WO2008129276A1 - Disulfonamides utiles dans le traitement de l'inflammation - Google Patents

Disulfonamides utiles dans le traitement de l'inflammation Download PDF

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WO2008129276A1
WO2008129276A1 PCT/GB2008/001380 GB2008001380W WO2008129276A1 WO 2008129276 A1 WO2008129276 A1 WO 2008129276A1 GB 2008001380 W GB2008001380 W GB 2008001380W WO 2008129276 A1 WO2008129276 A1 WO 2008129276A1
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compound
formula
ring
compounds
independently represent
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PCT/GB2008/001380
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Benjamin Pelcman
Kristofer Olofsson
Edgars Suna
Ivars Kalvins
Vita Ozola
Viktor Andrianov
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Boehringer Ingelheim International Gmbh
Biolipox Ab
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Publication of WO2008129276A1 publication Critical patent/WO2008129276A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of enzymes belonging to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
  • MAPEG membrane-associated proteins in the eicosanoid and glutathione metabolism
  • Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1 ), 5-lipoxygenase-activating protein (FLAP), leukotriene C 4 synthase and microsomal glutathione S-transferases (MGST1 , MGST2 and MGST3).
  • the compounds are of potential utility in the treatment of inflammatory diseases including respiratory 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.
  • Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
  • Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.
  • Asthma is a disease of the airways that contains elements of both inflammation and bronchoconsthction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists which affect the bronchoconsthction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
  • COPD chronic obstructive pulmonary disease
  • COX cyclooxygenase
  • COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 (PGH 2 ).
  • PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 20 , PGD 2 , prostacyclin and thromboxane A 2 .
  • PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2
  • PGF 20 metabolizes arachidonic acid to the unstable intermediate prostaglandin H 2
  • PGD 2 oxidized to the oxide
  • prostacyclin and thromboxane A 2 metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
  • PGE 2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE 2 .
  • NSAIDs non-steroidal antiinflammatory drugs
  • coxibs selective COX-2 inhibitors
  • the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH 2 , some of which are known to have beneficial properties.
  • drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects.
  • the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
  • Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
  • An alternative treatment of inflammatory diseases that does not give rise to the above-mentioned side effects would thus be of real benefit in the clinic.
  • a drug that inhibits (preferably selectively) the transformation of PGH 2 to the pr ⁇ -inflammatory mediator PGE 2 might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites. Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.
  • PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E synthase
  • the leukotrienes are formed from arachidonic acid by a set of enzymes distinct from those in the COX / PGES pathway.
  • Leukotriene B 4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing ieukotrienes C 4 , D 4 and E 4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma.
  • the biological activities of the CysLTs are mediated through two receptors designated CySLT 1 and CysLT 2 .
  • leukotriene receptor antagonists LTRas
  • These drugs may be given orally, but do not control inflammation satisfactorily.
  • the presently used LTRas are highly selective for CySLT 1 . 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. Among these proteins, 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and leukotriene C 4 synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB 4 .
  • mPGES-1 , FLAP and leukotriene C 4 synthase belong to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
  • Other members of this family include the microsomal glutathione S- transferases (MGST1 , MGST2 and MGST3).
  • MGST1 , MGST2 and MGST3 microsomal glutathione S- transferases
  • compounds prepared as antagonists to one of the MAPEGs may also exhibit inhibitory activity towards other family members, c.f. J. H Hutchinson et al in J. Med. Chem. 38, 4538 (1995) and D.
  • agents that are capable of inhibiting the action of mPGES-1 and thus reducing the formation of the specific arachidonic acid metabolite PGE 2 , are likely to be of benefit in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.
  • all of these documents disclose compounds in which the requisite bicyclic ring system is substituted, for example via a linker group, with an aromatic or bicyclic group.
  • Q x and Q y independently represent a direct bond or C 1-6 alkylene optionally substituted by one or more substituents selected from Z 1 ;
  • T 1 or T 2 represents H, and the other represents H or R 3a ;
  • the A ring may represent:
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 independently represent, at each occurrence when used herein, hydrogen or a substituent selected from Z 2 ;
  • Z 1 and Z 2 independently represent, on each occasion when used herein, halo, -R 3a , -CN, -C(O)R 3b , -C(O)OR 3c , -C(O)N(R 4a )R 5a , -N(R 4b )R 5b , -N(R ⁇ )C(O)R 40 , -N(R 3e )C(O)N(R 4d )R 5d , -N(R 3 ⁇ C(O)OR 46 , -N 3 , -NO 2 , -N(R 3g )S(O) 2 N(R 4f )R 5f , -OR 3h , -OC(O)N(R 49 )R 5g , -OS(O) 2 R 3 ', -S(0) m R 3j , -N(R 3k )S(O) 2 R 3m , -OC(O)R 3n
  • n O, 1 or 2;
  • X a and X c independently represent, at each occurrence when used herein, hydrogen or R 3a ;
  • X b and X d independently represent, at each occurrence when used herein, hydrogen, -R 3a , -C(0)R 3b , -C(O)OR 3c or -C(O)N(R 4a )R 5a ;
  • R 3c , R 31 , R 3j , R 3m and R 3p independently represent R 3a ;
  • G 1 and G 2 independently represent -CH 3 , -CF 3 or -N(R 14a )R 15a ;
  • R 8a and R 11a independently represent H, -CH 3 , -CH 2 CH 3 , -CF 3 or -CHF 2 ;
  • R 9a , R 1Oa , R 12a , R 13a , R 14a and R 15a independently represent H, -CH 3 or -CH 2 CH 3 ,
  • 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 chromatographic (e.g. 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.
  • C ⁇ alkyl (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 three) of carbon atoms be branched-chain, and/or cyclic (so forming a C 3-q cycloalkyl group).
  • groups 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, a C 2-q alkenyl or a C 2-q alkynyl group).
