WO2008038011A1 - Pyrimidine derivatives as aurora a and aurora b inhibitors - Google Patents
Pyrimidine derivatives as aurora a and aurora b inhibitors Download PDFInfo
- Publication number
- WO2008038011A1 WO2008038011A1 PCT/GB2007/003688 GB2007003688W WO2008038011A1 WO 2008038011 A1 WO2008038011 A1 WO 2008038011A1 GB 2007003688 W GB2007003688 W GB 2007003688W WO 2008038011 A1 WO2008038011 A1 WO 2008038011A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- piperidin
- hydroxy
- nitrogen atom
- Prior art date
Links
- 239000005441 aurora Substances 0.000 title description 13
- 239000003112 inhibitor Substances 0.000 title description 12
- 150000003230 pyrimidines Chemical class 0.000 title description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 18
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 230000005764 inhibitory process Effects 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical group 0.000 claims abstract 9
- -1 -C(=O)OH Chemical group 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 21
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
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- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
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- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- This invention relates to substituted pyrimidine compounds having Aurora A and Aurora B inhibitory activity, to the use of such compounds in medicine, in relation to the treatment of disorders which are responsive to inhibition of Aurora A and Aurora B such as cancer, and to pharmaceutical compositions containing such compounds.
- Aurora family of serine/threonine protein kinases are critical for proper regulation of mitosis in many organisms. They play a key role in diverse cell cycle events such as entry to mitosis, centrosome function, mitotic spindle formation, chromosome segregation and cytokinesis. Overexpression of Aurora kinases occur in a wide range of human tumours and have been implicated in human tumourigenesis. Mammals express three Aurora Kinase paralogues and at least two (Aurora A and Aurora B) are commonly overexpressed in human tumours. 1
- the present invention relates to a class of substituted pyrimidine compounds useful as inhibitors of Aurora A and Aurora B, for example, for the treatment of cancer.
- a core amino pyrimidine ring substituted on the heterocyclic ring with an oxymethyl piperidine is a principal characterising feature of the compounds with which the invention is concerned.
- Re is hydrogen, C1-C3 alkyl, or fluoro(CrC 3 )alkyl
- R 7 is Ci-C 3 alkyl, hydroxy-(Ci-C 6 )alkyl, hydroxy-(Ci-C 6 )alkyl substituted on the alkyl portion by phenyl, C 1 -C 3 alkoxy ⁇ (Ci-C 3 )alkyl, halo(Ci-C 4 )alkyl, or C 3 - C 6 cycloalkyl;
- R 6 and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
- Rs is selected from hydrogen, C 1 -C 3 alkyl, fluoro(Ci-C 3 )alkyl, or a radical of formula -AIk-N(Rg)-R 10 ;
- R 9 and R10 are independently selected from hydrogen, C 1 -C 3 alkyl, or
- Rg and R10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
- -AIk- is a divalent (Ci-C 4 )alkylene radical
- X is halogen, cyano or triflouromethyl
- Z is O or S
- Y is selected from -NH-, -N(Ci-C 3 alkyl)-, -(CH 2 )-, or is absent;
- Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, C1-C3 alkyl radicals or trifluoromethyl radicals.
- the active compounds of formula (I) are inhibitors of Aurora Kinases, both A and B paralogues, and are useful for the treatment, prevention and suppression of diseases mediated by Aurora Kinases.
- the invention is concerned with the use of these compounds to selectively inhibit Aurora Kinases and, as such, in the treatment of cancer.
- carboxy refers to a group of formula -COOH.
- (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.
- cycloalkyl refers to a 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. Illustrative of such radicals are phenyl, biphenyl and napthyl.
- Carbocyclic refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl, cycloalkyl and cycloalkenyl radicals.
- heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O.
- 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 particular means a mono-, bi- or tricyclic 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, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, hydroxy, hydroxy(C- ⁇ -C 6 )alkyl, mercapto, mercapto(Ci-C 6 )alkyl, (Ci-C 6 )alkylthio, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, - COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -CONR A R B , -SO 2 NR A R B
- an “optional substituent” may be one of the foregoing substituent groups.
- substituents Ci-C 6 )alkyl, halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl are those most commonly regarded as lipophilic.
- substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.
- salt includes base addition, acid addition and quaternary salts.
- Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily 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-
- Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, be4nzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
- 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-toluene
- lipophilic as used herein in relation to a substituent means that it has a positive substituent hydrophobicity constant (D).
- D hydrophobicity constant
- 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
- solvent molecules for example, ethanol.
- 'hydrate' is employed when said solvent is water.
- Compounds with which the invention is concerned which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis.
- the invention includes all such enantiomers and diastereoisomers and mixtures thereof.
- So-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention.
- certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
- Such derivatives are referred to as 'prodrugs'.
- Further information on the use of prodrugs may be found in Pro-dru ⁇ s as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
- Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
- metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug are also included within the scope of the invention.
- Some examples of metabolites include
- R 1 is selected from - AIk- N(Re)-R 7 , or -O-Alk-N(R 6 )-R 7 .
- AIk is a divalent (Ci-C 4 )alkylene radical
- R 6 is hydrogen or C 1 -C 3 alkyl
- R 7 is Ci-C 3 alkyl, hydroxy-(Ci- Ce)alkyl, hydroxy-(C-i-C 6 )alkyl substituted on the alkyl portion by phenyl, Ci-C 3 alkoxy-(Ci-C 3 )alkyl, halo C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; or alternatively R 6 and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring.
- AIk is methylene, -(CH 2 ) 2 - or -(CH 2 ) 3 -, R 6 is hydrogen, methyl or ethyl, and R 7 is methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2- trifluoroethyl, cyclopentyl, -CH(IPr)-CH 2 -OH Or-CH(Ph)-CH 2 -OH.
- R 6 and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring, with morpholinyl, piperidinyl or piperazinyl optionally substituted by hydroxy methyl, fluoro, hydroxy, methyl, 2-hydroxyethyl, or trifluoromethyl presently preferred.
- AIk is methylene or -(CH 2 ) 2 -
- R 6 is hydrogen, methyl or ethyl
- R 7 is 2-hydroxyethyl, 2-methoxyethyl, - CH(JPr)-CH 2 -OH Or-CH(Ph)-CH 2 -OH
- AIk is methylene or -(CH 2 ) 2 -, and R 6 and R 7 taken together with the nitrogen atom to which they are attached form 1 -fluoro-piperidin-3-yl, 1 -hydroxy-piperidin-3-yl, 1 -hydroxymethyl-piperidin-3- yl, 1-hydroxymethyl-piperidin-4-yl, 1 -methyl-piperidin-3-yl, 1-(2-hydroxyethyl)- piperidin-3-yl, or 1-trifluoromethyl-piperidin-3-yl.
- R 8 is selected from hydrogen, Ci-C 3 alkyl or a radical of formula -AIk-N(Rg)-RiO, wherein AIk is a divalent (C 1 -C 4 )alkylene radical and R 9 and R 1 O are independently selected from hydrogen or Ci-C 3 alkyl; or Rg and R 10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring.
- R 8 is a radical of formula -AIk- N(Rg)-R 10 , wherein AIk is methylene or -(CH 2 ) 2 -, and Rg and Ri 0 taken together with the nitrogen atom to which they are attached form optionally substituted piperidinyl or pyrrolidinyl.
