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WO2010005385A1 - 2-amino-6-alkyl substituted pyridine derivatives useful as p2y12 inhibitors 308 - Google Patents

2-amino-6-alkyl substituted pyridine derivatives useful as p2y12 inhibitors 308 Download PDF

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Publication number
WO2010005385A1
WO2010005385A1 PCT/SE2009/050876 SE2009050876W WO2010005385A1 WO 2010005385 A1 WO2010005385 A1 WO 2010005385A1 SE 2009050876 W SE2009050876 W SE 2009050876W WO 2010005385 A1 WO2010005385 A1 WO 2010005385A1
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Prior art keywords
alkyl
cyano
formula
piperidine
unsubstituted
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French (fr)
Inventor
Ruth Bylund
Daniel Hovdal
Johan Johansson
Mikael Sellén
Fredrik Zetterberg
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 6-alkyl substituted pyridine derivatives and their use in the treatment of cardiovascular disorders.
  • the present invention provides novel pyridine compounds, their use as medicaments, compositions containing them and processes for their preparation.
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion. Haemostasis is controlled via a tight balance between platelet aggregation, coagulation and fibrinolysis.
  • Thrombus formation under pathological conditions like e.g. arteriosclerotic plaque rupture, is firstly initiated by platelet adhesion, activation and aggregation. This results not only in the formation of a platelet plug but also in the exposure of negatively charged phospholipids on the outer platelet membrane promoting blood coagulation. Inhibition of the build-up of the initial platelet plug would be expected to reduce thrombus formation and reduce the number of cardiovascular events as was demonstrated by the anti-thrombotic effect of e.g. Aspirin (BMJ 1994; 308: 81-106 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients).
  • Platelet activation/aggregation can be induced by a variety of different agonists. However, distinct intracellular signalling pathways have to be activated to obtain full platelet aggregation, mediated via G-proteins G q , G 12 / 13 and G 1 (Platelets, AD Michelson ed., Elsevier Science 2002, ISBN 0-12-493951-1; 197-213: D Woulfe, et al.
  • the G-protein coupled receptor P2Y i2 (previously also known as the platelet P 2T , P2T ac , or P2Y cyc receptor) signals via Gi, resulting in a lowering of intra-cellular cAMP and full aggregation (Nature 2001; 409: 202-207 G Hollopeter, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs.). Released ADP from dense- granules will positively feedback on the P2Y12 receptor to allow full aggregation.
  • WO 2002/098856 and WO 2004/052366 describe piperazino-carbonylmethylaminocarbonyl-naphtyl or -quinolyl derivatives as ADP receptor antagonist.
  • Clinical evidence for the key-role of the ADP-P2Yi2 feedback mechanism is provided by the clinical use of clopidogrel, an thienopyridine prodrug which active metabolite selectively and irreversibly binds to the P2Yi 2 receptor, that has shown in several clinical trials to be effective in reducing the risk for cardiovascular events in patients at risk (Lancet 1996; 348: 1329-39: CAPRIE Steering committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE); N Engl J Med 2001; 345 (7): 494-502): The Clopidogrel in Unstable Angina to prevent Recurrent Events Trial Investigators.
  • Some thienopyrimidines have been described as P2Yi 2 antagonists in WO 2003/022214, WO 2006/103544, WO 2006/079916, WO 2006/100591, WO 2006/103545 and WO 2006/103555.
  • WO 2001/057037 discloses some sulfonyl derivatives as platelet ADP receptor inhibitors. None of these are 2-pyridyl-5-keto derivatives.
  • WO 2007/056219 a quinazoline dione derivative is presented as P2Yi 2 antagonist, and in WO 2007/056167 a process for its preparation is presented.
  • WO 2006/073361 discloses some P2Yi 2 antagonists for the potential treatment of thrombosis.
  • WO 2007/008140 discloses further P2Y i2 antagonists for the potential treatment of thrombosis.
  • Other patent applications disclosing P2Yi 2 antagonists for the potential treatment of thrombosis are WO 2008/002247, WO 2008/004941, WO 2008/004942, WO 2008/004943, WO 2008/004944, WO 2008/004945 and WO 2008/004946.
  • the compounds of the invention are reversible and selective P2Yi 2 antagonists, hereinafter referred to as the compounds of the invention.
  • the compounds of the invention having improved stability towards esterases in Ri -position and against oxidative metabolism caused by the cytochrome P-450 system present in the liver, unexpectedly exhibit improved beneficial properties that render them particularly suitable for use in the treatment of diseases/conditions as described below (See p.69-70).
  • beneficial properties are high potency, high selectivity, metabolic stability, beneficial pharmacokinetic properties and an advantageous therapeutic window.
  • Ri represents R 7 C(O);
  • R 2 represents unsubstituted (Ci-C3)alkyl
  • R 7 represents (Ci-Ci 2 )alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -Ce)cycloalkyl, hydroxy(Ci-Ci 2 )alkyl, aryl or heterocyclyl; B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Cg)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Cg)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C 3 - Ce)cycloalkyl and heterocyclyl; further Ri 4 represents aryl, aryl(Ci-Cg)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)cycloalkyl(Ci-
  • R c represents an unsubstituted or monosubstituted or polysubstituted (Ci- C 4 )alkylene group, wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxyl, oxy-(Ci-C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 - C 4 )alkynyl, (C 3 -Ce)cycloalkyl, carboxyl, carboxy-(Ci-C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R ⁇ (RC) and R b(Rc) together with the nitrogen
  • Ri 9 represents H or (Ci-C 4 )alkyl
  • R d represents (Ci-Ci 2 )alkyl, (C 3 -Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-Ci 2 )alkyl, (Ci-Ci 2 )alkoxyC(O), (C 1 - Ci 2 )alkoxy, halogen substituted (C 1 -C 12 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, (C 1 -o Ci 2 )alkylsulfmyl, (Ci-Ci 2 )alkylsulfonyl, (Ci-Ci 2 )alkylthio, (C 3 -C 6 )cycloalkylthio, arylsulfmyl, arylsulf
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-memberedo monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • An alternative embodiment of formula (I) or a pharmaceutically acceptable salt thereof is:
  • Ri represents R 7 C(O);
  • R 2 represents unsubstituted (Ci-C3)alkyl
  • R 7 represents (Ci-Ci 2 )alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -Ce)cycloalkyl, hydroxy(Ci-Ci 2 )alkyl, aryl or heterocyclyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Rn is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri 4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Cg)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or (Ci-Cg)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C 3 - Ce)cycloalkyl and heterocyclyl; further Ri 4 represents aryl, aryl(Ci-C 8 )alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C 3 -Ce)cycloalkyl, (C 3 - C6)cycloalkyl
  • R c is methylene (-CH 2 -);
  • R d represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C 6 )alkoxy group;
  • X represents a single bond, imino (-NH-), methylene (-CH 2 -), iminomethylene (-
  • CH 2 -NH- wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH 2 -) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C 6 ) alkyl;
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • the compounds of the invention may exist in, and be isolated in, optically active or racemic form.
  • the invention includes any optically active or racemic form of a compound of formula I which act as P2Yi 2 receptor antagonists.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic mixture, by chiral chromatography, synthesis from optically active starting materials or by asymmetric synthesis.
  • the compounds of the formula I may exhibit the phenomenon of tautomerism
  • the present invention includes any tautomeric form of a compound of formula I which is a P2Yi 2 receptor antagonist.
  • alkyl include both the straight chain and branched chain groups such as butyl and tert-butyl.
  • butyl when a specific term such as “butyl” is used, it is specific for the straight chain or "normal” butyl group, branched chain isomers such as “t-butyl” being referred to specifically when intended.
  • alkyl is unsubstituted or substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (C 1 -C 12 )alkyl, halogen substituted (Ci-Ci 2 )alkyl, unsubstituted (C 1 - Ci 2 )alkoxyC(O), halogensubstituted (Ci-Ci 2 )alkoxyC(O), unsubstituted (Ci-Ci 2 )alkoxy, halogensubstituted (Ci-Ci 2 )alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl
  • alkyl includes both linear or branched chain groups, unless otherwise specified. In one embodiment alkyl is optionally substituted by one or more halogens (F, Cl, Br or I) or mixed halogen atoms.
  • alkyl when substituted by one or more halogen atoms is alkyl substituted by one or more fluorine atoms.
  • halogen substituted alkyl includes perfluoroalkyl groups such as trifluoromethyl, and pentafluoroethyl.
  • aryl(Ci-C6)alkyl means a (Ci-C 6 ) alkyl group substituted by an aryl group.
  • alkyl optionally interrupted by oxygen or “alkyl interrupted by oxygen”means that the optional oxygen atom is placed inside the alkyl group between two carbon atoms of the considered alkyl group, and not in any of the ends thereof.
  • cycloalkyl generally denotes a substituted or unsubstituted (C 3 -C 6 ), unless other chain length specified, cyclic hydrocarbon.
  • -cycloalkyl-cycloalkyl, -cycloalkyl-heterocyclyl and -cycloalkyl-aryl are intended to be covered, but -cycloalkyl-cycloalkyl-cycloalkyl as well as -cycloalkyl-aryl-cycloalkyl or - cycloalkyl-heterocyclyl-aryl or even longer such chains are intended to be excluded from the invention.
  • cycloalkyl denotes a substituted hydrocarbon according to above, it denotes a cyclic hydrocarbon according to above which is being substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci 2 )alkyl, halogen substituted (Ci-Ci 2 )alkyl, unsubstituted (Ci-Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci 2 )alkoxy, halogensubstituted (Ci-Ci 2 )alkoxy, unsubstituted (C 3 -C 6 )cycloalkyl, halogensubstituted (C3-C 6 )cycloalkyl, unsubstituted (C 3
  • alkoxy includes both linear or branched chain groups, unless otherwise specified optionally substituted by one or more halogens (F, Cl, Br or I) or mixed halogen atoms.
  • aryl in general without other specification denotes a substituted or unsubstituted (Cg-C 14) aromatic hydrocarbon and includes, but is not limited to, phenyl, naphthyl, tetrahydronaphtyl, indenyl, indanyl, antracenyl, fenantrenyl, and fluorenyl.
  • aryl when aryl is substituted with cycloalkyl, heterocyclyl or another aryl, that substituent is not again substituted with another one of any one of these groups. It is not contemplated in this invention to create a "polymer" compound.
  • -aryl-aryl, - aryl-heterocyclyl and -aryl-cycloalkyl are intended to be covered, but -aryl-aryl-aryl as well as -aryl-cycloalkyl-aryl or aryl-heterocyclyl-cycloalkyl or even longer such chains are intended to be excluded from the invention.
  • aryl When said aryl is being substituted, it is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogensubstituted (Ci-Ci2)alkyl, unsubstituted (C 1 - Ci 2 )alkoxyC(O), halogensubstituted (Ci-Ci 2 )alkoxyC(O), unsubstituted (Ci-Ci 2 )alkoxy, halogensubstituted (Ci-Ci 2 )alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocycly
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci 2 )alkyl, halogensubstituted (Ci-Ci 2 )alkyl, unsubstituted (Ci-Ci 2 )alkoxyC(O), halogensubstituted (Ci-Ci 2 )alkoxyC(O), unsubstituted (Ci-Ci 2 )alkoxy, halogensubstituted (Ci-Ci 2 )alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C 3 -Ce)cycloalkyl,
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, cyano, unsubstituted (Ci-C 6 )alkyl, and unsubstituted (Ci-Ce)alkoxy.
  • halogen F, Cl, Br or I
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (C 1 - Ce)alkoxy.
  • halogen F, Cl, Br or I
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more atoms selected from F and Cl and mixtures thereof, and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
  • aryl in general without other specification denotes a substituted phenyl group, which is substituted by one or more atoms selected from F and Cl and mixtures thereof, and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms or one of the following groups, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
  • halogen F, Cl, Br or I
  • aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more of the following groups, unsubstituted (Ci-C 6 )alkyl, and unsubstituted (Ci-Ce)alkoxy.
  • aryl in general without other specification denotes a phenyl group substituted by one or more of fluoro and/or methyl.
  • aryl in general without other specification denotes a phenyl group substituted by one or more fluorine atoms.
  • heterocyclyl denotes a substituted or unsubstituted, 4- to 10- membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon, for example nitrogen, oxygen or sulfur, especially 4-, 5- or 6-membered aromatic or aliphatic hetorocyclic groups, and includes, but is not limited to azetidine, furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxathiolane, oxazolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, oxadiazole,
  • heterocyclyl may be embodified by one selection among the given possible embodiments for a variable and embodified by another (or the same) selection for another variable, eg. R 2 when selected as heterocyclyl may be a furan, when R d (also when selected as heterocyclyl) may be a pyrrole.
  • -heterocyclyl-heterocyclyl, -heterocyclyl-aryl, and -heterocyclyl-cycloalkyl are intended to be covered, but -heterocyclyl-heterocyclyl-heterocyclyl as well as -heterocyclyl- cycloalkyl-aryl or heterocyclyl-cycloalkyl-heterocyclyl or even longer such chains are intended to be excluded from the invention.
  • heterocyclyl denotes a substituted ring system according to above, it denotes a ring system according to above which is being substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogensubstituted (Ci-Ci 2 )alkyl, unsubstituted (Ci-Ci 2 )alkoxyC(O), halogensubstituted (Ci-Ci 2 )alkoxyC(O), unsubstituted (Ci-Ci 2 )alkoxy, halogen substituted (Ci-Ci 2 )alkoxy, unsubstituted (C3- Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl
  • the heterocyclyl group comprises an aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, and an aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur which is fused to a benzene ring;
  • the heterocyclyl group is a non- aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, fused to a benzene ring.
  • the heterocyclyl group is a group chosen among furyl, pyrrolyl, thienyl, pyridyl, N-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl, indolyl, benzdihydrofuranyl, benzodioxolyl (such as 1,3-benzodioxolyl), benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3- dihydrobenzofuran, isoxazo
  • More particular values include, for example, furyl, pyrrolyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3-dihydrobenzofuran, isoxazole, 1,2- benzisoxazole, dihydropyrazole and benzdioxanyl (such as 1,4-benzdioxanyl).
  • the heterocyclyl group is a group chosen among furyl, pyrrolyl, thienyl, pyridyl, N-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3-dihydrobenzofuran, isoxazole, 1 ,2-benzisoxazole or dihydropyrazole.
  • Ri is R 7 C(O) wherein R 7 can be methyl, ethyl, isopropyl, cyclo-propyl, iso-butyl, n-butyl, cyclo-butyl, n-propyl, or tertbutyl.
  • Ri is R 7 C(O) wherein R 7 is (Ci-Ce)alkyl. In an other further embodiment of the invention Ri is R 7 C(O) and wherein R 7 is selected among propyl and butyl.
  • Embodiments for R 2 include unsubstituted (C2-C3)alkyl. Another embodiment for R 2 is unsubstituted (Ci-C 2 )alkyl.
  • R 2 is represented by methyl.
  • R 2 is represented by ethyl. In one other further alternative embodiment of the invention R 2 is represented by n- propyl or isopropyl.
  • R 7 is (Ci-C 6 )alkyl, aryl or hydroxy(Ci-C 6 )alkyl.
  • R 7 is (Ci-Ce)alkyl or hydroxy(Ci-C 6 )alkyl. In an alternative embodiment of the invention R 7 is (Ci-Ce)alkyl or aryl.
  • R 7 is (Ci-Ce)alkyl or heterocyclyl.
  • R 7 is aryl or heterocyclyl.
  • R 7 is (Ci-C 6 )alkyl.
  • R 7 is (Ci-C 4 )alkyl. In another further embodiment of the invention R 7 is (C 2 -C 4 )alkyl.
  • R 7 is chosen among propyl and butyl.
  • R 7 is propyl
  • Ri 4 is selected from a group consisting of hydrogen, methyl and amino.
  • Ri 4 is hydrogen or methyl. In a further embodiment Ri 4 is hydrogen or amino. In an alternative embodiment of the invention Ri 4 represents H.
  • R d represents (Ci-Ci 2 )alkyl.
  • R d includes aryl or heterocyclyl, more particularly, aryl ( aromatic heterocyclyl.
  • R d include, aryl such as phenyl and aromatic heterocyclyl such as thienyl.
  • Rd is phenyl substituted by 0,1 or 2 fluorine or chlorine atoms.
  • Rd is phenyl substituted by 0,1 or 2 fluorine atoms. In an even further embodiment Rd is phenyl substituted by 0,1 or 2 fluorine atoms or by 1 chlorine atom.
  • R d include phenyl which optionally may be substituted.
  • R d represents aryl, heterocyclyl or (C 3 -Ce)cycloalkyl, and anyone of these groups are optionally substituted with one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms, and/or one or more of the following groups, OH, CN, NO 2 , (Ci-Ci 2 )alkyl, (Ci-Ci 2 )alkoxyC(O), (Ci-Ci 2 )alkoxy, halogen substituted (Ci-Ci 2 )alkyl, (C 3 - Ce)cycloalkyl, aryl, heterocyclyl, (Ci-Ci 2 )alkylsulfmyl, (Ci-Ci 2 )alkylsulfonyl, (Ci- Ci 2 )alkylthio, (C3-Ce)cycloalkylthio, arylsulfmyl, arylsulfon
  • R d include phenyl optionally substituted at the 2,3,4 or 5-positions as well as any combination thereof.
  • substituents are cyano, tetrazol-5-yl, methoxy, trifluoromethoxy, methyl, trifluoromethyl, fluoro, chloro, bromo, methylsulfonyl, nitro, 3-methyl-5-oxo-4,5-dihydro-lH-pyrazol-l-yl. Two adjacent positions (e.g. 2,3) may also be connected to form a ring.
  • Example of such a substituent is 2-naphtyl.
  • heteroaryls 2-chloro-5-thienyl, 3-bromo-5- chloro-2-thienyl, 2,l,3-benzoxadiazol-4-yl, 2,4-dimethyl-l,3-thiazol-5-yl, 2,3-dihydro-l,4- benzodioxin-6-yl, 5-chloro-3-methyl-l-benzothien-2-yl, 2,l,3-benzothiadiazol-4-yl, 2,5- dimethyl-3-furyl, 6-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-5-yl, 2,3-dihydro-l -benzofuran-5-yl, 5-chloro-3-thienyl, 5-isoxazol-5-yl-2-thienyl, 5-isoxazol-3-yl-2-thienyl, 4-bromo-5 -chloro- 2-thienyl, 5-bromo-6-ch
  • R d include phenyl optionally substituted at the 2,3,4,5 or 6-positions as well as any combination thereof.
  • substituents are cyano, tetrazol-5-yl, methoxy, trifluoromethoxy, methyl, trifluoromethyl, fluoro, chloro, bromo, methylsulfonyl, nitro, 3-methyl-5-oxo-4,5-dihydro-lH-pyrazol-l-yl.
  • Two adjacent positions e.g. 2,3 may also be connected to form a ring.
  • Example of such a substituent is 2-naphtyl.
  • heteroaryls 2-chloro-5-thienyl, 3-bromo-5- chloro-2-thienyl, 2,l,3-benzoxadiazol-4-yl, 2,4-dimethyl-l,3-thiazol-5-yl, 2,3-dihydro-l,4- benzodioxin-6-yl, 5-chloro-3-methyl-l-benzothien-2-yl, 2,l,3-benzothiadiazol-4-yl, 2,5- dimethyl-3-furyl, 6-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-5-yl, 2,3-dihydro-l -benzofuran-5-yl, 5-chloro-3-thienyl, 5-isoxazol-5-yl-2-thienyl, 5-isoxazol-3-yl-2-thienyl, 4-bromo-5 -chloro- 2-thienyl, 5-bromo-6-ch
  • R c represents an unsubstituted or monosubstituted or disubstituted (Ci-C4)alkylene group wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, OXy-(C 1 - C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, carboxyl, carboxy-(Ci- C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R ⁇ (RC) and R b(Rc) together with the
  • R c represents an unsubstituted or monosubstituted or disubstituted (Ci-C3)alkylene group wherein any substituents each individually and independently are selected from (d-C 4 )alkyl, (d-C 4 )alkoxyl, oxy-(Cr C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -Ce)cycloalkyl, carboxyl, carboxy-(Ci- C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a ⁇ - Rc ⁇ and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R al - Rc Vnd R b(Rc
  • R c represents an unsubstituted or monosubstituted or disubstituted (Ci-C 4 )alkylene group wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxyl, oxy-(Ci- C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -Ce)cycloalkyl, carboxyl, carboxy-(Ci- C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R a ⁇ Rc) and R b
  • R c represents an unsubstituted or monosubstituted or disubstituted (Ci-C3)alkylene group wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, oxy-(Ci- C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, carboxyl, carboxy-(Ci- C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R a ⁇ Rc) and R b(
  • R c represents an unsubstituted or monosubstituted or disubstituted Ci-alkylene group wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, oxy-(Ci- C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, carboxyl, carboxy-(Ci- C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R ⁇ (RC) and R b(Rc) together with the
  • R c represents imino (-NH-) or N- methylimino (-N(CH 3 )-).
  • R c is methylene (-CH 2 -).
  • R 19 represents hydrogen. In another embodiment of the invention R 19 represents methyl.
  • R c R d represents a benzyl group, or a benzyl group which is substituted according to what is described in connection to substitution of the aryl group.
  • R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2,3,4 or 5 halogen atoms.
  • R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2 or 3 halogen atoms.
  • R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 halogen atoms.
  • Embodiments of R c R d aacording to the invention also comprises that R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2,3,4 or 5 fluorine atoms. Further, embodiments of R c R d aacording to the invention also comprises that R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2 or 3 fluorine atoms.
  • R c R d aacording to the invention also comprises that R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms or 1 chlorine atom.
  • R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms.
  • R c R d aacording to the invention also comprises that R c R d represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms or with a methoxy group.
  • X represents a single bond. In another embodiment of the invention X represents imino (-NH-) or methylene (- CH 2 - ). In yet another embodiment X represents imino (-NH-) . In a further embodiment X represents methylene (-CH 2 - ).
  • Suitable values for the B ring/ring system include, for example, diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene and azetidinylene, wherein anyone of them may be presents in any of their isomeric forms (e.g. piperazin -tetrahydropyridazin- tetrahy dropyrimidin) .
  • Embodiments for the B ring/ring system include, for example, diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene and azetidinylene. Further embodiments include these groups which are substituted with Ri 4 having a (Ci-C 6 )alkyl group, wherein the (Ci-Ce)alkyl group optionally is substituted with OH, COOH or COOR e group(s), e.g.
  • R e represents H, aryl, cycloalkyl, heterocyclyl or (Ci- Ci 2 )alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) or mixed halogen atoms, OH, aryl, cycloalkyl and heterocyclyl.
  • the embodiment include diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene or azetidinylene groups which are substituted with Ri 4 having a (Ci-C6)alkyl group, wherein the (Ci-Ce)alkyl group optionally is substituted with OH, COOH or COOR e group(s), e.g.
  • R e represents H, aryl, cycloalkyl, heterocyclyl or (C 1 - Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) or mixed halogen atoms, OH, aryl, cycloalkyl and heterocyclyl.
  • halogen includes only fluorine and chlorine.
