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WO2013001310A1 - Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de cdk8 - Google Patents

Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de cdk8 Download PDF

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WO2013001310A1
WO2013001310A1 PCT/GB2012/051526 GB2012051526W WO2013001310A1 WO 2013001310 A1 WO2013001310 A1 WO 2013001310A1 GB 2012051526 W GB2012051526 W GB 2012051526W WO 2013001310 A1 WO2013001310 A1 WO 2013001310A1
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alkylene
optionally substituted
substituents selected
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formula
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Inventor
Joaquín PASTOR FERNÁNDEZ
Rosa María ÁLVAREZ ESCOBAR
Carmen Varela Busto
Ana Belén GARCÍA GARCÍA
Natasha DIMITRIEVICH ZARICH
Carmen Blanco Aparicio
Ana RODRÍGUEZ LÓPEZ
Julen Oyarzabal Santamarina
James Robert BISCHOFF
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Centro Nacional de Investigaciones Oncologicas CNIO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as kinase inhibitors (such as inhibitors of the CDK8).
  • the compounds are of potential utility in the treatment of diseases such as cancer (particularly colorectal/colon cancer).
  • the invention also relates to the use of such compounds as medicaments, to the use of such compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • PKs protein kinases
  • a large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs.
  • the enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
  • protein kinases are enzymes that mediate intracellular signalling by affecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signalling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are triggered in response to a variety of extracellular and other stimuli. Many diseases, such as those mentioned above (or hereinafter), are associated with abnormal cellular responses triggered by these types of protein kinase mediated events.
  • CDK8 is a kinase that is involved in cell cycle control and also implicated in the regulation of transcription.
  • CDK8 is a kinase that is encoded by the CDK8 gene. It has been found that CDK8 is an oncogene that regulates ⁇ -catenin activity (see e.g. Nature (2008) vol. 455 (25) p547-553 by Firestein et al and Cancer Research (2009); 69(20): p7899-7901 by Firestein et al). CDK8 has been identified as a gene that both modulates ⁇ -catenin activity and is essential for colon cancer cell proliferation. The gene, which encodes a member of the mediator complex, is located at 13q12.13, which has been found to be a region of recurrent copy number gain in a substantial fraction of colon cancers.
  • CDK8 may activate ⁇ -catenin and other genes to drive colon cancer progression.
  • inhibitors of CDK8 may be useful in the treatment of such cancers (by which we include reducing the progression thereof) given that they may inhibit the expression of genes important for oncogenic progression and controlled by CDK8 and/or they may regulate ⁇ -catenin activity.
  • the pivotal role of CDKs in co-ordinating and driving the cell cycle in proliferating cells is proven, as are the biochemical pathways they are involved in.
  • CDK8 is linked to certain cancers.
  • targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells).
  • targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.
  • Targeted therapies could potentially have other advantages over current anti-cancer treatments, for instance because it may not directly interact with DNA (compared to certain known anti-tumour therapies) and should therefore reduce the risk of secondary tumour development.
  • ring A represents aryl or pyridyl, both of which are optionally substituted by one or more substituents selected from R 4 ;
  • R 1 represents hydrogen or C -6 alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R i1 , R i2 , R j3 , R' 4 , R j5 , R j6 , R j7 and R j8 independently represent hydrogen or (e.g. C 1-4 ) alkyl optionally substituted by one or more substituents selected from halo and -OR h ;
  • R h represents hydrogen or C -4 alkyl optionally substituted by one or more halo atoms;
  • Z represents -C 3-9 alkylene-, -C ⁇ alkylene-T ⁇ -C ⁇ alkylene-, -C(0)N(H)-, -N(H)C(0)-, -C 1-7 alkylene-T 5 -, -T 6 -C 1-7 alkylene- or -C 1-2 alkylene-N(H)-C(0)- d ⁇ alkylene-NCH)-, wherein the alkylene moieties are each optionally and independently substituted by one or more substituents selected from E 2 ; each T 4 represents -0-, -N(R 13 )-, -N(R )-C(0)-, -C(0)-N(R 15 )-, -C(O)-, -cycloalkylene-T 7 -, -heterocycloalkylene-T 7 -, -arylene-T 8 - (e.g.
  • each T 5 and T 6 independently represent -C(0)N(H)-, -N(H)C(0)-, -C(O)-, -cycloalkylene-T 7 -, -heterocycloalkylene-T 7 -, -arylene-T 8 - (e.g. -phenylene-) or -heteroarylene-T 9 - (e.g.
  • each T 7 , T 8 and T 9 independently represent a direct bond or -C(O)-; each R 10 , R 11 , R 12 , R 3 , R 14 and R 5 independently represent hydrogen or C 1-12 alkyl optionally substituted by one or more substituents selected from E 4 ; each E , E 2 , E 3 and E 4 independently represent:
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • esters and amides of the compounds of the invention are also included within the scope of the invention.
  • Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide.
  • esters of carboxylic acids of compounds of the invention
  • pharmaceutically acceptable esters include optionally substituted C -6 alkyl, C 5 . 0 aryl and/or C 5-10 aryl-C 1-6 alkyl- esters.
  • Pharmaceutically acceptable amides of carboxylic acids of compounds of the invention
  • C 1-6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.
  • Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.
  • prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
  • Compounds of the invention may contain double bonds and may thus exist as E ⁇ entalle) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
  • tautomer or tautomeric form
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • derivatisation i.e. a resolution, including a dynamic resolution
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereoisomers are included within the scope of the invention.
  • all stereoisomers are contemplated and included as the compounds of the invention.
  • stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, C, 13 C, 1 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l, and 125 l.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in schemes and/or the Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • C 1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C 3-q -cycloalkyl group).
  • Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2 . q alkenyl or a C 2 - q alkynyl group).
  • C -q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group). However, such C -q alkylene groups are preferably not branched.
  • C 3-q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bonds (forming for example a cycloalkenyl or cycloalkynyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
  • substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings, so forming a spiro-cycle.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Heterocycloalkyi groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is from five to ten (such as between five and ten). Such heterocycloalkyi groups may also be bridged. Further, such heterocycloalkyi groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2 . q heterocycloalkenyl (where q is the upper limit of the range) or a C 7 .
  • heterocycloalkynyl group C 2 .
  • q heterocycloalkyi groups that may be mentioned include 7- azabicyclo[2.2.1 ]heptanyl, 6-azabicyclo[3.1.1 ]heptanyl, 6-azabicyclo[3.2.1 ]- octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazoliny
  • heterocycloalkyi groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyi groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings (so forming a spiro cycle).
  • bicyclic e.g. when employed in the context of heterocycloalkyi groups refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring.
  • bridged e.g. when employed in the context of cycloalkyl or heterocycloalkyi groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6 .io aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have from 6 to 10 (such as between 6 and 10) ring carbon atoms, in which at least one ring is aromatic.
  • C 6- io aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • optional substituents may also be other cyclic groups, which may be, when attached to a non-aromatic ring of an aryl group, attached via a single carbon atom common to both rings (so forming a spiro-cycle).
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S.
  • Heteroaryl groups include those which have from 5 to 10 (such as between 5 and 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4- dihydro-2AY-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselena- diazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1
  • Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • optional substituents may also be other cyclic groups, which may be, when attached to a non-aromatic ring of a heteroaryl group, attached via a single carbon atom common to both rings (so forming a spiro-cycle).
  • heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • the heteroaryl group is monocyclic or bicyclic.
  • the heteroaryl may be consist of a five-, six- or seven-mem bered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulphur.
  • Linker groups for example as defined by Y and Z are specified with hyphens C'-"s) at the respective ends, depicting the points of attachment with the rest of the compound of formula I.
  • the first hyphen of the linking moiety is the point at which that moiety links to the requisite -N(R 1 )- moiety and the last hyphen depicts the linking point to the Y group.
  • the first hyphen represents the point of attachment to the Z group and the last hyphen represents the point of attachment to ring A.
  • cyclic substituents e.g. cycloalkyi or heterocycloalkyi groups
  • groups such as alkyl groups
  • compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
  • R 10 to R 15 this will be understood by the skilled person to mean R 10 , R 11 , R 2 , R 13 , R 14 and R 15 , inclusively.
  • Ring A represents phenyl or pyridyl (e.g. 3-pyridyl), both of which are optionally substituted by one or more substituents selected from R 4 ; preferably, ring A groups have a 1 ,3-linkage to the bicyclic core and Y group; more preferably still ring A represents one of the following groups:
  • squiggly lines represent the point of attachment to the bicyclic core and to the Y moiety, and the floating R 4 substituent represents one or more R 4 substituents attached to to relevant aromatic ring;
  • each R 4 independently represents represents halo (e.g. fluoro or chloro), -OR j2 , -N(R' )R j5 or -N(R i7 )C(0)R i8 ;
  • R j2 , R j4 , R j5 and R j7 independently represent hydrogen or C -4 alkyl (preferably unsubstituted);
  • R j8 represents C 1-4 alkyl (preferably unsubstituted, e.g. methyl).
  • each Q 7 and Q 8 independently represents -N(R 50 )R 51 , -OR 50 or, preferably, halo (e.g. fluoro) or C 1-3 alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms;
  • each R 50 , R 51 , R 52 and R 53 substituent independently represents, on each occasion when used herein, hydrogen or C 1-6 (e.g. C 1-3 ) alkyl optionally substituted by one or more substituents selected from fluoro;
  • R 60 , R 61 and R 62 independently represent methyl or hydrogen.
