EP2545036A1 - Bis aromatic compounds for use as ltc4 synthase inhibitors - Google Patents

Bis aromatic compounds for use as ltc4 synthase inhibitors

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Publication number
EP2545036A1
EP2545036A1 EP11713851A EP11713851A EP2545036A1 EP 2545036 A1 EP2545036 A1 EP 2545036A1 EP 11713851 A EP11713851 A EP 11713851A EP 11713851 A EP11713851 A EP 11713851A EP 2545036 A1 EP2545036 A1 EP 2545036A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
optionally substituted
group
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11713851A
Other languages
German (de)
French (fr)
Inventor
Peter Nilsson
Benjamin Pelcman
Martins Katkevics
Robert RÖNN
Christian Krog-Jensen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biolipox AB
Original Assignee
Biolipox AB
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Filing date
Publication date
Priority claimed from PCT/GB2010/000438 external-priority patent/WO2010103278A1/en
Application filed by Biolipox AB filed Critical Biolipox AB
Publication of EP2545036A1 publication Critical patent/EP2545036A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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

There is provided compounds of formula (I): wherein E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, L2 and Y2 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of leukotriene C4 synthase is desired and/or required, and particularly in the treatment of a respiratory disorder and/or inflammation.

Description

BIS AROMATIC COMPOUNDS FOR USE AS LTC4 SYNTHASE INHIBITORS
Field of the Invention This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of the production of leukotrienes, such as leukotriene C4. 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.
Background of the Invention
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. Such 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)). Huge efforts have been devoted towards the development of drugs that inhibit the action of these metabolites as well as the biological processes that form them.
Of the leukotrienes, leukotriene (LT) B4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C4, D4 and E4 (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 CysLT2, 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, . It may be hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRas, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs; 5-LO, 5-lipoxygenase-activating protein (FLAP), and leukotriene C4 synthase may be mentioned. However, a 5-LO or a FLAP inhibitor would also decrease the formation of LTB4. For a review on leukotrienes in asthma, see H.-E Claesson and S.-E. Dahlen J. Internal Med. 245, 205 (1999).
There are many diseases/disorders that are inflammatory in their nature or have an inflammatory component. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
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 β-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.
There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, LTRas have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily.
This combination of factors has led to at least 50% of all asthma patients being inadequately treated.
A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. 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.
Chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD.
Other inflammatory disorders which may be mentioned include:
(a) pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very bad prognosis. No curative treatment exists);
(b) inflammatory bowel disease (a group of disorders with a high morbidity rate. Today only symptomatic treatment of such disorders is available); and
(c) rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints. There are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions). Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients. Thus, new and/or alternative treatments for respiratory and/or inflammatory disorders would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective antiinflammatory drug capable of treating inflammatory disorders, in particular asthma and COPD, with no real or perceived side effects.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
International patent application WO 2008/107661 discloses various biphenyl/diphenyl compounds that may be useful as LTC synthase inhibitors, and of use therefore in the treatment of inflammation. However, the two phenyl rings are linked together with via a methylene group. Further, international patent application WO 2009/030887 discloses, for that same use, various biaryl compounds linked together with a carbonyl group (i.e. diarylketones). However, there is no specific disclosure in that application of a biaryl/diaryl compound in which one of the requisite aromatic rings is a heteroaryl group.
International patent application WO 2010/103278 also discloses diarylketones, for use in the treatment of inflammation.
Disclosure of the Invention
According to the invention, there is provided a compound of formula I
wherein one of E2a, E2b and E2c represents -C(-L3-Y3)= and the other two respectively represent E2 and E3;
Y represents -C(O)- or -C(=N-OR28)-;
R28 represents hydrogen or Ci-6 alkyl optionally substituted by one or more fluoro atoms; at least one or two of Pi, D2 and D3 represent(s) -N=; and/or at least one or two of E1 t E2, E3 and E represent(s) -N=; and those (or the) remaining D2 and D3 group(s) each independently represent -C(R1)=; and those remaining Ei, E2, E3 and E4 groups each independently represent -C(R2)=; each R1 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X1; each R2 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X2;
Y1 represents -C(0)OR9a or 5-tetrazolyl;
R9a represents:
(i) hydrogen; or
(ii) Ci-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; one of Y2 and Y3 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:
(a) an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A); or
(b) d. 2 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
A represents, on each occasion when used herein:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) Ci-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G and/or Z1; or
III) a G1 group;
X1, X2, G1 and B independently represent halo, -R5a, -C(0)R5b, -CN, -N02, -C(0)N(R6a)R7a, -N(R6b)R7b, -N(R5c)C(0)R6c, -N(RM)C(0)OR6d, -OR5e, -OS(0)2R5f, -S(0)mR59, -OC(0)R5h or -S(0)2N(R6e)R e; R5b to R5e, R5g, R5 , R6a to R6c, R6e, R7a, R7b and R7e independently represent, on each occasion when used herein, H or R5a; or any of the pairs R6a and R7a, R6b and R7b, or R6e and R7e may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from fluoro, =0, -OR5e and/or R5a;
R5f and R6d independently represent R5a; R5a represents, on each occasion when used herein:
(i) C -6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, =0, -OR83, -N(R8 )R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8 ; or
(ii) aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from halo, -CN, -OR8a, -N(R8b)R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f; n represents 0, 1 or 2; each R8 , R3d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, =0, -OR a and/or -N(R12a)R12b; each R8a, R8c and R8f independently represent H or C1-3 alkyl optionally substituted by one or more substituents selected from F, =0, -OR13a, -N(R14a)R14 , -S(0)2CH3, -S(0)2CHF2 and/or -S(0)2CF3; or
R8 and R8c and/or R8e and R8< 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;
R1 a and R13a independently represent H or Ci-3 alkyl optionally substituted by one or more fluoro atoms;
R1Za, R 2b, R14a and R1 b independently represent H, -CH3 or -CH2CH3;
Z1 represents, on each occasion when used herein, =0 or =NOR16b; R16b represents hydrogen or alkyl optionally substituted by one or more fluoro atoms; L1 represents a single bond or -(CH2)p-Q-(CH2)q-; Q represents -C^XR*2)-, -C(O)-, -N(Ry3)- 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 L2 and L3 represents -C(0)-A17- (e.g. -C(O)-) and the other may represent a single bond or a spacer group selected from -S(0)nr, -C(Ry4)(Ry5)-A16, -N(R17a)-A16-, -OA17- and -C(0)-A17- (e.g. -C(O)-); n1 represents 0, 1 or 2;
A16 represents a direct (i.e. a single) bond, -C(Ry6)(Ry7)-, -C(O)-, -C(0)N(R17b)-, -C(0)C(Ry6)(Ry7)- or -S(0)2-; each A17 independently represents a direct bond or -C(Ry8)(Ry9)-; each Ry\ Ry2, Ry4, Ry5, Ry6, Ry7, Ry8 and Ry9 independently represent H, fluoro or C-i.3 alkyl optionally substituted by one or more fluoro atoms; or
Ry and Ry2, Ry4 and Ry5, R^ and Ry7 and Ry8 and Ry9 may be linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and C1-2 alkyl;
Ry3 represents hydrogen or d.3 alkyl;
R17a and R17 independently represent hydrogen, C1-6 alkyl (optionally substituted by one or more substituents selected from heterocycloalkyl, aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from R30), fluoro, -CN, -OR19 and/or =0), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from R31); R30 and R3 independently represent halo, -R18a, -C(0)R18b, -CN, -C(O)N(R180)R18d, -N(R18e)R18f, -N(R18g)C(0)R18h, -N(R18i)C(0)OR18i, -OR 8k, -OS(0)2R18m, -S(0)mR18n, -OC(0)R18p or -S(0)2N(R18q)R18r); m represents, on each occasion when used herein, 0, 1 or 2;
R18a, R18b, R18c, R18d, R18e, R18f, R189, R18h, R18i, R18k, R18n, R18p, R18q and R18r independently represent hydrogen or Ci-3 alkyl optionally substituted by one or more fluoro atoms;
R18i and R18m independently represent C1-3 alkyl optionally substituted by one or more fluoro atoms; R19 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". Such compounds are characterised in that at least one of D2, D3, EL E2, E3 and E4 represents -N=. That is, either one of (or both) the to D3- containing ring and the Ei to E -containing ring contains (at least one) -N=. 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 (entgegen) 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 exhibit tautomerism. All tautomeric forms 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. Alternatively 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.
Unless otherwise specified, 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. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2.q alkenyl or a C2.q alkynyl group). Where the number of carbon atoms permits, C1K, 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. The term "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). Further, such heterocycloalkyi groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2-q (e.g. C4-q) heterocycloalkenyl (where q is the upper limit of the range) or a C7.q heterocycloalkynyl group. C2 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 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. 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. At each occurrence when mentioned herein, a heterocycloalkyi group is preferably a 3- to 8-membered heterocycloalkyi group (e.g. a 5- or 6-membered heterocycloalkyi group). For the avoidance of doubt, the term "bicyclic" (e.g. when employed in the context of heterocycloalkyi groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term "bridged" (e.g. when employed in the context of heterocycloalkyi groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
Aryl groups that may be mentioned include (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. C6-i4 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, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2, 1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4- dihydro-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselena- diazolyl (including 2, 1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (such as imidazo[4,5- £>]pyridyl, imidazo[5,4-6]pyridyl and, preferably, imidazo[1 ,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8- tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1 ,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on 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. However, when heteroaryl groups are 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. For the avoidance of doubt, in cases in which 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. For example, in the situation in which X1 and X2 both represent R5a, i.e. a C-i-6 alkyl group optionally substituted as hereinbefore defined, the alkyl groups in question may be the same or different. Similarly, when 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. For example, when there are two X1 substituents present, which represent -R5a and -C(0)R5 in which R5 represents R5a, then the identities of the two R5a groups are not to be regarded as being interdependent. Likewise, when Y2 or Y3 are substituted by more than one G1 group, then such substituents are not interdependent (i.e. they may be the same or different G1 groups). For example, when Y2 or Y3 represent e.g. an aryl group substituted by G1 in addition to, for example, Ci.8 alkyl, which latter group is substituted by G1, the identities of the two G1 groups are not to be regarded as being interdependent. For the avoidance of doubt, when a term such as "R53 to R5 " is employed herein, this will be understood by the skilled person to mean R5a, R5b, R5c, R5d, R5e, R5', R59 and R5h inclusively. For the avoidance of doubt, when the term "an R5 group" is referred to herein, we mean any one of R5a to R5h. For the avoidance of doubt, the term "E-, to Er containing ring" refers to the ring containing E2a, E2b, E2c and E4. Further, the term "D7 to Ds-containing ring" refers to the ring containing Di, D2 and D3. For the avoidance of doubt, the following compounds of formula la, lb and Ic are included within the scope of the compounds of formula I:
wherein the integers are as defined above. The skilled person will further appreciate that compounds of formula la and Ic may be identical, due to rotation around the bond linking the Y group to the Ei to E4-containing ring or to the Di to D3-containing ring. Hence, the skilled person will appreciate that, given that there is an essential '-L3-Y3' group present in the compound of formula I, then one -L3-Y3 group, as it is an essential feature.
Compounds of the invention, for instance those compounds of formula I in which L2 represents -C(O)- (and Y2 is as defined herein), L1 represents a single bond and Y1 represents -C(0)OR9a (and R9a is preferably hydrogen), may exist in cyclised form and/or in equilibrium with a corresponding compound in cyclised form. By 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 Y2 represents C1-12 alkyl as hereinbefore defined (e.g. acyclic CL12 alkyl). Such compounds are encompassed within the scope of compounds of the invention (and fall within the scope of compounds of formula I). Hence, compounds of formula I in which Y2 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). In such instances, 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. In a further embodiment of the invention, there is provided a compound of formula IA as such and as defined above (which would include corresponding compounds of formula I in which Y2 represents -C(O)-).
Compounds of the invention that may be mentioned include those in which:
n1 represents 1 ;
A16 represents a direct bond, -C(O)-, -C(0)N(R17 )-, -C(0)C(RyS)(Ry7)- or -S(0)2-; R5a represents, on each occasion when used herein, d-e alkyl optionally substituted by one or more substituents selected from fluoro, -CN, =0, -OR8a, -N(R8b)R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f;
R17a and R17b independently represent hydrogen, Ci_6 alkyl (optionally substituted by one or more substituents selected from fluoro, -CN, -OR19 and/or =0), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from halo, -R18a, -C(0)R18 , -CN, -C(0)N(R18c)R18d,
-N(Rl8e)R18f, -N(R18g)C(0)R18h, -N(R18i)C(0)OR18', -OR18k, -OS(0)2R18m
-S(0)mR 8n, -OC(0)R18p or -S(0)2N(R 8q)R 8r);
X1, X2, G1 and B independently represent halo, -R5a, -C(0)R5b, -CN,
-C(0)N(R6a)R7a, -N(R6b)R7 , -N(R5c)C(0)R6c, -N(R5d)C(0)OR6d, -OR5e, -OS(0)2R5 ,
-S(0)mR59, -OC(0)R5h or -S(0)2N(R6e)R7e; each R , R , R8d and R8e independently represent H or Ci-6 alkyl optionally substituted by one or more substituents selected from fluoro, =0, -OR11a and/or -N(R12a)R12 ;
when L2 or L3 represent C(Ry4)(Ry5)-A16 in which A16 is other than a direct/single bond, then A16 is preferably -C(O)-.
Further compounds of the invention that may be mentioned include those in which:
when DL D2, D3I E, , E2I E3 and E4 represents -C(R1)= or -C(R )= (as appropriate), in which R1 or R2 represent a substituent defined by R5a, then R5a preferably represents alkyl optionally substituted as defined herein;
when L2 or L3 (especially L2) represents a single bond, then Y2 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).
Further compounds of the invention that may be mentioned include those in which:
L2 represents a single bond or a spacer group selected from -C(Ry4)(Ry5)-, -N(R17a)-A16- and -OA17- (in which case L3 must represent -C(0)-A17-);
L2 represents a spacer group selected from -S(O)-, -C(Ry4)(Ry5)-, -N(R17a)-A16- and -OA17- (in which case L3 must represent -C(0)-A17-);
L2 represent a spacer group selected from -C(Ry4)(Ry5)-, -N(R 7a)-A16- and -OA17- (in which case L3 must represent -C(0)-A17-).
