WO2020030924A1 - Thiazole-urées en tant qu'agents anticancéreux - Google Patents

Thiazole-urées en tant qu'agents anticancéreux Download PDF

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Publication number
WO2020030924A1
WO2020030924A1 PCT/GB2019/052242 GB2019052242W WO2020030924A1 WO 2020030924 A1 WO2020030924 A1 WO 2020030924A1 GB 2019052242 W GB2019052242 W GB 2019052242W WO 2020030924 A1 WO2020030924 A1 WO 2020030924A1
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Prior art keywords
compound
alkyl
mmol
methyl
formula
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PCT/GB2019/052242
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English (en)
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WO2020030924A4 (fr
Inventor
Peter BLENCOWE
Mark Charles
Tennyson Ekwuru
Ellen Macdonald
Hollie MCCARRON
Laurent Rigoreau
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Artios Pharma Limited
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Publication of WO2020030924A4 publication Critical patent/WO2020030924A4/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • 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. PNAS 2013, 110 (19), 7720-7725).
  • R 1 represents Ci-e alkyl, halogen, haloCi- 6 alkyl, haloCi- 6 alkoxy, -S-haloCi- 6 alkyl, -Ci-e alkoxy, -X-C 3-8 cycloalkyl, -X-aryl, -X-heterocyclyl or -X-heteroaryl, wherein said cycloalkyl, heterocyclyl or heteroaryl groups of R 1 may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R 4 groups;
  • X represents a bond, -0-, -CH2-O- or -CH2-CH2-O-;
  • R 2 represents -(CH 2 ) 3 0H, heterocyclyl or heteroaryl, wherein said heterocyclyl or heteroaryl groups of R 2 may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R 5 groups;
  • R 5 represents Ci-e alkyl, halogen, haloCi- 6 alkyl, Ci-e alkoxy, oxo or Ci-e alkylamino;
  • R 3 represents Ci-e alkyl, halogen, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxy, Ci-e alkoxy, cyano or amino;
  • Ci- 6 alkoxy refers to a Ci- 6 alkyl group which contains one or more oxygen atoms wherein Ci- 6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy or propoxy.
  • haloCi- 6 alkoxy refers to a -O-C1 -6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term‘haloCi- 6 alkoxy’ therefore includes monohaloCi- 6 alkoxy, and also polyhaloCi- 6 alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi- 6 alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • C 3-8 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.
  • polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring examples include, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1 ,4]dioxine, benzo[1 ,3]dioxole, 4, 5, 6, 7- tetra hydro be nzofu ran, tetrahydrotriazolopyrazine (e.g.
  • heterocyclyl include morpholine, piperidine (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinone, pyrrolidine (e.g.
  • -C1 -6 alkoxy (such as ethoxy, propoxy, isopropoxy, methoxyethoxy, methoxypropoxy, n-butoxy, i-butoxy or s-butoxy);
  • -X-aryl such as -O-Chh-phenyl
  • cycloalkyl, heterocyclyl or heteroaryl groups of R 1 may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R 4 groups.
  • R 1 represents -X-heterocyclyl (such as oxetanyl, -O-Chh-oxetanyl, - 0-CH 2 -CH 2 -oxetanyl, dihydrofuranyl, -O-ChMetrahydrofuranyl, -O-CH2-CH2- tetrahydrofuranyl, -O-tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, -O-CH2- tetrahydropyranyl, -O-tetrahydropyranyl, pyrrolidinyl, -O-pyrrolidinyl, -O-Chh-pyrrolidinyl, -O- CH2-CH2-pyrrolidinyl, piperidinyl, -0-CH 2 -piperidinyl, morpholinyl, -O-CH2- oxabicyclo[2.2.1]heptanyl or
  • R 5 represents:
  • halogen such as fluorine or chlorine
  • halogen such as chlorine
  • the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-127 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.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • 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.
  • naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids is the hydrochloride salt.
  • 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.
  • inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid
  • organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-tolu
  • 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.
  • 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.
  • L 1 represents a suitable leaving group such as a halogen atom (e.g. chlorine), and a compound of formula R 2 -NH 2 , wherein R 2 is as defined herein;
  • Step (b) typically comprises reacting a compound of formula (XI) with a suitable base, such as lithium hydroxide, in the presence of suitable solvents, such as tetrahydrofuran and water, under suitable conditions, such as by heating.
  • a suitable base such as lithium hydroxide
  • 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- OCHaCeHs, -NH-Cbz or NH-Z); as a tert- butyl carbamate (-NHCOOC(CH 3 )3, NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OCCCHs ⁇ CekUCeHs, 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 ally
  • protecting groups for amines include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.
  • tosyl toluenesulfonyl
  • methanesulfonyl methanesulfonyl
  • benzyl groups such as a para-methoxybenzyl (PMB) group
  • TTP tetrahydropyranyl
  • 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 Ci- 7 haloalkyl ester (e.g. a C1-7 trihaloalkyl ester); a triCi-7 alkylsilyl-Ci-7 alkyl ester; or a C5-20 aryl-Ci- 7 alkyl ester (e.g. a benzyl ester; a
  • the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.
  • 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. In addition, the compounds of the invention may be useful in the treatment of diseases in which there is a disorder associated with cell accumulation.
