BENZODIAZOLIUM COMPOUNDS AS ENaC INHIBITORS

A compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof:

• wherein
• X− is an anion;
• R1 is:
• i. H or halo;
• or
• ii. -L1R10, wherein
• L1 is selected from:
• —Z1—, -Q1-, —Z1Q1-, -Q1Z1—, —Z1Q1Z2—, -Q1Q2-, -Q1Q2Z1—, -Q1Q2Z1Q3Z2—, —Z1Q1OQ2OQ3-;
• —OZ1—, —OQ1-, —OZ1Q1-, —OQ1Z1—, —OZ1Q1Z2—, —OQ1Q2-, —OQ1Q2Z1—, —OQ1Q2Z1Q3Z2—, —OZ1Q1OQ2OQ3-;
• —Z1N(R7)Z2—, -Q1N(R7)Z2—, —Z1N(R7)Z2Q 1-, -Q1N(R7)Z2Q2Z3—;
• —Z1O(CH2CH2O)nZ2—, —Z1O(CH2CH2O)nQ1-, —Z1O(CH2CH2O)nZ2Q1-, —Z1O(CH2CH2O)nQ1Z2—, -Q1Z1O(CH2CH2O)nZ2—, -Q1Z1O(CH2CH2O)nQ1-, -Q1Z1O(CH2CH2O)nZ2Q1, —Z1O(CH2CH2O)nZ2Q1Z3—;
• —C(O)Z1—, —C(O)Q1-, —C(O)Z1Q1-, —C(O)Z1Q1Z2—, —C(O)Q1Z1—, —C(O)Q1Q2-, —C(O)Q1Q2Z1—, —C(O)Q1N(R7)C(O)Z1—, —C(O)Q1N(R7)C(O)Z1Q2-, —C(O)Q1N(R7)C(O)Z1Q2Q3-, —C(O)Q1N(R7)C(O)Z1Q2Z2—, —C(O)Z1Q1OQ2OQ3-;
• —C(O)N(R7)Z1—, —C(O)N(R7)Q1-, —C(O)N(R7)Z1Q1-, —C(O)N(R7)Z1Q1Z2—, —C(O)N(R7)Q1Z1—, —C(O)N(R7)Q1Q2-, —C(O)N(R7)Q1Q2Z1—, —C(O)N(R7)Z1Q1Q2Z2—, —C(O)N(R7)Z1O(CH2CH2O)6Z2—, —C(O)N(R7)Z1O(CH2O)nZ2—, —C(O)N(R7)Z1Q1Z2N(R8)Z3—, —C(O)N(R7)Z1N(R8)Z2—, —C(O)N(R7)Q1Z1N(R8)Z2—, —C(O)N(R7)Z1Q1OQ2OQ3-, —C(O)N(R7)Z1Q1OQ2OQ3Z2—;
• —Z1C(O)N(R7)Z2—, —Z1C(O)N(R7)Q1-, —Z1C(O)N(R7)Z2Q1-, —Z1C(O)N(R7)Q1Z2—, —Z1C(O)N(R7)Q1Q2-, —Z1C(O)Q1-, —Z1C(O)Q1Z2—, —Z1C(O)Q1Q2-, —Z1C(O)N(R7)Q1Q2Z2—;
• —C(O)OZ1—, —C(O)OQ1-, —C(O)OZ1Q1-, —C(O)OZ1Q1Z2—, —C(O)OQ1Z1—, —C(O)OQ1Q2-, —C(O)OQ1Q2Z1—;
• -Q1C(O)Q2-, Q1C(O)Z1—, -Q1C(O)Q2Z1—, Q1C(O)Q2Q3-, Q1C(O)Z1Q2-, Q1C(O)Q2Q3Z1—;
• —C(═NR9)N(R7)Z1—, —C(═NR9)N(R7)Q1-, —C(═NR9)N(R7)Z1Q1-, —C(═NR9)N(R7)Z1Q1Z2—, —C(═NR9)N(R7)Q1Z1—, —C(═NR9)N(R7)Q1Q2- and C(═NR9)N(R7)Q1Q2Z1—;
• wherein
• each of Z1, Z2 and Z3 is independently selected from C1-12 alkylene, C2-12 alkenylene and C2-12 alkynylene any of which is optionally substituted by one or more substituents selected from halo, OH, C(O)NR15R16, C(O)OR15 and NR15R16;
• each R15 and R16 is independently selected from H and C1-6 alkyl;
• or
• R15 and R16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing one or more further heteroatoms selected from N, O and S;
• each of Q1, Q2 and Q3 is independently selected from carbocyclyl, heterocyclyl, aryl and heteroaryl any of which is optionally substituted with one or more substituents selected from halo, OH, C1-4 alkyl, C1-4 haloalkyl, C(O)NR15R16, C(O)OR15 and NR15R16, and, for cycloalkyl and heterocyclyl groups, oxo, wherein R15 and R16 are as defined above;
• n is 1 to 6;
• each R7 and R8 is independently selected from H and C1-12 alkyl optionally substituted with one or more halo or OH groups, or
• when an R7 and an R8 or two R8 groups are attached to a nitrogen atom they combine, together with the nitrogen atom, to form a 5- or 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from N, O and S;
• R9 is H or C1-6 alkyl;
• R10 is H, —N(R7)R8, —N(R7)C(═NR9)N(R8)2, —N(R7)—C(O)OR8, OR7 or —C(O)OR7;
• or
• a cationic group selected from —N(R7)—C(O)—(C1-3 alkylene)-N+(R8)3 and —N+(R8)3, in which case, the compound comprises an additional anion X−;
• and
• R7, R8 and R9 are as defined above;
• or
• iii. —R12, —OR12 —SO2R12, —C(O)OR12, —C(O)NR12R13, —C(═NR9)NR12R13, -Q1R12—, -Q1OR12-Q1SO2R12, -Q1C(O)OR12, -Q1C(O)NR12R13, -Q1C(═NR7)NR12R13, -Q1Q2OR12, -Q1SO2R12, -Q1Q2C(O)OR12, -Q1Q2C(O)NR12R13 or -Q1Q2C(═NR9)NR12R13;
• wherein
• Q1 and Q2 are defined as above;
• and
• each R12 and R13 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl and C3-8 heterocyclyl, any of which is optionally substituted by one or more substituents selected from halo, OR7, C(O)OR7, —N(R7)R8 and C(O)N(R7)R8and, in the case of cycloalkyl or heterocyclyl groups, oxo;
• wherein
• R7, R8 and R9 are as defined above;
• each of R2 and R3 is independently selected from C1-10 alkyl, wherein one or more —CH2— groups is optionally replaced by —O—, —S— or —NR7— provided that adjacent —CH2— groups are not so replaced and which is optionally substituted with one or more substituents selected from halo, OH, SH, N(R7)R8, aryl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)OR7, —C(O)N(R7)R8, OR7 and —N(R7)R8, wherein R7 and R8 are as defined above;
• R4 is selected from H, halo, cyano, C1-6 alkyl, C(O)OR16 and C(O)N(R16)R17;
• wherein alkyl groups are optionally substituted with one or more substituents selected from halo, —OR7 and —N(R7)R8, wherein R7 and R8 are as defined above;
• each R16 and R17 is independently selected from H and C1-6 alkyl;
• or R16 and R17 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing one or more further heteroatoms selected from O, N and S;
• and
• R5 is H or methyl.