  • Preferred compounds of the invention include those in which:
  • R 20 , R 21 and R 22 independently represent hydrogen or, preferably, C 1-4 alkyl; or
  • R 20 and R 21 when attached to the same nitrogen atom are linked together to form a 5- or 6-membered ring, optionally containing a further heteroatom (e.g. nitrogen, or, preferably, oxygen) so forming, e.g. a morpholinyl group;
  • a further heteroatom e.g. nitrogen, or, preferably, oxygen
  • R 22 represents hydrogen
  • R 1 represents hydrogen or C 1-3 alkyl optionally substituted by one or more substituents selected from E 1 ; each R 2 and R 3 independently represent hydrogen or R j ;
  • R j1 represents C 1-2 alkyl (e.g. methyl; preferably unsubstituted);
  • Y represents -T - or -C 1-2 alkylene-T 3 - each T 1 represents -O- or -N(R 12 )C(0)-;
  • each T 3 preferably represents -0-;
  • Z represents -C 3 . 9 alkylene-, -Cvealkylene-T ⁇ -d-ealkylene- or -C -7 alkylene-T 5 -; more preferably, Z represents C 5 alkylene, -C ⁇ alkylene-T'-C ⁇ alkylene-, or -C 3 alkylene-T 5 -;
  • each T 4 represents -0-, -N(R 13 )- or -heterocycloalkylene-T 7 - (in which the net group is preferably a piperidinyl, e.g. 1 ,4-piperidinyl group);
  • each T 5 represents -N(H)C(0)-;
  • T 7 represents a direct bond or -C(O)-
  • each R 10 , R 11 , R 12 , R 3 , R 14 and R 15 independently represent hydrogen or C 1-4 alkyl optionally substituted by one or more substituents selected from E 4 ;
  • E 1 represents: (i) C 3-6 cycloalkyl (e.g. cyclopropyl) or a 5- or 6-membered heterocycloalkyl group (e.g. containing one or two heteroatoms, so forming e.g. a morpholinyl group), both of which are optionally substituted by one or more substituents selected from Q 5 (but which are preferably unsubstituted); or (ii) aryl (e.g. phenyl) optionally substituted by one or more substituents selected from Q 6 ;
  • E 4 represents: (i) Q 4 ; (ii) acyclic Ci -4 alkyl (e.g. methyl), C 3 - 6 cycloalkyl (e.g.
  • cyclopropyl or a 4-, 5- or 6-membered heterocycloalkyl group (e.g. containing one or two heteroatoms, so forming e.g. a morpholinyl, azetidinyl or piperidinyl group), both of which are optionally substituted by one or more substituents selected from Q 5 (but which are preferably unsubstituted); or (iii) aryl (e.g. phenyl) optionally substituted by one or more substituents selected from Q 6 ;
  • aryl e.g. phenyl
  • Q 4 represents -N(R 20 )R 21 or -OR 20 ;
  • Q 6 represents halo (e.g. chloro or fluoro);
  • R 20 and R 21 independently represent hydrogen or C -3 alkyl optionally substituted by one or more substituents selected from J 4 ;
  • J 4 represents Q 7 ;
  • Q 7 represents -OR 50 ;
  • R 50 represents hydrogen or preferably C 1-2 alkyl.
  • Particular compounds of the invention include compounds of formula I,
  • ring A represents phenyl optionally substituted by one or more substituents selected from R 4 ;
  • R 1 represents hydrogen or C 1-2 alkyl optionally substituted by one or more substituents selected from E 1 ;
  • Y represents -T - or -C -2 alkylene-, wherein the alkylene moieties are each independently substituted with one or more substituents selected from R 5 ;
  • T 1 represents -0-, -C(0)N(R 11 )- or -N(R 12 )C(0)-;
  • each R 2 , R 3 , R 4 and R 5 independently represents hydrogen or a substituent selected from halo, R j1 , -OR' 2 , -N(R j4 )R j5 , and -N(R i7 )C(0)R j8 ;
  • R j1 , R j2 , R j4 , R' 5 , R j7 and R j8 independently represent hydrogen or C 1-2 alkyl;
  • Z represents -C 3 . 9 alkylene-, or -C ⁇ alkylene-T ⁇ C ⁇ alkylene-; each T 4 represents -0-, -N(R 13 )-, -N(R 1 )-C(0)-, -C(0)-N(R 15 )-, or -heterocycloalkylene-T 7 -;
  • T 7 represents a direct bond or -C(O)-
  • Each R 11 , R 13 , R 4 and R 15 independently represents hydrogen or C 1-2 alkyl optionally substituted by one or more substituents selected from E 4 ; each E 1 and E 4 independently represents:
  • each Q 4 and Q 6 independently represents, on each occasion when used herein: halo, -N(R 20 )R 21 , or -OR 20 ; each R 20 and R 21 independently represents, on each occasion when used herein, hydrogen, or C -2 alkyl optionally substituted by one or more substituents selected from J 4 ;
  • J 4 represents -O-methyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • Particular compounds of the invention include compounds of formula I,