  • the RoIQ 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 RoIq ⁇ may be given along with another DDR modulator such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a weel inhibitor or a CHK1 inhibitor.
  • the pharmaceutical composition of the present invention additionally comprises a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor.
  • the RoIQ 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 RoIQ. 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 RoIQ 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 Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.
  • 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.
  • said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV),
  • CMML myelomonocytic leukemia
  • hypereosinophilic syndrome 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,
  • 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 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), 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.
  • carriers e.g. a solid, liquid or semi-solid carrier
  • adjuvants e.g. a solid, liquid or semi-solid carrier
  • 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 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 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.
  • preservatives wetting agents, emulsifying agents, and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • 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.
  • 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 Gl tract.
  • the solid dosage forms can be coated or un-coated. 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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 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 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).
  • 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 g.
  • 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 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.
  • 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.
  • 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:
  • Topoisomerase I inhibitors for example camptothecin compounds, for example
  • camptothecin irinotecan(CPT11), SN-38, or topotecan;
  • Antimetabolites for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide);
  • 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
  • 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 I KB kinase inhibitor such as SAR- 113945, bar
  • dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621 , BMS- 387032 (a.k.a. SNS-032), PHA533533, PD332991 , ZK-304709, or AZD-5438;
  • 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. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024
  • 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;
  • Hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (a.k.a. diethylstilboestrol) or octreotide;
  • CYP17 Steroidal cytochrome P450 17alpha-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, chlamy
  • HDAC
  • interleukins e.g. interleukin 2
  • interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b;
  • Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;
  • Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or
  • DNA damage response inhibitors such as ATM inhibitors AZD0156 MS3541 , ATR
  • inhibitors AZD6738, M4344, M6620 wee1 inhibitor AZD1775;
  • Agonists of Death receptor e.g. TNF-related apoptosis inducing ligand (TRAIL) receptor
  • TRAIL TNF-related apoptosis inducing ligand
  • mapatumumab previously HGS-ETR1
  • conatumumab formerly 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,
  • hormones in patients with acromegaly or other rare hormone-producing tumours, such as synthetic forms of the hormone somatostatin e.g. octreotide acetate,
  • NSAID non-steroidal anti-inflammatory drugs
  • COX-2 inhibitors for example celecoxib, etoricoxib and lumiracoxib
  • agents for mucositis e.g. palifermin
  • agents for the treatment of side-effects including anorexia, cachexia, oedema or thromoembolic episodes, such as megestrol acetate.
  • 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 m/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,
  • GSK121 120212 in particular Raf inhibitors (e.g. vemurafenib) or MEK inhibitors (e.g.
  • 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 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 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
  • doxorubicin in a dosage of about 40 to 75 mg/m 2
  • daunorubicin in a dosage of about 25 to 45mg/m 2
  • idarubicin in a dosage of about 10 to 15 mg/m 2 per course of treatment.
  • Anastrozole is advantageously administered orally in a dosage of about 1mg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20-1 OOmg 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 g 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 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.
  • they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.
  • 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.
  • 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.
  • 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.
  • radiosensitizer is defined as a molecule administered to patients in
  • therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics.
  • the compound of the invention is administered with a "radiosensitizer” and/or“chemosensitizer”. In one embodiment the compound of the invention is
  • radiosensitizer is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to a RoIQ 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, E09, RB 6145, nicotinamide, 5- bromodeoxyuridine (BUdR), 5- iododeoxyuridine (ILIdR), bromodeoxycytidine,
  • 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;
  • 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. BCG).
  • immune checkpoint antibodies e.g. CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD
  • 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 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.
  • other therapeutic agents e.g. anticancer agents
  • 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.
  • Step b A solution of methanolic HCI was prepared by dissolving acetyl chloride (0.03 ml_,
  • Step c A solution of 2-[4-(trifluoromethyl)phenyl]thiazol-4-amine (86 mg, 0.35 mmol) in DCM (4 ml_) was treated with 3-isocyanatopyridine (64 mg, 0.53 mmol). The suspension was stirred at rt overnight. The suspension was diluted with MeOH and the resultant solution evaporated. The crude product was dissolved in DMSO and purified by mass-directed prep HPLC. Fractions were absorbed onto a 1g SCX-2 cartridge, washing with MeOH. The product was eluted with 2M methanolic ammonia.
  • Step a A solution of 2-[4-(trifluoromethyl)phenyl]thiazol-4-amine (prepared as described for Example 1 , steps a, b; 50 mg, 0.205 mmol) and 4-nitrophenyl chloroformate (43 mg, 0.215 mmol) in DCM (3.5 ml_) was stirred at rt for 30 min. A solution of 4-aminopyridine (38 mg, 0.409 mmol) and TEA (0.09 ml_, 0.61 mmol) in DCM (1 ml_) was added and the resulting reaction mixture stirred for 16 h at rt.
  • Step a A mixture of tert-butyl (2-bromothiazol-4-yl)carbamate (1.75 g, 6.27 mmol), 4-bromo- 3-methoxyphenylboronic acid (1.59 g, 6.90 mmol), Pd(PPh3)4 (0.35 g, 0.31 mmol) and K 2 CO 3 (2.6 g, 18.8 mmol) in 1 ,4-dioxane (42 ml_) and water (14 mL) was heated to 90°C for 2 h. The temperature was lowered to 70°C and the reaction was stirred overnight.