Compounds of the invention that may be mentioned include those in which:
when R5a represents C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -OR8a (hence, when R5a represents C1-6 alkyl, then it may not be substituted by a -C(0)OR8a group); when R5a represents alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -N(R8 )R8c (hence, when R5a represents C1-6 alkyl, then it may not be substituted by a -C(0)N(R8 )R8c group); when any of R8a, R8 , R8d and R8e represent C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -0R11a (hence, when such groups represent Ci.6 alkyl, then it may not be substituted by a -C(0)OR1 a group);
when any of R8a, R8b, R8d and RBe represent C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -N(R 2a)R12b (hence, when such groups represent C1-6 alkyl, then it may not be substituted by a -C(0)N(R12a)R12b group);
when any of R8c and/or R8f represent C1.3 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -OR13a (hence, when such groups represent alkyl, then it may not be substituted by a -C(0)OR13a group);
when any of R8c and/or R8f represent C1-3 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both =0 and -N(R1 a)R14b (hence, when such groups represent C1-3 alkyl, then it may not be substituted by a -C(0)N(R14a)R14b group);
when R17a or R17 represent a C,.6 alkyl group, then that alkyl group may not be substituted at a terminal position by both a =0 and -OR19, i.e. it may not be substituted by a -COOR19 group.
Further compounds of the invention that may be mentioned include those in which:
R5a represents, on each occasion when used herein, C -6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, -0R8a, -N(R8b)R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f; or
R5a represents, on each occasion when used herein, C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, =0, -N(R8 )R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f;
R8a, R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -0R11a and/or -N(R12a)R12b; or R8a, R8b, R8d and R8e independently represent H or alkyl optionally substituted by one or more substituents selected from fluoro, =0 and/or -N(R a)R12 ; R8c and R8f independently represent H or CV3 alkyl optionally substituted by one or more substituents selected from F, -OR13a, -N(R14a)R1 b, -S(0)2CH3, -S(0)2CHF2 and/or -S(0)2CF3; or
R8c and R8f independently represent H or d.3 alkyl optionally substituted by one or more substituents selected from F, =0, -N(Rl4a)R14b -S(0)2CH3, -S(0)2CHF2 and/or -S(0)2CF3; and/or
when R 7a and R17 represent optionally substituted alkyl, then the optional substituents are preferably selected from fluoro, -CN and/or -OR19 (or may alternatively be selected from fluoro, -CN and =0);
when alkyl groups mentioned herein are substituted by halo, then that halo group is preferably fluoro.
In the compounds of the invention, when any of the pairs R6a and R7a, R6b and R7 and/or RSe and R7e are linked together to form a 3- to 6-membered ring, then preferably:
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 R6 and R7 groups are necessarily attached);
when such rings are substituted with R5a then R5a 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);
such rings may be substituted with one or more substitutents selected from -OR5h (e.g. -OH, -OCH3, -OCF3 or -OCHF2) and, preferably, fluoro, =0 and, especially, R5a (for example, as defined above), but are more preferably unsubstituted.
In the compounds of the invention, when any of the pairs R8 and R8c and/or R8e and R8f, are linked together to form a 3- to 6-membered ring, then preferably: such rings are preferably 5- or 6-membered;
when such rings are substituted, then they are preferably substituted with one or two substituents;
such rings are preferably unsubstituted.
In the compounds of the invention, when any of the pairs Ry1 and Ry2, Ry4 and Ry5, Ry6 and Ry7 and/or Ry8 and Ry9 are linked together to form a 3- to 6- membered ring, then preferably: such rings are preferably 4-membered or, more preferably, 3-membered;
when such rings are substituted, then they are preferably substituted with one or two substituents;
such rings are preferably unsubstituted.
As stated herein, compounds of the invention that may be mentioned include those in which one or two of Di, D2 and D3 represent(s) -N= and/or one or two of EL E2, E3 and E4 represent(s) -N=. The skilled person will appreciate that in the compounds of the invention at least one of the D, to D3-containing ring and Ei to E4-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)). Preferably, either one or the other of those Di to D3-containing ring and to E4-containing rings (preferably the to E4-containing ring) contains two or preferably one nitrogen atom(s), and the other does not contain any nitrogen atoms (i.e. the relevant moieties D-,, D2, D3, E1 ( E2, E3 and E4 represent -C(R1)= or -C(R2)= as appropriate).
Compounds of the invention that may be mentioned include those in which:
any one or two of E1 t E2) E3 and E4 represent(s) -N=, and the others each independently represent -C(R2)=);
each of Di, D2 and D3 independently represent -C(R )=, or each of D2 and D3 may alternatively and independently represent -N=.
Preferred compounds of the invention include those in which:
(i) either: at least one or two of Di, D2 and D3 represent(s) -N=; or at least one or two of E E2, E3 and E4 represent(s) -N= (and those remaining Di, D2 and D3 groups each independently represent -C(R1)=, and those remaining Ei, E2> E3 and E4 groups each independently represent -C(R2)=);
(ii) when at least one or two of D-,, D2 and D3 represent(s) -N=, then E1 ( E2, E3 and E each independently represent -C(R2)=;
(iii) when at least one or two of Ei, E2, E3 and E4 represent(s) -N=, then D-i, D2 and D3 each independently represent -C(R1)=;
(iv) any one or two of Ε·,, E2, E3 and E4 represent(s) -N=, and the others independently represent -C(R2)=, and each of Di, D2 and D3 respectively represent -C(R1)=; (v) any one or two of D1 t D2 and D3 represent(s) -N=, and the others independently represent -C(R1)=, and each of E1† E2, E3 and E respectively represent -C(R2)=.
The most preferred of the above preferences are (i) and, especially, (iv).
Preferred compounds of the invention that may be mentioned include those in which:
Y2 and Y3 independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
when Y2 or Y3 represent optionally substiuted d.12 alkyl, then it is preferably optionally substituted cycloalkyl (such as C3-12 (e.g. C3-8) cycloalkyl and, preferably, C5.6 alkyl);
Y2 and Y3 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 G1 and/or Z );
Y represents -C(O)-.
Further preferred compounds of the invention that may be mentioned include those in which:
one of L2 and L3 represent(s) a spacer group selected from -C(Ry )(Ry5)-. -N(R17a)- A 6-, and -OA17- (and the other represents the requisite -C(0)-A17- moiety);
(e.g. one of) Y2 and Y3 represent an aryl group optionally substituted as defined herein;
when L2 or L3 represent -N(R 7a)A16-, in which A16 represents a single bond and R17a represents H, then Y2 or Y3 (as appropriate) preferably does/do not represent a benzimidazolyl (e.g. benzimidazol-2-yl) group.
Preferred rings that the to D3-containing ring may represent include 2- or 4- pyridyl (relative to the point of attachment to the -C(O)- (or -C(=N-OR28)-) moiety) or, most preferably, phenyl. Preferred rings that the ΕΊ to E4-containing ring may represent include pyrazinyl, pyrimidinyl, pyridazinyl and, preferably, pyridyl groups. For example: when two of Ei, E2, E3 and E4 represent -N=, then preferably the Ei to E4- containing ring represents a pyrazinyl, pyrimidinyl or pyridazinyl (e.g. ΕΊ and E2c, E2a and E4, Ei and E2b, E2a and E2c, E2b and E4> E and E , Ei and E2a, E2a and E2b, E2b and E2c, or E2c and E may be the two E, to E4 groups that represent -N= so forming for example, a 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl or 4-pyridazinyl) group (especially preferred are 2-pyrimidinyl groups);
preferably, only one of Ei, E2a, E2b, E2c and E4 (e.g. E2b, preferably, E2a or E2c, or, especially, one of E^ or E4, i.e. one of the ortho positions, relative to the point of attachment with the Y moiety) represents -N= (and the others each independently represent -C(R2)=, as appropriate), and hence the Ei to E4-containing ring is preferably a pyridyl (e.g. 4-pyridyl, 3-pyridyl or especially a 2-pyridyl) group.
Preferred aryl and heteroaryl groups that Y2 and Y3 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. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyI, isoquinolinyl, 1 ,2,3,4- tetrahydroisoquinolinyl, quinolizinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group. Preferred groups include thienyl, thiazolyl, oxazolyl and phenyl.
Preferred substituents on Y2 and Y3 groups include:
halo (e.g. bromo or, preferably, fluoro or chloro);
cyano;
Ci.$ alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C1-4 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);
heterocycloalkyl, such as a 5- or 6-membered heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, which heterocycloalkyi group is optionally substituted by one or more (e.g. one or two) substituents selected from C 3 alkyl (e.g. methyl) and =0;
-OR26;
-C(0)R26;
-C(0)OR26;
-N(R26)R27; and
-S(0)mR26 (in which m is 0, 1 or 2);
wherein R26 and R27 independently represent, on each occasion when used herein, H, Ci-6 alkyl, such as C1-4 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.2) alkyl groups (which alkyl group is optionally substituted by one or more halo (e.g. fluoro) atoms). Preferably, when the substituent is -S(0)R26 or -S(0)2R26, then R26 does not represent hydrogen.
Preferred compounds of the invention include those in which:
any two (preferably any one or, more preferably, none) of D2 and D3 represents -N=;
any one of E^ E2, E3 and E4 represents -N= and the others independently represent -C(R2)=;
ET (or E4) represents -N= or -C(R2)=;
E2A (or E2C) represents -C(R2)= or -N=;
E2B represents -C(-L3-Y3)=;
when three R2 groups are present, then at least one (e.g. at least two) of those R2 groups represents hydrogen;
when two R2 groups are present, then at least one of them represents hydrogen; at least one (e.g. at least two) R1 group that may be present represents hydrogen; X1, X2, G1 and B independently represent -C(0)N(R6a)R7a, -N(R6b)R7b or, preferably, halo (e.g. chloro or fluoro), -R5a, -OR5e or -S(0)mR5g;
R8a, R8 , R8d and R8e independently represent hydrogen or d.6 (e.g. C^) alkyl optionally substituted by one or more substituents selected from -OR11a, preferably, =0, and especially, fluoro (most preferably, R8a, R8b, R8d and R8e independently represent -CF3, methyl or particularly, hydrogen);
R8c and R8f independently represent hydrogen or C1-3 (e.g. Ci-2) alkyl optionally substituted by one or more substituents selected from -OR13a, preferably, =0, and especially, fluoro (most preferably, R c and R8f independently represent -CF3, methyl or particularly, hydrogen);
R a and R 3a independently represent -CF3, preferably ethyl, and particularly hydrogen and/or methyl;
R12a, R12 , R14a and R14b independently represent methyl or hydrogen (particularly, methyl);
L1 represents a single bond;
Y1 represents 5-tetrazolyl (which is preferably unsubstituted) or, preferably, -C(0)OR9a;
R9a represents Ci-6 alkyl (optionally substituted by one or more G1 and/or Z1 substituents; but preferably unsubstituted) or, preferably, hydrogen;
at least one of Y2 and Y3 represents aryl (e.g. phenyl) optionally substituted as defined herein;
Y2 and Y3 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 G1 or C1-6 (e.g. alkyl (e.g. butyl (such as n-butyl) or methyl) optionally substituted by one or more substituents selected from G ;
R5a represents C1-6 (e.g. C1-4) alkyl optionally substituted by one or more substituents selected from -N(R8b)R8c and, preferably, fluoro and -OR8a;
R6a and R7a, R6b and R7 and/or R6e and R7e are preferably not linked together; when R5e represents R5a, then R5a preferably represents C1-6 (e.g. d- alkyl
(which group may be substituted by one or more fluoro atoms, but is more preferably unsubstituted);
Z represents =0;
R16b represents Ci.2 alkyl (e.g. methyl) or, preferably, hydrogen;
L represents a single bond;
Q represents -C(Ry1)(Ry2)-;
p and q represent 0 or 1 ;
the sum of p and q is 0 or 1 ;
Ry and Ry2 independently represent fluoro, methyl or, preferably, hydrogen;
Ry1 and Ry2 are preferably not linked together;
Ry3 represents hydrogen or methyl;
one of L2 and L3 represents -C(0)-A17- and the other represents a single bond or, more preferably, -N(R17a)-A16- or -OA17-;
A16 represents a direct bond, -C(O)- or -S(0)2-; Ry4, Ry5, Ry6, Ry7, RyS and R^ independently represent fluoro, methyl or, preferably, hydrogen;
Ry4 and R 5, R≠ and Ry7 and/or Ry8 and Ry9 are preferably not linked together; when R 7a or R17 represent optionally substituted aryl or heteroaryl, then those optional substituents are preferably selected from halo (e.g. fluoro and chloro) and R18a;
R17a and R17b represents hydrogen or Ci.6 alkyl optionally substituted as hereinbefore defined (for example, by one or more substituents selected from fluoro, -CN, -OH, -OCH3 and -OCH2CH3);
p18a p18b p18c p18d p18e p18f p18g p18h p18i p18 p18n ^18p p18q gn(-j p18r independently represent -CHF2 or, preferably, hydrogen, methyl or -CF3;
R18j and R18m independently represent -CHF2 or, preferably, methyl or -CF3;
when Y2 and/or Y3 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);
R28 represents hydrogen or unsubstituted Ci.3 (e.g. C^) alkyl (e.g. methyl).
