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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to imidazopyridine compounds which inhibit members of the aurora kinase family of enzymes and to their use in the treatment of cell proliferative diseases, including cancer, and inflammation.
• DNA is packaged with histones, to form chromatin.
• chromatin Approximately 150 base pairs of DNA are wrapped twice around an octamer of histones (two each of histones 2A, 2B, 3 and 4) to form a nucleosome, the basic unit of chromatin.
• the ordered structure of chromatin needs to be modified in order to allow transcription of the associated genes. Transcriptional regulation is key to differentiation, proliferation and apoptosis, and is, therefore, tightly controlled. Control of the changes in chromatin structure (and hence of transcription) is mediated by covalent modifications to histones, most notably of the N-terminal tails.
• Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
• Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
• Covalent modifications of the side chains of amino acids are enzymatically mediated
• a review of the covalent modifications of histones and their role in transcriptional regulation can be found in Berger SL 2001 Oncogene 20, 3007-3013; See Grunstein, M 1997 Nature 389, 349-352; Wolffe AP 1996 Science 272, 371-372; and Wade PA et al 1997 Trends Biochem Sci 22, 128-132 for reviews of histone acetylation and transcription).
• the aurora kinases are a family of serine/threonine kinases which have been identified as key regulators of the mitotic cell division process (Bischoff and Plowman, 1999 Trends Cell Biol 9, 454-459) which may become deregulated in cancer and other hyperproliferative diseases (Warner et al, 2003, MoI Can Ther 2, 589-595).
• the three members of this family identified so far are referred to as Aurora- A, Aurora-B and Aurora-C.
• Higher eukaryotic cells typically express two or more Aurora kinases. It has been shown that inhibition of Aurora B affects several facets of mitosis including histone H3 phosphorylation, chromosome segregation and cytokinesis.
• Aurora A and C localise to spindle poles with Aurora A being required for bipolar spindle formation in a number of systems (Giet and Prigent, 1999, J. Cell. Sci 11 , 3591-3601).
• Aurora A and B have been shown to be overexpressed in a number of human cancers and their overexpression in cells in vitro leads to transformation, centrosome abnormalities and aneuploidy (Bischoff et al, 1998, EMBO J. 17, 3052).
• Cells which overexpress Aurora A have been shown to form tumours in aythymic mice.
• the observations contained in these manuscripts suggest that increase in Aurora kinase activity may serve to promote tumour development by providing growth advantage or by inducing genetic instability and that Aurora Kinase inhibition should have therapeutic benefit in cancer.
• aurora kinase inhibitors see for example WO 02/00649, WO 2004/000833, WO 03/055491, WO 2004/058752, WO 2004/058781 , WO 04105765, WO 05004872, WO 04113324, US 6143764 and US 2004/0049032, but the foregoing is by no means an exhaustive list.
• This invention makes available another class of aurora kinase inhibitors, and provides for their use in treatment of cell proliferative diseases, including cancer and rheumatoid arthritis.
• the compounds of the invention are substituted imidazopyridines.
• X is -N-, -CH 2 -N-, -CH 2 -CH-, or -CH-;
• R 1 is a radical of formula (IA)
• Z is -CH 2 -, -NH-, -O-, -S(O)- S, SO 2 or a divalent monocyclic carbocyclic or heterocyclic radical having 3-7 ring atoms;
• AIk is an optionally substituted divalent CrC 6 alkylene radical
• A is hydrogen or an optionally substituted monocyclic carbocyclic or heterocyclic ring having 5-7 ring atoms;
• r, s and t are independently 0 or 1 , provided that when A is hydrogen then at least one of r and s is 1 ;
• R 2 is halogen, -CN, -CF 3 , -OCH 3 , or cyclopropyl
• R 3 is a radical of formula (IB)
• Q is hydrogen or an optionally substituted phenyl or monocyclic heterocyclic ring with 5 or 6 ring atoms;
• AIk 1 and AIk 2 are, independently, optionally substituted divalent C 1 -C 3 alkylene radicals
• n and p are independently 0 or 1.
• the present invention includes compounds of formula (I) and all tautomers thereof, as well as mixtures thereof in any proportions.
• References to compounds of formula (I) herein are to be taken as including references to compounds of formula (II) and (III) and mixtures thereof.
• the invention provides the use of a compound of formula (I) as defined above, or an N-oxide, salt, hydrate or solvate thereof in the preparation of a composition for inhibiting the activity of an aurora kinase enzyme, aurora-A and/or aurora-B and/or Aurora C.
• the compounds with which the invention is concerned may be used for the inhibition of aurora kinase activity, such as aurora-A and/or aurora-B, and/or aurora C activity, ex vivo or in vivo.
• the compounds of the invention may be used in the preparation of a composition for the treatment of cell-proliferation disease, for example cancer cell proliferation and autoimmune diseases.