  • Cycloalkyl groups may be monocyclic or bicyclic non-aromatic alkyl groups, which may be bridged (so forming, for example, fused ring systems). Cycloalkyl groups may also include spiro-cyclic groups. Cycloalkyl groups may be saturated or unsaturated, e.g. containing one or more double bond (forming for example a C 3 ⁇ , cycloalkenyl). Optional substituents may be attached at any point on the cycloalkyl group. Cycloalkyl groups that may be mentioned include C 3 .
  • cycloalkyl groups for instance a 3- to 7-membered monocyclic cycloalkyl group or a C 8 - H bicyclic cycloalkyl group.
  • the term 'acyclic' alkyl group when used herein refers to an alkyl group that is not cyclic, but may be part cyclic, branched-chain or, is preferably, straight-chain.
  • bicyclic when employed in the context of cycloalkyl, refers to such groups in which the second ring is formed between two adjacent atoms of the first ring (i.e. systems of two rings share one bond formed with two adjacent carbon atoms).
  • bridged when employed in the context of cycloalkyl groups refers to cycloalkyl groups in which two non-adjacent atoms are linked by an alkylene chain.
  • spiro-cyclic group refers to a cycloalkyl group that is substituted with a further cycloalkyl group via a single carbon atom.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Aryl groups that may be mentioned include C 6-14 (e.g. C 6 - I o) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic.
  • C 6 - M aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl.
  • aryl groups may be via any atom of the ring system, for instance when aryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring.
  • Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. between 5 and 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-b]pyridyl, oxazolo[5,4-/b]pyridyl, oxazolo[4,5- c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5- bjpyridyl, thiazoio[5,4- ⁇ fc>]pyridyl, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl) and, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl,
  • 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 heteroaryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl 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). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q heterocycloaikynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7-azabicycio- [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-dihydropyrro!yl), dioxolanyl (including 1 ,3- dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyi (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicycl
  • Substituents on 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.
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulfur.
  • R 1 represents phenyl substituted by -R 3a and -OR 3h , in which R 3h represents R 3a , and, in each case R 3a represents Ci -6 alkyl, the identities of the two R 3a groups are not to be regarded as being interdependent.
  • Q x and Q y independently represent a direct bond
  • R 1 and R 2 independently represent aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from Z 1 ;
  • R 46 represents R 3a ;
  • Preferred compounds of the invention include those in which: when any of the pairs R 43 and R 5a , R 4b and R 5b , R 4 " and R 5d , R 4f and R 5f , R 4g and R 59 or R 4h and R 5h are linked together, they form a 5- or 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) and is optionally substituted by one or more (e.g.
  • T 1 and T 2 represents H and the other either represents C 1-3 alkyl (e.g.
  • X 1 and X 2 represent Z 2 and the other represents hydrogen; or both X 1 and X 2 represent H, for example when at least one of Y 1 or Y 4 (when the
  • a ring is ring Ia) or at least one of Y 5 or Y 7 (when the A ring is ring Ib) represents -N(H)-;
  • X c and X d preferably represent H, and X 6 preferably represents H or
  • R 1 and R 2 are each, independently, substituted with less than three (e.g. one or two) substituent(s) selected from Z 1 ;
  • Z 1 substituents on R 1 and R 2 groups are preferably in the positions ⁇ - or ⁇ - relative to the point of attachment of the R 1 and/or R 2 group to the rest of the compound of formula I (e.g. when R 1 and/or R 2 represent phenyl, then the optional substituents are preferably in the ortho- and/or the mefa-position);
  • halo e.g. chloro, fluoro
  • R 4a , R 5a , R 4b and R 5b independently represent H, methyl or ethyl;
  • R 3h represents H or R 3a ;
  • R 40 represents R 3a ; when R 3d represents R 3a , then R 3a preferably represents C 1-2 alkyl (e.g. methyl); when R 3h represents R 3a , then R 3a preferably represents C 1-6 alkyl as hereinbefore defined or, more preferably, C 1-3 (e.g. C 1-2 ) alkyl optionally substituted by one or more fluoro atoms (e.g.
  • R 3h may represent cyclopentyl, cyclopropyl, preferably ethyl, difluoromethyl or, more preferably, methyl or trifluoromethyl); when R 40 represents R 3a , then R 3a preferably represents C 1-6 alkyl as hereinbefore defined and, preferably, unsubstituted C 1-6 alkyl such as cyclohexyl, cyclopropyl, terf-butyl, isopropyl, ethyl or, more preferably, methyl); R 6a , R 6b and R 7b independently represent H or C 1-6 alkyl optionally substituted by one or more fluoro atoms.
  • Preferred aryl and heteroaryl groups that R 1 and R 2 may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. thien-2-yl or thien-3-yl), pyrazolyl, imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
  • Preferred groups include optionally substituted pyridyl (e.g. 2- or 4-pyridyl), pyrazinyl (e.g. 2-pyrazinyl), furanyl, thienyl, oxazolyl, thiazolyl and, more preferably, optionally substituted phenyl.
  • Preferred essential bicyciic ring systems of the compounds of the invention include: when the A ring represents ring Ia, optionally substituted quinoxaline (e.g. 3-oxo-
  • 3,4-dihydroquinoxaline or, more particularly, optionally substituted quinoline or 1 ,2,3,4-tetrahydroquinoline (e.g. in which the requisite nitrogen atom of the quinoline or tetrahydroquinoline is present at the Y 4 or, preferably, Y 1 position), optionally substituted isoquinoline or 1 ,2,3,4-tetrahydroisoquinoline (e.g.
  • 2,3- dihydrobenzimidazole such as 2-oxo-2,3-dihydrobenzimidazole, or, more particularly, benzimidazole) or, more particularly, benzoxazole (in which the requisite nitrogen atoms of the latter three groups are preferably present in the Y 7 or, more particularly, the Y 5 position).
  • preferred A rings include optionally substituted pyridine, piperidine, cyclohexyl, oxazole, imidazole, 2,3-dihydroimidazol-2-one and 1 ,3- dihydroimidazol-2-one.