More preferred compounds of the invention include those in which:
E2b represents -C(-L3-Y3)= (and hence, E2a and E2c respectively represent E2 and
E3);
Ei represents -N=;
E4 represents -N= or, preferably, -C(R2)=;
E2 and E3 independently represent -C(R2)=;
each R2 independently represents hydrogen;
D2 represents -C(R1)=;
Di and D3 independently represent -C(R1)= or -N=;
most preferably, each D2 and D3 independently represents -C(R1)= (e.g. D2 and D3 independently represent -C(H)=);
each R1 independently represents, on each occasion when used herein, hydrogen;
only one of the to D3-containing ring and the Ετ to E4-containing ring (preferably the Ei to E4-containing ring) contains a nitrogen atom (i.e. -N=) and the other (preferably the to D3-containing ring) does not contain a nitrogen atom;
when the D to D3-containing ring contains a nitrogen atom, then preferably, either Di or D3 represents -N= and D2 represents -C(R1)= (so forming, for example, a 2-pyridyl group);
when the Ei to E4-containing ring contains a nitrogen atom, then preferably, either or E4 or both E and E4 represent(s) -N= and E2 and E3 independently represent -C(R2)= (so forming, for example, a 2-pyridyl group or a 2-pyrimidinyl group);
X1 , X2 and B independently represent halo (e.g. chloro or fluoro), -R5a or -OR5e
(most preferably, X1, X2 and B independently represent -R5a or, preferably, halo
(e.g. chloro or fluoro));
Y represents -C(O)-;
L represents a single bond;
Y represents -C(0)OR9a;
R9a represents hydrogen;
one of L2 and L3 represents -C(0)-A17- (e.g. -C(O)-) and the other represents a single bond, or, preferably -N(R17a)-A16- or -OA17-;
A16 represents a direct bond, -C(O)- or -S(0)2-;
when L3 (or L2) represents -N(R17a)-A16-, then A16 preferably represents a direct bond;
A17 represents a direct bond;
R17a represents hydrogen or C1-6 alkyl optionally substituted by one or more (e.g. one) substituent(s) selected from -OCH3, -OCH2CH3 and -CN;
when R17a represents optionally substituted Ci_s alkyl, then 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 -OCH3, -OCH2CH3 and/or -CN, so forming for example a methoxyethyl (i.e. -(CH2)2-OCH3), ethoxyethyl or cyanopropyl (i.e. -(CH2)3-CN); a part cyclic Ci-6 alkyl group (for example Cv2 alkyl (e.g. methyl) substituted by C3.5 cycloalkyl), such as cyclopropylmethyl (i.e. -CH2-cyclopropyl), cyclobutylmethyl or cyclopentylmethyl; a linear saturated Ci.6 (e.g. Ci-4, such as C1-3) alkyl group (in which the unsaturation is preferably one double or one triple bond), such as allyl (i.e. -CH2-CH=CH) or propynyl (i.e. -CHrCHsCH); Y2 and Y3 independently represent an aryl (e.g. phenyl) or heteroaryl (e.g. triazolyl, or, preferably, thiazolyl, oxazolyl or thienyl) group optionally substituted by one or more substitutents selected from A;
A represents aryl (optionally substituted by halo, such as chloro), or, preferably, G1;
G1 represents halo (e.g. chloro or fluoro), -R5a, -OR5e or -S(0)mR¾;
R59 represents R5a;
R5a 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 -CF3 group);
when R5e represents R5a, then R5a preferably represents C1-6 (e.g. d^) alkyl (which group may be substituted by one or more fluoro atoms, but is more preferably unsubstituted);
when R5g represents R5a, then R5a preferably represents unsubstituted (e.g. CM) alkyl.
Provided that at least one of L2 and L3 represents -C(0)-A17- (e.g. -C(O)-), then particularly preferred:
L2 groups (i.e. when L3 represents -C(0)-A17-) include a single bond, or, L2 preferably represents -0-, -N(H)-, -N(H)C(0)- and -N(H)S(0)2- (especially preferred are -O- linker groups); and
L3 groups (i.e. when L2 represents -C(0)-A17-) include -N(CH3)-, -N(ethyl)-, -N(cycloprppylmethyl)-, -N(cyclobutylmethyl)-, -N(cyclopentylmethyl)-, -N(2-ethoxyethyl)-, -N(allyl)-, -N(2-propynyl) and -N(3-cyanopropyl)- (especially preferred are -N(CH3)-, -N(cyclobutylmethyl)-, -N(cyclopentylmethyl)-, -N(2-ethoxyethyl)-, -N(allyl)- and -N(2-propynyl).
Preferred Y2 and Y3 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). Especially preferred are optionally substituted phenyl groups (e.g. chlorophenyl and trifluoromethylphenyl). Particularly preferred phenyl groups that Y2 and Y3 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-SCH3)phenyl), 2-methylsulfinylphenyl (i.e. (2- S(0)CH3)phenyl), methylsulfonylmethylphenyl (i.e. (2-S(0)2CH3)phenyl), 2- hydroxy-5-chlorophenyl and 4-n-butoxyphenyl. Especially preferred are unsubstituted phenyl and chlorophenyl (e.g. 4-chlorophenyl and 4- trifluoromethylphenyl). Preferred substituents on Y2 and Y3 groups (e.g. when they represent aryl or heteroaryl) include halo (e.g. chloro or fluoro), (e.g. C1-4) alkyl (such as methyl or butyl, e.g. n- or f-butyl; which alkyl group is optionally substituted by one or more fluoro atoms, so forming for example, a -CF3 group), -S-Cv3 alkyl (e.g. -S-CH3), -S(0)-C1-3 alkyl (e.g. -S(0)CH3), -S(0)2-C1-3 alkyl (e.g. -S(0)2CH3), hydroxy (i.e. -OH), -0-C1-6 (e.g. -0-C ) alkyl (e.g. -0- ?-butyl). Especially preferred substituents on such Y2 and Y3 groups are halo (e.g. chloro) and C 2 alkyl (e.g. methyl) optionally (and preferably) substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group). Particularly preferred compounds of the invention include those of the following formula:
wherein
Y represents -C(O)- or -C(=N-OR28)-;
R28 represents hydrogen or alkyl;
either: one or two of Di, D2 and D3 represents -N=; or one or two of E1 ( E2> E3 and E4 represent(s) -N= (i.e. either the to D3-containing ring or the E, to E4- containing ring contains one or two -N= moieties);
either: (i) one of E2, E3 and E4 (e.g. or E4) represents -N= and the others independently represent -C(R2)=; and D2 and D3 each independently represent -C(R1)=;
(ii) one of D2 and D3 (e.g. D or D3) represents -N= and the others independently represent -C(R1)=; and Ei, E2, E3 and E4 each independently represent -C(R2)=; or
(iii) two of E1 f E2) E3 and E4 (e.g. Ei and E4) represent -N= and the others independently represent -C(R2)=; and D2 and D3 each independently represent -C(R1)=;
each R1 and R2 independently represent H;
Y1 represents -C(0)OR9a;
R9a represents: (i) hydrogen; or (ii) C-,.8 alkyl optionally substituted by one or more substituents selected from G1 and/or Z1 (but preferably unsubstituted);
L1 represents a single bond;
one of L2 and L3 (e.g. L2) represents -C(0)-A17 (e.g. -C(O)-, -C(0)-CH2- or -C(O)- cyclopropylene-, i.e. -C(0)-C-(-CH2-CH2-)-) and the other is as defined herein;
L2 represents -C(0)-A17 (e.g. -C(O)-, -C(0)-CH2- or -C(0)-cyclopropylene-, i.e.
-C(0)-C-(-CH2-CH2-)-) or, when L3 represents -C(0)-A17-, L2 may represent a single bond, -OA17-, -N(R17a)-A16 (e.g. -N(R17a)-CH2-, -N(R17a)-, -N(R17a)-C(0)- or -N(R17a)-S(0)2-), -S- or -S(O)-;
L3 represents (when L2 represents -C(0)-A17-) a single bond, -N(R17a)-A16- (e.g.
-N(R17a)-) or -OA17 (e.g. -OCH2-);
A16 represents -CH2- or, preferably, a direct bond, -C(O)- or -S(0)2-;
A17 represents a direct bond or -C(Ry8)(Ry9)- (in which Ry8 and Ry9 represent hydrogen, or, are linked together to form a cyclopropyl group);
R17a 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, -OR19 (e.g. -OCH2CH3), 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);
Y2 represents acyclic C-|.6 (e.g. C -6) alkyl or Y2 more preferably represents: (i) phenyl; (ii) 5- or, preferably, 6-membered heteroaryl (e.g. in which there is preferably one heteroatom, preferably selected from nitrogen, oxygen and sulfur, so forming e.g. thienyl or, preferably, pyridyl); (iii) 9- or 10-membered bicyclic heteroaryl group (e.g. consisting of a benzene ring fused to a 5- or 6-membered heteroaryl or heterocycloalkyl group, so forming e.g. 3,4-methylenedioxyphenyl or 3,4-ethylenedioxyphenyl); (iv) C3-a (e.g. C5-6) cycloalkyl; (v) or 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 Z1);
when Y2 or Y3 represent alkyl, then such groups are preferably cycloalkyl;
Y3 may represents a group as defined above for Y2 (provided that at least one of Y2 and Y3 represent an aromatic group), but Y3 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 G1 or Ci_4 (e.g. d.2) alkyl (e.g. ferf-butyl or methyl) optionally substituted by one or more substituents selected from G1 (preferably A only represents an aryl (e.g. phenyl) substituent when it is on a Y2 or Y3 (e.g. Y2) group that is an aromatic group, i.e. aryl or heteroaryl);
G represents halo (e.g. chloro, fiuoro or bromo), -CN, -N02, -OR5e, -S(0)mR5g or -S(0)2N(R6e)R7e;
B represents halo (e.g. chloro or fiuoro);
m represents 0, 1 or 2;
R5e 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;
R5g represents C1-4 alkyl (e.g. methyl);
R6e and R7e independently represent hydrogen or, preferably, Ci.2 alkyl (e.g. methyl);
Z represents, on each occasion when used herein, =0;
A substituents (i.e. on Y2 or Y3 groups) 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). For the avoidance of doubt, all individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
Other preferred compounds of the invention that may be mentioned include those in which:
Y represents -C(O)-;
one of E2, E3 and E4 (e.g. or E4) represents -N=, and the others independently represent -C(R2)=; and D2 and D3 each independently represent -C(R )=;
each R1 and R2 independently represent H;
Y1 represents -C(0)OR9a;
R9a represents hydrogen;
L1 represents a single bond;
L2 represents -C(0)-A17- (especially, -C(O)-);
L3 represents -N(R17a)-A16-, -C(0)-A17- (especially, -C(O)-) or -C(Ry4)(Ry5)-A16-; A16 represents a direct bond;
Ry4 and Ry5 independently represent hydrogen;
A17 represents a direct bond or -C(Ry8)(Ry9)- (in which Ry8 and Ry9 independently represent hydrogen, C1-2 alkyl (e.g. methyl) or, are linked together to form a 3- to 6-membered cycloalkyl group, e.g. cyclopropyl, cyclopentyl or cyclohexyl);
R17a represents Ci_s alkyl (e.g. methyl, cyclopropylmethyl)
Y2 may also represent, in addition to the groups mentioned hereinbefore: a fused and/or bridged C6.12 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, -CH2-f- butyl or ethyl) or C3.6 cycloakyl (e.g. cyclopropyl or cyclopentyl), which latter two groups are optionally substituted by one or more substituents selected from G1; G may also represent, in addition to the groups mentioned hereinbefore, R5a or -C(0)R5 ;
R5a may also represent, in addition to the groups mentioned hereinbefore, Ci.6 alkyl (e.g. C3-5 cycloalkyl, such as cyclohexyl) or aryl (e.g. phenyl), preferably unsubstituted;
R5b represents hydrogen. Other preferred compounds of the invention that may be mentioned include those in which:
one of Y2 and Y3 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, C3-6 cycloalkyl or bridged C6-12 cycloalkyl, e.g. terf-butyl, n-hexyl, cyclohexyl, cyclopentyl, adamantyl, bicyclo[2.2.1]heptanyl, -CH2-f-butyl, cyclopropyl, methyl or ethyl; optionally substituted by one or more (e.g. one) substituent(s) selected from G1), 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
Y2 and Y3 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;
when Y2 or Y3 represents aryl, it is preferably (optionally substituted) phenyl;
when Y2 or Y3 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
5-6 membered heteroaryl group), for instance (optionally substituted) thienyl (e.g.
