WO2011114103A1 - Pyrimidinones pour usage médicamenteux - Google Patents

Pyrimidinones pour usage médicamenteux Download PDF

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Publication number
WO2011114103A1
WO2011114103A1 PCT/GB2011/000370 GB2011000370W WO2011114103A1 WO 2011114103 A1 WO2011114103 A1 WO 2011114103A1 GB 2011000370 W GB2011000370 W GB 2011000370W WO 2011114103 A1 WO2011114103 A1 WO 2011114103A1
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compound
formula
optionally substituted
substituents selected
compounds
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PCT/GB2011/000370
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English (en)
Inventor
Benjamin Pelcman
Christina Krog-Jensen
Kiyo No
Andrei Sanin
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Biolipox Ab
Mcneeney, Stephen, Phillip
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Publication of WO2011114103A1 publication Critical patent/WO2011114103A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Definitions

  • the present invention is directed to substituted pyrimidinone and/or tetrahydropyrimidinone compounds and their uses as therapeutic agents, especially PDE4 inhibitors.
  • Inflammation is an essential localized host response to invading microorganisms or tissue injury which involves cells of the immune system.
  • the classic signs of inflammation include redness (erythema), swelling (edema), pain and increased heat production (pyrema) at the site of injury.
  • the inflammatory response allows the body to specifically recognize and eliminate an invading organism and/or repair tissue injury.
  • Many of the acute changes at the site of inflammation are either directly or indirectly attributable to the massive influx of leukocytes (e.g., neutrophils, eosinophils, lymphocytes, monocytes) which is intrinsic to this response.
  • leukocytes e.g., neutrophils, eosinophils, lymphocytes, monocytes
  • Leukocytic infiltration and accumulation in tissue results in their activation and subsequent release of inflammatory mediators such as LTB 4 , prostaglandins, TNF-a, IL- ⁇ ⁇ , IL-8, IL-5, IL-6, histamine, proteases and reactive oxygen species for example.
  • inflammatory mediators such as LTB 4 , prostaglandins, TNF-a, IL- ⁇ ⁇ , IL-8, IL-5, IL-6, histamine, proteases and reactive oxygen species for example.
  • Normal inflammation is a highly regulated process that is tightly controlled at several levels for each of the cell types involved in the response.
  • expression of the pro-inflammatory cytokine TNF-a is controlled at the level of gene expression, translation, post-translational modification and release of the mature form from the cell membrane.
  • Many of the proteins up-regulated during inflammation are controlled by the transcription factor, NF- ⁇ .
  • Pro-inflammatory responses are normally countered by endogenous anti-inflammatory mechanisms such as generation of IL-10 or IL-4.
  • a characteristic of a normal inflammatory response is that it is temporary in nature and is followed by a resolution phase which brings the state of the tissue back to its prior condition.
  • the resolution phase is thought to involve up-regulation of anti-inflammatory mechanisms, such as IL-10, as well as down-regulation of the proinflammatory processes.
  • Inflammatory disease occurs when an inflammatory response is initiated that is inappropriate and/or does not resolve in the normal manner but rather persists and results in a chronic inflammatory state. Inflammatory disease may be systemic (e.g. lupus) or localized to particular tissues or organs and exerts an enormous personal and economic burden on society. Examples of some of the most common and problematic inflammatory diseases are rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, chronic obstructive pulmonary disease, emphysema, colitis and ischemia- reperfusion injury.
  • a common underlying theme in inflammatory disease is a perturbation of the cellular immune response that results in recognition of host proteins (antigens) as foreign.
  • the inflammatory response becomes misdirected at host tissues with effector cells targeting specific organs or tissues often resulting in irreversible damage.
  • the self- recognition aspect of auto-immune disease is often reflected by the clonal expansion of T-cell subsets characterized by a particular T-cell receptor (TCR) subtype in the disease state.
  • TCR T-cell receptor
  • inflammatory disease is also characterized by an imbalance in the levels of T-helper (Th) subsets (i.e., Th1 cells vs. Th2 cells).
  • Therapeutic strategies aimed at curing inflammatory diseases usually fall into one of two categories: (a) down-modulation of processes that are up-regulated in the disease state or (b) up-regulation of anti-inflammatory pathways in the affected cells or tissues. Most regimes currently employed in the clinic fall into the first category. Some examples of which are corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • an assay for scavengers of ROS allows detection of compounds with potential therapeutic efficacy.
  • Cellular assays to detect inhibitors of TNF-a release from stimulated macrophage or monocytic cells are an important component of an in vitro model for inflammation as this cytokine is upregulated and has been shown to contribute to the pathology in many inflammatory diseases. Since elevated cAMP in affected cells has been shown to modulate or dampen the inflammatory response, monitoring cellular cyclic AMP (cAMP) levels, and the activity of pathways controlling cAMP levels allows for the detection of potential anti-inflammatory compounds. Assays may include monitoring the level of cAMP itself, phosphodiesterase activity, or changes in cAMP response element (CRE)- luciferase activity.
  • CRE cAMP response element
  • cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), play a key role in regulating cell function and phosphodiesterases (PDEs) provide the main route for the degradation of cyclic nucleotides.
  • cAMP is now known to control the functional and genomic responses for a variety of cellular functions triggered by a wide array of receptors (Beavo, J. A. and Brunton, L.L., Nat. Rev. Mol. Cell Biol., 3, 710-718 (2002)).
  • Local control of cAMP signalling is affected by a complex pattern of localized synthesis, by adenylate cyclise (AC), and by phosphodiesterase (PDE)-mediated enzymatic degradation.
  • AC adenylate cyclise
  • PDE phosphodiesterase
  • the PDEs are a family of enzymes that catalyze the hydrolysis of 3',5'-cyclic nucleotides to 5' nucleoside monophosphates, including the conversion of cAMP to AMP and cGMP to GMP.
  • PDE enzymes are collectively grouped as a superfamily of eleven different, but homologous, gene-families with a highly conserved catalytic domain (Soderling, S.H. and Beavo, J.A., Curr. Opin. Cell Biol., 12, 174-179 (2000)).
  • S.H. and Beavo, J.A., Curr. Opin. Cell Biol., 12, 174-179 (2000) At present twenty-one different mammalian PDE genes have been identified. Many of these genes are expressed in multiple isoforms either by differing initiation sequences or splicing patterns.
  • PDEs in families 5, 6 and 9 specifically catalyze the hydrolysis of cGMP while PDEs 4, 7 and 8 are specific for cAMP.
  • Enzymes belonging to the other PDE families (1 , 2, 3, 10 and 11 ) catalyze the hydrolysis of both cAMP and cGMP with differing kinetics.
  • Different PDE isozymes can have specific tissue, cellular and subcellular distributions and more than one type of PDE is usually present in any given cell. The types of PDEs expressed in a cell, together with their relative proportions and subcellular localization, control the cyclic nucleotide phenotype of that cell.
  • the PDE4 enzyme is responsible for selective, high affinity hydrolytic degradation of the second messenger cAMP, has a low Michaelis constant and is sensitive to inhibition by rolipram.
  • the PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme (PDE4A, PDE4B, PDE4C, and PDE4D) (Wang et al., "Expression, Purification, and Characterization of human cAMP Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem", Biophys. Res. Comm., 234, 320-324 (1997)).