  • the reaction mixture was diluted with EtOAc (250 mL), washed with water (2 x 250 mL), dried and evaporated.
  • the crude product was purified using column chromatography, eluting with 0-20% EtOAc / cyclohexane.
  • Step b A mixture of tert-butyl N-[2-(4-bromo-3-methoxy-phenyl)thiazol-4-yl]carbamate (1.82 g, 4.72 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (1.09 g, 5.19 mmol), K2CO3 (1.96 g, 14.1 mmol) and Pd(PPh3) 4 (0.26 g, 0.24 mmol) in 1 ,4-dioxane (42 mL) and water (14 mL) was heated at 100°C for 3 h. The reaction mixture was diluted with EtOAc (250 mL), washed with water (250 mL) and brine (250 mL), dried and
  • Step c To a solution of tert-butyl N-[2-[4-(3,6-dihydro-2H-pyran-4-yl)-3-methoxy-phenyl]- thiazol-4-yl]carbamate (1.12 g, 2.88 mmol) in MeOH (50ml_) was added acetyl chloride (4.1 ml_, 58 mmol) dropwise at 0°C. The reaction mixture was warmed to rt and stirred for 40 h.
  • the title compounds were prepared as a racemic mixture in a similar manner to Example 10, using (3,4)-cis-tert-butyl 3-amino-4-fluoropiperidine-1-carboxylate (CAS 1273565-65-3) in step d.
  • the mixture of enantiomers were separated by chiral SFC using the following conditions: Lux C3 (21.2mm x 250mm, 5um); column temperature 40°C; flow rate 50 mL/min; detector wavelength 215 nm; isocratic gradient 50:50 MeOH:CC>2 (0.1% v/v NH3).
  • Step a A mixture of 2-bromothiazole-4-carboxylic acid (4.0 g, 19.2 mmol), DPPA (6.2 ml_, 29 mmol) and TEA (4.0 ml_, 29 mmol) in toluene (80 ml_) was heated at reflux for 45 min. The colourless mixture turned brown with strong evolution of gas which ceased after a few minutes to give a refluxing black solution. The mixture was cooled and treated with (S)-tert- butyl 3-aminopiperidine-carboxylate (CAS 625471-18-3; 3.85 g, 19.2 mmol) and the mixture heated at reflux.
  • S S-tert- butyl 3-aminopiperidine-carboxylate
  • Step c To tert-butyl (3S)-3-[[2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazol-4-yl]carbamoyl- amino]piperidine-1-carboxylate (0.06 g, 0.123 mmol) in DCM (10 ml_) was added TFA (1.5 ml_, 0.12 mmol) and the mixture stirred at rt overnight. The reaction mixture was evaporated and the resultant gum was purified by preparatory LCMS. A solution of the product in MeOH (3 ml_) was loaded onto an SCX-2 cartridge and washed with MeOH (10 ml_).
  • Steps b, c A solution tert-butyl (3S)-3-[[2-(4-bromo-3-methoxy-phenyl)thiazol-4-yl]- carbamoyl-amino]piperidine-1-carboxylate (120 mg, 0.235 mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (54 mg, 0.258 mmol), K2CO3 (97 mg, 0.70 mmol) and Pd(PPh3) 4 (13 mg, 0.012 mmol) in 1,4-dioxane (3 ml_) and water (1 mL) was heated in the microwave at 100°C for 30 min.
  • Step a A mixture tert-butyl (3S)-3-[(2-bromothiazol-4-yl)carbamoylamino]piperidine-1- carboxylate (prepared as described for Example 15, step a; 1.2 g, 2.96 mmol), 4-bromo-3- chloro-phenylboronic acid (0.7 g, 2.961 mmol), Pd(PPh 3 ) 2 Cl 2 (0.1 g, 0.148 mmol), K 2 CO 3 (1.23 g, 8.88 mmol) in 1 ,4-dioxane (6 ml_) and water (2 ml_) was heated at reflux for 3 h.
  • Steps b, c A mixture of tert-butyl (3S)-3-[[2-(4-bromo-3-chloro-phenyl)thiazol-4-yl]- carbamoylamino]piperidine-1-carboxylate (0.1 g, 0.194 mmol), 3,6-dihydro-2H-pyran-4- ylboronic acid (CAS 1002127-60-7; 0.02 g, 0.194 mmol), Pd(PPh 3 ) 2 CI 2 (0.01 g, 0.01 mmol), K2CO3 (0.08 g, 0.58 mmol) in 1 ,4-dioxane (6 ml_) and water (2 ml_) was heated in the microwave at 130°C for 30 min.
  • Step a A mixture of Example 44 (1 15 mg, 0.277 mmol), 1-fluoro-2-iodo-ethane (0.03 ml_, 0.42 mmol) and K2CO3 (1 15 mg, 0.832 mmol) in DMF (2 ml_) was heated at 65°C for 3 h. Further 1-fluoro-2-iodoethane (0.75 equiv) was added and the mixture heated for an additional 16 h. The mixture was evaporated and partitioned between EtOAc and water. The organic extract was dried and evaporated to give a crude yellow oil, which was purified by preparative LCMS.
  • the title compound was prepared in a similar manner to Example 54, using 1 , 1 -difluoro-2- iodoethane.