  • R 1 , R 2 or the essential bicycles of compounds of the invention include:
  • Ci- 6 alkyl which alkyl group may be cyclic (e.g. C 1-6 alkyl such as cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. allyl), linear or branched
  • Ci- 4 alkyl such as ethyl, n-propyl, isopropyl, n-butyl, f-butyl or, preferably, methyl
  • halo e.g. fluoro
  • R 16 to R 18 e.g.
  • R 16 and R 18 independently represent, on each occasion when mentioned above, H or R 19 ; and each R 19 independently represents (and R 17 preferably represents) Ci -6 alkyl, such as C 1-4 alkyl (e.g. ethyl, n-propyl, n- butyl, f-butyl or, preferably, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group).
  • halo e.g. fluoro
  • Preferred compounds of the invention include those in which:
  • R 1 and R 2 independently represent phenyl optionally substituted by one or two substituents selected from Z 1 ; when R 1 or R 2 represent optionally substituted C 3-12 cycloalkyl, then such a group preferably represents C 3-8 cycloalkyl (e.g.
  • R 1 or R 2 represent optionally substituted heteroaryl, then they preferably represent a 5- or 6-membered heteroaryl group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, oxygen and particularly, nitrogen (so forming for example a pyridyl group); when R 1 or R 2 represent optionally substituted heterocycloalkyl, then they preferably represent a 5- or 6-membered heterocycloalkyl group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, particularly, oxygen and more particularly, nitrogen (so forming for example a pyrrolidinyl group);
  • R 1 and R 2 are the same;
  • Z 1 represents halo (e.g. chloro or fluoro) or R 3a ;
  • X 1 represents H or, more preferably, Z 2 ; when the A ring represents ring Ia, then when Y 1 or Y 4 represents -N(H)-, then X 1 represents Z 2 or, more preferably, H; when the A ring represents ring Ib, then when Y 5 or Y 7 represents -N(H)-, then X 1 represents Z 2 or, more preferably, H; when X 1 represents Z 2 , then Z 2 is preferably -OR 3h , -N(R 4b )R 5b or
  • R 4c represents R 3a ;
  • X 2 represents Z 2 or, more preferably, H; when X 2 represents Z 2 , then Z 2 is preferably halo (e.g. fluoro or chloro), R 3a (e.g.
  • X 3 represents H or Z 2 (and most preferably Y 2 and Y 4 independently represent
  • X 4 represents Z 2 or, preferably, H
  • X a represents Z 2 or, preferably, H; one of X 4 and X a represents H and the other represents Z 2 or, preferably, H; when X 4 or X a represent Z 2 , then Z 2 represents halo (e.g. chloro), -N(R 4b )R 5b ,
  • R 3a in which R 3a preferably represents d- 3 (e.g. Ci -2 ) alkyl (e.g. methyl)); only one of X 4 or X a is present that represents a substituent selected from Z 2 ;
  • X b represents H;
  • R 3h represents H
  • R 3d , R 4b and R 5b independently represent C 1-3 (e.g. Ci -2 ) alkyl (e.g. methyl) or, preferably, H; when the A ring represents ring Ib, then neither of the dotted lines represent double bonds or, more preferably, one of the dotted lines (e.g. the one between
  • X 5 represents H or, more preferably, Z 2 ; only one X 5 is present that represents a substituent selected from Z 2 ; when X 5 represents Z 2 , then Z 2 represents -OR 3h (e.g. -OH) or, more preferably,
  • R 3a represents C 1-6 (e.g. C 1-4 or, preferably, C 1-2 ) alkyl (e.g. butyl, such as tert- butyl, or, preferably, cyclohexyl or methyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifiuoromethyl group);
  • C 1-6 e.g. C 1-4 or, preferably, C 1-2
  • alkyl e.g. butyl, such as tert- butyl, or, preferably, cyclohexyl or methyl
  • halo e.g. fluoro
  • X c and X 6 independently represent H
  • X d represents H or C 1-4 (e.g. C 1-2 ) alkyl (e.g. methyl).
  • Further preferred compounds of the invention include those in which: when the A ring represents ring Ia, and both dotted lines represent single bonds, then preferably: all of Y 1 to Y 4 independently represent -C(X 4 )(X a )-, or any one of Y 1 to Y 4 (e.g. Y 1 or Y 3 ) represents -N(X b )- and the others independently represent -C(X 4 )(X a )-; when the A ring represents ring Ia, and both dotted lines represent double bonds, then preferably: one of Y 1 and Y 4 (e.g.
  • R 1 and R 2 groups include 4,4-dimethylcyclohexyl and, preferably, 2- methyl-3-chlorophenyl and 2-methyl-3-fluorophenyl.
  • Preferred substituents on R 1 and R 2 groups include C 1-3 (e.g. Ci -2 ) alkyl (e.g. methyl) and halo (e.g. chloro and fluoro).
  • Preferred substituents that X 1 and X 2 may represent include -OH, -NH 2 and -N(H)C(O)CH 3 .
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • L 1a and L 1b independently represent a suitable leaving group such as chloro, bromo, fluoro or -0-C 1-3 alkyl optionally substituted by one or more fluoro atoms (so forming for e.g. methoxy or trifluoromethoxy), and the A ring, X 1 and X 2 are as hereinbefore defined, with a compound of formula III or, with two different compounds of formula III,
  • R x represents R 1 and/or R 2 (as appropriate)
  • Q xy represents Q x and/or Q y (as appropriate)
  • T x represents T 1 and/or T 2 (as appropriate)
  • R 1 , R 2 , T 1 and T 2 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 40-180 0 C), optionally in the presence of a suitable base (e.g.
