# US 2019/0315757 A1 · BENZODIAZOLIUM COMPOUNDS AS ENaC INHIBITORS

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- Number: US 2019/0315757 A1
- Document ID: US20190315757A1
- Status: Published application
- Kind: A1
- Application number: 16/462,794
- Filed: 2017-11-22
- Published: 2019-10-17
- Earliest claimed: 2016-11-22
- Assignees: Enterprise Therapeutics Limited
- Applicants: Enterprise Therapeutics Limited
- Inventors: Clive McCARTHY; Jonathan David HARGRAVE; Duncan Alexander HAY; Thomas Beauregard SCHOFIELD; Naomi WENT
- Web page: https://patentgrep.com/patent/US20190315757A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61P 11/12: Mucolytics
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of general formula (I) wherein R1, R2, R3, R4, R5 and X are as defined herein are inhibitors of the epithelial sodium channel (ENaC) and are useful for the treatment or prevention respiratory diseases and conditions, skin conditions and ocular conditions.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A compound according to claim 1 which is a compound of general formula (IA):
wherein R1, R2, R3, R4, R5 and X− are as defined for general formula (I); or
a compound of general formula (IB):
wherein R1, R2, R3, R4, R5 and X− are as defined for general formula (I).

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 is:
H, halo, —R12, —C(O)OR12 or —OR12.

### Claim 4

(canceled)

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R1 is -L1R10.

### Claim 6

(canceled)

### Claim 7 (depends on 5)

A compound according to claim 5 wherein L1 is selected from:
—Z1—, -Q1-, -Q1Z1—, -Q1Q2—, -Q1Q2Z1—;
—OZ1—;
—C(O)Q1-, —C(O)Q1Z1—;
—C(O)N(R7)Z1—, C(O)N(R7)Q1-, —C(O)N(R7)Z1Q1-, —C(O)N(R7)Q1Z1—, —C(O)N(R7)Z1Q1Q2Z2—, —C(O)N(R7)Z1O(CH2CH2O)nZ2— and —C(O)N(R7)Z1Q1Z2N(R8)Z3—.

### Claim 8 (depends on 5)

A compound according to claim 5 wherein R10 is H, —N(R7)R8, —N(R7)C(═NR9)N(R8)2, —N(R7)C(O)OR8, —N(R7)—C(O)—(C1-3 alkylene)-N+(R8)3, —N+(R8)3, OR7 or —C(O)OR7.

### Claim 9

(canceled)

### Claim 10 (depends on 5)

A compound according to claim 5 wherein R10 is H; and wherein:
a) L1 is —OZ1, wherein Z1 is C1-4 alkylene; or
b) L1 is selected from -Q1-, -Q1Q2- and —C(O)N(R7)Q1-, where the Q1 group or, for -Q1Q2-, the Q2 group is a nitrogen-containing heterocyclyl group which is linked to the R10 group via a ring nitrogen atom; or
c) L1 is selected from:
—Z1—, Q1, -Q1Z1—, -Q1Q2, -Q1Q2Z1—;
—OZ1—, —OQ1Z1—, —OQ1Q2Z1—;
—C(O)Z1—, —C(O)Q1Z1—, —C(O)Q1Q2Z1—;
—C(O)N(R7)Z1—, —C(O)N(R7)Q1Z1—, —C(O)N(R7)Q1Q2Z1—;
—C(O)OZ1—, —C(O)OQ1Z1—, —C(O)OQ1Q2-, C(O)OQ1Q2Z1—;
—C(═NR9)N(R7)Z1—, —C(═NR9)N(R7)Q1Z1— and C(═NR9)N(R7)Q1Q2Z1—; or
d) L1 is selected from:
-Q1Z1—, —Z1Q1Z2—, -Q1Q2Z1—;
—OQ1Z1—, —OZ1Q1Z2—, —OQ1Q2Z1—;
—Z1O(CH2CH2O)nQ1Z2—, -Q1Z1O(CH2CH2O)nZ2—, —Z1O(CH2CH2O)nZ2Q1Z3—;
—C(O)Z1Q1Z2—, —C(O)Q1Z1—, —C(O)Q1Q2Z1—, —C(O)Q1N(R7)C(O)Z1Q2Z2—, —C(O)N(R7)Z1Q1Z2—, —C(O)N(R7)Q1Z1—;
—C(O)N(R7)Q1Q2Z1—, —C(O)N(R7)Z1Q1Q2Z2—, —C(O)N(R7)Z1Q1OQ2OQ3Z2—;
Z1C(O)N(R7)Q1Z2—, —Z1C(O)Q1Z2—, Z1C(O)N(R7)7Q1Q2Z2—;
—C(O)OZ1Q1Z2—, —C(O)OQ1Z1—, —C(O)OQ1Q2Z1—;
Q1C(O)Q2Z1—, Q1C(O)Q2Q3Z1—;
—C(═NR9)N(R7)Z1Q1Z2—, —C(═NR9)N(R7)Q1Z1— and —C(═NR9)N(R7)Q1Q2Z1—;
and
the cyclic group Q1, Q2 or Q3 is a nitrogen containing heterocyclyl group linked to Z1 or Z2 or Z3 via a ring nitrogen atom; or
e) L1 contains a moiety Z1, Z2 or Z3 which is linked directly to R10 and is —CH2[CH(OH)]4—CH(OH)— such that the group Z1R10, Z2R10 or Z3R10 is a moiety —CH2[CH(OH)]4—CH2OH.