  • Step a A mixture tert-butyl (3S)-3-[[2-(4-bromo-3-methoxy-phenyl)thiazol-4-yl]carbamoyl- amino]piperidine-1-carboxylate (prepared as described for Example 44, step a; 20 mg,
  • Step a A mixture of tert-butyl (3S)-3-[(2-bromothiazol-4-yl)carbamoylamino]piperidine-1- carboxylate (prepared as described for Example 15, step a; 0.28 g, 0.69 mmol), 4-hydroxy- 3-methylbenzeneboronic acid (0.12 g, 0.76 mmol), Pd(PPh3)4 (0.04 g, 0.035 mmol) and K2CO 3 (0.29 g, 2.07 mmol) in 1 ,4-dioxane (3 ml_) and water (1 ml_) was heated at 90°C in the microwave for 30 min. The reaction mixture was diluted with EtOAc (50ml_), washed with water (2x 50 ml_) and evaporated. The crude product was purified using column
  • Step b To a stirring solution of tert-butyl (3S)-3-[[2-(4-hydroxy-3-methyl-phenyl)thiazol-4- yl]carbamoylamino]piperidine-1-carboxylate (0.1 g, 0.23 mmol) in MeCN (5 ml_) was added 3-(iodomethyl)oxetane (0.07 ml_, 0.69 mmol) and K2CO 3 (0.1 g, 0.69 mmol) and the reaction mixture was heated to reflux for 20 h. The reaction was cooled and diluted with EtOAc (50 ml_), washed with water (2x 50 ml_), dried and evaporated to give 137 mg of crude material.
  • 3-(iodomethyl)oxetane (0.07 ml_, 0.69 mmol)
  • K2CO 3 0.1 g, 0.69 mmol
  • Step a A mixture of 2-bromothiazole-4-carboxylic acid (2.02 g, 9.69 mmol) and (S)-1- methyl-piperidin-3-ylamine dihydrochloride (1.81 g, 9.69 mmol) in toluene (35 ml_) was treated with DPPA (2.1 ml_, 9.7 mmol) and TEA (4.7 ml_, 34 mmol) and heated to reflux for 1 h. The mixture was diluted with EtOAc, washed with water (x2) and brine, dried and evaporated. The resultant brown oil was purified by column chromatography, eluting with a gradient of 0 - 10% MeOH/DCM. Fractions were combined and evaporated to give 1-(2- bromothiazol-4-yl)-3-[(3S)-1-methyl-3-piperidyl]urea, (0.612 g, 20%).
  • Step b A mixture of 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (2.04 g, 8.72 mmol), 1-(2-bromothiazol-4-yl)-3-[(3S)-1-methyl-3-piperidyl]urea (2.53 g, 7.93 mmol) and K2CO3 (3.29 g, 23.8 mmol) in 1 ,4-dioxane (30 ml_) and water (10 ml_) was degassed with nitrogen bubbling for 5 min.
  • the reaction mixture was treated with Pd(PPh 3 )4 (0.46 g, 0.396 mmol) and degassed for a further 5 min before heating to reflux for 3 h.
  • the mixture was diluted with EtOAc (300 ml_), washed with water (100 ml_) and brine (100 ml_).
  • the aqueous was extracted with EtOAc (2 x 100 ml_) and the combined organic extracts were dried and evaporated.
  • the crude brown oil was loaded onto an SCX-2 cartridge (25 g) in MeOH and then washed with further MeOH (150 ml_).
  • Step c A mixture of 1-[2-(4-hydroxy-3-methyl-phenyl)thiazol-4-yl]-3-[(3S)-1-methyl-3- piperidyl]urea (0.12 g, 0.35 mmol), 1-bromo-2-methylpropane (0.04 ml_, 0.35 mmol), Kl (0.06 g, 0.35 mmol) and K 2 CO 3 (0.05 g, 0.35 mmol) in DMF (10 ml_) was heated at reflux for 2 days. The reaction mixture was evaporated, re-dissolved in DCM and washed with water.
  • Example 92 1 -(2-(4-(((S)-1 -Acryloylpyrrolidin-3-yl)methoxy)-3-methylphenyl)thiazol-4- yl)-3-((S)-1-methylpiperidin-3-yl)urea
  • the aqueous was extracted into EtOAc (x2) and the combined organic extracts were washed with brine, dried and evaporated.
  • the crude was purified by prep LCMS and the relevant fractions were loaded onto an SCX-2 cartridge and eluted with MeOH followed by 2M methanolic ammonia and the basic fractions were reduced to give a pale-yellow solid.
  • Step b To a solution of 1-[(3S)-1-methyl-3-piperidyl]-3-[2-[3-methyl-4-[[(3S)-pyrrolidin-3- yl]methoxy]phenyl]thiazol-4-yl]urea dihydrochloride (70 mg, 0.139 mmol) and TEA (0.39 ml_, 2.79 mmol) in DCM (3 ml_) was added acryloyl chloride (0.01 ml_, 0.064 mmol) and the mixture stirred for 30 min. Further acryloyl chloride (0.01 ml_, 0.064 mmol) was added and the mixture stirred for a total of 2 h.