  • cAMP activity is important in many biological processes, including inflammation, depression and cognitive function.
  • Chronic inflammation is a multitude of heterogeneous diseases characterized in part by activation of multiple inflammatory cells, particularly cells of lymphoid lineage (including T lymphocytes) and myeloid lineage (including granulocytes, macrophages, and monocytes).
  • Activation of these inflammatory cells results in production and release of proinflammatory mediators, including cytokines and chemokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1 ).
  • TNF tumor necrosis factor
  • IL-1 interleukin-1
  • Discovery of a molecule that suppresses or inhibits such cellular activation and proinflammatory mediator release would be useful in the therapeutic treatment of inflammatory diseases. Elevated cAMP levels suppress inflammatory cell activation.
  • PDE4 inhibitors have recently shown clinical utility in mitigating the effects of the chronic pulmonary inflammatory diseases of asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Roflumilast a selective PDE4 inhibitor, demonstrated improvements in measures of airway function (forced expiratory volume in 1 second; FEV1 , and peak expiratory flow; PEF) in mild asthmatics in a recently published clinical trial of 12 weeks duration (Bateman et al., Ann. Allergy Asthma Immunol., 96(5): 679-86 (2006)).
  • PDE4 inhibition has also been demonstrated in disorders of the central nervous system.
  • PDE4 inhibition by rolipram improves cognitive function in rodents and was developed as an antidepressant in humans.
  • cAMP acts as a second messenger for neurotransmitters, and thus mediates their cellular responses.
  • the therapeutic effects of PDE4 inhibitors in cognition and depression likely originate from enhancement of the cAMP-dependent cellular responses.
  • At least one of the dotted lines represents a bond (thereby forming a double bond), and the other represents an optional bond (and therefore denotes the presence of an optional further double bond); when the dotted line between the carbon and nitrogen is present, then R 2 is absent, and when the dotted line between the carbon and nitrogen is absent, then R 2 is present;
  • m represents 0, 1 , 2, 3 or 4;
  • n represents 0, 1 , 2 or 3; at least one of R 1 and, if present, R 2 represents -A 1 -T z -B 1 and the other (if present) represents R 5 ;
  • carbon atoms of the requisite central pyrimidinone ring to which any two R 6 groups may be attached may be linked together to form a further ring, which is formed either by the two relevant groups being linked together by a direct bond or Ci.5 alkylene;
  • T z represents a direct bond, -N(R w1 )- or -C(0)N(R w2 )-;
  • R w and R" 2 independently represent hydrogen, 0 1-12 alkyl (optionally substituted by one or more substituents selected from X 7 ) or -B 5 ;
  • B 1 represents:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 X 11 and X 12 independently represent B 6 , halo, -CN, -N0 2 , -Si(R 8a ) 3 , -OR 9a , -OC(0)-R 9b , -N(R 9c )R 9d , -C(0)R 9e , -C(0)OR 9f , -C(0)N(R")R 9h , -N(R 9i )C(0)OR 8b , -N(R 9j )C(0)R 8c , -N(R 9k )S(0) t R 8d , -S(0) t OR 8e , -S(0) p R 8f , -S(0) T N(R 9M )R 9N , -N(R 9P )C(0)N(R
  • t represents, at each occurrence when used herein, 1 or 2;
  • p represents 0, 1 or 2;
  • E ⁇ E 2 , E 3 and E 4 independently represent halo, -CN, -N0 2 , -OR 10a , -OC(O)-R 10b , -N(R 0c )R 10d , -C(O)R 10e , -C(0)OR 10f , -C(O)N(R 10g )R 10h , -N(R 0i )C(O)OR 11a , -N(R 10i )C(O)R 1b , -N(R 10k )S(O) t1 R
  • t1 represents, at each occurrence when used herein, 1 or 2;
  • p1 represents 0, 1 or 2, or a pharmaceutically acceptable salt thereof, which compounds are hereinafter referred to as the "compounds of the invention".
  • 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 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.
  • C 1-q alkyl, and Ci-q alkylene, 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, in the case of alkyl, a C 3-q cycloalkyl group or, in the case of alkylene, a C 3-q cycloalkylene group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms and unless otherwise specified, be unsaturated (forming, for example, in the case of alkyl, a C 2- q alkenyl or a C 2 .q alkynyl group or, in the case of alkylene, a C 2-q alkenylene or a C 2 .q alkynylene group).
  • alkylene groups it is preferred that they are acyclic and/or straight-chain, but may be saturated or unsaturated.
  • C 1-q alkyl groups may also be spiro-groups (i.e. two cycloalkyl 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, bicyclic and tricyclic (e.g. monocyclic or 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).
  • heterocycloalkyi groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 4-q heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q heterocycloalkynyl group.
  • C 2 may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 4-q heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q heterocycloalkynyl group.
  • 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-
  • heterocycloalkyl 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 heterocycloalkyl group, forming a so-called "spiro'-compound.
  • the point of attachment of heterocycloalkyl 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.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form. Most preferably, heterocycloalkyl groups that may be mentioned include 5- or 6-membered monocyclic heterocycloalkyl groups.
  • bicyclic refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring.
  • Bicyclic also includes bridged bicyclic groups.
  • 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 C 6 .i 4 (such as C 6- 13 (e.g. C 6 . 10 )) aryl groups. Such groups may be polycyclic (e.g.
  • 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 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 acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2 - -1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridy
  • 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.
  • Particularly preferred compounds of formula I include those of formula lb depicted above, i.e. the following compounds in which the dotted line that is not attached to a nitrogen atom represents a double bond:
  • -(R 7 ) n represents between one and three optional (i.e. R 7 may not be present) substituents (as n may be 0, 1 , 2 or 3), which may be attached to any one of the three free positions of the requisite benzene ring of the compound of formula I (to which -(R 7 ) n is bound).
  • -(R 6 ) m represents between one and four optional (i.e.
  • R 6 may not be present) substituents, which may be attached to any one of the free positions of the ring to which -(R 6 ) m ring is attached, as permitted by the standard valencies of the relevant atoms in the rings.
  • substituents which may be attached to any one of the free positions of the ring to which -(R 6 ) m ring is attached, as permitted by the standard valencies of the relevant atoms in the rings.
  • R 1 d represents Ci. 3 alkyl optionally substituted by one or more halo atoms
  • halo group is preferably fluoro
  • alkyl groups mentioned herein are more preferably 0 1-6 alkyl groups.
  • Preferred compounds of the invention that may be mentioned include those in which: there are one or two R 6 groups present;
  • R 6 groups when there are two R 6 groups present, then these may be (and preferably are) located on the same carbon atom (of the requisite central pyrimidinone ring), for instance forming two separate C 1-12 (e.g. Ci- 6 , such as C ) alkyl groups (e.g. methyl) or, in which those two R 6 moieties (attached to the same carbon atom of the requisite central pyrimidinone ring) are linked together to form a C 3 -8 (e.g. C ⁇ ) cycloalkyl group (e.g. cyclopropyl; which is a spiro-cyclo group, as it is attached to the central ring via a single common carbon atom).