- Particulary preferred compounds are those wherein AIk is methylene or -(CH 2 ) 2 -, and R 9 and R 10 taken together with the nitrogen atom to which they are attached form piperidin-1-yl, 1- methyl-piperidin-2-yl, 1-hydroxy-piperidin-4-yl, or 1 -ethyl-pyrrolidin-2-yl.
- Ri is selected from hydroxy(Ci-C 3 )alkyl. It is presently preferred that Ri is hydroxymethyl or 2- hydroxyethyl.
- Ri is selected from carboxy(Ci-C 3 )alkyl. It is presently preferred that Ri is carboxymethyl or 2- carboxyethyl.
- R2, R3, R 4 and R 5 are independently selected as for R 1 .
- R 1 , R 2 , R 3 , R 4 and R 5 generally at least three are hydrogen. Preferred cases are wherein Ri, R 2 and R 5 are hydrogen; R-i, R 2 , R 4 and R5 are hydrogen; or R 1 , R 2 , R 3 and R 5 are hydrogen. Particularly preferred cases are wherein R 1 , R 2 , R 4 and R 5 are hydrogen; or Ri, R 2 , R3 and R 5 are hydrogen.
- Group X X is halogen, cyano or triflouromethyl. Preferred structures are those wherein X is halogen, with fluoro particularly preferred.
- Z is oxygen or sulphur and Y is selected from -NH-, -N(Ci-C 3 alkyl)-, -(CH 2 )-, or is absent.
- Z is oxygen and Y is selected from -NH- , -(CH 2 )-, or is absent.
- preferred compounds Z is oxygen and Y is nitrogen.
- Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, C 1 -C 3 alkyl radicals or trifluoromethyl radicals. It is presently preferred that aryl is phenyl and heteroaryl is pyridyl or N-oxido-pyridyl. Particularly preferred structures are those wherein Ar is 3-fluorophenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 2,4 difluorophenyl, 3-chlorophenyl or 3-methylphenyl.
- R 3 is hydrogen or C 1 -C 3 alkyl
- R 4 is C- 1 -C 3 alkyl, hydroxy-(Ci-C 6 )alkyl, hydroxy-(Ci-C- 6 )alkyl substituted on the alkyl portion by phenyl, C 1 -C 3 alkoxy-(CrC 3 )alkyl, halo C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
- R 3 and R 4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring;
- R 5 and R 6 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
- Ar 1 is -1 ,3-phenylene or -1 ,4-phenylene
- Y is -NH-, -CH 2 -, or is absent
- Ar 2 is halo- or C 1 -C 3 alkyl- substituted phenyl.
- a method of treatment of a disorder mediated by Aurora Kinases comprising administration to a subject in need of such treatment an effective dose of the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
- the present invention is particularly directed to a hyperproliferative disease such as cancer, wherein the cancer is colorectal, breast, lung, prostate, bladder, renal or pancreatic cancer, or leukaemia or lymphoma.
- the present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
- treatment includes prophylactic treatment.
- the compound of formula (I) may be used in combination with one or more additional drugs useful in the treatment of the disorders mentioned above, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
- a suitable dose for orally administrabie formulations will usually be in the range of 0.1 to 3000 mg, once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes.
- optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art.
- the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
- the orally administrabie 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; non-aqueous 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
- non-aqueous vehicles which may include edible oils
- almond oil fractionated coconut oil
- oily esters such as glycerine, propylene
- 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 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.
- example 15 was identical to example 1 LCMS (RT 1.89 minutes, [M+H] + 567)
- example 3 The method used to prepare example 3 was identical to example 1 LCMS (RT 1.87 minutes, [M+H] + 567)
- Examples 4 to 42 listed in the following table were prepared by methods analogous to Examples 1 , 2 and 3 above. All 42 compounds were tested for activity in kinase assays described below in the Assay section.
- characterization and/or purification were performed using standard spectroscopic and chromatographic techniques, including liquid chromatography-mass spectroscopy (LC-MS) and high performance liquid chromatography (HPLC) 1 using the conditions described in methods A and B.
- LC-MS liquid chromatography-mass spectroscopy
- HPLC high performance liquid chromatography
- Ionization was positive or negative ion electrospray Molecular weight scan range was 120-1000
- Ionization was positive or negative ion electrospray
- Aurora A Assays for the Aurora A Kinase activity were carried out by monitoring the phosphorylation of a synthetic peptide, Kemptide (LRRASLG).
- the assay mixture containing the inhibitor, Aurora A enzyme, and peptide was mixed together in a microtiter plate in a final volume of 50 ⁇ l and incubated for 30min at 30°C.
- the assay mixture contained 0.01 mM unlabeled ATP, 0.01 ⁇ Ci/ ⁇ l 33 P- ⁇ -ATP, 0.2mM peptide, 0.1 mg/ml BSA, 7.5mM magnesium acetate, 0.04M MOPS, pH 7, 1mM EDTA.
- the reaction was stopped by adding 50 ⁇ l of 5OmM phosphoric acid.
- Assays for Aurora Kinase activity and compound inhibition were carried out by monitoring the phosphorylation of a synthetic peptide, STK substrate-biotin in a HTRF-assay format.
- the assay mixture contains the inhibitor, Aurora enzyme, peptide and ATP mixed together in a microtiter plate in a final volume of 10ml and incubated for 15 minutes at room temperature.
- 10ul of development solution containing streptavidin-XL665 and STK antibody crypatate, in Hepes 25OmM (pH 7), BSA 0.1%, KF 0.8M and EDTA is added.
- the plate was incubated at room temperature for 1 hour and read using time resolved fluorescence at excitation wavelength 360nm and emission at 620and 655nm, on an Anaylst plate reader.
- Example 17 gave an IC 50 versus Aurora A kinase of 0.056 ⁇ M. All examples demonstrate greater than 50-fold selectivity for Aurora kinases over AGC kinases PDK1 , CDK2, PKA, AKT, Gsk3b and CHK1. In a broader kinase panel, Example 17 exhibited selectivity of greater than 1000-fold versus the kinases listed in the table below.
- Fluorescence-activated cell-sorting is a trademarked employed by Becton-Dickinson to describe their method of flow cytometry (FCM).
- FCM Fluorescence-activated cell-sorting
- FCM flow cytometry
- a flow cytometer operates by causing a fluid stream to pass single file through a beam of light usually generated by a laser.
- the photons of light emitted by the cells, following their interaction with the laser beam, are separated into constituent wavelengths by a series of filters and mirrors. This separated light falls upon individual detectors that generate electrical impulses or analogue signals proportional to the amount of light striking the detectors.
- Each analogue signal is converted to a digital signal which is accumulated in a frequency distribution or histogram (see figure below).
- FCM is commonly used to quantify the volume and morphological complexity of cells, enzymatic activity and the quantification and measurement of DNA degradation.
- the assay has been designed for DNA cell cycle analysis using Propidium Iodide staining of the DNA.
- HCT-116 cells are grown and maintained by methods that will be familiar to those skilled in the art. For flow cytometry cells are counted and split into a 24-well plate at 30000 cells/well. The next day putative Aurora inhibitors are added at a range of appropriate concentrations (usually tripling dilution series are used). 48 hours later, floating cells are removed, then combined with the corresponding adherent cells that released by treatment with trypsin using methods familiar to those skilled in the art.
- the combined cell population is pelleted by 5 minutes centrifugation at 200 x g, washed with phosphate buffered saline, then resuspended in a solution containing (50 ug/ml propidium iodide and 0.5 mg/ml RNAase A). 1 hour of incubation at 37 C is sufficient for the digestion of cellular RNAs enabling the amount of propidium iodide associated with cells to be proportional to their DNA content.
