BENZODIAZOLIUM COMPOUNDS AS ENaC INHIBITORS

• US 20190315757A1
• Filed: 11/22/2017
• Published: 10/17/2019
• Est. Priority Date: 11/22/2016
• Status: Active Grant

• Current Assignee: Enterprise Therapeutics Limited
• Original Assignee: Enterprise Therapeutics Limited
• Inventors: McCARTHY, Clive, HARGRAVE, Jonathan David, HAY, Duncan Alexander, SCHOFIELD, Thomas Beauregard, WENT, Naomi
• Granted Patent: US 10,941,149 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61P 11/12 Mucolytics
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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

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

2. A compound according to claim 1 which is a compound of general formula (IA):

3. A compound according to claim 1 wherein R¹ is:

H, halo, —

R¹², —

C(O)OR¹² or —

OR¹².

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

7. 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—

.

8. 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)—

(C_1-3 alkylene)-N⁺(R⁸)₃, —

N⁺(R⁸)₃, OR⁷ or —

C(O)OR⁷.

10. A compound according to claim 5 wherein R¹⁰ is H;

and wherein;

a) L¹ is —

OZ¹, wherein Z¹ is C_1-4 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.

12. 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—

.

13. 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.

15. A compound according to claim 13 wherein R¹⁰ is

—

N{CH₂[CH(OH)]₄—

CH₂OH}₂.

16. 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 C_1-4 alkyl; and

one or both R⁸ groups are —

CH₂[CH(OH)]₄—

CH₂OH.

18. A compound according to claim 1 wherein R² and R³ are the same or different and are both unsubstituted C_1-4 alkyl.

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

20. 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.

21. A process for the preparation of a compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof:

25. 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.

26. 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.

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

28. 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.

29. A pharmaceutical composition according to claim 27, further including an additional active agent selected from:

β

2 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.

30. 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:

β

2 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.

4. (canceled)

6. (canceled)

9. (canceled)

11. (canceled)

14. (canceled)

17. (canceled)

22-24. -24. (canceled)

31. (canceled)