  • C 1-12 e.g. Ci- 6 , such as C
  • alkyl groups e.g. methyl
  • C 3 -8 e.g. C ⁇
  • cycloalkyl group e.g. cyclopropyl; which is a spir
  • n 0 (i.e. there are no R 6 substituents present).
  • compounds of the invention include those in which there are not two R 6 groups attached to the same carbon atom and any two R 6 groups present on the same carbon atom are not linked together; hence, in this instance there is no tetra-substituted carbon atom in the main pyrimidinone ring of the compound of formula I.
  • Preferred compounds of the invention include those in which: the requisite central ring of the compound of formula I contains two double bonds (i.e. in which both dotted lines represent a bond, so forming a central pyrimidinone ring) or it contains one double bond between two carbon atoms of the requisite central ring (i.e. the dotted line between two carbon atoms represents a bond, so forming a dihydropyrimidinone ring);
  • B 1 when B 1 represents a 6-membered monocyclic heteroaryl group, then it preferably contains one or two (e.g. one) heteroatom(s) preferably selected from nitrogen
  • B 1 more preferably represents optionally substituted phenyl
  • R 3 when R 3 is -OR a , at least one of -R 4 and -R a is other than acyclic 0 1-12 alkyl (e.g. methyl);
  • R 3 is -OR 43 , at least one of -R 4 and -R 4a is cycloalkyl or heterocycloalkyl as defined herein;
  • R 4 and -R 4a are other than acyclic CM 2 alkyl (for example, R 4a is cycloalkyl or heterocycloalkyl as defined herein) and the other (e.g. R 4 ) represents acyclic Ci -12 (e.g. alkyl.
  • Preferred compounds of the invention include those in which:
  • n 3, preferably, 2, or, more preferably, 0 or 1 ;
  • n 2 or, preferably, 0 or 1 ;
  • R 1 represents -A 1 -T z -B 1 ;
  • R 4 and R 4a independently represent C 1-12 alkyl, then they may represent acyclic Ci_6 alkyl or, preferably, a (e.g. Cs-e) cycloalkyi group (both of which may be optionally substituted as defined herein);
  • R 4 and R 43 are acyclic (e.g. acyclic alkyl as defined herein) and the other is acyclic (e.g. acyclic 0 1-6 alkyl as defined herein) or, preferably, cyclic (e.g. a C3-8 (e.g. C 5 -6) cycloalkyi group), i.e. most preferably, one of R 4 and R 43 is acyclic and the other is preferably cyclic;
  • R 4a more preferably represents a 5- or 6-membered (e.g. 5-membered) heterocycloalkyl group (e.g. in which the heterocycloalkyl group contains two or preferably one heteroatom, preferably selected from nitrogen or, especially oxygen) or, R 4a more preferably represents C 3 _3 cycloalkyi (e.g. C M cycloalkyi), which heterocycloalkyl and cycloalkyi groups are optionally substituted as hereinbefore defined, but which are preferably unsubstituted;
  • a 5- or 6-membered (e.g. 5-membered) heterocycloalkyl group e.g. in which the heterocycloalkyl group contains two or preferably one heteroatom, preferably selected from nitrogen or, especially oxygen
  • R 4a more preferably represents C 3 _3 cycloalkyi (e.g. C M cycloalkyi), which heterocycloalkyl and cycloalkyi groups are optionally substituted as here
  • R 4a represents substituted alkyl as defined herein (e.g. substituted C 1-12 alkyl) or substituted cycloalkyi as defined herein (e.g. substituted 0 3-8 cycloalkyi such as cycloalkyi) then the preferred substituent(s) is/are fluoro;
  • R 4 more preferably represents C 1-12 alkyl, such as acyclic C 1 -6 alkyl (e.g. Ci -3 alkyl, such as methyl), which group may be substituted as defined herein, but is preferably unsubstituted;
  • R 4a represents substituted alkyl as defined herein (e.g. substituted d - 2 (e.g. C ⁇ , such as C 1-3 ) alkyl) then the preferred substituent(s) is/are fluoro (so forming e.g. a -CF 3 or -CHF 2 group);
  • R w1 and RTM 2 independently represent C 1-3 alkyl (e.g. methyl) or, preferably, hydrogen;
  • B 1 represents phenyl optionally substituted with one or more substituents selected from X 8 ;
  • B 1 moieties e.g. phenyl; which may contain one or more, e.g. one or two substituents), i.e. X 8
  • substituents on B 1 moieties include halo (e.g. F or CI), C 1-3 alkyl (e.g. CH 3 or CF 3 ) or -OR 9e (e.g. OCH 3 or OCF 3 ), and, more preferably, the X substituents are e.g. halo or Ci-3 alkyl, e.g. tirfluoromethyl or, more preferably, chloro or methyl);
  • the heteroatom(s) is/are preferably selected from oxygen and nitrogen (further, in the case where B 2 , B 3 and B 3a represent heteroaryl, then the heteroatom(s) may also be selected from sulfur);
  • B 2 , B 3 and B 3a represent a 5- or 6-membered heterocycioalkyi or heteroaryl group, then those groups contain two or, preferably, one heteroatom(s);
  • heteroatom(s) is/are preferably selected from oxygen and nitrogen;
  • B 4 and B 5 represent a 5- or 6-membered heterocycioalkyi group, then those groups contain two or, preferably, one heteroatom(s);
  • B 3 represents a five-membered heteroaryl or heterocycioalkyi group, in which the heteroatom is preferably oxygen (so forming, e.g. a furanyl or tetrahydrofuranyl group);
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 independently represent B 6 , preferably,
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 independently represents, at each occurrence when used herein, B 6 , -CN, -N0 2 , halo (e.g. fluoro),
  • R 8a , R 8 , R 8d , R 8e , R 89 and R 8h independently represent d- ⁇ (e.g. C1.3) alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 8c R 8f R 9a R 9b R 9c R 9d R e R 9 * R 9a R 9h R 9i R 9 ' R 9k R 9m R 9n R 9p R 9q R r R 9s R 9t and R 9u independently represent hydrogen or C 1 -6 (e.g. d-4 or, preferably, Ci -3 ) alkyl (e.g. i-butyl or, preferably, methyl) optionally substituted by one or more substituents selected from E 2 ; or
  • B 6 represents (acyclic or, e.g. preferably, cyclic) C 3-8 alkyl, 5- or 6-membered heterocycloalkyl (both of which are optionally substituted by one or more E 3 substituents), preferably, heteroaryl or, more preferably, aryl (e.g. phenyl), which latter two groups are optionally substituted by one or more E 4 substituents;
  • E 1 , E 2 , E 3 and E 4 independently represent -N(R 10k )S(O) t1 R 11c , -S(O) t1 N(R 10m )R 0n , preferably, -N0 2 , -C(O)OR 10f , or, more preferably, halo, -CN, -OR 10a , -N(R 0c )R 10d , -C(O)N(R 109 )R 10h and/or -N(R 0) )C(O)R 11b (particularly preferred groups, e.g. E 2 groups, include -C(O)N(R 1 ° 9 )R 10h );
  • R 10t , R 10u and R 11b independently represent hydrogen, -CH 3 or -CF 3 (e.g. R 109 and R 10h independently represent hydrogen);
  • R 11a , R 11c , R 11d , R 1e , R 11f , R 119 and R 11h independently represent -CH 3 or -CF 3 .