2-thienyl), 3,4-methylenedioxyphenyl or 3,4-ethylenedioxyphenyl;
A represents G1 or C1-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more G1 groups (e.g. in which G1 is fluoro, so forming e.g. a -CF3 group, or chloro, so forming e.g. dichloromethyl);
G (e.g. when A represents G ) represents halo (e.g. chloro or fluoro), R5a, -C(0)R5b, -N02 or -OR5e;
G may also represent (e.g. when Y2 or Y3 represent alkyl substituted by G1) R5a, in which R5a represents C3-6 cycloalkyl (e.g. cyclohexyl or cyclopentyl) or aryl (e.g. phenyl; preferably unsubstituted);
R5e represents hydrogen or R5a;
R5b represents R5a or, preferably, hydrogen;
R5a represents (e.g. C1-3) alkyl (e.g. methyl or ethyl) optionally substituted by one or more fluoro atoms;
Y2 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;
Y3 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.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:
(i) for compounds of formula I in which Y represents -C(O)-, oxidation of a compo wherein ring E1 t E2a, E2b> E2c, E2d, E4, D1( D2, D3l L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable oxidising agent;
(ia) for compounds of formula I in which Y represents -C(O)-, oxidation of a compound of formula IIA,
wherein Ei, E2a, E2b, E2C, E2_, E4, D D2, D3, L , Y , L2 and Y2 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);
(ii) for compounds of formula I in which L2 or L3 represents -N(R17a)A16- (and the other represents -C(0)-A17-) in which R17a represents H (and, preferably, Y is -C(O)- or R28 is Ci-6 alkyl optionally substituted by one or more halo atoms), reaction of a compound of formula III, or a protected derivative thereof (e.g. an amino-protected derivative or a keto- protecting group, such as a ketal or thioketal) wherein one of E2ai , E2bi , E2ci represents -C(-L3A)= and the other two respectively represent E2 and E3, one of LZa and L3a represents -NH2 and the other represents -C(0)-A17-Y2 or -C(0)-A17-Y3 as appropriate, and Y, EL E2, E3I E4I DL D2, D3, L1 and Y1 are as hereinbefore defined, with: (A) when A16 represents -C(0)N(R 7 )-, in which R17B represents H:
(a) a compound of formula IV,
YA_N=C=0 IV ; or
(b) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or Co2(CO)8)) or a reagent such as phosgene or triphosgene in the presence of a compound of formula V, Ya-NH2 V wherein, in both cases, Ya represents Y2 or Y3 (as appropriate/required) as hereinbefore defined. For example, in the case of (a) above, in the presence of a suitable solvent (e.g. THF, dioxane or diethyl ether) under reaction conditions known to those skilled in the art (e.g. at room temperature). In the case of (b), 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. The skilled person will appreciate that 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). The skilled person will appreciate that for preparation of compounds of formula I in which -L2-Y2 represents -N(H)C(0)N(H)-Y2 and -L3-Y3 represents -N(H)C(0)N(H)-Y3 and Y2 and Y3 are different, two different compounds of formula IV or V (as appropriate) will need to be employed in successive reaction steps. For the preparation of such compounds starting from compounds of formula III in which both of L2a and L3a represent -NH2, then mono-protection (at a single amino group) followed by deprotection may be necessary, or the reaction may be performed with less than 2 equivalents of the compound of formula IV or V (as appropriate); (B) when A16 represents a direct bond, with a compound of formula VI,
Ya-La VI wherein La represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(0)2CF3, -OS(0)2CH3, -OS(0)2PhMe 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) and Ya 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, Pd2(dba)3 or NiCI2 and an optional additive such as Ph3P, 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, Et3N, pyridine, /V.W-dimethylethylenediamine, Na2C03, K2C03, K3P04, Cs2C03, f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or a mixture thereoO or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when Ya represents phenyl and La represents bromo, i.e. bromobenzene). This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation; (C) when A16 represents -S(0)2- -C(O)- or -C(0)-C(Ry6)(Ry7)-, with a compound of formula VII, a 16a a VII wherein A16a represents -S(0)2-, -C(O)- or -C(0)-C(Ry6)(Ry7)-, and Ya and La are as hereinbefore defined, and La is preferably, bromo or chloro, under reaction conditions known to those skilled in the art, the reaction may be performed at around room temperature or above (e.g. up to 40-180°C), optionally in the presence of 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. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, tnfluoromethylbenzene, dioxane or triethylamine);
(iii) for compounds of formula I in which one of L2 and L3 represents -C(0)-A17- and the other represents -N(R 7a)C(0)N(R17b)-, in which R 7a and R 7 represent H, and, preferably, Y is -C(O)- or R28 is Ci.6 alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula VIII,
wherein one of E2a2, E2b2, E2c2 represents -C(-J )= and the other two respectively represent E2 and E3, one of J1 and J2 represents -N=C=0 and the other represents -C(0)-A17-Y2 or -C(0)-A17-Y3 (as appropriate), and Y, E,, E2, E3, E4, Di, D2, D3, L1 and Y1 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;
(iv) for compounds of formula I in which, preferably, Y is -C(O)- or R28 is Ci-s alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula IX,
wherein one of E2a3, E2b3, E2c3 represents -C(-Z )= and the other two respectively represent E2 and E3> at least one of Z* and Zy represents a suitable leaving group and the other may also independently represent a suitable leaving group, or, Zy may represent -L2-Y2 and Zx may represent -L3-Y3, in which the suitable leaving group may independently be fluoro or, preferably, chloro, bromo, iodo, a sulfonate group (e.g. -OS(0)2CF3, -OS(0)2CH3, -OS(0)2PhMe or a nonaflate), -B(OH)2, -BiOR*");?, -Sni ^ or diazonium salts, in which each Rwx 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, E2, E3, E , D,, D2, D3, L1, Y1, L2, Y2, L3 and Y3 are as hereinbefore defined, with a (or two separate) compound(s) (as appropriate/required) of formula X,
Y3-Lx-H X wherein Lx represents L2 or L3 (as appropriate/required; in which they are preferably and independently selected from -N(R 7a)-A16- and -OA17-, provided that at least one of L2 and L3 represent -C(0)A17-Ya), and Ya 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. (1 (B)), 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, Pd2(dba)3 or NiCI2 and an optional additive such as Ph3P, 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, Et3N, pyridine, Ν,Ν1- dimethylethylenediamine, Na2C03, K2C03l K3P04, Cs2C03, f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, A/-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). Alternatively, for example, when L2 or L3 represent -O- or -S- (and hence the compound of formula X is an alcohol, e.g. a phenol or a thiol, e.g. thiophenol), or, L2 or L3 represent single bonds, and Y2 or Y3 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/AI203 (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 Zy may represent in the compound of formula IX is preferably fluoro). The skilled person will appreciate that when compounds of formula I in which L2 and L3 are different are required, then reaction with different compounds of formula X may be required;
(v) compounds of formula I in which there is a R17a or R17 group present that does not represent hydrogen (or if there is R5, R6, R7, R8, R9, R11, R 2, R13, R14, R16, R17 or R18 group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XI, wherein R* represents either R17a or R17b (as appropriate) as hereinbefore defined provided that it does not represent hydrogen (or R^ represents a R5 to R18 group in which those groups do not represent hydrogen), and Lb represents a suitable leaving group such as one hereinbefore defined in respect of La or -Sn(alkyl)3 (e.g. -SnMe3 or -SnBu3), or a similar group known to the skilled person, under reaction conditions known to those skilled in the art, for example such as those described in respect of process step (ii)(C) above. The skilled person will appreciate that various groups (e.g. primary amino groups) may need to be mono-protected and then subsequently deprotected following reaction with the compound of formula XI; (vi) for compounds of formula I that contain only saturated alkyl groups, reduction of a corresponding compound of formula I that contains an unsaturation, such as a double or triple bond, in the presence of suitable reducing conditions, for example by catalytic (e.g. employing Pd) hydrogenation; (vii) for compounds of formula I in which Y1 represents -C(0)OR9a, in which R9a represent hydrogen (or other carboxylic acid or ester protected derivatives (e.g. amide derivatives)), hydrolysis of a corresponding compound of formula I in which R9a does not represent H, under standard conditions, for example in the presence of an aqueous solution of base (e.g. aqueous 2M NaOH) optionally in the presence of an (additional) organic solvent (such as dioxane or diethyl ether), which reaction mixture may be stirred at room or, preferably, elevated temperature (e.g. about 120°C) for a period of time until hydrolysis is complete (e.g. 5 hours). Alternatively, non-hydrolytic means may be employed to convert esters to acids e.g. by hydrogentation or oxidation (e.g. for certain benzylic groups) known to those skilled in the art;
(viii) for compounds of formula I in which Y1 represent -C(0)OR9a and R9a does not represent H:
(A) esterification (or the like) of a corresponding compound of formula I in which R9a represents H; or
(B) trans-esterification (or the like) of a corresponding compound of formula I in which R9a does not represent H (and does not represent the same value of the corresponding R9a group in the compound of formula I to be prepared),
under standard conditions in the presence of the appropriate alcohol of formula XII,
R9zaOH XII in which R9za represents R a provided that it does not represent H, for example further in the presence of acid (e.g. concentrated H2S0 ) at elevated temperature, such as at the reflux temperature of the alcohol of formula XII;
(ix) for compounds of formula I in which Y1 preferably represents -C(0)OR9a, in which R9a is other than H, and L1 is as hereinbefore defined, provided that it does not represent -(CH2)p-Q-(CH2)q- in which p represents 0 and Q represents -0-, and, preferably, Y is -C(O)- or R28 is Ci-6 alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula XIII,
wherein 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, E2a, E2 , E2c, E4, D,, D2, D3, L2 and Y2 are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIII in which L5a represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XIII in which L5a 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,
L6-Lxy.Yb X|V wherein represents L1 (provided that it does not represent -(CH2)p-Q-(CH2)q- in which p represents 0 and Q represents -0-) and Yb represents -C(0)OR9a, in which R9a is other than H, and L6 represents a suitable leaving group known to those skilled in the art, such as C-|.3 alkoxy and, preferably, halo (especially chloro or bromo). For example, the compound of formula XIV may be CI-C(0)OR9a. 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 L1 preferably represents a single bond, and Y1 represents 5-tetrazolyl (and, preferably, Y is -C(O)- or R28 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)OR9a in which R9a is H, (and, preferably, Y is -C(O)- or R28 is alkyl optionally substituted by one or more halo atoms), reaction of a compound of formula XIII as hereinbefore defined but in which L5a represents either:
(I) an alkali metal (for example, such as one defined in respect of process step (ix) above); or
(II) -Mg-halide,
with carbon dioxide, followed by acidification under standard conditions known to those skilled in the art, for example, in the presence of aqueous hydrochloric acid; (xii) for compounds of formula I in which L1 represents a single bond, and Y1 represents -C(0)OR9a (and, preferably, Y is -C(O)- or R28 is d-6 alkyl optionally substituted by one or more halo atoms), reaction of a corresponding compound of formula XIII as hereinbefore defined but in which L5a is a suitable leaving group known to those skilled in the art (such as a sulfonate group (e.g. a inflate) or, preferably, a halo (e.g. bromo or iodo) group) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or Co2(CO)8)), in the presence of a compound of formula XV,
R9aOH XV wherein R9a is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI2, Pd(OAc)2, Pd(Ph3P)2CI2, Pd(Ph3P)4, Pd2(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
wherein (in all cases) Ε·,, E2a, E2b, E2c, E4, D ( D2l D3, L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable reagent that converts the carboxylic acid group of the compound of formula XVI or XVII to a more reactive derivative (e.g. 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 POCI3, in the presence of ZnCI2, for example as described in Organic and Biomolecular Chemistry (2007), 5(3), 494-500 or, more preferably, PCI3, PCI5, SOCI2 or (COCI)2. Alternatively, such a reaction may be performed in the presence of a suitable catalyst (for example a Lewis acid catalyst such as SnCI4), 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. Alternatively, such a reaction between the two relevant compounds may be performed under coupling reaction conditions (e.g. Stille coupling conditions), for example as described in Bioorganic and Medicinal Chemistry Letters (2004), 14(4), 1023-1026;
(xiv) for compounds of formula I in which Y represents -C(O)-, reaction of either a compound of formula XX or XXI,
with a compound of formula XXII or XXIII,
II
respectively, wherein L5b represents L5a 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 E2A, E2t>, E2C, E L D2, D3, L1 , Y1 , L2 and Y2 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. 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 XXIII (as hereinbefore defined), respectively, for example under reaction conditions such as those hereinbefore described in respect of process step (xiii) above;
(xvi) for compounds of formula I in which Y represents -C(=N-OR28)-, reaction of a corresponding compound of formula I in which Y represents -C(O)-, with a compound of formula XXI I IA,
H2N-0-R28 XXIIIA wherein R28 is represents hydrogen or C1-6 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);
(xvii) for compounds of formula I in which Y represents -C(=N-OR28)- and R28 represents Ci-6 alkyl optionally substituted by one or more halo atoms, reaction of a corresponding compound of formula I, in which R28 represents hydrogen, with a compound of formula XXI I IB,
>28a L7 XXIIIB wherein R 8a represents R28, provided that it does not represent hydrogen and L7 represents a suitable leaving group, such as one hereinbefore defined in respect of La (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). Preferably, 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. When acidic conditions are employed, precipitation of the compound of formula II may be effected by the neutralisation (for example by the addition of 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.
Compounds of formula IIA may be prepared by reaction of a compound of formula XXIIIC or XXIIID,
XXIIIC
XXIIID wherein E,, E2a, E2b, E2c, E4, D2, D3, L1, L2, Y1 and Y2 are as hereinbefore defined, with a compound of formula XXII or XXIII, respectively, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (xiii)).
Compounds of formulae III, VIII, IX and XIII in which Y represents -C(O)-, may be prepared by oxidation of a compound of formulae XXIV, XXV, XXVI and XXVII, respectively, wherein Ei, E2ai , ΕΣΜ , E2C1. 2a2, E2b2i E2C2, E2a, E2t>, E2C, E4, D1 t D2, D3> I1, Y1, L2a, J2, Zy, L2, Y2 and L5a 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). The skilled person will appreciate that, similarly, 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,
XXVIII
wherein T represents -C(O)- (in the case where compounds of formula III are to be prepared) or, preferably, -CH2- (in the case where compounds of formula XXIV are to be prepared), one of E2a4, E2 4 and E2C4 represents -C(-Zz2)=, and the others respectively represent E2 and E3, one of Zz and Z represents -N3 or -N02, and the other represents -C(0)-A17-Y2 or -C(0)-A17-Y2 (as appropriate), under standard reaction conditions known to those skilled in the art, in the presence of a suitable reducing agent, for example reduction by catalytic hydrogenation (e.g. in the presence of a palladium catalyst in a source of hydrogen) or employing an appropriate reducing agent (such as trialkylsilane, e.g. triethylsilane). The skilled person will appreciate that where the reduction is performed in the presence of a -C(O)- group (e.g. when T represents -C(O)-), a chemoselective reducing agent may need to be employed.
Compounds of formula III in which one of L and L represents -NH2 (or a protected derivative thereof) may also be prepared by reaction of a compound of formula IX as defined above, with ammonia, or preferably with a protected derivative thereof (e.g. benzylamine or Ph2C=NH), under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (iv) above).
Compounds of formulae III, IX, XXIV or XXV in which L1 represents a single bond, and Y1 represents -C(0)OR9a, may be prepared by:
(I) reaction of a compound of formula XXIX wherein one of E2a5, E2B5 and E2C5 represents -C(-ZQ2)=, and the others respectively represent E2 and E3, ZQ1 and ZQ2 respectively represent ZY and ZX (in the case of preparation of compounds of formulae IX or XXV), they respectively represent L2a and L3a (in the case of preparation of compounds of formulae III or XXIV), and EL E2, E3, E4, DI, D2, D3, ZX, ZY, L2a, L3a and T are as hereinbefore defined, with a suitable reagent such as phosgene or triphosgene in the presence of a Lewis acid, followed by reaction in the presence of a compound of formula XV as hereinbefore defined, hence undergoing a hydrolysis or alcoholysis reaction step; (II) for such compounds in which R represents hydrogen, formylation of a compound of formula XXIX as hereinbefore defined, for example in the presence of suitable reagents such as P(0)CI3 and DMF, followed by oxidation under standard conditions;
(III) reaction of a compound of formula XXX,
wherein W1 represents a suitable leaving group such as one defined by Zx and Zy above, and E1 ( E2a5, E2b5, E2c5, E4l D1 f D2, D3, Zq1 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 Co2(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;
(IV) reaction of a compound of formula XXXI,
wherein W2 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, and E^ E2a5, E2b5, E2c5, E4, Di, D2, D3, Zq and T are as hereinbefore defined, with e.g. C02 (in the case where R9a in the compounds to be prepared represents hydrogen) or a compound of formula XIV in which represents a single bond, Yb represents -C(0)OR9a, in which R9a is other than hydrogen, and L6 represents a suitable leaving group, such as chloro or bromo or a Ci-i4 (such as Ci-e (e.g. d.3) alkoxy group), under reaction conditions known to those skilled in the art. The skilled person will appreciate that this reaction step may be performed directly after (i.e. in the same reaction pot) the preparation of compounds of formula XXXI (which is described hereinafter).
Compounds of formula IX in which Z and/or 2y represent a sulfonate group may be prepared from corresponding compounds in which the Z* and Zy 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 3PO4 in toluene) preferably at or below 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 L5b 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.
Compounds of formulae XXII and XXIII in which L5b represents a -Mg-halide may be prepared by reaction of a compound corresponding to a compound of formula XXII or XXIII but in which L5 represents a halo group (e.g. bromo or iodo), under standard Grignard formation conditions, for example in the presence of /-PrMgCI (or the like) in the presence of a polar aprotic solvent (such as THF) under inert reaction condition, and preferably at low temperature (such as at below 0°C, e.g. at about 30°C). The skilled person will appreciate that these compounds may be prepared in situ (see e.g. the process for the preparation of compounds of formula I (process steps (xvi) and (xvii)).