  • a 2nd embodiment of formula I is defined by; Ri represents R 7 C(O);
  • R 2 represents unsubstituted (Ci-C3)alkyl
  • R 7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -Ce)cycloalkyl, hydroxy(Ci-C 6 )alkyl, aryl or heterocyclyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Rn is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection); Ri 4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or (Ci-Ce)alkyl optionally substituted by one or more of hal
  • R c represents an unsubstituted or monosubstituted or polysubstituted (Ci- C 4 )alkylene group, wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxyl, oxy-(Ci-C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 - C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, carboxyl, carboxy-(Ci-C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R ⁇ (RC) and R b(Rc) together with the
  • Ri 9 represents H or (Ci-C 4 )alkyl
  • R d represents (Ci-Ce)alkyl, (C 3 -Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxyC(O), (Ci- C 6 )alkoxy, halogen substituted (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, (C 1 - C 6 )alkylsulfmyl, (Ci-C 6 )alkylsulfonyl, (Ci-C 6 )alkylthio, (C 3 -C 6 )cycloalkylthio, arylsulf ⁇ nyl, arylsulfonyl, aryl
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • R 2 represents unsubstituted (Ci-C 3 )alkyl
  • R 7 represents (Ci-C 6 )alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -C 6 )cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -C 6 )cycloalkyl, hydroxy(Ci-C 6 )alkyl, aryl or heterocyclyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C 3 - Ce)cycloalkyl and heterocyclyl; further Ri 4 represents aryl, aryl(Ci-C 6 )alkyl, aryl(Ci- C 3 )alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C 3 -C 6 )cycloalkyl, (C 3 - C6)cycloal
  • R c is methylene (-CH 2 -);
  • R d represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-Ce)alkoxy group;
  • Aryl denotes a substituted or unsubstituted (C 6 -C 14 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • Ri represents RyC(O);
  • R 2 represents unsubstituted (Ci-C 3 )alkyl
  • R 7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -C 6 )cycloalkyl, hydroxy(Ci-C 6 )alkyl, aryl or heterocyclyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Rn represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents (Ci-C 6 )alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s); further Ri 4 represents aryl, aryl(Ci-C 6 )alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C 3 -Ce)cycloalkyl, (C 3 - C 6 )Cy cloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cyclo
  • R c represents an unsubstituted or monosubstituted or polysubstituted (Ci-
  • C 4 )alkylene group wherein any substituents each individually and independently are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxyl, oxy-(Ci-C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 - C 4 )alkynyl, (C 3 -Ce)cycloalkyl, carboxyl, carboxy-(Ci-C 4 )alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NR a(Rc) R b(Rc) in which R a(Rc) and R b(Rc) individually and independently from each other represents hydrogen, (Ci-C 4 )alkyl or R a ⁇ Rc) and R b(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine; further R c represents im
  • Ri9 represents H or (Ci-C 4 )alkyl
  • R d represents (Ci-Ce)alkyl, (C 3 -Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-Ce)alkyl, (Ci-Ce)alkoxyC(O), (Ci- Ce)alkoxy, halogen substituted (Ci-Ce)alkyl, (C 3 -Ce)cycloalkyl, aryl, heterocyclyl, (C 1 - C 6 )alkylsulfmyl, (Ci-C 6 )alkylsulfonyl, (Ci-C 6 )alkylthio, (C 3 -C 6 )cycloalkylthio, arylsulf ⁇ nyl, arylsulfonyl, arylthio, aryl
  • X represents a single bond, imino (-NH-), methylene (-CH 2 -), iminomethylene (- CH 2 -NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH 2 -) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C 6 ) alkyl;
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • Ri represents R 7 C(O);
  • R 2 represents unsubstituted (Ci-C 3 )alkyl
  • R 7 represents (Ci-C 6 )alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -C 6 )cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -C 6 )cycloalkyl, hydroxy(Ci-C 6 )alkyl, aryl or heterocyclyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri 4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COOR e ; wherein R e represents (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s); further R i4 represents aryl, aryl(d-C 6 )alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C 3 -Ce)cycloalkyl, (C 3 -
  • R c is methylene (-CH 2 -);
  • R d represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group;
  • X represents a single bond, imino (-NH-), methylene (-CH 2 -), iminomethylene (- CH 2 -NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH 2 -) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C 6 ) alkyl;
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • Ri represents RyC(O);
  • R 2 represents unsubstituted (Ci-C3)alkyl
  • R 7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -C 6 )cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -C 6 )cycloalkyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH and COOH; further Ri 4 represents a halogen (F, Cl, Br or I) atom, (C 3 -Ce)cycloalkyl, (Ci-Ce)alkoxy, (C 3 -C 6 )CyClOaIkOXy, or a group of formula NR a(14) R b(14) in which R a(14) and R b(14) independently represent H, (Ci-C 6 )alkyl, (Ci-C 6 )alkylC(O), (Ci-C 6 )alkoxyC(O) or R a(14) and R b(14) together with the nitrogen atom represent piperidine, pyrrolidine, azet
  • R c represents imino (-NH-), N-substituted imino (-NR19-), (Ci-C4)alkyleneimino or N-substituted (Ci-C 4 )alkyleneimino ( -N(Ri 9 )-((Ci-C 4 )alkylene) or an unsubstituted or monosubstituted or polysubstituted (Ci-C4)alkylene group wherein any substitutents are selected from the group consisting of (Ci-C4)alkyl, (Ci-C4)alkoxyl and one or more halogen (F, Cl, Br or I) atom(s) or mixed halogen atoms; Ri9 represents H or (Ci-C4)alkyl;
  • R d represents (Ci-Ce)alkyl, (C 3 -Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxyC(O), (C 1 - Ce)alkoxy, halogen substituted (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl, heterocyclyl, (C 1 - C 6 )alkylsulfmyl, (Ci-C 6 )alkylsulfonyl, (Ci-C 6 )alkylthio, (C 3 -C 6 )cycloalkylthio, arylsulf ⁇ nyl, arylsulfonyl, arylthio,
  • X represents a single bond, imino (-NH-) or methylene (-CH 2 -), and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C 6 ) alkyl;
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • R 2 represents unsubstituted (Ci-C 3 )alkyl
  • R 7 represents (Ci-C 6 )alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C 3 -Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R 7 represents (C 3 -C 6 )cycloalkyl;
  • B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri 4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
  • Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-C 6 )alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH and COOH; further Ri 4 represents a halogen (F, Cl, Br or I) atom, (C 3 -Ce)cycloalkyl, (Ci-Ce)alkoxy, (C 3 -C 6 )CyClOaIkOXy, or a group of formula NR a(14) R b(14) in which R a(14) and R b(14) independently represent H, (Ci-C 6 )alkyl, (Ci-C 6 )alkylC(O), (C r C 6 )alkoxyC(O) or R a(14) and R b(14) together with the nitrogen atom represent piperidine, pyrrolidine, aze
  • R c is methylene (-CH 2 -);
  • R d represents phenyl having 0,1 or 2 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group;
  • X represents a single bond, imino (-NH-) or methylene (-CH 2 -), and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C 6 ) alkyl;
  • Aryl denotes a substituted or unsubstituted (C 6 -Ci 4 ) aromatic hydrocarbon
  • Heterocyclyl denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
  • a 5th embodiment of formula I is defined by that; Ri is chosen from the group consisting of n-propylcarbonyl and n-butylcarbonyl;
  • R 2 is methyl
  • R 7 is n-propyl or n-butyl
  • B is chosen from the group consisting of 3-azetidin-l-ylene and 4-piperidin-l- ylene, and the substituent Ri 4 is connected to the B ring/ring system, in such a way that no quarternary ammonium compounds are formed (by this connection);
  • R c is chosen from the group consisting of methylene (-CH 2 -), methylmethylene (-CH(CH 3 )-), ethylene (-CH 2 -CH 2 -) and methylimino (-N(CH 3 )-);
  • Ri9 (when present) is methyl
  • R d is chosen from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, 4- methylcyclohexyl, phenyl, 4-methylphenyl, 2-cyanophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,4- difluorophenyl, 3,4-difluorophenyl and 3-fluoro-4-methyl-phenyl; and
  • X is a single bond.
  • Ri is chosen from the group consisting of n-propylcarbonyl and n-butylcarbonyl;
  • R 2 is methyl
  • R 7 is n-propyl or n-butyl
  • B is chosen from the group consisting of 3-azetidin-l-ylene and 4-piperidin-l- ylene, and the substituent Ri 4 is connected to the B ring/ring system, in such a way that no quarternary ammonium compounds are formed (by this connection);
  • R c is methylene (-CH 2 -);
  • R d is chosen from the group consisting of phenyl, 2-fluorophenyl, 3 -fluorophenyl,
  • X is a single bond.
  • formula (I) is defined as being any compound(s) of formula (Ia)-(Ii):
  • formula (I) is defined as being any compound(s) of formula (Ia) or (Ig):
  • formula (I) is defined as being any compound(s) of formula (Iaa)-
  • formula (I) is defined as being any compound(s) of formula (Iaa)-
  • Examples of specific compounds according to the invention can be selected as one or more from;
  • examples of specific compounds can be selected as one or more from;
  • the compound of Formula I is;
  • the compound of Formula I is; l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide; or a pharmaceutically acceptable salt thereof.
  • X is a single bond or (-CH2-), with a compound of formula ( III ) in which R c and R d are defined as in formula ( I ) above.
  • the reaction is generally carried out in an inert organic solvent such as dichloromethane at ambient temperature.
  • the reaction may be carried out using standard conditions or in the presence of TBTU, EDCI, PyBrop, PyBOP or the combination of EDCI and HOBt.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • the reaction is generally carried out in an inert solvent such as DCM.
  • the reaction may be carried out in the presence of CDI.
  • the reaction may be carried out in the presence of an organic base such as triethylamine, DBU or DIPEA.
  • reaction in which R c and R are defined as in formula ( I ) above.
  • the reaction is generally carried out in an inert solvent such as THF.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • the reaction is generally carried out in an inert solvent such as DMA.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • Compounds of formula ( I ) may also be prepared by reacting a compound of formula ( VII ) in which Ri and R 2 are defined as in formula ( I ) above and L is a suitable leaving group, such as chloro, bromo, iodo, fluoro, benzotriazolyloxy(OBt), triflate (OTf) mesylate (OMs) or tosylate (OTs),
  • a suitable leaving group such as chloro, bromo, iodo, fluoro, benzotriazolyloxy(OBt), triflate (OTf) mesylate (OMs) or tosylate (OTs)
  • the reaction is generally carried out in an inert solvent such as DCM, THF or DMA.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • a compound of formula (I) in which R 1 , R 2 , B, R14, and R d are defined as in formula ( I ) above and R c represents imino (-NH-) or (Ci-C 4 )alkylimino the imino group can be substituted using standard methods, e.g.
  • R 1 , R 2 , B, Ri 4 , and R d are defined as in formula ( I ) above and R c represents N- substituted imino (-NR19-) or N-substituted (Ci-C 4 )alkylimino ( -N(Ri 9 )-((Ci-C 4 )alkyl), optionally in the presence of a strong base such as NaH.
  • R 2 , B, Ri 4 , X, R c and R d are as defined in formula ( I ) above and LG is a leaving group such as Cl or F with a reagent of general formula R 7 -MgX', in which R 7 is defined as in formula ( I ) above, and X' is a halogen.
  • the reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as for example FeCl 3 .
  • an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as for example FeCl 3 .
  • the reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0 C and O 0 C.
  • the reaction may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX', wherein X' is a halogen).
  • organocopper- or organocuprate reagent such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX', wherein X' is a halogen).
  • the reaction is carried out using standard conditions in an inert solvent such as DCM or THF.
  • the reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0 C and 0 0 C.
  • the intermediates referred to above may be prepared by, for example, the methods/processes outlined below.
  • B and Ri 4 are defined as in formula ( I ) above and X is a single bond or (-CH 2 -).
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • the reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water.
  • the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature.
  • the reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
  • reaction can be performed using known reagents like CDI, EDCI or the combination of EDCI and HOBt to give a compound of the general formula ( XII ).
  • R 2 , B and Ri 4 is as defined in formula ( I ) above, X is a single bond or (- CH 2 -) and LG is a leaving group such as Cl or F with a reagent of general formula R 7 - MgX', in which R 7 is defined as in formula ( I ) above, and X' is a halogen.
  • the reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as for example FeCl 3 .
  • the reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0 C and O 0 C.
  • the recation may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX').
  • an organocopper- or organocuprate reagent such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX').
  • the reaction is carried out using standard conditions in an inert solvent such as DCM or THF.
  • the reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0 C and 0 0 C. (See for example Cais, M; Mandelbaum, A in Patai "The Chemistry of the Carbonyl Group, vol. 1, Wiley, NY, 1966, p. 303.)
  • Compounds of general formula ( XIII ) above can by prepared by reacting a compound of general formula ( XI ) defined as above using standard methods, e.g. with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCI 3 ( e.g. when LG is
  • the reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine (e.g. when LG is F)
  • the reaction may be performed in an inert solvent such as DCM or toluene.
  • the reaction is carried out at ambient temperature or at elevated temperatures.
  • reaction is carried out in an inert solvent such as THF at ambient temperature in the presence of a suitable base such as sodium pentoxide or NaH.
  • a suitable base such as sodium pentoxide or NaH.
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • the reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water.
  • the reaction may be carried out in the prescence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as DCM or THF 5 at ambient temperature.
  • the reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
  • reaction can be performed using known reagents like CDI, EDCI or the combination of EDCI and HOBt to give a compound of the general formula ( XVIII ).
  • R 2 , B and R 14 are as defined in formula ( I ) above, X is (-NH 2 ), (-CH 2 -NH 2 ) or a single bond connected to a nitrogen which is a member of the B ring and LG is a leaving group such as Cl or F with a reagent of general formula R 7 -MgX', in which R 7 is defined as in formula ( I ) above, and X' is a halogen.
  • the reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as FeCl 3 .
  • an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as FeCl 3 .
  • the reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0 C and 0 0 C.
  • the recation may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX').
  • an organocopper- or organocuprate reagent such as for expemple R 7 Cu, (R 7 ) 2 CuLi or (R 7 ) 2 CuMgX').
  • the reaction is carried out using standard conditions in an inert solvent sauch as DCM or THF.
  • the reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0 C and 0 0 C.
  • Compounds of general formula ( XIX ) above can by prepared by reacting a compound of general formula ( XVII ) defined as above using standard methods, e.g. with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCl 3 ( e.g. when LG is Cl).
  • a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCl 3 (e.g. when LG is Cl).
  • Advantageously dimethylformamide may be used as catalyst.
  • the reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine ( e.g. when LG is F).
  • the reaction may be performed in an inert solvent such as DCM or toluene.
  • the reaction is carried out at ambient temperature or at elevated temperatures.
  • the reaction is generally carried at elevated temperature using standard equipment. Preferentially the reaction is carried out under acidic conditions in an inert solvent such as MeCN or THF.
  • an inert solvent such as MeCN or THF.
  • reaction is carried out in an inert solvent such as THF at ambient temperature in the presence of a suitable base such as sodium pentoxide or NaH.
  • a suitable base such as sodium pentoxide or NaH.
  • reaction may be performed in an inert solvent such as DCM.
  • the inert solvent is toluene.
  • the reaction may also be carried out with PyBOP or methyl sulfonyl chloride in the presence of a base, such as DIPEA, in an inert solvent such as DCM.
  • R 2 is defined as in formula ( I ) according to any of the procedures described in b3) to b8) above.
  • the reaction is generally performed in an inert solvent such as ethanol, optionally in the presence of a strong base such as sodium ethoxide at ambient temperature.
  • a strong base such as sodium ethoxide at ambient temperature.
  • the reaction is generally performed in an inert solvent such as ethanol, optionally in the presence of an organic base such as TEA or DIPEA at ambient temperature
  • R 2 is defined as in formula ( I ) above with dimethoxy-N,N- dimethy lmethaneamine .
  • the reaction is carried out in an inert organic solvent such as EtOH.
  • Compounds of the general formula ( VIII ) can be formed in one of the processes (el-e4).
  • the compounds of formula ( VIII ) are advantageously isolated as a zwitterion.
  • a ring nitrogen of compounds of formula ( X ) and ( XVI ) used in the below steps may be protected by a protective group such as t-butyloxycarbonyl.
  • a compound of formula (VIII) which is protected with t-butoxy carbonyl may be transformed into a compound without the protective group using standard procedures or a reagent such as HCl, FA or TFA.
  • Componds of general formula ( IX ) defined as above may be prepared by reacting a compound of general formula ( XXV )
  • R 2 , B, Ri 4 , X, R c and R d are as defined in formula ( I ) above using standard methods, e.g. reacting with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCls( e.g. when LG is Cl).
  • a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCls( e.g. when LG is Cl).
  • Advantageously dimethylformamide may be used as catalyst.
  • the reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine ( e.g. when LG is F)
  • the reaction may be performed in an inert solvent such as DCM or toluene.
  • the reaction is carried out at ambient temperature or at elevated temperatures.
  • R 2 is defined as in formula (I) above and L is a suitable leaving group (such as fluoro, chloro, bromo, iodo, triflate (OTf) mesylate (OMs) or tosylate (OTs)), with a compound of the general formula ( X ) defined as above .
  • L is a suitable leaving group (such as fluoro, chloro, bromo, iodo, triflate (OTf) mesylate (OMs) or tosylate (OTs)), with a compound of the general formula ( X ) defined as above .
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • the reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water.
  • the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature.
  • the reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
  • a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
  • the reaction may also be carried out with methyl sulfonyl chloride in the presence of a base, such as DIPEA, in an inert solvent such as DCM.
  • a base such as DIPEA
  • DCM inert solvent
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • the reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water.
  • the reaction may be carried out in the prescence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature.
  • the reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop preferentially in the precence of an organic base such as TEA or DIPEA.
  • the compounds of formula ( XXV ) in which R 2 , B, R44, X, R c and R d are as defined in formula ( I ) above may be prepared by reacting a compound of formula ( XXVI ) defined as above with a compound of the general formula ( VIII ) defined as above .
  • the reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven.
  • the reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water.
  • the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature.
  • the reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
  • the reaction is generally carried out in an inert organic solvent such as dichloromethane at ambient temperature.
  • the reaction may be carried out using standard conditions or in the presence of TBTU, EDCI, PyBrop, PyBOP or the combination of EDCI and HOBt.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • the reaction is generally carried out in an inert solvent such as DCM.
  • the reaction may be carried out in the presence of CDI.
  • the reaction may be carried out in the presence of an organic base such as triethylamine, DBU or DIPEA.
  • Compounds of formula ( XXV ) in which R 2 , B, R44, R c and R d are defined as in formula ( I ) above X is (-NH-), (-CH 2 -NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( XVII 5 ) which is defined as above, with a compound of formula ( V ) defined as above.
  • the reaction is generally carried out in an inert solvent such as THF.
  • the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • an organic base such as triethylamine or DIPEA.
  • the reaction is generally carried out in an inert solvent such as DMA.
  • the reaction5 may be carried out in the presence of an organic base such as triethylamine or DIPEA.
  • the preparation of compounds of the formula (III) comprises the below processes (]l-j3).
  • o jl A compound of the formula LR c R d wherein L is a suitable leaving group, such as chloro, bromo, iodo can be transformed to the corresponding compound (III) using a sequence of reactions using first SMOPS* (*Baskin and Wang. Tetrahedron Letters, 2002, 43, 8479-83. See esp. page 8480, left hand column.) then followed by hydrolysis using a base like NaOMe in an inert solvent like DMSO at room temperature and further followed5 by treatment with NH 2 OSOsH and NaOAc to give a compound of formula (III).
  • a compound of the formula LSO 2 R c R d wherein L is a suitable leaving group, such as chloro, bromo, iodo can be reacted with ammonium hydroxide in an inert solvent such as DCM to give a compound of formula (III).
  • a compound of the formula LR c R d wherein L is a suitable leaving group, such as chloro, bromo, iodo can be transformed to the corresponding compound (III) using a sequence of reactions, first reacting with Na 2 SO 3 , followed by a using a reagent such as PCI5, POCI3 or SOCl 2 on the obtained product, and then treating with ammoium hydroxide to give a compound of formula (III).
  • the compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl.
  • Suitable protecting groups for carboxylic acids include (Ci-Ce)alkyl or benzyl esters.
  • Suitable protecting groups for amino include allyl, t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)ethoxymethyl or 2-trimethylsilylethoxycarbonyl (Teoc).
  • the protection and deprotection of functional groups may take place before or after any reaction in the above mentioned processes.
  • protecting groups are fully described in "Protective groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis", 4 th edition, T.W. Greene & P.G.M Wutz, Wiley-Interscince (2007).
  • Protected derivatives of the invention may be converted chemically to compounds of the invention using standard deprotection techniques (e.g. under alkaline or acidic conditions).
  • deprotection techniques e.g. under alkaline or acidic conditions.
  • certain compounds of formula ( II )-( XXVI ) may also be referred to as being "protected derivatives"
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereo isomers may be separated using conventional techniques, e.g. chromatography or crystallization.
  • the various stereisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, 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 epimerization, or by derivatisation, for example with a homochiral acid followed by separation of the diasteromeric derivatives by conventional means (e.g. HPLC, chromatography over silica or crystallization).
  • Stereo centers may also be introduced by asymmetric synthesis, (e.g. metalloorganic reactions using chiral ligands). All stereoisomers are included within the scope of the invention. It will also be understood that some of the compounds described in the processes above may exhibit the phenomenon of tautomerism and the processes described above includes any tautomeric form.
  • Salts of the compounds of formula ( I ) may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or a derivative thereof, with one or more equivalents of the appropriate base (for example ammonium hydroxide optionally substituted by Ci_C 6 - alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a hydrohalic (especially HCl ), sulphuric, oxalic or phosphoric acid).
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g.
  • reaction may also carried out on an ion exchange resin.
  • the non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product.
  • Functional inhibition of- the P2Yi 2 receptor can be measured by in vitro assays using cell membranes from P2Yi 2 transfected CHO-cells, the methodology is indicated below.
  • Functional inhibition of 2-Me-S-ADP induced P2Yi 2 signalling 5 ⁇ g of membranes were diluted in 200 ⁇ l of 20OmM NaCl, ImM MgCl 2 , 5OmM HEPES (pH 7.4), 0.01% BSA, 30 ⁇ g/ml saponin and lO ⁇ M GDP. To this was added an ECgo concentration of agonist (2-methyl-thio-adenosine diphosphate), the required concentration of test compound and 0.1 ⁇ Ci 35 S-GTPyS.
  • x is the original known x values.
  • Y is the original known y values.
  • Most of the compounds of the invention have an activity, when tested in the functional inhibition of 2-Me-S-ADPinduced P2Yi 2 signalling assay described, at a concentration of around 2 ⁇ M or below, whereas the exemplified compounds having R c R d embodified with R c being a methylene group and R d being phenyl or halogen or methoxy substituted phenyl are having an average IC50 of 0.14 ⁇ M.
  • the exemplified compounds having R c R d embodified with R c being a methylene group and R d being a fluorine substituted phenyl are having an average IC 50 of 0.08 ⁇ M.
  • the compounds of the invention act as P2Yi 2 receptor antagonists and are therefore useful in therapy.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy is provided.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment of a platelet aggregation disorder.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the inhibition of the P2Yi 2 receptor.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as an inhibitor of the P2Yi 2 receptor.
  • An alternative aspect of the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating platelet aggregation disorder.
  • Another even further aspect of the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in preventing thrombosis.
  • the compounds are useful in therapy, especially adjunctive therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaen
  • platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process.
  • the invention there is further provided the use of a compound according to the invention in the manufacture of a medicament for the treatment of the above disorders.
  • the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and angina, especially unstable angina.
  • the invention also provides a method of treatment of the above disorders which comprises administering to a patient suffering from such a disorder a therapeutically effective amount of a compound according to the invention.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, adjuvant and/or carrier.
  • the compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally .
  • the compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.
  • a pharmaceutically acceptable diluent, adjuvant or carrier particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
  • Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol.
  • Suitable carriers include sugars and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • Another possibility is to process the finely divided powder into spheres, which break up during the inhalation procedure.
  • This spheronized powder may be filled into the drug
  • a multidose inhaler e.g. that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active compound with or without a carrier substance is delivered to the patient.
  • the pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
  • the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the compound may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • Mass spectra was recorded on a Finnigan LCQ Duo ion trap mass spectrometer equipped with an electrospray interface (LC-MS) or LC-MS system consisting of a Waters ZQ using a LC-Agilent 1100 LC system.
  • LC-MS electrospray interface
  • LC-MS system consisting of a Waters ZQ using a LC-Agilent 1100 LC system.
  • HPLC separations were performed on a Waters YMC-ODS AQS-3 120 Angstrom 3 x 500 mm or on a Waters Delta Prep Systems using Kromasil Cs, 10 ⁇ m columns.
  • Purification Method A The purification system and LC-MS system used in purification Method A, referred to in some of the Examples below , was Waters Fraction Lynx I Purification System: Column: Sunfire Prep C 18, 5 mm OBD, 19 x 150 mm column.
  • IUPAC names were generated with ACDLabs Name: Release 9:00, Product version 9.04.
  • Triethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t..
  • a solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL).
  • EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL I M HCl. The organic phase was cooled to O 0 C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off , washed with 50 % EtOH ( 500 mL + 2 x 1500 rnL) and dried in a vaccum oven at 25 oC to give tert-butyl 4-
  • tert-Butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate (583 g, 1524 mmol) was suspended in formic acid (3000 mL) under a nitrogen atmosphere and the reaction was stirred for 20 minutes. The reaction was foaming due to the gas evolution and formic acid ( 500 mL) was used to wash down the foam from the reaction vessel walls. After 2 hours the foaming had stopped and the reaction was clear with a few solids left. The reaction was stirred over night and 2500 ml of formic acid was removed in vaccuo. Water (1000 mL) was added and the reaction was filtered. The clear solution was evaporated and water (3000 mL) was added.
  • Oxalyl chloride (949 mg, 4.8 mmol) and DMF (1 drop) was added to a slurry of 6- ⁇ 4- [(benzylsulfonyl)carbamoyl]piperidin-l-yl ⁇ -5-cyano-2-methylnicotinic acid (1.05 g, 2.37 mmol) in DCM (20 mL) and the reaction was stirred at r.t. until all acid was consumed. The solvent and excess reagents were evaporated and the residue was dissolved in THF (30 mL). Ferric acetylacetonate (37 mg, 0.105 mmol) was added and the mixture was cooled in an ice/water bath.
  • n-Butylmagnesium bromide was added dropwise to the red solution and the mixture was stirred for 10 minutes. Methanol (2 mL) was added and the solvent was evaporated. The residue was taken up in DCM and the organic phase was washed with water (emulsion). The mixture was acidified with 2 M HCl (10 mL) and the phases were separated. The organic phase was passed through a phase separator and evaporated to give 1.4 g of a crude product. The crude product was purified by preparative HPLC (Kromasil C 8 , using an increasing gadient of MeCN in water/0.2 % HOAc).
  • Oxalylchloride (20 mL, 282.5 mmol) and DMF (8 drops) were added to a suspension of 6- ⁇ 4-[(benzylsulfonyl)carbamoyl]piperidin-l-yl ⁇ -5-cyano-2-methylnicotinic acid (Example l(g)) (5O g, 113 mmol) in DCM (1750 mL) and the slurry was stirred for 3 hours at r.t.. An additional amount of oxalylchloride (2 mL, 28.2 mmol) was added and the stirring was continued for an additional 1.5 hours.
  • Oxalyl chloride (5.76 g, 45.38 mmol) and DMF (166 mg, 2.27 mmrnol) was added to a slurry of 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinic acid (8.25 g, 22.69 mmol) in DCM (100 mL) at 0 0 C. The mixture was stirred for 20 minutes at r.t. and the solvent and excess reagents were evaporated.
  • n-Propylmagnesium bromide 25 mL, 1 M solution in THF, 25 mmol was added dropwise to a cold (0 0 C) solution of tert-butyl l-[5-(chlorocarbonyl)-3-cyano-6-methylpyridin-2- yl]piperidine-4-carboxylate (9 g, 22.76 mmol, 92% pure) and ferric acetylacetonate (121 mg, 0.341 mmol) in THF (60 mL) and the mixture was stirred for 30 minutes. Addition of water and concentration gave an oil that was partioned between DCM and water(acidic, FA).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3,4- difluorophenyl)methanesulfonamide (82 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3,4-difluorobenzyl)sulfonyl]piperidine-4-carboxamide Yield: 61 mg ( 41 %).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methylcyclohexyl)methanesulfonamide (75 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano- 6-methylpyridin-2-yl)-N- ⁇ [(4-methylcyclohexyl)methyl]sulfonyl ⁇ piperidine-4- carboxamide. Yield: 54 mg (37 %). MS m / z : 489 (M+ 1), 487 (M-I). GTPyS(IC 50 ⁇ M): 1.08
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methoxyphenyl)methanesulfonamide (78 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-methoxybenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 30 mg (20%).
  • Example 10 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-phenylethyl)sulfonyl]piperidine-4- carboxamide o
  • Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and 2- phenylethanesulfonamide (72 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-phenylethyl)sulfonyl]piperidine-4-carboxamide.Yield: 51 mg (35 %).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- chlorophenyl)methanesulfonamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 63 mg
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3-fluoro-4- methylphenyl)methanesulfonamide (79 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3-fluoro-4-methylbenzyl)sulfonyl]piperidine-4-carboxamide.
  • Example 14 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-cyanobenzyl)sulfonyl]piperidine-4- carboxamide o
  • Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2- cyanophenyl)methanesulfonamide (76 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-cyanobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 60 mg (41%).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 48 mg (33 %).
  • Example 16 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine-4- carboxamide
  • l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 60 mg 5 (41%).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6-0 methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 46 mg (31%).
  • Example 18 o l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-methylbenzyl)sulfonyl]piperidine- 4-carboxamide
  • Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methylphenyl)methanesulfonamide (72 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-methylbenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 32 mg 5 (22%).
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2-0 chlorophenyl)methanesulfonamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 15 mg
  • Example 4(i) Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and N-(4- fluorophenyl)-N-methylsulfamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N- ⁇ [(4-fluorophenyl)(methyl)amino]sulfonyl ⁇ piperidine-4- carboxamide. Yield: 67 mg (45 %).
  • the solution was prepared as a hydroxypropyl- ⁇ -cyclodextrine solution, comprising 28% w/w of the cyclodextrin in water, buffered to pH 9.
  • the rats Two days prior to dosing, the rats were prepared by cannulation of the left carotid artery for blood sampling and, for the i.v. administration rats, by cannulation of the right jugular vein.
  • the catheters were filled with heparin (100 IU/mL), exteriorised at the nape of the neck and sealed.
  • the surgery was performed under isoflurane (Forene®, Abbott) anaesthesia.
  • the rats were housed individually and had free access to food and water. About 16 hours prior to dosing the animals were deprived of food, and fasting until 4 hours after dosing. The rats had free access to drinking water during the experiment.
  • a cage card number identified the rats.
  • the p.o. test formulation was administered orally by gavage, with the dose being 5 ⁇ mol/kg , whereas the intravenously administered dose was given in the jugular vein, with the dose being 2 ⁇ mol/kg.
  • blood samples of about 0.150 mL were withdrawn from the carotid artery, up to 24 h after dosing. About 10 samples were withdrawn. The blood samples were collected in heparinized plastic tubes and centrifuged, within 30 minutes, for five minutes at 10 000 g and +4°C. The plasma was transferred to a 96-well plate and stored at -20 0 C until analysis.
  • the plasma concentrations of the test item were determined by liquid chromatography and mass-spectrometric detection.
  • the concentrations of the test item in the formulation were confirmed by liquid chromatography and mass-spectrometric detection.
  • AUC (0-t) The area under the plasma concentration-time curve following oral and intravenous administration, AUC (0-t) , was calculated using a combination of the linear and logarithmic trapezoidal rule from the time of administration to the sampling time with the last determinable plasma concentration.
  • C(O) concentration at time zero
  • the AUC (01) was extrapolated to AUC by adding C t /k.
  • C 1 is the predicted plasma concentration at the time of the last plasma sample with a determinable concentration
  • k is the apparent terminal rate constant.
  • C t and k were obtained by linear least squares regression analysis of the logarithm of the last 3 to 5 plasma concentrations versus time.
  • the apparent terminal half-life (fc /2 ) was calculated as In 2/k.
  • the bioavailability (F) was calculated as
  • a compound (the compound of Example 3) of the invention was compared to a known compound with regard to stability against metabolic degradation caused by the cytochrome P-450 system present in the liver.

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Abstract

The present invention relates to certain new pyridin analogues of Formula ( I ) to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.

Description

6-alkyl substituted pyridine derivatives and their use in the treatment of cardiovascular disorders.
Field of the invention The present invention provides novel pyridine compounds, their use as medicaments, compositions containing them and processes for their preparation.
Background of the invention
Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion. Haemostasis is controlled via a tight balance between platelet aggregation, coagulation and fibrinolysis. Thrombus formation under pathological conditions, like e.g. arteriosclerotic plaque rupture, is firstly initiated by platelet adhesion, activation and aggregation. This results not only in the formation of a platelet plug but also in the exposure of negatively charged phospholipids on the outer platelet membrane promoting blood coagulation. Inhibition of the build-up of the initial platelet plug would be expected to reduce thrombus formation and reduce the number of cardiovascular events as was demonstrated by the anti-thrombotic effect of e.g. Aspirin (BMJ 1994; 308: 81-106 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients).
Platelet activation/aggregation can be induced by a variety of different agonists. However, distinct intracellular signalling pathways have to be activated to obtain full platelet aggregation, mediated via G-proteins Gq, G12/13 and G1 (Platelets, AD Michelson ed., Elsevier Science 2002, ISBN 0-12-493951-1; 197-213: D Woulfe, et al. Signal transduction during the initiation, extension, and perpetuation of platelet plug formation) In platelets, the G-protein coupled receptor P2Yi2 (previously also known as the platelet P2T, P2Tac, or P2Ycyc receptor) signals via Gi, resulting in a lowering of intra-cellular cAMP and full aggregation (Nature 2001; 409: 202-207 G Hollopeter, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs.). Released ADP from dense- granules will positively feedback on the P2Y12 receptor to allow full aggregation. WO 2002/098856 and WO 2004/052366 describe piperazino-carbonylmethylaminocarbonyl-naphtyl or -quinolyl derivatives as ADP receptor antagonist.
Clinical evidence for the key-role of the ADP-P2Yi2 feedback mechanism is provided by the clinical use of clopidogrel, an thienopyridine prodrug which active metabolite selectively and irreversibly binds to the P2Yi2 receptor, that has shown in several clinical trials to be effective in reducing the risk for cardiovascular events in patients at risk (Lancet 1996; 348: 1329-39: CAPRIE Steering committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE); N Engl J Med 2001; 345 (7): 494-502): The Clopidogrel in Unstable Angina to prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.). In these studies, the clinical benefit with a reduced bleeding risk as compared to thienopyridines (Sem Thromb Haemostas 2005; 31 (2): 195-204 JJJ van Giezen & RG Humphries. Preclinical and clinical studies with selective reversible direct P2Yi2 antagonists. WO 2005/000281 describes a serie of pyrazolidine-3,5-dione derivatives and WO 2006/114774 describes a serie of phenyl-pyrimidine derivatives which both series have been described as P2Yi2 antagonists for the potential treatment of thrombosis.
Some thienopyrimidines have been described as P2Yi2 antagonists in WO 2003/022214, WO 2006/103544, WO 2006/079916, WO 2006/100591, WO 2006/103545 and WO 2006/103555.
WO 2001/057037 discloses some sulfonyl derivatives as platelet ADP receptor inhibitors. None of these are 2-pyridyl-5-keto derivatives.
Furthermore, in WO 2007/056219 a quinazoline dione derivative is presented as P2Yi2 antagonist, and in WO 2007/056167 a process for its preparation is presented. WO 2006/073361 discloses some P2Yi2 antagonists for the potential treatment of thrombosis. WO 2007/008140 discloses further P2Yi2 antagonists for the potential treatment of thrombosis. Other patent applications disclosing P2Yi2 antagonists for the potential treatment of thrombosis are WO 2008/002247, WO 2008/004941, WO 2008/004942, WO 2008/004943, WO 2008/004944, WO 2008/004945 and WO 2008/004946.
It is an object of the present invention to provide improved, potent, reversible and selective P2Yi2-antagonists having beneficial properties as anti-thrombosis agents.
Summary of the invention
When testing a compound similar to formula I but having an ester function in Reposition, in rats and humans, unexpectedly low plasma concentrations of that compound was found but high plasma levels of the corresponding inactive free acid was also found. Besides hydrolysis of the esterfunction in the Ri -position, other substituents in that position may also be metabolized in vivo (with decreased plasma levels of the active compound as result) such as when the Ri -position is occupied by a substituted oxazole group.
We have now surprisingly found that certain pyridine compounds of Formula (I) or a pharmaceutically acceptable salt thereof
Figure imgf000004_0001
are reversible and selective P2Yi2 antagonists, hereinafter referred to as the compounds of the invention. The compounds of the invention, having improved stability towards esterases in Ri -position and against oxidative metabolism caused by the cytochrome P-450 system present in the liver, unexpectedly exhibit improved beneficial properties that render them particularly suitable for use in the treatment of diseases/conditions as described below (See p.69-70). Examples of such beneficial properties are high potency, high selectivity, metabolic stability, beneficial pharmacokinetic properties and an advantageous therapeutic window. It is believed that the metabolic stability is connected to the absence of ester groups or substituted oxazole groups in the Ri-position, and that the high potency exhibited for certain compounds of the invention is related to the selection of certain substituents in the RcRd-position, examples of such RcRd substituents are Rc being a methylene group and Rd being phenyl or halogen substituted phenyl .The fact that they are stable against esterase activity in Ri-position will inhibit degradation to inactive free acid in vivo, which inhibition of degradation is further improved by the metabolic stability. It is believed that thereby the desired plasma concentration levels of the active compound will be maintained in humans and/or animals.
Detailed description of the invention
According to the present invention there is provided a novel compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
(I) wherein
Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-Ci2)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-Ce)cycloalkyl, hydroxy(Ci-Ci2)alkyl, aryl or heterocyclyl; B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Cg)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Cg)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C3- Ce)cycloalkyl and heterocyclyl; further Ri4 represents aryl, aryl(Ci-Cg)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)cycloalkyl(Ci-C8)alkoxy, hydroxy(Ci-Cg)alkyl, (Ci-Cg)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Cg)alkylsulfmyl, (Ci-Cg)alkylsulfonyl, (Ci-Cg)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (C1- C8)alkyl, (Ci-Cg)alkylC(O), (Ci-Cg)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rc represents an unsubstituted or monosubstituted or polysubstituted (Ci- C4)alkylene group, wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, oxy-(Ci-C4)alkyl, (C2-C4)alkenyl, (C2- C4)alkynyl, (C3-Ce)cycloalkyl, carboxyl, carboxy-(Ci-C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or RΆ(RC) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine; further Rc represents imino (-NH-), N-substituted imino (-NR19-), (Ci-C4)alkyleneimino or N-substituted (Ci-C4)alkyleneimino ( -N(Ri9)-((Ci-C4)alkylene) wherein the mentioned alkylene groups are unsubstituted or monosubstituted or polysubstituted with any substituents according to above; preferably Rc represents imino, N-substituted imino or (Ci-C4)alkyleneimino or an unsubstituted or monosubstituted or polysubstituted (C1- C4)alkylene group with any substituents according to above;
Ri9 represents H or (Ci-C4)alkyl;
5
Rd represents (Ci-Ci2)alkyl, (C3-Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-Ci2)alkyl, (Ci-Ci2)alkoxyC(O), (C1- Ci2)alkoxy, halogen substituted (C1-C 12)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, (C1-o Ci2)alkylsulfmyl, (Ci-Ci2)alkylsulfonyl, (Ci-Ci2)alkylthio, (C3-C6)cycloalkylthio, arylsulfmyl, arylsulfonyl, arylthio, aryl(Ci-Ci2)alkylthio, aryl(Ci-Ci2)alkylsulfϊnyl, aryl(Ci-Ci2)alkylsulfonyl, heterocyclyl(Ci-Ci2)alkylthio, heterocyclyl(Ci-Ci2)alkylsulfϊnyl, heterocyclyl(Ci-Ci2)alkylsulfonyl, (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfϊnyl, (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfonyl or a group ofs formula NR a(Rd) R b(Rd) in which R a(Rd) and R b(Rd) independently represent H, (C1-C12)alkyl,
(Ci-Ci2)alkylC(O) or Ra(Rd) and Rb(Rd) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (-o CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl; further X may represent a group (-CH2-)n wherein n= 2-6, which optionally is unsaturated and/or substituted by one or more substituent chosen among halogen, hydroxyl or (Ci-Ce)alkyl;5 the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-memberedo monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon. An alternative embodiment of formula (I) or a pharmaceutically acceptable salt thereof is:
Figure imgf000008_0001
(I) wherein
Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-Ci2)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-Ce)cycloalkyl, hydroxy(Ci-Ci2)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Rn is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Cg)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Cg)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C3- Ce)cycloalkyl and heterocyclyl; further Ri4 represents aryl, aryl(Ci-C8)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)cycloalkyl(Ci-C8)alkoxy, hydroxy(Ci-C8)alkyl, (Ci-C8)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C8)alkylsulfmyl, (d-C8)alkylsulfonyl, (d-C8)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (C1- C8)alkyl, (Ci-C8)alkylC(O), (Ci-C8)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rc is methylene (-CH2-);
Rd represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C6)alkoxy group;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (-
CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl; further X may represent a group (-CH2-)n wherein n= 2-6, which optionally is unsaturated and/or substituted by one or more substituent chosen among halogen, hydroxyl or (Ci-Ce)alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
Preferred values of each variable group or specific embodiments of variable groups or terms are as follows. Such values or embodiments may be used where appropriate with any of the values, definitions, claims, aspects, embodiments or embodiments of the invention defined hereinbefore or hereinafter. In particular, each may be used as an individual limitation on the broadest definition of formula (I).
For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.
It will be understood that when formula I compounds contain a chiral centre, the compounds of the invention may exist in, and be isolated in, optically active or racemic form. The invention includes any optically active or racemic form of a compound of formula I which act as P2Yi2 receptor antagonists. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic mixture, by chiral chromatography, synthesis from optically active starting materials or by asymmetric synthesis.
It will also be understood that the compounds of the formula I may exhibit the phenomenon of tautomerism, the present invention includes any tautomeric form of a compound of formula I which is a P2Yi2 receptor antagonist.
It will also be understood that in so far as compounds of the present invention exist as solvates, and in particular hydrates, these are included as part of the present invention.
It is also to be understood that generic terms such as "alkyl" include both the straight chain and branched chain groups such as butyl and tert-butyl. However, when a specific term such as "butyl" is used, it is specific for the straight chain or "normal" butyl group, branched chain isomers such as "t-butyl" being referred to specifically when intended.
Generally, alkyl is unsubstituted or substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (C1-C 12)alkyl, halogen substituted (Ci-Ci2)alkyl, unsubstituted (C1- Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci2)alkoxy, halogensubstituted (Ci-Ci2)alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl, halogensubstituted heterocyclyl, unsubstituted (Ci-Ci2)alkylsulfmyl, halogensubstituted (Ci-Ci2)alkylsulfϊnyl, unsubstituted (Ci-Ci2)alkylsulfonyl, halogensubstituted (C1- Ci2)alkylsulfonyl, unsubstituted (Ci-Ci2)alkylthio, halogensubstituted (Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkylthio, halogensubstituted (C3-C6)cycloalkylthio, unsubstituted arylsulfinyl, halogensubstituted arylsulfϊnyl, unsubstituted arylsulfonyl, halogensubstituted arylsulfonyl, unsubstituted arylthio, halogensubstituted arylthio, unsubstituted aryl(Ci-Ci2)alkylthio, halogensubstituted aryl(Ci-Ci2)alkylthio, unsubstituted aryl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted aryl(Ci-Ci2)alkylsulfinyl, unsubstituted aryl(Ci-Ci2)alkylsulfonyl, halogensubstituted aryl(Ci-Ci2)alkylsulfonyl, unsubstituted heterocyclyl(Ci-Ci2)alkylthio, halogensubstituted heterocyclyl(Ci-Ci2)alkylthio, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfinyl, halogensubstituted heterocyclyl(Ci- Ci2)alkylsulfinyl, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, unsubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted (C3-C6)cycloalkyl(Ci- Ci2)alkylsulfinyl, unsubstituted (C3-C6)cycloalkyl(Ci -C i2)alkylsulfonyl, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfonyl or a group of formula NRaRb in which Ra and Rb independently represent H, unsubstituted (Ci-Ci2)alkyl, unsubstituted (C1- Ci2)alkylC(O) or Ra and Rb together with the nitrogen atom represent unsubstituted piperidine, unsubstituted pyrrolidine, unsubstituted azetidine or unsubstituted aziridine.
The term "alkyl" includes both linear or branched chain groups, unless otherwise specified. In one embodiment alkyl is optionally substituted by one or more halogens (F, Cl, Br or I) or mixed halogen atoms.
One embodiment of alkyl when substituted by one or more halogen atoms (F, Cl, Br or I) is alkyl substituted by one or more fluorine atoms. Another embodiment of halogen substituted alkyl includes perfluoroalkyl groups such as trifluoromethyl, and pentafluoroethyl. As used herein, when two or more groups are used in connection with each other, it means that the latter group is substituted by the immediately preceding group. For instance, aryl(Ci-C6)alkyl means a (Ci-C6) alkyl group substituted by an aryl group.
As used herein, the expression "alkyl optionally interrupted by oxygen", or "alkyl interrupted by oxygen"means that the optional oxygen atom is placed inside the alkyl group between two carbon atoms of the considered alkyl group, and not in any of the ends thereof.
The term "cycloalkyl" generally denotes a substituted or unsubstituted (C3-C6), unless other chain length specified, cyclic hydrocarbon.
Generally, when cycloalkyl is substituted with aryl, heterocyclyl or another cycloalkyl, that substituent is not again substituted with another one of any one of these groups. It is not contemplated in this invention to create a "polymer" compound. Thus, e.g. -cycloalkyl-cycloalkyl, -cycloalkyl-heterocyclyl and -cycloalkyl-aryl are intended to be covered, but -cycloalkyl-cycloalkyl-cycloalkyl as well as -cycloalkyl-aryl-cycloalkyl or - cycloalkyl-heterocyclyl-aryl or even longer such chains are intended to be excluded from the invention.
When the term "cycloalkyl" denotes a substituted hydrocarbon according to above, it denotes a cyclic hydrocarbon according to above which is being substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogen substituted (Ci-Ci2)alkyl, unsubstituted (Ci-Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci2)alkoxy, halogensubstituted (Ci-Ci2)alkoxy, unsubstituted (C3-C6)cycloalkyl, halogensubstituted (C3-C6)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl, halogensubstituted heterocyclyl, unsubstituted (Ci- Ci2)alkylsulfmyl, halogensubstituted (Ci-Ci2)alkylsulfinyl, unsubstituted (Ci- Ci2)alkylsulfonyl, halogensubstituted (Ci-Ci2)alkylsulfonyl, unsubstituted (Ci- Ci2)alkylthio, halogensubstituted (Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkylthio, halogensubstituted (C3-C6)cycloalkylthio, unsubstituted arylsulfinyl, halogensubstituted arylsulfinyl, unsubstituted arylsulfonyl, halogensubstituted arylsulfonyl, unsubstituted arylthio, halogensubstituted arylthio, unsubstituted aryl(Ci-Ci2)alkylthio, halogensubstituted aryl(Ci-Ci2)alkylthio, unsubstituted aryl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted aryl(Ci-Ci2)alkylsulfinyl, unsubstituted aryl(Ci-Ci2)alkylsulfonyl, halogensubstituted aryl(Ci-Ci2)alkylsulfonyl, unsubstituted heterocyclyl(Ci-Ci2)alkylthio, halogensubstituted heterocyclyl(Ci-Ci2)alkylthio, unsubstituted heterocyclyl(Ci- Ci2)alkylsulfinyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfϊnyl, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, halogensubstituted heterocyclyl(Ci -C i2)alkylsulfonyl, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, halogensubstituted (C3-
C6)cycloalkyl(Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfinyl, unsubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfonyl, halogensubstituted (C3-C6)Cy cloalkyl(Ci- Ci2)alkylsulfonyl or a group of formula NRaRb in which Ra and Rb independently represent H, unsubstituted (C1-C 12)alkyl, unsubstituted (Ci-Ci2)alkylC(O) or Ra and Rb together with the nitrogen atom represent unsubstituted piperidine, unsubstituted pyrrolidine, unsubstituted azetidine or unsubstituted aziridine.
The term "alkoxy" includes both linear or branched chain groups, unless otherwise specified optionally substituted by one or more halogens (F, Cl, Br or I) or mixed halogen atoms.
The term aryl in general without other specification denotes a substituted or unsubstituted (Cg-C 14) aromatic hydrocarbon and includes, but is not limited to, phenyl, naphthyl, tetrahydronaphtyl, indenyl, indanyl, antracenyl, fenantrenyl, and fluorenyl.
