WO2011110824A1 - Composés bis aromatiques destinés à être utilisés en tant qu'inhibiteurs de ltc4 synthase - Google Patents

Composés bis aromatiques destinés à être utilisés en tant qu'inhibiteurs de ltc4 synthase Download PDF

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WO2011110824A1
WO2011110824A1 PCT/GB2011/000358 GB2011000358W WO2011110824A1 WO 2011110824 A1 WO2011110824 A1 WO 2011110824A1 GB 2011000358 W GB2011000358 W GB 2011000358W WO 2011110824 A1 WO2011110824 A1 WO 2011110824A1
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formula
compound
optionally substituted
group
alkyl
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PCT/GB2011/000358
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English (en)
Inventor
Peter Nilsson
Benjamin Pelcman
Martins Katkevics
Robert RÖNN
Christian Krog-Jensen
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Biolipox Ab
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Priority claimed from PCT/GB2010/000438 external-priority patent/WO2010103278A1/fr
Application filed by Biolipox Ab filed Critical Biolipox Ab
Priority to EP11713851A priority Critical patent/EP2545036A1/fr
Priority to US13/634,221 priority patent/US20130035358A1/en
Publication of WO2011110824A1 publication Critical patent/WO2011110824A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of the production of leukotrienes, such as leukotriene C 4 .
  • the compounds are of potential utility in the treatment of respiratory and/or inflammatory diseases.
  • the invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • Arachidonic acid is a fatty acid that is essential in the body and is stored in cell membranes. They may be converted, e.g. in the event of inflammation, into mediators, some of which are known to have beneficial properties and others that are harmful.
  • mediators include leukotrienes (formed by the action of 5-lipoxygenase (5-LO), which acts by catalysing the insertion of molecular oxygen into carbon position 5) and prostaglandins (which are formed by the action of cyclooxygenases (COXs)).
  • 5-LO 5-lipoxygenase
  • COXs cyclooxygenases
  • leukotriene (LT) B 4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C 4 , D 4 and E 4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma. It has also been suggested that the CysLTs play a role in inflammatory mechanisms. The biological activities of the CysLTs are mediated through two receptors designated CysLT, and CysLT 2 , but the existence of additional CysLT receptors has also been proposed.
  • Leukotriene receptor antagonists (LTRas) have been developed for the treatment of asthma, but they are often highly selective for CysLT, .
  • Asthma is a chronic inflammatory disease affecting 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen.
  • Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.
  • Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat.
  • COPD chronic obstructive pulmonary disease
  • Y 1 represents -C(0)OR 9a or 5-tetrazolyl
  • R 9a represents:
  • Ci-8 alkyl or a heterocycloalkyl group both of which are optionally substituted by one or more substituents selected from G 1 and/or Z 1 ;
  • one of Y 2 and Y 3 represents an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A) and the other represents either:
  • Ci-8 alkyl or a heterocycloalkyl group both of which are optionally substituted by one or more substituents selected from G and/or Z 1 ; or
  • X 1 , X 2 , G 1 and B independently represent halo, -R 5a , -C(0)R 5b , -CN, -N0 2 , -C(0)N(R 6a )R 7a , -N(R 6b )R 7b , -N(R 5c )C(0)R 6c , -N(R M )C(0)OR 6d , -OR 5e , -OS(0) 2 R 5f , -S(0) m R 59 , -OC(0)R 5h or -S(0) 2 N(R 6e )R e ; R 5b to R 5e , R 5g , R 5 , R 6a to R 6c , R 6e , R 7a , R 7b and R 7e independently represent, on each occasion when used herein, H or R 5a ; or any of the pairs R 6a and R 7a , R 6b and R 7b , or R 6e and R 7e
  • R 5f and R 6d independently represent R 5a ;
  • R 5a represents, on each occasion when used herein:
  • aryl or heteroaryl both of which are optionally substituted by one or more substituents selected from halo, -CN, -OR 8a , -N(R 8b )R 8c , -S(0) n R 8d and/or -S(0) 2 N(R 8e )R 8f ;
  • n represents 0, 1 or 2;
  • R 8 and R 8c and/or R 8e and R 8 ⁇ may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, optionally substituted by one or more substituents selected from fluoro and C -2 alkyl;
  • R 1 a and R 13a independently represent H or Ci -3 alkyl optionally substituted by one or more fluoro atoms;
  • R 1Za , R 2b , R 14a and R 1 b independently represent H, -CH 3 or -CH 2 CH 3 ;
  • R 16b represents hydrogen or alkyl optionally substituted by one or more fluoro atoms;
  • L 1 represents a single bond or -(CH 2 )p-Q-(CH 2 )q-;
  • Q represents -C ⁇ XR* 2 )-, -C(O)-, -N(R y3 )- or -0-;
  • p and q independently represent 0, 1 or 2, but wherein the sum of p and q does not exceed 2;
  • one of L 2 and L 3 represents -C(0)-A 17 - (e.g.
  • n1 represents 0, 1 or 2;
  • a 16 represents a direct (i.e. a single) bond, -C(R y6 )(R y7 )-, -C(O)-, -C(0)N(R 17b )-, -C(0)C(R y6 )(R y7 )- or -S(0) 2 -; each A 17 independently represents a direct bond or -C(R y8 )(R y9 )-; each R y ⁇ R y2 , R y4 , R y5 , R y6 , R y7 , R y8 and R y9 independently represent H, fluoro or C-i.3 alkyl optionally substituted by one or more fluoro atoms; or
  • R y and R y2 , R y4 and R y5 , R ⁇ and R y7 and R y8 and R y9 may be linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and C 1-2 alkyl;
  • R y3 represents hydrogen or d. 3 alkyl
  • R 30 and R 3 independently represent halo, -R 18a , -C(0)R 18b , -CN, -C(O)N(R 180 )R 18d , -N(R 18e )R 18f , -N(R 18g )C(0)R 18h , -N(R 18i )C(0)OR 18i , -OR 8k , -OS(0) 2 R 18m , -S(0) m R 18n , -OC(0)R 18p or -S(0) 2
  • R 18a , R 18b , R 18c , R 18d , R 18e , R 18f , R 189 , R 18h , R 18i , R 18k , R 18n , R 18p , R 18q and R 18r independently represent hydrogen or Ci -3 alkyl optionally substituted by one or more fluoro atoms;
  • R 18i and R 18m independently represent C 1-3 alkyl optionally substituted by one or more fluoro atoms;
  • R 19 represents hydrogen or alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically-acceptable salt thereof, which compounds and salts are referred to hereinafter as "the compounds of the invention".
  • Pharmaceutically-acceptable 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.
  • Compounds of the invention may contain double bonds and may thus exist as E (entadel) and Z ⁇ zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • 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. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • Ci.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 group).
  • Such cycloalkyi 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.
  • alkyl groups may also be spiro-groups (i.e. two cycloalkyi rings linked together by a single common carbon atom), although they are preferably not so.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Heterocycloalkyi groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyi groups (which groups may further be bridged) 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 between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyi group).
  • such heterocycloalkyi groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q (e.g.
  • C 4-q ) heterocycloalkenyl (where q is the upper limit of the range) or a C 7 . q heterocycloalkynyl group.
  • C 2 1 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
  • Substituents on heterocycloalkyi groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyi group, forming a so- called "spiro"-compound.
  • 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.
  • Heterocycloalkyi groups may also be in the N- or S- oxidised form.
  • a heterocycloalkyi group is preferably a 3- to 8-membered heterocycloalkyi group (e.g. a 5- or 6-membered heterocycloalkyi group).
  • 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 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 (such as (e.g. C ⁇ o)) aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic.
  • C 6 -i 4 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl.
  • 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 preferably linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom).
  • Heteroaryl groups that may be mentioned include oxazolopyridyl (including oxazolo[4,5-6]pyridyl, oxazolo[5,4-b]pyridyl and, in particular, oxazolo[4,5-c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5-6]pyridyl, thiazolo[5,4-b]pyridyl and, in particular, thiazolo[4,5- cjpyridyl and thiazolo[5,4-c]pyridyl) and, more preferably, benzothiadiazolyl (including 2, 1 ,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, be
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of 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 when polycyclic, they are preferably linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
  • the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.
  • the alkyl groups in question may be the same or different.
  • groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent.
  • R 53 to R 5 when a term such as "R 53 to R 5 " is employed herein, this will be understood by the skilled person to mean R 5a , R 5b , R 5c , R 5d , R 5e , R 5 ', R 59 and R 5h inclusively.
  • an R 5 group when the term “an R 5 group” is referred to herein, we mean any one of R 5a to R 5h .