- Samples are then read on a BD FACSArray with the amount of propidium iodine staining being measured for each cell; this yields a fluorescence histogram that plots the number of cells with a particular fluorescence against propidium iodide fluorescence.
- Untreated cells are bimodally distributed on such a fluorescence histogram with a large peak representing cells with a 2n DNA content (G 1 cells) and a smaller peak composed of cells with approximately double the fluorescence of the first peak representing cells with a 4n DNA content (cells in G2 and mitosis); cells with an intermediate fluorescence represent cells in S phase.
- Treatment with a pure Aurora A inhibitor is predicted to lead to a sharp increase in the number of cells with a 4n DNA content (though this was not observed for our compounds).
- Treatment of cells with an Aurora B inhibitor leads to failed cell division, followed by an attempt to re-replicate the genome which leads to the appearance of an 8n peak.
- the co- inhibition of kinases required for replication will prevent the appearance of the 8n peak and the co-inhibition of kinases required for survival under the culture conditions of the HCT116 cells will result in the appearance of apoptotic cells, which due to the activation of nucleases, will have a DNA content of ⁇ 2n.
- the range of doses that leads to the appearance of a peak of 8n cells, without the induction of a major sub 2n peak can be used as an indication of the dose range at which an inhibitor imposes an Aurora B blockade without confounding effects on other targets.
- Example 17 shows 8n down to 37nM.
- Example 26 shows 8n down to 33OnM.
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Abstract
Compounds of formula (I) and their use in therapy, particularly for the treatment of a disorder responsive to inhibition of Aurora kinase A and/or B, formula ((I) wherein R1, R2, R3, R4 and R5 are independently selected from hydrogen, hydroxy, C1-C3 alkyl, fluoro(C1-C3)alkyl, hydroxy(C1-C3)alkyl, C1-C3 alkoxy, fluoro(C1-C3)alkoxy, -N(R6)-R7, - AIk-N(R6)-R7, -O-Alk-N(R6)-R7, -C(O)OH, carboxy(C1-C3)alkyl or -C(O)-NH-R8; R6, R7, R8 and -AIk- are as defined herein; X is halogen, cyano or triflouromethyl; Z is O or S; Y is selected from -NH-, -N(C1-C3 alkyl)-, -(CH2)-, or is absent; and Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, C1-C3 alkyl radicals or trifluoromethyl radicals; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Description
PYRIMIDINE DERIVATIVES AS AURORA A AND AURORA B
This invention relates to substituted pyrimidine compounds having Aurora A and Aurora B inhibitory activity, to the use of such compounds in medicine, in relation to the treatment of disorders which are responsive to inhibition of Aurora A and Aurora B such as cancer, and to pharmaceutical compositions containing such compounds.
Background to the invention
Aurora Kinases
The Aurora family of serine/threonine protein kinases are critical for proper regulation of mitosis in many organisms. They play a key role in diverse cell cycle events such as entry to mitosis, centrosome function, mitotic spindle formation, chromosome segregation and cytokinesis. Overexpression of Aurora kinases occur in a wide range of human tumours and have been implicated in human tumourigenesis. Mammals express three Aurora Kinase paralogues and at least two (Aurora A and Aurora B) are commonly overexpressed in human tumours.1
Inhibition of the Aurora Kinase activity in tumour cell lines typically leads to the accumulation of polyploid cells, apoptosis and block of proliferation.2'3 In-vivo "small molecule" inhibitors of Aurora kinases have recently demonstrated remarkable efficacy in animal tumour models. VX-680, a potent specific inhibitor or Aurora A and Aurora B kinases, has been shown to suppress tumour growth in-vivo and this agent has progressed into clinical trials.4 Agents that inhibit Aurora kinases may therefore be useful for the therapy of cancer.
1 EMBO J. 1998, 17, 3052
2 EMBO J. 2002, 21 , 483
3 J. Cell Biol. 2003, 161(2), 267-280
4 Nat. Med. 2004, 10(3), 262-327
Brief description of the invention
The present invention relates to a class of substituted pyrimidine compounds useful as inhibitors of Aurora A and Aurora B, for example, for the treatment of cancer. A core amino pyrimidine ring substituted on the heterocyclic ring with an oxymethyl piperidine is a principal characterising feature of the compounds with which the invention is concerned.
Detailed description of the invention
According to the present invention, there is provided a compound of (I) or a salt, hydrate or solvate thereof:
wherein
Ri. R2, R3, R4 and R5 are independently selected from hydrogen, hydroxy, d- C3 alkyl, fluoro(Ci-C3)alkyl, hydroxy(Ci-C3)alkyl, C1-C3 alkoxy, fluoro(Ci- C3)alkoxy, -N(Re)-Ry1 - AIk-N(Re)-R7, -0-AIk-N(Re)-R7, -C(=O)OH, carboxy(d- C3)alkyl or -C(^O)-NH-R8;
Re is hydrogen, C1-C3 alkyl, or fluoro(CrC3)alkyl, and
R7 is Ci-C3 alkyl, hydroxy-(Ci-C6)alkyl, hydroxy-(Ci-C6)alkyl substituted on the alkyl portion by phenyl, C1-C3 alkoxy~(Ci-C3)alkyl, halo(Ci-C4)alkyl, or C3- C6 cycloalkyl;
or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
Rs is selected from hydrogen, C1-C3 alkyl, fluoro(Ci-C3)alkyl, or a radical of formula -AIk-N(Rg)-R10;
or Rg and R10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
-AIk- is a divalent (Ci-C4)alkylene radical;
X is halogen, cyano or triflouromethyl;
Z is O or S;
Y is selected from -NH-, -N(Ci-C3 alkyl)-, -(CH2)-, or is absent; and
Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, C1-C3 alkyl radicals or trifluoromethyl radicals.
The active compounds of formula (I) are inhibitors of Aurora Kinases, both A and B paralogues, and are useful for the treatment, prevention and suppression of diseases mediated by Aurora Kinases. The invention is concerned with the use of these compounds to selectively inhibit Aurora Kinases and, as such, in the treatment of cancer.
As used herein the term "carboxy" refers to a group of formula -COOH.
As used herein, the term "(Ca-Cb)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 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.
As used herein the term "divalent (Ca-Cb)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.
As used herein the term "cycloalkyl" refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
As used herein the term "carbocyclic" refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl, cycloalkyl and cycloalkenyl radicals.
As used herein the term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. 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.
As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in particular means a mono-, bi- or tricyclic 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. Illustrative of such 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.
Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (Ci-C6)alkyl, (Ci-C6)alkoxy, hydroxy, hydroxy(C-ι-C6)alkyl, mercapto, mercapto(Ci-C6)alkyl, (Ci-C6)alkylthio, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, - COOH, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -SO2NHRA, -CONRARB, -SO2NRARB, -NH2, -NHRA, -NRARB, -OCONH2, -OCONHRA , -OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA, -NHSO2ORA, -NR5SO2OH, -NRBSO2ORA,-NHCONH2, -NRACONH2, -NHCONHR6 -NRACONHRB, -NHCONRARB or -NRACONRARB wherein RA and RB are independently a (CrC6)alkyl group. An "optional substituent" may be one of the foregoing substituent groups. Of the above substituents, (Ci-C6)alkyl, halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl are those most commonly regarded as lipophilic. Other substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.
As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily 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. Those compounds (I) which are basic can form salts, including
pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, be4nzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
The term "lipophilic" as used herein in relation to a substituent means that it has a positive substituent hydrophobicity constant (D). (A positive value for D indicates that the substituent is more lipophilic than hydrogen, whereas a negative value indicates it is less lipophilic, i.e. more hydrophilic, than hydrogen).