  • Preferred optional substituents on B groups include alkyl (e.g. -C(O)O-f-butyl); or, preferably, C, alkyl (e.g. methyl) optionally substituted by one or more halo atoms (so forming, for example, a difluoromethyl or trifluoromethyl group); halo (e.g. chloro or fluoro); -CN; and -O-d-4 alkyl (e.g.
  • substituents selected from -C(0)N(R 18 ) 2 in which R 8 is preferably hydrogen; so forming, for example an acetamidoxy substituent) or, more preferably, halo (so forming, for example, a difluoromethoxy or trifluoromethoxy group).
  • substituents include fluoro atoms. More preferred compounds of the invention include those in which:
  • n 0;
  • n 0;
  • the dotted lines both represent bonds (i.e. there are two double bonds in the requisite 6- membered ring of formula I, thereby forming a pyrimidinone), or one of the dotted lines (e.g. the dotted line between two carbon atoms) represents a bond (i.e. such that there is one double bond present between two carbon atoms in the requisite 6-membered ring of formula I, thereby forming a 3,4-dihydropyrimidin-2-one group);
  • R 3 represents -OR 4a ;
  • R a preferably represents furanyl (e.g. 3-furanyl), tetrahydrofuranyl (e.g. 3- tetrahydrofuranyl) or, more preferably, cyclopentyl;
  • R 4 represents trifluoromethyl, difluoromethyl or, preferably, methyl
  • R 5 represents H; A 1 represents -CH 2 -;
  • T z represents a direct bond
  • B 1 represents phenyl (preferably unsubstituted or, more preferably, substituted with at least one substituent (e.g. two or, preferably, one) selected from X 8 , which is preferably located at the meta position;
  • alkyl e.g. -C(O)O-f-butyl
  • -OCi. 2 alkyl e.g. -OCH 3 ; optionally substituted by one or more F, so forming e.g. -OCF 3
  • halo e.g. -F and/or
  • Particularly preferred compounds of the invention include:
  • both dotted lines denote a bond (so forming two double bonds; in which case R 2 is absent) or the dotted line between the two carbon bonds is present (only, so forming one double bond in the central ring, and in which case R 2 is present);
  • n and m independently represent 0;
  • R 1 represents -A 1 -T z -B 1 ;
  • R 2 represents hydrogen
  • a 1 represents Ci -3 (e.g. Ci. 2 ) alkylene (optionally substituted as herein defined, but preferably unsubstituted) and A 1 most preferably represents -CH 2 -;
  • T z represents a direct bond
  • B 1 represents phenyl optionally substituted by one or more (e.g. one) substituent(s) (e.g. in which one is located at the meta position) selected from X 8 ;
  • X 8 represents halo, -CN, -OR 9a or, preferably, B s ;
  • R 9a represents hydrogen or, preferably, d -3 (e.g. C 1-2 ) alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms;
  • B 6 represents Ci -3 (e.g. C 1-2 ) alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms (and, most preferably, B 6 represents unsubstituted C -2 alkyl, such as methyl);
  • R 3 represents -OR a ;
  • R 4a represents C 1-6 alkyl (optionally substituted by one or more substituents as defined herein, e.g. by one or two X 2 substituents, but preferably unsubstituted) and the most preferred C -6 alkyl groups are C 3 ⁇ cycloalkyl (e.g. Cs ⁇ cycloalkyl such as cyclopentyl; which cycloalkyl groups are also preferably unsubstituted);
  • R 4 represents C 1 -6 (e.g. Ci -4 ) alkyl (optionally substituted by one or more substituents as defined herein, e.g. by one or two X 2 (e.g. fluoro) substituents, but preferably unsubstituted) and the most preferred alkyl groups are alkyl (e.g. Ci -2 alkyl, such as methyl; preferably unsubstituted).
  • substituents as defined herein, e.g. by one or two X 2 (e.g. fluoro) substituents, but preferably unsubstituted
  • 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.
  • B 1 -T z -A 1 -L 1 III wherein B 1 , T z and A 1 are as hereinbefore defined, and L 1 represents a suitable leaving group, such as a sulfonate group or, more preferably an iodo, bromo or chloro group, in the presence of a base, such as a strong base, for instance an alkali metal-based base such as NaH and/or KO-ie/ -butyl, optionally in the presence of an additive (for example, a sodium or potassium co-ordinating agent, such as a crown ether (e.g. 15-crown-5)), for example in the presence of a suitable solvent, such as a polar aprotic solvent (e.g.
  • a base such as a strong base, for instance an alkali metal-based base such as NaH and/or KO-ie/ -butyl
  • an additive for example, a sodium or potassium co-ordinating agent, such as a
  • tetrahydrofuran or diethyl ether for example at sub-ambient temperatures (e.g. 0°C to -78°C) under an inert atmosphere.
  • any suitable base/conditions may be employed.
  • bases include Et 3 N, pyridine, ⁇ /,/V- dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K 3 P0 4 , Cs z C0 3 and/or i-BuONa.
  • Suitable optional solvents include tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, acetone and dioxane.
  • the base may need to be added to the compound of formula II before the addition of the compound of formula III (e.g. when NaH is employed as the base).
  • one leaving group may be converted into another leaving group (e.g. into a stronger/better leaving group in the compound of formula III, for instance by iodide exchange, e.g. by adding an iodide source (e.g. Kl) to a compound of formula III in which L 1 is chloro, thereby exchanging the chloride with iodide);
  • R 2a — L 2 IV wherein R 2a represents R 2 as hereinbefore defined provided that it does not represent H, and L 2 represents a suitable leaving group, such as one hereinbefore defined in respect of L , under suitable conditions, such as those hereinbefore described in respect of process step (i);
  • R 2 is H and R ⁇ R 3 , R 4 , R 6 , R 7 , n and m are as hereinbefore defined, or protected derivatives thereof, for example under standard conditions, such as in the presence of a suitable reagent (e.g. DDQ (2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone)) and/or by heating in the presence of Pd/C;
  • a suitable reagent e.g. DDQ (2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone)
  • R 3 , R 4 R 6 R 7 and n are as hereinbefore defined, and ml is 0, 1 or 2 (the skilled person will appreciate that -(R 6 ) m represents two optional Re substituents, and that the structure of the compound of formula VI dictates that these substituents may only be positioned at the carbonyl carbon and or in the ⁇ position relative to the carbonyl carbon) and Y A is -OH or -NYV 3 , where Y 3 and Y B are independently alkyl (e.g.