  • E-, to E r containing ring refers to the ring containing E 2a , E 2b , E 2c and E 4 .
  • D 7 to Ds-containing ring refers to the ring containing Di, D 2 and D 3 .
  • the following compounds of formula la, lb and Ic are included within the scope of the compounds of formula I:
  • cyclised form we mean a form in which two substituents of the same molecule undergo an intramolecular cyclisation (e.g. a reversible intramolecular cyclisation), including the following compounds of formula IA, in which the integers are as defined herein (i.e. in respect of compounds of formula I and other preferred compounds of the invention).
  • Such compounds may exist in particular when Y 2 represents C 1-12 alkyl as hereinbefore defined (e.g. acyclic C L12 alkyl). Such compounds are encompassed within the scope of compounds of the invention (and fall within the scope of compounds of formula I).
  • compounds of formula I in which Y 2 represents -C(O)- may exist as such, may exist as compounds of formula IA, or may exist as a mixture of both (i.e. the compounds may be in equilibrium, such as a slow or rapid equilibrium measured on an NMR time scale).
  • the exact amount of compound of formula I or compound of formula IA may depend on the acidity of the environment, the solvent, concentration, temperature, and other factors known to the skilled person.
  • a compound of formula IA as such and as defined above (which would include corresponding compounds of formula I in which Y 2 represents -C(O)-).
  • n1 1 ;
  • a 16 represents a direct bond, -C(O)-, -C(0)N(R 17 )-, -C(0)C(R yS )(R y7 )- or -S(0) 2 -;
  • X 1 , X 2 , G 1 and B independently represent halo, -R 5a , -C(0)R 5b , -CN,
  • a 16 is preferably -C(O)-.
  • R 1 or R 2 represent a substituent defined by R 5a
  • R 5a preferably represents alkyl optionally substituted as defined herein;
  • Y 2 preferably does not represent a 5-membered heteroaryl group, an o/tho-substituted phenyl group (in which the ortho substituent is e.g. an aromatic group, alkyl or heterocycloalkyi moiety, especially an aromatic group), naphthyl, a 9- or 10-membered heteroaryl group, a cycloalkyl group or a vinyl moiety (e.g. a bicyclic 5,6-fused heteroaryl group linked via the 5-membered ring; a 5-membered heteroaryl group substituted with at least one aromatic, alkyl or heterocycloalkyi (e.g. aromatic) group; a phenyl group substituted at the orffto-position e.g. with an aromatic group; or a vinylic moiety terminally substituted with e.g. an aromatic group).
  • the ortho substituent is e.g. an aromatic group, alkyl or heterocycloalkyi moiety, especially an aromatic group
  • L 2 represents a single bond or a spacer group selected from -C(R y4 )(R y5 )-, -N(R 17a )-A 16 - and -OA 17 - (in which case L 3 must represent -C(0)-A 17 -);
  • L 2 represents a spacer group selected from -S(O)-, -C(R y4 )(R y5 )-, -N(R 17a )-A 16 - and -OA 17 - (in which case L 3 must represent -C(0)-A 17 -);
  • L 2 represent a spacer group selected from -C(R y4 )(R y5 )-, -N(R 7a )-A 16 - and -OA 17 - (in which case L 3 must represent -C(0)-A 17 -).
  • R 5a represents C 1-6 alkyl
  • R 5a represents C 1-6 alkyl, then it may not be substituted by a -C(0)OR 8a group
  • R 5a represents alkyl
  • R 8c and/or R 8f represent C 1-3 alkyl
  • R 17a or R 17 represent a C,. 6 alkyl group
  • R 5a represents, on each occasion when used herein, C -6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, -0R 8a , -N(R 8b )R 8c , -S(0) n R 8d and/or -S(0) 2 N(R 8e )R 8f ; or
  • R 7a and R 17 represent optionally substituted alkyl
  • halo group is preferably fluoro
  • Such rings are preferably 5- or 6-membered
  • the ring so formed does not contain any further heteroatoms (other than the requisite nitrogen atom to which the relevant R 6 and R 7 groups are necessarily attached);
  • R 5a represents C 3 alkyl (e.g. ethyl, /7-propyl or, more preferably, methyl) optionally substitiuted by one or more fluoro atoms (so forming, for example, a trifluoromethyl or difluoromethyl group);
  • -OR 5h e.g. -OH, -OCH 3 , -OCF 3 or -OCHF 2
  • fluoro, 0 and, especially, R 5a (for example, as defined above)
  • any of the pairs R 8 and R 8c and/or R 8e and R 8f are linked together to form a 3- to 6-membered ring, then preferably: such rings are preferably 5- or 6-membered;
  • Such rings are preferably unsubstituted.
  • any of the pairs R y1 and R y2 , R y4 and R y5 , R y6 and R y7 and/or R y8 and R y9 are linked together to form a 3- to 6- membered ring, then preferably: such rings are preferably 4-membered or, more preferably, 3-membered;
  • Such rings are preferably unsubstituted.
  • at least one of the D, to D 3 -containing ring and Ei to E 4 -containing ring contains (a) nitrogen atom(s) (i.e. either one of those rings, or both of those rings contains two or preferably one nitrogen atom(s)).
  • Preferred compounds of the invention include those in which:
  • Preferred compounds of the invention that may be mentioned include those in which:
  • Y 2 and Y 3 independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
  • Y 2 or Y 3 represent optionally substiuted d. 12 alkyl, then it is preferably optionally substituted cycloalkyl (such as C 3-12 (e.g. C 3-8 ) cycloalkyl and, preferably, C 5 . 6 alkyl);
  • Y 2 and Y 3 independently represent cyclic groups optionally substituted as defined herein, i.e. aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from A), cycloalkyl or heterocycloalkyl (which latter two groups are as defined herein; and both of which are optionally substituted by one or more substituents selected from G 1 and/or Z );
  • Y represents -C(O)-.
  • one of L 2 and L 3 represent(s) a spacer group selected from -C(R y )(R y5 )-. -N(R 17a )- A 6 -, and -OA 17 - (and the other represents the requisite -C(0)-A 17 - moiety);
  • Y 2 and Y 3 represent an aryl group optionally substituted as defined herein;
  • Y 2 or Y 3 preferably does/do not represent a benzimidazolyl (e.g. benzimidazol-2-yl) group.
  • Preferred rings that the ⁇ to E 4 -containing ring may represent include pyrazinyl, pyrimidinyl, pyridazinyl and, preferably, pyridyl groups.
  • the Ei to E 4 - containing ring represents a pyrazinyl, pyrimidinyl or pyridazinyl (e.g.
  • E 2b preferably, E 2a or E 2c , or, especially, one of E ⁇ or E 4 , i.e. one of the ortho positions, relative to the point of attachment with the Y moiety
  • the Ei to E 4 -containing ring is preferably a pyridyl (e.g. 4-pyridyl, 3-pyridyl or especially a 2-pyridyl) group.
  • Preferred aryl and heteroaryl groups that Y 2 and Y 3 may independently represent include optionally substituted (i.e. by A) phenyl, naphthyl (e.g. 5,6,7,8- tetrahydronaphthyl), pyrrolyl, furanyl, thienyl (e.g. 2-thienyl or 3-thienyl), imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl (e.g.
  • Preferred groups include thienyl, thiazolyl,
  • Preferred substituents on Y 2 and Y 3 groups include:
  • halo e.g. bromo or, preferably, fluoro or chloro
  • alkyl which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C 1-4 alkyl (such as ethyl, n-propyl, isopropyl, f-butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);
  • halo e.g. fluoro
  • R 26 and R 27 independently represent, on each occasion when used herein, H, Ci -6 alkyl, such as C 1-4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a perfluoroethyl or, preferably, a trifluoromethyl group) or aryl (e.g. phenyl) optionally substituted by one or more halo or C ⁇ . 2 (e.g. Ci.
  • C 1-4 alkyl e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl or isopropyl
  • halo e.g. fluoro
  • aryl e.g. phenyl
  • R 26 does not represent hydrogen.