• the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of a compound of formula (I) as defined above.
• (C a -C b )alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
• a 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
• divalent (C a -C b )alkylene radical wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.
• Carbocyclic refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
• cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond. Illustrative of such radicals are phenyl, biphenyl and napthyl.
• heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond.
• Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
• heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
• radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
• substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C r C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, (C r C 6 )alkoxy including methylenedioxy and ethylenedioxy, hydroxy, hydroxy(Ci-C 6 )alkyl, mercapto, mercaptoCCrCeJalkyl, (d-C 6 )alkylthio, phenyl, monocyclic heterocyclic, benzyl, phenoxy, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR A , -COR A , -S0 2 R A , -CONH 2 , -SO
• salt includes base addition, acid addition and quaternary salts.
• Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
• bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl pipe
• hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
• organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
• X is -N-, -CH 2 -N-, -CH 2 -CH-, or -CH-, ie the ring containing X is selected from radicals A-D:
• X be -N- (ie the ring containing X is a piperazine ring A).
• the group R 1 is a radical of formula (IA)
• Z when present, may be, for example, a divalent radical selected from:
• AIk (when present) may be, for example, optionally substituted -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
• Optional substituents in AIk include a primary, secondary or cyclic amino group.
• AIk may be substituted on a terminal carbon by a primary, secondary or cyclic amino group.
• AIk may be substituted by -NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1 -C 3 alkyl, or R 5 and R 6 taken together with the nitrogen to which they are attached form a 3-7 membered ring. In the latter case R 5 and R 6 taken together with the nitrogen to which they are attached may form a piperidine, piperazine, N-methylpiperazine, or morpholine ring.
• r and s are both 0, and A is optionally substituted phenyl, or optionally substituted heteroaryl having 5 or 6 ring atoms.
• the phenyl or heteroaryl ring A may be substituted, for example, by a group -(CH 2 ) V NR 5 R 6 wherein v is 0, 1 , 2, 3 or 4, especially 1 or 2, and R 5 and R 6 are independently hydrogen or Ci-C 3 alkyl such as methyl or ethyl, or R 5 and R 6 taken together with the nitrogen to which they are attached form a 3-7 membered ring.
• R 5 and R 6 taken together with the nitrogen to which they are attached may form a piperidine, piperazine, N-methylpiperazine, morpholine or pyrazole ring.
• the phenyl or heteroaryl ring A may be substituted by a group -O(CH 2 ) V NR 5 R 6 wherein v is 0, 1 , 2, 3 or 4, and R 5 and R 6 are independently hydrogen or CrC 3 alkyl, such as methyl or ethyl, or R 5 and R 6 taken together with the nitrogen to which they are attached may form a piperidine, piperazine, N-methylpiperazine, morpholine or pyrazole ring.
• the phenyl or heteroaryl ring A may be substituted by a group -OCH 3 , or -O(CH 2 ) 2 ⁇ H.
• the phenyl or heteroaryl ring A may be substituted by an optional substituent which is recognised as a solubilising substituent in medicinal chemistry.
• R 2 is attached to the non- bridging carbon atom adjacent the group:
• R 2 may be selected from -CN, -CF 3 , -OCH 3 , cyclopropyl, and halogen, in particular Cl and Br.
• R 3 in the compounds of the invention is a radical of formula (IB) as defined above:
• Q may be, for example, optionally substituted phenyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, thiazolyl, oxazolyl, thiadiazolyl, or oxadiazolyl.
• AIk 1 and AIk 2 may be independently selected from optionally substituted - CH 2 -, -CH 2 CH 2 - and -CH 2 CH 2 CH 2 - is a radical of formula (IB).
• Z 1 may be -N(R 4 )- wherein R 4 is hydrogen, C 1 -C 3 alkyl for example methyl or ethyl, cycloalkyl for example cyclopropyl, or benzyl and an adjacent carbon atom of AIk 1 or AIk 2 may be substituted by oxo, whereby R 3 includes an amido or reverse amido link.
• R 3 has formula (IB):
• radical R 3 has formula (IC):
• AIk 1 and Q as defined in relation to formula (I) 1 .
• AIk 1 may be, for example -CH(R)-, -CH(R)CH(R)-,or -CH(R)CH(R)CH(R)- wherein each R is independently hydrogen or methyl.
• Specicic examples of AIk 1 are -CH 2 -.or -CH(CH 3 )-.
• Q may be selected from, for example, optionally substituted phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrimidinyl and pyridyl.
• R 3 has formula (IB)
• the cases where Q is thiazol-2-yl, 3- methylisoxazol-5-yl, 4-methylthiazol-2-yl, phenyl or 3-chlorophenyl are currently preferred.
• R 3 has formula (IC)
• the cases where Q is phenyl, 4- chlorophenyl, 5-methyl-isoxazol-3-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl or 2- methylthiazol-4-yl are currently preferred.