  • CM 2 alkyl including cycloalkyl), heterocycloalkyl, aryl and/or heteroaryl, or Y 3 and Y 5 may be joined to form a ring optionally containing one or more additional heteroatom, with a compound of formula VII,
  • B ⁇ T z and A 1 are as hereinbefore defined, under suitable conditions, for example under acid reaction conditions (e.g. in the presence of a hydrogen halide (e.g. HCI) optionally in a suitable solvent, such as an alcoholic solvent, e.g. ethanol);
  • a hydrogen halide e.g. HCI
  • a suitable solvent such as an alcoholic solvent, e.g. ethanol
  • R 3 , R 4 , R 7 and n are as hereinbefore defined, with a compound of formula VII as hereinbefore defined and in the presence of a suitable reagent such as an ester (e.g. ester) of formic acid (e.g. methyl or ethyl formate) or a suitable equivalent thereof (e.g. triethyl orthoformate) under conditions known to one skilled in the art, such as standard Aldol-type reaction conditions, conditions such as those hereinbefore defined in respect of process step (v) or, when e.g. triethyl formate is employed under acidic reaction conditions;
  • a suitable reagent such as an ester (e.g. ester) of formic acid (e.g. methyl or ethyl formate) or a suitable equivalent thereof (e.g. triethyl orthoformate) under conditions known to one skilled in the art, such as standard Aldol-type reaction conditions, conditions such as those hereinbefore defined in respect of process step (
  • L 5a represents a suitable leaving group, such as one hereinbefore defined in respect of L 5 , e.g. chloro, bromo, iodo, a sulfonate group (e.g.
  • each R" independently represents a C1-5 alkyl group, or, in the case of -B(OR wx )2, the respective FT" 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 L 5a preferably represents -B(OH) 2 , with a compound of formula X,
  • R 3 , R 4 , R 7 and n are as hereinbefore defined, and L represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g.
  • each R m independently represents a C 1-6 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 L 6 preferably represents bromo (the skilled person will also appreciate that L 5 and L 6 should be mutually compatible, and may also be interchanged), for example, in the presence of a suitable catalyst system, e.g.
  • a metal such as Cul, Pd/C, PdCI 2> Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or NiCI 2 and a ligand such as f-Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2- bis(diphenylphosphino)ethane, 2,2'-bis(di-ierf-butylphosphino)-1 ,1 , -biphenyl, 2,2'- bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1 , 1 '-bis(diphenylphosphinoferrocene), 1 ,3- bis(diphenyl-phosphino)propane, xantphos, or
  • R ⁇ R 2 , R 6 , R 7 , m, n and the dotted lines are as hereinbefore defined and L 7 represents L or R 3 as hereinbefore defined, and L 8 represents L x or -OR 4 as hereinbefore defined, and L represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g.
  • each R n independently represents a 0 1-6 alkyl group with a compound of formula XII,
  • R 4x -OH XII wherein R x represents R 4 or R a as required/appropriate, under suitable conditions, 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-dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K 3 P0 4 , Cs 2 C0 3 , f-BuONa or
  • 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;
  • R 4y -L 9 XIII wherein R y represents R 4 or R a as required/appropriate, and L 9 represents a suitable leaving group such as one defined hereinbefore in respect of L ⁇ under suitable reaction conditions, for example such as those hereinbefore described in respect of process step
  • L 10 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 and R 2 , R 3 , R 4 , R 6 , R 7 , m, n and the dotted lines are as hereinbefore defined, with a compound of formula XV,
  • an appropriate solvent e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine
  • a further additive e.g. 1-hydroxybenzotriazole hydrate
  • the carboxylic acid group of the compound of formula XVI may be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of SOCI 2 or oxalyl chloride), which acyl chloride is then reacted with a compound of formula XVII, for example under similar conditions to those mentioned above.
  • L 3 represents a suitable leaving group as hereinbefore defined in respect of L 1
  • R 3 , R 4 , R 7 B 1 , T z , A 1 and n are as hereinbefore defined, under suitable conditions, such as those hereinbefore described in respect of process step (i) (preparation of compounds of formula I);
  • R 1 , R 3 , R 4 , R 6 , R 7 , m and n are as hereinbefore defined, and R 2 is present and is as hereinbefore defined, with a compound of formula XX, where L 4 and L 5 independently represent a suitable leaving group, such as -O-Ci-s alkyl (e.g. -OEt), a heterocycle (e.g. imidazole) wherein the heterocycle is bound to the carbonyl group at the heteroatom (e.g. 1 ,1'-carbonyldiimidazole) or a chloro group (e.g.
  • a suitable leaving group such as -O-Ci-s alkyl (e.g. -OEt)
  • a heterocycle e.g. imidazole
  • the heterocycle is bound to the carbonyl group at the heteroatom (e.g. 1 ,1'-carbonyldiimidazole) or a chloro group (e.g.
  • phosgene or a suitable phosgene derivative such as triphosgene
  • a suitable base such as an amine base (e.g. pyridine)
  • a suitable solvent such as a polar aprotic solvent (e.g. toluene, preferably, tetrahydrofuran or diethyl ether).
  • Compounds of formula VI in which Y 1 represents -OH may be prepared by hydrolysis of a compound of formula VI wherein Y 1 represents -NY ⁇ Y 6 , under conditions known to those skilled in the art, for example in the presence of an aqueous base (e.g. aqueous NaOH) and optionally in the presence of a suitable solvent or solvent mixture (e.g. ethanol and water).
  • an aqueous base e.g. aqueous NaOH
  • a suitable solvent or solvent mixture e.g. ethanol and water
  • Compounds of formula VI in which Y represents -OH may also be prepared by reaction of a compound of formula VIII with a suitable ester of formic acid (e.g. methyl or ethyl formate) or the like, for example under reaction conditions known to those skilled in the art, such as those hereinbefore described in respect of preparation of compounds of formula I (process step (v)).
  • a suitable ester of formic acid e.g. methyl or ethyl formate
  • Compounds of formula XVI may be prepared by reaction of a compound of formula II as hereinbefore defined, with a compound of formula XXI, L 11 -A 1 -i C(0)OH XXI or a protected derivative (e.g. ester) thereof, wherein L 11 represents a suitable leaving group, for example one hereinbefore defined in respect of L 1 (e.g. bromo) and A 1 is as hereinbefore defined, under standard reaction conditions known to those skilled in the art, for example such as those hereinbefore defined in respect of preparation of compounds of formula I (process step (i) above).
  • R 3 , R 4 , R 7 , A 1 , T z , B 1 and n are as hereinbefore defined, with a suitable halogenating agent, for example, where L 3 represents a bromo group, reaction with CBr 4 and PPh 3 in the presence of a suitable solvent (e.g. dichloromethane).
  • a suitable solvent e.g. dichloromethane
  • Compounds of formula XVIII wherein L 3 represents a sulfonate group may be prepared by reaction of a compound of formula XXII as hereinbefore defined, or a suitable protected derivative thereof, with a suitable sulfonyl chloride, for example trifluoromethane sulfonylchloride or p-toluene sulfonylchloride, optionally in the presence of a suitable amine base (e.g. pyridine or triethyl amine) and in the presence of a suitable solvent (e.g. dichloromethane).
  • a suitable amine base e.g. pyridine or triethyl amine
  • a suitable solvent e.g. dichloromethane
  • R 3 , R 4 , R 7 and n are as hereinbefore described, under conditions known to one skilled in the art, for example by reaction with a suitable reagent, for example a suitable reagent (e.g. triphenylphosphine), optionally in presence of a suitable solvent (e.g. THF).
  • a suitable reagent e.g. triphenylphosphine
  • a suitable solvent e.g. THF
  • R 3 , R 4 , R 7 and n are as hereinbefore defined, with
  • a suitable sulfonating agent e.g. p-toluenesulfonyl chloride
  • a suitable base e.g. pyridine
  • a suitable catalyst e.g. DMAP
  • a suitable solvent e.g. THF or DC
  • an azide nucleophile for example an azide salt (e.g. sodium azide), under conditions known to one skilled in the art, for example in the presence of a suitable solvent (e.g. DMF) and optionally in the presence of a suitable metal ion complexing agent, for example a crown ether (e.g. 15-crown- 5).