  • Preferred compounds of the invention include those in which:
  • At least one (e.g. at least two) of those R 2 groups represents hydrogen
  • R 2 groups when two R 2 groups are present, then at least one of them represents hydrogen; at least one (e.g. at least two) R 1 group that may be present represents hydrogen; X 1 , X 2 , G 1 and B independently represent -C(0)N(R 6a )R 7a , -N(R 6b )R 7b or, preferably, halo (e.g. chloro or fluoro), -R 5a , -OR 5e or -S(0) m R 5g ;
  • halo e.g. chloro or fluoro
  • R a and R 3a independently represent -CF 3 , preferably ethyl, and particularly hydrogen and/or methyl;
  • R 12a , R 12 , R 14a and R 14b independently represent methyl or hydrogen (particularly, methyl);
  • L 1 represents a single bond
  • Y 1 represents 5-tetrazolyl (which is preferably unsubstituted) or, preferably, -C(0)OR 9a ;
  • R 9a represents Ci -6 alkyl (optionally substituted by one or more G 1 and/or Z 1 substituents; but preferably unsubstituted) or, preferably, hydrogen;
  • Y 2 and Y 3 represents aryl (e.g. phenyl) optionally substituted as defined herein;
  • Y 2 and Y 3 may be the same or different;
  • A represents aryl or heteroaryl (e.g. aryl, such as phenyl optionally substituted by halo, e.g. fluoro or chloro), but A preferably represents G 1 or C 1-6 (e.g. alkyl (e.g. butyl (such as n-butyl) or methyl) optionally substituted by one or more substituents selected from G ;
  • R 5a represents C 1-6 (e.g. C 1-4 ) alkyl optionally substituted by one or more substituents selected from -N(R 8b )R 8c and, preferably, fluoro and -OR 8a ;
  • R 6a and R 7a , R 6b and R 7 and/or R 6e and R 7e are preferably not linked together; when R 5e represents R 5a , then R 5a preferably represents C 1-6 (e.g. d- alkyl
  • R 16b represents Ci. 2 alkyl (e.g. methyl) or, preferably, hydrogen;
  • L represents a single bond
  • Q represents -C(R y1 )(R y2 )-;
  • p and q represent 0 or 1 ;
  • R y and R y2 independently represent fluoro, methyl or, preferably, hydrogen;
  • R y1 and R y2 are preferably not linked together;
  • R y3 represents hydrogen or methyl
  • one of L 2 and L 3 represents -C(0)-A 17 - and the other represents a single bond or, more preferably, -N(R 17a )-A 16 - or -OA 17 -;
  • a 16 represents a direct bond, -C(O)- or -S(0) 2 -;
  • R y4 , R y5 , R y6 , R y7 , R yS and R ⁇ independently represent fluoro, methyl or, preferably, hydrogen;
  • R y4 and R 5 , R ⁇ and R y7 and/or R y8 and R y9 are preferably not linked together; when R 7a or R 17 represent optionally substituted aryl or heteroaryl, then those optional substituents are preferably selected from halo (e.g. fluoro and chloro) and R 18a ;
  • R 17a and R 17b represents hydrogen or Ci. 6 alkyl optionally substituted as hereinbefore defined (for example, by one or more substituents selected from fluoro, -CN, -OH, -OCH 3 and -OCH 2 CH 3 );
  • p18a p18b p18c p18d p18e p18f p18g p18h p18i p18 p18n ⁇ 18p p18q g n( -j p18r independently represent -CHF 2 or, preferably, hydrogen, methyl or -CF 3 ;
  • R 18j and R 18m independently represent -CHF 2 or, preferably, methyl or -CF 3 ;
  • phenyl group when Y 2 and/or Y 3 represent an optionally substituted phenyl group, then that phenyl group may be substituted with a single substituent (e.g. at the para-, meta- or ortho- position) or with two substituents (e.g. with one at the para-position and the other at the mefa-position or with one at the ortho- and the other at the mefa- position, so forming for example a 3,4-substituted or 2,5-substituted phenyl group);
  • a single substituent e.g. at the para-, meta- or ortho- position
  • two substituents e.g. with one at the para-position and the other at the mefa-position or with one at the ortho- and the other at the mefa- position, so forming for example a 3,4-substituted or 2,5-substituted phenyl group
  • R 28 represents hydrogen or unsubstituted Ci. 3 (e.g. C ⁇ ) alkyl (e.g. methyl).
  • More preferred compounds of the invention include those in which:
  • each R 2 independently represents hydrogen
  • each R 1 independently represents, on each occasion when used herein, hydrogen
  • D to D 3 -containing ring contains a nitrogen atom
  • X 1 , X 2 and B independently represent halo (e.g. chloro or fluoro), -R 5a or -OR 5e
  • X 1 , X 2 and B independently represent -R 5a or, preferably, halo
  • Y represents -C(O)-
  • L represents a single bond
  • Y represents -C(0)OR 9a ;
  • R 9a represents hydrogen
  • one of L 2 and L 3 represents -C(0)-A 17 - (e.g. -C(O)-) and the other represents a single bond, or, preferably -N(R 17a )-A 16 - or -OA 17 -;
  • a 16 represents a direct bond, -C(O)- or -S(0) 2 -;
  • a 16 preferably represents a direct bond
  • a 17 represents a direct bond
  • R 17a represents hydrogen or C 1-6 alkyl optionally substituted by one or more (e.g. one) substituent(s) selected from -OCH 3 , -OCH 2 CH 3 and -CN;
  • R 17a represents optionally substituted Ci_s alkyl
  • that group may represent: a linear unsaturated d. 6 (e.g. C ⁇ , such as Ci -3 ) alkyl group (e.g. methyl, ethyl or propyl) optionally substituted by -OCH 3 , -OCH 2 CH 3 and/or -CN, so forming for example a methoxyethyl (i.e. -(CH 2 )2-OCH 3 ), ethoxyethyl or cyanopropyl (i.e. -(CH 2 ) 3 -CN); a part cyclic Ci -6 alkyl group (for example C v2 alkyl (e.g.
  • aryl e.g. phenyl
  • heteroaryl e.g. triazolyl, or, preferably, thiazolyl, oxazoly
  • A represents aryl (optionally substituted by halo, such as chloro), or, preferably, G 1 ;
  • G 1 represents halo (e.g. chloro or fluoro), -R 5a , -OR 5e or -S(0) m R 3 ⁇ 4 ;
  • R 59 represents R 5a ;
  • R 5a represents 0 -6 (e.g. C ⁇ ) alkyl (such as methyl or butyl, e.g. n- or i-butyl; which alkyl group is optionally substituted by one or more fluoro atoms, so forming for example, a -CF 3 group);
  • R 5e represents R 5a
  • R 5a preferably represents C 1-6 (e.g. d ⁇ ) alkyl (which group may be substituted by one or more fluoro atoms, but is more preferably unsubstituted);
  • R 5g represents R 5a
  • R 5a preferably represents unsubstituted (e.g. C M ) alkyl.
  • L 2 and L 3 represents -C(0)-A 17 - (e.g. -C(O)-), then particularly preferred:
  • L 2 groups include a single bond, or, L 2 preferably represents -0-, -N(H)-, -N(H)C(0)- and -N(H)S(0) 2 - (especially preferred are -O- linker groups); and
  • L 3 groups (i.e. when L 2 represents -C(0)-A 17 -) include -N(CH 3 )-, -N(ethyl)-, -N(cycloprppylmethyl)-, -N(cyclobutylmethyl)-, -N(cyclopentylmethyl)-, -N(2-ethoxyethyl)-, -N(allyl)-, -N(2-propynyl) and -N(3-cyanopropyl)- (especially preferred are -N(CH 3 )-, -N(cyclobutylmethyl)-, -N(cyclopentylmethyl)-, -N(2-ethoxyethyl)-, -N(allyl)- and -N(2-propynyl).
  • Preferred Y 2 and Y 3 groups that may be mentioned include optionally substituted phenyl (e.g. halophenyl (such as monohalo- or dihalo-phenyl, in which the halo atom is/are preferably chloro and/or fluoro), trifluoromethylphenyl, tert- butylphenyl, thiomethylphenyl (i.e. methylsulfanylphenyl), methylsulfinylphenyl, methylsulfonylmethylphenyl, hydroxyphenyl, n-butoxyphenyl) and thienyl (e.g. 2- thienyl; which is preferably unsubstituted).
  • phenyl e.g. halophenyl (such as monohalo- or dihalo-phenyl, in which the halo atom is/are preferably chloro and/or fluoro)
  • trifluoromethylphenyl tert- but
  • phenyl groups e.g. chlorophenyl and trifluoromethylphenyl.
  • Particularly preferred phenyl groups that Y 2 and Y 3 may represent include unsubstituted phenyl, 4-chlorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 3- trifluoromethylphenyl, 3,4-difluorophenyl, 4-tert-butylphenyl, 2-thiomethylphenyl (or 2-methylsulfanylphenyl, i.e. (2-SCH 3 )phenyl), 2-methylsulfinylphenyl (i.e.
