Pyridine compounds and their use as p2y12 antagonists

A compound of formula I or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 represents R6OC(O), R7C(O), R16SC(O), R17S, R18C(S) or a group gII
• R2 represents CN, halogen, (C4-C8)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, or heterocyclyl;
• or R2 represents (C2-C3)alkyl interrupted by oxygen;
• or R2 represents (C1-C3)alkyl substituted by one or more of OH, aryl, aryl(C1-C3)alkyloxy, cycloalkyl and heterocyclyl, with the proviso that any such OH group must be at least 2 carbon atoms away from any oxygen;
• or R2 represents unsubstituted (C1-C12)alkoxy, (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl, (C1-C12)alkylC(O), (C1-C12)alkylthioC(O), (C1-C12)alkylC(S), (C1-C12)alkoxyC(O), (C3-C6)cycloalkoxy, aryl, arylC(O), aryl(C1-C12)alkylC(O), heterocyclyl, heterocyclylC(O), heterocyclyl(C1-C12)alkylC(O), (C1-C12)alkylsulfinyl, (C1-C12)alkylsulfonyl, unsubstituted (C1-C12)alkylthio, (C3-C6)cycloalkylthio, arylsulfinyl, arylsulfonyl, arylthio, aryl(C1-C12)alkylthio, aryl(C1-C12)alkylsulfinyl, aryl(C1-C12)alkylsulfonyl, heterocyclyl(C1-C12)alkylthio, heterocyclyl(C1-C12)alkylsulfinyl, heterocyclyl(C1-C12)alkylsulfonyl, (C3-C6)cycloalkyl(C1-C12)alkylthio, (C3-C6)cycloalkyl(C1-C12)alkylsulfinyl, (C3-C6)cycloalkyl(C1-C12)alkylsulfonyl;
• R4 represents H, CN, a halogen atom, (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, COOH, (C1-C6)alkoxycarbonyl, or one or more halogen atoms;
• or R4 represents hydroxy(C1-C12)alkyl, (C1-C12)alkoxy wherein the alkoxy group may optionally be substituted by one or more halogen atoms, OH and/or COOH and/or (C1-C6)alkoxycarbonyl;
• or R4 represents aryl(C1-C6)alkyl, (C1-C12)alkylsulfinyl, (C1-C12)alkylsulfonyl, (C1-C12)alkylthio, (C3-C6)cycloalkyl(C1-C12)alkylsulfinyl, (C3-C6)cycloalkyl(C1-C12)alkylsulfonyl, (C3-C6)cycloalkyl(C1-C12)alkoxy, aryl(C1-C6)alkoxy or a group of formula NRa(4)Rb(4) in which Ra(4) and Rb(4) independently represent H, (C1-C12)alkyl, or (C1-C12)alkylC(O) or Ra(4) and Rb(4) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
• R6 represents (C1-C12)alkyl optionally interrupted by oxygen, (with the proviso that any such oxygen must be at least 2 carbon atoms away from the ester-oxygen connecting the R6 group) and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R6 represents (C3-C6)cycloalkyl, hydroxy(C2-C12)alkyl, aryl or heterocyclyl;
• R7 represents (C1-C12)alkyl optionally interrupted by oxygen, and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R7 represents (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl, aryl or heterocyclyl;
• R8 represents H, (C1-C12)alkyl optionally interrupted by oxygen, and/or optionally substituted by aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R8 represents (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl, (C1-C12)alkoxy, (C3-C6)cycloalkoxy, aryl, heterocyclyl;
• R14 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, (C1-C8)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe;
• wherein Re represents aryl, cycloalkyl, heterocyclyl or (C1-C8)alkyl optionally substituted by one or more of halogen atom(s), OH, aryl, cycloalkyl and heterocyclyl;
• or R14 represents aryl, aryl(C1-C8)alkyl, aryl(C1-C3)alkoxy, heterocyclyl, a halogen atom, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C8)alkoxy, hydroxy(C1-C8)alkyl, (C1-C8)alkoxy, (C3-C6)cycloalkoxy, (C1-C8)alkylsulfinyl, (C1-C8)alkylsulfonyl, (C1-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, (C1-C8)alkylC(O), (C1-C8)alkoxyC(O) or Ra(14) and Rb(14) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