  • a suitable solvent e.g. DMF
  • a suitable metal ion complexing agent for example a crown ether (e.g. 15-crown- 5).
  • R 3 , R 4 , R 7 and n are as hereinbefore defined, under conditions known to one skilled in the art, for example in the presence of a suitable reducing agent, such as a suitable borane or complex thereof (e.g. BH 3 THF) and in the presence of a suitable solvent (e.g. THF).
  • a suitable reducing agent such as a suitable borane or complex thereof (e.g. BH 3 THF) and in the presence of a suitable solvent (e.g. THF).
  • a suitable solvent e.g. THF
  • Compounds of formula XXIII may also be obtained by reaction of a compound of formula XXVII as hereinbefore defined, or preferably a suitably protected derivative thereof, for example, an ester derivative (e.g. a methyl ester), with:
  • a suitable sulfonating agent e.g. p-toluenesulfonyl chloride, so forming a tosylate group; alternatively, the skilled person will appreciate that corresponding compounds in which the tosylate group is replaced with a different leaving group, such as chloro, bromo or iodo, may also be employed
  • a suitable base e.g. pyridine
  • a suitable catalyst e.g. DMAP
  • a suitable solvent e.g. THF or DCM
  • an azide nucleophile for example an azide salt (e.g. sodium azide), under conditions known to one skilled in the art, for example in the presence of a suitable solvent (e.g. DMF) and optionally in the presence of a suitable metal ion complexing agent, for example a crown ether (e.g. 15-crown- 5); followed by
  • a suitable solvent e.g. DMF
  • a suitable metal ion complexing agent for example a crown ether (e.g. 15-crown- 5); followed by
  • a suitable reducing agent e.g. lithium aluminum hydride (LiAIH 4 )
  • a suitable solvent e.g. tetrahydrofuran
  • R u1 and R u2 do not represent hydrogen.
  • R u1 and R u2 When R u1 and R u2 are linked together, they may together form the following group (i.e. U may represent the following group):
  • Compounds of formula XXVIII may be prepared by reaction of a compound of formula XXIX (as hereinbefore defined) or a compound of formula XXXIII as defined hereinafter with a compound of formula XXXI,
  • compounds of formula XXVIII may be prepared by reaction of a compound corresponding to a compound of formula X but in which L 6 represents a metal-containing group, such as Li, MgBr, ZnCI or the like (which may be prepared by reaction of a corresponding compound of formula X in which L 6 represents halo, by e.g. lithiation, a Grignard-forming reaction, followed by, if necessary, metal-exchange reactions and the like) with a compound of formula XXXII,
  • the substituents either in final compounds of the invention or in relevant intermediates (as appropriate) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. 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.
  • transformation steps include the conversion of one L 6 group (in the compound of formula XII) into another L 6 group (e.g. the conversion of one halo group, such as chloro, into another halo group, such as iodo, for example by reaction in the presence of potassium iodide), or even the conversion of a hydroxy group to a boronic acid group.
  • Other transformation steps include the reduction of a nitro group to an amino group, the hydrolysis of a nitrile group to a carboxylic acid group, and standard nucleophilic aromatic substitution reactions.
  • certain compounds e.g. compounds of formula lc as hereinbefore defined
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, methyl and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.
  • a carbonyl group may be protected as the silyl enol ether, which may be introduced under standard conditions, and converted back to the enolate (or carbonyl compound) by reaction in the presence of fluoride ions (or a suitable source thereof).
  • Protecting groups may be added or removed in accordance with standard techniques (for example a methyl protecting group on a hydroxy group may be removed by reaction in the presence of a suitable 'cleaving reagent' such as BBr 3 ), which are known to one skilled in the art and as described herein.
  • a suitable 'cleaving reagent' such as BBr 3
  • the use of protecting groups is described in detail in Green, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin or a 2- chlorotrityl-chloride resin.
  • 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.
  • certain compounds of the invention 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 (e.g. compounds of the invention) that possess pharmacological activity as 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
  • prodrugs 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.
  • composition/formulation including a compound of the invention as hereinbefore defined in admixture with a pharmaceutically acceptable adjuvant, carrier, diluent or excipient.
  • compositions 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.
  • Such compositions/formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • 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.
  • the invention further provides a process for the preparation of a pharmaceutical composition/formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable derivative (e.g. salt) thereof, with a pharmaceutically-acceptable adjuvant, carrier, diluent or excipient.
  • a pharmaceutically acceptable derivative e.g. salt
  • Compounds of the invention may be useful as inhibitors of certain enzymes such as a cyclic AMP phosphodiesterase, a phosphodiesterase 7; a phosphodiesterase 4; a phosphodiesterase 3; or a cyclic GMP phosphodiesterase.
  • compounds of the invention may be useful as inhibitors of a phosphodiesterase 7 and, particularly, a phosphodiesterase 4.
  • this invention is directed to methods for treating or preventing an inflammatory disease or condition in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as hereinbefore described.
  • 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.
  • inflammation thus also includes, for the purposes of this invention, inflammatory pain and pain generally.
  • condition has an inflammatory component associated with it, or a condition characterised by inflammation as a symptom
  • compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition.
  • the inflammatory condition or disease may be an autoimmune condition or disease; the inflammatory condition or disease may involve acute or chronic inflammation of bone and/or cartilage compartments of joints; the inflammatory condition or disease may be an arthritis selected from rheumatoid arthritis, gouty arthritis or juvenile rheumatoid arthritis; the inflammatory condition or disease may be a respiratory disorder selected from asthma or a chronic obstructive pulmonary disease (COPD, e.g., emphysema or chronic bronchitis); the condition or disease may be associated with the disregulation of T-cells; the condition or disease may be associated with elevated levels of inflammatory cytokines (e.g., wherein the inflammatory cytokine is IL-2, or wherein the inflammatory cytokine is IFN- ⁇ , or wherein the inflammatory cytokine is TNF-a); the inflammatory condition or disease may be multiple sclerosis; the inflammatory condition or disease may be pulmonary sarcadosis.; the inflammatory condition or disease may
  • Compounds of the invention may be useful in modulating intracellular cyclic adenosine ⁇ -monophosphate levels within a mammal, preferably a human.
  • this invention is directed to methods for modulating intracellular cyclic adenosine 5'-monophosphate levels within a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof an amount of a compound of the invention (e.g. those hereinbefore defined) or a pharmaceutical formulation/composition of the invention as hereinbefore described effective to modulate the intracellular cyclic adenosine 5'-monophosphate levels of the mammal.
  • a compound of the invention e.g. those hereinbefore defined
  • a pharmaceutical formulation/composition of the invention as hereinbefore described effective to modulate the intracellular cyclic adenosine 5'-monophosphate levels of the mammal.
  • the mammal preferably a human
  • Compounds of the invention may be useful in treating or preventing a disease or condition in a mammal, preferably a human, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers.
  • this invention is directed to methods for treating or preventing a disease or condition in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation/composition of the invention as hereinbefore described, and the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers.