  • a ring, X 1 , X 2 , R 1 , R 2 , T 1 , T 2 , Q x , Q y , L 1a and L 1b are as hereinbefore defined, with a compound of formula III as hereinbefore defined, in which R x represents R 1 , Q xy represents Q x and T represents T 1 (for reaction with compounds of formula IV) or R x represents R 2 , Q xy represents Q y and T represents T 2 (for reaction with compounds of formula V) under standard reaction conditions, such as those described hereinbefore in respect of process step (i);
  • L 2 represents a suitable leaving group, such as chloro, bromo or iodo and Z x represents halo, -R 3a , -C(O)R 3b , -C(O)OR 3c , -C(O)N(R 4a )R 5a , -S(O) m R 3j or -S(O) 2 N(R 4h )R 5h , and R 3b , R 4a , R 5a , R 4h and R 5h are as hereinbefore defined, provided that they do not represent hydrogen, and R 3a , R 3c and R 3j are as hereinbefore defined, under standard reaction conditions.
  • a metal may be synthesised under standard conditions by metallation (e.g. lithiation) of a corresponding compound of formula I in which X 3 and/or X 4 (as appropriate) represents H, in the presence of a suitable organometallic reagent (such as an organolithuium base (e.g. n-BuLi, s- BuLi or NBuLi)) in the presence of a suitable solvent (e.g. a polar aprotic solvent such as THF or diethyl ether), at a suitable temperature (e.g. between -78°C and 0°C).
  • a suitable organometallic reagent such as an organolithuium base (e.g. n-BuLi, s- BuLi or NBuLi)
  • a suitable solvent e.g. a polar aprotic solvent such as THF or diethyl ether
  • a suitable temperature e.g. between -78°C and 0
  • a magnesium-containing group may be synthesised under standard Grignard conditions (e.g. employing magnesium or a suitable reagent such as a mixture of C 1-6 alkyl-Mg-halide and ZnCI 2 or LiCI), followed by reaction with a compound of formula I in which X 3 and/or X 4 represents halo (e.g. bromo), optionally in the presence of a catalyst (e.g. FeCI 3 ).
  • a catalyst e.g. FeCI 3
  • the magnesium of the magnesium- containing reagent e.g. Grignard reagent
  • the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to zinc (e.g. using ZnCI 2 ) and the intermediate so formed may then be subjected to reaction with a compound of formula Vl, for example under reaction conditions described above;
  • L 3 represents a suitable leaving group, such as chloro, bromo, iodo or a triflate (e.g. -OS(O) 2 CF 3 ) and R 3a is as hereinbefore defined, under standard conditions known to those skilled in the art, for example in the presence of a suitable base, such as one described hereinbefore in respect of process step (i).
  • a suitable base such as one described hereinbefore in respect of process step (i).
  • the relevant group e.g. -N(R 4d )R 5d
  • reaction with an anion of a compound of formula I 1 e.g.
  • a reagent that is a source of another appropriate nucleophile e.g. a source of anions such as cyano, oxy or S ' anions
  • a compound of formula VIII for the introduction of the other Z 1 and/or Z 2 substituents mentioned above
  • Z y represents -CN, -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , -N(R 3e )C(O)N(R 4d )R 5d , -N(R 3 ⁇ C(O)OR 46 , -N(R 39 )S(O) 2 N(R 4f )R 5f , -OR 3h , -SR 3j or -N(R 3k )S(O) 2 R 3m , and R 3d , R 3e , R 3f , R 39 , R 3h , R 3j , R 3k , R 3m , R 4b , R 4c , R M , R 46 , R 4f , R 5b , R 5d and R 5f are as hereinbefore defined, or a suitable derivative (e.g.
  • the reaction may be performed in the presence of a suitable catalyst, for example a metal catalyst containing, preferably, Pd or Cu, and a base and, optionally in the presence of solvent and a ligand.
  • a suitable catalyst for example a metal catalyst containing, preferably, Pd or Cu, and a base and, optionally in the presence of solvent and a ligand.
  • Catalysts that may be mentioned include Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium(O)), bases that may be mentioned include cesium carbonate, ligands that may be mentioned include 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl and solvents that may be employed include toluene.
  • Such reactions may be performed at elevated temperature (e.g. at about 90 0 C) under an inert (e.g. argon) atmosphere.
  • reaction may be performed in the presence of CsOH (e.g.
  • T and L 3 are as hereinbefore defined, under standard reaction conditions, for example at around room temperature or above (e.g. up to 40- 18O 0 C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropyl-ethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, ⁇ /-ethyl-diisopropylamine, ⁇ /-(methylpolystyrene)-4- (methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or
  • (x) compounds of formula I in which Z 1 or Z 2 is present and represents -OR 3h in which R 3h represents H may be prepared by deprotection of a corresponding compound of formula I in which the -OH group is protected.
  • protected derivatives may already be compounds of formula I.
  • protected derivatives include corresponding compounds of formula I in which R 3h represents methyl (in this case deprotection may be effected by employing: a suitable reagent such as BBr 3 ; a compound that is a source of anions of an aryl or alkyl sulfide, e.g.