Generally, when aryl is substituted with cycloalkyl, heterocyclyl or another aryl, that substituent is not again substituted with another one of any one of these groups. It is not contemplated in this invention to create a "polymer" compound. Thus, e.g. -aryl-aryl, - aryl-heterocyclyl and -aryl-cycloalkyl are intended to be covered, but -aryl-aryl-aryl as well as -aryl-cycloalkyl-aryl or aryl-heterocyclyl-cycloalkyl or even longer such chains are intended to be excluded from the invention. When said aryl is being substituted, it is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogensubstituted (Ci-Ci2)alkyl, unsubstituted (C1- Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci2)alkoxy, halogensubstituted (Ci-Ci2)alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl, halogensubstituted heterocyclyl, unsubstituted (Ci-Ci2)alkylsulfmyl, halogensubstituted (Ci-Ci2)alkylsulfϊnyl, unsubstituted (Ci-Ci2)alkylsulfonyl, halogensubstituted (C1- Ci2)alkylsulfonyl, unsubstituted (Ci-Ci2)alkylthio, halogensubstituted (Ci-Ci2)alkylthio, unsubstituted (C3-Ce)cycloalkylthio, halogensubstituted (C3-Ce)cycloalkylthio, unsubstituted arylsulfinyl, halogensubstituted arylsulfϊnyl,unsubstituted arylsulfonyl, halogensubstituted arylsulfonyl, unsubstituted arylthio, halogensubstituted arylthio,unsubstituted aryl(Ci-Ci2)alkylthio, halogensubstituted aryl(Ci-Ci2)alkylthio, unsubstituted aryl(Ci-Ci2)alkylsulfmyl, halogensubstituted aryl(Ci-Ci2)alkylsulfinyl, unsubstituted aryl(Ci-Ci2)alkylsulfonyl, halogensubstituted aryl(Ci-Ci2)alkylsulfonyl, unsubstituted heterocyclyl(Ci-Ci2)alkylthio, halogensubstituted heterocyclyl(Ci- Ci2)alkylthio, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfmyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfϊnyl, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, unsubstituted (C3-C6)cycloalkyl(Ci- Ci2)alkylthio, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, unsubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted (C3-C6)cycloalkyl(Ci- Ci2)alkylsulfinyl, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfonyl, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfonyl or a group of formula NRaRb in which Ra and Rb independently represent H, unsubstituted (Ci-Ci2)alkyl, unsubstituted (Ci-Ci2)alkylC(O) or Ra and Rb together with the nitrogen atom represent unsubstituted piperidine, unsubstituted pyrrolidine, unsubstituted azetidine or unsubstituted aziridine.
In one embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogensubstituted (Ci-Ci2)alkyl, unsubstituted (Ci-Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci2)alkoxy, halogensubstituted (Ci-Ci2)alkoxy, unsubstituted (C3-Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl, halogensubstituted heterocyclyl, unsubstituted (Ci-Ci2)alkylsulfinyl, halogensubstituted (Ci-Ci2)alkylsulfϊnyl, unsubstituted (Ci-Ci2)alkylsulfonyl, halogensubstituted (Ci-Ci2)alkylsulfonyl, unsubstituted (C1- Ci2)alkylthio, halogensubstituted (Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkylthio, halogensubstituted (C3-C6)cycloalkylthio, unsubstituted arylsulfϊnyl, halogensubstituted arylsulfinyl,unsubstituted arylsulfonyl, halogensubstituted arylsulfonyl, unsubstituted arylthio, halogensubstituted arylthio,unsubstituted aryl(Ci-Ci2)alkylthio, halogensubstituted aryl(Ci-Ci2)alkylthio, unsubstituted aryl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted aryl(Ci-Ci2)alkylsulfinyl, unsubstituted aryl(Ci-Ci2)alkylsulfonyl, halogensubstituted aryl(Ci-Ci2)alkylsulfonyl, unsubstituted heterocyclyl(Ci-Ci2)alkylthio, halogensubstituted heterocyclyl(Ci-Ci2)alkylthio, unsubstituted heterocyclyl(Ci- Ci2)alkylsulfinyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfϊnyl, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, halogensubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfinyl, unsubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfonyl, halogensubstituted (C3-C6)Cy cloalkyl(Ci-
Ci2)alkylsulfonyl or a group of formula NRaRb in which Ra and Rb independently represent H, unsubstituted (C1-C 12)alkyl, unsubstituted (Ci-C12)alkylC(O) or Ra and Rb together with the nitrogen atom represent unsubstituted piperidine, unsubstituted pyrrolidine, unsubstituted azetidine or unsubstituted aziridine.
In another embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, cyano, unsubstituted (Ci-C6)alkyl, and unsubstituted (Ci-Ce)alkoxy. In a further embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (C1- Ce)alkoxy.
In an alternative further embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more atoms selected from F and Cl and mixtures thereof, and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
In a second alternative further embodiment of the invention, the term aryl in general without other specification denotes a substituted phenyl group, which is substituted by one or more atoms selected from F and Cl and mixtures thereof, and/or one of the following groups, cyano, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
In an even further embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms or one of the following groups, unsubstituted (Ci-Ce)alkyl, and unsubstituted (Ci-Ce)alkoxy.
In another even further embodiment of the invention, the term aryl in general without other specification denotes a substituted or unsubstituted phenyl group, which when substituted is substituted by one or more of the following groups, unsubstituted (Ci-C6)alkyl, and unsubstituted (Ci-Ce)alkoxy.
In an alternative other embodiment of the invention, the term aryl in general without other specification denotes a phenyl group substituted by one or more of fluoro and/or methyl.
In a 2nd alternative other embodiment of the invention, the term aryl in general without other specification denotes a phenyl group substituted by one or more fluorine atoms. The term "heterocyclyl" denotes a substituted or unsubstituted, 4- to 10- membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon, for example nitrogen, oxygen or sulfur, especially 4-, 5- or 6-membered aromatic or aliphatic hetorocyclic groups, and includes, but is not limited to azetidine, furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxathiolane, oxazolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, oxadiazole, furazan, triazole, thiadiazole, pyran, pyridine as well as pyridine-N-oxide, piperidine, dioxane, morpholine, dithiane, oxathiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, thiadiazine, dithiazine, azaindole, azaindoline, indole, indoline, naphthyridine, benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3- dihydrobenzofuran, isoxazole, 3-benzisoxazole, 1 ,2-benzisoxazole, dihydropyrazole groups, and shall be understood to include all isomers of the above identified groups. For the above groups, e.g. azetidinyl, the term "azetidinyl" as well as "azetidinylene", etc., shall be understood to include all possible regio isomers. It is further to be understood that the term heterocyclyl may be embodified by one selection among the given possible embodiments for a variable and embodified by another (or the same) selection for another variable, eg. R2 when selected as heterocyclyl may be a furan, when Rd (also when selected as heterocyclyl) may be a pyrrole.
Generally, when heterocyclyl is substituted with cycloalkyl, aryl or another heterocyclyl, that substituent is not again substituted with another one of any one of these groups. Thus it is not contemplated in this invention to create a "polymer" compound. . It is not contemplated in this invention to create a "polymer" compound. Thus, e.g., -heterocyclyl-heterocyclyl, -heterocyclyl-aryl, and -heterocyclyl-cycloalkyl are intended to be covered, but -heterocyclyl-heterocyclyl-heterocyclyl as well as -heterocyclyl- cycloalkyl-aryl or heterocyclyl-cycloalkyl-heterocyclyl or even longer such chains are intended to be excluded from the invention. When the term "heterocyclyl" denotes a substituted ring system according to above, it denotes a ring system according to above which is being substituted by one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms and/or one or more of the following groups, OH, CN, unsubstituted (Ci-Ci2)alkyl, halogensubstituted (Ci-Ci2)alkyl, unsubstituted (Ci-Ci2)alkoxyC(O), halogensubstituted (Ci-Ci2)alkoxyC(O), unsubstituted (Ci-Ci2)alkoxy, halogen substituted (Ci-Ci2)alkoxy, unsubstituted (C3- Ce)cycloalkyl, halogensubstituted (C3-Ce)cycloalkyl, unsubstituted aryl, halogensubstituted aryl, unsubstituted heterocyclyl, halogensubstituted heterocyclyl, unsubstituted (Ci- Ci2)alkylsulfϊnyl, halogensubstituted (Ci-Ci2)alkylsulfϊnyl, unsubstituted (Ci- Ci2)alkylsulfonyl, halogensubstituted (Ci-Ci2)alkylsulfonyl, unsubstituted (Ci-
Ci2)alkylthio, halogensubstituted (Ci-Ci2)alkylthio, unsubstituted (C3-Ce)cycloalkylthio, halogensubstituted (C3-Ce)cycloalkylthio, unsubstituted arylsulfmyl, halogensubstituted arylsulfinyl, unsubstituted arylsulfonyl, halogensubstituted arylsulfonyl, unsubstituted arylthio, halogensubstituted arylthio, unsubstituted aryl(Ci-Ci2)alkylthio, halogensubstituted aryl(Ci-Ci2)alkylthio, unsubstituted aryl(Ci-Ci2)alkylsulfϊnyl, halogensubstituted aryl(Ci-Ci2)alkylsulfinyl, unsubstituted aryl(Ci-Ci2)alkylsulfonyl, halogensubstituted aryl(d-Ci2)alkylsulfonyl, unsubstituted heterocyclyl(Ci-Ci2)alkylthio, halogensubstituted heterocyclyl(Ci-Ci2)alkylthio, unsubstituted heterocyclyl(Ci- Ci2)alkylsulfinyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfϊnyl, unsubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, halogensubstituted heterocyclyl(Ci-Ci2)alkylsulfonyl, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylthio, halogensubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylthio, unsubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfmyl, halogensubstituted (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfinyl, unsubstituted (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfonyl, halogensubstituted (C3-Ce)cycloalkyl(C 1- Ci2)alkylsulfonyl or a group of formula NRaRb in which Ra and Rb independently represent H, unsubstituted (Ci-Ci2)alkyl, unsubstituted (Ci-Ci2)alkylC(O) or Ra and Rb together with the nitrogen atom represent unsubstituted piperidine, unsubstituted pyrrolidine, unsubstituted azetidine or unsubstituted aziridine.
In another embodiment of the invention the heterocyclyl group comprises an aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, and an aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur which is fused to a benzene ring;
In an alternative embodiment of the invention the heterocyclyl group is a non- aromatic 5-membered or 6-membered heterocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, fused to a benzene ring.
In a further embodiment of the invention the heterocyclyl group is a group chosen among furyl, pyrrolyl, thienyl, pyridyl, N-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl, indolyl, benzdihydrofuranyl, benzodioxolyl (such as 1,3-benzodioxolyl), benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3- dihydrobenzofuran, isoxazole, dihydropyrazole and benzdioxanyl (such as 1 ,4- benzdioxanyl). More particular values include, for example, furyl, pyrrolyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3-dihydrobenzofuran, isoxazole, 1,2- benzisoxazole, dihydropyrazole and benzdioxanyl (such as 1,4-benzdioxanyl).
In an even further embodiment of the invention the heterocyclyl group is a group chosen among furyl, pyrrolyl, thienyl, pyridyl, N-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoxadiazole, dihydrobenzodioxin, benzothiophene, benzothiadiazole, imidazothiazole, 2,3-dihydrobenzofuran, isoxazole, 1 ,2-benzisoxazole or dihydropyrazole.
In one embodiment of the invention Ri is R7C(O) wherein R7 can be methyl, ethyl, isopropyl, cyclo-propyl, iso-butyl, n-butyl, cyclo-butyl, n-propyl, or tertbutyl..
In a further embodiment of the invention Ri is R7C(O) wherein R7 is (Ci-Ce)alkyl. In an other further embodiment of the invention Ri is R7C(O) and wherein R7 is selected among propyl and butyl.
Embodiments for R2 include unsubstituted (C2-C3)alkyl. Another embodiment for R2 is unsubstituted (Ci-C2)alkyl.
In one other embodiment of the invention R2 is represented by methyl.
In one other further embodiment of the invention R2 is represented by ethyl. In one other further alternative embodiment of the invention R2 is represented by n- propyl or isopropyl.
In one embodiment of the invention R7 is (Ci-C6)alkyl, aryl or hydroxy(Ci-C6)alkyl.
In another embodiment of the invention R7 is (Ci-Ce)alkyl or hydroxy(Ci-C6)alkyl. In an alternative embodiment of the invention R7 is (Ci-Ce)alkyl or aryl.
In an another alternative embodiment of the invention R7 is (Ci-Ce)alkyl or heterocyclyl.
In an further alternative embodiment of the invention R7 is aryl or heterocyclyl.
In an even further alternative embodiment of the invention R7 is (Ci-C6)alkyl.
In a further embodiment of the invention R7 is (Ci-C4)alkyl. In another further embodiment of the invention R7 is (C2-C4)alkyl.
In a particular further embodiment R7 is chosen among propyl and butyl.
In another particular embodiment of the invention R7 is propyl.
In one embodiment of the invention Ri4 is selected from a group consisting of hydrogen, methyl and amino.
In another embodiment Ri4 is hydrogen or methyl. In a further embodiment Ri4 is hydrogen or amino. In an alternative embodiment of the invention Ri4 represents H.
In one embodiment of the invention Rd represents (Ci-Ci2)alkyl.
Further embodiments for Rd includes aryl or heterocyclyl, more particularly, aryl ( aromatic heterocyclyl.
Another embodiment for Rd include, aryl such as phenyl and aromatic heterocyclyl such as thienyl. In a further embodiment Rd is phenyl substituted by 0,1 or 2 fluorine or chlorine atoms.
In another further embodiment Rd is phenyl substituted by 0,1 or 2 fluorine atoms. In an even further embodiment Rd is phenyl substituted by 0,1 or 2 fluorine atoms or by 1 chlorine atom.
Other embodiments of Rd include phenyl which optionally may be substituted.
In a special embodiment Rd represents aryl, heterocyclyl or (C3-Ce)cycloalkyl, and anyone of these groups are optionally substituted with one or more halogen (F, Cl, Br or I) atoms or mixed halogen atoms, and/or one or more of the following groups, OH, CN, NO2, (Ci-Ci2)alkyl, (Ci-Ci2)alkoxyC(O), (Ci-Ci2)alkoxy, halogen substituted (Ci-Ci2)alkyl, (C3- Ce)cycloalkyl, aryl, heterocyclyl, (Ci-Ci2)alkylsulfmyl, (Ci-Ci2)alkylsulfonyl, (Ci- Ci2)alkylthio, (C3-Ce)cycloalkylthio, arylsulfmyl, arylsulfonyl, arylthio, aryl(Ci- Ci2)alkylthio, aryl(Ci-Ci2)alkylsulfmyl, aryl(Ci-Ci2)alkylsulfonyl, heterocyclyl(Ci- Ci2)alkylthio, heterocyclyl(Ci-Ci2)alkylsulfϊnyl, heterocyclyl(Ci-Ci2)alkylsulfonyl, (C3- C6)cycloalkyl(Ci-Ci2)alkylthio, (C3-C6)cycloalkyl(Ci-Ci2)alkylsulfmyl, (C3- C6)cycloalkyl(Ci-Ci2)alkylsulfonyl or a group of formula NRa(Rd)Rb(Rd) in which Ra(Rd) and Rb(Rd) independently represent H, (Ci-Ci2)alkyl, (Ci-Ci2)alkylC(O) or Ra(Rd) and Rb(Rd) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine.
Even further embodiments for Rd include phenyl optionally substituted at the 2,3,4 or 5-positions as well as any combination thereof. Example of substituents are cyano, tetrazol-5-yl, methoxy, trifluoromethoxy, methyl, trifluoromethyl, fluoro, chloro, bromo, methylsulfonyl, nitro, 3-methyl-5-oxo-4,5-dihydro-lH-pyrazol-l-yl. Two adjacent positions (e.g. 2,3) may also be connected to form a ring. Example of such a substituent is 2-naphtyl. Further more specific values for heteroaryls are 2-chloro-5-thienyl, 3-bromo-5- chloro-2-thienyl, 2,l,3-benzoxadiazol-4-yl, 2,4-dimethyl-l,3-thiazol-5-yl, 2,3-dihydro-l,4- benzodioxin-6-yl, 5-chloro-3-methyl-l-benzothien-2-yl, 2,l,3-benzothiadiazol-4-yl, 2,5- dimethyl-3-furyl, 6-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-5-yl, 2,3-dihydro-l -benzofuran-5-yl, 5-chloro-3-thienyl, 5-isoxazol-5-yl-2-thienyl, 5-isoxazol-3-yl-2-thienyl, 4-bromo-5 -chloro- 2-thienyl, 5-bromo-6-chloropyridin-3-yl, 5-bromo-2-thienyl, 5-pyridin-2-yl-2-thienyl, 2,5- dichloro-3-thienyl, 4,5-dichloro-2-thienyl,benzothien-3-yl, 2,5-dimethyl-3-thienyl, 3- thienyl,2-thienyl, 5-methylisoxazol-4-yl, pyridin-3-yl, [l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl]-2-thienyl, 5-chloro- 1 ,3-dimethyl- lH-pyrazol-4-yl, 4-[(4- chlorophenyl)sulfonyl]-3-methyl-2-thienyl, 5-(methoxycarbonyl)-2-furyl and A- (methoxycarbonyl)-5-methyl-2-furyl.
Even another further embodiments for Rd include phenyl optionally substituted at the 2,3,4,5 or 6-positions as well as any combination thereof. Example of substituents are cyano, tetrazol-5-yl, methoxy, trifluoromethoxy, methyl, trifluoromethyl, fluoro, chloro, bromo, methylsulfonyl, nitro, 3-methyl-5-oxo-4,5-dihydro-lH-pyrazol-l-yl. Two adjacent positions (e.g. 2,3) may also be connected to form a ring. Example of such a substituent is 2-naphtyl. Further more specific values for heteroaryls are 2-chloro-5-thienyl, 3-bromo-5- chloro-2-thienyl, 2,l,3-benzoxadiazol-4-yl, 2,4-dimethyl-l,3-thiazol-5-yl, 2,3-dihydro-l,4- benzodioxin-6-yl, 5-chloro-3-methyl-l-benzothien-2-yl, 2,l,3-benzothiadiazol-4-yl, 2,5- dimethyl-3-furyl, 6-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-5-yl, 2,3-dihydro-l -benzofuran-5-yl, 5-chloro-3-thienyl, 5-isoxazol-5-yl-2-thienyl, 5-isoxazol-3-yl-2-thienyl, 4-bromo-5 -chloro- 2-thienyl, 5-bromo-6-chloropyridin-3-yl, 5-bromo-2-thienyl, 5-pyridin-2-yl-2-thienyl, 2,5- dichloro-3-thienyl, 4,5-dichloro-2-thienyl,benzothien-3-yl, 2,5-dimethyl-3-thienyl, 3- thienyl,2-thienyl, 5-methylisoxazol-4-yl, pyridin-3-yl, [l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl]-2-thienyl, 5-chloro- 1 ,3-dimethyl- lH-pyrazol-4-yl, 4-[(4- chlorophenyl)sulfonyl]-3-methyl-2-thienyl, 5-(methoxycarbonyl)-2-furyl and A- (methoxycarbonyl)-5-methyl-2-furyl.
In one embodiment of the invention Rc represents an unsubstituted or monosubstituted or disubstituted (Ci-C4)alkylene group wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, OXy-(C1- C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, carboxyl, carboxy-(Ci- C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or RΆ(RC) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine, and Rd represents aryl, i.e RcRd represents an aryl-(Ci-C4)alkylene group with any substituents according to above.
In a preferred embodiment of the invention Rc represents an unsubstituted or monosubstituted or disubstituted (Ci-C3)alkylene group wherein any substituents each individually and independently are selected from (d-C4)alkyl, (d-C4)alkoxyl, oxy-(Cr C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-Ce)cycloalkyl, carboxyl, carboxy-(Ci- C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra<-Rc^and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or Ral-RcVnd Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine , and Rd represents aryl, i.e RcRd represents an aryl-(Ci- Cs)alkylene group with any substituents according to above.
In a further embodiment of the invention Rc represents an unsubstituted or monosubstituted or disubstituted (Ci-C4)alkylene group wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, oxy-(Ci- C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-Ce)cycloalkyl, carboxyl, carboxy-(Ci- C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or Ra^Rc) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine, and Rd represents heterocyclyl, i e. Rc Rd represents a heterocyclyl-(Ci-C4)alkylene group with any substituents according to above.
In a further preferred embodiment of the invention Rc represents an unsubstituted or monosubstituted or disubstituted (Ci-C3)alkylene group wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, oxy-(Ci- C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, carboxyl, carboxy-(Ci- C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or Ra^Rc) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine, and Rd represents heterocyclyl, i e. Rc Rd represents a heterocyclyl-(Ci-C3)alkylene group with any substituents according to above.
In a further particular embodiment of the invention Rc represents an unsubstituted or monosubstituted or disubstituted Ci-alkylene group wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, oxy-(Ci- C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, carboxyl, carboxy-(Ci- C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or RΆ(RC) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine, and Rd represents aryl, i.e RcRd represents an aryl-Ci-alkylene group with any substituents according to above.
In an alternative embodiment of the invention Rc represents imino (-NH-) or N- methylimino (-N(CH3)-).
In a further alternative embodiment of the invention Rc is methylene (-CH2-).
In one embodiment of the invention R19 represents hydrogen. In another embodiment of the invention R19 represents methyl.
In a most particular embodiment of the invention Rc Rd represents a benzyl group, or a benzyl group which is substituted according to what is described in connection to substitution of the aryl group.
In another particular embodiment of the invention Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2,3,4 or 5 halogen atoms. In an even further particular embodiment of the invention Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2 or 3 halogen atoms.
In an alternative further particular embodiment of the invention Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 halogen atoms.
Embodiments of Rc Rd aacording to the invention also comprises that Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2,3,4 or 5 fluorine atoms. Further, embodiments of Rc Rd aacording to the invention also comprises that RcRd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1,2 or 3 fluorine atoms.
Even further, embodiments of Rc Rd aacording to the invention also comprises that Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms or 1 chlorine atom.
In another further, embodiment of RcRd aacording to the invention Rc Rd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms.
Utterly further, embodiments of RcRd aacording to the invention also comprises that RcRd represents a benzyl group, or a benzyl group which is substituted in the phenyl ring with 0,1 or 2 fluorine atoms or with a methoxy group.
In one embodiment of the invention X represents a single bond. In another embodiment of the invention X represents imino (-NH-) or methylene (- CH2- ). In yet another embodiment X represents imino (-NH-) . In a further embodiment X represents methylene (-CH2- ).
Suitable values for the B ring/ring system include, for example, diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene and azetidinylene, wherein anyone of them may be presents in any of their isomeric forms (e.g. piperazin -tetrahydropyridazin- tetrahy dropyrimidin) .
Embodiments for the B ring/ring system include, for example, diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene and azetidinylene. Further embodiments include these groups which are substituted with Ri4 having a (Ci-C6)alkyl group, wherein the (Ci-Ce)alkyl group optionally is substituted with OH, COOH or COORe group(s), e.g. a 2-carboxyethyl group, and wherein Re represents H, aryl, cycloalkyl, heterocyclyl or (Ci- Ci2)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) or mixed halogen atoms, OH, aryl, cycloalkyl and heterocyclyl.
In an alternative to the embodiment for the B ring/ring system above, the embodiment include diazepanylene, piperazinylene, piperidinylene, pyrrolidinylene or azetidinylene groups which are substituted with Ri4 having a (Ci-C6)alkyl group, wherein the (Ci-Ce)alkyl group optionally is substituted with OH, COOH or COORe group(s), e.g. a 2-carboxyethyl group, and wherein Re represents H, aryl, cycloalkyl, heterocyclyl or (C1- Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) or mixed halogen atoms, OH, aryl, cycloalkyl and heterocyclyl.
In one embodiment of the invention the term halogen includes only fluorine and chlorine.