### Claim 11

(canceled)

### Claim 12 (depends on 8)

A compound according to claim 8 wherein:
a) R10 is —C(O)OR7; and
L1 is selected from:
-Q1- and -Q1Q2- where Q1 or, for -Q1Q2-, Q2 is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring carbon atom; or
C(O)N(R7)Q1, where Q1 is a is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring nitrogen atom; or
b) R10 is selected from —N(R7)R8, —N(R7)C(═NR9)N(R8)2 and —N(R7)C(O)OR8—; and
L1 is selected from:
—Z1—,
—OZ1—;
—C(O)N(R7)Z1—, —C(O)N(R7)Z1Q1Q2Z2—, —C(O)N(R7)Z1Q1Z2N(R8)Z3, —C(O)N(R7)Z1O(CH2CH2O)nZ2;
—C(O)N(R7)Q1-, —C(O)N(R7)Z1Q1- and —C(O)Q1-, where Q1 is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring carbon atom;
and
C(O)Q1Z1—.

### Claim 13 (depends on 12)

A compound according to claim 12, wherein R10 is —N(R7)R8; and one or both of R7 and R8 is a moiety —CH2[CH(OH)]4—CH2OH.

### Claim 14

(canceled)

### Claim 15 (depends on 13)

A compound according to claim 13 wherein R10 is
—N{CH2[CH(OH)]4—CH2OH}2.

### Claim 16 (depends on 12)

A compound according to claim 12 wherein R10 is ——N(R7)C(═NR9)N(R8)2; and
each of R7 and R9 is selected from H and C1-4 alkyl; and
one or both R8 groups are —CH2[CH(OH)]4—CH2OH.

### Claim 17

(canceled)

### Claim 18 (depends on 1)

A compound according to claim 1 wherein R2 and R3 are the same or different and are both unsubstituted C1-4 alkyl.

### Claim 19 (depends on 1)

A compound according to claim 1 wherein R4 and/or R5 is H.

### Claim 20 (depends on 1)

A compound according to claim 1 having a cation selected from:
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-fluoro-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1-ethyl-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-6-(trifluoromethoxy)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-methoxy-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-(carboxylatomethyl)-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-(carbamoylmethyl)-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-[2-(methylsulfanyl)ethyl]-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-(2-hydroxyethyl)-6-methoxy-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-6-methoxy-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-benzyl-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-6-chloro-1-ethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-ethyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-6-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-methyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-{[(tert-butoxy)carbonyl]amino}propoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-aminoethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-aminopropoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-aminopropyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-(piperidin-4-yl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-carbamimidamidoethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-carbamimidamidopropyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{[(tert-butoxy)carbonyl]amino}propyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium formic acid;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}carbamoyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{[(tert-butoxy)carbonyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-aminopropyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-[(piperidin-4-yl)carbamoyl]-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-aminopiperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-aminopiperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-(1-{1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-({1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}carbamoyl)-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbarnoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium;
2-[({3-arnino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)(methyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-5-{[(14S,15R,16R,17R)-14,15,16,17,18-pentahydroxy-12-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-3,6,9-trioxa-12-azaoctadecan-1-yl]carbarnoyl}-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-({2-[4′-(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethyl)-[1,1′-biphenyl]-4-yl]ethyl}carbamoyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[(3S)-3-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)amino]-3-carbamoylpropyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[4-(4-{3-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)amino]-3-carbamoylpropyl}phenyl)butyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;
2-[({3-amino-7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; and
2-[({3-amino-7-cyano-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-methoxy-1H-1,3-benzodiazol-3-ium;
and having an anion X− as defined in claim 1.