  • Example 93 1 -(2-(4-(((R)-1 -Acryloylpyrrolidin-3-yl)methoxy)-3-methylphenyl)thiazol-4- yl)-3-((S)-1-methylpiperidin-3-yl)urea
  • Example 94 1 -(2-(3-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)thiazol-4-yl)-3-(6- methylpyridin-3-yl)urea
  • Step a A mixture of DPPA (6.64 g, 24.0 mmol), TEA (5.0 ml_, 36 mmol), 5-amino-2-methyl- pyridine (2.6 g, 24 mmol) and 2-bromothiazole-4-carboxylic acid (5.0 g, 24 mmol) in toluene (50ml_) was heated at reflux for 2 h. The reaction mixture was evaporated and purified by column chromatography using cyclohexane/EtOAc as eluent to give 1-(2-bromothiazol-4-yl)- 3-(6-methyl-3-pyridyl)urea, (2.68 g, 35%) as a powder
  • Step b A mixture of 1-(2-bromothiazol-4-yl)-3-(6-methyl-3-pyridyl)urea (0.5 g, 1.6 mmol), K2CO 3 (0.66 g, 4.79 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (0.37 g, 1.6 mmol), Pd(PPh3)2Cl2 (0.06 g, 0.08 mmol) in 1 ,4-dioxane (12 ml_) and water (3 ml_) was heated with microwave irradiation at 130°C for 30 min.
  • Step c To a stirring solution of 3-bromomethyl-3-methyloxetane (0.12 ml_, 0.95 mmol) in MeCN (6ml_) was added K2CO 3 (0.13 g, 0.95 mmol) and 1-[2-(4-hydroxy-3-methyl-phenyl)- thiazol-4-yl]-3-(6-methyl-3-pyridyl)urea (0.11 g, 0.317 mmol) and the reaction mixture was heated to reflux for 4 h. A white solid was removed by filtration and the filtrates were evaporated and purified by column chromatography eluting with a gradient of 0-10%
  • Example 44 The title compound was prepared in a similar manner to Example 44, using 1-(2- bromothiazol-4-yl)-3-(6-methyl-3-pyridyl)urea (prepared as described for Example 94, step a) in step a.
  • Example 96 1 -(2-(3-Methyl-4-(((re/-3S,4S)-4-methyltetrahydrofuran-3-yl)oxy)phenyl)- thiazol-4-yl)-3-((S)-piperidin-3-yl)urea Cis Racemate
  • Step a A solution of tert-butyl (3S)-3-[[2-(4-hydroxy-3-methyl-phenyl)thiazol-4-yl]- carbamoylamino]piperidine-1-carboxylate (prepared as described for Example 58, step a; 0.15 g, 0.347 mmol), trans-4-methyltetrahydrofuran-3-ol (0.04 g, 0.416 mmol), DIAD (0.10 ml_, 0.52 mmol) and triphenylphosphine (0.14 g, 0.52 mmol) in THF (2ml_) was stirred for 18 hours at rt.
  • Example 98 1 -(2-(4-(((R)-1 -Acetylpyrrolidin-3-yl)oxy)-3-methylphenyl)thiazol-4-yl)-3- ((S)-piperidin-3-yl)urea
  • Example 99 1 -(2-(3-Methyl-4-(2-(3-methyloxetan-3-yl)ethoxy)phenyl)thiazol-4-yl)-3-(1 - methylpiperidin-3-yl)urea
  • Step a To a mixture of (4-fluoro-3-nitro-phenyl)boronic acid (0.2 g, 1.08 mmol) and 2,6- dimethylmorpholine (0.29 ml_, 2.16 mmol) in MeOH (10 ml_) was added TEA (0.6 ml_, 4.33 mmol) and the mixture was heated at reflux for 5 days. The reaction mixture was evaporated to give [4-(2,6-dimethylmorpholin-4-yl)-3-nitro-phenyl]boronic acid as a red gum which was used in the next step of the reaction sequence without further purification
  • Step b A mixture of [4-(2,6-dimethylmorpholin-4-yl)-3-nitro-phenyl]boronic acid (0.3 g, 1.06 mmol), K 2 C0 3 (0.44 g, 3.18 mmol), Pd(PPh 3 )2Cl2 (0.04 g, 0.053 mmol), tert-butyl (3S)-3-[(2- bromothiazol-4-yl)carbamoylamino]piperidine-1-carboxylate (prepared as described for Example 15, step a; 0.43 g, 1.06 mmol) in 1 ,4-dioxane (15 ml_) and water (5 mL) was heated with microwave radiation at 130°C for 30 min.
  • reaction mixture was evaporated, treated with water and 0.5M HCI and extracted into DCM.
  • organic extract was evaporated and purified by column chromatography using cyclohexane/EtOAc as eluent to give tert-butyl (3S)-3-[[2-[4-(2,6-dimethylmorpholin-4-yl)-3-nitro-phenyl]thiazol-4-yl]- carbamoylamino]piperidine-1-carboxylate, (0.52 g, 87%) as a red powder after evaporation m/z ES+ [M+H]+ 561.
  • the cartridge was eluted with MeOH (60 ml_) and then the amine was liberated by eluting with 2M methanolic ammonia (40 ml_) to provide tert-butyl (3S)-3-[[2-[3-amino-4- (2,6-dimethylmorpholin-4-yl)phenyl]thiazol-4-yl]carbamoylamino]piperidine-1-carboxylate (0.40 g, 81 %) as a brown powder after evaporation.