  • alkyl group is optionally substituted by one or more fluoro atoms, so forming for example, a -CF 3 group), -S-Cv 3 alkyl (e.g. -S-CH 3 ), -S(0)-C 1-3 alkyl (e.g. -S(0)CH 3 ), -S(0) 2 -C 1-3 alkyl (e.g. -S(0) 2 CH 3 ), hydroxy (i.e. -OH), -0-C 1-6 (e.g. -0-C ) alkyl (e.g. -0- ?-butyl).
  • Especially preferred substituents on such Y 2 and Y 3 groups are halo (e.g.
  • R 28 represents hydrogen or alkyl
  • each R 1 and R 2 independently represent H
  • Y 1 represents -C(0)OR 9a ;
  • R 9a represents: (i) hydrogen; or (ii) C-,.8 alkyl optionally substituted by one or more substituents selected from G 1 and/or Z 1 (but preferably unsubstituted);
  • L 1 represents a single bond
  • L 2 and L 3 represents -C(0)-A 17 (e.g. -C(O)-, -C(0)-CH 2 - or -C(O)- cyclopropylene-, i.e. -C(0)-C-(-CH 2 -CH 2 -)-) and the other is as defined herein;
  • L 2 represents -C(0)-A 17 (e.g. -C(O)-, -C(0)-CH 2 - or -C(0)-cyclopropylene-, i.e.
  • L 2 may represent a single bond, -OA 17 -, -N(R 17a )-A 16 (e.g. -N(R 17a )-CH 2 -, -N(R 17a )-, -N(R 17a )-C(0)- or -N(R 17a )-S(0) 2 -), -S- or -S(O)-;
  • L 3 represents (when L 2 represents -C(0)-A 17 -) a single bond, -N(R 17a )-A 16 - (e.g.
  • a 16 represents -CH 2 - or, preferably, a direct bond, -C(O)- or -S(0) 2 -;
  • a 17 represents a direct bond or -C(R y8 )(R y9 )- (in which R y8 and R y9 represent hydrogen, or, are linked together to form a cyclopropyl group);
  • R 17a represents hydrogen or Ci. 6 alkyl (e.g. methyl, ethyl, propyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl and/or propynyl) optionally substituted (e.g. terminally substituted) by one or more (e.g. one) substituent(s) selected from fluoro, -CN, -OR 19 (e.g. -OCH 2 CH 3 ), heterocycloalkyl (which may be attached via a single common carbon atom; e.g oxetanyl), or aryl (e.g. phenyl; so forming e.g. a benzyl group);
  • substituent(s) selected from fluoro, -CN, -OR 19 (e.g. -OCH 2 CH 3 ), heterocycloalkyl (which may be attached via a single common carbon atom; e.g oxetanyl), or
  • Y 2 represents acyclic C-
  • C 3-a e.g. C 5-6 ) cycloalkyl;
  • a 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyl group e.g. piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or the 1 ,1-dioxo derivative thereof, or, tetrahydrofuranyl, all of which groups are optionally substituted by one or more substituents selected from A (or which alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from G and Z 1 );
  • Y 3 may represents a group as defined above for Y 2 (provided that at least one of Y 2 and Y 3 represent an aromatic group), but Y 3 preferably represents phenyl optionally substituted by one or more substituents selected from A;
  • A represents aryl or heteroaryl (e.g. phenyl or pyridyl; both of which aryl and heteroaryl groups are optionally substituted by one or more B substituents) or A more preferably represents G 1 or Ci_4 (e.g. d.2) alkyl (e.g. ferf-butyl or methyl) optionally substituted by one or more substituents selected from G 1 (preferably A only represents an aryl (e.g. phenyl) substituent when it is on a Y 2 or Y 3 (e.g. Y 2 ) group that is an aromatic group, i.e. aryl or heteroaryl);
  • G represents halo (e.g. chloro, fiuoro or bromo), -CN, -N0 2 , -OR 5e , -S(0) m R 5g or -S(0) 2 N(R 6e )R 7e ;
  • B represents halo (e.g. chloro or fiuoro);
  • n 0, 1 or 2;
  • R 5e represents hydrogen, alkyl (which alkyl group is optionally substituted by one or more halo (e.g. fiuoro) atoms; which alkyl group includes part-cyclic alkyl groups), or aryl (e.g. phenyl) or heteroaryl (e.g. pyridyl), which latter two aryl and heteroaryl groups are each optionally substituted by one or more (e.g. one) substituent(s) selected from fiuoro, chloro and -CN;
  • halo e.g. fiuoro
  • aryl e.g. phenyl
  • heteroaryl e.g. pyridyl
  • R 5g represents C 1-4 alkyl (e.g. methyl);
  • R 6e and R 7e independently represent hydrogen or, preferably, Ci. 2 alkyl (e.g. methyl);
  • a substituents include halo (e.g. chloro or fiuoro), cyano, -NO2, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy, phenoxy (e.g. cyano-phenoxy, 2,4-difluoro-phenoxy, 2-chloro-phenoxy or 2-fluoro-phenoxy), 3- hydroxypropyl, methylsulfonyl, methylsulfanyl, methylsulfinyl and pyridyloxy (e.g. 3-pyridyloxy).
  • halo e.g. chloro or fiuoro
  • cyano e.g. chloro or fiuoro
  • cyano e.g. cyano-phenoxy, 2,4-difluoro-phenoxy, 2-chloro-phenoxy or 2-fluoro-phenoxy
  • 3- hydroxypropyl methylsulfonyl, methylsulfanyl,
  • Y represents -C(O)-
  • each R 1 and R 2 independently represent H
  • Y 1 represents -C(0)OR 9a ;
  • R 9a represents hydrogen
  • L 1 represents a single bond
  • L 2 represents -C(0)-A 17 - (especially, -C(O)-);
  • L 3 represents -N(R 17a )-A 16 -, -C(0)-A 17 - (especially, -C(O)-) or -C(R y4 )(R y5 )-A 16 -;
  • a 16 represents a direct bond;
  • R y4 and R y5 independently represent hydrogen
  • a 17 represents a direct bond or -C(R y8 )(R y9 )- (in which R y8 and R y9 independently represent hydrogen, C 1-2 alkyl (e.g. methyl) or, are linked together to form a 3- to 6-membered cycloalkyl group, e.g. cyclopropyl, cyclopentyl or cyclohexyl);
  • R 17a represents Ci_s alkyl (e.g. methyl, cyclopropylmethyl)
  • Y 2 may also represent, in addition to the groups mentioned hereinbefore: a fused and/or bridged C 6 .12 cycloalkyl group, such as an adamantyl group or a bicyclo[2.2.1]heptanyl group; a Ci. 6 acyclic alkyl group (e.g. methyl, ethyl, -CH 2 -f- butyl or ethyl) or C 3 . 6 cycloakyl (e.g. cyclopropyl or cyclopentyl), which latter two groups are optionally substituted by one or more substituents selected from G 1 ; G may also represent, in addition to the groups mentioned hereinbefore, R 5a or -C(0)R 5 ;
  • R 5a may also represent, in addition to the groups mentioned hereinbefore, Ci. 6 alkyl (e.g. C 3-5 cycloalkyl, such as cyclohexyl) or aryl (e.g. phenyl), preferably unsubstituted;
  • Ci. 6 alkyl e.g. C 3-5 cycloalkyl, such as cyclohexyl
  • aryl e.g. phenyl
  • R 5b represents hydrogen.
  • Other preferred compounds of the invention that may be mentioned include those in which:
  • one of Y 2 and Y 3 represents aryl or hetoaryl (both of which are optionally substituted by one or more (e.g. one or two) substitutent(s) selected from A) and the other represents C1.12 alkyl (e.g. acyclic Ci -6 alkyl, C 3-6 cycloalkyl or bridged C 6 -12 cycloalkyl, e.g.