### Claim 21 (depends on 1)

A process for the preparation of 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—, -Q1Z1N(R7)Z2—, —Z1N(R7)Z2Q1-, -Q1Z1N(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)nZ2—, —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 independentlyselected from C1-12 alkylene, C2-12 alken lene 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)R8 and, in the case of cycloalkyl or heterocyclyl groups, oxo; wherein
R7, R8 and R9 are as defined above;
each of R2 and R3 is inde endentl 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;
wherein the process comprises
A. reacting a compound of general formula (II) or a salt or activated derivative thereof:
wherein R4 and R5 are as defined for general formula (I);
with a salt of general formula (III):
wherein R1, R2 and R3 are as defined for general formula (I); and
X− is as defined in claim 1 and is the same or different from the X− of the product of general formula (I); or
B. reacting a compound of general formula (XVIII):
wherein Rl, R3, R4 and R5 are as defined for general formula (I);
with a compound of general formula (IX):
R2—X1 (IX)
wherein R2 is as defined for general formula (I) and X1 is a leaving group; or
with a compound of general formula (IXA):
R2a—X1 (IXA)
wherein X1 is as defined above for general formula (IX) and R2a is a protected R2 group; or
C. converting a compound of general formula (I) in which R3 comprises a —C(O)OR7 group wherein R7 is other than H or a —C(O)N(R7)R8 group;
to a compound of general formula (I) in which R3 comprises a —C(O)OH or C(O)O− group;
by hydrolysis; or
D. converting a compound of general formula (I) wherein R1 is L1R10 where R10 is —N(R7)—C(O)OR8;
to a compound of general formula (I) wherein R10 is —NHR7;
by hydroloysis; or
E. converting a compound of general formula (I) wherein R1 is L1R10, and L1 comprises a moiety Q1, Q2 or Q3 which is linked to R10 via a ring nitrogen atom; and
R10 is C(O)OR7;
to a compound of general formula (I) wherein R1 is L1R10 and R10 is H;
by hydrolysis; or
F. converting a compound of general formula (I) wherein R1 is L1R10 and R10 is —NH2;
to a compound of general formula (I) wherein R1 is L1R10, and R10 is N(R7)R8 where R7 is CH2—R7a and R8 is CH2—R8a, and one of R7a and R8a is C1-11 alkyl optionally substituted with one or more halo or OH groups; and the other of R7a and R8a is H or C1-11 alkyl optionally substituted with one or more halo or OH groups;
by reductive amination with an aldehyde, acetal or cyclic hemiacetal equivalent compound;
or
G. converting a compound of general formula (I) wherein R1 is L1R10; and L1 comprises a moiety Q1, Q2 or Q3 linked to R10 via a ring nitrogen atom; and R10 is H;
to a compound of general formula (I) wherein R1 is L1R10; and L1 comprises a moiety Q1, Q2 or Q3 linked to a Z1, Z2 or Z3 moiety via a ring nitrogen atom, wherein Z1, Z2 or Z3 is CH2—C1-11 alkyl optionally substituted with one or more halo or OH groups; and R10 is H;
by reductive amination with an aldehyde, acetal or cyclic hemiacetal equivalent compound;
or
H. converting a compound of general formula (I) in which R1 is L1R10 and R10 is NH2;
to a compound of general formula (I) in which R1 is L1R10 and R10 is —NHC(═NR9)N(R8)2;
by reaction with a carboximidamide or a salt thereof; or
I. converting a compound of general formula (I) in which R1 is C(O)OH;
to a compound of general formula (I) in which R1 is —C(O)NR12R13, wherein R12 and R13 are as defined for general formula (I); or
to a compound of general formula (I) in which R1 is L1R10 and
L1 is selected from —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)nZ2— —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—; or
L1 is selected from —C(O)Q1-, —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- or —C(O)Q1NR(R7)C(O)Z1Q2Z2—, wherein Q1 is a heterocyclyl ring linked to the —C(O) moiety via a ring nitrogen atom;
by reaction with an appropriate amine or ammonium salt.

### Claim at position 22

22-24. (canceled)

### Claim 25 (depends on 1)

A method for the treatment or prophylaxis of respiratory diseases and conditions, skin conditions or ocular conditions, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

### Claim 26 (depends on 25)

A method according to claim 25, wherein:
the respiratory diseases and conditions are selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia;
the skin conditions are selected from psoriasis, atopic dermatitis and ichthyosis; and
the ocular condition is dry eye disease.

### Claim 27 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

### Claim 28 (depends on 27)

A pharmaceutical composition according to claim 27 formulated for nasal, bronchial (inhaled) or buccal administration as a dry powder for inhalation, an aerosol or a spray.

### Claim 29 (depends on 27)

A pharmaceutical composition according to claim 27, further including an additional active agent selected from:
β2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol;
antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H4 receptor antagonists;
dornase alpha;
corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate;
leukotriene antagonists such as montelukast and zafirlukast;
CFTR repair therapies e.g. CFTR potentiators such as Ivacaftor and CFTR correctors such as Lumacaftor and Tezacaftor;
TMEM16A modulators, particularly TMEM16A potentiators; and
antibiotics.

### Claim 30 (depends on 1)

A product comprising a compound according to claim 1 and an additional agent useful in the treatment or prevention of respiratory conditions as a combined preparation for simultaneous, sequential or separate use in the treatment of a respiratory disease or condition, wherein the additional active agent is selected from:
β2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol;
antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H4 receptor antagonists;
dornase alpha;
corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate;
Leukotriene antagonists such as montelukast and zafirlukast; and
antibiotics.

### Claim 31

(canceled)