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 L5b 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 -CH2- 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 LiAIH4, NaBH4 or trialkylsilane (e.g. triethylsilane) or reduction by hydrogenation (e.g. in the presence of Pd/C).
Alternatively, compounds of formulae XXIX or XXX in which T represents -CH2- may be prepared by reaction of a compound of formula XXXII,
XXXII
wherein Yy represents a suitable group such as -OH, bromo, chloro or iodo, and EL E2a5, E2b5, E2C5 and E4 are as hereinbefore defined, with a compound of formula XXXIII,
XXXIII
wherein M represents hydrogen and W1 represents hydrogen (for compounds of formula XXIX) or W (for compounds of formula XXX) and Di, D2, D3 and Zq are as hereinbefore defined, under standard conditions, for example in the presence of a Lewis or Bnansted acid. Alternatively, such compounds may be prepared from reaction of a compound of formula XXXII in which Yy represents bromo or chloro with a compound corresponding to a compound of formula XXXIII but in which M represents -BF3K (or the like), for example in accordance with the procedures described in Molander et al, J. Org. Chem. 71 , 9198 (2006).
Compounds of formulae XXIX or XXX in which T represents -C(O)- may be prepared by reaction of a compound of formula XXXIV, XXXIV
wherein Tx represents -C(0)CI or -C=N-NH(f-butyl) (or the like) Ei, E2a5, E2b5, E2c5 and E4 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-,, D2, D3, Zq1 and W are as hereinbefore defined, under reaction conditions known to those skilled in the art. For example in the case of reaction of a compound of formula XXXIV in which Tx represents -C(0)CI with a compound of formula XXXIII in which M represents hydrogen, in the presence of an appropriate Lewis acid. In the case where M represents an appropriate alkali metal group, a -Mg-halide or a zinc-based group, under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formulae III, IX, XXIV or XXV (process step (IV) above) and preparation of compounds of formula XXXI (see below). In the case of a reaction of a compound of formula XXXIV in which Tx represents -C=N-NH(f-butyl) (or the like) with a compound of formula XXXIII in which M represents bromo, under reaction conditions such as those described in Takemiya et a/, J. Am. Chem. Soc. 128, 1 800 (2006).
For compounds corresponding to compounds of formula XXIX or XXX but in which T represents -CH(OH)-, reaction of a compound corresponding to a compound of formula XXXIV, but in which T represents -C(0)H, with a compound of formula XXXIII as defined above, under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formulae XXIX or XXX in which T represents -C(O)-.
Compounds of formula XXXI may be prepared in several ways. For example, compounds of formula XXXI in which W2 represents an alkali metal such as lithium, may be prepared from a corresponding compound of formula XXIX (in particular those in which Zq1 and/or Zq2 represents a chloro or sulfonate group or, especially, a protected -NH2 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. phenylsulfonamide), by reaction with an organolithium base, such as /7-BuLi, s-BuLi, f-BuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine (which 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. tetramethylethylenediamine (TMEDA), (-)sparteine or 1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone (DMPU) and the like)), for example in the presence of 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. Alternatively, such compounds of formula XXXI may be prepared by reaction of a compound of formula XXX in which W1 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 W2 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. FeCI3) under standard Grignard conditions known to those skilled in the art. The skilled person will also appreciate that the 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 W2 represents a zinc-based group (e.g. using ZnCI2).
Compounds mentioned herein (e.g. those of formulae IV, V, VA, VI, VII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIIIA, XXIIIB, XXV, XXVII, XXVIII, XXXII, XXXIII and XXXIV) are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further, the compounds described herein may also be prepared in accordance with synthetic routes and techniques described in international patent application WO 2006/077366. The substituents Ei f E2a, E2b, E2c, E4, D1 f D2, D3, L1, Y1, L2, Y2, L3 and Y3 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications (e.g. from a carboxylic acid, e.g. in the presence of H2S04 and appropriate alcohol or in the presence of K2C03 and alkyl iodide), etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. For example, in cases where Y1 represents -C(0)OR9a in which R9a does not initially represent hydrogen (so providing at least one ester functional group), the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant R9a-containing group may be hydrolysed to form a carboxylic acid functional group (i.e. a group in which R9a represents hydrogen). In this respect, 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. Other specific 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 FeCI3 trihydrate and zinc powder); and the oxidation of a sulfide to a sulfoxide or to a sulfone (e.g. conversion of a -SCH3 substituent to a -S(0)CH3 or -S(0)2CH3 substituent in the presence of a suitable oxidising agent such as Oxone or mefa-chloroperbenzoic acid (MCPBA)), or the reverse reduction in the presence of a suitable reducing agent.
Other 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 tri-(d^ alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the 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 NaN02 and a strong acid, such as HCI or H2S04, 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. 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 NaN3, CuCN or NaCN; the conversion of -C(0)OH to a -NH2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN3 (which may be formed in by contacting NaN3 with a strong acid such as H2SC\,), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)2P(0)N3) 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)NH2 to -NH2, for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br2) which may result in the formation of a carbamate intermediate; the conversion of -C(0)N3 (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaN02 and a strong acid such as H2S04 or HCI) to -NH2, for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to -NH2l by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AICI3 or FeCI3).
Further, the skilled person will appreciate that the Di to D3-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, 3rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry ΙΓ 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). Hence, 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.
Compounds of the invention may be isolated (or purified) from their reaction mixtures using conventional techniques (e.g. crystallisations, recrystallisations or chromatographic techniques). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
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. By '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. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is described in e.g. "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
Medical and Pharmaceutical Uses
Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.
Although 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.
By "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.
Furthermore, certain compounds of the invention, including, but not limited to:
(a) compounds of formula I in which Y1 represents -C(0)OR9a in which R9a is/are other than hydrogen, so forming an ester group; and/or
(b) compounds of formula I in which Y represents -C(=N-OR28)-, i.e. the following compound of formula la, in which the integers are as hereinbefore defined (and the squiggly line indicates that the oxime may exist as a cis or trans isomer, as is apparent to the skilled person), may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such, including, but not limited to:
(A) corresponding compounds of formula I, in which Y represents -C(0)OR9a in which R9a represent hydrogen (see (a) above); and/or
(B) corresponding compounds of formula I in which Y represents -C(O)-, for example in the case where the oxime or oxime ether of the compound of formula la (see (b) above) is hydrolysed to the corresponding carbonyl moiety.
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".
Thus, 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) C4 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. LTC4, LTD4 or LTE4 is inhibited or decreased, or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LTi or Cys-LT2) is inhibited or attenuated. 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 LTD4, LTE or, especially, LTC4.
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 LTC4 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 LTC4), for example a respiratory disorder and/or inflammation. The term "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.
The term "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.
Accordingly, 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. rheumatoid arthritis, arthrosis, psoriasis arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), 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, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, bacterial infections (e.g. from Helicobacter pylori, Pseudomonas aerugiosa or Shigella dysenteriae), fungal infections (e.g. vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis, parainfluenza and respiratory syncytial virus), sickle cell anemia, hypereosinofilic syndrome, and malignancies (e.g. Hodgkins lymphoma, leukemia (e.g. eosinophil leukemia and chronic myelogenous leukemia), mastocytos, polycytemi vera, and ovarian carcinoma). In particular, 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. According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, LTC4 synthase and/or a method of treatment of a disease in which inhibition of the synthesis of LTC4 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.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
The 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).
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined; and
(B) another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation,
wherein 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).
Thus, there is further provided:
(1) 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; and
(2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) 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. By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.
Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be: (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
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
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. For e.g. oral administration, 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. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, 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.
In any event, 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. By definition, 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 (especially those in which L2 represents -C(0)-A17-, e.g. -C(O)-) may exhibit improved solubility properties (for instance compared to certain compounds disclosed in the prior art). Greater aqueous solubility (or greater aqueous thermodynamic solubility) may have advantages related to the effectiveness of the compounds of the invention (especially those in which L2 represents -C(0)-A17-, 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 LTC4 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.
Examples
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
Abbreviations:
aq aqueous
BINAP 2,2'-bis(diphenylphosphino)-1 , 1'-binaphthyl
brine saturated aqueous solution of NaCI DCM dichloromethane
DDQ 2,3-dicyano-5,6-dichloro-1 ,4-benzoquinone
DMAP /V,A/-dimethyl-4-aminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
EtOH ethanol
MeCN acetonitrile
MeOH methanol
NMR nuclear magnetic resonance
Oxone potassium peroxymonosulfate (2KHS05'KHSGyK2S04)
Pd2dba3 tris(dibenzylideneacetone)dipalladium(0)
dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
rt room temperature
rx reflux
sat saturated
THF tetrahydrofuran
Biological Test
Test 1
In vitro assay
In the assay, LTC4 synthase catalyses the reaction where the substrate LTA4 is converted to LTC4. Recombinant human LTC4 synthase is expressed in Piccia pastoralis 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:
1. 48 μΙ_ LTC4 synthase in PBS with 5 mM GSH. The total protein concentration in this solution is 0.5 pg/mL
2. 1 pL inhibitor in DMSO (final concentration 10 μΜ).
3. Incubation of the plate at room temperature for 10 min.
4. 1 μΙ_ L ΓΑι (final concentration 2.5 μΜ).
5. Incubation of the plate at room temperature for 5 min. 6. 10 yL of the incubation mixture is analysed using homogenous time resolved fluorescent (HTRF) detection.
Test 2
For certain compounds, in order to obtain ICso-values for the compounds, following procedure was used:
1. A volume (24 pL) of 0.25 yg/mL LTC4 synthase in 75 m tris (pH -8.5), 0.5 mM MgCI2 and 3 mM GSH was preincubated for 10 min with 0.5 yL of compound of interest in DMSO at ten different concentrations, typically in the range 10"9,5-10"5 M as well as with DMSO only. The buffer is used as background. Runs are performed in duplicates.
2. The enzymatic reaction is initiated by addition of 0.5 yL LTA4 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:H20: acetic acid 70:30:1 ).
4. After 15 fold dilution in PBS, LTC4 formation is detected with LTC4 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.
The detected product concentration, with background subtracted, is plotted versus compound concentration and IC50 is determined as 50% of maximum inhibition. Biological Examples
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 LTC4 synthase. Title compounds of the examples exhibit a certain IC50 value, which shows that they inhibit LTC4 synthase. IC50 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).
In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).
The compounds of the examples (see hereinafter, and tables) 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). Hence, the characterising data (e.g. NMR data) presented below may refer to the cyclised form of that compound. Alternatively, 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). Example 1
Example 1 :1
2-Benzoyl-5-(5-[(4-chlorophenyl)(methyl)aminolpicolinoyl)benzoic acid
(a) 2-Benzoyl-5-bromobenzoic acid methyl ester
The sub-title compound was obtained from 5-bromo-2-iodobenzoic acid methyl ester and benzoyl chloride in accordance with standard procedures. For instance, 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 NH4CI (aq, sat) and extractive workup (EtOAc, H20, brine) and purification by chromatography).
(b) 2-Benzoyl-5-iodobenzoic acid methyl ester
A mixture of 2-benzoyl-5-bromobenzoic acid methyl ester (5.207 g, 16.31 mmol),
Cul (0.311 g, 1.63 mmol), Nal (4.889 g, 32.62 mmol), N1,N2-dimethylethane-1 ,2- diamine (0.351 μΐ_, 3.26 mmol) and dioxane (20 mL) was heated at 120 °C for 18 h. Extractive workup (EtOAc, NH4CI (aq, sat), H20, brine), drying (Na2S04), concentration and purification by chromatography gave the sub-title compound. Yield: 4.633 g (78%). (c) 2-Benzoyl-5-f(5-bromo-2-pyridyl)hvdroxymethyllbenzoic acid methyl ester The sub-title compound was obtained from 2-benzoyl-5-iodobenzoic acid methyl ester and 5-bromopicolinaldehyde in accordance with the procedures described in step (a) above. (d) 2-Benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester
Oxidation of 2-benzoyl-5-[(5-bromo-2-pyridyl)hydroxymethyl]benzoic acid methyl ester in accordance with standard procedures gave the sub-title compound. For instance, pyridinium chlorochromate (1 equivalent or slight excess) may added to the product in DCM at rt. After reaction, the mixture may be filtered through Celite, concentrated, treated with EtOAc:hexanes (1 :2), filtered through silica and concentrated again.
(e) 2-Benzoyl-5-(5-[(4-chlorophenyl)methylamino1picolinoyl)benzoic acid methyl ester
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. For instance, the compounds may be mixed/reacted with a catalyst system (e.g. Pd(OAc)2, (catalytic amount), BINAP, base such as Cs2C03 (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.
(f) 2-Benzoyl-5-(5-[(4-chlorophenyl)(methyl)aminolpicolinoyl)benzoic acid The title compound was prepared from 2-benzoyl-5-{5-[(4-chlorophenyl)- methylamino]picolinoyl}benzoic acid methyl ester in accordance with standard procedures. For instance, NaOH in H20 may be added to the compound dissolved in hot EtOH. The mixture may be heated at rx (e.g. for 30 min), cooled, concentrated and acidified with HCI to pH ~2. This may be followed by extractive workup (EtOAc, H20, brine), drying (Na2S0 ), concentration and purification by chromatography to give the title compound. 1H NMR (DMSO-d6) δ: 8.44-8.40 (1 H, m) 8.20 (1 H, d, J= 2.8 Hz) 8.06-8.01 (1H, m) 7.97 (1 H, d, J= 8.9 Hz) 7.58-7.53 (2H, m) 7.53-7.46 (3H, m) 7.44-7.34 (4H, m) 7.31-7.23 (2H, m) 3.38 (3H, s). IC50 = 72 n . Examples 1:2 - 1:6
The title compounds were prepared in accordance with Example 1:1 using the appropriate acid chloride in step 1:1 (a), the appropriate amine in step 1 :1 (e), alkylation (when appropriate) in accordance with standard procedures (e.g. in the presence of base, such as NaH in an appropriate solvent, such as a polar aprotic solvent, and the alkylating reagent) followed by hydrolysis in accordance with Example 1 :1 , step (e).
Example 1 :7
5-{5-f(4-Chlorophenyl)(methyl)aminolpicolinoyl}-2-(3-methoxybenzoyl)benzoic acid
(a) 5-{5-[(4-Chlorophenyl)(methyl)aminolpicolinoyl)-2-trimethylstannanyl- benzoic acid methyl ester
A mixture of 2-bromo-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (100 mg, 0.217 mmol, see Example 2, step (c) hereinafter), 1 ,1,1 ,2,2,2-hexamethyldistannane (86 mg, 0.261 mmol), PdCI2(PPh3)2 (5 mg, 0.0073 mmol) and toluene ( 5 mL) was stirred at 105 °C for 5 h. The mixture was cooled to rt, filtered through Celite, washed with EtOAc, concentrated and purified by chromatography to give the sub-title compound. Yield: 95 mg (80%).