  • terf-butyl n-hexyl, cyclohexyl, cyclopentyl, adamantyl, bicyclo[2.2.1]heptanyl, -CH 2 -f-butyl, cyclopropyl, methyl or ethyl; optionally substituted by one or more (e.g. one) substituent(s) selected from G 1 ), a 5- to 6- membered heterocycloalkyl group (e.g. tetrahydrofuranyl), aryl or hetoaryl, both of which latter two groups are optionally substituted by one or more (e.g. one or two) substitutent(s) selected from A; or
  • Y 2 and Y 3 independently represent aryl or heteroaryl, both of which are optionally substituted by one or more (e.g. one or two) substitutent(s) selected from A;
  • Y 2 or Y 3 represents aryl, it is preferably (optionally substituted) phenyl;
  • Y 2 or Y 3 represents heteroaryl, it is preferably a 5 to 6-membered monocyclic group or a 9- to 10-membered bicyclic group (e.g. benzene fused to a
  • A represents G 1 or C 1-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more G 1 groups (e.g. in which G 1 is fluoro, so forming e.g. a -CF 3 group, or chloro, so forming e.g. dichloromethyl);
  • G (e.g. when A represents G ) represents halo (e.g. chloro or fluoro), R 5a , -C(0)R 5b , -N0 2 or -OR 5e ;
  • halo e.g. chloro or fluoro
  • G may also represent (e.g. when Y 2 or Y 3 represent alkyl substituted by G 1 ) R 5a , in which R 5a represents C3-6 cycloalkyl (e.g. cyclohexyl or cyclopentyl) or aryl (e.g. phenyl; preferably unsubstituted);
  • R 5a represents C3-6 cycloalkyl (e.g. cyclohexyl or cyclopentyl) or aryl (e.g. phenyl; preferably unsubstituted);
  • R 5e represents hydrogen or R 5a ;
  • R 5b represents R 5a or, preferably, hydrogen
  • R 5a represents (e.g. C 1-3 ) alkyl (e.g. methyl or ethyl) optionally substituted by one or more fluoro atoms;
  • Y 2 represents unsubstituted phenyl, methoxyphenyl, ethoxyphenyl, trifluoromethylphenyl, nitrophenyl, halophenyl, diethoxyphenyl, thienyl (e.g. 2- thienyl), 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, trifluoromethoxy- henyl, dihalomethylphenyl or hydroxyphenyl;
  • Y 3 represents halophenyl, dihalophenyl, trifluoromethylphenyl, alkylphenyl (e.g. methylphenyl or ethylphenyl) or halo-alkyl-phenyl.
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • Ei, E 2 a, E 2b , E 2C , E 2 _, E 4 , D D 2 , D 3 , L , Y , L 2 and Y 2 are as hereinbefore defined, in the presence of a suitable oxidising agent, for example, pyridinium chlorochromate (PCC) or the like (e.g. pyridinium dichromate; PDC);
  • a suitable oxidising agent for example, pyridinium chlorochromate (PCC) or the like (e.g. pyridinium dichromate; PDC);
  • one of L Za and L 3a represents -NH 2 and the other represents -C(0)-A 17 -Y 2 or -C(0)-A 17 -Y 3 as appropriate
  • Y, E L E 2 , E 3I E 4I D L D 2 , D 3 , L 1 and Y 1 are as hereinbefore defined, with: (A) when A 16 represents -C(0)N(R 7 )-, in which R 17B represents H:
  • suitable conditions will be known to the skilled person, for example the reactions may be carried out in the presence of an appropriate catalyst system (e.g. a palladium catalyst), preferably under pressure and/or under microwave irradiation conditions.
  • an appropriate catalyst system e.g. a palladium catalyst
  • the compound so formed may be isolated by precipitation or crystallisation (from e.g. n-hexane) and purified by recrystallisation techniques (e.g. from a suitable solvent such as THF, hexane (e.g. n-hexane), methanol, dioxane, water, or mixtures thereof).
  • L a represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 , -OS(0) 2 PhMe or a nonaflate) or -B(OH) 2 (or a protected derivative thereof, e.g.
  • an alkyl protected derivative so forming, for example a 4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl group
  • Y a is as hereinbefore defined, for example optionally 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 , 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 or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, /V.W-dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 ,
  • This reaction may be carried out at room temperature or above (e.g.
  • a suitable base e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, /V-ethyldiisopropylamine, A/-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)- amide, sodium bis(trimethylsilyl)amide, potassium rert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g.
  • a suitable base e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyr
  • Y, E,, E 2 , E 3 , E 4 , Di, D 2 , D 3 , L 1 and Y 1 are as hereinbefore defined, with a compound of formula V as hereinbefore defined, under reaction conditions known to those skilled in the art, such as those described hereinbefore in respect of process step (ii)(A)(b) above;
  • each R wx independently represents a d -6 alkyl group, or, in the case of -BiOR ⁇ , the respective R ⁇ 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), and Y, Ei, E 2 , E 3 , E , D,, D 2 , D 3 , L 1 , Y 1 , L 2 , Y 2 , L 3 and Y 3 are as hereinbefore defined, with a (or two separate) compound(s) (as appropriate/required) of formula X,
  • L x represents L 2 or L 3 (as appropriate/required; in which they are preferably and independently selected from -N(R 7a )-A 16 - and -OA 17 -, provided that at least one of L 2 and L 3 represent -C(0)A 17 -Y a ), and Y a is as hereinbefore defined, under suitable reaction conditions known to those skilled in the art, e.g. such as those hereinbefore described in respect of process (ii) above (e.g.
  • L 2 or L 3 represent single bonds, and Y 2 or Y 3 are to be attached to the requisite biaryl moiety (of the compounds of the invention, which may alternatively be termed the diaryl; for the purposes herein both terms may be interchangeably employed) via a heteroatom, e.g. nitrogen), the reaction may be performed in the presence of a mixture of KF/AI 2 0 3 (e.g. in the presence of a suitable solvent such as acetonitrile, at elevated temperature, e.g. at about 100°C; in this instance the leaving group that Z* or Z y may represent in the compound of formula IX is preferably fluoro).
  • a suitable solvent such as acetonitrile
  • R 9za OH XII in which R 9za represents R a provided that it does not represent H, for example further in the presence of acid (e.g. concentrated H 2 S0 ) at elevated temperature, such as at the reflux temperature of the alcohol of formula XII;
  • acid e.g. concentrated H 2 S0
  • L represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH) 2 , or a protected derivative thereof (e.g. an alkyl protected derivative, so forming for example a 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl group), and Y, Ei, E 2a , E 2 , E 2c , E 4 , D,, D 2 , D 3 , L 2 and Y 2 are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIII in which L 5a represents an alkali metal (e.g.
  • a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XIII in which L 5a represents halo, for example under conditions such as Grignard reaction conditions, halogen-lithium exchange reaction conditions, which latter two may be followed by transmetallation, all of which reaction conditions are known to those skilled in the art), with a compound of formula XIV,
  • V wherein represents L 1 (provided that it does not represent -(CH 2 ) p -Q-(CH 2 ) q - in which p represents 0 and Q represents -0-) and Y b represents -C(0)OR 9a , in which R 9a is other than H, and L 6 represents a suitable leaving group known to those skilled in the art, such as C-
  • the compound of formula XIV may be CI-C(0)OR 9a .
  • the reaction may be performed under standard reaction conditions, for example in the presence of a polar aprotic solvent (e.g. THF or diethyl ether);
  • (x) compounds of formula I in which L 1 preferably represents a single bond, and Y 1 represents 5-tetrazolyl (and, preferably, Y is -C(O)- or R 28 is C -6 alkyl optionally substituted by one or more halo atoms), may be prepared in accordance with the procedures described in international patent application WO 2006/077366; (xi) for compounds of formula I in which L represents a single bond, and Y represents -C(0)OR 9a in which R 9a is H, (and, preferably, Y is -C(O)- or R 28 is alkyl optionally substituted by one or more halo atoms), reaction of a compound of formula XIII as hereinbefore defined but in which L 5a represents either:
  • R 9a OH XV wherein R 9a is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or the like) under conditions known to those skilled in the art; (xiii) for compounds of formula I in which Y represents -C(O)-, reaction of either a compound of formula XVI or XVII, respectively with a compound of formula XVIII or XIX, I
  • a palladium catalyst such as PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or the like
  • reactive derivative an acid chloride or acid anhydride, or the like; which reactive derivative may itself be separately prepared and/or isolated, or where such a reactive derivative may be prepared in situ) such as POCI 3 , in the presence of ZnCI 2 , for example as described in Organic and Biomolecular Chemistry (2007), 5(3), 494-500 or, more preferably, PCI 3 , PCI 5 , SOCI 2 or (COCI) 2 .
  • such a reaction may be performed in the presence of a suitable catalyst (for example a Lewis acid catalyst such as SnCI 4 ), for example as described in Journal of Molecular Catalysis A: Chemical (2006), 256(1-2), 242-246 or under alternative Friedel-crafts acylation reaction conditions (or variations thereupon) such as those described in Tetrahedron Letters (2006), 47(34), 6063-6066; Synthesis (2006), (21 ), 3547-3574; Tetrahedron Letters (2006), 62(50), 1 1675- 1 1678; Synthesis (2006), (15), 2618-2623; Pharmazie (2006), 61 (6), 505-510; and Synthetic Communications (2006), 36(10), 1405-141 1.