  • ring A represents phenyl optionally substituted by one or more substituents selected from R 4 ;
  • R 1 represents hydrogen or C 1-2 alkyl optionally substituted by one or more substituents selected from E ;
  • Y represents -0-, or -N(R 12 )C(0)-; each R 2 , R 3 , R 4 independently represents hydrogen or a substituent selected from halo;
  • Z represents -C 4 . 7 alkylene-, or -C-
  • T 4 represents -0-, -N(R 13 )- or -heterocycloalkylene-T 7 -; T 7 represents a direct bond;
  • R 13 represents hydrogen or methyl optionally substituted by one or more substituents selected from E 4 ; each E 1 and E 4 independently represents C -4 alkyl, heterocycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • Z 1 represents -C 1-6 alkylene-C(0)OH, -Ci -6 alkylene-N(R 1 )H, -C(0)OH, -NH 2 , -C 1-7 alkylene-C(0)OH, -C 1-7 alkylene-NH 2 , -C ⁇ alkylene-NHz
  • Z 2 respectively represents HN(R 15 )-C 1-6 alkylene-, HO(0)C-C 1-6 alkylene-, H 2 N-, HO(0)C-, H 2 N-, HO(0)C- and HO(0)C-C 1-2 alkylene-N(H)- (or derivatives thereof, such as carboxylic acid ester derivatives)
  • R 1 , R 2 , R 3 , R 4 , X, Y and ring A are as hereinbefore defined, which reaction is an amide coupling, which may be performed under standard reaction conditions, for instance the reaction may be performed in the presence of a suitable coupling reagent (e.g.
  • an appropriate solvent e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine
  • Preferred amide coupling reaction conditions include reaction in the presence of a coupling reagent HATU, PyBOP and/or HOAt, in the presence of a base (preferably DIPEA and, optionally D AP) and solvent (preferably DMF).
  • a base preferably DIPEA and, optionally D AP
  • solvent preferably DMF
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • acyl halide e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like
  • Z 3 represents -d. 6 alkylene-OH, -C 1-6 alkylene-N(R 13 )H or -C 1-6 alkylene-L x (in which L x is a suitable leaving group, such as chloro, bromo, iodo or a sulfonate group such as -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe), and Z 4 represents L y -Ci -6 alkylene-, HO-C -6 alkylene- or H(R 13 )N-Ci.
  • L x is a suitable leaving group, such as chloro, bromo, iodo or a sulfonate group such as -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe
  • Z 4 represents L y -Ci -6 alkylene-, HO-C -6 alkylene- or H(R 13 )N-Ci.
  • R 1 , R 2 , R 3 , R 4 , X, Y and ring A are as hereinbefore defined, which reaction may be peformed under standard nucleophilic substitution reaction conditions, for instance in the presence of a suitable base (e.g.
  • reaction may be performed in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex), copper tris(triphenyl- phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone)-dipalladium(0) (Pd 2 (dba) 3 ) or NiCI 2 and an optional additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-1 ,1'-bin
  • This reaction may be carried out under microwave irradiation reaction conditions or, alternatively, the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent;
  • R 1 , R 2 , R 3 , R 4 , X, Y and ring A are as hereinbefore defined, under reaction conditions such as those described hereinbefore in respect of process step (ii);
  • Y y represents HO(0)C-, HN(R 11 )-, HO(0)C-C 1-2 alkylene- or HN(R 11 )-C 1-2 - alkylene-
  • Z 6 represents -C 3-9 alkylene-N(R 11 )H, -C 3 . 9 alkylene-C(0)OH, -d- 6 alkylene-T -d-6alkylene-N(R 11 )H or -d- 6 alkylene-T -d- 6 alkylene-C(0)OH
  • R 1 , R 2 , R 3 , R 4 , X, Y and ring A are as hereinbefore defined, under reaction conditions such as those described hereinbefore in respect of process step (i);
  • R 10a"15a represents Ci -5 alkyl optionally substituted by one or more halo atoms, under reductive amination reaction conditions (for example in the presence of a chemoselective reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, or alternatively, as a two-step process included condensation and then reduction, which reduction step in this instance may be performed in the presence of a stronger reducing agent such as sodium borohydride or LiAIH 4 ); (vi) compounds of formula I containing a -N(R 10 )-CH 2 - or -N(R 13 )-CH 2 - moiety (e.g.