(b) 5-(5-f(4-Chlorophenyl)(methyl)aminolpicolinoyl)-2-(3-methoxybenzoyl)- benzoic acid methyl ester
A mixture of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-trimethylstannanyl- benzoic acid methyl ester (90 mg, 0.165 mmol), 3-methoxybenzoyl chloride (31 mg, 0.182 mmol), PdCI2(PPh3)2 (2.2 mg, 0.0032 mmol) and toluene (1 mL) was stirred at 105 °C for 3 h. The mixture was cooled to rt and MeOH (2 mL) was added. The mixture was stirred at rt for 10 min, filtered through Celite, washed with EtOAc, concentrated and purified by chromatography to give the sub-title compound. Yield: 35 mg (40%).
(c) 5-{5-f(4-Chlorophenyl)(methyl)amino]picolinoyl -2-(3-methoxyben2oyl)- benzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]- picolinoyl}-2-(3-methoxybenzoyl)benzoic acid methyl ester in accordance with Example 1 :1 , step (f). 1H NMR (DMSO-cfe) δ: 8.54-8.43 (1 H, m) 8.19 (1 H, d, J= 2.3 Hz) 8.10 (1 H, d, J= 6.7 Hz) 7.98 (1 H, d, J= 8.6 Hz) 7.55-7.45 (2H, m) 7.42- 7.24 (5H, m) 7.22-7.15 (1 H, m) 7.15-7.08 (1 H, m) 7.04 (1 H, d, J= 7.4 Hz) 3.74 (3H, s) 3.38 (3H, s). IC50 = 36 nM.
Examples 1 :8 - 1 :20 and 1 :24 - 1 :29
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, Pd2dba3> or Pd(P(t-Bu)3)2 with toluene or MeCN as solvent. Examples 1 :21 - 1 :23
The title compounds were prepared in accordance with Example 1 :1 using the appropriate amine in step (e), followed by hydrolysis in accordance with Example 1 :1 , step (f).
Table 1 (in which the compounds may exist as the cyclised form; see above).
Example 2
5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-(dichloromethyl)benzoyl)- benzoic acid
(a) 5-((4-Chlorophenyl)(methyl)amino)picolinaldehvde
4-Chloro-A/-methylaniline (1.6 mL, 12.9 mmol) in toluene (44 mL) was added to a mixture of Cs2C03 (4.9 g, 15.05 mmol), Pd(OAc)2 (0.121 g, 0.538 mmol), BINAP (0.502 g, 0.806 mmol) and 5-bromopicolinaldehyde (2.00 g, 10.75 mmol). The mixture was stirred at 85 °C for 15 h and after cooling filtered through Celite. The solids were washed with EtOAc. The combined filtrates were concentrated and the residue purified by chromatography to give the sub-title compound. Yield: 1.537 g (58%).
(b) 2-Bromo-5-((5-((4-chlorophenyl)(methyl)amino)pyridin-2-yl)(hydroxy)- methvQbenzoic acid methyl ester
/'-PrMgCI (1.54 mL, 3.08 mmol, 2 M in THF) was added to 2-bromo-5-iodobenzoic acid methyl ester (1.0 g, 2.93 mmol) in THF (10 mL) at -15 °C. The mixture was cooled to -45 °C and a cold (-45 °C) solution of 5-((4-chlorophenyl)(methyl)- amino)picolinaldehyde (0.80 g, 3.23 mmol) in THF (20 mL) was added. The mixture was allowed to reach rt and stirred for 16 h. NH4CI (aq, sat, 30 mL) was added at 0 °C and the mixture was stirred at rt for 30 min. Extractive workup (EtOAc, water, brine), drying (Na2S04) and purification by chromatography gave the sub-title compound. Yield: 1.1 g (73%). (c) 2-Bromo-5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)benzoic acid methyl ester
A mixture of 2-bromo-5-((5-((4-chlorophenyl)(methyl)amino)pyridin-2-yl)(hydroxy)- methyl)benzoic acid methyl ester (10.65 g, 23.06 mmol), DDQ (6.28 g, 27.68 mmol) and dioxane (75 mL) was stirred at rt for 1.5 h. The mixture was filtered through celite and the solids washed with EtOAc. The combined filtrates were concentrated and the residue purified by chromatography to give the sub-title compound. Yield: 6.23 g (58%).
(d) 5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-trimethylstannanyl- benzoic acid methyl ester
A mixture of 2-bromo-5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)benzoic acid methyl ester (100 mg, 0.217 mmol), 1 ,1 ,1 ,2,2,2-hexamethyldistannane (86 mg, 0.261 mmol), PdCI2(PPh3)2 (5 mg, 0.0073 mmol) and toluene (15 mL) was stirred at 105 °C for 5 h. The mixture was cooled to rt, filtered through Celite, washed with EtOAc, concentrated and purified by chromatography to give the sub-title compound. Yield: 95 mg (80%).
(e) 5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-dichloromethyl- benzovPbenzoic methyl ester
A mixture of 3-dichloromethylbenzoyl chloride (90 mg, 0.405 mmol), allylpalladium chloride dimer (6.6 mg) and toluene (0.5 mL) was added to 5-(5- ((4-chlorophenyl)(methyl)amino)picolinoyl)-2-trimethylstannanylben acid methyl ester (200 mg, 0.368 mmol) in toluene (1.5 mL) at it The mixture was heated at 44 °C for 4.5 h and cooled to rt. Extractive workup (EtOAc, water, brine), drying (Na2S04) and purification by chromatography gave the sub-title compound. Yield: 64 mg (30%).
(f) 5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-dichloromethyl- benzovDbenzoic acid
A mixture of 5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)-2-(3- dichloromethylbenzoyl)benzoic methyl ester (54 mg, 0.095 mmol), EtOH (30 mL), water (6 mL) and NaOH (19 mg, 0.475 mmol) was stirred at 65 °C for 5 min. The pH was adjusted to ~5 with HCI (aq, 1 M). Concentration, extractive workup (EtOAc, water, brine), drying (Na2S04) and purification by chromatography gave the title compound. Yield: 50 mg (95%).1H N R (DMSO-cfe) δ: 8.54-8.46 (1 H, m) 8.20 (1 H, d, J=2.7 Hz) 8.18-8.09 (1H, m) 7.99 (1H, d, J=9.0 Hz) 7.96-7.91 (1 H, m) 7.86-7.78 (1 H, m) 7.56 (1 H, s) 7.55-7.46 (4H, m) 7.46-7.33 (3H, m) 7.29 (1 H, dd, J=9.0, 2.7 Hz) 3.38 (3H, s). IC50 = 34 nM.
Example 3
5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-formylbenzoyl)benzoic acid
A mixture of 5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)-2-(3-(dichloro- methyl)benzoyl)benzoic acid (20 mg, 0.036 mmol), NaOH (0.3 mL, 1 (aq)), water (2.5 mL), dimethylamine hydrochloride (1.0 g, 0.012 mmol) and EtOH (2 mL) was heated at 60 °C for 50 h. After cooling to rt, the pH was adjusted to ~5 with HCI (aq, 1 M). Concentration, extractive workup (EtOAc, water, brine), drying (Na2S04) and purification by chromatography gave the title compound. Yield: 15 mg (83%).1H NMR (DMSO-cf6) δ: 10.0 (1 H, s) 8.54-8.45 (1 H, m) 8.20 (1H, d, J=2.7 Hz) 8.16-8.09 (1 H, m) 8.08-8.02 (2H, m) 7.99 (1 H, d, J=9.0 Hz) 7.92-7.83 (1 H, m) 7.72-7.63 (1 H, m) 7.52-7.48 (2H, m) 7,42-7.32 (3H, m) 7.29 (1 H, dd, J=9.0, 2.7 Hz) 3.38 (3H, s). IC50 - 52 nM. Example 4
5-(5-((4-Chlorophenyl)(cvclopropylmethyl)amino)picolinoyl)-2-(2,3-dihvdrobenzo- fbin ,41dioxine-6-carbonyl)benzoic acid
(a) 5-((4-Chlorophenyl)amino)picolinaldehyde
The sub-title compound was prepared in accordance with example 2 step (a) using 4-chloroaniline.
(b) 5-((4-Chlorophenyl)(cyclopropylmethyl)amino)picolinaldehyde
Sodium hydride (0.68 g, 17.17 mmol, 60% in mineral oil) was added to a mixture of 5-((4-chlorophenyl)amino)picolinaldehyde (3.70 g, 15.9 mmol), (bromomethyl)cyclopropane (6.44 g, 47.7 mmol) and DMF (70 mL) at 0 °C. The mixture was stirred at rt for 5 h. Water was added and the mixture was stirred for another 0.5 h. Extractive workup (EtOAc, water, brine), drying (Na2S04) and purification by chromatography gave the sub-title compound. Yield: 3.60 g (79%).
(c) 5-(5-((4-Chlorophenyl)(cvclopropylmethyl)amino)picolinoyl)-2-(2,3-dihvdro- benzoffcin ,41dioxine-6-carbonyl)benzoic acid
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). H N R (DMSO-cfe) δ: 13.6-13.0 (1H, br s) 8.56-8.48 (1 H, m) 8.18 (1 H, d, J=2.7 Hz) 8.17-8.08 (1 H, m) 8.03 (1 H, d, J=9.0 Hz) 8.63-7.52 (2H, m) 7.46-7.33 (3H, m) 7.29 (1H, dd, J=9.0, 2.7 Hz) 7.18-7.04 (2H, m) 6.98-6.91 (1H, m) 4.35-4.30 (2H, m) 4.30-4.25 (2H, m) 3.75 (2H, d, J=6.7 Hz) 1.15-1.11 (1 H, m) 0.51-0.43 (2H, m) 0.22-0.14 (2H, m). IC50 = 21 nM. Example 5
2-Benzoyl-5-(5-(4-chlorobenzoyl)picolinoyl)benzoic acid
(a) 2-Benzoyl-5-bromobenzoic acid methyl ester
The sub-title compound was obtained from 5-bromo-2-iodobenzoic acid methyl ester and benzoyl chloride in accordance with Example 2, step (b). (b) 2-Benzoyl-5-iodobenzoic acid methyl ester
A mixture of 2-benzoyl-5-bromobenzoic acid methyl ester (5.207 g, 16.31 mmol), Cul (0.31 1 g, 1.63 mmol), Nal (4.889 g, 32.62 mmol), /v -dimethylethane-l ^- diamine (0.351 μΙ_, 3.26 mmol) and dioxane (20 mL) was heated at 120 "C for 18 h in a closed vessel. Extractive workup (EtOAc, NH CI (aq, sat), H20, brine), drying (Na2S04), concentration and purification by chromatography gave the subtitle compound. Yield: 4.633 g (78%).
(c) 2-Benzoyl-5-((5-bromo-2-pyridyl)hvdroxymethyl)benzoic acid methyl ester The sub-title compound was obtained from 2-benzoyl-5-iodobenzoic acid methyl ester and 5-bromopicolinaldehyde in accordance with Example 2, step (b).
(d) 2-Benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester
Pyridinium chlorochromate (0.457 g, 2.12 mmol) was added to 2-benzoyl-5-((5- bromo-2-pyridyl)hydroxymethyl)benzoic acid methyl ester (0.904 g, 2.12 mmol) in DCM (10 mL) at 0 °C. After 1 h stirring at 0 °C, a second portion of pyridinium chlorochromate (46 mg, 0.21 mmol) was added. After 25 min, a third portion of pyridinium chlorochromate (38 mg, 0.18 mmol) was added. After a further 1.5 h stirring at 0 °C the mixture was diluted with EtOAc. Extractive workup (EtOAc, HCI (aq, 1 ), brine), drying (Na2S04), concentration and purification by chromatography gave the sub-title compound. Yield: 373 mg (41 %). (e) 2-Benzoyl-5-(5-(4-chlorobenzoyl)picolinoyl)benzoic acid
The title compound was prepared from 2-benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester and 4-chlorobenzoyl chloride in accordance with Example 2, steps (d-f).
1H NMR (DMSO-d6) δ: 13.5-13.4 (1 H, br s) 9.05-9.03 (1H, m) 8.62-8.59 (1 H, m) 8.40 (1 H, dd, =8.1 , 2.2 Hz) 8.35 (1 H, dd, .7=7.9, 1.7 Hz) 8.27-8.24 (1 H, m) 7.91- 7.86 (2H, m) 7.71-7.61 (6H, m) 7.56-7.50 (2H, m). IC50 = 1286 nM.
Example 6
5-(5-(4-Chlorobenzyl)picolinoyl)-2-(3-methoxybenzoyl)benzoic acid
(a) 5-(5-Bromopicolinoyl)-2-(3-methoxybenzoyl)benzoic acid methyl ester The sub-title compound was obtained from 5-bromo-2-iodobenzoic acid methyl ester and m-anisoyl chloride in accordance with Example 5, steps (a-d).
(b) 5-(5-(4-Chlorobenzyl)pico moyl)-2-(3-methoxybenzoyl)benzoic acid methyl ester
A mixture of potassium(4-chlorobenzyl)trifluoroborate (128 mg, 0.55 mmol), 5-(5- bromopicolinoyl)-2-(3-methoxybenzoyl)benzoic acid methyl ester (250 mg, 0.55 mmol), PdCI2(dppf) CH2CI2 (40 mg, 0.05 mmol), Cs2C03 (538 mg, 1.65 mmol), water (0.3 mL) and THF (4 mL) was heated at rx for 19 h. Concentration and extractive workup (EtOAc, HCI (aq, 1M), brine), drying (Na2S04) and purification by chromatography gave the sub-title compound. Yield: 125 mg (45%).
(c) 5-(5-(4-Chlorobenzyl)picolinoyl)-2-(3-methoxybenzoyl)benzoic acid
The title compound was obtained after hydrolysis of 5-(5-(4- chlorobenzyl)picolinoyl)-2-(3-methoxybenzoyl)benzoic acid methyl ester in accordance with Example 2, step (f). 1H NMR (DMSO-c/e) δ: 13.7-13.2 (1H, br s) 8.71 ( H, d, J=2.0 Hz) 8.56 (1 H, d, J=1.5 Hz) 8.29 (1H, dd, J=8.0, 1.5 Hz) 8.06 (1 H, d, J=8.0 Hz) 7.93 (1H, dd, J=8.0, 2.0 Hz) 7.57 (1H, d, J=8.0 Hz) 7.45-7.33 (5H, m) 7.27-7.19 (2H, m) 7.10 (1 H, d, J=8.0 Hz) 4.13 (2H, s) 3.80 (3H, s). IC50 155 nM.