A 2nd embodiment of formula I is defined by; Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-Ce)cycloalkyl, hydroxy(Ci-C6)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Rn is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection); Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C3- Ce)cycloalkyl and heterocyclyl; further Ri4 represents aryl, aryl(Ci-C6)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)cycloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfϊnyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci- C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rc represents an unsubstituted or monosubstituted or polysubstituted (Ci- C4)alkylene group, wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, oxy-(Ci-C4)alkyl, (C2-C4)alkenyl, (C2- C4)alkynyl, (C3-C6)cycloalkyl, carboxyl, carboxy-(Ci-C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or RΆ(RC) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine; further Rc represents imino (-NH-), N-substituted imino (-NR19-), (Ci-C4)alkyleneimino or N-substituted (Ci-C4)alkyleneimino ( -N(Ri9)-((Ci-C4)alkylene) wherein the mentioned alkylene groups are unsubstituted or monosubstituted or polysubstituted with any substituents according to above; preferably Rc represents imino, N-substituted imino or (Ci-C4)alkyleneimino or an unsubstituted or monosubstituted or polysubstituted (C 1- C4)alkylene group with any substituents according to above;
Ri9 represents H or (Ci-C4)alkyl;
Rd represents (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-C6)alkyl, (Ci-C6)alkoxyC(O), (Ci- C6)alkoxy, halogen substituted (Ci-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, (C1- C6)alkylsulfmyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, arylsulfϊnyl, arylsulfonyl, arylthio, aryl(Ci-C6)alkylthio, aryl(Ci-C6)alkylsulfϊnyl, aryl(Ci- C6)alkylsulfonyl, heterocyclyl(Ci-C6)alkylthio, heterocyclyl(Ci-C6)alkylsulfϊnyl, heterocyclyl(Ci-C6)alkylsulfonyl, (C3-C6)cycloalkyl(Ci-C6)alkylthio, (C3-
C6)cycloalkyl(Ci-C6)alkylsulfϊnyl, (C3-C6)cycloalkyl(Ci-C6)alkylsulfonyl or a group of formula NR a(Rd) R b(Rd) in which R a(Rd) and R b(Rd) independently represent H, (C1-C6)alkyl,
(Ci-C6)alkylC(O) or Ra(Rd) and Rb(Rd) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl; further X may represent a group (-CH2-)n wherein n= 2-6, which optionally is unsaturated and/or substituted by one or more substituent chosen among halogen, hydroxyl or (Ci-Ce)alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
An alternative 2nd embodiment of formula I is defined by; Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-C6)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-C6)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl, hydroxy(Ci-C6)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C3- Ce)cycloalkyl and heterocyclyl; further Ri4 represents aryl, aryl(Ci-C6)alkyl, aryl(Ci- C3)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-C6)cycloalkoxy, (Ci-C6)alkylsulfmyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci- C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rcis methylene (-CH2-);
Rd represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-Ce)alkoxy group;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl; further X may represent a group (-CH2-)n wherein n= 2-6, which optionally is unsaturated and/or substituted by one or more substituent chosen among halogen, hydroxyl or (Ci-Ce)alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-C14) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
A 3rd embodiment of formula I is defined by; Ri represents RyC(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl, hydroxy(Ci-C6)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Rn represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents (Ci-C6)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s); further Ri4 represents aryl, aryl(Ci-C6)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)Cy cloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfmyl, (d-C6)alkylsulfonyl, (d-C6)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (C1- C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rc represents an unsubstituted or monosubstituted or polysubstituted (Ci-
C4)alkylene group, wherein any substituents each individually and independently are selected from (Ci-C4)alkyl, (Ci-C4)alkoxyl, oxy-(Ci-C4)alkyl, (C2-C4)alkenyl, (C2- C4)alkynyl, (C3-Ce)cycloalkyl, carboxyl, carboxy-(Ci-C4)alkyl, aryl, heterocyclyl, cyano, halogeno (F, Cl, Br or I), hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (Ci-C4)alkyl or Ra^Rc) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine; further Rc represents imino (-NH-), N-substituted imino (-NR19-), (Ci-C4)alkyleneimino or N-substituted (Ci-C4)alkyleneimino ( -N(Ri9)-((Ci-C4)alkylene) wherein the mentioned alkylene groups are unsubstituted or monosubstituted or polysubstituted with any substituents according to above; preferably Rc represents imino, N-substituted imino or (Ci-C4)alkyleneimino or an unsubstituted or monosubstituted or polysubstituted (Ci- C4)alkylene group with any substituents according to above;
Ri9 represents H or (Ci-C4)alkyl;
Rd represents (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-Ce)alkyl, (Ci-Ce)alkoxyC(O), (Ci- Ce)alkoxy, halogen substituted (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl, heterocyclyl, (C1- C6)alkylsulfmyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, arylsulfϊnyl, arylsulfonyl, arylthio, aryl(Ci-C6)alkylthio, aryl(Ci-C6)alkylsulfinyl, aryl(Ci- C6)alkylsulfonyl, heterocyclyl(Ci-C6)alkylthio, heterocyclyl(Ci-C6)alkylsulfmyl, heterocyclyl(Ci-C6)alkylsulfonyl, (C3-C6)cycloalkyl(Ci-C6)alkylthio, (C3- C6)cycloalkyl(Ci-C6)alkylsulfϊnyl, (C3-C6)cycloalkyl(Ci-C6)alkylsulfonyl or a group of formula NR a(Rd) R b(Rd) in which R a(Rd) and R b(Rd) independently represent H, (C1-C6)alkyl,
(Ci-Ce)alkylC(O) or Ra(Rd) and Rb(Rd) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
An alternative 3rd embodiment of formula I is defined by;
Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-C6)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-C6)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl, hydroxy(Ci-C6)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s); further Ri4 represents aryl, aryl(d-C6)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3-
C6)cycloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfmyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (C1- C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rcis methylene (-CH2-);
Rd represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon. A 4rth embodiment of formula I is defined by; Ri represents RyC(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-C6)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH and COOH; further Ri4 represents a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (Ci-Ce)alkoxy, (C3-C6)CyClOaIkOXy, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci-C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rc represents imino (-NH-), N-substituted imino (-NR19-), (Ci-C4)alkyleneimino or N-substituted (Ci-C4)alkyleneimino ( -N(Ri9)-((Ci-C4)alkylene) or an unsubstituted or monosubstituted or polysubstituted (Ci-C4)alkylene group wherein any substitutents are selected from the group consisting of (Ci-C4)alkyl, (Ci-C4)alkoxyl and one or more halogen (F, Cl, Br or I) atom(s) or mixed halogen atoms; Ri9 represents H or (Ci-C4)alkyl;
Rd represents (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen (F, Cl, Br or I) atoms and/or one or more of the following groups, OH, CN, (Ci-C6)alkyl, (Ci-C6)alkoxyC(O), (C1- Ce)alkoxy, halogen substituted (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, aryl, heterocyclyl, (C1- C6)alkylsulfmyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, arylsulfϊnyl, arylsulfonyl, arylthio, aryl(d-C6)alkylthio, aryl(d-C6)alkylsulfinyl, aryl(Ci- C6)alkylsulfonyl, heterocyclyl(Ci-C6)alkylthio, heterocyclyl(Ci-C6)alkylsulfinyl, heterocyclyl(Ci-C6)alkylsulfonyl, (C3-C6)cycloalkyl(Ci-C6)alkylthio, (C3- C6)cycloalkyl(Ci-C6)alkylsulfϊnyl, (C3-C6)cycloalkyl(Ci-C6)alkylsulfonyl or a group of formula NR a(Rd) R b(Rd) in which R a(Rd) and R b(Rd) independently represent H, (C1-C6)alkyl,
(Ci-C6)alkylC(O) or Ra(Rd) and Rb(Rd) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
X represents a single bond, imino (-NH-) or methylene (-CH2-), and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
An alternative 4rth embodiment of formula I is defined by; Ri represents R7C(O);
R2 represents unsubstituted (Ci-C3)alkyl; R7 represents (Ci-C6)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-C6)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH and COOH; further Ri4 represents a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (Ci-Ce)alkoxy, (C3-C6)CyClOaIkOXy, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci-C6)alkyl, (Ci-C6)alkylC(O), (CrC6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rcis methylene (-CH2-);
Rd represents phenyl having 0,1 or 2 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group;
X represents a single bond, imino (-NH-) or methylene (-CH2-), and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
A 5th embodiment of formula I is defined by that; Ri is chosen from the group consisting of n-propylcarbonyl and n-butylcarbonyl;
R2 is methyl;
R7 is n-propyl or n-butyl;
B is chosen from the group consisting of 3-azetidin-l-ylene and 4-piperidin-l- ylene, and the substituent Ri4 is connected to the B ring/ring system, in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 is H;
Rc is chosen from the group consisting of methylene (-CH2-), methylmethylene (-CH(CH3)-), ethylene (-CH2-CH2-) and methylimino (-N(CH3)-);
Ri9 (when present) is methyl;
Rd is chosen from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, 4- methylcyclohexyl, phenyl, 4-methylphenyl, 2-cyanophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,4- difluorophenyl, 3,4-difluorophenyl and 3-fluoro-4-methyl-phenyl; and
X is a single bond.
An alternative 5th embodiment of formula I is defined by that; Ri is chosen from the group consisting of n-propylcarbonyl and n-butylcarbonyl;
R2 is methyl;
R7 is n-propyl or n-butyl;
B is chosen from the group consisting of 3-azetidin-l-ylene and 4-piperidin-l- ylene, and the substituent Ri4 is connected to the B ring/ring system, in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 is H;
Rc is methylene (-CH2-);
Rd is chosen from the group consisting of phenyl, 2-fluorophenyl, 3 -fluorophenyl,
4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,4- difluorophenyl, and 3,4-difluorophenyl; and
X is a single bond.
In a 6th embodiment of formula (I), formula (I) is defined as being any compound(s) of formula (Ia)-(Ii):
Figure imgf000038_0001
(Ia)
Figure imgf000039_0001
Figure imgf000039_0002
(Ic)
Figure imgf000039_0003
Figure imgf000039_0004
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
Figure imgf000040_0004
In the above Ia to Ii the various values of R are as defined above and include any of the previously mentioned embodiments.
In an alternative 6th embodiment of formula (I), formula (I) is defined as being any compound(s) of formula (Ia) or (Ig):
Figure imgf000041_0001
Figure imgf000041_0002
In the above Ia and Ig the various values of R are as defined above and include any of the previously mentioned embodiments.
In a 7 7 th embodiment formula (I) is defined as being any compound(s) of formula (Iaa)-
(igg);
Figure imgf000041_0003
(Iaa)
Figure imgf000042_0001
In the above Iaa to Igg the various values of R (except Ri4 being H) are as defined above and include any of the previously mentioned embodiments.
In a 7th embodiment formula (I) is defined as being any compound(s) of formula (Iaa)-
(igg);
Figure imgf000042_0002
Figure imgf000042_0003
In the above Iaa and Igg the various values of R (except R44 being H) are as defined above and include any of the previously mentioned embodiments.
Examples of specific compounds according to the invention (embodiments of Formula I) can be selected as one or more from;
N-(benzylsulfonyl)-l-(3-cyano-6-methyl-5-pentanoylpyridin-2-yl)piperidine-4- carboxamide, N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)azetidine-3- carboxamide,
N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(l-phenylethyl)sulfonyl]piperidine-4- carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 ,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(cyclopentylmethyl)sulfonyl]piperidine-4-carboxamide, 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- { [(4- methylcyclohexyl)methyl]sulfonyl}piperidine-4-carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(4- methoxybenzyl)sulfonyl]piperidine-4-carboxamide, 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(cyclohexylmethyl)sulfonyl]piperidine-4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-phenylethyl)sulfonyl]piperidine-4- carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide, 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N-
[(cyclobutylmethyl)sulfonyl]piperidine-4-carboxamide, 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 -fluoro-4- methylbenzyl)sulfonyl]piperidine-4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-cyanobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine-
4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-methylbenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide, 1 -(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide and
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- { [(4- fluorophenyl)(methyl)amino]sulfonyl}piperidine-4-carboxamide; and pharmaceutically acceptable salts thereof.
In an alternative embodiment of the invention examples of specific compounds (embodiments of Formula I) can be selected as one or more from;
N-(benzylsulfonyl)-l-(3-cyano-6-methyl-5-pentanoylpyridin-2-yl)piperidine-4- carboxamide, N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methy lpyridin-2-yl)azetidine-3 - carboxamide,
N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 ,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(4- methoxybenzyl)sulfonyl]piperidine -4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 -fluoro-4- methylbenzyl)sulfonyl]piperidine-4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine-
4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide and
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(2,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide; or pharmaceutically acceptable salts thereof.
In one other alternative embodiment of the invention the compound of Formula I is;
N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide; or a pharmaceutically acceptable salt thereof.
In an even further alternative embodiment of the invention the compound of Formula I is; l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide; or a pharmaceutically acceptable salt thereof.
Processes
The following processes together with the intermediates are provided as a further feature of the present invention. Compounds of formula ( I ) may be prepared by the following processes al-a7;
al) Compounds of formula ( I ) in which R1, R2, B, R14, Rc and Rd are defined as in formula ( I ) above, X is a single bond or (-CH2-), can be formed by reacting a compound of formula ( II ), in which R1, R2, B and R14 are defined
Figure imgf000046_0001
as in formula ( I ) above, X is a single bond or (-CH2-), with a compound of formula ( III ) in which Rc and Rd are defined as in formula ( I ) above.
H2NSO2- Rc-Rd ( III )
The reaction is generally carried out in an inert organic solvent such as dichloromethane at ambient temperature. The reaction may be carried out using standard conditions or in the presence of TBTU, EDCI, PyBrop, PyBOP or the combination of EDCI and HOBt. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
al) Compounds of formula ( I ) in which R1, R2, B, Ri4, Rc and Rd are defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( IV ), in which R1, R2, B and R14 are defined as in formula ( I ) above and X is (-NH2), (-CH2- NH2) or a hydrogen that is connected to a nitrogen which is a member of the B-ring, with a compound of the general
Figure imgf000047_0001
formula ( III ) which is defined as above.
The reaction is generally carried out in an inert solvent such as DCM. The reaction may be carried out in the presence of CDI. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine, DBU or DIPEA.
a3) Compounds of formula ( I ) in which R1, R2, B, Ri4, Rc and R are defined as in formula ( I ) above X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( IV ) which is defined in a2) above, with a compound of formula ( V )
O= C= N— SCL- RcRd
( V ) in which Rc and R are defined as in formula ( I ) above. The reaction is generally carried out in an inert solvent such as THF. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
cι4) Compounds of formula ( I ) in which R1, R2, B, Ri4, Rc and Rd are defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( IV ) which is defined in above, with a compound of formula ( VI ),
> dτ-> c
RαRc -SO2NH-COOCH2CCI3 ( VI ) in which Rc and Rd are defined as in formula ( I ) above. The reaction is generally carried out in an inert solvent such as DMA. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
a5) Compounds of formula ( I ) may also be prepared by reacting a compound of formula ( VII ) in which Ri and R2 are defined as in formula ( I ) above and L is a suitable leaving group, such as chloro, bromo, iodo, fluoro, benzotriazolyloxy(OBt), triflate (OTf) mesylate (OMs) or tosylate (OTs),
Figure imgf000048_0001
with a compound of the general formula ( VIII ) in which B, X, Ri4, Rc and Rd are defined as in formula ( I ) above.
Figure imgf000048_0002
The reaction is generally carried out in an inert solvent such as DCM, THF or DMA. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. For some compounds, it is advantageous to carry out the reaction in ethanol in the presence of an organic base such as triethylamine.
a6) A compound of formula (I) in which R1, R2, B, R14, and Rd are defined as in formula ( I ) above and Rc represents imino (-NH-) or (Ci-C4)alkylimino the imino group can be substituted using standard methods, e.g. using an alkylating agent like L-R19, in which Rig is defined as in formula ( I ) above and L is a leaving group exemplified by chloro, bromo, iodo, triflate(OTf) or tosylate(OTs), to give compounds of formula (I) in which R1, R2, B, Ri4, and Rd are defined as in formula ( I ) above and Rc represents N- substituted imino (-NR19-) or N-substituted (Ci-C4)alkylimino ( -N(Ri9)-((Ci-C4)alkyl), optionally in the presence of a strong base such as NaH.
a7) Compounds of formula ( I ) in which R1, R2, B, Ri4, X, Rc and Rd are as defined in formula ( I ) above may be prepared by reacting a compound of formula ( IX )
Figure imgf000049_0001
in which R2, B, Ri4, X, Rc and Rd are as defined in formula ( I ) above and LG is a leaving group such as Cl or F with a reagent of general formula R7-MgX', in which R7 is defined as in formula ( I ) above, and X' is a halogen.
The reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as for example FeCl3.
The reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0C and O 0 C.
(See for example Fϋrstner A et al, J. Org Chem, 2004, pp 3943-3949) The reaction may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R7Cu, (R7)2CuLi or (R7)2CuMgX', wherein X' is a halogen).
The reaction is carried out using standard conditions in an inert solvent such as DCM or THF.
The reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0C and 0 0C.
(See for example Cais, M; Mandelbaum, A in Patai "The Chemistry of the Carbonyl Group, vol. 1, Wiley, NY, 1966, p. 303.)
The intermediates referred to above may be prepared by, for example, the methods/processes outlined below.
bl) The compounds of formula ( II ) in which Ri1 R2, B, and Ri4 are defined as in formula ( I ) above, X is a single bond or (-CH2-), may be prepared by reacting a compound of formula ( VII ) defined above and wherein L is a suitable leaving group (such as fluoro, chloro, bromo, iodo, triflate (OTf), benzotriazolyloxy (OBt), mesylate (OMs) or tosylate (OTs)), with a compound of the general formula ( X ),
Figure imgf000050_0001
in which B and Ri4 are defined as in formula ( I ) above and X is a single bond or (-CH2-).
The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. The reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water. Optionally the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
b2) The compounds of formula ( II ) in which Ri1 R2, B and Ri4 are defined as in formula ( I ) above, X is a single bond or (-CH2-), may be prepared by reacting a compound of formula ( VII ) defined above except that L is a hydroxy group with a compound of the general formula ( X ) in which B and R14 are defined as in formula ( I ) above.
The reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature. The reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
Compounds of the general formula ( II ), in which Ri , R2, R7, B and R14 are defined as in formula ( I ) above, X is a single bond or (-CH2-) also comprises the following steps (b3-b4):
b3) Reacting a compound of the general formula ( XI ) with N,O-dimethylhydroxylamine.
Figure imgf000051_0001
The reaction can be performed using known reagents like CDI, EDCI or the combination of EDCI and HOBt to give a compound of the general formula ( XII ).
Figure imgf000051_0002
b4) Reacting compounds of the general formula ( XII ), defined as above, with a reagent of the general formula R7-MgX', in which R7 is defined as in formula ( I ) above and X' is a halogen, or a reagent of the formula R7-M, in which M is a metal examp lifted by Zn and Li.
Synthesis of compounds of the general formula ( II ), in which Ri , R2, R7, B and R14 are defined as in formula ( I ) above, X is a single bond or (-CH2-) also comprises the following steps (b5-b6):
b5) Reacting compounds of general formula (XIII)
Figure imgf000052_0001
wherein R2, B and Ri 4 is as defined in formula ( I ) above, X is a single bond or (- CH2-) and LG is a leaving group such as Cl or F with a reagent of general formula R7- MgX', in which R7 is defined as in formula ( I ) above, and X' is a halogen. The reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as for example FeCl3.
The reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0C and O 0 C.
(See for example Fϋrstner A et al, J. Org Chem, 2004, pp 3943-3949)
The recation may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R7Cu, (R7)2CuLi or (R7)2CuMgX').
The reaction is carried out using standard conditions in an inert solvent such as DCM or THF. The reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0C and 0 0C. (See for example Cais, M; Mandelbaum, A in Patai "The Chemistry of the Carbonyl Group, vol. 1, Wiley, NY, 1966, p. 303.)
b6) Compounds of general formula ( XIII ) above can by prepared by reacting a compound of general formula ( XI ) defined as above using standard methods, e.g. with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCI3 ( e.g. when LG is
Cl). Advantageously dimethylformamide may be used as catalyst.
The reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine ( e.g. when LG is F) The reaction may be performed in an inert solvent such as DCM or toluene. The reaction is carried out at ambient temperature or at elevated temperatures.
Compounds of the general formula ( II ), in which Ri is R7C(O) and R7 is a group containing a CH2 group next to the carbonyl in R1, i.e. R7 in this case is referred to below as Rr-CH2) and R2, R7, B and R14 are defined as in formula ( I ) above, X is a single bond or (-CH2-) also comprises the following steps (b7-b8):
b7) By double decarboxylation of a compound of general formula ( XIV )
Figure imgf000053_0001
The reaction is generally carried at elevated temperature using standard equipment. Preferentially the reaction is carried out under acidic conditions in an inert solvent such as MeCN or THF. b8) Compounds of the formula ( XIV ) above can be prepared by reaction of a compound of formula ( XIII ) with a compound of formula ( XV )
Figure imgf000054_0001
The reaction is carried out in an inert solvent such as THF at ambient temperature in the presence of a suitable base such as sodium pentoxide or NaH. (For similar chemistry see, Asish D. et al, J. Chem. Soc. Perkin Treans. I, 1989, pp 603- 607 and Rathke, M et al, J. Org. Chem. 1985, pp 2622-24).
cl) Compounds of formula (IV) which are defined as above may be prepared by reacting the corresponding compound of formula ( VII ) which is defined above, with a compound of formula ( XVI ) in which B and Ri4 are defined as in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring.
Figure imgf000054_0002
The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. The reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water. Optionally the reaction may be carried out in the prescence of an organic base such as TEA or DIPEA.
c2) Compounds of formula (IV) which are defined as above may be prepared by reacting the corresponding compound of formula ( VII ) which is defined above except that L is a hydroxy group, with a compound of formula ( XVI ) in which B and Ri4 are defined as in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring.
The reaction is generally carried out in an inert organic solvent such as DCM or THF 5 at ambient temperature. The reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
Synthesis of compounds of the general formula ( IV ), in which Ri1 R2, R7, B, Ri4 are0 defined as in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring, comprises the following steps (c3-c4).
c3) Reacting a compound of the general formula ( XVII )
Figure imgf000055_0001
with N,O-dimethylhydroxylamine. The reaction can be performed using known reagents like CDI, EDCI or the combination of EDCI and HOBt to give a compound of the general formula ( XVIII ). o
Figure imgf000055_0002
( XVIII ) c4) A compound of the general formula ( XVIII ), which is defined as above can be reacted with a reagent of the general formula R7-MgX, in which R7 is defined as in formula ( I ) above and X is a halogen, or a reagent of the formula R7-M, in which M is a metal exemplified by Zn and Li.
Synthesis of compounds of the general formula ( IV ), in which R1, R2, R7, B and R14 are defined as in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring, also comprises the following steps (c5-c6).
c5) Reacting compounds of general formula (XIX)
Figure imgf000056_0001
wherein R2, B and R14 are as defined in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring and LG is a leaving group such as Cl or F with a reagent of general formula R7-MgX', in which R7 is defined as in formula ( I ) above, and X' is a halogen.
The reaction is carried out using standard conditions in an inert solvent such as THF catalyzed by ferric acetylacetonate or other suitable ferric salts such as FeCl3.
The reaction may be performed at ambient temperature or preferentially at lower temperatures for example in the range of -78 0C and 0 0C.
(See for example Fϋrstner A et al, J. Org Chem, 2004, pp 3943-3949).
The recation may alternatively be performed by using an organocopper- or organocuprate reagent (such as for expemple R7Cu, (R7)2CuLi or (R7)2CuMgX').
The reaction is carried out using standard conditions in an inert solvent sauch as DCM or THF. The reaction may be performed at ambient temperature or preferentially at lower temperature for example in the range of -78 0C and 0 0C.
(See for example Cais, M; Mandelbaum, A in Patai "The Chemistry of the Carbonyl Group, vol. 1, Wiley, NY, 1966, p. 303.)
c6) Compounds of general formula ( XIX ) above can by prepared by reacting a compound of general formula ( XVII ) defined as above using standard methods, e.g. with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCl3( e.g. when LG is Cl). Advantageously dimethylformamide may be used as catalyst. The reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine ( e.g. when LG is F).
The reaction may be performed in an inert solvent such as DCM or toluene. The reaction is carried out at ambient temperature or at elevated temperatures.