  • Z when Z contains a -N(R 3 )-CH 2 - moiety or Y contains a -N(R 0 )-CH 2 - moiety) may be prepared by reduction of a corresponding compound of formula I containing a -C(0)N(R 11 ), -N(R 12 )C(0)-, -N(R 14 )C(0)- or -C(0)N(R 15 ) moiety (e.g. when Z contains a -N(R 14 )-C(0)- moiety), for example in the presence of appropriate reduction reaction conditions, e.g. in the presence of a chemoselective reducing agent such as LiAIH 4 .
  • a chemoselective reducing agent such as LiAIH 4
  • L 2 represents a suitable leaving group, such as such as iodo, bromo, chloro, a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe), or a sulfide group (e.g. -S-C 1-6 alkyl, such as -SCH 3 ),
  • Z x represents Z Z 3 , Z 5 or Z 6 (depending on whether compound of formula II, III, IV or V is being prepared) and R 1 , R 2 , R 3 and ring X are as hereinbefore defined, with a compound of formula IX,
  • Y z represents ⁇ 2 - ⁇ -, ⁇ 4 - ⁇ -, Y - or Y y -
  • L 3 represents a suitable group, such as -B(OH) 2 , -B(OR wx ) 2 or -Sn ⁇ ),, in which each R wx independently represents a C 1-6 alkyl group, or, in the case of -B(OR wx ) 2 , the respective R wx groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), thereby forming e.g.
  • a pinacolato boronate ester group (or L 3 may represent iodo, bromo or chloro, provided that L 2 and L 3 are mutually compatible), and R 4 and ring A are as hereinbefore defined, under standard reaction conditions, for instance in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • a suitable catalyst system e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • catalysts include palladium and a ligand such as PdCI 2 (dppf).DCM, f-Bu 3 P, (C 6 Hii) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-terf-butyl- phosphino)-1 , 1 '-biphenyl, 2,2'-bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1 , 1 '- bis(diphenyl-phosphino-ferrocene), 1 ,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof (preferred ligands include PdCI 2 (dppf).DCM, f-Bu 3 P, (C 6 Hii) 3 P, Ph 3 P, AsPh 3 , P(o-
  • L 3 represents a sulfide (e.g. -SCH 3 )
  • an additive such as CuMeSal (copper(l) 3-methylsalicylate) or CuTC (copper(l)thiophene-2-carboxylate) may also be employed.
  • the reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system).
  • Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature, e.g. of about 130°C.
  • compounds of formula II, III, IV or V may be prepared by reaction of a compound of formula X,
  • L represents a suitable leaving group such as one hereinbefore defined for L 2
  • R 1 , R 2 , R 3 , R 4 , X, Y z and ring A are as hereinbefore defined, with a compound of formula XI, H(R 1 )N-Z X XI wherein R and Z x are as hereinbefore defined, under standard coupling reaction conditions, for instance in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone)- dipalladium(O) (Pd 2 (dba) 3 ) or NiCI 2 and an optional additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal
  • This reaction may be carried out under microwave irradiation reaction conditions or, alternatively, the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent.
  • L 4 represents a suitable leaving group, such as one hereinbefore defined for L x (e.g. chloro, bromo or iodo) and Z x is as hereinbefore defined, under standard reaction conditions such as those hereinbefore described in respect of process step (ii) above.
  • L 2 , L 2a , R 2 and R 3 are as hereinbefore defined, with a compound of formula XI as hereinbefore defined, under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula II, III, IV and V (reaction of compounds X and XI).
  • Compounds of formula II, III, IV, V, X and XII may be prepared by reaction of a compound of formula XV,
  • X z represents (R 1 )(Z 1 )N-, (R )(Z 3 )N-, (R )(Z 5 )N-, (R )(Z 6 )N-, L 2a or H 2 N- (or mono-protected derivative thereof) (depending on the compound to be prepared, i.e. if it is a compound of formula II, III, IV, V, X or XII), L 5 represents a suitable leaving group such as one hereinbefore defined for L 2 , and R 2 , R 3 and X are as hereinbefore defined, with a compound of formula XVI,
  • L 6 represents a suitable group such as one hereinbefore defined for L 3
  • Y z , R 4 and ring A are as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of compounds of formula II, III, IV or V (reaction between compounds VIII and IX).
  • Compounds containing a halo atom e.g.
  • a source of halide ions for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, N- iodosuccinimide, a source of bromide ions includes /V-bromosuccinimide and bromine, and a source of chloride ions includes /V-chlorosuccinimide, chlorine and iodine monochloride.
  • a source of halide ions for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, N- iodosuccinimide, a source of bromide ions includes /V-bromosuccinimide and bromine, and a source of chloride ions includes /V-chloro
  • Compounds containing a -OH moiety may be converted to a suitable leaving group, e.g. by conversion to a corresponding bromo or iodo moiety (e.g. by reaction in the presence of HBr or l 2 /Ph 3 P) or by conversion to a sulfonate (e.g. by reaction with a sulfonyl chloride).