Example 7
5-(5-((4-Chlorophenyl)(methyl)amino)pico moyl)-2-(3-hvdroxybenzoyl)benzoic acid
(a) 5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-hvdroxybenzoyl)- benzoic acid methyl ester
BBr3 (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. An additional amount of BBr3 (156 mg, 0.621 mmol) was added at -10 "C and stirring was continued for 3 h at -10 °C. MeOH was added and the mixture was stirred at rt for 30 min. Concentration, extractive workup (EtOAc, H20, brine), drying (Na2S04) and purification by chromatography gave the sub-title compound. Yield: 30 mg (38%).
(b) 5-(5-((4-Chlorophenyl)(methyl)amino)picolinoyl)-2-(3-hydroxybenzoyl)- benzoic acid
The title compound was obtained from 5-(5-((4-chlorophenyl)- (methyl)amino)picolinoyl)-2-(3-hydroxybenzoyl)benzoic acid methyl ester in accordance with Example 2, step (f). 1H NMR (DMSO-d6) δ: 13.6-13.2 (1 H, br s) 9.76 (1 H, s) 8.52 (1 H, d, J=1.4 Hz) 8.30-8.17 (2H, m) 8.02 (1 H, d, J=9.0 Hz) 7.59- 7.43 (3H, m) 7.42-7.21 (4H, m) 7.11-6.93 (3H, m) 3.40 (3H, s). IC50 = 83 nM. Examples 9-12, 15-21
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 2, steps (e) and (f), see Table 2. Examples 8, 22-24
The title compounds were prepared from 5-((4-chlorophenyl)- (cyclopropylmethyl)amino)picolinaldehyde (Example 3, step (b) and the appropriate acid chloride in accordance with Example 2 steps (b-f) see Table 1.
Example 13
The title compound was prepared from 5-(5-bromopicolinoyl)-2-(3- methoxybenzoyl)benzoic acid methyl ester (prepared in accordance with Example 5, steps (a-d) using m-anisoyl chloride in step (a)), followed by amination with 4-choroaniline, alkylation with (bromomethyl)cycopropane in accordance with Example 4 steps (a-b) and hydrolysis in accordance with Example 2 step (f). Example 14
The title compound was prepared in accordance with Example 7, steps (a-b) using the penultimate intermediate in Example 13.
Table 2 (in which the compounds may exist in cyclised form; see above)
Example 25
By definition, the 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.
Method and Materials
Preparation of USP Phosphate Buffer, pH 7.4
Prepare 0.2 M monobasic potassium phosphate solution by dissolving 27.22 g of KH2P04 (MW= 136.09 g/mol) in water, dilute with water to 1000 mL.
Add 250 mL of the monobasic potassium phosphate solution in a 1000 mL volumetric flask together with 195.5 mL 0.2M NaOH (aq). Add water to 1000 mL. Check pH.
Test compounds
Compounds of the invention/examples to be tested were provided as solid material, weighed into glass vials (2 mL). Each vial contains approximately 1 mg solid compound, two vials / compound are prepared, i.e. duplicate samples of each compound. If a freshly prepared 10 mM DMSO stock solution was available, this solution was used for MS optimization and preparation of standards. If a DMSO-stock solution was not available, a 0 mM solution from solid material 1 mg was prepared.
Methods
Day one
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.
Day two
Take out the 1 mM DMSO-stock solutions of compounds that are to be tested from freezer. If no 1 mM solutions are available, use master solutions with concentration of 10 mM. Allow the solutions to thaw at rt.
· Collect two 96-deep well plates, glass inserts, sealing film, and an 8-channel expandable pipette with tall tips.
Abort shaking after 24 hour.
Note if samples are saturated or if compounds have dissolved.
Transfer 720 μΙ_ of sample slurry from each sample vial into glass inserts in a 96-deep well plate using an 8-channel expandable pipette. Samples 1 and 2 are transferred to separate plates. Thus, all samples 1 are placed in one plate and all samples 2 in the second plate.
Seal the plates using sealing film.
Centrifuge the plates at 3000 rpm for 15 min at rt. Set acceleration to 9 and brake to 7 (9=fastest acc/brake, 0=slowest acc/brake).
Transfer the supematants to new glass inserts using an 8-channel pipette, centrifuge samples a second time.
Repeat the procedure above, i.e. centrifuge samples a third time.
After the third centrifugation, transfer supernatant to glass vials, seal vials with screw caps. Control that the solutions are clear and that no particles are present in sample. If solid material is observed, an additional centrifugation step is performed.
Standards are prepared from DMSO-stock solutions (1 or 10 mM).
For each compound, transfer 10 of 1 mM solution to a glass vial, add DMSO (90 μΙ_) to reach a final concentration of 100 μΜ, seal with screw cap and mix solution quickly on a vortex mixer. Further dilute the 100 μΜ solution with a 1 :1 mixture of acetonitrile and USP phosphate buffer (pH 7.4) to standards with concentration 1000, 500,100, 25, 2, and 1 nM. Standards are prepared in test tubes. Preparation of 1000 nM standard: Transfer 10 μΙ_ from 100 μΜ DMSO-solution to a test tube, add 990 μΙ_ of acteonitrile: buffer, mix solution quickly on a vortex mixer
Preparation of 500 nM standard: Transfer 500 μί. from 1000 nM standards, dilute with 500 μΐ acteonitrile: buffer, mix solution quickly on a vortex mixer.
Preparation of 100 nM standard: Transfer 200 μΙ_ from 500 nM standards, dilute with 800 μΐ acteonitrile:buffer, mix solution quickly on a vortex mixer.
Preparation of 25 nM standard: Transfer 250 μΙ_ from 100 nM standards, dilute with 750 μΐ. acteonitrile:buffer, mix solution quickly on a vortex mixer.
Preparation of 2 nM standard: Transfer 80 μΙ_ from 25 nM standards, dilute with 920 μΙ_ acteonitrile: buffer, mix solution quickly on a vortex mixer.
Preparation of 1 nM standard: Transfer 40 μΙ_ from 25 nM standards, dilute with 960 μΙ_ acteonitrile:buffer, mix solution quickly on a vortex mixer. Preparation of 0 nM standard: use acetonitrile:buffer
Standards are transferred to a deep well plate containing glass inserts (700 μΙ_) 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.
Scheme 1. Standard solutions (nM) are place as indicated.
Place standards in autosampler.
Try out the dilution of solubility samples so that their response will be within the standard curve. Dilute solubility sample one (or two) with the 1 :1 mixture of acetonitrile: buffer. For highly soluble compounds, start with a 5000x dilution, for less soluble compounds start with a 1000x dilution. Control the dilutions: Analyze standards (1000 nM) and the test dilutions using sample list format templat in MassLynx. In Microsoft explorer, create/load the MS-files.
Use the dilution that gives rise to an acceptable response of each compound. Dilute all solubility samples twice to minimize the risk of overestimation of the solubility due to particles (undissolved material) left after centrifugation, that are dissolved in acetonitrile: buffer (i.e. all test samples are diluted twice with MeCN/buffer solution).
Place solubility samples in vials according to scheme 2. Seal the plate with a silicone/Teflon cap map.
Scheme 2. Solubility samples are placed as indicated, starting with compound 1 in row A, compound 2 in row B etc.
Place the plate in autosampler.
Make a sample list using a sample list format.
Start the LC-MS/MS analysis.
Results and calculations
On MS-computer, analyze the LC-MS/MS data using QuanLynx and plot the solubility data. The thermodynamic aqueous solubilities of representative examples are presented in the table below:

Claims

Claims
A compound of formula I,
wherein one of L2 and L3 represents -C(0)-A17- and the other may represent:
a single bond or a spacer group selected from -S(0)n1-, -C(Ry4)(Ry5)-A16, -N(R17a)-A16-, -OA17- and -C(0)-A17-; one of E2a, E2 and E2c represents -C(-L3-Y3)= and the other two respectively represent E2 and E3;
Y represents -C(O)- or -C(=N-OR28)-;
R28 represents hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; one or two of D-i , D2 and D3 represent(s) -N=; and/or one or two of Ei , E2, E3 and E4 represent(s) -N=; and those (or the) remaining D,, D2 and D3 group(s) each independently represent -C(R1)=; and those remaining Ei, E2> E3 and E4 groups each independently represent -C(R2)=; each R1 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X1; each R2 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X2;
Y1 represents -C(0)OR9a or 5-tetrazolyl;
R9a represents:
(i) hydrogen; or
(ii) Ci.s alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1 ; one of Y2 and Y3 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:
(a) an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A); or
(b) Cv12 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1 ;
A represents, on each occasion when used herein:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) Ci-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G and/or Z1; or
III) a G1 group;
X1, X2, G1 and B independently represent halo, -R5a, -C(0)R5b, -CN, -N02, -C(0)N(R6a)R7a, -N(R6b)R7b, -N(R5c)C(0)R6c, -N(R5d)C(0)OR6d, -OR56, -OS(0)2R5f, -S(0)mR59, -OC(0)R5h or -S(0)2N(R6e)R7e; R5 to R5e, R59, R5h, R6a to R6c, R6e, R7a, R7b and R7e independently represent, on each occasion when used herein, H or R5a; or
any of the pairs R6a and R7a, R6 and R7b, or R6e and R7e may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from fluoro, =0, -OR5e and/or R5a;
R5f and R6d independently represent R5a;
R5a represents, on each occasion when used herein:
(i) C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, =0, -OR8a, -N(R8b)R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f; or
(ii) aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from halo, -CN, -OR8a, -NiR^R* -S(0)nR8d and/or
-S(0)2N(R8e)R8f; n represents 0, 1 or 2; each R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, =0, -OR11a and/or -N(R12a)R12b; each R8a, R8c and R8 independently represent H or C1-3 alkyl optionally substituted by one or more substituents selected from F, =0, -OR13a, -N(R1 a)R14b, -S(0)2CH3, -S(0)2CHF2 and/or -S(0)2CF3; or
R8b and R8c and/or R8e and R8f 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;
R11a and R13a independently represent H or C1-3 alkyl optionally substituted by one or more fluoro atoms; R12a, R12b, R1 a and R 4b independently represent H, -CH3 or -CH2CH3;
Z1 represents, on each occasion when used herein, =0 or =NOR16b;
R16 represents hydrogen or Ci.6 alkyl optionally substituted by one or more fluoro atoms; L1 represents a single bond or -(CH2)p-Q-(CH2)q-;
Q represents -C(Ry1)(Ry2)-, -C(O)-, -N(Ry3)- or -0-; p and q independently represent 0, 1 or 2, but wherein the sum of p and q does not exceed 2; n1 represents 0, 1 or 2; A16 represents a direct bond, -C(Ry6)(Ry7)-, -C(O)-, -C(0)N(Rl7b)-, -C(0)C(Ry6)(Ry7)- or -S(0)2-;
A17 represents a direct bond or -C(Ry8)(Ry9)-; each Ry1 , Ry2, Ry4, Ry5, Ry6, Ry7, Ry8 and Ry9 independently represent H, fluoro or C1.3 alkyl optionally substituted by one or more fluoro atoms; or
Ry1 and Ry2, Ry4 and RyS, Ry6 and Ry7 and/or Ry8 and R^ may be linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and C1-2 alkyl;
Ry3 represents hydrogen or C 3 alkyl;
R17a and R 7b independently represent hydrogen, alkyl (optionally substituted by one or more substituents selected from heterocycloalkyl, aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from R30), fluoro, -CN, -OR19 and/or =0), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from R31); R30 and R31 independently represent halo, -R18a, -C(0)R18b, -CN, -C(0)N(R18c)R18d, -N(R18e)R18f, -N(R18g)C(0)R18h, -N(R18i)C(0)OR18j, -OR 8k, -OS(0)2R18m, -S(0)mR18n, -OC(0)R18p or -S(0)2N(R18q)R 8r); m represents 0, 1 or 2; 18n
R 18r
, R18p, R18q and R independently represent hydrogen or C1-3 alkyl optionally substituted by one or more fluoro atoms; R18' and R18m independently represent C1-3 alkyl optionally substituted by one or more fluoro atoms;
R19 represents hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically-acceptable salt thereof.
2. A compound as claimed in Claim 1 , wherein the compound of formula I represents:
in which:
represents -N=;
E4 represents -N= or -C(R2)=;
E2 and E3 independently represent -C(R )=;
each R2 independently represents hydrogen;
D2 represents -C(R1)=;
Di and D3 independently represent -C(R1)= or -N=;
only one of the Di to D3-containing ring and the E-i to E4-containing ring contains a nitrogen atom (i.e. -N=);
each R1 independently represents, on each occasion when used herein, hydrogen;
L represents a single bond;
Y1 represents -C(0)OR9a;
one of L2 and L3 represents -C(0)-A17- and the other may represent:
a single bond or a spacer group selected from -S(0)n , -C(Ry4)(Ry5)-A16, -N(Rl7a)-A16-, -OA17- and -C(0)-A17-;
A16 represents -CH2-, a direct bond, -C(O)- or -S(0)2-;
A17 represents a direct bond or -C(Ry8)(Ry9)-; Ry8 and Ry9 independently represent H, fluoro, C1.3 alkyl (optionally substituted by one or more fluoro atoms) or are linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and d.2 alkyl;
R17a represents hydrogen or alkyl optionally substituted by one or more substituents selected from fluoro, -CN, -OR19, heterocycloalkyi and/or aryl;
one of Y2 and Y3 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 an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A) or C1.12 alkyl or a heterocycloalkyi group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
A represents aryl or heteroaryl (both of which are optionally substituted by one or more B substituents) or A represents G1 or C1- alkyl optionally substituted by one or more substituents selected from G1 ;
G1 represents halo, -R5a, -OR5e, -SiO^R59, -C(0)N(R6a)R7a or -N(R6b)R7 , m represents 0, 1 or 2;
B represents halo (e.g. chloro or fluoro);
R5e represents hydrogen, alkyl (which alkyl group is optionally substituted by one or more halo atoms) or aryl or heteroaryl, which latter two aryl and heteroaryl groups are each optionally substituted by one or more substituents selected from fluoro, chloro and -CN;
R59 represents C1-4 alkyl;
R6e and R7e independently represent hydrogen or C1-2 alkyl; and/or
Z1 represents, on each occasion when used herein, =0.
