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New Pyridine Analogues II

  • US 20070244088A1
  • Filed: 06/26/2007
  • Published: 10/18/2007
  • Est. Priority Date: 06/28/2006
  • Status: Abandoned Application
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Assignment
First Claim
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1. 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 H, CN, halogen, NO2, (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;

    or R2 represents (C1-C12)alkoxy optionally substituted by one or more halogen atoms;

    or R2 represents (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, (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(2)Rb(2) in which Ra(2) and Rb(2) independently represent H, (C1-C12)alkyl, (C1-C12)alkylC(O) or Ra(2) and Rb(2) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;

    or R1 and R2, together (with two carbon atoms of the pyridine ring), may form a 5-membered or 6-membered cyclic lactone;

    R3 represents H, CN, NO2, halogen, (C1-C12)alkyl optionally interrupted by oxygen and/or optionally substituted by OH, aryl, cycloalkyl, heterocyclyl or one or more halogen atoms;

    or R3 represents (C1-C12)alkoxy optionally substituted by one or more halogen atoms;

    or R3 represents (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, (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(3)Rb(3) in which Ra(3) and Rb(3) independently represent H, (C1-C12)alkyl, (C1-C12)alkylC(O) or Ra(3) and Rb(3) together with the nitrogen atom represent piperidine, pyrrolidine, azetidine or aziridine;

    R4 represents a halogen atom or is CN;

    Z represents O or S;

    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, (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 or (C3-C6)cycloalkyl(C1-C12)alkylsulfonyl;

    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-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 atoms, OH, aryl, cycloalkyl and heterocyclyl;

    or R14 represents aryl, heterocyclyl, one or more halogen atoms, (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl, (C1-C12)alkoxy, (C3-C6)cycloalkoxy, (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 or (C3-C6)cycloalkyl(C1-C12)alkylsulfonyl, a group of formula NRa(14)Rb(14) in which Ra(14) and Rb(14) independently represent H, (C1-C12)alkyl, (C1-C12)alkylC(O), (C1-C12)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 atoms, OH, aryl, cycloalkyl and heterocyclyl;

    or R15 represents aryl, heterocyclyl, one or more halogen atoms, (C3-C6)cycloalkyl, hydroxy(C1-C12)alkyl, (C1-C12)alkoxy, (C3-C6)cycloalkoxy, (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(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;

    Y represents imino (—

    NH—

    ) or is absent;

    Rc represents imino or (C1-C4)alkyleneimino or an unsubstituted or monosubstituted or polysubstituted (C1-C4)alkylene group or (C1-C4)oxoalkylene 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, halogen, 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;

    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, aryloxy, 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 represents 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;

    the 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);

    with the proviso that the compound or the pharmaceutically acceptable salt thereof is not;

    3-pyridinecarboxylic acid, 5-cyano-6-[4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-(trifluoromethyl)-, ethyl ester or ethyl 6-(4-{[(4-chlorophenyl)amino]carbonyl}piperazin-1-yl)-5-cyano-2-(trifluoromethyl)nicotinate or ethyl 6-[4-(anilinocarbonyl)piperazin-1-yl]-5-cyano-2-(trifluoromethyl)nicotinate or ethyl 5-cyano-2-(trifluoromethyl)-6-(4-{[3-(trifluoromethyl)phenyl]carbamoyl}piperazin-1-yl)nicotinate or ethyl 6-{4-[(4-tert-butylphenyl)carbamoyl]piperidin-1-yl}-5-chloronicotinate.

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