  • enzymes may be a cyclic AMP phosphodiesterase; a phosphodiesterase 7; a phosphodiesterase 4; a phosphodiesterase 3; or a cyclic GMP phosphodiesterase.
  • the enzymes may be both phosphodiesterase 4 and phosphodiesterase 3.
  • the enzyme that may be inhibited is a phosphodiesterase 7 or, preferably, a phosphodiesterase 4.
  • Compounds of the invention may be useful in treating or preventing uncontrolled cellular proliferation in a mammal, preferably a human.
  • this invention is directed to methods for treating or preventing uncontrolled cellular proliferation in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount (e.g. an amount effective to treat or prevent uncontrolled cellular) of a compound of the invention or a pharmaceutical formulation/composition of the invention as hereinbefore described.
  • the uncontrolled cellular proliferation may be caused by a cancer selected from leukaemia and solid tumors.
  • Compounds of the invention may be useful in treating or preventing transplant rejection in a mammal, preferably a human.
  • this invention is directed to methods for treating or preventing transplant rejection in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount (e.g. an amount effective to treat or prevent transplant rejection in the mammal) of a compound of the invention.
  • the rejection may be due to graft versus host disease.
  • Compounds of the invention may be useful in treating or preventing conditions associated with the central nervous system (CNS) in a mammal, preferably a human.
  • CNS central nervous system
  • this invention is directed to methods for treating or preventing conditions associated with the central nervous system in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount (e.g. an amount effective to treat or prevent conditions associated with the central nervous system (CNS) in the mammal) of a compound of the invention as described above (e.g. those hereinbefore defined) or a pharmaceutical formulation/composition of the invention as hereinbefore described.
  • a therapeutically effective amount e.g. an amount effective to treat or prevent conditions associated with the central nervous system (CNS) in the mammal
  • a compound of the invention as described above (e.g. those hereinbefore defined) or a pharmaceutical formulation/composition of the invention as hereinbefore described.
  • the condition associated with the central nervous system (CNS) may be depression.
  • compounds of the invention are inhibitors of PDE7 and, preferably, PDE4.
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognised as a disease but only as an undesirable condition or syndrome, wherein a more-or-less specific set of symptoms have been identified by clinicians.
  • inflammation includes, without limitation, ankylosing spondylitis, arthritis (e.g. juvenile arthritis and rheumatoid arthritis), asthma, COPD, chronic bronchitis, respiratory distress syndrome, rhinitis, allergic rhinitis, Crohn's disease, nephritis, eczema, dermatitis (e.g.
  • atopic dermatitis urticaria, conjunctivitis, ulcerative colitis, rheumatoid arthritis, osteoarthritis, eosinophilic gastrointestinal disorders, vascular disease, diabetes mellitus, fibromyalgia syndrome, gout, inflammations of the brain (including multiple sclerosis, AIDS dementia, Lyme encephalopathy, herpes encephalitis, Creutzfeld-Jakob disease, and cerebral toxoplasmosis), emphysema, inflammatory bowel disease, irritable bowel syndrome, ischemia-reperfusion injury juvenile erythematosus pulmonary sarcoidosis, Kawasaki disease, osteoarthritis, pelvic inflammatory disease, psoriatic arthritis, psoriasis, tissue/organ transplant, scleroderma, spondyloarthropathies, systemic lupus erythematosus, pulmonary sarcoidosis, ulcerative colitis, viral
  • proliferative disorders includes, without limitation, all cancers, leukemias and solid tumors that are susceptible to undergoing differentiation or apoptosis upon interruption of their cell cycle.
  • the compounds and compositions of the invention may also be useful for treating diseases associated with the central nervous system. Such diseases include cognitive function, Alzheimer's disease and other neurodegenerative disorders, learning and memory disorders.
  • Compounds of the invention may inhibit disease induction, for example in the models in the biological examples, at doses of less than 500 mg/kg.
  • the Biological Examples below outline some, but not all, of the preclinical models that may be used to support the claims of this patent. For instance, compounds of the examples are tested in the Biological Example 1 , and are found to exhibit at least 50% inhibition of PDE4 at a concentration of 10 ⁇ or below (and more preferably at a concentration of 0.3 ⁇ or below).
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of the conditions described herein.
  • the compounds of the invention may be combined with other compounds that may be useful in the treatment of:
  • a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers (e.g. a cyclic AMP phosphodiesterase; a phosphodiesterase 4; a phosphodiesterase 3; a cyclic GMP phosphodiesterase; or both phosphodiesterase 4 and phosphodiesterase 3), which disorder may be an inflammatory disorder (it is most preferred that compounds of the invention are combined (an) inhibitor(s) of PDE7 or, in particular, (an) inhibitor(s) of PDE4);
  • enzymes associated with secondary cellular messengers e.g. a cyclic AMP phosphodiesterase; a phosphodiesterase 4; a phosphodiesterase 3; a cyclic GMP phosphodiesterase; or both phosphodiesterase 4 and phosphodiesterase 3
  • a disorder associated with the central nervous system comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.
  • a pharmaceutically-acceptable adjuvant diluent, carrier or excipient.
  • 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/composition including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of i), ii), iii), iv), v) or vi) above (e.g. a therapeutic agent that is useful in the treatment of an inflammatory disorder), and a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient; and (2) a kit of parts comprising components:
  • a pharmaceutical formulation/composition including another therapeutic agent that is useful in the treatment of i), ii), iii), iv), v) or vi) above e.g. a therapeutic agent that is useful in the treatment of an inflammatory disorder
  • a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient e.g. a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient
  • 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 derivative (e.g. salt) thereof with another therapeutic agent that is useful in the treatment of i), ii), iii), iv), v) or vi) above (e.g. a therapeutic agent that is useful in the treatment of an inflammatory disorder), and at least one pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.
  • a pharmaceutically acceptable derivative e.g. salt
  • kits of parts as hereinbefore defined, by bringing the two components "into association with” each other, we include that the two components of the kit of parts may be:
  • the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease or condition; and the subject undergoing therapy.
  • 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 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.
  • a pharmaceutical composition containing a compound of the invention when employed, it shall contain an appropriate amount/concentration/ratio of the active ingredient.
  • the ranges of effective doses provided herein are not intended to be limiting and represent preferred dose ranges.
  • the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts, (see, e.g., Berkow er a/., eds., The Merck Manual, 16 th edition, Merck and Co., Rahway, N.J., 1992; Goodmanetna., eds.,Goodman and Oilman's The Pharmacological Basis of Therapeutics, 10 th edition, Pergamon Press, Inc., Elmsford, N.Y., (2001 ); Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins, Baltimore, MD.
  • the physician or the skilled person, will be able to determine the actual dosage and/or route of administration 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.
  • Compounds of the invention may have the advantage that they are effective inhibitors (and hence particularly effective in the treatment of the conditions described herein), and in particular effective PDE inhibitors (such as PDE7 inhibitors and especially effective PDE4 inhibitors).
  • 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.
  • PDE4 U937 cytoplasmic extracts are prepared by a modified procedure of the assay described in MacKenzie, S.J. and Houslay, M.D., "Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response- element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells", Biochem J. (2000), 347(Pt 2):571-8, by lysis of U937 cells (ATCC: Catalogue No. CRL-159) in M-PER Lysis buffer (Pierce) containing 10% protease inhibitor cocktail (Sigma).