3. A compound as claimed in Claim 1 or Claim 2, wherein:
one of L2 and L3 represents -C(0)-A17- and the other represents a single bond, -OA17-, -N(R17a)-A16, -C(0)-A17, -S- or -S(O)-;
Ry8 and Ry9 represent hydrogen, or, are linked together to form a cyclopropyl group;
Y2 represents: acyclic C1.6 alkyl; phenyl; 5- or 6-membered heteroaryl; 9- or 10- membered bicyclic heteroaryl group; C3.8 cycloalkyl; or a 4- to 8-membered heterocycloalkyi group, all of which groups are optionally substituted by one or more substituents selected from A, G1 and Z1 (as appropriate); Y3 represents phenyl optionally substituted by one or more substituents selected from A; and/or
G1 represents halo, -CN, -N02, -OR5e, -S(0)mRS9 or -S(0)2N(R6e)R7e
4. A compound as claimed in any one of the preceding claims, wherein: n1 represents 1 ;
one of L2 and L3 (e.g. L2) represents -C(0)-A17- and the other independently represents a single bond or a spacer group selected from -S(O)-, -C(Ry )(Ry5)-, -N(R17a)-A16- and -OA17-;
A16 represents a direct bond, -C(O)-, -C(0)N(R17b)-, -C(0)C(Ry6)(Ry7)- or -S(0)2-; R5a represents, on each occasion when used herein, C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -CN, =0, -OR8a, -N(R8b)R8c, -S(0)nR8d and/or -S(0)2N(R8e)R8f;
R ?a and Rl7b independently represent hydrogen, C1-6 alkyl (optionally substituted by one or more substituents selected from fluoro, -CN, -OR19 and/or =0), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from halo, -R18a, -C(0)R18b, -CN, -C(0)N(R18c)R18d,
-N(R18e)R18f, -N(R189)C(0)R18h, -N(R18i)C(0)OR18i, -OR18k, -OS(0)2R18m,
-S(0)mR18n, -OC(0)R 8p or -S(0)2N(R18q)R18r);
X1, X2, G1 and B independently represent halo, -R5a, -C(0)R5 , -CN,
-C(0)N(R6a)R7a, -N(R6b)R7b, -N(R5c)C(0)R6c, -N(R5d)C(0)OR6d, -OR5e, -OS(0)2R5f,
-S(0)mR59, -OC(0)R5h or -S(0)2N(R6e)R7e;
each R8a, R8 , R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, =0, -OR11a and/or -N(R12a)R12 ; and/or
when L2 or L3 represent C(Ry4)(Ry5)-A16 in which A16 is other than a direct/single bond, then A16 is preferably -C(O)-.
5. A compound as claimed in any one of the preceding claims, wherein: one of L2 and L3 (e.g. L2) represents -C(0)-A17-, and the other (e.g. L3) represents a single bond, or, preferably -N(R17a)-A16- or -OA17- (especially -N(R17a)-A16-);
A16 represents a direct bond, -C(O)- or -S(0)2-;
when L3 represents -N(R 7a)-A16-, then A16 represents a direct bond;
A17 represents a direct bond; R 7a represents hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from -OCH3, -OCH2CH3 and -CN;
when R17a represents optionally substituted C1-6 alkyl, then that group may represent: a linear unsaturated alkyl group optionally substituted by -OCH3, -OCH2CH3 and/or -CN; a part cyclic alkyl group; a linear saturated C1-6 alkyl group;
Y2 and Y3 independently represent an aryl or heteroaryl group optionally substituted by one or more substitutents selected from A;
A represents aryl (optionally substituted by halo, such as chloro), or, A represents G1;
G1 represents halo, -R5a, -OR5e or -S(0)mR59;
R5g represents R5a;
R5a represents C^e alkyl (optionally substituted by one or more fluoro atoms); when R5e represents R a, then R5a represents Ci-6 alkyl; and/or
when R5g represents R5a, then R5a represents unsubstituted C1. alkyl.
6. A compound as claimed in any one of the preceding claims, wherein Y2 and Y3 independently represent optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl or, more preferably, Y2 and Y3 independently represent optionally substituted phenyl, thiazolyl, oxazolyl or thienyl.
7. A compound as claimed in Claim 6, wherein the optional substituents are selected from halo; cyano; C -6 alkyl optionally substituted with one or more halo groups; heterocycloalkyl optionally substituted by one or more substituents selected from C1.3 alkyl and =0; -OR26; -C(0)R26; -C(0)OR26; -N(R26)R27; -S(0)mR26 (in which m represents 0, 1 or 2) wherein R26 and R27 independently represent H, Ci-6 alkyl (optionally substituted by one or more halo groups) or aryl (optionally substituted by one or more halo or C1-3 alkyl groups (which alkyl group is optionally substituted by one or more halo atoms)).
8. A compound of formula I as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
9. A pharmaceutical formulation including a compound of formula I, as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
10. A compound, as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which inhibition of the synthesis of leukotriene C4 is desired and/or required.
11. Use of a compound of formula I, as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the synthesis of leukotriene C4 is desired and/or required.
12. A compound as claimed in Claim 10 or a use as claimed in Claim 11 , wherein the disease is a respiratory disease, inflammation and/or has an inflammatory component.
13. A compound or use as claimed in Claim 12 wherein the disease is an allergic disorder, asthma, childhood wheezing, a chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, an interstitial lung disease, an ear nose and throat disease, an eye disease, a skin diseases, a rheumatic disease, vasculitis, a cardiovascular disease, a gastrointestinal disease, a urologic disease, a disease of the central nervous system, an endocrine disease, urticaria, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhoea, a burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, a bacterial infection, a fungal infection, a viral infection, sickle cell anaemia, hypereosinofilic syndrome, or a malignancy.
14. A compound or use as claimed in Claim 13, wherein the disease is an allergic disorder, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, an eosinophilic gastrointestinal disease, an inflammatory bowel disease, rheumatoid arthritis, osteoarthritis or pain.
15. A method of treatment of a disease in which inhibition of the synthesis of leukotriene C4 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 7, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
16. A combination product comprising:
(A) a compound of formula I as defined in any one of Claims 1 to 7, or a pharmaceutically-acceptable salt thereof; and
(B) another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
17. A combination product as claimed in Claim 16 which comprises a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 7, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
18. A combination product as claimed in Claim 16 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 7, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) 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.
19. A process for the preparation of a compound of formula I as defined in Claim 1 , which process comprises:
(i) for compounds of formula I in which Y represents -C(O)-, oxidation of a compound of formula II,
or a compound corresponding to a compound of formula II, but in which the methylene bridge represents -C(H)(OH)-, wherein ring E^ E2a, E2b, E2c, E2d, E4l D1 r D2, D3, L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable oxidising agent;
(ia) for compounds of formula I in which Y represents -C(O)-, oxidation of a compound of formula IIA,
wherein ring Ei, E2a, E2t>, E2c, E2d, E4, DL D2> [¾, L1 , Y1 , L2 and Y2 are as defined in Claim 1 ;
(ii) for compounds of formula I in which L2 or L3 represents -N(R17a)A16- (and the other represents -C(0)-A17-), reaction of a compound of formula III,
or a protected derivative thereof wherein one of E2ai, Ε2Μ, E2ci represents -C(- L3a)= and the other two respectively represent E2 and E3, one of L2a and L3a represents -NH2 and the other represents -C(0)-A 7-Y2 or -C(0)-A17-Y3 as appropriate, and Y, E1 t E2, E3l E4, D2, D3, L and Y1 are as defined in Claim 1 , with:
(A) when A16 represents -C(0)N(R17b)-, in which R17b represents H:
(a) a compound of formula IV,
Ya-N=C=0 IV
; or
(b) with CO (or a reagent that is a suitable source of CO) or phosgene or triphosgene in the presence of a compound of formula V,
Ya-NH2 V
wherein, in both cases, Ya represents Y2 or Y3 (as appropriate/required) as defined in Claim 1 ; (B) when A16 represents a direct bond, with a compound of formula VI,
Ya-La VI
wherein La represents a suitable leaving group and Ya is as defined above;
(C) when A16 represents -S(0)2-, -C(O)- or -CiC -CiR^XR*7)-, with a compound of formula VII,
Ya-A 6a-La VII
wherein A16a represents -S(0) , -C(O)- or -C(0)-C(Ry6)(Ry7)-, and Ya and La are as defined above;
(iii) for compounds of formula I in which one of L2 and L3 represents -C(0)-A17- and the other represents -N(R 7a)C(0)N(R 7b)-, in which R17a and R17b represent H, reaction of a compound of formula VIII,
wherein one of E2a2, E2B2, E2C2 represents -C(-J1)= and the other two respectively represent E2 and E3, one of J1 and J2 represents -N=C=0 and the other represents -C(0)-A 7-Y2 or -C(0)-A17-Y3 (as appropriate), and Y, E,, E2, E3, E4, DL D2, D3, I1 and Y1 are as defined in Claim 1 , with a compound of formula V as defined above;
(iv) reaction of a compound of formula IX,
wherein one of E2a3, E2b3l E2c3 represents -C(-Zx)= and the other two respectively represent E2 and E3, at least one of Zx and Zy represents a suitable leaving group and the other may also independently represent a suitable leaving group, or, Zv may represent -L -Y2 and Zx may represent -L3-Y3, and Y, Ε·,, E2, E3, E , D2, D3, L1, Y1, L2, Y2, L3 and Y3 are as defined in Claim 1 , with a (or two separate) compound(s) (as appropriate/required) of formula X,
Ya-Lx-H X
wherein Lx represents L2 or L3 (as appropriate/required; in which they are preferably and independently selected from -N(R17a)-A16- and -OA17-, provided that at least one of L2 and L3 represent -C(0)A17-Ya), and Ya is as defined above; (v) compounds of formula I in which there is a R17a or R17b group present that does not represent hydrogen (or if there is R5, R8, R7, R8, R9, R11, R 2, R13, R 4, R16, R17 or R18 group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XI,
R^-L" XI
wherein R^ represents either R17a or R 7 (as appropriate) as hereinbefore defined provided that it does not represent hydrogen (or R^ represents a R5 to R18 group in which those groups do not represent hydrogen), and Lb represents a suitable leaving group;
(vi) for compounds of formula I that contain only saturated alkyl groups, reduction of a corresponding compound of formula I that contains an unsaturation, in the presence of suitable reducing conditions;
(vii) for compounds of formula I in which Y represents -C(0)OR9a, in which R9a represent hydrogen (or other carboxylic acid or ester protected derivatives), hydrolysis of a corresponding compound of formula I in which R9a does not represent H;
(viii) for compounds of formula I in which Y1 represent -C(0)OR9a and R9a does not represent H:
(A) esterification (or the like) of a corresponding compound of formula I in which R9a represents H; or
(B) trans-esterification (or the like) of a corresponding compound of formula I in which R9a does not represent H (and does not represent the same value of the corresponding R9a group in the compound of formula I to be prepared),
in the presence of the appropriate alcohol of formula XII,
R9zaOH XII
in which R9za represents R9a provided that it does not represent H;
(ix) for compounds of formula I in which Y1 represents -C(0)OR9a, in which R9a is other than H, and L is as defined in Claim 1 , provided that it does not represent -(CH2)p-Q-(CH2)q- in which p represents 0 and Q represents -0-, reaction of a compound of formula XIII,
wherein L5a represents an appropriate alkali metal group, a -Mg-halide, a zinc- based group or a suitable leaving group, and Y, E1 ( E2a, E2t>, E2c, E4, Di, D2, D3, L2 and Y2 are as defined in Claim 1 , with a compound of formula XIV,
ί ΐ^-Υ XIV
wherein L* represents L1 (provided that it does not represent -(CH2)p-Q-(CH2)q- in which p represents 0 and Q represents -0-) and Yb represents -C(0)OR9a, in which R9a is other than H, and L6 represents a suitable leaving group;
(x) compounds of formula I in which L1 represents a single bond, and Y1 represents 5-tetrazolyl, may be prepared in accordance with the procedures described in international patent application WO 2006/077366;
(xi) for compounds of formula I in which L1 represents a single bond, and Y represents -C(0)OR9a in which R9a is H, reaction of a compound of formula XIII as defined above but in which L5a represents either:
(I) an alkali metal; or
(II) -Mg-halide,
with carbon dioxide, followed by acidification;
(xii) for compounds of formula I in which L represents a single bond, and Y1 represents -C(0)OR9a, reaction of a corresponding compound of formula XIII as defined above but in which L5a is a suitable leaving group, with CO (or a reagent that is a suitable source of CO), in the presence of a compound of formula XV,
R9aOH XV
wherein R9a is as hereinbefore defined, and an appropriate catalyst system;
(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, XVIII
wherein (in all cases) Ε·,, E2a, E2b, E2c> E4, D2l D3, L1, Y1, L2 and Y2 are as defined in Claim 1 ;
(xiv) for compounds of formula I in which Y represents -C(O)-, reaction of either a compound of formul
with a compound of formula XXII or XXIII, II
respectively, wherein L5b represents L5a as defined above, and (in all cases) E ( E2a, E2b, E2c, E4, D1 ( D2, D3, L1, Y1, L2 and Y2 are as defined in Claim 1 ;
(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 defined above, with a compound of formula XXII or XXIII (as defined above), respectively;
(xvi) for compounds of formula I in which Y represents -C(=N-OR28)-, reaction of a corresponding compound of formula I in which Y represents -C(O)-, with a compound of formula XXIIIA,
H2N-O-R28 XXIIIA
wherein R28 is represents hydrogen or C1-6 alkyl optionally substitutued by one or more halo atoms;
(xvii) for compounds of formula I in which Y represents -C(=N-OR28)- and R28 represents C 6 alkyl optionally substituted by one or more halo atoms, reaction of a corresponding compound of formula I, in which R28 represents hydrogen, with a compound of formula XXIIIB,
R28a-L7 XXIIIB
wherein R 8a represents R28, provided that it does not represent hydrogen and L7 represents a suitable leaving group.
20. A process for the preparation of a pharmaceutical formulation as defined in Claim 9, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
21. A process for the preparation of a combination product as defined in any one of Claims 16 to 18, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 7, 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.
EP11713851A 2010-03-12 2011-03-14 Bis aromatic compounds for use as ltc4 synthase inhibitors Withdrawn EP2545036A1 (en)

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PCT/GB2010/000438 WO2010103278A1 (en) 2009-03-12 2010-03-12 Bis aromatic compounds for use as ltc4 synthase inhibitors
PCT/GB2011/000358 WO2011110824A1 (en) 2010-03-12 2011-03-14 Bis aromatic compounds for use as ltc4 synthase inhibitors

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