency and isoform-selectivity in comparison to the new dual-binding inhibitors ( 13 ) and ( 14 ) (see Table 1). Inhibitor compounds ( 13) and ( 14 ) were also tested against other PARPs (see Table 1).
  • the nicotinamide-site binder XAV939 1 showed good potency and 25- and 4-fold selectivity comparing TNKS1 with PARPl and PARP2, respectively, and 131- and 22-fold selectivity for inhibition of TNKS2 vs. PARPl and PARP2, respectively.
  • the designed compounds ( 13) and ( 14) are extremely potent and selective inhibitors of TNKSs, in comparison with the nicotinamide mimic and lead inhibitor 1 and the adenosine-site-binding 3. Both inhibited TNKS2 in the pM range and TNKS1 in the low nM range. Interestingly, ( 13 ) and ( 14 ) have similar activities against the TNKSs, showing that the 8 -Me does not contribute significantly to binding, unlike in the less potent simple 2-arylquinazolin-4-ones.
  • Inhibitor ( 13) is 9 x 10 4 -fold selective for TNKS2 vs. PARPl and 6.9 x 10 4 -fold selective for TNKS2 vs. PARP2.
  • ( 14 ) is 7 x 10 4 -fold selective for TNKS2 vs. PARPl and 1.2 x 10 5 -fold selective for TNKS2 vs. PARP2.
  • the somewhat lesser potency of these agents in TNKSl corresponds to selectivities for TNKSl vs. PARPl and PARP2 in the range 1-2.3 x 10 3 -fold.
  • DLD-1 cells were seeded in DMEM medium ( lx catalogue # 41966-029 ; gibco life technologies) supplemented with 10 % FBS. Plates contained 1000 cells per well and incubated at 37°C in 5% CO 2 for 16 hr after which, 2 mL of tankyrase inhibitors (2 x final concentration) was added to the appropriate wells containing 2 mL of media to give the final concentration of inhibitor in each well (4mL total volume) and a final DMSO concentration of 1% (v/ v). Media was replenished every 72 h until colony formation in the inhibitor treated wells was observed (18 days). Cells were viewed using a MotiTM AE 2000 light microscope equipped with MoticamTM5.0 Mega Pixel camera and a computer monitor for visualisation.
  • Colonies contained a minimum of 50 cells. After colony formation, media was removed and washed with lx PBS solution (2 mL). Cells were fixed using 70 % EtOH and water solution (2 mL) for 5 minutes at room temperature. The fixing solution was removed and the cells were stained with a solution Trypan Blue ( 1 mL; 0.4% v/ v; Sigma Aldrich catalogue # T8 154) at room temperature for 15 minutes. The stain was removed and cells were washed gently with PBS (lx) solution. Colonies were visually counted using a MotiTM AE 2000 light microscope equipped with MoticamTM5.0 Mega Pixel camera.
  • 3T3-L1 fibroblasts were obtained from the American Type Culture Collection, cultured in DMEM and differentiated to adipocytes by treatment with insulin, dexamethasone and isobutylmethylxanthine, as described previously. 28 On the day of the experiment, 10- 12 d post-differentiation, the cells were incubated with serum-free DMEM for 2 h at 37°C. Cells in the treatment group were treated with increasing concentrations of ( 13 ) or ( 14 ) for 1 h.
  • the cells were washed three times with Krebs-Ringer-HEPES (KRH) buffer ( 140 mM NaCl, 4.7 mM KC1, 2.5 mM CaCl 2 , 1.25 mM MgS0 4 , 2.5 mM NaH 2 P0 4 , 10 mM HEPES, (pH 7.4)) and incubated for 30 min in the presence of ( 13) or ( 14 ) and in either the absence or presence of insulin (100 nM) at 37°C.
  • KRH Krebs-Ringer-HEPES
  • 2-deoxy-D-[2,6- 3 H]glucose (final concentration 50 ⁇ , 0.1 ⁇ / ⁇ 11) was added for 5 min and the cells were washed four times with ice-cold KRH buffer. Nonspecific uptake of 2-deoxy-D-glucose was measured in the presence of 10 ⁇ cytochalasin B. The cells were lysed in aq.
  • TNKS-KIF3A complex The axin-TNKS-KIF3A complex is stabilized through inhibition of TNKS. 12 Ablation of expression of TNKSs has been reported to upregulate GLUT4 at the post- transcriptional level, potentially increasing uptake of glucose into adipocytes. 14 To address this pharmacologically, our highly potent and selective TNKS inhibitors were examined for their ability of insulin -stimulated uptake of glucose. Adipocyte cells, derived from 3T3-L1 fibroblasts, were treated with ( 13 ) and ( 14 ) in the presence of insulin (100 nM). 28 XAV939 1 was used for comparison, as a standard but weaker and less selective inhibitor of TNKSs.
  • Example images of PC3 colony forming assays for each of these five samples are shown in Figure 10.
  • This novel data suggests potent and isoform-selective tankyrase inhibition, such as that achieved by using compounds ( 13 ) and ( 14 ) , antagonises colony formation of PC3 metastatic androgen-independent cells. Colonies were imaged using an inverted light microscope which was attached to a Moticam 5.0MP camera. In most cases, compound ( 13 ) and compound ( 14 ) gave fewer and smaller colonies compared to DMSO (as control 1% DMSO v/ v only) ( C) , XAV939 ( 1) or IWR- 1 (3 ) as shown Figure 11.
  • the potent and isoform-selective tankyrase inhibitors such as compound ( 13 ) and compound ( 14 ) , reduce the density and size of PC3 cell colonies.
  • Colonies were counted and those that were difficult to visualise by eye were viewed under an inverted light microscope under magnification to verify colony formation and colony density.
  • potent and isoform-selective tankyrase inhibitors such as compounds ( 13) and ( 14 ) , reduce colony survival of prostate cancer cells, such as androgen-independent prostate cancer cells.
  • the compounds were designed by molecular modelling so that the quinazolin-4-one moiety occupied the nicotinamide-binding site, setting up the linker so that the quinoline moiety interacts with the adenosine-binding region.
  • Cellular uptake of these agents was demonstrated by their potent inhibition of Wnt / ⁇ -catenin signalling in the low nM range.
  • Significant anti-proliferative activity was demonstrated in DLD- 1 human colon carcinoma cells even in the presence of ⁇ inhibitor.
  • Compounds of the present invention are efficient molecular tools as Wnt antagonists and in relation to diabetes-related cancers. These results also indicate that potent and selective inhibition of TNKSs can increase the uptake of glucose in response to insulin ; high doses of insulin can cause dysregulation of various signalling cascades (PI3K / Akt / mTOR). 29 Such compounds can be used for investigating the activity and/ or expression of TNKSs and are useful in diagnostic methods for diseases connected with TNKSs activity. The compounds may be used to treat diseases or conditions modulated by TNKSs such as cancer.