For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
Compounds with which the invention is concerned which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis. The invention includes all such enantiomers and diastereoisomers and mixtures thereof.
So-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such
derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-druαs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites include
(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH):
(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);
(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -> -NHR1 or -NHR2);
(iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2);
(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and
(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH).
The radical R1
Ri is selected from hydrogen, hydroxy, C1-C3 alkyl, fluoro(Ci-C3)alkyl, hydroxyCCrC-Oalkyl, C1-C3 alkoxy, f IuOrO(C1 -C3)alkoxy, -N(R6)-R7, - AIk-N(R6)- R7, -O-Alk-N(R6)-R7l -C(=O)OH, carboxy(CrC3)alkyl or -C(=O)-NH-R8.
One subclass of compounds are those wherein R1 is selected from - AIk- N(Re)-R7, or -O-Alk-N(R6)-R7. In such cases AIk is a divalent (Ci-C4)alkylene radical; R6 is hydrogen or C1-C3 alkyl, and R7 is Ci-C3 alkyl, hydroxy-(Ci- Ce)alkyl, hydroxy-(C-i-C6)alkyl substituted on the alkyl portion by phenyl, Ci-C3 alkoxy-(Ci-C3)alkyl, halo C1-C4 alkyl, or C3-C6 cycloalkyl; or alternatively R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring. It is currently preferred that AIk is methylene, -(CH2)2- or -(CH2)3-, R6 is hydrogen, methyl or ethyl, and R7 is methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2- trifluoroethyl, cyclopentyl, -CH(IPr)-CH2-OH Or-CH(Ph)-CH2-OH. Alternatively, R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring, with morpholinyl, piperidinyl or piperazinyl optionally substituted by hydroxy methyl, fluoro, hydroxy, methyl, 2-hydroxyethyl, or trifluoromethyl presently preferred. In a particulary preferred subclass of compounds AIk is methylene or -(CH2)2-, R6 is hydrogen, methyl or ethyl, and R7 is 2-hydroxyethyl, 2-methoxyethyl, - CH(JPr)-CH2-OH Or-CH(Ph)-CH2-OH; or AIk is methylene or -(CH2)2-, and R6 and R7 taken together with the nitrogen atom to which they are attached form 1 -fluoro-piperidin-3-yl, 1 -hydroxy-piperidin-3-yl, 1 -hydroxymethyl-piperidin-3- yl, 1-hydroxymethyl-piperidin-4-yl, 1 -methyl-piperidin-3-yl, 1-(2-hydroxyethyl)- piperidin-3-yl, or 1-trifluoromethyl-piperidin-3-yl.
Another subclass of compounds are those wherein R1 is selected from - C(=O)-NH-R8. In such cases R8 is selected from hydrogen, Ci-C3 alkyl or a radical of formula -AIk-N(Rg)-RiO, wherein AIk is a divalent (C1-C4)alkylene radical and R9 and R1O are independently selected from hydrogen or Ci-C3 alkyl; or Rg and R10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered
heterocyclic ring. It is presently preferred that R8 is a radical of formula -AIk- N(Rg)-R10, wherein AIk is methylene or -(CH2)2-, and Rg and Ri0 taken together with the nitrogen atom to which they are attached form optionally substituted piperidinyl or pyrrolidinyl. Particulary preferred compounds are those wherein AIk is methylene or -(CH2)2-, and R9 and R10 taken together with the nitrogen atom to which they are attached form piperidin-1-yl, 1- methyl-piperidin-2-yl, 1-hydroxy-piperidin-4-yl, or 1 -ethyl-pyrrolidin-2-yl.
In another subclass of compounds Ri is selected from hydrogen.
In yet another subclass of compounds Ri is selected from hydroxy.
Another subclass of compounds are those wherein Ri is selected from hydroxy(Ci-C3)alkyl. It is presently preferred that Ri is hydroxymethyl or 2- hydroxyethyl.
In a further subclass of compounds Ri is selected from -C(=O)OH.
Another subclass of compounds are those wherein Ri is selected from carboxy(Ci-C3)alkyl. It is presently preferred that Ri is carboxymethyl or 2- carboxyethyl.
The radicals R2, R3, R4 and R5
R2, R3, R4 and R5 are independently selected as for R1.
Of the radicals R1, R2, R3, R4 and R5, generally at least three are hydrogen. Preferred cases are wherein Ri, R2 and R5 are hydrogen; R-i, R2, R4 and R5 are hydrogen; or R1, R2, R3 and R5 are hydrogen. Particularly preferred cases are wherein R1, R2, R4 and R5 are hydrogen; or Ri, R2, R3 and R5 are hydrogen.
Group X
X is halogen, cyano or triflouromethyl. Preferred structures are those wherein X is halogen, with fluoro particularly preferred.
The Group -C(=Z)-Y-
Z is oxygen or sulphur and Y is selected from -NH-, -N(Ci-C3 alkyl)-, -(CH2)-, or is absent. In preferred compounds Z is oxygen and Y is selected from -NH- , -(CH2)-, or is absent. In particulary preferred compounds Z is oxygen and Y is nitrogen.
Group Ar
Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, C1-C3 alkyl radicals or trifluoromethyl radicals. It is presently preferred that aryl is phenyl and heteroaryl is pyridyl or N-oxido-pyridyl. Particularly preferred structures are those wherein Ar is 3-fluorophenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 2,4 difluorophenyl, 3-chlorophenyl or 3-methylphenyl.
A preferred subclass of the compounds with which the invention is concerned has formula (II):
wherein
R1 is hydrogen, hydroxy, hydroxy(C1-C3)alkyl, -C(=O)OH, carboxy(Ci- C3)alkyl, a radical of formula -(CH2)n-N(R3)-R4 wherein n is 1 or 2, a radical of
formula -O-(CH2)n-N(R3)-R4 wherein n is 1 or 2, or a radical of formula - C(=O)-NH-(CH2)p-N(R5)-R6 wherein p is 1 , 2 or 3;
R3 is hydrogen or C1-C3 alkyl, and
R4 is C-1-C3 alkyl, hydroxy-(Ci-C6)alkyl, hydroxy-(Ci-C-6)alkyl substituted on the alkyl portion by phenyl, C1-C3 alkoxy-(CrC3)alkyl, halo C1-C4 alkyl, or C3-C6 cycloalkyl;
or R3 and R4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring;
R5 and R6 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
Ar1 is -1 ,3-phenylene or -1 ,4-phenylene;
Y is -NH-, -CH2-, or is absent; and
Ar2 is halo- or C1-C3 alkyl- substituted phenyl.
Specific compounds with which the invention is concerned include those of the Examples, particularly those exemplified compounds which have structure (II) above.
According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I).
According to a further aspect of the invention, there is provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disorder mediated by Aurora Kinases.
According to a further aspect of the present invention there is provided a method of treatment of a disorder mediated by Aurora Kinases comprising
administration to a subject in need of such treatment an effective dose of the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
The present invention is particularly directed to a hyperproliferative disease such as cancer, wherein the cancer is colorectal, breast, lung, prostate, bladder, renal or pancreatic cancer, or leukaemia or lymphoma.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
As used herein, the term "treatment" as used herein includes prophylactic treatment.
