Bispidine compounds useful in the treatment of cardiac arrythmias

A compound of formula II

• wherein R5a and R5b independently represent H, C1-3 alkyl or C3 cycloalkoxy;
• R2 and R3 independently represent H, C1-4 alkyl (optionally substituted with one or more nitro or cyano groups), C3-4 cycloalkyl, OR7, N(R7a) R7b, OC(O)R8 or together form —O—(CH2)2—O—, —(CH2)3—, —(C H2)4— or —(CH2)5—;
• R7 and R8 independently represent H, C1-6 alkyl, or —(CH2)b-aryl (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, and/or C3-4 cycloalkyl);
• R7a and R7b independently represent H, C1-6 alkyl or C3-6 cycloalkyl;
• b represents 0, 1, 2, 3 or 4;
• R4 represents H, C1-6 alkyl or C3-6 cycloalkyl;
• D represents H, —OH, or —(CH2)nN(R10)(R11);
• c represents 0, 1, 2, 3 or 4;
• R10 represents H, C1-6 alkyl, C3-6 cycloalkyl, —(CH2)d-aryl, —C(NH)NH2, —S(O)2R13, —[C(O)]eN(R4)(R15), —C(O)R16 or —C(O)OR17;
• e represents 1 or 2;
• R11 represents H, C1-6alkyl, —C(O)R18 or —(CH2)f-aryl (which latter group is optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• R14, R15, R16, R17 and R18 independently represent H, C1-6alkyl, C3-6 cycloalkyl, Het2 or —(CH2)g-aryl (which latter three groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• R13 represents C1-6 alkyl, C3-6 cycloalkyl, aryl or —(CH2)h-aryl (all of which are all optionally substituted by one or more substituents chosen from halo, nitro, C1-6 alkyl C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• d, f, g and h independently represent 0, 1, 2, 3 or 4;
• Het2 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• R6 represents one or more optional substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl (optionally terminated by —N(H)C(O)OR18a), C1-6 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, —C(O)N(H)R19, —NHC(O)N(H)R20, —N(H)S(O)2R21 and/or —OS(O)2R22;
• R19 and R20 independently represent H, C1-6 alkyl or C3-6 cycloalkyl;
• R18a, R21 and R22 independently represent C1-6 alkyl or C3-6 cycloalkyl;
• A represents a single bond, C1-6 alkylene, —N(R23)(CH2)j—, —O(CH2)j— or —(CH2)C(H)(OR23)(CH2)j— (in which latter three groups, the —(CH2)j— group is attached to the bispidine nitrogen atom, and which latter four groups are all optionally substituted by one or more OH groups);
• B represents a single bond, C1-4 alkylene, —(CH2)mN(R24)—, (CH2)mS(O)n—, —(CH2)]O— (in which three latter groups, the —(CH2)m— group is attached to the carbon atom bearing D and R4), —C(O)N(R24)— (in which latter group, the —C(O)— group is attached to the carbon atom bearing D and R4), N(R24)C(O)O(CH2)m— or —N(R24)(CH2)m(in which lattertwo groups, the N(R24) group is attached to the carbon atom bearing D and R4);
• j, k and m independently represent 0, 1, 2, 3 or 4;
• n represents 0, 1 or 2;
• R23 represents H, C1-6 alkyl, C3-6 cycloalkyl or C(O)R25
• R24 represents H, C1-6 alkyl or C3-6 cycloalkyl;
• R25 represents H, C1-6 alkyl, C3-6 cycloalkyl, Het3 or —(CH2)p-aryl (which latter two groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• Het3 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• p represents 0, 1, 2, 3 or 4;
• wherein alkyl groups that R2, R3, R4, R5, Rb, R6, R7, R7a, R7b, R8, R, R, R13 R14 R15, R16, R7 R18, R1, R19, R20, R21 R22, R23, R24, R25 and D may represent, and with which R7, R8, R11, R13 R14, R15, R16, R17 R16 and R25 may be substituted;
• and
• alkoxy groups that R6 may represent, and with which R7, R8, R11, R13, R14, R15, R16, R17, R18 and R25 may be substituted, may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cycloalkyl or cycloalkoxy with carbon ranges as defined above, and wherein, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be part cycloalkyl/acyclic or cycloalkoxy/acyclic with carbon ranges as defined above, and wherein such alkyl and alkoxy groups may, when there is a sufficient number (i.e. two) of carbon atoms, be interrupted by oxygen and/or substituted by one or more fluoro groups;
• and
• wherein alkylene groups that A and B may represent, and —(CH2)— containing groups that R2 and R3 (together), R7, R8, R10, R11, R3, R14, R R16, R17, R18, R25, A, B and D may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched, and wherein such alkylene groups and —(CH2)— containing chains may, when there is a sufficient number (i.e. two) of carbon atoms, be interrupted by oxygen,
• provided that when R5a and R5b both represent H, then D does not represent H or OH.