Synthesis of compounds of the general formula ( IV ), in which Ri is RyC(O) and R7 is a group containing a CH2 group next to the cabonyl in R1, i.e. R7 in this case is referred to below as Ry-CH2) and R2, B and Ri4 are defined as in formula ( I ) above, X is (-NH2), (-CH2-NH2) or a single bond connected to a nitrogen which is a member of the B ring, also comprises the following steps (c7-c8).
c 7) By double decarboxylation of a compound of general formula ( XX )
Figure imgf000057_0001
The reaction is generally carried at elevated temperature using standard equipment. Preferentially the reaction is carried out under acidic conditions in an inert solvent such as MeCN or THF.
c8) Compounds of the formula ( XX ) above can be prepared by reaction of a compound of formula ( XIX ) with a compound of formula ( XV )
Figure imgf000058_0001
The reaction is carried out in an inert solvent such as THF at ambient temperature in the presence of a suitable base such as sodium pentoxide or NaH.
(For similar chemistry see, Asish D. et al, J. Chem. Soc. Perkin Treans. I, 1989, pp 603-607 and Rathke, M et al, J. Org. Chem. 1985, pp 2622-24).
dl) Compounds of the general formula ( VII ) which are defined as above can be formed by reacting a compound of formula ( XXI)
Figure imgf000058_0002
using standard methods, e.g. with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCI3. Advantageously dimethylformamide may be used. The reaction may be performed in an inert solvent such as DCM. Advantageously the inert solvent is toluene. The reaction may also be carried out with PyBOP or methyl sulfonyl chloride in the presence of a base, such as DIPEA, in an inert solvent such as DCM.
d2) Compounds of general formula ( XXI ) defined as above may be prepared by reacting a compound of formula ( XXII )
Figure imgf000059_0001
wherein R2 is defined as in formula ( I ) according to any of the procedures described in b3) to b8) above.
d3) Compound ( XXII ) defined as above may be prepared by reacting a compound of formula ( XXIII)
Figure imgf000059_0002
with a compound of the formula NC-CH2C(O)NH2.
The reaction is generally performed in an inert solvent such as ethanol, optionally in the presence of a strong base such as sodium ethoxide at ambient temperature.
d4) Compound ( XXII ) defined as above may alternatively be prepared by reacting a compound of formula ( XXIII)
Figure imgf000060_0001
with a compound of the formula NC-CH2-CN.
The reaction is generally performed in an inert solvent such as ethanol, optionally in the presence of an organic base such as TEA or DIPEA at ambient temperature
d5) compound of general formula ( XXIII ) defined as above can be made by reacting a compound of the formula ( XXIV)
in which R2 is defined as in formula ( I ) above with dimethoxy-N,N- dimethy lmethaneamine .
The reaction is carried out in an inert organic solvent such as EtOH.
Compounds of the general formula ( VIII ) can be formed in one of the processes (el-e4). The compounds of formula ( VIII ) are advantageously isolated as a zwitterion. A ring nitrogen of compounds of formula ( X ) and ( XVI ) used in the below steps may be protected by a protective group such as t-butyloxycarbonyl.
el) Compounds of the general formula ( VIII ) in which B, Ri4, Rc and R are defined as in formula ( I ) above, X is a single bond or (-CH2-), may be formed by reacting a compound of formula ( X ) with a compound of formula ( III ). The reaction is generally carried out in an inert organic solvent such as dichloromethane at ambient temperature. The reaction may be carried out using standard conditions or in the presence of EDCI, PyBroP or PyBOP or the combination of EDCI and HOBt. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA. e2) Compounds of the general formula ( VIII ) in which B, Ri4, Rc and Rd are defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( XVI ) defined as above with a compound of formula ( V ), defined as above. The reaction is generally carried out in an inert solvent such as THF. The reaction may also be carried out in the presence of an organic base such as triethylamine or DIPEA.
e3) Compounds of the general formula ( VIII ) in which B, Ri4, Rc and Rd defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can also be formed by reacting a compound of formula ( XVI ) with a compound of formula ( VI ) which is defined as above. The reaction is generally carried out in a solvent such as DMA. This reaction may also be carried out in the presence of an organic base such as triethylamine or DIPEA
e4) A compound of formula (VIII) which is protected with t-butoxy carbonyl may be transformed into a compound without the protective group using standard procedures or a reagent such as HCl, FA or TFA.
fl) Componds of general formula ( IX ) defined as above may be prepared by reacting a compound of general formula ( XXV )
in which R2, B, Ri4, X, Rc and Rd are as defined in formula ( I ) above using standard methods, e.g. reacting with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCls( e.g. when LG is Cl). Advantageously dimethylformamide may be used as catalyst. The reaction can also be performed using standard conditions with cyanuric fluoride preferentially in the precence of pyridine ( e.g. when LG is F)
The reaction may be performed in an inert solvent such as DCM or toluene. The reaction is carried out at ambient temperature or at elevated temperatures.
gl) The compounds of formula ( XI ) in which R2, B, and R14 are defined as in formula ( I ) above, X is a single bond or a carbon atom, may be prepared by reacting a compound of formula ( XXVI )
Figure imgf000062_0001
wherein R2 is defined as in formula (I) above and L is a suitable leaving group (such as fluoro, chloro, bromo, iodo, triflate (OTf) mesylate (OMs) or tosylate (OTs)), with a compound of the general formula ( X ) defined as above .
The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. The reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water. Optionally the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
g2) The compounds of formula ( XI ) in which R2, B and R14 are defined as in formula ( I ) above, X is a single bond or a carbon atom, may be prepared by reacting a compound of formula ( XXVI ) defined above except that L is a hydroxy group with a compound of the general formula ( X ) in which B and R14 are defined as in formula ( I ) above.
The reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature. The reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA. g3) Compounds of the general formula ( XXVI ) defined as above may be prepared by reacting a compound of general formula ( XXII ) using standard conditions or with a chlorinating reagent such as oxalyl chloride, thionyl chloride or POCI3. Advantageously dimethylformamide may be used. The reaction may be performed in an inert solvent such as DCM. Advantageously the inert solvent is toluene.
The reaction may also be carried out with methyl sulfonyl chloride in the presence of a base, such as DIPEA, in an inert solvent such as DCM.
hi) Compounds of formula ( XVII ) which are defined as above may be prepared by reacting the corresponding compound of formula ( XXVI ) defined as above, with a compound of formula ( XVI ) defined as above.
The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. The reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water. Optionally the reaction may be carried out in the prescence of an organic base such as TEA or DIPEA.
h2) Compounds of formula (XVII) which are defined as above may be prepared by reacting the corresponding compound of formula ( XXVI ) which is defined above except that L is a hydroxy group, with a compound of formula ( XVI ) defined as above.
The reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature. The reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop preferentially in the precence of an organic base such as TEA or DIPEA.
H) The compounds of formula ( XXV ) in which R2, B, R44, X, Rc and Rd are as defined in formula ( I ) above may be prepared by reacting a compound of formula ( XXVI ) defined as above with a compound of the general formula ( VIII ) defined as above . The reaction is generally carried out at elevated temperatures using standard equipment or in a single-node microwave oven. The reaction can be carried out in an inert solvent such as ethanol, DMA or a mixture of solvents such as ethanol-water. Optionally the reaction may be carried out in the presence of an organic base such as TEA or DIPEA.
12) The compounds of formula ( XXV ) in which R2, B, Ri4, X, Rc and Rd are as defined in formula ( I ) above may be prepared by reacting a compound of formula ( XXVI ) defined above except that L is a hydroxy group, with a compound of the general formula ( VIII ) defined above.
The reaction is generally carried out in an inert organic solvent such as DCM or THF at ambient temperature. The reaction is carried out in the precence of a suitable coupling reagent such as for example PyBrop or PyBOP preferentially in the precence of an organic base such as TEA or DIPEA.
13) Compounds of formula ( XXV ) in which R2, B, Ri4, Rc and Rd are defined as in formula ( I ) above, X is a single bond or (-CH2-), can be formed by reacting a compound of formula ( XI ), in which R2, B and R14 are defined as in formula ( I ) above, X is a single bond or (-CH2-), with a compound of formula ( III ) defined as above.
The reaction is generally carried out in an inert organic solvent such as dichloromethane at ambient temperature. The reaction may be carried out using standard conditions or in the presence of TBTU, EDCI, PyBrop, PyBOP or the combination of EDCI and HOBt. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA.
i4) Compounds of formula ( XXV ) in which R2, B, Ri4, Rc and Rd are defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( XVII ) wherein R2, Ri4 and B are defined as in formula ( I ) above and X is (-NH2), (-CH2-NH2) or a hydrogen that is connected to a nitrogen which is a member of the B-ring, with a compound of the general formula ( III ) which is defined as above. The reaction is generally carried out in an inert solvent such as DCM. The reaction may be carried out in the presence of CDI. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine, DBU or DIPEA. i5) Compounds of formula ( XXV ) in which R2, B, R44, Rc and Rd are defined as in formula ( I ) above X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( XVII 5 ) which is defined as above, with a compound of formula ( V ) defined as above.
The reaction is generally carried out in an inert solvent such as THF. Optionally, the reaction may be carried out in the presence of an organic base such as triethylamine or DIPEA. 0 i6) Compounds of formula ( XXV ) in which R2, B, R14, Rc and Rd are defined as in formula ( I ) above, X is (-NH-), (-CH2-NH-) or a single bond connected to a nitrogen which is a member of the B ring, can be formed by reacting a compound of formula ( XVII ) which is defined in above, with a compound of formula ( VI ) defined as above. The reaction is generally carried out in an inert solvent such as DMA. Optionally, the reaction5 may be carried out in the presence of an organic base such as triethylamine or DIPEA.
The preparation of compounds of the formula (III) comprises the below processes (]l-j3). o jl) A compound of the formula LRcRd wherein L is a suitable leaving group, such as chloro, bromo, iodo can be transformed to the corresponding compound (III) using a sequence of reactions using first SMOPS* (*Baskin and Wang. Tetrahedron Letters, 2002, 43, 8479-83. See esp. page 8480, left hand column.) then followed by hydrolysis using a base like NaOMe in an inert solvent like DMSO at room temperature and further followed5 by treatment with NH2OSOsH and NaOAc to give a compound of formula (III).
j2) A compound of the formula LSO2RcRd wherein L is a suitable leaving group, such as chloro, bromo, iodo can be reacted with ammonium hydroxide in an inert solvent such as DCM to give a compound of formula (III). 0 j3) A compound of the formula LRcRd wherein L is a suitable leaving group, such as chloro, bromo, iodo can be transformed to the corresponding compound (III) using a sequence of reactions, first reacting with Na2SO3, followed by a using a reagent such as PCI5, POCI3 or SOCl2 on the obtained product, and then treating with ammoium hydroxide to give a compound of formula (III).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated that by those skilled in the art that in the processes described above and hereinafter the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for carboxylic acids include (Ci-Ce)alkyl or benzyl esters. Suitable protecting groups for amino include allyl, t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)ethoxymethyl or 2-trimethylsilylethoxycarbonyl (Teoc).
The protection and deprotection of functional groups may take place before or after any reaction in the above mentioned processes.
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and on some occasions more convenient, manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.
Persons skilled in the art will appreciate that starting materials for any of the above processes can in some cases be commercially available. Persons skilled in the art will appreciate that processes could for some starting materials above be found in the general common knowledge.
The type of chemistry involved will dictate the need for protecting groups as well as sequence for accomplishing the synthesis.
The use of protecting groups is fully described in "Protective groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 4th edition, T.W. Greene & P.G.M Wutz, Wiley-Interscince (2007). Protected derivatives of the invention may be converted chemically to compounds of the invention using standard deprotection techniques (e.g. under alkaline or acidic conditions). The skilled person will also appreciate that certain compounds of formula ( II )-( XXVI ) may also be referred to as being "protected derivatives"
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereo isomers may be separated using conventional techniques, e.g. chromatography or crystallization. The various stereisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. 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 epimerization, or by derivatisation, for example with a homochiral acid followed by separation of the diasteromeric derivatives by conventional means (e.g. HPLC, chromatography over silica or crystallization). Stereo centers may also be introduced by asymmetric synthesis, (e.g. metalloorganic reactions using chiral ligands). All stereoisomers are included within the scope of the invention. It will also be understood that some of the compounds described in the processes above may exhibit the phenomenon of tautomerism and the processes described above includes any tautomeric form.
All novel intermediates form a further aspect of the invention.
Salts of the compounds of formula ( I ) may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or a derivative thereof, with one or more equivalents of the appropriate base (for example ammonium hydroxide optionally substituted by Ci_C6- alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a hydrohalic ( especially HCl ), sulphuric, oxalic or phosphoric acid). The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. water, ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also carried out on an ion exchange resin. The non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product.
Pharmacological data
Functional inhibition of- the P2Yi2 receptor can be measured by in vitro assays using cell membranes from P2Yi2 transfected CHO-cells, the methodology is indicated below. Functional inhibition of 2-Me-S-ADP induced P2Yi2 signalling: 5μg of membranes were diluted in 200 μl of 20OmM NaCl, ImM MgCl2, 5OmM HEPES (pH 7.4), 0.01% BSA, 30μg/ml saponin and lOμM GDP. To this was added an ECgo concentration of agonist (2-methyl-thio-adenosine diphosphate), the required concentration of test compound and 0.1 μCi 35S-GTPyS. The reaction was allowed to proceed at 3O0C for 45 min. Samples were then transferred on to GF/B filters using a cell harvester and washed with wash buffer (5OmM Tris (pH 7.4), 5mM MgCl2, 5OmM NaCl). Filters were then covered with scintilant and counted for the amount of 35S-GTPyS retained by the filter. Maximum activity was that determined in the presence of the agonist and minimum activity in the absence of the agonist following subtraction of the value determined for non-specific activity. The effect of compounds at various concentrations was plotted according to the equation y = A+((B-A)/(l+((C/x)ΛD))) and IC50 estimated where A is the bottom plateau of the curve i.e. the final minimum y value B is the top of the plateau of the curve i.e. the final maximum y value
C is the x value at the middle of the curve. This represents the log EC50 value when A + B = 100 D is the slope factor. x is the original known x values.
Y is the original known y values.
Most of the compounds of the invention have an activity, when tested in the functional inhibition of 2-Me-S-ADPinduced P2Yi2 signalling assay described, at a concentration of around 2 μM or below, whereas the exemplified compounds having RcRd embodified with Rc being a methylene group and Rd being phenyl or halogen or methoxy substituted phenyl are having an average IC50 of 0.14 μM. The exemplified compounds having RcRd embodified with Rc being a methylene group and Rd being a fluorine substituted phenyl are having an average IC50 of 0.08 μM.
For example the compounds described in Examples 4 and 15 gave the following test result in the functional inhibition of 2-Me-S-ADPinduced P2Yi2 signalling assay described.
IC50 (μM)
Example 4 0. .26
Example 15 0. .10
The compounds of the invention act as P2Yi2 receptor antagonists and are therefore useful in therapy. Thus, according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
Thus, according to another further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
In a further aspect there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of a platelet aggregation disorder. In another aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the inhibition of the P2Yi2 receptor. In yet another aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an inhibitor of the P2Yi2 receptor.
In still another aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of platelet aggregation disorder.
An alternative aspect of the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating platelet aggregation disorder.
Another even further aspect of the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in preventing thrombosis.
The compounds are useful in therapy, especially adjunctive therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic complications of septicaemia, adult respiratory distress syndrome, anti- phospholipid syndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venous thrombosis such as deep vein thrombosis, venoocclusive disease, haematological conditions such as myeloproliferative disease, including thrombocythaemia, sickle cell disease; or in the prevention of mechanically-induced platelet activation in vivo, such as cardio-pulmonary bypass and extracorporeal membrane oxygenation (prevention of microthromboembolism), mechanically-induced platelet activation in vitro, such as use in the preservation of blood products, e.g. platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process.
According to the invention there is further provided the use of a compound according to the invention in the manufacture of a medicament for the treatment of the above disorders. In particular the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and angina, especially unstable angina. The invention also provides a method of treatment of the above disorders which comprises administering to a patient suffering from such a disorder a therapeutically effective amount of a compound according to the invention. In a further aspect the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, adjuvant and/or carrier.
The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally .
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers include sugars and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres, which break up during the inhalation procedure. This spheronized powder may be filled into the drug
® reservoir of a multidose inhaler, e.g. that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound with or without a carrier substance is delivered to the patient.
The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved either in a readily volatile organic solvent or an aqueous solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The invention will be further illustrated with the following non- limiting examples:
EXAMPLES
General Experimental Procedure
Mass spectra was recorded on a Finnigan LCQ Duo ion trap mass spectrometer equipped with an electrospray interface (LC-MS) or LC-MS system consisting of a Waters ZQ using a LC-Agilent 1100 LC system.
1H NMR measurements were performed on Varian INOVA 400, 500 and 600 spectrometers, operating at IH frequencies of 400, 500 and 600 MHz respectively. Chemical shifts are given in ppm with the solvent as internal standard. Protones on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therfore be missing.
The solutions for the 1H-NMR spectra recorded for Examples 4 to 21
Below are taken from a concentrated sample solved in (CHs)2SO and are diluted with (CD3)2SO. Since an substantial amount of (CH3 )2SO is present in the sample, first a pre- scan is run and analysed to automatically suppress the (CH3)2SO (2.54 ppm) and H2O (3.3 ppm) peaks. This means that in this so-called wet ID experiment the intensity of peaks that reside in these areas around 3.3 ppm and 2.54 ppm is reduced. Furthermore impurities are seen in the spectrum which gives rise to a triplet at 1.12 ppm, a singlet at 2.96 and two multiplets between 2.76-2.70 ppm and 2.61-2.55 ppm. Most probably these impurities are dimethylsulfone and diethylsulfoxide. The 2-pyridyl methyl (CH3) singlett and in some cases also other lH-signals are overlapping with the supressed DMSOZH2O signal and are difficult to see in the NMR-spectra.
HPLC separations were performed on a Waters YMC-ODS AQS-3 120 Angstrom 3 x 500 mm or on a Waters Delta Prep Systems using Kromasil Cs, 10 μm columns.
Purification Method A: The purification system and LC-MS system used in purification Method A, referred to in some of the Examples below , was Waters Fraction Lynx I Purification System: Column: Sunfire Prep C 18, 5 mm OBD, 19 x 150 mm column.
Gradient 5-95 % CH3CN in 0.1 mM HCOOH (pH = 3). MS triggered fraction collection was used. Mass spectra were recorded on either Micromass ZQ single quadropole or a Micromass quattro micro, both equipped with a pneumatically assisted electrospray interface.
Reactions performed in a microwave reactor were performed in a Personal Chemistry Smith Creator, Smith synthesizer or an Emrys Optimizer.
IUPAC names were generated with ACDLabs Name: Release 9:00, Product version 9.04.
The GTPγS values (IC50 in μM) mentioned in the examples below were measured by the method described previously under the heading "Functional inhibition of 2-Me-S-ADP induced P2Yi2 signalling:"
List of used abbreviations
Abbreviation Explanation aq Aqueous
Boc tert-butyloxycarbonyl br Broad
BSA Bovine Serum Albumine
CDI Carbonyldiimidazole d Doublet dba 1 ,5-diphenylpenta- 1 ,4-dien-3-one
DBU 2,3,4,6,7,8,9,10-octahydropyrimido[l,2,a]azepine
DCM Dichloromethane
DIPEA N ,N-Diisopropy lethy lamine
DMA N,N-Dimethylacetamide
DMF N,N-dimethylformamide
DMSO Dimethylsulphoxide
EDCI N- [3 -(dimethylamino)propyl] -N'-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate
EtOH Ethanol
FA formic acid g gram h hours
HEPES [4-(2-hydroxyethyl)- 1 - piperazineethanesulfonic acid
HFA Hydro fluoroalkanes
HOAc Acetic acid
HOBt 1 -Hydroxybenzotriazole
HPLC High-performance liquid chromatography
Hz Hertz
J Coupling constant
LC Liquid chromatography m Multiplet
MeCN acetonitrile
MeOH Methanol nig milligram
MHz Megahertz min minutes niL Millilitre mniol Millimole
MS Mass spectra
Ms methylsulfonyl
NMR Nuclear magnetic resonance
OAc acetate
Obt lH-benzo[d][l,2,3]triazol-l-yloxy
PyBOP (Benzotriazol- 1 -yloxy)tripyrrolidino- phosphoniumhexafluorophosphate PyBroP Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate q Quartet r.t. Room temperature S Singlet sat. Saturated t triplet
TB Tyrodes Buffer TBTU N-[(lH-l,2,3-benzotriazol-l- yloxy)(dimethylamino)methylene]-N- methylmethanaminium tetrafluoroborate
TEA Triethylamine
Tf trifluoromethylsulfonyl
TFA Trifluoroacetic acid
THF Tetrahydrofurane
TMEDA N,N,N ' ,N ' -tetramethylethylendiamine
Ts p-toluenesulfonyl
SULFONE AMIDES
Synthesis of sulfone amides
The synthesis of the sulfonamides used in the examples below was made with one of the three methods described below:
i) By reacting the corresponding sulfonyl chloride with ammonia in THF or MeOH or by treatment with ammonium hydroxide in methylene chloride. The sulfonamides obtained was used without further purification. ii) By essentially following the procedure described by Seto, T. et. al. in J. Organic Chemistry, VoI 68, No 10 (2003), pp. 4123-4125. or iii) By essentially following the procedure described by Wang, Z et. al. in Tetrahedron Letters, VoI 43 (2002), pp 8479-8483. Example 1
N-(Benzylsulfonyl)-l-(3-cyano-6-methyl-5-pentanoylpyridin-2-yl)piperidine-4- carboxamide
(a) Ethyl 2-((dimethylamino)methylene)-3-oxobutanoate
l,l-dimethoxy-N,N-dimethylmethanamine (500 g, 4195 mmol) was added to ethyl 3- oxobutanoate (461.6 g, 3547 mmol) under an atmosphere of nitrogen at r.t. during 13 minutes(weak exotherm). The orange red solution was stirred for 22 hours and concentrated in vaccuo. The residue was co-evaporated with toluene (3 times 200 ml each) and used without no need for further purification in the next step. MS m/z: 186 (M+ 1).
(b) Ethyl S-cyano-l-methyl-ό-oxo- 1 ,6-dihydropyridine-3-carboxylate
Sodium ethoxide (1240.7 g of a 21 wt % solution in EtOH, 3829 mmol) was added to a stirred suspension of 2-cyanoacetamide (298 g, 3544 mmol) in EtOH (3000 mL) during 8 minutes under an atmosphere of nitrogen at r.t.. The crude condensation product from step (a) above dissolved in 950 ml EtOH was added slowly (slightly exothermic reaction) and after about one third had been added further EtOH (1000 mL) was added to allow efficient stirring (suspension) followed by the addition of the rest of the condensation product (total addition time 30 min). After stirring over night at r.t.. HOAc (526 g, 8759 mmol) was added to the reaction and the mixture was concentrated in vaccuo leaving a thick orange slurry (volume about 3000 mL), 1 M HCl (4628 mL, 4628 mmol) was added during 10 min followed by water (500 mL). The stirring was stopped and the precipitate was filtered off and washed with water (200 mL). NMR showed the presence of about 5-10 % of the corresponding acid (in the 3 -position) and the solid was washed by stirring with further water (1500 mL + 3 x 1000 mL), a solution of saturated NaHCO3 (400 mL) in water (600 mL) and finally water (1000 mL). Filtration of the solid and drying in vaccuo at 80 0C gave pure ethyl S-cyano^-methyl-ό-oxo-l^-dihydropyridine-S-carboxylate. Yield: 493 g (67 %). 1H NMR (400 MHz, DMSO-d6): δ 1.36 (3H, t, J= 7.1 Hz), 2.62 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 8.71 (IH, s), 12.79 (IH, br s).
(c) Ethyl ό-chloro-S-cyano-l-methylnicotinate
Toluene (4000 niL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano- 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 0C (oil bath temperature) and DMF (100 g, 1368 mmol) was added during 2 minutes. The temperature was raised to 80 0C (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4 % NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give ethyl 6-chloro-5-cyano-2- methylnicotinate as a dark red crude solid which was used without further purification. Yield: 301 g (75 %).
1H NMR (400 MHz, CDCl3): δ 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s).