The compound of formula (I) may be used in combination with one or more additional drugs useful in the treatment of the disorders mentioned above, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
It will be understood that 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 causative mechanism and severity of the particular disease undergoing therapy. In general, a suitable dose for orally administrabie formulations will usually be in the range of 0.1 to 3000 mg, once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes. However, optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art.
The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrabie 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; non-aqueous 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.
For topical application to the skin, 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 active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention is concerned, but all rely on known
chemistry, known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature and are well-known to the one skilled in the art. Typical literature sources are "Advanced organic chemistry", 4th Edition (Wiley), J March, "Comprehensive Organic Transformation", 2nd Edition (Wiley), R.C. Larock , "Handbook of Heterocyclic Chemistry", 2nd Edition (Pergamon), A.R. Katritzky), review articles such as found in "Synthesis", "Ace. Chem. Res." , "Chem. Rev", or primary literature sources identified by standard literature searches online or from secondary sources such as "Chemical Abstracts" or "Beilstein". Such literature methods include those of the preparative Examples herein, and methods analogous thereto.
Suitable routes to compounds of formula (I) are shown below in schemes 1 , 2, 3, 4 and 5.
Scheme 1
Scheme 2
Scheme 4
Scheme 5
Examples
The following examples illustrate the preparation and activities of specific compounds of the invention.
Example 1
1Og of 4-piperidine methanol was dissolved in 10OmIs of dichloromethane and the solution treated with 14.5mls of triethylamine under nitrogen. The mixture was cooled to O0C using an ice bath and stirred. 19g of boc anhydride was added portionwise to the mixture over 15 minutes. The reaction mixture was then stirred overnight allowing the whole to warm to RT. The reaction mixture was diluted with a further 30OmIs dichloromethane and washed with 1 N HCI(aq) (250ml) followed by a wash with brine before drying over anhydrous magnesium sulphate. The dried organics were filtered and evaporated to dryness to give 17.8g of colourless crystalline solid.
1H-NMR (400MHz, CD3OD) OH 4.88(2H s) 4.08(1 H d), 3.39(1 H d), 1.70(1 H d), 1.60(1 H m), 1.44(9H s), 1.08(2H m)
1.2 Synthesis of 4-(2-Chloro-5-fluoro-pyrimidin-4-yl oxymethyl)-piperidine-1- carboxylic acid tert-butyl ester
A solution of 1 Og 4-Hydroxymethyl-piperidine-1-carboxylic tert-butyl ester was dissolved in THF under nitrogen and cooled with use of an ice bath. Sodium hydride (60% suspension in mineral oil) (1.96g) ( was added portionwise to control evolution of hydrogen gas. The resultant salt was allowed to stir ice cooled for a further hour.
In parallel, a solution of 2,4-dichloro-5-fluoro-pyimidine (7.7g) in THF was cooled to -78°C (CO2 dry ice / acetone) under nitrogen and treated drop wise with 4-Hydroxymethyl-piperidine-1-carboxylic tert-butyl ester sodium salt
solution. After addition the whole was allowed to warm towards room temperature overnight while stirred. The organics were reduced in volume and taken up in water. The pH was adjusted to 7 before partioned with ethyl acetate. The organics were dried, (magnesium sulphate) filtered and evaporated. The residue was loaded onto silica and eluted using neat hexane to ethyl acetate/ hexane mixtures. Selected fractions were taken and evaporated to afford 4-(2-Chloro-5-fluoro-pyrimidin-4-yl oxymethyl)-piperidine- 1-carboxylic acid tert-butyl ester as a crystalline solid. (15.5g) LCMS (RT 2.67 minutes, [M+Na]+ 368);
1H-NMR (400MHz, D6 DMSO) 8.606 (1 H, d, J=2.74), 4.288 (2H, d, J=11.45), 3.964 (2H, m), 2.733 (2H, m), 1.986 (1 H, m), 1.708 (2H, m), 1.391 (9H, s), 1.158 (2H1 m)
1.3 Synthesis of 4[5-fluoro-2-(4-hydroxymethyl-phenylamino)-pyrimidin- 4yloxymethyl]~piperidine-1-carboxylic acid tert-butyl ester
0.8g of 4-(2-Chloro-5-fluoro-pyrimidin-4-yl oxymethyl)~piperidine-1-carboxylic acid tert-butyl ester (1.1) was dissolved in THF (16ml_) and treated with 4- amino benzyl alcohol (0.86g), potassium phosphate (0.68g), catalytic amount of ligand, P(Cy)2 biphenyl (80mg) and catalytic amount Pd(dba) (80mg). The whole was heated to 12O0C in the microwave for 30 minutes. The reaction mixture was filtered and reduced in volume. The residual organics were then partitioned between 1 N HCI (aq) and dichloromethane. The dried organics (anhydrous magnesium sulphate) were again filtered before evaporation. The residue was purified by flash column chromatography eluting ethylacetate hexane mixtures. 4[5~fluoro-2-(4-hydroxymethyl-phenylamino)-pyrimidin-
4yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester was isolated as a colourless crystalline solid (0.56g) LCMS (RT 2.50 minutes, [M+Hf 433) Method A
1.4 Synthesis of 4[5-fluoro-2-(4-formyl-phenylamino)-pyrimidin-4yloxymethyl]- piperidine-1-carboxylic acid tert-butyl ester
0.56g of 4[5-fluoro-2-(4-hydroxymethyl-phenylamino)-pyrimidin-4yloxymethyl]- piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2OmIs THF and treated with 1g IBX (Angewandte Chemie, International Edition 2006, 45(18 ), 2929-2934) and refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature and then further cooled on ice. The liquor was filtered to remove IBX and iodobenzoic acid & the filtrate evaporated. The residual glass foam was used crude without further purification (0.23g). LCMS (RT 2.71 minutes, [M+H]+ 431 & [M+Na]+ 453) Method A.
1.5 Synthesis of 4-[5-fluoro~2-(formyl-phenylamino)-pyrimidin-4-yloxymethyl]- piperidine-1-carboxylic acid (3-fluoro-phenyl)-amide
0.23g 4[5-fluoro-2-(4-formyl-phenylamino)-pyrimidin-4yloxymethyl]-piperidine- 1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (5mls) and treated with trifluoroacetic acid (5mL) and the mixture stirred under nitrogen for 3hrs. The whole was evaporated to dryness and re-evaporated twice from a suspension in toluene. The resultant salt without further purification was stirred in dichloromethane under nitrogen and treated with triethylamine (140μL) followed by 3-fluorophenylisocyanate (73mg) and the mixture stirred for 16hrs. The reaction mixture was partitioned between dichloromethane and water and the organics loaded onto silica cartridge (2Og) The cartridge was eluted using gradient of neat dichloromethane to 10% methanol, dichloromethane and selected fractions evaporated to furnish Synthesis of 4- [5-fluoro-2-(formyl-phenylamino)-pyrimidin-4-yloxymethyl]-piperidine-1- carboxylic acid (3-fluoro-phenyl)-amide as a glass solid (170mg). LCMS (RT 2.53 minutes, [M+H]+ 468) Method A
1.6 Synthesis of 4-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}- phenylamino)-5-fluoro-pyrimidin-4-yloxymethyl]-piperidne-1 -carboxylic acid (3- fluoro-phenyl)-amide
50mg 4-[5-fluoro-2-(formyl-phenylamino)-pyrimidin-4-yloxymethyl]-piperidine- 1 -carboxylic acid (3-fluoro-phenyl)-amide was dissolved in 2% methanolic dichloromethane and treated with excess 2-aminoethyl ethanol (50μL) followed by sodium triacetoxyborohydride (100mg). The mixture was stirred at RT for 16hrs under nitrogen. The mixture was diluted with further dichloromethane and washed with saturated sodium bicarbonate (aq). The
organic layer was soaked onto silica cartridge (1Og) and eluted using methanol, dichloromethane & methanolic ammonia mixtures. Selected fractions were evaporated to furnish 4-[2-(4-{[Ethyl-(2~hydroxy-ethyl)~amino]- methyl}-phenylamino)-5-fluoro-pyrimidin-4-yloxymethyl]-piperidne-1-carboxylic acid (3-fluoro-phenyl)-amide as a colourless solid. (22mg) LCMS (RT 1.89 minutes, [M+H]+ 541)
Example 2
Synthesis of 4~{5-Fluoro-2-[4-(3-hydroxymethyl-piperidin-1 -ylmethyl)- phenylamino]-pyrimidin-4~yloxymethyl}-piperidin-1 -carboxylic acid (3-fluoro- phenyl)-amide
The method used to prepare example 15 was identical to example 1 LCMS (RT 1.89 minutes, [M+H]+ 567)
1H NMR (400 MHz, CD3OD) 8.06 (1H, d, J3.02), 7.67 (1H, s), 7.58 (1H, m), 7.24 (3H1 m), 7.11 (1 H, m), 6.98 (1 H, d, J7.53), 6.70 (1 H1 m), 4.35 (2H, d, J6.49), 4.23 (2H, d, J13.47), 3.69 (2H, s), 3.38 (2H, m), 3.15 (1 H, m), 3.01 (1 H, m), 2.92 (2H, m), 2.17 (2H1 m), 1.98 (1 H1 m), 1.73 (6H1 m), 1.39 (2H1 m), 1.02 (1 H, m).