  • a suitable catalyst for example a Lewis acid catalyst such as SnCI 4
  • L 5b represents L 5a as hereinbefore defined, and which may therefore represent -B(OH) 2 (or a protected derivative thereof), an alkali metal (such as lithium) or a -Mg-halide (such as -Mgl or, preferably, -MgBr), and (in all cases) EL E 2A , E 2 t>, E 2C , E L D 2 , D 3 , L 1 , Y 1 , L 2 and Y 2 are as hereinbefore defined, and (in the case of compounds of formulae XXII and XXIII), for example in the presence of a suitable solvent, optionally in the presence of a catalyst, for example, as described in Organic Letters (2006), 8(26), 5987-5990.
  • a suitable solvent optionally in the presence of a catalyst
  • Compounds of formula I may also be obtained by performing variations of such a reaction, for example by performing a reaction of a compound of formula XX or XXI respectively with a compound of formula XVIII or XIX as hereinbefore defined, for example under conditions described in Journal of Organic Chemistry (2006), 71(9), 3551-3558 or US patent application US 2005/256102; (xv) for compounds of formula I in which Y represents -C(O)-, reaction of an activated derivative of a compound of formula XVI or XVII as hereinbefore defined (for example an acid chloride; the preparation of which is hereinbefore described in process step (xiii) above), with a compound of formula XXII or XIII (as hereinbefore defined), respectively, for example under reaction conditions such as those hereinbefore described in respect of process step (xiii) above;
  • R 28 is represents hydrogen or C 1-6 alkyl optionally substitutued by one or more halo atoms, under standard condensation reaction conditions, for example in the presence of an anhydrous solvent (e.g. dry pyridine, ethanol and/or another suitable solvent);
  • anhydrous solvent e.g. dry pyridine, ethanol and/or another suitable solvent
  • L 7 XXIIIB wherein R 8a represents R 28 , provided that it does not represent hydrogen and L 7 represents a suitable leaving group, such as one hereinbefore defined in respect of L a (e.g. bromo or iodo), under standard alkylation reaction conditions, such as those hereinbefore described in respect of process step (ii) (e.g. (ii)(C)).
  • R 8a represents R 28 , provided that it does not represent hydrogen and L 7 represents a suitable leaving group, such as one hereinbefore defined in respect of L a (e.g. bromo or iodo), under standard alkylation reaction conditions, such as those hereinbefore described in respect of process step (ii) (e.g. (ii)(C)).
  • Compounds of formula II may be prepared by reaction of a compound of formula XVIII with a compound of formula XIX, both as hereinbefore defined, with formaldehyde (e.g. in the form of paraformaldehyde or an aqueous solution of formaldehyde such as a 3% aqueous solution), for example under acidic conditions (e.g. in the presence of aqueous HCI) at or above room temperature (e.g. at between 50°C and 70°C).
  • the formaldehyde is added (e.g. slowly) to an acidic solution of the compound of formula XVIII at about 50°C, with the reaction temperature rising to about 70°C after addition is complete.
  • precipitation of the compound of formula II may be effected by the neutralisation (for example by the addition of a base such as ammonia).
  • a base such as ammonia
  • Compounds of formula I may also be prepared in accordance with such a procedure, for example under similar reaction conditions, employing similar reagents and reactants.
  • I 1 , Y 1 , L 2a , J 2 , Z y , L 2 , Y 2 and L 5a are as hereinbefore defined, under standard oxidation conditions known to those skilled in the art, for example such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above).
  • compounds of formulae XXIV, XXV, XXVI and XXVII may be prepared by reduction of corresponding compounds of formulae III, VIII, IX and XIII, under standard reaction conditions, such as those described herein.
  • Compounds of formula III in which Y represents -C(O)-, or, preferably, compounds of formula XXIV (or protected, e.g. mono-protected derivatives thereof) may be prepared by reduction of a compound of formula XXVIII,
  • T represents -C(O)- (in the case where compounds of formula III are to be prepared) or, preferably, -CH 2 - (in the case where compounds of formula XXIV are to be prepared)
  • one of Z z and Z represents -N 3 or -N0 2
  • the other represents -C(0)-A 17 -Y 2 or -C(0)-A 17 -Y 2 (as appropriate)
  • a suitable reducing agent for example reduction by catalytic hydrogenation (e.g.
  • a chemoselective reducing agent may need to be employed.
  • W 1 represents a suitable leaving group such as one defined by Z x and Z y above
  • E 1 E 2a 5, E 2b5 , E 2c5 , E 4l D 1 f D 2 , D 3 , Z q1 and T are as hereinbefore defined, are as hereinbefore defined, with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO) 6 or Co 2 (CO) 8 ) followed by reaction in the presence of a compound of formula XV as hereinbefore defined, under reaction conditions known to those skilled in the art, for example such as those hereinbefore described in respect of preparation of compounds of formula I (process step (ii), e.g. (ii)(A)(b) above), e.g. the carbonylation step being performed in the presence of an appropriate precious metal (e.g. palladium) catalyst;
  • an appropriate precious metal e.g. palladium
  • W 2 represents a suitable group such as an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide or a zinc-based group
  • E ⁇ E 2a5 , E 2b 5, E 2c5 , E 4 , Di, D 2 , D 3 , Z q and T are as hereinbefore defined, with e.g.
  • Compounds of formula IX in which Z and/or 2 y represent a sulfonate group may be prepared from corresponding compounds in which the Z* and Z y groups represent a hydroxy group, with an appropriate reagent for the conversion of the hydroxy group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art, for example in the presence of a suitable base and solvent (such as those described above in respect of process step (i), e.g. an aqueous solution of 3PO 4 in toluene) preferably at or below room temperature (e.g. at about 10°C).
  • an appropriate reagent for the conversion of the hydroxy group to the sulfonate group e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like
  • room temperature e.g. at about 10°C
  • Compounds of formulae XX and XXI may be prepared, for example, by reaction of a corresponding compound of formula XXIII or XXII, respectively (all of which are as hereinbefore defined, e.g. in which L 5b represents bromo or, preferably, iodo), for example, in the presence of a nucleophile that is a source of cyano ions, e.g. potassium or, preferably, copper cyanide.
  • a nucleophile that is a source of cyano ions, e.g. potassium or, preferably, copper cyanide.
  • Compounds of formulae XXIIIC or XXIIID may be prepared by reaction of a corresponding compound of formula XXIII or XXII, as hereinbefore defined (and preferably one in which L 5b is a -Mg-halide, such as -Mg-I), with dimethylformamide (or a similar reagent for the introduction of the aldehyde group), under standard Grignard reaction conditions known to those skilled in the art (for example those described herein).
  • Compounds of formulae XXIX or XXX in which T represents -CH 2 - may be prepared by reduction of a corresponding compound of formulae XXIX or XXX in which T represents -C(O)- (or from compounds corresponding to compounds of formulae XXIX or XXX but in which T represents -CH(OH)-), for example under standard reaction conditions known to those skilled in the art, for example reduction in the presence of a suitable reducing reagent such as LiAIH 4 , NaBH 4 or trialkylsilane (e.g. triethylsilane) or reduction by hydrogenation (e.g. in the presence of Pd/C).
  • a suitable reducing reagent such as LiAIH 4 , NaBH 4 or trialkylsilane (e.g. triethylsilane) or reduction by hydrogenation (e.g. in the presence of Pd/C).
  • compounds of formulae XXIX or XXX in which T represents -CH 2 - may be prepared by reaction of a compound of formula XXXII,
  • Y y represents a suitable group such as -OH, bromo, chloro or iodo
  • EL E 2a 5, E 2 b5, E 2C5 and E 4 are as hereinbefore defined, with a compound of formula XXXIII,
  • M represents hydrogen and W 1 represents hydrogen (for compounds of formula XXIX) or W (for compounds of formula XXX) and Di, D 2 , D 3 and Z q are as hereinbefore defined, under standard conditions, for example in the presence of a Lewis or Bnansted acid.
  • such compounds may be prepared from reaction of a compound of formula XXXII in which Y y represents bromo or chloro with a compound corresponding to a compound of formula XXIII but in which M represents -BF 3 K (or the like), for example in accordance with the procedures described in Molander et al, J. Org. Chem. 71 , 9198 (2006).
  • Ei, E 2a5 , E 2b 5, E 2c5 and E 4 are as hereinbefore defined, with a compound of formula XXXIII, as defined above, but in which M represents hydrogen or an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide or a zinc- based group, or, a bromo group, and D-,, D 2 , D 3 , Z q1 and W are as hereinbefore defined, under reaction conditions known to those skilled in the art.