  • sodium salts of thiophenol or dodecanthiol; or a suitable strong acid such as chlorosulfonic acid, HBr (in water or AcOH) and HI), or such protected derivatives may also include compounds in which the -OH group is protected with a benzyl group (in which case deprotection may be effected by hydrogenation under standard conditions, e.g. employing Pd/C);
  • compounds of formula I in which Z 1 or Z 2 is present and represents -NH 2 may be prepared by reduction of compounds corresponding to compounds of formula I but in which the relevant Z 1 or Z 2 group represents -NO 2 , for example under hydrogenation conditions in the presence of a catalyst (e.g. palladium on carbon), with a source of hydrogen (e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)), optionally in the presence of a solvent (such as an alcoholic solvent (e.g. methanol));
  • a catalyst e.g. palladium on carbon
  • a source of hydrogen e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)
  • a solvent such as an alcoholic solvent (e.g. methanol)
  • X 1 , X 2 , X d , T 1 , T 2 , Q x , Q y , R 1 and R 2 are as hereinbefore defined, with (for compounds of formula I in which X 5 represents hydrogen), paraformaldehyde or, preferably, CH(OEt) 3 , or the like, for example in the presence of a suitable Lewis acid, such as BF 3 * OEt 2 , or with (for compounds of formula I in which X 5 represents a Z 2 substituent, such as R 3a ), a compound of formula VIIIC,
  • L 4 represents a suitable leaving group, such bromo, chloro or -OH (or an ester thereof, e.g. a C 1-6 alkyl ester, which alkyl moiety is optionally substituted with one or more halo groups, or an activated derivative of -OH, which group may be activated using a suitable coupling agent such as 1 ,1 '-carbonyldiimidazole, ⁇ /./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (or hydrochloride thereof), or the like) and X 5 is as hereinbefore defined, for example a R 3a substituent, which reaction may be performed under standard conditions;
  • one of Q a and Q b represents -N(X d )H, and the other represents -N(H)-C(O)X 5 (when X d represents hydrogen or a substituent as hereinbefore defined, e.g. R 3a ), or -0-C(O)X 5 or -S-C(O)X 5 (when X d represents hydrogen only), and X 5 , X 1 , X 2 , X d , T 1 , T 2 , Q x , Q y , R 1 and R 2 are as hereinbefore defined, under standard conditions known to those skilled in the art, for example in the presence of a suitable acid (e.g. a strong acid such as HCI) and a suitable solvent (e.g. acetic acid); or
  • a suitable acid e.g. a strong acid such as HCI
  • a suitable solvent e.g. acetic acid
  • a ring, X 1 and X 2 are as hereinbefore defined, with a suitable reagent for the introduction of the sulfonyl halide group (e.g. halosulfonic acid), under conditions known to those skilled in the art (e.g. employing an excess of the halosulfonic acid).
  • a suitable reagent for the introduction of the sulfonyl halide group e.g. halosulfonic acid
  • a salt thereof e.g. a metal salt such as magnesium, sodium or, preferably, lithium
  • a suitable halogenating reagent such as PCI 5 , PCI 3 or SOCI 2 (as chlorinating reagents) or a reagent such as ⁇ /-chlorosuccinimde (e.g. in the case where a lithium salt of the sulfonic acid of formula Xl is to be converted, for example under oxidative chlorination conditions) or CuCI (e.g.
  • compounds of formulae II, IV and V in which L 1a and/or L 1b (as appropriate) represents as chloro may be prepared by reaction of a corresponding compound of: (a) formula IXA,
  • J 1 represents -N 2 + (i.e. a diazonium ion) or -S-Si(R ⁇ ) 3 , in which each R 22 independently represents C 1-6 alkyl (e.g. isopropyl; so forming for example a -S-Si(isopropyl) 3 group), and the A ring, X 1 , X 2 , R 1 , R 2 , Q x , Q y , T 1 and T 2 are as hereinbefore defined, under conditions known to those skilled in the art.
  • J 1 represents a diazonium ion
  • reaction with SO 2 or a compound that is a source of SO 2
  • a suitable reagent containing the appropriate chloride ions e.g. CuCI
  • a suitable solvent such as acetic acid
  • J 1 represents -S-Si(R ⁇ ) 3
  • reaction with Cl 2 in acetic acid preferably in the presence of a suitable solvent such as dichloromethane.
  • Compounds of formula IV and V may alternatively be prepared by reaction of a compound of formula Il with less than 2 equivalents of a compound of formula III in which R x represents R 1 or R 2 (as appropriate) and T represents T 1 or T 2 (as appropriate), under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above).
  • Such conditions include reaction in the presence of a reagent such as P 2 O 5 or an acid (such as concentrated acetic acid or a sulfonic acid such as para-toluenesulfonic acid monohydrate) at room or, preferably, elevated temperature (e.g. at reflux).
  • a reagent such as P 2 O 5 or an acid (such as concentrated acetic acid or a sulfonic acid such as para-toluenesulfonic acid monohydrate) at room or, preferably, elevated temperature (e.g. at reflux).
  • Compounds of formula IX may be prepared by reaction of the corresponding compound of formula VIIIB with a suitable reagent for the introduction of the sulfonic acid group.
  • suitable reagents include sulfuric acid at an appropriate concentration (e.g. concentrated, fuming or H 2 SO 4 * H 2 O), SO 3 and/or a halosulfonic acid, under conditions known to those skilled 1 in the art.
  • a ring, X 1 , X 2 , R 1 , R 2 , T 1 and T 2 are as hereinbefore defined, under standard oxidation conditions, for example employing HNO 3 (e.g. boiling nitric acid) or m-chloroperbenzoic acid in, where necessary, an appropriate solvent system (e.g. dichloromethane).
  • HNO 3 e.g. boiling nitric acid
  • m-chloroperbenzoic acid e.g. dichloromethane
  • compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIA
  • a ring, X 1 , X 2 , R 1 , R 2 , T 1 and T 2 are as hereinbefore defined, by conversion of the relevant bromo group(s) of the compounds of formulae XIIA, XIIIA or XIVA to a Grignard reagent (e.g. -Mg-Br) or, preferably, a metal (such as lithium), followed by quench with SO 2 (or a compound that is a source of SO 2 ).
  • a Grignard reagent e.g. -Mg-Br
  • a metal such as lithium
  • the conversion step may be performed under conditions such as those described hereinbefore in respect of preparation of compounds of formula 1 (process step (iii) above), for example conversion of the bromo group(s) to (a) lithium group(s) may be effected under halogen-lithium exchange reaction conditions in the presence of an organolithium base (e.g. t- or ⁇ -BuLi) in a polar aprotic solvent (e.g. THF or diethyl ether) at low temperature (e.g. -78°C).
  • organolithium base e.g. t- or ⁇ -BuLi
  • a polar aprotic solvent e.g. THF or diethyl ether
  • compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIB
  • a ring, X 1 , X 2 , R 1 , R 2 , T 1 and T 2 are as hereinbefore defined, by conversion of the amino group to a diazonium salt (employing reagents and conditions known to those skilled in the art, e.g. NaNO 2 and HCI at 5 0 C), followed by quenching by addition of with SO 2 (or a compound that is a source of SO 2 ).