Example 3
Synthesis of 4-{5-Fluoro-2-[4-(4-hydroxymethyl-pip8ridin-1 -ylmethyl)- phenylamino]-pyrimidin-4-yloxymethyl}-piperidin-1 -carboxylic acid (3-fluoro- phenyl)-amide
The method used to prepare example 3 was identical to example 1 LCMS (RT 1.87 minutes, [M+H]+ 567)
1H NMR (400 MHz, CD3OD) 8.06 (1H, d, J3.04), 7.74 (1 H, s), 7.63 (1 H, m), 7.27 (3H, m), 7.12 (1H, m), 7.03 (1 H, d, J7.60), 6.70 (1 H, m), 4.34 (2H, d, J6.53), 4.21 (2H, d, J13.48), 3.91 (2H, s), 3.40 (2H, d, J6.23), 3.34 (2H, s), 3.26 (2H, m), 2.93 (2H, m), 2.57 (2H, m), 2.14 (1 H, m), 1.86 (2H, m), 1.60 (1 H, m), 1.38 (4H, m).
Examples 4 to 42 listed in the following table were prepared by methods analogous to Examples 1 , 2 and 3 above. All 42 compounds were tested for activity in kinase assays described below in the Assay section.
In the examples, characterization and/or purification were performed using standard spectroscopic and chromatographic techniques, including liquid chromatography-mass spectroscopy (LC-MS) and high performance liquid chromatography (HPLC)1 using the conditions described in methods A and B. NMR experiments were conducted on a Bruker DPX400 ultra shield NMR spectrometer in the specified solvent. Reactions carried out under microwave irradiation were conducted in a Biotage Initiator.
LCMS Method A
Instrument: HP1100 Column: Gemini 3 μm, C18(2), 30 mm x 4.6 mm i.d. from
Phenomenex
Temperature: 22 °C Solvents: A - Water + 10 mmol / L ammonium acetate + 0.08% (v/v) formic acid
B - 95% Acetonitrile-5% Solvent A + 0.08% (v/v) formic acid
Gradient:
Detection: UV detection at 230, 254 and 270 nm Mass Spec: HP1100 MSD, series A
Ionization was positive or negative ion electrospray
Molecular weight scan range was 120-1000
Method B
Instrument: Waters FractionLynx MS autopurification system Column: Luna 5 μm, C18(2), 100 mm x 21.2 mm i.d. from
Phenomenex
Temp: ambient Solvents: A- water + 0.08% (v/v) formic acid
B- 95% methanol-water + 0.08% (v/v) formic acid
Flow rate: 20 cm3 min"1
Gradient:
Detection: Photodiode array 210 to 400 nm Mass spec: MicroMass ZQ
Ionization was positive or negative ion electrospray
Molecular weight scan range was 150-1000
Collection: Triggered on selected mass ion
Assay Protocols
Aurora A
Assays for the Aurora A Kinase activity were carried out by monitoring the phosphorylation of a synthetic peptide, Kemptide (LRRASLG). The assay mixture containing the inhibitor, Aurora A enzyme, and peptide was mixed together in a microtiter plate in a final volume of 50μl and incubated for 30min at 30°C. The assay mixture contained 0.01 mM unlabeled ATP, 0.01 μCi/μl 33P-γ-ATP, 0.2mM peptide, 0.1 mg/ml BSA, 7.5mM magnesium acetate, 0.04M MOPS, pH 7, 1mM EDTA. The reaction was stopped by adding 50μl of 5OmM phosphoric acid. 90μl of the mixture were transferred to a pre-wetted 96-well Multiscreen MAPHNOB filtration plate (Millipore) and filtered on a vacuum manifold. The filter plate was washed with 3 successive additions of 200μl 5OmM phosphoric acid and then with 100μl methanol. The filtration plate was dried for 10 min at 650C, scintillant added and phosphorylated peptide quantified in a scintillation counter (Trilux, Perkin Elmer).
Aurora A and B
Assays for Aurora Kinase activity and compound inhibition were carried out by monitoring the phosphorylation of a synthetic peptide, STK substrate-biotin in a HTRF-assay format. The assay mixture contains the inhibitor, Aurora enzyme, peptide and ATP mixed together in a microtiter plate in a final volume of 10ml and incubated for 15 minutes at room temperature. 10ul of development solution containing streptavidin-XL665 and STK antibody crypatate, in Hepes 25OmM (pH 7), BSA 0.1%, KF 0.8M and EDTA is added. The plate was incubated at room temperature for 1 hour and read using time resolved fluorescence at excitation wavelength 360nm and emission at 620and 655nm, on an Anaylst plate reader.
All compounds tested in the above assays were found to have Aurora kinase inhibition in the range IC50 = 0.004 μM to 1 μM.
By way of illustration, the compound of Example 17 gave an IC50 versus Aurora A kinase of 0.056μM.
All examples demonstrate greater than 50-fold selectivity for Aurora kinases over AGC kinases PDK1 , CDK2, PKA, AKT, Gsk3b and CHK1. In a broader kinase panel, Example 17 exhibited selectivity of greater than 1000-fold versus the kinases listed in the table below.
ABL1 (T315I)
BRAF
CK1 alpha 1
MEK1 p38 alpha
P70S6K
TSSK1
Cellular responses to Aurora inhibition
Specific Aurora A inhibitors will arrest cells with a 4n DNA content (a phenotype also imposed by the inhibition of several other kinases). Compounds with substantial Aurora B inhibitory activity will promote mitotic exit without cell division. If these cells are capable of replicating their DNA (which implies that various other kinases are not inhibited including Cdc7, CDK2 etc) then a peak of 8n cells will appear.
Flow Cytometry Assay
Fluorescence-activated cell-sorting (FACS) is a trademarked employed by Becton-Dickinson to describe their method of flow cytometry (FCM). FCM is a method for sorting a suspension of biological cells into two or more containers one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell. In this particular implementation the cells are not collected post sorting.