  • M represents hydrogen or an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium)
  • a -Mg-halide or a zinc- based group or, a bromo group
  • D-,, D 2 , D 3 , Z q1 and W are as hereinbefore defined, under reaction conditions known to those skilled in
  • Compounds of formula XXXI may be prepared in several ways.
  • compounds of formula XXXI in which W 2 represents an alkali metal such as lithium may be prepared from a corresponding compound of formula XXIX (in particular those in which Z q1 and/or Z q2 represents a chloro or sulfonate group or, especially, a protected -NH 2 group, wherein the protecting group is preferably a lithiation-directing group, e.g. an amido group, such as a pivaloylamido group, or a sulfonamido group, such as an arylsulfonamido group, e.g.
  • organolithium base such as /7-BuLi, s-BuLi, f-BuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine
  • organolithium base is optionally in the presence of an additive (for example, a lithium coordinating agent such as an ether (e.g. dimethoxyethane) or an amine (e.g.
  • TEDA tetramethylethylenediamine
  • DMPU 1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone
  • a suitable solvent such as a polar aprotic solvent (e.g. tetrahydrofuran or diethyl ether), at sub-ambient temperatures (e.g. 0°C to -78°C) under an inert atmosphere.
  • a suitable solvent such as a polar aprotic solvent (e.g. tetrahydrofuran or diethyl ether)
  • sub-ambient temperatures e.g. 0°C to -78°C
  • such compounds of formula XXXI may be prepared by reaction of a compound of formula XXX in which W 1 represents chloro, bromo or iodo by a halogen-lithium reaction in the presence of an organolithium base such as t- or n-butyllithium under reaction conditions such as those described above.
  • Compounds of formula XXXI in which W 2 represents -Mg-halide may be prepared from a corresponding compound of formula XXX in which W represents halo (e.g. bromo), for example optionally in the presence of a catalyst (e.g. FeCI 3 ) under standard Grignard conditions known to those skilled in the art.
  • magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to form compounds of formula XXXI in which W 2 represents a zinc-based group (e.g. using ZnCI 2 ).
  • Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications (e.g. from a carboxylic acid, e.g. in the presence of H 2 S0 4 and appropriate alcohol or in the presence of K 2 C0 3 and alkyl iodide), etherifications, halogenations or nitrations.
  • esterifications e.g. from a carboxylic acid, e.g. in the presence of H 2 S0 4 and appropriate alcohol or in the presence of K 2 C0 3 and alkyl iodide
  • etherifications e.g. from a carboxylic acid, e.g. in the presence of H 2 S0 4 and appropriate alcohol or in the presence of K 2 C0 3 and alkyl iodide
  • etherifications e.g. from a carboxylic acid, e.g. in the presence of H 2 S0 4 and appropriate alcohol or in the presence of K 2 C0
  • R 9a represents hydrogen
  • the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant R 9a -containing group may be hydrolysed to form a carboxylic acid functional group (i.e. a group in which R 9a represents hydrogen).
  • the skilled person may also refer to " Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995.
  • transformation steps include: the reduction of a nitro group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; 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, preferably, potassium cyanide) as a reagent alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed; the reduction of an azido group to an amino group (e.g. in the presence of FeCI 3 trihydrate and zinc powder); and the oxidation of a sulfide to a sulfoxide or to a sulfone (e.g.
  • transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-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-(d ⁇ 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 reagent/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 reagent anion for example by reaction in the presence of a reagent that is a source of halogen (e.g. CuCI, CuBr or Nal), or a reagent that is a source of azido or cyanide anions, such as NaN 3 , CuCN 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 SC ⁇ ,), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO) 2 P(0)N 3 ) in the presence of an alcohol, such as fe/1-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
  • the Di to D 3 -containing ring, as well as the A ring may be heterocycles, which moieties may be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry ⁇ by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996 or “Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006).
  • the reactions disclosed herein that relate to compounds containing hetereocycles may also be performed with compounds that are precursors to heterocycles, and which pre-cursors may be converted to those heterocycles at a later stage in the synthesis.
  • 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.
  • 'protecting group' we also include suitable alternative groups that are precursors to the actual group that it is desired to protect. For example, instead of a 'standard' amino protecting group, a nitro or azido group may be employed to effectively serve as an amino protecting group, which groups may be later converted (having served the purpose of acting as a protecting group) to the amino group, for example under standard reduction conditions described herein.
  • Protecting groups that may be mentioned include lactone protecting groups (or derivatives thereof), which may serve to protect both a hydroxy group and an ct- carboxy group (i.e. such that the cyclic moiety is formed between the two functional groups.
  • lactone protecting groups or derivatives thereof
  • the type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
  • protecting groups are described in e.g. "Protective Groups in Organic Synthesis", 3 rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • prodrug of a compound of the invention we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
  • Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
  • the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
  • Compounds of the invention may inhibit leukotriene (LT) C 4 synthase, for example as may be shown in the test described below, and may thus be useful in the treatment of those conditions in which it is required that the formation of e.g. LTC 4 , LTD 4 or LTE 4 is inhibited or decreased, or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LTi or Cys-LT 2 ) is inhibited or attenuated.
  • LT leukotriene
  • the compounds of the invention may also inhibit microsomal glutathione S-transferases (MGSTs), such as MGST-I, MGST-II and/or MGST-III (preferably, MGST-II), thereby inhibiting or decreasing the formation of LTD 4 , LTE or, especially, LTC 4 .
  • MGSTs microsomal glutathione S-transferases
  • Compounds of the invention may also inhibit the activity of 5-lipoxygenase- activating protein (FLAP), for example as may be shown in a test such as that described in Mol. Pharmacol., 41 , 873-879 (1992). Hence, compounds of the invention may also be useful in inhibiting or decreasing the formation of LTC 4 and/or LTB . Compounds of the invention are thus expected to be useful in the treatment of disorders that may benefit from inhibition of production (i.e. synthesis and/or biosynthesis) of leukotrienes (such as LTC 4 ), for example a respiratory disorder and/or inflammation.
  • FLAP 5-lipoxygenase- activating protein
  • inflammation will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
  • inflammation will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
  • compounds of the invention may be useful in the treatment of allergic disorders, asthma, childhood wheezing, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, and usual interstitial in pneumonia), ear nose and throat diseases (e.g. rhinitis, nasal polyposis, and otitis media), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, dermatitis, and eczema), rheumatic diseases (e.g.
  • vasculitis e.g. Henoch- Schonlein purpura, Loffler ' s syndrome and Kawasaki disease
  • cardiovascular diseases e.g. atherosclerosis
  • gastrointestinal diseases e.g. eosinophilic diseases in the gastrointestinal system, inflammatory bowel disease, irritable bowel syndrome, colitis, celiaci and gastric haemorrhagia
  • urologic diseases e.g.
  • glomerulonephritis interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity
  • diseases of the central nervous system e.g. cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing
  • endocrine diseases e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • urticaria e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • urticaria e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • urticaria e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • urticaria e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • urticaria e.g. autoimmune thyreoiditis, diabetes-related inflammation
  • compounds of the invention may be useful in treating allergic disorders, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, eosinophilic gastrointestinal diseases, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and pain.
  • Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, LTC 4 synthase and/or a method of treatment of a disease in which inhibition of the synthesis of LTC 4 is desired and/or required (e.g. respiratory disorders and/or inflammation), 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.
  • Patients include mammalian (including human) patients.
  • 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 (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • Compounds of the invention will normally 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.
  • Such formulations may be prepared 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 or carrier.
  • a pharmaceutically acceptable adjuvant i.e. active ingredient
  • pharmaceutical formulations 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 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 salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of a respiratory disorder (e.g. leukotriene receptor antagonists (LTRas), glucocorticoids, antihistamines, beta-adrenergic drugs, anticholinergic drugs and PDE inhibitors and/or other therapeutic agents that are useful in the treatment of a respiratory disorder) and/or other therapeutic agents that are useful in the treatment of inflammation and disorders with an inflammatory component (e.g.
  • NSAIDs coxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activting protein), immunosuppressants and sulphasalazine and related compounds and/or other therapeutic agents that are useful in the treatment of inflammation).
  • analgesics inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activting protein), immunosuppressants and sulphasalazine and related compounds and/or other therapeutic agents that are useful in the treatment of inflammation).
  • FLAP 5-lipoxygenase activting protein
  • immunosuppressants sulphasalazine and related compounds and/or other therapeutic agents that are useful in the treatment of inflammation.
  • 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 a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation 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 salt thereof with the other therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • bringing into association we mean that the two components are rendered suitable for administration in conjunction with each other.