  • Step d A mixture of tert-butyl (3S)-3-[[2-[3-amino-4-(2,6-dimethylmorpholin-4-yl)phenyl]- thiazol-4-yl]carbamoylamino]piperidine-1-carboxylate (100 mg, 0.188 mmol) and cone HCI (4.0 ml_, 0.19 mmol) and the mixture was cooled to 0°C. Sodium nitrite was added and the reaction mixture was stirred at 0°C for 20 min.
  • the title compound was prepared in a similar manner to Example 100, using 4- (hydroxymethyl)piperidine (CAS 6457-49-4) in step a.
  • the title compound was prepared in a similar manner to Example 100, using 2,2- dimethylmorpholine (CAS 147688-58-2) in step a.
  • Step b A mixture of 2-(4-bromo-3-ethyl-phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (40 mg, 0.13 mmol), tert-butyl (3S)-3-[(2-bromothiazol-4-yl)carbamoylamino]piperidine-1- carboxylate (prepared as described for Example 15, steps a; 0.05 g, 0.13 mmol), Pd(PPh3)4 (0.01 g, 0.006 mmol) and K 2 CO 3 (0.05 g, 0.39 mmol) in 1 ,4-dioxane (3 ml_) / water (1 ml_) was heated in the microwave at 100°C for 0.5 h.
  • Step c A mixture of tert-butyl (3S)-3-[[2-(4-bromo-3-ethyl-phenyl)thiazol-4-yl]- carbamoylamino]piperidine-1-carboxylate (86 mg, 0.169 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (46 mg, 0.219 mmol), Pd(PPh3)4 (9 mg, 0.008 mmol) and K2CO3 (70 mg, 0.506 mmol) in 1 ,4-dioxane (3 ml_) / water (1 ml_) was heated in the microwave at 100°C for 0.5 h.
  • Step a A mixture of methyl 2-bromothiazole-4-carboxylate (2.0 g, 9.0 mmol, 4-bromo-3- methoxyphenylboronic acid (2.5 g, 10.8 mmol), K2CO 3 (3.73 g, 27.02 mmol) and Pd(PPh3)4 (0.5 g, 0.45 mmol) in 1 ,4-dioxane (24 ml_) and water (8 ml_) was heated to reflux for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried and evaporated.
  • Step b A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (1.0 g, 4.75 mmol), methyl 2-(4-bromo-3-methoxy-phenyl)thiazole-4-carboxylate (1.3 g, 3.96 mmol), Pd(PPh3) 4 (0.22 g, 0.20 mmol) and K2CO 3 (1.64 g, 1 1.9 mmol) in 1 ,4-dioxane (12 ml_) and water (4 ml_) was heated at reflux for 90 min.
  • the first aqueous extract was acidified with 2M HCI and further extracted with EtOAc (x2). The organics were washed with brine, dried and evaporated to give 2-[4-(3,6-dihydro-2H- pyran-4-yl)-3-methoxy-phenyl]thiazole-4-carboxylic acid, (0.130 g, 10%) as a yellow oily solid, which was used without further purification.
  • Step c A mixture of 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3-methoxy-phenyl]thiazole-4-carboxylic acid (0.89 g, 2.80 mmol), DPPA (0.73 ml_, 3.36 mmol) and TEA (0.59 ml_, 4.21 mmol) in toluene (28 ml_) was stirred for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried and evaporated.
  • Example 7 Examples in Table 7 were made in a similar manner to Example 105. Examples 111, 112 and 113 were made from the corresponding BOC protected amines, with a BOC
  • Example 112 was prepared as a racemate and the enantiomers separated by chiral preparatory LCMS. Column details: Lux C4 (21.2mm x 250mm, 5um), Flow rate: 21 mL/min, Detector wavelength: 217 nm, Injection volume: 400 uL (4 mg), Isocratic conditions: 40:60 heptane:EtOH. Example 112 was iolstaed as the first eluting isomer.
  • Step a A solution of 4-fluoro-3-methylbenzonitrile (0.13 g, 0.95 mmol), (3-methyloxolan-3- yl)methanol (0.1 g, 0.86 mmol) and CS2CO3 (0.31 g, 0.95 mmol) in DMF (5 ml_) was stirred at 100°C for 16 h. The reaction mixture was diluted with water (25 ml_) and extracted into EtOAc (25 ml_). The aqueous layer was acidified to pH 2 with 2M HCI, and further extracted with EtOAc (2 x 25 ml_).
  • Step b A solution of 3-methyl-4-[(3-methyltetrahydrofuran-3-yl)methoxy]benzonitrile (0.68 g, 2.92 mmol) and diammonium sulfide, 40-48 wt% in water (0.44 ml_, 6.42 mmol) and MeOH
  • Step d Lithium hydroxide (0.18 g, 4.32 mmol) was added to ethyl 2-[3-methyl-4-[(3-methyl- tetrahydrofuran-3-yl)methoxy]phenyl]thiazole-4-carboxylate (0.52 mg, 1.44 mmol) in THF (20 mL) and water (5 mL) and stirred for 2 h. The reaction mixture was evaporated, partitioned between EtOAc and water and acidified with 2M aq HCI. The layers were separated and the aqueous further extracted with EtOAc.