  • the cell lysates are then centrifuged at 30,000 rpm for 15 minutes at 4 °C.
  • the supernatants are aliquoted and stored at -80 °C.
  • PDE4 has been shown to be the predominant cyclic nucleotide phosphodieterase activity in U937 cells.
  • PDE4 enzymes are from recombinant human PDE4 obtained from baculovirus-SF9 cells expression system. cDNA containing PDE4D1 is cloned into a baculovirus vector, insect cells (SF9) are then infected and cells cultured to express the PDE4 protein. The cells are lysed and used directly in assay or partially purified using standard procedures. The process can be used for other PDE4 and PDE enzymes. Compounds of the invention are evaluated for inhibitory activity against PDE4 enzymes by the following assay Method A or B.
  • PDE4 assay based on modified procedure of Phosphodiesterase [ 3 H]cAMP SPA Enzyme Assay (Amersham Biosciences, code TRKQ 7090).
  • PDE4 enzymes converts [ 3 H]cAMP to [ 3 H]5'-AMP.
  • the assay is quenched by the addition of SPA yttrium silicate beads which preferentially bind linear nucleotides over cyclic nucleotides in the presence of zinc sulphate.
  • the amount of [ 3 H]5'-AMP formed is proportional to the PDE4 activity, hence PDE4 inhibitors would decrease the amount of [ 3 H]5'-AMP formed.
  • Reactions are performed in duplicate by the addition of 10 ⁇ PDE4 enzyme (U937 lysate or recombinant hPDE4) to 20 pL of assay mix and 20 ⁇ _ of test compounds in Isoplates (Wallac) for 30 minutes, at 37 °C.
  • the final assay mixture contained: 50 mM Tris (pH 7.5), 8.3 mM MgCI 2 , 1.7 mM EGTA and [ 3 H]cAMP (0.025 pCi) (Amersham).
  • Assay is terminated by addition 25 pL SPA beads. The plate is sealed, shaken for 1 minute and then allowed to settle 30 minutes and the cpm is determined using a Wallac Micobeta.
  • Method B Method B:
  • PDE4 assay based on modified procedure of Thompson and Appleman (Biochemistry (1971); 10; 311-316).
  • PDE4 enzymes converts [ 3 H]cAMP to [ 3 H]5'-AMP.
  • the [ 3 H]5'-AMP is then converted to [ 3 H]adenosine and phosphate by nucleotidase.
  • the amount of [ 3 H]adenosine formed is proportional to the PDE4 activity, hence PDE4 inhibitors would decrease the amount of [ 3 H]adenosine formed.
  • PDE reactions are performed for 30 minutes at 37 °C in 100 ⁇ _ volumes in 1 ⁇ cAMP, 0.05 ⁇ [ 3 H]cAMP (Amersham), 0.5 U/mL 5'-nucleotidase (Sigma), 50 mM Tris, 10 mM MgCt 2 pH 7.5. Reactions are performed in duplicate. Reactions are terminated by boiling for 2 minutes at 100 "C followed by the addition of 200 ⁇ _ Dowex 1-8 400 CI ' anion exchange resin in a ratio of 1 resin:2 methanol: 1 H 2 0. Samples are mixed by inversion and then allowed to settle for 2-3 hours. An aliquot of 75 ⁇ _ is transferred to Isoplates (Wallac), 150 ⁇ _ of scintillation fluid added and the plate sealed and shaken for 30 minutes. The cpm is determined using a Wallac Micobeta.
  • Compounds of invention are dissolved in 100% DMSO and diluted such that the final DMSO concentration in the assay does not exceed 1% to avoid affecting the PDE4 activity.
  • PDE4 enzyme is added in quantities such that less than 15% of substrate is consumed (linear assay conditions).
  • Test compounds are assayed at 6-8 concentrations ranging from 0.1 nM to 30 ⁇ and IC 50 values are determined from the concentration curves by nonlinear regression analysis (GraphPad Prism® 4).
  • the PDE7 assay is based on a modified procedure if the phosphodiesterase [ 3 H]cAMP SPA Enzyme Assay (Amersham Biosciences code TRKQ 7090).
  • PDE7 enzyme(s) convert [ 3 H]cAMP to [ 3 H]5'-AMP.
  • the assay is quenched by the addition of ice-cold SPA yttrium silicate beads which preferentially binds linear nucleides, eg 5'- AMPover cycling nucleotides in the presence of zinc sulphate.
  • the amount of [ 3 ⁇ ]5'- AMP formed is proportional to the activity of the PDE7, and hence inhibitors of the enzyme would decrease the amount of [ 3 H]5'-AMP formed.
  • Reactions are performed in duplicate by the addition of 15 pL of PDE7 (Baculovirus lysate) to 10 pL of assay mix and 25 pL test compounds in 96-well flat-bottom plate for 60 min at ambient temperature.
  • the Assay mixture contains 50 itiM Tris (pH 7.5), 8.3 mM MgCI 2 , 1.7 mM EGTA and [ 3 H]cAMP (0.025 pCi) (Amersham).
  • the assay is terminated by addition 25 pL SPA beads.
  • the plate is sealed, shaken for 1 minute and then allowed to settle for 20 to 45 minutes and the cpm is determined using a Packard Topcount Scintillation counter.
  • Compounds of the invention may inhibit PDE7, as demonstrated by the above assay.
  • PBMC Peripheral blood mononuclear cells
  • FBS Fetal bovine serum
  • the PBMC cells in 384 well microtiter plate (100 000 cells/ well) were induced with 2 mg/mL lipopolysaccharide (LPS) giving a final concentration of 10 pg/mL.
  • LPS lipopolysaccharide
  • the cells were incubated with substance for 18 h at 37 °C and 5% C0 2 in a humidified chamber.
  • TNF-a was detected according to Cisbio ' s TNF-a HTRF assay (Cisbio, ref no 62TNFPEB). The cell assay was incubated with 5 pL of each HTRF reagent during 3 h. The amount of TNF-a was detected on a Tecan Saphire 2.
  • Chemicals employed in the synthesis of the compounds in the examples may be commercially available from, e.g. Sigma-Aldrich Fine Chemicals or Acros or Int. Alfa Aesar, Menai Organics, Chembrige and Matrix Scientific.

Abstract

L'invention concerne des composés de formule (I) dans lesquels les lignes pointillées, R1, R2, R3, R4, R6, R7, m et n ont des significations données dans la description, et des dérivés pharmaceutiquement acceptables de ces composés, les composés étant utiles comme inhibiteurs de la PDE7 et, en particulier, de la PDE4, et par conséquent utiles, par exemple, dans le traitement de maladies et de troubles associés à l'inflammation.
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* Cited by examiner, † Cited by third party
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WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf
WO2024038089A1 (fr) 2022-08-18 2024-02-22 Mitodicure Gmbh Utilisation d'un agent thérapeutique ayant une activité inhibitrice de phosphodiestérase-7 pour le traitement et la prévention de maladies associées à la fatigue, à l'épuisement et/ou à l'intolérance à l'effort chroniques

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