  • the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
  • Compounds of the invention may be administered at varying doses.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.
  • the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient.
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
  • compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Aqueous solubility is a fundamental molecular property that governs a large range of physical phenomena related to the specific chemical compound including e.g. environmental fate, human intestinal absorption, effectiveness of in vitro screening assays, and product qualities of water-soluble chemicals.
  • the solubility of a compound is the maximum quantity of compound that can dissolve in a certain quantity of solvent at a specified temperature.
  • Knowledge of a compound's aqueous solubility can lead to an understanding of its pharmacokinetics, as well as an appropriate means of formulation.
  • Compounds of the invention may exhibit improved solubility properties (for instance compared to certain compounds disclosed in the prior art).
  • Greater aqueous solubility may have advantages related to the effectiveness of the compounds of the invention (especially those in which L 2 represents -C(0)-A 17 -, e.g. -C(O)-), for instance improved absorption in vivo (e.g. in the human intestine) or the compounds may have other advantages associated with the physical phenomena related to improved aqueous stability (see above).
  • Good (e.g. improved) aqueous solubility may aid the formulation of compounds of the invention, i.e. it may be easier and/or less expensive to manufacture tablets which will dissolve more readily in the stomach as potentially one can avoid esoteric and/or expensive additives and be less dependent on particle-size (e.g. micronization or grinding may be avoided) of the crystals, etc, and it may be easier to prepare formulations intended for intravenous administration.
  • Compounds of the invention may have the advantage that they are effective inhibitors of LTC 4 synthase.
  • 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.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • LTC 4 synthase catalyses the reaction where the substrate LTA 4 is converted to LTC 4 .
  • Recombinant human LTC 4 synthase is expressed in Piccia tourismis and the purified enzyme is dissolved in 25 mM tris-buffer pH 7.8 supplemented with 0.1 mM glutathione (GSH) and stored at -80 °C.
  • the assay is performed in phosphate buffered saline (PBS) pH 7.4 and 5 mM GSH in 384-well plates. The following is added chronologically to each well:
  • the enzymatic reaction is initiated by addition of 0.5 yL LTA 4 in diglyme (final assay concentration 8 yM). 3. The reaction is stopped after 1 min by addition of double the reaction volume of a stop solution (MeOH:H 2 0: acetic acid 70:30:1 ).
  • LTC 4 HTRF kit (Cisbio, cat. No 64LC4PEC) and a fluorescence reader. Typically 10 yL of sample is mixed with 5 yL of each of the HTRF reagents d2 and k and analyzed as described in the kit manual.
  • Title compounds of the Examples were tested in the biological in vitro assay described above (either Test 1 or Test 2 above) and were found to inhibit LTC 4 synthase.
  • Title compounds of the examples exhibit a certain IC 50 value, which shows that they inhibit LTC 4 synthase.
  • IC 50 values for title compounds of the examples are depicted in the tables hereinafter (where, they are the values obtained using Test 1 , unless otherwise indicated).
  • the compounds of the examples may exist as a cyclised form, i.e. in a form depicted hereinbefore by compounds of formula I (whereby the compound depicted below may undergo an intramolecular cyclisation).
  • the characterising data e.g. NMR data
  • the compounds (of formula I; e.g. see the compounds of the examples depicted below) may exist in rapid or slow equilibrium (on an NMR time scale) with the cyclised form (of formula IA) and hence the spectra may represent either one of the compounds or both of the compounds (e.g. spectra for single compounds may be observed, or spectra for two compounds, which spectra may for instance overlap or merge).
  • the sub-title compound was obtained from 5-bromo-2-iodobenzoic acid methyl ester and benzoyl chloride in accordance with standard procedures.
  • the iodo moiety may be converted to a Grignard reagent (e.g. by use of / ' -PrMgCI in THF) and the benzoyl chloride may then be added e.g. at low temperatures, such as below 0°C (e.g. at -15 °C for 1 h) followed by standard work up (e.g. quenching with NH 4 CI (aq, sat) and extractive workup (EtOAc, H 2 0, brine) and purification by chromatography).
  • the title compound was prepared from 2-benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester and 4-chloro-/V-methylaniline in accordance with standard procedures.
  • the compounds may be mixed/reacted with a catalyst system (e.g. Pd(OAc) 2 , (catalytic amount), BINAP, base such as Cs 2 C0 3 (e.g. at least one equivalent) and toluene and the reaction may be stirred for a period of time (e.g. at 80 °C for 20 h in a sealed tube).
  • the mixture may be diluted with solvent (e.g. EtOAc) and filtered through Celite.
  • the title compounds were prepared from 5- ⁇ 5-[(4-chlorophenyl)(methyl)amino]- picolinoyl ⁇ -2-trimethylstannanylbenzoic acid methyl ester and the appropriate acid chloride in accordance with Example 1 :7, steps (b) and (c), see Table 1.
  • the palladium source in step (b) was allylpalladium(ll) chloride dimer, Pd 2 dba 3> or Pd(P(t-Bu) 3 ) 2 with toluene or MeCN as solvent. Examples 1 :21 - 1 :23
  • the sub-title compound was prepared in accordance with example 2 step (a) using 4-chloroaniline.
  • the title compound was prepared from 5-((4-chlorophenyl)(cyclo- propylmethyl)amino)picolinaldehyde and 3,4-ethylenedioxybenzoyl chloride in accordance with Example 2, steps (b-f).
  • BBr 3 (156 mg, 0.621 mmol) was added dropwise to a solution of 5-(5-((4- chlorophenyl)(methyl)amino)picolinoyl)-2-(3-methoxybenzoyl)benzoic acid methyl ester (prepared in accordance to Example 2 step (e) from 5-(5-((4- chlorophenyl)(methyl)amino)picolinoyl)-2-trimethylstannanylbenzoic acid methyl ester and m-anisoyl chloride, 80 mg, 0.155 mmol) in DCM (3 mL) at -10 °C. The mixture was stirred at -10 °C for 1 h and at rt for 30 min.
  • solubility of a compound is the maximum quantity of com that can dissolve in a certain quantity of solvent at a specified temperature.
  • the method described here was developed to accurately determine the aqueous solubility of compounds of the invention in buffer solution at a given pH. The test is built as a classical thermodynamic solubility method with an assumption that saturation of solution incubated with an excess of solid material, is achieved after 24h.
  • Solid material (1 mg) of test compound is added to a glass vial followed by 1 ml of buffer solution (pH 7.4 if another pH not is stated). The solution is left on an orbital shaker for 24h at 20 °C. After incubation, the remaining solid material is separated from solution and the solubility is quantified using LC-MS/MS.
  • Test compounds are employed as solid material. Since duplicate samples are prepared for each compound, each test compound arrives in two vials (1+1 mg). Samples are denoted as sample 1 and 2. Note amount of substance in each vial. Add USP phosphate buffer pH 7.4 (1 mL) to each sample vial and seal vials using screw caps. Determine whether the solutions are saturated or if compounds are dissolved, note appearance and time. Start incubation; the samples are incubated on an orbital shaker (450 rpm) at 20 °C for 24 hours.
  • Standards are transferred to a deep well plate containing glass inserts (700 ⁇ _) starting with compound 1 in row A, compound 2 in row B etc. Place standards as indicated in scheme 1. Seal the plate with a cap mat.
  • thermodynamic aqueous solubilities of representative examples are presented in the table below:

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Abstract

L'invention concerne des composés de formule (I) : dans laquelle E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, L2 et Y2 ont les significations données dans la description, et leurs sels pharmaceutiquement acceptables, lesdits composés étant utiles pour le traitement de maladies dans le cadre desquelles une inhibition de la leucotriène C4 synthase est souhaitée et/ou requise, et notamment pour le traitement d'un trouble respiratoire et/ou d'une inflammation.
PCT/GB2011/000358 2009-03-12 2011-03-14 Composés bis aromatiques destinés à être utilisés en tant qu'inhibiteurs de ltc4 synthase WO2011110824A1 (fr)

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WO2016177845A1 (fr) 2015-05-06 2016-11-10 Astrazeneca Ab Dérivés d'acide cyclopropane carboxylique et leurs utilisations pharmaceutiques
US9657001B2 (en) 2015-05-06 2017-05-23 Astrazeneca Ab Compounds and uses
WO2022034529A1 (fr) * 2020-08-14 2022-02-17 Novartis Ag Dérivés de spiropipéridinyle substitués par hétéroaryle et leurs utilisations pharmaceutiques
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AU2021325431B2 (en) * 2020-08-14 2024-01-18 Novartis Ag Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof

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