  • Example 116 1 -(2-(3-Methyl-4-((-3-methyltetrahydrofuran-3-yl)methoxy)phenyl)thiazol- 4-yl)-3-((S)-1-methylpiperidin-3-yl)urea isomer 1
  • Step a A mixture of Example 114 (76 mg, 0.18 mmol) and paraformaldehyde aqueous solution (0.66 ml_, 0.88 mmol) in THF (4 ml_) and MeOH (0.2 ml_) was treated with acetic acid (0.01 ml_, 0.18 mmol) and stirred for 10 min. The reaction mixture was treated with then sodium triacetoxyborohydride (63 mg, 0.88 mmol) and stirred for 2 h. The mixture was quenched with saturated aqueous NaHCC>3 and water and extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried and evaporated to give a yellow solid. The mixture was loaded onto SCX-2 in MeOH and eluted with MeOH followed by 2M methanolic ammonia and the basic fractions were reduced. The resultant solid was further dried under vacuum to give Example 116, (50 mg, 64%).
  • Example 117 was prepared from Example 115 as described above
  • Example 118 The title compound was prepared in a similar manner to Example 116/117, using Example 118.
  • Step a An oven-dried flask was charged with 3-bromo-tetrahydropyran (0.33 ml_, 2.95 mmol), nickel(ll) chloride ethylene glycol dimethyl ether complex (15 mg, 0.07 mmol), 1 , 10- phenanthroline (25 mg, 0.14 mmol), sodium tetrafluoroborate (154 mg, 1.40 mmol) and manganese (310 mg, 5.61 mmol). The flask was sealed, evacuated and refilled with nitrogen 3 times. MeOH (25 ml_) and 4-bromo-3-methylbenzonitrile (0.55 g, 2.81 mmol) were added and the reaction was heated at 80°C for 18 h.
  • Step b A solution of 3-methyl-4-tetrahydropyran-3-yl-benzonitrile (0.33 g, 1.65 mmol) and diammonium sulfide, 40-48 wt% in water (0.25 ml_, 3.63 mmol) in MeOH (10ml_) was heated to 130°C in the microwave for 30 min. Further diammonium sulfide, 40-48 wt% in water (0.25 ml_, 3.63 mmol) was added and the mixture was heated to 130°C in the microwave for a further 20 min. The mixture was evaporated, then partitioned between EtOAc and water. The aqueous layer was collected and further extracted with EtOAc. The combined organic extracts were washed with brine, dried and evaporated to give crude 3-methyl-4- tetrahydropyran-3-yl-benzenecarbothioamide, (0.188 g, 48%).
  • Step c A solution of ethyl bromopyruvate (0.1 ml_, 0.80 mmol) and 3-methyl-4- tetrahydropyran-3-yl-benzenecarbothioamide (0.19 g, 0.80 mmol) in EtOH (5 ml_) was heated in the microwave at 130°C for 30 min. The reaction mixture was purified by column chromatography, eluting with EtOAc / cyclohexane 0-70%. The desired fractions were combined and evaporated to give the ester intermediate as a yellow oil. A solution of the intermediate in EtOH (10 ml_) was treated with lithium hydroxide monohydrate (0.1 g, 2.40 mmol) and stirred overnight.
  • Step d To 2-(3-methyl-4-tetrahydropyran-3-yl-phenyl)thiazole-4-carboxylic acid (0.04 g, 0.142 mmol) in dry toluene (10 mL) was added TEA (0.03 mL, 0.213 mmol) and DPPA (0.04 mL, 0.17 mmol) and heated to reflux for 10 min. The mixture was removed from the heat and treated with a solution of (S)-(+)-3-amino-1-Boc-piperidine (0.03 g, 0.142 mmol) in toluene (2 mL) at a temperature between 90°C and 100°C. The mixture was heated at reflux for a further 1.5 h.
  • the title compound was prepared in a similar manner to Example 120, using 4-bromo- tetrahydropyran (CAS 25637-16-5) in step a.
  • Example 122 1-(2-(3-Chloro-4-(4-ethoxypiperidin-1-yl)phenyl)thiazol-4-yl)-3-(6- methylpyridin-3-yl)urea
  • Step a To a suspension of 4-bromo-3-chloro-benzonitrile (0.5 g, 2.31 mmol) and K 2 CO 3 (0.32 g, 2.31 mmol) in dry DMF (10ml_) was added 4-ethoxy-piperidine (0.41 ml_, 2.31 mmol) and the mixture was stirred at 100°C overnight under a nitrogen atmosphere. The solvent was evaporated and the resultant gum was dissolved in DCM and washed with water, dried and evaporated to give crude 3-chloro-4-(4-ethoxy-1-piperidyl)-benzonitrile, (0.55 g, 89%).
  • Step b To a mixture of 3-chloro-4-(4-ethoxy-1-piperidyl)benzonitrile (0.55 g, 2.08 mmol) and TEA (1.0 ml_, 7.2 mmol) in pyridine (10 mL) was added diammonium sulfide (1.0 ml_, 15 mmol). The mixture was stirred at 110°C for 2 h. The reaction mixture was treated with additional diammonium sulphide (0.5 mL) and TEA (0.5 mL) and stirred overnight at 50°C. The dark reaction mixture was poured into 2M HCI solution (40 mL) and extracted into DCM. The organic extract was evaporated to give 3-chloro-4-(4-ethoxy-1-piperidyl)-benzene- carbothioamide, (0.50 g, 80%) as a yellow/brown gum.