  • a diazonium salt employing reagents and conditions known to those skilled in the art, e.g. NaNO 2 and HCI at 5 0 C
  • SO 2 or a compound that is a source of SO 2
  • Compounds of formula IXA, XA and XIA in which J 1 represents a diazonium ion may be prepared from compounds corresponding to compounds of formula IXA, XA and XIA but in which the diazonium group is replaced with a nitro group, which reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (xi) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl).
  • reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (xi) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl).
  • R 22 is as hereinbefore defined, in the presence of an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 ,
  • 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 , trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]- dipalladium, or the like) optionally in the presence of a suitable additive (e.g.
  • Ph 3 P 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, NaI, an appropriate crown ether or, preferably, tri-terf-butyl-phosphonium tetrafluoroborate), optionally in the presence of a base (such as NaH, Et 3 N 1 pyridine, ⁇ /. ⁇ / 1 - dimethylethylenediamine, Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , f-BuONa or NBuOK) and suitable solvent (e.g.
  • a base such as NaH, Et 3 N 1 pyridine, ⁇ /. ⁇ / 1 - dimethylethylenediamine, Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , f-BuONa or NBuOK
  • suitable solvent e.g.
  • dichloromethane dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsuifoxide, acetonitrile, dimethylacetamide, ⁇ /-methylpyrrolidinone, tetrahydrofuran or a mixture thereof).
  • a ring is as hereinbefore defined, and X 1 and X 2 are as hereinbefore defined and, more preferably, H or R 3a , with a suitable reagent for the conversion of a carbonyl to a thiocarbonyl group (e.g. P 2 S 5 or Lawesson's reagent), under conditions known to those skilled in the art.
  • a suitable reagent for the conversion of a carbonyl to a thiocarbonyl group e.g. P 2 S 5 or Lawesson's reagent
  • L x represents a suitable leaving group (such as halo (e.g. bromo)) and the A ring, X 1 , X 2 , R 1 and T 1 are as hereinbefore defined, with a reagent that is a source of SH anions (e.g. NaSH), under standard conditions, for example such as those described hereinbefore in respect of preparation of compounds of formula I
  • bicyclic ring of formula I when the requisite bicyclic ring of formula I is heterocyclic, it may also 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 If 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) and/or made according to the following general procedures.
  • 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 If by A. R. Katr
  • the sulfonamide groups of compounds of formulae XIIIA and XIVA may be prepared from the corresponding sulfonyl chloride or sulfonic acid, and compounds of formulae XVII and XVIII may ultimately be prepared from the corresponding 1-nitro-3-amino compounds using the diazotisation reaction, followed by the SO 2 quench, oxidative chlorination and then coupling with an arylamine, all of which reactions are described herein.
  • compounds of the invention in which the -N(T 1 )-R 1 and -N(T 2 )-R 2 groups are different may be obtained.
  • a hydroxy substituent e.g.
  • a halo substituent may be replaced with a halo substituent by reaction in the presence of an appropriate reagent (e.g. POCI 3 for the introduction of a chloro group).
  • an appropriate reagent e.g. POCI 3 for the introduction of a chloro group.
  • a nitro substituent may be introduced onto an aromatic ring under standard aromatic nitration reaction conditions, for example, in the presence of a strong acid (e.g. H 2 SO 4 ) and HNO 3 .
  • an amino group (such a phenyl amino group), for example when attached to an aromatic ring (especially an aromatic ring containing electron withdrawing groups such as nitro and sulfonamido in the ortho and/or para-position), may be replaced with a hydroxy group or another suitable nucleophile (such as one mentioned hereinbefore in respect of process step (vii) above), for example, in the case of the introduction of a hydroxy group, by reaction in the presence of a suitable reagent (e.g. dioxane in aqueous NaOH).
  • a suitable reagent e.g. dioxane in aqueous NaOH.
  • Other transformations that may be mentioned include the conversion of a nitro group to an amino group (for example under reaction conditions described herein; e.g. for preparation of compounds of formula I) and the conversion of an amino group to a diazonium ion (for example under conditions described herein; e.g. for preparation of compounds of formula IX, X or X
  • the substituents X 1 , X 2 , T 1 , T 2 and optional substituents on R 1 and R 2 and, if present, X 3 , X 4 , X 5 , X 6 , X a , X b , X c and X d in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations.
  • 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. In this respect, the skilled person may also refer to "Comprehensive
  • transformations include the conversion of a hydroxy group to a halo (e.g. chloro) group (e.g. employing SOCI 2 ), one halo group to another halo group, or of a halo group (preferably iodo or bromo) to a cyano or 1- alkynyl group (e.g. by reaction with a compound which is a source of cyano anions (e.g. sodium, potassium, copper (I) or zinc cyanide) or with a 1-alkyne, as appropriate).
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g.
  • a W-(Ci -6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine.
  • amino groups and hydroxy groups may be introduced in accordance with standard conditions using reagents known to those skilled in the art.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • 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. Specific examples of protecting groups that may be employed include a methyl protecting group for a hydroxy group (so forming a methoxy group), which groups may be deprotected under standard conditions, for example employing a suitable reagent such as BBr 3 .
  • 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.
  • 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 of the invention that possess pharmacological activity as such.
  • 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 are particularly useful because they may inhibit the activity of a member of the MAPEG family.
  • Compounds of the invention are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1 )), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below.
  • Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
  • Compounds of the invention are thus expected to be useful in the treatment of inflammation.
  • 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.
  • a condition has an inflammatory component associated with it, or a condition characterised by inflammation as a symptom, the skilled person will appreciate that compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition.
  • compounds of the invention may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g.
  • hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
  • Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of the invention may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC 4 synthase and/or FLAP and/or a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1 ), LTC 4 synthase and/or FLAP is desired and/or required (e.g. 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.
  • a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC 4 synthase and/or FLAP
  • a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1
  • 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.