  • a suitable leaving group e.g. by conversion to a corresponding bromo or iodo moiety (e.g. by reaction in the presence of HBr or l 2 /Ph 3 P) or by conversion to a sulfonate (e.g. by reaction with a sulfonyl chloride).
  • Wiley &Sons Ltd Chichester, UK, 2002, and references cited therein;
  • oxidations for example of a moiety containing an alcohol group (e.g. -CH 2 OH) to an aldehyde (e.g. -C(O)H) or of a -S- moiety to a -S(O)- or -S(0) 2 - moiety (or the reverse reduction reaction), for example in the presence of a suitable oxidising agent, e.g. Mn0 2 or mcpba or the like;
  • a suitable oxidising agent e.g. Mn0 2 or mcpba or the like
  • a reducing agent such as a chemoselective one mentioned above or NaBH 4 , AIH 4 , or the like
  • a reducing agent such as sodium cyanaoborohydride (i.e. overall a reductive amination)
  • an amide or sulfonamide for example by reaction of a sulfonyl choride with an amine or by an amide coupling reaction, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example -C(0)OH (or an ester thereof), may be converted to -C(O)N(R 20 )R 21 group (in which R 20 and R 2 are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. for -COOH) be performed in the presence of a suitable coupling reagent (e.g.
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R Z0 )R 21 (in which R 20 and R 21 are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • nucleophilic substitution e.g. aromatic nucleophilic substitution
  • any nucleophile replaces a leaving group e.g. an amine may replace a -S(0)CH 3 leaving group
  • deprotection steps such as deprotection of an A/-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a tert-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF);
  • TBAF reagent tetrabutylammonium fluoride
  • aromatic nitration reactions for instance which may be performed on compounds corresponding to compounds of formula X, but in which the -NH 2 group is replaced with a -N0 2 group; subsequent conversion of the nitro group may take place separately - see (xii) below); e.g. by reaction in the presence of nitric acid at low temperature, followed by addition of cone. H 2 S0 4 );
  • the substituents R 1 , R 2 , R 3 , R 4 , Y and Z (or substituents on the main core structure, including substituents on ring A or on linker groups Y and Z) in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • the relevant ester group may be hydrolysed to form a carboxylic acid functional group.
  • transformation steps include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed).
  • a source of cyanide ions e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst
  • transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a -alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g.
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g.
  • a tri-(C 1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine
  • introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 4 , at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g.
  • diazotisation e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 4 , at low temperature such as at 0°C or below, e.g. at about -5°C
  • a source of the relevant anions for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN 3 or NaCN; the conversion of -C(0)OH to a -NH 2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN 3 (which may be formed in by contacting NaN 3 with a strong acid such as H 2 S0 4 ), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO) 2 P(0)N 3 ) in the presence of an alcohol, such as ferf-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH 2 to -NH 2 , for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br 2 ) which may result in the formation of a
  • Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, ⁇ , ⁇ -disubstituted carboxamides, carboxylic acids, and the like.
  • the operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C.
  • Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide.
  • carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art.
  • amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like.
  • an acid e.g. HCI in water/alcohol (e.g. MeOH)
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • CDK8 kinase activity may be implicated in the regulation of nuclear ⁇ -catenin activity
  • the compounds of the invention may therefore be useful in the treatment of disorders in an individual in which the inhibition of CDK8 is desired/required (which includes disorders in which the regulation, or reduction of, nuclear ⁇ -catenin activity and/or inhibition, or modulation of, the expression of CDK8 (i.e. the oncogene) is desired/required).
  • the term "inhibit" may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. CDK8) activity.
  • the reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. CDK8) in the absence of a compound of the invention, as would be apparent to those skilled in the art.
  • the measurable change may be objective (e.g. measurable by some test or marker, for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be found to exhibit 50% inhibition of a protein kinase activity (e.g. CDK8) at a concentration of 100 ⁇ or below (for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇ ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person.
  • a protein kinase activity e.g. CDK8
  • Compounds of the invention are thus expected to be useful in the treatment of a disorder in which a protein kinase (e.g. CDK8) is known to play a role and which is characterised by or associated with an overall elevated activity of that kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase).
  • a protein kinase e.g. CDK8
  • the compounds of the invention may also be useful in the treatment of conditions/disorders associated with elevated nuclear ⁇ -catenin activity and/or elevated expression (or over-expression) of CDK8 (i.e. the known oncogene).
  • compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein kinase (e.g. CDK8).
  • diseases/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders, neurological disorders and autoimmune disorders.
  • conditions/disorders include cancers, especially specific cancers such as colon/colorectal cancer(s) and it is therefore particularly preferred that compounds of the invention may be of use in treating such specific cancers.