• R15 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, (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by one or more of OH, COOH and COORe;
• wherein Re represents aryl, cycloalkyl, heterocyclyl or (C1-C12)alkyl optionally substituted by one or more of halogen atom(s), OH, aryl, cycloalkyl and heterocyclyl;
• or R15 represents aryl, aryl(C1-C8)alkyl, aryl(C1-C3)alkoxy, heterocyclyl, a halogen atom, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C8)alkoxy, hydroxy(C1-C12)alkyl, (C1-C12)alkoxy, (C3-C6)cycloalkoxy, (C1-C12)alkylsulfinyl, (C1-C12)alkylsulfonyl, (C1-C12)alkylthio, (C3-C6)cycloalkylthio, or a group of formula NRa(15)Rb(15) in which Ra(15) and Rb(15) independently represent H, (C1-C12)alkyl, (C1-C12)alkylC(O), (C1-C12)alkoxyC(O) or Ra(15) and Rb(15) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
• R16 represents (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R16 represents (C3-C6)cycloalkyl, hydroxy(C2-C12)alkyl, (C1-C12)alkoxy, (C3-C6)cycloalkoxy, aryl or heterocyclyl;
• R17 represents (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R17 represents (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl,(C1-C12)alkoxy, (C3-C6)cycloalkoxy, aryl or heterocyclyl;
• R18 represents (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;
• or R18 represents (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl,(C1-C12)alkoxy, (C3-C6)cycloalkoxy, aryl or heterocyclyl;
• Rc is a direct bond or represents an unsubstituted or monosubstituted or polysubstituted (C1-C4)alkylene group, (C1-C4)oxoalkylene group, (C1-C4)alkyleneoxy or oxy-(C1-C4)alkylene group, wherein any substituents each individually and independently are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, oxy-(C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, carboxyl, carboxy-(C1-C4)alkyl, aryl, heterocyclyl, nitro, cyano, halogeno hydroxyl, NRa(Rc)Rb(Rc) in which Ra(Rc) and Rb(Rc) individually and independently from each other represents hydrogen, (C1-C4)alkyl or Ra(Rc) and Rb(Rc) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;
• or Rc represents imino (—NH—), N-substituted imino (—NR19—), (C1-C4)alkyleneimino or N-substituted (C1-C4)alkyleneimino (—N(R19)—((C1-C4)alkylene) wherein the mentioned alkylene groups are unsubstituted or monosubstituted or polysubstituted with any substituents according to above;
• R19 represents H or (C1-C4)alkyl;
• Rd represents (C1-C12)alkyl, (C3-C8)cycloalkyl, aryl or heterocyclyl, and anyone of these groups optionally substituted with one or more halogen atoms and/or one or more of the following groups, OH, CN, NO2, (C1-C12)alkyl, (C1-C12)alkoxyC(O), (C1-C12)alkoxy, halogen substituted (C1-C12)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, (C1-C12)alkylsulfinyl, (C1-C12)alkylsulfonyl, (C1-C12)alkylthio, (C3-C6)cycloalkylthio, arylsulfinyl, arylsulfonyl, arylthio, aryl(C1-C12)alkylthio, aryl(C1-C12)alkylsulfinyl, aryl(C1-C12)alkylsulfonyl, heterocyclyl(C1-C12)alkylthio, heterocyclyl(C1-C12)alkylsulfinyl, heterocyclyl(C1-C12)alkylsulfonyl, (C3-C6)cycloalkyl(C1-C12)alkylthio, (C3-C6)cycloalkyl(C1-C12)alkylsulfinyl, (C3-C6)cycloalkyl(C1-C12)alkylsulfonyl or a group of formula NRa(Rd)Rb(Rd) in which Ra(Rd) and Rb(Rd) independently represent H, (C1-C12)alkyl, (C1-C12)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 substituted with (C1-C6) alkyl;
• or 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 (C1-C6)alkyl;
• and
• 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;
• wherein substituents R14 and R15 are connected to the B ring/ring system in such a way that no quarternary ammonium compounds are formed (by these connections).