(d) tert-Buty\ 4-{[(benzylsulfonyl)amino]carbonyl}piperidine-l-carboxylate
Triethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t.. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL I M HCl. The organic phase was cooled to O0C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off , washed with 50 % EtOH ( 500 mL + 2 x 1500 rnL) and dried in a vaccum oven at 25 oC to give tert-butyl 4-
[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate as a white solid. Yield 584 g (78 %). 1H NMR (400 MHz, CDCl3): δ 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19- 2.27 (IH, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (IH, br s).
(e) N-(Benzylsulfonyl)piperidine-4-carboxamide
tert-Butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate (583 g, 1524 mmol) was suspended in formic acid (3000 mL) under a nitrogen atmosphere and the reaction was stirred for 20 minutes. The reaction was foaming due to the gas evolution and formic acid ( 500 mL) was used to wash down the foam from the reaction vessel walls. After 2 hours the foaming had stopped and the reaction was clear with a few solids left. The reaction was stirred over night and 2500 ml of formic acid was removed in vaccuo. Water (1000 mL) was added and the reaction was filtered. The clear solution was evaporated and water (3000 mL) was added. A saturated ammonium hydroxide solution in water was used (totally 390 mL was added and the pH was going from 3.10 to 6.10) to neutralize the acidic solution and at the endpoint (pH=6.10) a heavy precipitate of the product was formed. The mixture was stirred over night and the precipitate was filtered off and washed with water (1000 mL). Drying in a vaccum oven at 250C gave N-(benzylsulfonyl)piperidine-4- carboxamide as a white powder. Yield 372.4 g (87%).
1H NMR (400 MHz, DMSO- d6): δ 1.60-1.72 (2H, m), 1.75-1.84 (2H, m), 2.10-2.19 (IH, m), 2.77-2.87 (2H, m), 3.10-3.18 (2H, m), 4.23 (2H, s), 7.18-7.28 (5H, m), 8.17 (IH, br s).
(f) 6-(4-{[(Benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester
A solution of ethyl 6-chloro-5-cyano-2-methylnicotinate (47.5 g, 211 mmol) and triethyl amine (58.36 g, 577 mmol) in EtOH (314 ml) was added to a stirred mixture of N- (benzylsulfonyl)piperidine-4-carboxamide (53.55 g, 189.7 mmol, and EtOH (100 ml) at r.t. and the mixture was heated to 100 0C (bath temperature, 20-100 oC during 40 minutes, 100 0C 15 minutes then cool to r.t.) for 15 minutes. A solution of KHSO4 (142.93 g in 900 mL water) was added to make the product precipitate out. The precipitate was filtered off and washed with water (2 x 250 mL) to give 87 g of a crude product (84 % pure ). The crude product was slurried in 50 % EtOH (1200 mL) and heated to 50 0C (bath temperature) for 2 hours and 45 minutes followed by stirring over night at r.t.. Filtration gave a crude product which was further washed by stirring with 25 % EtOH (1600 mL) at 50 0C for 2 hours followed by 20 % EtOH (1000 mL) at 50 0C for 2 hours. (An attempt to purify the material by using a 50% EtOH/water solution was not successful because it dissolved to much of the product). The solid obtained after the washings above (89 % pure) was dissolved in 700 mL EtOAc at 70 0C and the solution was left to crystallise at r.t. over night. The crystals was filtered off and washed with EtOAc (200 mL) to give pure 6-(4- {[(benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester as an orange solid (fine needles) after drying. Yield: 54.94 g of . Recrystallization of the solids from the motherliquor using EtOAc gave another 10.50 g. Yield 65.44 g (73%). 1H NMR (400 MHz, CDCl3): δ 1.38 (3H, t, J= 7.0 Hz), 1.77-1.91 (4H, m), 2.37-2.44 (IH, m), 2.73 (3H, s), 3.10-3.17 (2H, m), 4.33 (2H, q, J= 7.0 Hz), 4.64-4.68 (4H, m), 7.36-7.41 (5H, m), 8.36 (IH, s). MS m/z: 471(M+1).
(g) 6-{4-[(Benzylsulfonyl)carbamoyl]piperidin-l-yl}-5-cyano-2-methylnicotinic acid
A mixture of 6-(4- { [(benzylsulfonyl)amino] carbonyl} piperidin- 1 -y l)-5 -cyano-2- methylnicotinic acid ethyl ester (100 g, 212.5 mmol), 2 M NaOH (425 mL, 850 mmol) and MeOH (1000 mL) was heated to 75 0C for 1 hour and 45 minutes. The mixture was cooled and water (500 mL) was added and the recation mixture was filtered. The methanol was evaporated and acetic acid (51 g in 100 mL water) was added to the clear solution during 15 minutes followed by an additional 26 g acetic acid in 100 mL water (pH = 5.5). The precipitated product was filtered off, washed with water (3 x 400 mL) and heptane (400 mL) and dried in vaccuo at 40 0C over night to give 6- {4-
[(benzylsulfonyl)carbamoyl]piperidin-l-yl}-5-cyano-2-methylnicotinic acid as a yellow solid. Yield 90.1 g (91 %). 1H NMR (600 MHz, DMSO-d6): δ 1.59-1.67 (2H, m), 1.80-1.85 (2H, m), 2.53-2.61 (IH, m), 2.64 (3H, s), 3.08-3.15 (2H, m), 4.48-4.54 (2H, m), 4.68 (2H, s), 7.27-7.30 (2H, m), 7.36-7.42 (3H, m), 8.30 (IH, s), 11.60 (IH, br s).
(h) N-(Benzylsulfonyl)-l-(3-cyano-6-methyl-5-pentanoylpyridin-2-yl)piperidine-4- carboxamide
Oxalyl chloride (949 mg, 4.8 mmol) and DMF (1 drop) was added to a slurry of 6-{4- [(benzylsulfonyl)carbamoyl]piperidin-l-yl}-5-cyano-2-methylnicotinic acid (1.05 g, 2.37 mmol) in DCM (20 mL) and the reaction was stirred at r.t. until all acid was consumed. The solvent and excess reagents were evaporated and the residue was dissolved in THF (30 mL). Ferric acetylacetonate (37 mg, 0.105 mmol) was added and the mixture was cooled in an ice/water bath. n-Butylmagnesium bromide was added dropwise to the red solution and the mixture was stirred for 10 minutes. Methanol (2 mL) was added and the solvent was evaporated. The residue was taken up in DCM and the organic phase was washed with water (emulsion). The mixture was acidified with 2 M HCl (10 mL) and the phases were separated. The organic phase was passed through a phase separator and evaporated to give 1.4 g of a crude product.The crude product was purified by preparative HPLC (Kromasil C8, using an increasing gadient of MeCN in water/0.2 % HOAc). This gave N- (benzylsulfonyl)- 1 -(3 -cyano-6-methyl-5 -pentanoylpyridin-2-yl)piperidine-4-carboxamide as a white solid. Yield: 823 mg (72%).
1H-NMR (500 MHz, CDCl3) δ 0.95 (3H, t), 1.39 (2H, sextett), 1.67 (2H, quintett), 1.75- 1.93 (4H, m), 2.39-2.46 (IH, m), 2.67 (3H, s), 2.80 (2H, t), 3.11-3.19 (2H, m), 4.67 (2H, s), 4.65-4.72 (2H, m), 7.32-7.36 (2H, m), 7.37-7.44 (3H, m), 7.60 (IH, s), 8.13 (IH, s). MS m/z: 483 (M+ 1), 481 (M-I). GTPyS(IC50 μM): 0.110
Example 2
N-(Benzylsulfonyl)-l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)azetidine-3- carboxamide
(a) 1- [3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl] azetidine-3-carboxylic acid Ethyl ό-chloro-S-cyano^-methylnicotinate (See Example l(c))(50.98 g, 227 mmol), azetidine-3-carboxylic acid (24.09 g, 238 mmol) and DIPEA (118.9 mL, 681 mmol) were suspended in EtOH (250 mL) and heated at reflux for 1 h. The reaction mixture was cooled to r.t. and added drop-wise to KHSO4 (154.5 g, 1135 mmol) in water (3000 mL). The solids were collected by filtration and dried under vacuum to afford l-[3-cyano-5- (ethoxy carbonyl)-6-methylpyridine -2 -yl] azetidine-3-carboxylic acid as a solid, which was used without further purification. Yield: 65.33 g (100%).
1H NMR (400 MHz, CDCl3): δ 1.37 (3H, t, J= 7.1 Hz), 2.72 (3H, s), 3.59-3.68 (IH, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.68 (4H, m), 8.28 (IH, s). MS m/z: 290 (M+ 1).
(b) Ethyl 6-{3-[(benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinate
l-[3-Cyano-5-(ethoxycarbonyl)-6-methylpyridine-2-yl]azetidine-3-carboxylic acid (20.00 g, 69.14 mmol), EDCI (19.88 g, 103.7 mmol), 1-phenylmethanesulfonamide (15.39 g, 89.88 mmol), HOBt (10.276 g, 76.049 mmol) and DIPEA (36.127 mL, 207.41 mmol) were suspended in DCM (500 mL) and stirred at r.t. for 5 minutes until homogenous. Then the reaction mixture was refluxed for 3 h. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The crude reaction mixture was dissolved in EtOH (400 mL) and added drop-wise to a rapidly stirred solution of KHSO4 (47.07 g, 345.68 mmol) in water (4000 mL). The product was collected by filtration, washed with water (3 x 500 mL) and dried under vaccum (30.61 g of dry product). The dry product was slurried in EtOH (1500 mL) and stirred and heated at 50 0C for 1 h. The compound was isolated by filtration and dried under high vaccum to afford the desired material as crystals .Yield: 27.65 g (90%).
1H NMR (400 MHz, DMSO-d6) δ 1.23 (t, J= 7.2 Hz, 3H), 2.57 (s, 3H), 3.43 (m, IH), 4.17 (q, J= 7.1 Hz, 2H), 4.23 (t, J= 7.1 Hz, 2H), 4.34 (t, J= 8.9 Hz, 2H), 4.68 (s, 2H), 7.29 (m, 5H), 8.33 (s, IH), 11.75 (s, IH) MS m/z: 443 (M+ 1)
(c) 6-{3-[(Benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinic acid NaOH (11.3 niL, IM, 11.3 mmol) was added to a solution of ethyl 6-{3- [(benzylsulfony^carbamoy^azetidin-l-yll-S-cyano^-methylnicotinate (1.0 g, 2.26 mmol) in Methanol (10 mL) and the mixture was stirred at r.t. for 2 hours. The methanol was evaporated and the aqueous phase was acidified to pH 1 with KHSθ4(aq) to precipitate the product. The crude 6-{3-[(benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2- methylnicotinic acid was isolated by filtration and used without further purification in the next step. Yield: 750 mg (80%).
1H NMR (400 MHz, DMSO-d6) δ 2.65 (3H, s), 3.50-3.59 (IH, m), 4.26-4.33 (2H, m), 4.36-4.45 (2H, m), 4.74 (2H, s), 7.30-7.41 (5H, m), 8.28 (IH, s), 11.81 (IH, br s), 12.86 (IH, br s).
(d) 6-{3-[(Benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinoyl fluoride
Cyanuric fluoride (179 mg, 1.33 mmol) was added to a cold (0 0C) mixture of 6-{3-
[(benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinic acid (500 mg, 1.21 mmol) in DCM (10 mL) and pyridine (200 mg, 2.53 mmol). The reaction mixture was stirred for two hours and the mixture was filtered and the solid was washed with additional DCM. The organic phase was washed with water and evaporated to give 6-{3-
[(benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinoyl fluoride which was used without further purification assuming quantitative yield.
(e) N-(Benzylsulfonyl)-l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)azetidine-3- carboxamide
Ferric acetylacetonate ( 21 mg, 0.06 mmol) was added to a solution of 6-{3- [(benzylsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-methylnicotinoyl fluoride (502 mg, 1.206 mmol) in dry THF (10 mL, freshly distilled from Na) and the temperature was lowered to 0 0C. n-propyl manesiumbromide (3 mL, 1.2 M in THF) was added dropwise over 2 hours and the reaction was monitored by LCMS. A colour change to dark black was observed upon addition of the grignard reagent which quickly turned to the original yellowish color.The reaction mixture was quenched with IM NH4Cl(aq) followed by addition of DCM. The solids were filtered off and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (x2) and the organics were combined and the solvent was removed in vacuo to give a crude product. Purification using preparative HPLC (Kromasil Cg using an increasing gradient of MeCN in water/0.2 % FA) Yield: 187 mg (35 %). MS m/z: 441 (M+ 1) GTPyS(IC50 μM): 0.227
Example 3
N-(Benzylsulfonyl)-l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide
Oxalylchloride (20 mL, 282.5 mmol) and DMF (8 drops) were added to a suspension of 6- {4-[(benzylsulfonyl)carbamoyl]piperidin-l-yl}-5-cyano-2-methylnicotinic acid (Example l(g)) (5O g, 113 mmol) in DCM (1750 mL) and the slurry was stirred for 3 hours at r.t.. An additional amount of oxalylchloride (2 mL, 28.2 mmol) was added and the stirring was continued for an additional 1.5 hours. The solvent and excess reagents were evapoarted and the residue was co-evaporated with THF (500 mL). The residue was dissolved in THF (1500 mL) and ferric acetylacetonate (1.995 g, 5.65 mmol) was added and the mixture was placed under an atmosphere of nitrogen and cooled to 0 0C. n-propylmagnesium bromide (2 M in THF) was added dropwise until all the startingmaterial was consumed according to LC-MS (total amount of grignard reagent 141 mL). The reaction was quenched with MeOH (100 mL). The solvents was evaporated and the residue was taken up in DCM (1000 mL)/ 1 M HCl (1000 mL). The phases were separated and the acidic water phase was extracted with DCM (500 mL). The combined organic phase was washed with water (500 mL), dried (MgSO4), filtered and evapoarted to give 56.44 g of the crude product. The crude was slurried in EtOH (500 mL, 95%) and heated to 60 0C for 1 hour. The mixture was cooled to r.t. and the solid was filtered and washed with EtOH (2 x 250 mL, 95%) and dried in vaccuo at 40 0C over night to give N-(Benzylsulfonyl)-l-(5-butyryl-3- cyano-6-methylpyridin-2-yl)piperidine-4-carboxamide. Yield: 38.6 g (71%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (3H, t), 1.55 (2H, sextett), 1.58-1.68 (2H, m), 1.78- 1.86 (2H, m), 2.54 (3H, s), 2.54-2.60 (IH, m), 2.86 (2H, t), 3.05-3.15 (2H, m), 4.47- 4.55 (2H, m), 4.68 (2H, s), 7.25-7.30 (2H, m), 7.35-7.42 (3H, m), 8.51 (IH, s), 11.59 (IH, br s). GTPyS(IC50 μM): 0.115
Example 4 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(l-phenylethyl)sulfonyl] piperidine-4- carboxamide
(a) Ethyl 2-((dimethylamino)methylene)-3-oxobutanoate
l,l-dimethoxy-N,N-dimethylmethanamine (500 g, 4195 mmol) was added to ethyl 3- oxobutanoate (461.6 g, 3547 mmol) under an atmosphere of nitrogen at r.t. during 13 minutes(weak exotherm). The orange red solution was stirred for 22 hours and concentrated in vaccuo. The residue was co-evaporated with toluene (3 times 200 ml each) and used without no need for further purification in the next step. MS m/z: 186 (M+ 1).
(b) Ethyl S-cyano-l-methyl-ό-oxo- 1 ,6-dihydropyridine-3-carboxylate
Sodium ethoxide (1240.7 g of a 21 wt % solution in EtOH, 3829 mmol) was added to a stirred suspension of 2-cyanoacetamide (298 g, 3544 mmol) in EtOH (3000 mL) during 8 minutes under an atmosphere of nitrogen at r.t.. The crude condensation product from step (a) above dissolved in 950 ml EtOH was added slowly (slightly exothermic reaction) and after about one third had been added further EtOH (1000 mL) was added to allow efficient stirring (suspension) followed by the addition of the rest of the condensation product (total addition time 30 min). After stirring over night at r.t.. HOAc (526 g, 8759 mmol) was added to the reaction and the mixture was concentrated in vaccuo leaving a thick orange slurry (volume about 3000 mL), 1 M HCl (4628 mL, 4628 mmol) was added during 10 min followed by water (500 mL). The stirring was stopped and the precipitate was filtered off and washed with water (200 mL). NMR showed the presence of about 5-10 % of the corresponding acid and the solid was washed by stirring with further water (1500 mL + 3 x 1000 niL), a solution of saturated NaHCO3 (400 mL) in water (600 mL) and finally water (1000 mL). Filtration of the solid and drying in vaccuo at 80 0C gave pure ethyl 5-cyano-2- methyl-6-oxo-l,6-dihydropyridine-3-carboxylate. Yield: 493 g (67 %). 1H NMR (400 MHz, DMSO-d6): δ 1.36 (3H, t, J= 7.1 Hz), 2.62 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 8.71 (IH, s), 12.79 (IH, br s).
(c) Ethyl ό-chloro-S-cyano-l-methylnicotinate
Toluene (4000 mL) and thionylchloride (507 g, 4262 mmol) were added to ethyl 5-cyano- 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (293 g, 1421 mmol) under an atmosphere of nitrogen and the mixture was heated to 50 0C (oil bath temperature) and DMF (100 g, 1368 mmol) was added during 2 minutes. The temperature was raised to 80 0C (oil bath temperature) and the stirring was continued for 2 hours. The mixture was concentrated in vaccuo (about 3500 ml was evaporated off) leaving a red oil. EtOH (1000 mL, 99%) was added and then evaporated off. Dichloromethane (4000 mL) was added followed by 4 % NaHCO3 solution (4000 mL) and the mixture was stirred for 15 minutes. The organic phase was separated and evaporated to give crude ethyl 6-chloro-5-cyano-2- methylnicotinate as a dark red solid which was used without further purification. Yield: 301 g (75 %). 1H NMR (400 MHz, CDCl3): δ 1.42 (3H, t, J = 7.1 Hz), 2.91 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 8.49 (IH, s).
(d) Ethyl 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinate
A 20 mL microwave vial was charged with ethyl 6-chloro-5-cyano-2-methylnicotinate (5 g, 22.3 mmol), tert-butyl piperidine-4-carboxylate (4.11 g, 22.3 mmol), TEA (4.5 g, 44.5 mmol) and MeCN and heated, single nodeheating, to 100 0C for 5 minutes. The reaction was concentrated and MeCN/water was added to precipitate the product. Filtration of the solid and drying gave ethyl 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2- methylnicotinate as an orange colored solid. Yield: 6.99 g (77%). 1H NMR (400 MHz, DMSO-d6): δ 1.30 (3H, t), 1.40 (9H, s), 1.32-1.64 (2H, m), 1.88-1.96 (2H, m), 2.55-2.60 (IH, m), 2.63 (3H, s), 3.20-3-30 (2H, m), 4.24 (2H, q), 4.39-4.47 (2H, m), 8.31 (IH, s).
(e) 6-[4-(tert-Butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinic acid
NaOH (1.8 g, 45 mmol) dissolved in water (total amount of 27 mL) was added portionwise to a solution of ethyl 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinate (13 g, 24.4 mmol) at 80 0C until the startingmaterial was consumed (some hydrolysis of the tert-buthyl ester was also observed). Addition of FA (pH=3) followed by concentration of the mixture and addition of water (20 mL) initiated precipitation. The solid was filtered off and dried to give 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinic acid as a light yellow solid. Yield: 8.25 g (98%). MS m/z: 346 (M+ 1), 344 (M-I).
(f) tert-Butyl 1- [5-(chlorocarbonyl)-3-cyano-6-methylpyridin-2-yl] piperidine-4- carboxylate
Oxalyl chloride (5.76 g, 45.38 mmol) and DMF (166 mg, 2.27 mmrnol) was added to a slurry of 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinic acid (8.25 g, 22.69 mmol) in DCM (100 mL) at 0 0C. The mixture was stirred for 20 minutes at r.t. and the solvent and excess reagents were evaporated. This gave tert-butyl l-[5- (chlorocarbonyl)-3-cyano-6-methylpyridin-2-yl]piperidine-4-carboxylate as an orange colored solid which was used in the next step without further purification. Yield. 9.00 g (98%).
MS m/z: 428 (M+ 1) (detected as the N-methylpiperazin adduct by quencing with N- methylpiperazin).
(g) tert-Butyl l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)piperidine-4-carboxylate
n-Propylmagnesium bromide (25 mL, 1 M solution in THF, 25 mmol) was added dropwise to a cold (0 0C) solution of tert-butyl l-[5-(chlorocarbonyl)-3-cyano-6-methylpyridin-2- yl]piperidine-4-carboxylate (9 g, 22.76 mmol, 92% pure) and ferric acetylacetonate (121 mg, 0.341 mmol) in THF (60 mL) and the mixture was stirred for 30 minutes. Addition of water and concentration gave an oil that was partioned between DCM and water(acidic, FA). Collection of the organic phase and concentration gave tert-butyl l-(5-butyryl-3- cyano-6-methylpyridin-2-yl)piperidine-4-carboxylate as an oil that solidified upon standing. The crude material was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ 0.98 (3H, t), 1.45 (9H, s), 1.66-1.85 (4H, m), 1.95-2.05 (2H, m), 2.48-2.58 (IH, m), 2.66 (3H, s), 2.77 (2H, t), 3.23-3.33 (2H, m), 4.55-4.63 (2H, m), 8.11 (1H, s).
(h) l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)piperidine-4-carboxylic acid
TFA (25 mL, 324 mmol) was added to a solution of tert-butyl l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)piperidine-4-carboxylate (10.8 g, 26.17 mmol) in DCM (50 mL at 0 0C. The reaction mixture was allowed to reach r.t. and stirred for 5 hours. The solvent and excess TFA was evaporated and the residue was dissolved in EtOH and precipitated by addition of water. The product was filtered off and dried to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)piperidine-4-carboxylic acid as an off white solid. Yield: 6.15 g (75%). 1H NMR (400 MHz, DMSO-d6): δ 0.90 (3H, t), 1.50-1.67 (4H, m), 1.90-2.00 (2H, m), 2.55 (3H, s), 2.57-2.65 (IH, m), 2.88 (2H, t), 3.20-3.30 (2H, m), 4.40-4.48 (2H, m), 8.52 (IH, s), 12.31 (IH, s).