  • 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 inflammation (e.g. NSAIDs, coxibs and glucocorticoids).
  • 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 inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and (2) a kit of parts comprising components:
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of 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, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • 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.
  • Compounds of the invention may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E - synthase-1 (mPGES-1).
  • PGES prostaglandin E synthases
  • mPGES-1 microsomal prostaglandin E - synthase-1
  • the compounds of the invention may reduce the formation of the specific arachidonic acid metabolite PGE 2 without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
  • 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
  • mPGES-1 catalyses the reaction where the substrate PGH 2 is converted to PGE 2 .
  • mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 2OmM NaPi-buffer pH 8.0 and stored at -80 0 C.
  • mPGES-1 is dissolved in 0,1 M KPi-buffer pH 7,35 with 2,5mM glutathione.
  • the stop solution consists of H 2 O, containing FeCI 2 (25 mM) and HCI (0.15 M).
  • the assay is performed at room temperature in 384-well plates. Analysis of the amount of PGE 2 is performed with a commercially available PGE2 HTRF kit from CisBio or by reversed phase HPLC.
  • a 4 ⁇ l aliquot of this mixture is diluted 1 :750-fold in two steps before detection of PGE 2 with HTRF is performed.
  • the title compound was prepared from 8-hydroxyquinoline-5,7-disulfonyl dichloride in accordance with Example 1 , step (b).
  • the title compound was prepared from isoquinolin-5-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-fluoro-2-methyl- aniline in accordance with Example 1 , step (b).
  • the title compound was prepared from isoquinolin-5-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 2-methylaniline in accordance with Example 1 , step (b).
  • the title compound was prepared from ⁇ / 6 , ⁇ / e -bis(3-fluoro-2-methylphenyl)-5- hydroxyisoquinoline-6,8-disulfonamide (see Example 9) in accordance with Example 4.
  • the sub-title compound was prepared in 56% yield from ⁇ /-(5,6,7,8-tetrahydro- naphthalen-1-yl)acetamide (see step (a) above) and chlorosulfonic acid in accordance with Example 1 , step (a).
  • step (c) 4-Amino- ⁇ / 3 -bis(3-chloro-2-methylphenyl)-5.6J,8-tetrahvdronaphthalene- 1.3-disulfonamide
  • the sub-title compound was prepared in accordance with Example 14, step (c) from 4-hydroxy-2-methylbenzoxazole (see step (a) above) and chlorosulfonic acid.
  • the title compound was prepared by treating 2-chloro- ⁇ / 5 , ⁇ / 7 -bis(3-fiuoro-2- methylphenyl)-8-hydroxyquinoline-5,7-disulfonamide (see Example 19) with dimethylamine in EtOH.
  • the title compound was prepared by treating 2-chloro- ⁇ / 5 ,W 7 -bis(3-fluoro-2- methylphenyl)-8-hydroxyquinoline-5,7-disulfonamide (see Example 19) with CsOH in H 2 O.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention porte sur des composés de formule (I), dans laquelle le noyau A, X1, X2, R1, R2, Cx, Qy, T1 et T2 ont des significations données dans la description, et sur des sels pharmaceutiquement acceptables de celles-ci. Ces composés sont utiles dans le traitement de maladies dans lesquelles l'inhibition de l'activité d'un élément de la famille du MAPEG est souhaitée et/ou requise, et, en particulier, dans le traitement de l'inflammation.
PCT/GB2008/001380 2007-04-19 2008-04-21 Disulfonamides utiles dans le traitement de l'inflammation WO2008129276A1 (fr)

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WO2009082347A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Dérivés de bis-(sulfonylamino) destinés à être utilisés en thérapie
EP2217566A1 (fr) * 2007-11-15 2010-08-18 AstraZeneca AB Dérivés bis-(sulfonylamino) dans une thérapie 066
US8466186B2 (en) 2010-12-10 2013-06-18 Boehringer Ingelheim International Gmbh Compounds
US8486968B2 (en) 2010-12-10 2013-07-16 Boehringer Ingelheim International Gmbh Compounds
US8586604B2 (en) 2010-08-20 2013-11-19 Boehringer Ingelheim International Gmbh Inhibitors of the microsomal prostaglandin E2 synthase-1
US8598190B2 (en) 2008-09-25 2013-12-03 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8674113B2 (en) 2010-12-10 2014-03-18 Boehringer Ingelheim International Gmbh Compounds
US8759537B2 (en) 2010-08-20 2014-06-24 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8921405B2 (en) 2009-03-05 2014-12-30 Orexo Ab Compounds
JP2015526472A (ja) * 2012-08-22 2015-09-10 コーネル ユニヴァーシティー ファスシンを阻害する方法
WO2017108282A1 (fr) 2015-12-22 2017-06-29 Kancera Ab Acides hydroxamiques bicycliques utiles comme inhibiteurs de l'activité histone désacétylase chez le mammifère
US9902703B2 (en) 2015-07-01 2018-02-27 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
CN108003144A (zh) * 2017-12-15 2018-05-08 刘双伟 一种磺酰胺衍生物及其在骨质疏松药物中的应用
US10081614B2 (en) 2014-11-27 2018-09-25 Acturum Real Estate Ab Bis(sulfonamide) derivatives and their use as mPGES inhibitors
US10227296B2 (en) 2014-11-27 2019-03-12 Arcturum Real Estate AB Bis(sulfonamide) derivatives and their use as mPGES inhibitors
US10227345B2 (en) 2014-02-20 2019-03-12 Cornell University Compounds and methods for inhibiting fascin