A flow cytometer operates by causing a fluid stream to pass single file through a beam of light usually generated by a laser. The photons of light emitted by
the cells, following their interaction with the laser beam, are separated into constituent wavelengths by a series of filters and mirrors. This separated light falls upon individual detectors that generate electrical impulses or analogue signals proportional to the amount of light striking the detectors. Each analogue signal is converted to a digital signal which is accumulated in a frequency distribution or histogram (see figure below).
It is possible to deduce various facts about the physical and chemical structure of each particle from the data generated. FCM is commonly used to quantify the volume and morphological complexity of cells, enzymatic activity and the quantification and measurement of DNA degradation. However in this case the assay has been designed for DNA cell cycle analysis using Propidium Iodide staining of the DNA.
HCT-116 cells are grown and maintained by methods that will be familiar to those skilled in the art. For flow cytometry cells are counted and split into a 24-well plate at 30000 cells/well. The next day putative Aurora inhibitors are added at a range of appropriate concentrations (usually tripling dilution series are used). 48 hours later, floating cells are removed, then combined with the corresponding adherent cells that released by treatment with trypsin using methods familiar to those skilled in the art. The combined cell population is pelleted by 5 minutes centrifugation at 200 x g, washed with phosphate buffered saline, then resuspended in a
solution containing (50 ug/ml propidium iodide and 0.5 mg/ml RNAase A). 1 hour of incubation at 37 C is sufficient for the digestion of cellular RNAs enabling the amount of propidium iodide associated with cells to be proportional to their DNA content. Samples are then read on a BD FACSArray with the amount of propidium iodine staining being measured for each cell; this yields a fluorescence histogram that plots the number of cells with a particular fluorescence against propidium iodide fluorescence. Untreated cells are bimodally distributed on such a fluorescence histogram with a large peak representing cells with a 2n DNA content (G 1 cells) and a smaller peak composed of cells with approximately double the fluorescence of the first peak representing cells with a 4n DNA content (cells in G2 and mitosis); cells with an intermediate fluorescence represent cells in S phase.
Treatment with a pure Aurora A inhibitor is predicted to lead to a sharp increase in the number of cells with a 4n DNA content (though this was not observed for our compounds). Treatment of cells with an Aurora B inhibitor leads to failed cell division, followed by an attempt to re-replicate the genome which leads to the appearance of an 8n peak. Note that the co- inhibition of kinases required for replication will prevent the appearance of the 8n peak and the co-inhibition of kinases required for survival under the culture conditions of the HCT116 cells will result in the appearance of apoptotic cells, which due to the activation of nucleases, will have a DNA content of < 2n. Therefore the range of doses that leads to the appearance of a peak of 8n cells, without the induction of a major sub 2n peak can be used as an indication of the dose range at which an inhibitor imposes an Aurora B blockade without confounding effects on other targets.
80 27 g 3 1 330 110 37 uM uM UM uM uM nM nM nM
Example 26 shows 8n down to 33OnM.
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof
wherein
Riι R2, R3, R4 and R5 are independently selected from hydrogen, hydroxy, Ci- C3 alkyl, fluoro(Ci-C3)alkyl, hydroxy(Ci-C3)alkyl, Ci-C3 alkoxy, fluoro(Ci- C3)alkoxy, -N(Re)-R7, - AIk-N(Re)-R7, -0-AIk-N(Re)-R7, -C(O)OH1 carboxy(d- C3)alkyl or -C(O)-NH-R8;
R6 is hydrogen, Ci-C3 alkyl, or fluoro(Ci-C3)a!kyl, and
R7 is Ci-C3 alkyl, hydroxy-(Ci-C6)alkyl, hydroxy-(Ci-C6)alkyl substituted on the alkyl portion by phenyl, Ci-C3 alkoxy-(Ci-C3)alkyl, halo(Ci-C4)alkyl, or C3-C6 cycloalkyl;
or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
R8 is selected from hydrogen, CrC3 alkyl, fluoro(Ci-C3)alkyl, or a radical of formula -AIk-N(Rg)-Ri0; RΘ and R10 are independently selected from hydrogen, C1-C3 alkyl, or fluoro(Ci-C3)alkyl,;
or Rg and R10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
-AIk- is a divalent (Ci-C4)alkylene radical;
X is halogen, cyano or triflouromethyl;
Z is O or S;
Y is selected from -NH-, -N(Ci-C3 alkyl)-, -(CH2)-, or is absent; and
Ar is aryl or heteroaryl, optionally substituted with one or more halogen atoms, Ct-C3 alkyl radicals or trifluoromethyl radicals.
2. A compound as claimed in claim 1 wherein Ri to R5 are independently selected from hydrogen, hydroxy, hydroxy(Ci-C3)alkyl, -C(=O)OH, carboxy(Ci-C3)alkyl, - AIk-N(Re)-R7, -0-AIk-N(R6J-R7 or
-C(=O)-NH-R8.
3. A compound as claimed in claim 1 or claim 2 wherein Re is hydrogen, methyl or ethyl, and R7 is methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2- trifluoroethyl, cyclopentyl, -CH(JPr)-CH2-OH Or-CH(Ph)-CH2-OH.
4. A compound as claimed in claim 1 or claim 2 wherein RΘ and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring.
5. A compound as claimed in claim 4 wherein R6 and R7 taken together with the nitrogen atom to which they are attached form optionally substituted morpholinyl, piperidinyl or piperazinyl.
6. A compound as claimed in claim 4 or claim 5 wherein Re and R7 taken together with the nitrogen atom to which they are attached form morpholin-4- yl, 1-methyl-piperazin-4-yl, or piperidin-1-yl optionally substituted by hydroxymethyl, fluoro, hydroxy, methyl, 2-hydroxyethyl, or trifluoromethyl.
7. A compound as claimed in claim 6 wherein R6 and R7 taken together with the nitrogen atom to which they are attached form 1-fluoro-piperidin-3-yl, 1-hydroxy-piperidin-3-yl, 1-hydroxymethyl-piperidin-3-yl, 1-hydroxymethyl- piperidin-4-yl, 1-methyl-piperidin-3-yl, 1-(2-hydroxyethyl)-piperidin-3-yl, or 1- trifluoromethyl-piperidin-3-yl.
8. A compound as claimed in claim 1 or claim 2 wherein Rs is a radical of formula -AIk-N(Rg)-Ri0.
9. A compound as claimed in claim 8 wherein R9 and R10 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring.
10. A compound as claimed in claim 9 wherein Rg and Rio taken together with the nitrogen atom to which they are attached form optionally substituted piperidinyl or pyrrolidinyl.
11. A compound as claimed in claim 9 or claim 10 wherein Rg and R-io taken together with the nitrogen atom to which they are attached form piperidin-1-yl, 1-methyl-piperidin-2-yl, 1-hydroxy-piperidin-4-yl, or 1-ethyl- pyrrolidin-2-yl.
12. A compound as claimed in any of the preceding claims wherein AIk is methylene, -(CH2^- or -(CH2)3-.
13. A compound as claimed in any of the preceding claims wherein X is fluoro.
14. A compound as claimed in any of the preceding claims wherein Z is oxygen.
15. A compound as claimed in any of the preceding claims wherein Y is nitrogen.
16. A compound as claimed in any of the preceding claims wherein Ar is 3- fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4 difluorophenyl, 3- chlorophenyl or 3-methylphenyl.