  • Step c To a suspension of 3-chloro-4-(4-ethoxy-1-piperidyl)benzenecarbothioamide (0.5 g, 1.67 mmol) in EtOH (15 mL) was added ethyl bromopyruvate (0.21 mL, 1.67 mmol) and the mixture was heated at reflux overnight. The reaction mixture was evaporated and the crude oil was purified by column chromatography using cyclohexane/EtOAc to give ethyl 2-[3- chloro-4-(4-ethoxy-1-piperidyl)phenyl]thiazole-4-carboxylate, (0.26 g, 40%).
  • Step d A mixture of ethyl 2-[3-chloro-4-(4-ethoxy-1-piperidyl)phenyl]thiazole-4-carboxylate (0.27 g, 0.68 mmol) and lithium hydroxide hydrate (0.06 g, 1.35 mmol) in ethanol (10 ml_) and water (3 ml_) was stirred at rt for 2 h. The reaction mixture was evaporated and re dissolved in water (20 ml_) to give a brown solution which was acidified by the dropwise addition of 2M HCI.
  • Step e A mixture of DPPA (0.1 g, 0.35 mmol), 2-[3-chloro-4-(4-ethoxy-1-piperidyl)phenyl]- thiazole-4-carboxylic acid (0.13 g, 0.35 mmol), 5-amino-2-methylpyridine (0.04 g, 0.35 mmol) and TEA (0.07 ml_, 0.53 mmol) in toluene (10 ml_) was heated at reflux overnight.
  • reaction mixture was evaporated and purified by column chromatography using cyclohexane / EtOAc as eluent to give 1-[2-[3-chloro-4-(4-ethoxy-1-piperidyl)phenyl]thiazol-4-yl]-3-(6- methyl-3-pyridyl)urea, (0.048 g, 28%).
  • Example 123 1 -(2-(3-Chloro-4-(4-methylpiperidin-1 -yl)phenyl)thiazol-4-yl)-3-(6- methylpyridin-3-yl)urea
  • Step b A mixture of 2-(4-bromophenyl)thiazole-4-carboxylic acid (0.3 g, 1.06 mmol), DPPA (0.34 ml_, 1.58 mmol) and TEA (0.22 ml_, 1.58 mmol) in toluene (10ml_) was heated at reflux for 10 min. The reaction mixture was treated with (S)-(+)-3-amino-1-Boc-piperidine (0.21 g, 1.06 mmol) and heated to reflux for 1 h. The mixture was cooled and partitioned between EtOAc (50 ml_) and water (50 ml_).
  • Step c A mixture of tert-butyl (3S)-3-[[2-(4-bromophenyl)thiazol-4-yl]carbamoylamino]- piperidine-1-carboxylate (0.1 g, 0.21 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyran (0.04 g, 0.21 mmol), Pd(dppf)Cl2 (0.01 g, 0.01 mmol) and K2CO3 (0.09 g, 0.62 mmol) in 1 ,4-dioxane (3 ml_) and water (1 ml_) was heated at reflux for 3 h.
  • Step d A solution of tert-butyl (3S)-3-[[2-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]thiazol-4- yl]carbamoylamino]piperidine-1-carboxylate (0.030 g, 0.06 mmol) in DCM (10 ml_) and TFA (1.5 ml_, 0.12 mmol) was stirred at rt for 4 h. The reaction mixture was evaporated and the resultant gum was dissolved in MeOH (3ml) and passed through an SCX-2 1 G/ML cartridge followed by 10ml of MeOH. The product was released from the cartridge by passing 2M methanolic ammonia.
  • reaction mixture was diluted with EtOAc (20 ml_), washed with water (2x 20 ml_) and evaporated.
  • the crude intermediate was dissolved in DCM (2 ml_), treated with TFA (0.84 ml_, 1.68 mmol) and stirred overnight at rt.
  • the reaction mixture was evaporated and purified by preparatory LCMS (12 min method, 500 pl_ injections). The flow rate was 25 mL/min and the mobile phases of water and MeCN contained 0.1 % formic acid. The elution was started at 95% water:5% MeCN ramping up to 5% water:95% MeCN over 10 minutes. Fractions were adsorbed onto an SCX-2 cartridge and eluted with 2M methanolic ammonia.
  • PicoGreen assay was used to measure the ability of compounds to inhibit the activity of RoIQ in vitro.
  • N-His, C-term FLAG tagged RoIQ protein (amino acids 2-2590) expressed in baculovirus was purified and stored at -80°C in aliquots.
  • Assay measurements were performed with 1X buffer comprising 25 mM Tris HCI pH 7.5, 12.5 mM NaCI, 0.5 mM MgCI2, 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1 mM DTT.
  • Test compounds were prepared by dilution in 100% DMSO to give the correct dose range for 12 point concentration response and appropriate volume (60 nL) dispensed into 384 well micro assay plates (Perkin Elmer low volume black ProxiPlates product code 6008269) using a Labcyte Echo 550 acoustic dispenser. DMSO concentration was maintained at 1 % by back filling with DMSO solution.

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Abstract

L'invention concerne des dérivés hétérocycliques d'urée et leur utilisation dans le traitement et la prophylaxie du cancer, ainsi que des compositions contenant lesdits dérivés et des procédés pour leur préparation.
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WO2022167817A1 (fr) * 2021-02-07 2022-08-11 Artios Pharma Limited Nouveau procédé

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