US11028068B2 (en) 2017-07-25 2021-06-08 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
WO2021130259A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Composés dérivés de dihydrocyclopenta-isoquinoline-sulfonamide
WO2021130255A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de dihydro-cyclopenta-isoquinoline
WO2021130262A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Composés dérivés de tétrahydrobenzo-quinoléine sulfonamides
WO2021130257A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de dihydro-cyclopenta-isoquinoline sulfonamides
WO2021130260A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de tétrahydrobenzo-quinoléine sulfonamide utiles en tant que modulateurs d'ige

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WO2004080999A1 (fr) * 2003-03-14 2004-09-23 Biolipox Ab Composes de pyrazole utilises dans le traitement de l'inflammation
WO2005005415A1 (fr) * 2003-07-09 2005-01-20 Biolipox Ab Indoles utilises dans le traitement de l'inflammation
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EP2217566A1 (fr) * 2007-11-15 2010-08-18 AstraZeneca AB Dérivés bis-(sulfonylamino) dans une thérapie 066
EP2217566A4 (fr) * 2007-11-15 2011-11-23 Astrazeneca Ab Dérivés bis-(sulfonylamino) dans une thérapie 066
JP2011507837A (ja) * 2007-12-20 2011-03-10 アストラゼネカ・アクチエボラーグ 治療に使用するためのビス−（スルホニルアミノ）誘導体
EA017940B1 (ru) * 2007-12-20 2013-04-30 Астразенека Аб Бис(сульфониламино)производные для применения в терапии
WO2009082347A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Dérivés de bis-(sulfonylamino) destinés à être utilisés en thérapie
US9145380B2 (en) 2007-12-20 2015-09-29 Astrazeneca Ab Bis-(sulfonylamino) derivatives for use in therapy
US8916599B2 (en) 2008-09-25 2014-12-23 Orexo Ab 1H-benz imidazole-5-carboxamides as anti-inflammatory agents
US9040565B2 (en) 2008-09-25 2015-05-26 Orexo Ab 1H-benzimidazole-5-carboxamides as anti-inflammatory agents
US8598190B2 (en) 2008-09-25 2013-12-03 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8703796B2 (en) 2008-09-25 2014-04-22 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-B] pyridine-6-carboxamides as anti-inflammatory agents
US8921405B2 (en) 2009-03-05 2014-12-30 Orexo Ab Compounds
US8586604B2 (en) 2010-08-20 2013-11-19 Boehringer Ingelheim International Gmbh Inhibitors of the microsomal prostaglandin E2 synthase-1
US8759537B2 (en) 2010-08-20 2014-06-24 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8466186B2 (en) 2010-12-10 2013-06-18 Boehringer Ingelheim International Gmbh Compounds
US8486968B2 (en) 2010-12-10 2013-07-16 Boehringer Ingelheim International Gmbh Compounds
US8674113B2 (en) 2010-12-10 2014-03-18 Boehringer Ingelheim International Gmbh Compounds
JP2015526472A (ja) * 2012-08-22 2015-09-10 コーネル ユニヴァーシティー ファスシンを阻害する方法
US11866440B2 (en) 2012-08-22 2024-01-09 Cornell University Methods for inhibiting fascin
US10208043B2 (en) 2012-08-22 2019-02-19 Cornell University Methods for inhibiting fascin
US10941146B2 (en) 2012-08-22 2021-03-09 Novita Pharmaceuticals, Inc. Methods for inhibiting fascin
EP2888010A4 (fr) * 2012-08-22 2016-07-20 Univ Cornell Méthodes d'inhibition de la fascine
US10941141B2 (en) 2014-02-20 2021-03-09 Novita Pharmaceuticals, Inc. Compounds and methods for inhibiting fascin
US10227345B2 (en) 2014-02-20 2019-03-12 Cornell University Compounds and methods for inhibiting fascin
US11858929B2 (en) 2014-02-20 2024-01-02 Cornell University Compounds and methods for inhibiting fascin
US10227296B2 (en) 2014-11-27 2019-03-12 Arcturum Real Estate AB Bis(sulfonamide) derivatives and their use as mPGES inhibitors
US10081614B2 (en) 2014-11-27 2018-09-25 Acturum Real Estate Ab Bis(sulfonamide) derivatives and their use as mPGES inhibitors
US9902703B2 (en) 2015-07-01 2018-02-27 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
US10654814B2 (en) 2015-12-22 2020-05-19 Kancera Ab Bicyclic hydroxamic acids useful as inhibitors of mammalian histone deacetylase activity
WO2017108282A1 (fr) 2015-12-22 2017-06-29 Kancera Ab Acides hydroxamiques bicycliques utiles comme inhibiteurs de l'activité histone désacétylase chez le mammifère
US11028068B2 (en) 2017-07-25 2021-06-08 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
CN108003144A (zh) * 2017-12-15 2018-05-08 刘双伟 一种磺酰胺衍生物及其在骨质疏松药物中的应用
WO2021130262A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Composés dérivés de tétrahydrobenzo-quinoléine sulfonamides
WO2021130257A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de dihydro-cyclopenta-isoquinoline sulfonamides
WO2021130260A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de tétrahydrobenzo-quinoléine sulfonamide utiles en tant que modulateurs d'ige
CN114845777A (zh) * 2019-12-23 2022-08-02 Ucb生物制药有限责任公司 四氢苯并-喹啉磺酰胺衍生物化合物
CN114845776A (zh) * 2019-12-23 2022-08-02 Ucb生物制药有限责任公司 可用作ige调节剂的四氢苯并-喹啉磺酰胺衍生物
CN114845778A (zh) * 2019-12-23 2022-08-02 Ucb生物制药有限责任公司 二氢环戊二烯并异喹啉磺酰胺衍生物化合物
CN114867525A (zh) * 2019-12-23 2022-08-05 Ucb生物制药有限责任公司 二氢环戊二烯并异喹啉衍生物
CN114980975A (zh) * 2019-12-23 2022-08-30 Ucb生物制药有限责任公司 二氢环戊二烯并异喹啉磺酰胺衍生物
WO2021130255A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Dérivés de dihydro-cyclopenta-isoquinoline
WO2021130259A1 (fr) * 2019-12-23 2021-07-01 UCB Biopharma SRL Composés dérivés de dihydrocyclopenta-isoquinoline-sulfonamide

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