A compound of formula IV

• wherein R1 represents C1-12 alkyl, C3-12 cycloalkyl, —(CH2)a-aryl, or (CH2)aHet1 (all of which are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C1-4alkyl, C3-4 cycloalkyl and/or C1-4 alkoxy or C3-4 cycloalkoxy);
• a represents 0, 1, 2, 3, or 4;
• Het1 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• X represents O or S;
• R5a and R5b independently represent H, C1-3 alkyl or C3 cycloalkoxy;
• R2 and R3 independently represent H, C1-4 alkyl (optionally substituted with one or more nitro or cyano groups), C3-4 cycloalkyl, OR7, N(R7a)R7b, OC(O)R8 or together form —O—(CH2)2—O—, —(CH2)3—, —(CH2)4— or —(CH2)5—;
• R7 and R8 independently represent H, C1-6 alkyl, or —(CH2)b-aryl or (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, and/or C3-4 cycloalkyl);
• R7a and R7b independently represent H, C1-6 alkyl or C3-6 cycloalkyl;
• b represents 0, 1, 2, 3 or 4;
• wherein alkyl groups that R1, R2, R3, R5a, R5b, R7, R7a, R7b and R8 may represent, and with which R1, R7 and R8 may be substituted;
• and alkoxy groups and with which R1, R7 and R8 may be substituted, may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cycloalkyl or cycloalkoxy with carbon ranges as defined above, and wherein, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be part cycloalkyl/acyclic or cycloalkoxy/acyclic with carbon ranges as defined above, and wherein such alkyl and alkoxy groups may, when there is a sufficient number (i.e. two) of carbon atoms, be interrupted by oxygen and/or substituted by one or more fluoro groups;
• provided that when R5a and R5b both represent H, then at least one of R2 and R3 represents OR7, OC(O)R8 or C1-4 alkyl, which alkyl group is substituted with one or more nitro or cyano groups.

A compound of formula VIII

• wherein R1 represents C1-12alkyl, C3-12 cycloalkyl, —(CH2)a-aryl, or (CH2)aHet1 (all of which are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C1-4alkyl, C3-4 cycloalkyl and/or C1-4 alkoxy or C3-4 cycloalkoxy);
• a represents 0, 1, 2, 3, or 4;
• Het1 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• X represents O or S;
• R5a and R5b independently represent H, C3-6 alkyl or C3 cycloalkoxy;
• R4 represents H, C1-6 alkyl or C3-6 cycloalkyl;
• D represents H, —OH, or —(CH2)nN(R10)(R1);
• c represents 0, 1, 2, 3 or 4;
• R10 represents H, C1-6 alkyl, C3-6 cycloalkyl, —(CH2)d-aryl, —C(NH)NH2, —S(O)2R13, —[C(O)]eN(R14)(R15), —C(O)R16 or —C(O)OR17;
• e represents 1 or 2;
• R11 represents H, C1-6 alkyl, —C(O)R18 or —(CH2)f-aryl (which latter group is optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• R14, R's, R16, R17 and R18 independently represent H, C1-6alkyl, C3-6 cycloalkyl, Het2 or —(CH2)g-aryl (which latter three groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• R13 represents C1-6 alkyl, C3-6 cycloalkyl, aryl or —(CH2)h-aryl (all of which are all optionally substituted by one or more substituents chosen from halo, nitro, C1-6 alkyl C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• d, f, g and h independently represent 0, 1, 2, 3 or 4;
• Het2 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• R6 represents one or more optional substituents selected from —OH, cyano, halo, amino, nitro, C1-6alkyl (optionally terminated by —N(H)C(O)OR18a), C1-6 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, —C(O)N(H)R19, —NHC(O)N(H)R20, —N(H)S(O)2R21 and/or —OS(O)2R22;
• R19 and R20 independently represent H, C1-6 alkyl or C3-6 cycloalkyl;
• R18a, R21 and R22 independently represent C1-6 alkyl or C3-6 cycloalkyl;
• A represents a single bond, C1-6 alkylene, —N(R23)(CH2)j—O(CH2)1— or —(CH2)j(H)(OR23)(CH2)k— (in which latter three groups, the —(CH2)j— group is attached to the bispidine nitrogen atom, and which latter four groups are all optionally substituted by one or more OH groups);
• B represents a single bond, C1-4 alkylene, —(CH2)mN(R24)—(CH2)mS(O)n—, —(CH2)mO— (in which three latter groups, the —(CH2)m— group is attached to the carbon atom bearing D and R4), —C(O)N(R24)— (in which latter group, the —C(O)— group is attached to the carbon atom bearing D and R4), N(R24)C(O)O(CH2)m— or —N(R24)(CH2)m-(in which latter two groups, the N(R24) group is attached to the carbon atom bearing D and R4);
• j, k and m independently represent 0, 1, 2, 3 or 4;
• n represents 0, 1 or 2;
• R23 represents H, C1-6 alkyl, C3-6 cycloalkyl or C(O)R25 R24 represents H, C1-6 alkyl or C3-6 cycloalkyl;
• R2s represents H, C1-6 alkyl, C3-6 cycloalkyl, Het3 or —(CH2)p-aryl (which latter two groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and/or C3-6 cycloalkoxy);
• Het3 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;
• p represents 0, 1, 2, 3 or 4;
• wherein alkyl groups that R1, R4, R5a, R5b, R6, R, Ra, Rb, R8, R10, R11, R13 R14 R15, R16, R17, R18, R18a, R19, R20, R21, R22, R23, R24, R25 and D may represent, and with which R1, R7, R8, R11 R13, R14, R15 R16 R17 R18 and R25 may be substituted;
• and alkoxy groups that R5 may represent, and with which R1, R7, R8, R11, R13, R14, R5, R16, R17, R18 and R25 may be substituted, may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cycloalkyl or cycloalkoxy with carbon ranges as defined above, and wherein, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be part cycloalkyVacyclic or cycloalkoxy/acyclic with carbon ranges as defined above, and wherein such alkyl and alkoxy groups may, when there is a sufficient number (i.e. two) of carbon atoms, be interrupted by oxygen and/or substituted by one or more fluoro groups;
• and
• wherein alkylene groups that A and B may represent, and —(CH2)— containing groups that R1, R7, R8, R10, R11, R13, R14, R15, R16, R17, R18, R25, A, B and D may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched, and wherein such alkylene groups and —(CH2)— containing chains may, when there is a sufficient number (i.e. two) of carbon atoms, be interrupted by oxygen, provided that when R5a and R5b both represent H, then D does not represent H or OH.