  • the disorders/conditions that the compounds of the invention may be useful in treating hence includes cancer (such as lymphomas, solid tumours or a cancer as described hereinafter), obstructive airways diseases, allergic diseases, inflammatory diseases (such as asthma, allergy and Chrohn's disease), immunosuppression (such as transplantation rejection and autoimmune diseases), disorders commonly connected with organ transplantation, AIDS- related diseases and other associated diseases.
  • cancer such as lymphomas, solid tumours or a cancer as described hereinafter
  • obstructive airways diseases such as lymphomas, solid tumours or a cancer as described hereinafter
  • allergic diseases such as asthma, allergy and Chrohn's disease
  • immunosuppression such as transplantation rejection and autoimmune diseases
  • disorders commonly connected with organ transplantation such as asthma, allergy and Chrohn's disease
  • Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • non- malignant diseases such as benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • cardiovascular disease cardiovascular disease
  • stroke diabetes
  • diabetes hepatomegaly
  • Alzheimer's disease cystic fibrosis
  • hormone-related diseases immunodeficiency disorders
  • destructive bone disorders infectious diseases
  • conditions associated with cell death thrombin-induced platelet aggregation
  • chronic myelogenous leukaemia liver disease
  • pathologic immune conditions involving T cell activation and CNS disorders.
  • the compounds of the invention may be useful in the treatment of cancer. More, specifically, the compounds of the invention may therefore be useful in the treatment of a variety of cancer including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including non-small cell cancer and small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma, testis, genitourinary tract, larynx, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passage
  • carcinoma
  • a method of treatment of a disease which is associated with the inhibition of a protein kinase (e.g. CDK8) i.e. where such inhibition is desired and/or required (the disease may also be associated with increased nuclear ⁇ -catenin activity and/or elevated expression of CDK8), for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein kinases, e.g. CDK8, which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
  • a patients include mammalian (including human) patients.
  • the method of treatment discussed above may include the treatment of a human or animal body.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • the amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are inhibitors of kinases (e.g. protein por lipid kinases, such as CDK8) and/or useful in the treatment of a cancer and/or a proliferative disease.
  • Compounds of the invention may also be combined with other therapies (e.g. radiation).
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • kits of parts as hereinbefore defined, by bringing the two components "into association with” each other, we include that the two components of the kit of parts may be:
  • compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of the invention.
  • compounds of the invention may have the advantage that they are effective inhibitors of protein kinases (e.g. CDK8). Advantegously, compounds of the invention may inhibit (e.g. selectively) certain protein kinases (e.g. CDK8), without exhibiting inhibition (or significant inhibition) of other protein or lipid kinases. For instance, the compounds of the invention may selectively inhibit only one protein kinase (e.g. CDK8).
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
  • Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by interfering with or inhibiting it (e.g. in this case by inhibiting a protein kinase as hereinbefore described).
  • Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, such as colon/colorectal cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g. by preventing the killing of normal cells, as may occur using e.g. chemotherapy).
  • compounds of the invention may selectively target a particular protein kinase (e.g. CDK8) compared to other known protein or lipid kinases. Accordingly, compounds of the invention may have the advantage that certain, specific, cancers (e.g. colon/colorectal cancer) may be treated selectively, which selective treatment may also have the effect of reducing side effects.
  • a particular protein kinase e.g. CDK8
  • CDK8 protein kinase
  • compounds of the invention may have the advantage that certain, specific, cancers (e.g. colon/colorectal cancer) may be treated selectively, which selective treatment may also have the effect of reducing side effects.
  • Targeted therapies could potentially have other advantages over current anti-cancer treatments, for instance because it may not interact with DNA (compared to certain known anti-tumour therapies) and should therefore reduce the risk of secondary tumour development.
  • the biding assay relies on the LanthaScreenTM Eu-Kinase Binding Assay (Invitrogen. This is a kinase assay platform based on measuring the binding and displacement of an Alexa Fluor® 647 conjugate of an ATP-competitive kinase inhibitor (Kinase Tracer 236, PV5592) at a kinase active site. Binding of the tracer to the kinase is detected by addition of a europium (Eu)-labeled anti-His antibody (Invitrogen PV 5596), which specifically labels the kinase of interest. This binding results in a high degree of fluorescence resonance energy transfer (FRET), whereas displacement of the tracer with a kinase inhibitor results in a loss of FRET.
  • FRET fluorescence resonance energy transfer
  • the enzyme has been purchase from Invitrogen (PV4402) as a dimer of full- length His-tagged recombinant human proteins. Assay conditions were as indicated by the kit manufacturers with the following adaptations:
  • Assay buffer 50 mM HEPES, pH 7.5, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCI 2
  • Tested compound Serial 1 :3 dilutions
  • Assays were performed in 384-well plates. The final read out was generated using an EnVision plate reader (Perkin-Elmer). The emission ratio was calculated by dividing the acceptor/tracer emission (665 nm) by the antibody/donor emission (615 nm).