17. A compound as claimed in any of claims 1 to 15 wherein Ar is pyridyl or N-oxido-pyridyl optionally substituted with one or more halogen atoms, Ci-C3 alkyl radicals or trifluoromethyl radicals.
18. A compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof
wherein
R1 is hydrogen, hydroxy, hydroxy(C1-C3)alkyl, -C(=O)OH, carboxy(Ci- C3)alkyl, a radical of formula -(CH2)n-N(R3)-R4 wherein n is 1 or 2, a radical of formula -O-(CH2)n-N(R3)-R4 wherein n is 1 or 2, or a radical of formula - C(=O)-NH-(CH2)p-N(R5)-R6 wherein p is 1 , 2 or 3; R3 is hydrogen or CrC3 alkyl, and
R4 is Ci-C3 alkyl, hydroxy-(Ci-C6)alkyl, hydroxy-(Ci-C6)alkyl substituted on the alkyl portion by phenyl, Ci-C3 alkoxy-(Ci-C3)alkyl, halo Ci-C4 alkyl, or C3-C6 cycloalkyl;
or R3 and R4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 6-membered heterocyclic ring;
R5 and R6 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring;
An is -1 ,3-phenylene or -1 ,4-phenylene;
Y is -NH-, -CH2-, or is absent; and
Ar2 is halo- or C1-C3 alkyl- substituted phenyl;
19. A compound as claimed in claim 18 wherein Ri is hydrogen.
20. A compound as claimed in claim 18 wherein Ri is hydroxy.
21. A compound as claimed in claim 18 wherein Ri is hydroxy(Ci-C3)alkyl.
22. A compound as claimed in claim 18 wherein Ri is -C(=O)OH.
23. A compound as claimed in claim 18 wherein Ri is carboxy(Ci-C3)alkyl.
24. A compound as claimed in claim 18 wherein Ri is -CH2-N(R3)-R4.
25. A compound as claimed in claim 18 wherein Ri is -(CH2)2-N(R3)-R4.
26. A compound as claimed in claim 18 wherein Ri is -0-CH2-N (R3)-R4.
27. A compound as claimed in claim 18 wherein Ri is -O-(CH2)2~N(R3)-R4.
28. A compound as claimed in claim 18 wherein Ri is -C(=O)-NH-(CH2)P- N(R5)-R6 and p is 1 , 2 or 3.
29. A compound as claimed in claim 18 or claims 24 to 27 wherein R3 is hydrogen, methyl or ethyl, and R4 is methyl, ethyl, 2-hydroxyethyl, 2- methoxyethyl, 2,2,2-trifluoroethyl, cyclopentyl, -CH(JPr)-CH2-OH or-CH(Ph)- CH2-OH.
30. A compound as claimed in claim 18 or claims 24 to 27 wherein R3 and R4 taken together with the nitrogen atom to which they are attached form morpholin-4-yl, or piperidin-1-yl optionally substituted by hydroxymethyl, fluoro, hydroxy, methyl, 2-hydroxyethyl, or trifluoromethyl.
31. A compound as claimed in claim 30 wherein R3 and R4 taken together with the nitrogen atom to which they are attached form 1 -fluoro-piperidin-3-yl, i-hydroxy-piperidin-3-yl, 1-hydroxymethyl-piperidin-3-yl, 1-hydroxymethyl- piperidin-4-yl, 1~methyl-piperidin-3-yl, 1-(2-hydroxyethyl)-piperidin-3-yl, or 1- trifluoromethyl-piperidin-3-yl.
32. A compound as claimed in claim 18 or claim 28 wherein R5 and Re taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic 5- or 6-membered heterocyclic ring.
33. A compound as claimed in claim 32 wherein R5 and R6 taken together with the nitrogen atom to which they are attached form optionally substituted piperidinyl or pyrrolidinyl.
34. A compound as claimed in claim 32 or claim 33 wherein R5 and Re taken together with the nitrogen atom to which they are attached form piperidin-1-yl, 1-methyl-piperidin-2-yl, 1-hydroxy-piperidin-4-yl, or 1-ethyl- pyrrolidin-2-yl.
35. A compound as claimed in any of claims 18 to 34 wherein Y is -NH-.
36. A compound as claimed in any of claims 18 to 35 wherein Ar2 is 3- fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4 difluorophenyl, 3- chlorophenyl or 3-methylphenyl.
37. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims and a pharmaceutically acceptable carrier.
38. The use of a compound as claimed in any of the preceding claims in the preparation of a composition for the treatment of conditions responsive to inhibition of Aurora Kinase activity.
39. A method of treatment of a mammal suffering from a condition responsive to inhibition of Aurora Kinase activity, comprising administering to the mammal an amount of a compound as claimed in any of claims 1 to 36 effective to inhibit Aurora Kinase activity in the mammal.
40. The use as claimed in claim 38 or a method as claimed in claim 39 wherein the condition responsive to inhibition of Aurora Kinase activity is a hyperproliferative disease such as cancer.
41. The use or method as claimed in claim 40 wherein the cancer is colorectal, breast, lung, prostate, bladder, renal or pancreatic cancer, or leukaemia or lymphoma.
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Cited By (5)
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WO2011039344A1 (en) | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors |
WO2011147951A1 (en) | 2010-05-28 | 2011-12-01 | Prosidion Limited | Cycloamino derivatives as gpr119 antagonists |
US8785464B2 (en) | 2008-11-24 | 2014-07-22 | Boehringer Ingelheim International Gmbh | Pyrimidine derivatives that inhibit FAK/PTK2 |
US8846689B2 (en) | 2008-11-24 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Substituted pyrimidines for the treatment of diseases such as cancer |
US11578061B2 (en) | 2021-03-23 | 2023-02-14 | Halia Therapeutics, Inc. | Inhibitors of LRRK2 kinase |
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WO2004000833A1 (en) * | 2002-06-20 | 2003-12-31 | Vertex Pharmaceuticals Incorporated | Processes for preparing substituted pyrimidines and pyrimidine derivatives as inhibitors of protein kinase |
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WO2004000833A1 (en) * | 2002-06-20 | 2003-12-31 | Vertex Pharmaceuticals Incorporated | Processes for preparing substituted pyrimidines and pyrimidine derivatives as inhibitors of protein kinase |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8785464B2 (en) | 2008-11-24 | 2014-07-22 | Boehringer Ingelheim International Gmbh | Pyrimidine derivatives that inhibit FAK/PTK2 |
US8846689B2 (en) | 2008-11-24 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Substituted pyrimidines for the treatment of diseases such as cancer |
US9676762B2 (en) | 2008-11-24 | 2017-06-13 | Boehringer Ingelheim International Gmbh | Pyrimidine compounds containing seven-membered fused ring systems |
WO2011039344A1 (en) | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors |
CN102695700A (en) * | 2009-10-02 | 2012-09-26 | 贝林格尔.英格海姆国际有限公司 | Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors |
US8466155B2 (en) | 2009-10-02 | 2013-06-18 | Boehringer Ingelheim International Gmbh | Pyrimidines |
WO2011147951A1 (en) | 2010-05-28 | 2011-12-01 | Prosidion Limited | Cycloamino derivatives as gpr119 antagonists |
US11578061B2 (en) | 2021-03-23 | 2023-02-14 | Halia Therapeutics, Inc. | Inhibitors of LRRK2 kinase |
US11866423B2 (en) | 2021-03-23 | 2024-01-09 | Halia Therapeutics, Inc. | Inhibitors of LRRK2 kinase |
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