(i) l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(l-phenylethyl)sulfonyl] piperidine-4-carboxamide
PyBOP (187 mg, 0.36 mmol) was added to a solution of l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)piperidine-4-carboxylic acid (95 mg, 0.3 mmol) and DIPEA (194 mg, 1.5 mmol) in DCM (2 mL) and the mixture was stirred at r.t. for 30 minutes before 1- phenylethanesulfonamide (72 mg, 0.39 mmol) was added and the stirring was continued over night. Water (containing 2 % FA) was added and the solvent was removed in vaccuo. The crude product was purified by purification method A (see General Experimental Procedure) to give l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(l- phenylethyl)sulfonyl] piperidine-4-carboxamide. Yield: 57 mg (39%). 1H-NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.49 - 1.57 (4H, m), 1.59 - 1.70 (4H, m), 1.80 - 1.86 (2H, m), 2.86 (2H, t, J = 6.7 Hz), 3.03 - 3.13 (2H, m), 4.41 5 - 4.55 (2H, m), 4.77 (IH, q, J = 7.5 Hz), 7.29 - 7.42 (5H, m), 8.51 (IH, s), 11.54 (IH, s). (Three Hydrogens missing due to the wet signals) MS m/Z: 583 (M+ 1), 481 (M-I). GTPyS(IC50 μM): 0.257 o Example 5 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3,4- difluorophenyl)methanesulfonamide (82 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3,4-difluorobenzyl)sulfonyl]piperidine-4-carboxamide Yield: 61 mg ( 41 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.50 - 1.56 (2H, m),0 1.56 - 1.65 (2H, m), 1.77 - 1.84 (2H, m), 2.54 - 2.60 (IH, m), 2.86 (2H, t, J = 7.6 Hz), 3.07
- 3.15 (2H, m), 4.47 - 4.53 (2H, m), 4.70 (2H, s), 7.08 - 7.15 (IH, m), 7.31 - 7.38 (IH, m),
7.43 - 7.52 (IH, m), 8.50 (IH, s), 11.66 (IH, s). (Three Hydrogens missing due to the wet signals)
MS m/z: 505 (M+ 1), 503 (M-I). 5 GTPyS(IC50 μM): 0.168
Example 6 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-
[(cyclopentylmethyljsulfonyljpiperidine^-carboxamide o Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and 1- cyclopentylmethanesulfonamide (64 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(cyclopentylmethyl)sulfonyl]piperidine-4-carboxamide Yield: 47 mg ( 34 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.17 - 1.24 (2H, m), 1.41 - 1.50 (2H, m), 1.50 - 1.64 (6H, m), 1.79 - 1.84 (2H, m), 1.85 - 1.91 (2H, m), 2.07 - 2.18 (IH, m), 2.59 - 2.66 (IH, m), 2.85 (2H, t, J = 7.0 Hz), 3.11 - 3.15 (2H, m), 4.48 - 4.54 (2H, m), 8.49 (IH, s), 8.49 (IH, s). (Five Hydrogens missing due to the wet signals) MS m/z: 461 (M+ 1), 459 (M-I). GTPyS(IC50 μM): 0.369
Example 7 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-{[(4- methylcyclohexyl)methyl]sulfonyl}piperidine-4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methylcyclohexyl)methanesulfonamide (75 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano- 6-methylpyridin-2-yl)-N-{[(4-methylcyclohexyl)methyl]sulfonyl}piperidine-4- carboxamide. Yield: 54 mg (37 %). MS m/z: 489 (M+ 1), 487 (M-I). GTPyS(IC50 μM): 1.08
Example 8 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-methoxybenzyl)sulfonyl]piperidine- 4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methoxyphenyl)methanesulfonamide (78 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-methoxybenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 30 mg (20%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.49 - 1.65 (4H, m), 1.78 - 1.85 (2H, m), 2.86 (2H, t, J = 7.5 Hz), 3.06 - 3.15 (2H, m), 3.73 (3H, s), 4.48 - 4.54 5 (2H, m), 4.58 (2H, s), 6.93 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 8.50 (IH, s), 11.53 (IH, s). (Four Hydrogens missing due to the wet signal) MS m/z: 499(M+1), 497 (M-I). GTPyS(IC50 μM): 0.154 o Example 9 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N- [(cyclohexylmethyl)sulfonyl]piperidine-4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and 1-
(cyclohexyl)methanesulfonamide (69 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(cyclohexylmethyl)sulfonyl]piperidine-4-carboxamide. Yield: 38 mg (27%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.00 - 1.24 (5H, m),0 1.49 - 1.65 (7H, m), 1.73 - 1.81 (3H, m), 1.84 - 1.91 (2H, m), 2.60 - 2.64 (IH, m), 2.85
(2H, t, J = 7.0 Hz), 3.08 - 3.18 (2H, m), 3.23 - 3.27 (IH, m), 4.46 - 4.55 (2H, m), 8.49 (IH, s), 11.73 (IH, s). (Four Hydrogens missing due to the wet signal)
MS m/z: 475(M+1), 473 (M-I).
GTPyS(IC50 μM): 0.913 5
Example 10 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-phenylethyl)sulfonyl]piperidine-4- carboxamide o Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and 2- phenylethanesulfonamide (72 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-phenylethyl)sulfonyl]piperidine-4-carboxamide.Yield: 51 mg (35 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.48 - 1.60 (4H, m), 1.79 - 1.89 (2H, m), 2.85 (2H, t, J = 6.8 Hz), 2.91 - 2.98 (2H, m), 3.08 - 3.16 (2H, m), 3.61 5 - 3.67 (2H, m), 4.45 - 4.55 (2H, m), 7.17 - 7.31 (5H, m), 8.51 (IH, s), 11.74 (IH, s). (Four Hydrogens missing due to the wet signals) MS m/z: 483 (M+ 1), 481 (M-I). GTPyS(IC50 μM): 0.592 o Example 11 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine-4- carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- chlorophenyl)methanesulfonamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 63 mg
(42 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.51 - 1.57 (2H, m),0 1.57 - 1.65 (2H, m), 1.78 - 1.85 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 3.07 - 3.13 (2H, m), 4.48
- 4.54 (2H, m), 4.69 (2H, s), 7.28 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.6 Hz), 8.50 (IH, s),
8.50 (IH, s). (Four Hydrogens missing due to the wet signals)
MS m/z: 503 (M+l), 501 (M-I).
GTPyS(IC50 μM): 0.152 5
Example 12 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-
[(cyclobutylmethyl)sulfonyl]piperidine-4-carboxamide o Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and 1- (cyclobutyl)methanesulfonamide (58 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(cyclobutylmethyl)sulfonyl]piperidine-4-carboxamide. Yield: 51 mg (38%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.49 - 1.63 (4H, m), 1.71 - 1.81 (3H, m), 1.82 - 1.91 (3H, m), 2.01 - 2.08 (2H, m), 2.58 - 2.65 (IH, m), 2.85 5 (2H, t, J = 7.2 Hz), 3.09 - 3.16 (2H, m), 3.44 (2H, d, J = 6.8 Hz), 4.48 - 4.55 (2H, m), 8.51 (IH, s), 11.65 (IH, s). (Three Hydrogens missing - due to wet signals). MS m/z: 447 (M+l), 481 (M-I). GTPyS(IC50 μM): 0.918 o Example 13 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3-fluoro-4- methylbenzyl)sulfonyl]piperidine-4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2-5 yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3-fluoro-4- methylphenyl)methanesulfonamide (79 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3-fluoro-4-methylbenzyl)sulfonyl]piperidine-4-carboxamide.
Yield: 58 mg (38 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.50 - 1.56 (2H, m),0 1.56 - 1.65 (2H, m), 1.77 - 1.84 (2H, m), 2.21 (3H, s), 2.54 - 2.60 (IH, m), 2.86 (2H, t, J =
7.5 Hz), 3.06 - 3.15 (2H, m), 4.48 - 4.53 (2H, m), 4.66 (2H, s), 6.96 - 7.00 (IH, m), 7.01 -
7.06 (IH, m), 7.26 - 7.32 (IH, m), 8.50 (IH, s), 11.61 (IH, s). (Three Hydrogens missing due to the wet signals)
MS m/z: 501 (M+l), 499 (M-I). 5 GTPyS(IC50 μM): 0.279
Example 14 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-cyanobenzyl)sulfonyl]piperidine-4- carboxamide o Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2- cyanophenyl)methanesulfonamide (76 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-cyanobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 60 mg (41%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.50 - 1.57 (2H, m), 1.59 - 1.66 (2H, m), 1.84 - 1.92 (2H, m), 2.58 - 2.64 (IH, m), 2.86 (2H, t, J = 7.2 Hz), 3.08 - 3.17 (2H, m), 4.48 - 4.55 (2H, m), 4.86 (2H, s), 7.50 - 7.54 (IH, m), 7.56 - 7.62 (IH, m), 7.72 - 7.78 (IH, m), 7.87 - 7.92 (IH, m), 8.50 (IH, s), 11.87 (IH, s). (Three Hydrogens missing due to the wet signals) MS m/z: 494 (M+ 1), 492 (M-I). GTPyS(IC50 μM): 1.99
Example 15 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine-4- carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(3- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 48 mg (33 %). 1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.50 - 1.57 (2H, m), 1.56 - 1.64 (2H, m), 1.77 - 1.83 (2H, m), 2.55 - 2.59 (IH, m), 2.86 (2H, t, J = 7.8 Hz), 3.06 - 3.15 (2H, m), 4.47 - 4.53 (2H, m), 4.72 (2H, s), 7.08 - 7.13 (2H, m), 7.19 - 7.25 (IH, m), 7.40 - 7.46 (IH, m), 8.50 (IH, s), 11.64 (IH, s). (Three Hydrogens missing due to the wet signals) MS m/z: 487 (M+l), 485 (M-I). GTPyS(IC50 μM): 0.100
Example 16 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine-4- carboxamide Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 60 mg 5 (41%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.51 - 1.57 (2H, m), 1.58 - 1.67 (2H, m), 1.82 - 1.89 (2H, m), 2.55 - 2.61 (IH, m), 2.86 (2H, t, J = 7.2 Hz), 3.07 - 3.15 (2H, m), 4.48 - 4.56 (2H, m), 4.72 (2H, s), 7.21 - 7.27 (2H, m), 7.36 - 7.45 (2H, m), 8.50 (IH, s), 11.73 (IH, s). (Three Hydrogens missing due to the wet signals) o MS m/z: 487 (M+ 1), 485 (M-I). GTPyS(IC50 μM): 0.041
Example 17 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine-4-5 carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- fluorophenyl)methanesulfonamide (74 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6-0 methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 46 mg (31%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.48 - 1.66 (4H, m), 1.77 - 1.85 (2H, m), 2.86 (2H, t, J = 7.0 Hz), 3.05 - 3.15 (2H, m), 4.48 - 4.54 (2H, m), 4.67 (2H, s), 7.19 - 7.25 (2H, m), 7.28 - 7.33 (2H, m), 8.50 (IH, s), 11.59 (IH, s). (Four5 Hydrogens missing - 2-Me-Pyridine and one H in CH(Piperidine), due to wet) MS m/z: 487 (M+l), 485 (M-I). GTPyS(IC50 μM): 0.057
Example 18 o l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-methylbenzyl)sulfonyl]piperidine- 4-carboxamide Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(4- methylphenyl)methanesulfonamide (72 mg, 0.39 mmol) to give l-(5-Butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(4-methylbenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 32 mg 5 (22%).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.51 - 1.57 (2H, m), 1.58 - 1.64 (2H, m), 1.78 - 1.85 (2H, m), 2.53 - 2.60 (IH, m), 2.86 (2H, t, J = 7.2 Hz), 3.06 - 3.14 (2H, m), 4.48 - 4.53 (2H, m), 4.60 (2H, s), 7.14 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 8.50 (IH, s), 11.51 - 11.55 (IH, m). (Three Hydrogens missing due to the weto signal)
MS m/z: 483 (M+ 1), 481 (M-I). GTPyS(IC50 μM): 0.096
Example 19 s l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine-4- carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2-0 chlorophenyl)methanesulfonamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 15 mg
(10 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.3 Hz), 1.50 - 1.57 (2H, m),
1.58 - 1.67 (2H, m), 1.84 - 1.90 (2H, m), 2.56 - 2.62 (IH, m), 2.86 (2H, t, J = 7.2 Hz), 3.085 - 3.16 (2H, m), 4.48 - 4.55 (2H, m), 4.83 (2H, s), 7.36 - 7.43 (3H, m), 7.48 - 7.52 (IH, m),
8.50 (IH, s), 11.79 (IH, s). (Three Hydrogens missing due to the wet signals).
MS m/z: 503 (M+l), 501 (M-I).
GTPyS(IC50 μM): 0.397 o Example 20 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and l-(2,4- difluorophenyl)methanesulfonamide (81 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-[(2,4-difluorobenzyl)sulfonyl]piperidine-4-carboxamide. Yield: 61 mg (41 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.50 - 1.64 (4H, m), 1.81 - 1.88 (2H, m), 2.86 (2H, t, J = 7.2 Hz), 3.07 - 3.15 (2H, m), 4.49 - 4.55 (2H, m), 4.71 (2H, s), 7.11 - 7.19 (IH, m), 7.27 - 7.35 (IH, m), 7.39 - 7.47 (IH, m), 8.50 (IH, s), 11.73 (IH, s). (Four Hydrogens missing -due to the wet signals) MS m/z: 505 (M+l), 503 (M-I). GTPyS(IC50 μM): 0.047
Example 21 l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-{[(4- fluorophenyl)(methyl)amino]sulfonyl}piperidine-4-carboxamide
(a) N-(4-Fluorophenyl)-N-methylsulfamide Chlorosulfonyl isocyanate (3.51 mL)was dissolved in dry DCM (40 mL) and cooled to 0 0C with an icebath. tBuOH (3.78mL) was added dropwise and the ice bath was removed and the reaction was stirred at r.t. for lhour. The solution was cooled to 0 0C with an icebath and N-Methylaniline (4.56 mL) and TEA (8.4 mL) dissolved in dry DCM (2OmL) was added dropwise through a droppingfunnel, the icebath was removed and the reaction was stirred at r.t. for 3hours. The reaction mixture was washed with water, the organic phase was separated by a phase separator and concentrated. The crude product was dissolved in dry DCM (4OmL) and TFA (3 ImI) was added, the reaction was stirred at r.t. for 20 minutes. The solvent was evaporated and the residue was co-evaporated with DCM 3 times. The crude product was purified with column chromatography on silica gel (Biotage SP4) using heptane:EtOAc 65:35 as eluant. This gave N-(4-fluorophenyl)-N- methylsulfamide. Yield: 6.0 g (73 %). (b) l-(5-Butyryl-3-cyano-6-methylpyridin-2-yl)-N-{[(4- fluorophenyl)(methyl)amino]sulfonyl}piperidine-4-carboxamide
Prepared according to Example 4(i) from l-(5-butyryl-3-cyano-6-methylpyridin-2- yl)piperidine-4-carboxylic acid (Example 4(h)) (95 mg, 0.3 mmol) and N-(4- fluorophenyl)-N-methylsulfamide (80 mg, 0.39 mmol) to give l-(5-butyryl-3-cyano-6- methylpyridin-2-yl)-N-{[(4-fluorophenyl)(methyl)amino]sulfonyl}piperidine-4- carboxamide. Yield: 67 mg (45 %).
1H NMR (600MHz, (CD3)2SO, (CH3)2SO) δ 0.87 (3H, t, J = 7.5 Hz), 1.49 - 1.61 (4H, m), 1.73 - 1.80 (2H, m), 2.86 (2H, t, J = 7.2 Hz), 3.05 - 3.13 (2H, m), 4.45 - 4.52 (2H, m), 7.20 - 7.26 (2H, m), 7.31 - 7.37 (2H, m), 8.50 (IH, s), 11.64 (IH, s). (Seven Hydrogens missing due to the wet signals) MS m/z: 502 (M+l), 500 (M-I). GTPyS(IC50 μM): 0.188
Example 22 Bioavailability study
The oral bioavailability of the compound N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6- methylpyridin-2-yl)piperidine-4-carboxamide (Example 3) in rats, administrated as a solution was evaluated in rats, by comparing with intravenous administration of the same solution.
The solution was prepared as a hydroxypropyl-β-cyclodextrine solution, comprising 28% w/w of the cyclodextrin in water, buffered to pH 9.
Two rats were used both for i..v and p.o. administration in this study.
Two days prior to dosing, the rats were prepared by cannulation of the left carotid artery for blood sampling and, for the i.v. administration rats, by cannulation of the right jugular vein. The catheters were filled with heparin (100 IU/mL), exteriorised at the nape of the neck and sealed. The surgery was performed under isoflurane (Forene®, Abbott) anaesthesia. After surgery the rats were housed individually and had free access to food and water. About 16 hours prior to dosing the animals were deprived of food, and fasting until 4 hours after dosing. The rats had free access to drinking water during the experiment. A cage card number identified the rats.
The p.o. test formulation was administered orally by gavage, with the dose being 5 μmol/kg , whereas the intravenously administered dose was given in the jugular vein, with the dose being 2 μmol/kg.
At pre-defined time points, blood samples of about 0.150 mL were withdrawn from the carotid artery, up to 24 h after dosing. About 10 samples were withdrawn. The blood samples were collected in heparinized plastic tubes and centrifuged, within 30 minutes, for five minutes at 10 000 g and +4°C. The plasma was transferred to a 96-well plate and stored at -200C until analysis.
The plasma concentrations of the test item were determined by liquid chromatography and mass-spectrometric detection. The concentrations of the test item in the formulation were confirmed by liquid chromatography and mass-spectrometric detection.
Calculations
The area under the plasma concentration-time curve following oral and intravenous administration, AUC(0-t), was calculated using a combination of the linear and logarithmic trapezoidal rule from the time of administration to the sampling time with the last determinable plasma concentration. For the intravenous bolus dose, the concentration at time zero, C(O), was estimated by log linear regression of the first two concentration-time points. The AUC(01) was extrapolated to AUC by adding Ct/k. C1 is the predicted plasma concentration at the time of the last plasma sample with a determinable concentration, and k is the apparent terminal rate constant. Ct and k were obtained by linear least squares regression analysis of the logarithm of the last 3 to 5 plasma concentrations versus time. The apparent terminal half-life (fc/2) was calculated as In 2/k. The bioavailability (F) was calculated as
(AUCp-CXDOSe1-V., mean/AUCI-V-, meanXDθSep.o.)x 100 %.
The results obtained were;
Figure imgf000101_0001
Example 23
Comparison of metabolic stability in human liver microsomes
A compound (the compound of Example 3) of the invention was compared to a known compound with regard to stability against metabolic degradation caused by the cytochrome P-450 system present in the liver.
6 μl solution of the test substance 1.0 μM in DMSO was incubated with 30μl liver microsomes 0.5 mg/ml and 249 μl potassium phosphate buffer in a 96-well plate kept at 370C. The reaction in this incubation mixture was started by adding 12.75 μl NADPH solution (water, 1 mM).
Samples of the reaction mixture was taken after 7,15, 20 and 30 minutes and the reaction stopped by transfering aliquots of the test mixture into a cooled stop solution whereafter the the plate was centrifuged and the supernatant was analyzed by LC-MS. As stop solution was used acetonitrile containing 0.8 % formic acid and volume markers (0.10 μmol/1 verapamil and 1 μmol/1 5, 5-diethyl-l, 3-diphenyl-2-iminobarbituric acid ).
As a 0 minutes sample 40 μl cooled stop solution (from GenMate) and 37.5 μl incubation mixture was present already at the beginning in a 96-well plate kept at 370C before 2.25 μl NADPH (from GenMate) was added.
From the obtained analyzed values plots of log concentration of test substance versus time were made and the half-life was calculated. This was used to calculate an intrinsic clearance (CLint) value which is a value adjusted for the amount of liver microsomes present in the reaction mixture.
The higher this value is, the more of the tested substance is metabolized by the liver microsomes.
Compound Structure Metabolic Stability
(CL1n,)
Figure imgf000102_0001
From this application Compound Structure Metabolic Stability
Figure imgf000103_0001
It can be seen that the corresponding compound having an oxazole ring is more prone to metabolic degradation by the human liver microsomes.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:
Figure imgf000104_0001
(I) wherein Ri represents RyC(O);
R2 represents unsubstituted (Ci-C3)alkyl;
R7 represents (Ci-C6)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-Ce)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-Ce)cycloalkyl, hydroxy(Ci-C6)alkyl, aryl or heterocyclyl;
B is a monocyclic or bicyclic, 4 to 11-membered heterocyclic ring/ring system comprising one or more nitrogen and optionally one or more atoms selected from oxygen or sulphur, which nitrogen is connected to the pyridine-ring (according to formula I) and further the B-ring/ring system is connected to X in another of its positions; the substituent Ri4 is connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by this connection); Ri4 represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-Ce)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe; wherein Re represents aryl, (C3-Ce)cycloalkyl, heterocyclyl or (Ci-Ce)alkyl optionally substituted by one or more of halogen (F, Cl, Br or I) atom(s), OH, aryl, (C3- Ce)cycloalkyl and heterocyclyl; further Ri4 represents aryl, aryl(Ci-C6)alkyl, aryl(Ci- Cs)alkoxy, heterocyclyl, a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (C3- C6)cycloalkyl(Ci-C6)alkoxy, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfϊnyl, (Ci-C6)alkylsulfonyl, (Ci-C6)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci- C6)alkyl, (Ci-C6)alkylC(O), (Ci-C6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rcis methylene (-CH2-);
Rd represents phenyl having 0,1,2,3,4 or 5 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C6)alkoxy group;
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl; further X may represent a group (-CH2-)n wherein n= 2-6, which optionally is unsaturated and/or substituted by one or more substituent chosen among halogen, hydroxyl or (Ci-Ce)alkyl;
the term "Aryl" denotes a substituted or unsubstituted (C6-Ci4) aromatic hydrocarbon; and
the term "Heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or multicyclic ring system in which one or more of the atoms in the ring or rings is an element other than carbon.
2. A compound according to claim 1 wherein; RRdd rreepprreesseennttss pphheennyyll hhaavviinngg 00,,11,,22,,33,,44 oorr 55 ssiubstituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group; and
X represents a single bond, imino (-NH-), methylene (-CH2-), iminomethylene (- CH2-NH-) wherein the carbon is connected to the B-ring/ring system, methyleneimino (- NH-CH2-) wherein the nitrogen is connected to the B-ring/ring system and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl.
3. A compound according to claim 2 wherein; (F, Cl, Br or I)(F, Cl, Br or I)(F, Cl, Br or I)
R7 represents (Ci-Ce)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, (C3-C6)cycloalkyl, heterocyclyl or one or more halogen (F, Cl, Br or I) atoms; further R7 represents (C3-C6)cycloalkyl;
Rn represents H, OH with the proviso that the OH group must be at least 2 carbon atoms away from any heteroatom in the B ring/ring system, (Ci-C6)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH and COOH; further Ri4 represents a halogen (F, Cl, Br or I) atom, (C3-Ce)cycloalkyl, (Ci-Ce)alkoxy, (C3-C6)CyClOaIkOXy, or a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (Ci-C6)alkyl, (Ci-C6)alkylC(O), (CrC6)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
Rd represents phenyl having 0,1 or 2 substituents chosen among halogens or mixed halogens or phenyl having an unsubstituted (Ci-C3)alkoxy group; and X represents a single bond, imino (-NH-) or methylene (-CH2-), and any carbon and/or nitrogen in these groups may optionally be substitued with (Ci-C6) alkyl.
4. A compound according to claim 3 wherein;
Ri is chosen from the group consisting of n-propylcarbonyl and n-butylcarbonyl;
R2 is methyl;
R7 is n-propyl or n-butyl;
B is chosen from the group consisting of 3-azetidin-l-ylene and 4-piperidin-l- ylene, and the substituent Ri4 is connected to the B ring/ring system, in such a way that no quarternary ammonium compounds are formed (by this connection);
Ri4 is H;
Rc is methylene (-CH2-);
Rdis chosen from the group consisting of phenyl, 2-fluorophenyl, 3 -fluorophenyl,
4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,4- difluorophenyl, and 3,4-difluorophenyl; and
X is a single bond.
5. A compound according to any one of claims 1-4 which is of the formula (Ia):
Figure imgf000108_0001
6. A compound according to any one of claims 1-4 which is of the formula (Ig):
Figure imgf000108_0002
(Ig)
7. A compound according to claim 5 which is of the formula (Iaa):
Figure imgf000108_0003
8. A compound according to claim 1 selected as one or more from;
N-(benzylsulfonyl)- 1 -(3 -cyano-6-methyl-5 -pentanoylpyridin-2-yl)piperidine-4- carboxamide,
N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methy lpyridin-2-yl)azetidine-3 - carboxamide, N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 ,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide, 1 -(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4- methoxybenzyl)sulfonyl]piperidine-4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide,
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(3 -fluoro-4- methylbenzyl)sulfonyl]piperidine-4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(3-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-fluorobenzyl)sulfonyl]piperidine- 4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(4-fluorobenzyl)sulfonyl]piperidine-
4-carboxamide, l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide and
1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)-N- [(2,4- difluorobenzyl)sulfonyl]piperidine-4-carboxamide; or pharmaceutically acceptable salts thereof.
9. A compound according to claim 1 being;
N-(benzylsulfonyl)- 1 -(5 -butyryl-3 -cyano-6-methylpyridin-2-yl)piperidine-4- carboxamide; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 being; l-(5-butyryl-3-cyano-6-methylpyridin-2-yl)-N-[(2-chlorobenzyl)sulfonyl]piperidine- 4-carboxamide; or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 in combination with pharmaceutically acceptable adjuvants, diluents and/or carriers.
12. A compound according to any one of claims 1-10 for use in therapy.
13. Use of a compound according to any one of claims 1-10 for the manufacture of a medicament for treatment of platelet aggregation disorder.
14. Use of a compound according to any one of claims 1-10 for the manufacture of a medicament for the inhibition of the P2Yi2 receptor.
15. A method of treatment of a platelet aggregation disorder comprising administering to a patient suffering from such a disorder a therapeutically effective amount of a compound according to any one of claims 1-10.
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