  • Reporter system to assay ⁇ -catenin transcriptional activity Efficacy of compounds of the invention on the inhibition of the transcriptional activity of ⁇ -catenine driven by CDK8 is measured in a Luminescent reporter assay. EC 50 values are established for the tested compounds.
  • the TOPFIash luciferase reporter system has been adopted as a standard for detecting ⁇ -catenin driven transcriptional activation.
  • the reporter used is a 6X TOPFIash reporter meaning that it contains 6 TCF/LEF-1 binding sites upstream of a minimal promoter driving expression of Firefly luciferase.
  • a FOPFIash reporter which contains mutated TCF sites upstream of Renilla luciferase open frame in the enhancer region, is used as a negative control to show that the change in luciferase activity is specifically due to ⁇ -catenin transcriptional activity (Promega).
  • the detection is done with the Dual-Glo® Luciferase Assay System (Promega); this is a homogeneous reagent system that enables fast and simple quantitation of a stable luminescent signal from two reporter genes in a single sample. This convenient "add-and-read” system generates both firefly and Renilla luciferase luminescence signals from cells that have not been preconditioned or prelysed.
  • the assay was conducted in 96-well plates making it amenable to automated highthroughput screening (HTS).
  • HTC116 colon cancer cells were seeded, 15000 cells per well, into 96-well plates and incubated for 16 h at 37°C, 5% C0 2 .
  • the cells were transfected using Effectene reactive (Quiagen) with TOPFIash and FOPFIash luciferase reporters plasmids.
  • Cells were incubated with transfection complexes under normal growth conditions for 5h.
  • Eight serial 1 :3 compound dilutions are made in DMSO in a 96-well plate. The compounds are added to duplicate wells in 96-well cell plates using a FX BECKMAN robot (Beckman Coulter) and are incubated at 37°C under C0 2 atmosphere over night.
  • DCM dichloromethane
  • MeOH means methanol
  • THF means tetrahydrofuran
  • DMF means dimethylformamide
  • DME means 1 ,2-dimethoxyethane
  • EtOAc means ethyl acetate
  • Pd(PPh 3 ) 4 means tetrakis(triphenylphosphine)palladium
  • DIPEA means diisopropylethylamine
  • min means minutes
  • H means hours
  • eq means equivalents
  • nBuOH means n-butanol
  • mw means microwave
  • CCTLC means centrifugal circular thin-layer chromatography.
  • NMR spectra were recorded in a Bruker Avance II 300 spectrometer and Bruker Avance II 700 spectrometer fitted with 5mm QXI 700 S4 inverse phase, Z- gradient unit and variable temperature controller.
  • the HPLC measurements were performed using a HP 1100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas. Data acquisition was performed with ChemStation LC/MSD quad, software.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid. Gradient: 5% to 100% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid.
  • Gradient 5% to 40% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid. Gradient: 0% to 30% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid. Gradient: 10% to 95% of B within 4 min at 50°C, DAD.
  • Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid.
  • Gradient 0% to 30% of B within 4 min at 50°C, DAD.
  • the aldehyde contained an amine boc-protected, then, deprotection of the boc-protected obtained compounds was achieved by treatment with amberlyst(r) 15.
  • CDCI 3 ⁇ 8.28 (m, 1H), 7.74 (s, 1H), 7.58 (d,
  • CDCI3 ⁇ 9.19 (s, 1 H), 8.00 (s, 1 H), 7.87 (m, 2H), 7.72 (m, 1 H), 7.55 (m, 1 H), 7.43
  • CDCI3 ⁇ 9.16 (s, 1 H), 8.12 (s, 1 H), 7.94 (s, 1 H), 7.82 (m, 3H), 7.55 (m, 1H), 6.85 (d, J
  • CDCIs ⁇ 8.18 (m, 1 H), 7.81 (s, 1 H), 7.65 (d, J 9.9 Hz, 1H), 7.28 (m, 2H), 6.85 (m, 1 H),
  • Table 7 Cell Data. The following table demonstrates that representative compounds of the examples inhibit the transcriptional activity of ⁇ -catenine [EC50 values (nM)] driven by CDK8 in the cellular assay described hereinbefore.

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Abstract

L'invention concerne des composés de formule I, où R1, R2, R3, R4, X, Y, Z et le cycle A ont les significations données dans la description, et des esters, amides, solvates ou sels pharmaceutiquement acceptables de ceux-ci, les composés étant utiles dans le traitement de maladies dans lesquelles l'inhibition d'une protéine kinase ou d'une lipide kinase (par exemple CDK8) est souhaitée et/ou nécessaire, et particulièrement dans le traitement du cancer ou d'une maladie de prolifération.
PCT/GB2012/051526 2011-06-30 2012-06-29 Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de cdk8 Ceased WO2013001310A1 (fr)

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