Abstract

L'invention concerne des composés de formule (I) : (I) et des sels, des solvates, des tautomères et des stéréoisomères de ceux-ci, les définitions des variables étant fournies dans la description. L'invention concerne également des compositions pharmaceutiques comprenant des composés de formule (I) ainsi que l'utilisation de tels composés en tant qu'inhibiteurs de tankyrase et pour le traitement de maladies telles que le cancer.
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US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors

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US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
WO2019084060A1 (fr) 2017-10-24 2019-05-02 Silverback Therapeutics, Inc. Conjugués et leurs procédés d'utilisation pour l'administration sélective d'agents immunomodulateurs
US10562891B2 (en) 2017-12-21 2020-02-18 Ribon Therapeutics Inc. Quinazolinones as PARP14 inhibitors
US11958837B2 (en) 2017-12-21 2024-04-16 Ribon Therapeutics, Inc. Quinazolinones as PARP14 inhibitors
US11008308B2 (en) 2017-12-21 2021-05-18 Ribon Therapeutics Inc. Quinazolinones as PARP14 inhibitors
US10751339B2 (en) 2018-01-20 2020-08-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
WO2021207135A1 (fr) * 2020-04-06 2021-10-14 The Regents Of The University Of California Composés et procédés pour induire l'expression d'ucp1
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
CN112375066B (zh) * 2020-09-30 2022-05-27 大连理工大学 一类含8-(苯甲酰基氨基)喹啉的1，8-萘酐类衍生物及其合成和应用
CN112375066A (zh) * 2020-09-30 2021-02-19 大连理工大学 一类含8-（苯甲酰基氨基）喹啉的1，8-萘酐类衍生物及其合成和应用
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors

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