• one class of compounds of the invention has formual (ID):
• R is hydrogen or methyl;
• R 2 is chloro or bromo;
• Q is thiazol-2-yl, 3- methylisoxazol-5-yl, 4-methy ⁇ thiazol-2-yl, phenyl or 3-chlorophenyl;
• Z is -O-;
• r is 0 or 1 ;
• v is 1 , 2, or 3;
• R 5 and R 6 are independently hydrogen, methyl or ethyl, or R 5 and R 6 taken together with the nitrogen to which they are attached form a piperidinyl, morpholinyl, pyrazolyl or piperazinyl ring, the latter being optionally substituted on the second nitrogen.; and another class of compounds of the invention has formula (IE):
• R is hydrogen or methyl
• R 2 is chloro or bromo
• r is 0 or 1
• v is 1 , 2, or 3
• R 5 and R 6 are independently hydrogen, methyl or ethyl, or R 5 and R 6 taken together with the nitrogen to which they are attached form a piperidinyl, morpholinyl, pyrazolyl or piperazinyl ring, the latter being optionally substituted on the second nitrogen
• Q is phenyl, 4-chlorophenyl, 5-methyl-isoxazol-3-yl, pyrid-3-yl or pyrid-4-yl, pyrimidin- 5-yl or 2-methylthiazol-4-yl.
• one method of synthesis of the compounds involves reaction of a compound (IV) or (V) with an aldehyde R 1 CHO, under conditions for formation of the fused imidazo ring of compounds (I). Details of such conditions appear, for example, in the Examples herein.
• the compounds with which the invention is concerned are inhibitors of the Aurora kinase family, namely Aurora kinases A and/or B and/or C, and are therefore of use in the treatment of cell proliferative disease, such as cancer, and in treatment of inflammation, in humans and other mammals.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial as is required in the art.
• the invention also includes pharmaceutical composition comprising a compound of the invention, together with a pharmaceutically acceptable carrier.
• the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
• the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• nonaqueous vehicles which may include edible oils
• almond oil fractionated coconut oil
• oily esters such as glycerine, propylene glycol
• the drug may be made up into a cream, lotion or ointment.
• Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
• the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
• Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
• the active ingredient may also be administered parenterally in a sterile medium.
• the drug can either be suspended or dissolved in the vehicle.
• adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• Flash column chromatography was performed using Merck silica gel 60 (0.025 - 0.04 mm). Column chromatography was also performed on a FlashMaster personal unit using isolute Flash silica columns or a Biotage SP1 purification system using Biotage Flash silica cartridges. Ion exchange chromatography was performed using acidic Isolute Flash SCX-II cartridges. 1 H NMR spectra were recorded on a Bruker Avance dpx250 or a Bruker Avance-500. Samples were prepared as solutions in a deuterated solvent and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane.
• Method A (10 mins) - nominal mass, LC injection with a 10 minute gradient (MeOH and 0.1% formic acid), positive ionisation and an injection volume of 3 ⁇ L.
• Method B (6 mins) - nominal mass, LC injection with a 6 minute gradient (MeOH and 0.1% formic acid), positive ionisation and an injection volume of 2 ⁇ L.
• GC-MS Instrument: Thermo Finnigan TraceGC with Polaris Q Mass spec Ionisation method: Cl (Methane); Carrier Gas: Helium; Column: Phenomenex Zebron (length: 15m, i.d.: 0.25mm, thickness: 0.25 uM); Operating temperatures: 80-300 0 C
• the aqueous layer was extracted with ethyl acetate (2 x 30 ml), and the combined organics were washed with saturated aqueous NaHCO 3 (40 ml), brine (50 ml), dried (Na 2 SO 4 ), and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 50 g isolute silica column.
• reaction mixture was allowed to cool to room temperature, absorbed on silica gel, and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1 :1) and then 5% methanol in ethyl acetate/dichloromethane (v/v; 1 :1).
• the crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate 7:3 + 0.5% methanol to 2% methanol in ethyl acetate).
• the isolated product was further triturated in ether / methanol 9:1 , filtered, and dried in vacuo to give the title compound as a pale yellow solid (0.049 g, 34%);
• the crude product was purified by chromatography on silica gel (100% chloroform to chloroform / methanol 10:1 ). The isolated fraction was run through a 2g SCX cartridge and the compound eluted with 0.1 M NH 3 in methanol to give the title compound as a white solid (0.30 g, 68%);
• the crude product was purified by chromatography on silica gel (100% ethyl acetate to ethyl acetate/methanol 9:1 to chloroform/methanol 9:1). The isolated fraction was run through a 2g SCX cartridge and the compound was eluted with 0.1 M NH 3 in methanol to give the title compound as a glass solid (0.02Og, 20%);

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