DIAMINO-ALKYLAMINO-LINKED ARYLSULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS

• US 20200131167A1
• Filed: 11/13/2017
• Published: 04/30/2020
• Est. Priority Date: 11/17/2016
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Greshock, Thomas J., Mulhearn, James, Roecker, Anthony J., Jian, Tianying, Zhou, Gang, Guo, Liangqin, Won, Walter, Zhang, Ting, Anand, Rajan, Stelmach, John E., Wang, Deping, Kim, Ronald M., Layton, Mark E., Burgey, Christopher S., Nantermet, Philippe G.
• Granted Patent: US 10,968,210 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 277/52 to sulfur atoms, e.g. sulfonamides
• CPC Class Codes: C07D 285/08 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

Disclosed are compounds of Formula A, or a salt thereof: Formula (A), wherein: Het, Q and R^1A to R^4A are defined herein, which compounds have properties for blocking Na_v 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A or their salts, and methods of treating cough, itch, acute pain and neuropathic pain disorders using the same.

Claims

1. A compound of Formula A¹, or a pharmaceutically acceptable salt thereof:

2. A compound according to claim 1 of the structure of Formula A², or a pharmaceutically acceptable salt thereof:

3. A compound according to claim 1 of the structure of Formula A³, or a pharmaceutically acceptable salt thereof:

4. A compound of claim 1, or a salt thereof, wherein:

(i) R^1A is —

F, R^3A and R^4A are —

H, and R^2A is —

F, —

Cl,—

Br, —

CN, —

CH₃, or —

CF₃;

(ii) R^1A, R^2A and R^3A are —

H, and R^4A is —

Cl;

(iii) R^1A, R^3A and R^4A are —

H, and R^2A is —

CF₃;

or (iv) R^1A and R^2A are —

H, and R^3A and R^4A are —

F.

5. A compound of claim 2, or a salt thereof, wherein:

(i) R^1A2 is —

F, R^3A2 and R^4A2 are —

H, and R^2A2 is —

F, —

Cl,—

Br, —

CN, —

CH₃, or —

CF₃;

(ii) R^1A2, R^2A2 and R^3A2 are —

H, and R^4A2 is —

C;

(iii) R^1A2, R^3A2 and R^4A2 are —

H, and R^2A2 is —

CF₃;

or (iv) R^1A2 and R^2A2 are —

H, and R^3A2 and R^4A2 are —

F.

6. A compound of claim 3, or a salt thereof, wherein:

(i) R^1A3 is —

F, R^3A3 and R^4A3 are —

H, and R^2A3 is —

F, —

Cl,—

Br, —

CN, —

CH₃, or —

CF₃;

(ii) R^1A3, R^2A3 and R^3A3 are —

H, and R^4A3 is —

Cl;

(iii) R^1A3, R^3A3 and R^4A3 are —

H, and R^2A3 is —

CF₃;

or (iv) R^1A3 and R^2A3 are —

H, and R^3A3 and R^4A3 are —

F.

7. A compound of claim 1, or a salt of any thereof, wherein, if selected, said moiety of the formula:

8. A compound of claim 1, or a salt of any thereof, wherein said Het¹, Het², or Het³ is, independently, a heterocycle of the formula:

9. A compound according to claim 1, or a salt thereof, having the formula:

10. A compound according to claim 1, or a salt thereof, having the formula:

11. A compound according to claim 1, or a salt thereof, having the formula:

12. The compound of claim 11 wherein Q³ is a bridged heterocycle of the formula:

14. A formulation comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. A pharmaceutical formulation of claim 14 comprising additionally an effective amount of at least one other pharmaceutically active ingredient which is:

(i) an opiate agonist or antagonist;

(ii) a calcium channel antagonist;

(iii) an NMDA receptor agonist or antagonist;

(iv) a COX-2 selective inhibitor;

(v) an NSAID (non-steroidal anti-inflammatory drug);

or (vi) paracetamol (APAP), and a pharmaceutically acceptable carrier.

16. The formulation of claim 14 which is adapted for IV infusion or IV administration.

17. A method of treating an inflammatory or neuropathic pain disorder, cough, or acute itch or chronic itch disorder comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of claim 14.

18. A method of treating a neuropathic pain disorder comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of claim 14.

19. A method of treating acute pain comprising infusing a therapeutically sufficient amount of a composition of claim 16.

20. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 for use in therapy.

21. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 for treating neuropathic pain disorders.

13. A compound which is:

4-[(4-{[2-(benzylamino)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3R,5S)-5-phenylpyrrolidin-3-yl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)amino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(3S)-3-aminopyrrolidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(1,7-diazaspiro[4.4]non-1-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(1,8-diazaspiro[4.5]dec-8-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

(R)-5-chloro-2-fluoro-4-{[4-({[2-(4-methoxybenzyl)pyrrolidin-2-yl]methyl}amino) butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

(S)-5-chloro-2-fluoro-4-{[4-({[2-(4-methoxybenzyl)pyrrolidin-2-yl]methyl}amino) butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[2-(4-methoxybenzyl)pyrrolidin-2-yl]methyl}amino) butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(1R,4R,7S)-2-azabicyclo[2.2.1]hept-7-ylamino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

(R) 5-chloro-2-fluoro-4-({4-[(1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)amino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

(S) 5-chloro-2-fluoro-4-({4-[(1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)amino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)amino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(1R,4R,7S)-7-amino-2-azabicyclo[2.2.1]hept-2-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(3 aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(3aR,7aR)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(1S,4S)-2-azabicyclo[2.2.1]hept-5-ylamino]butylamino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(1S,4S,7R)-2-azabicyclo[2.2.1]hept-7-ylamino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(1R)-1-methyl-2-(tetrahydro-2H-pyran-4-ylamino)ethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[(5-phenylpiperidin-3-yl)amino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(2-amino-1-phenylethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[2-(3-methoxybenzyl)pyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(3R)-3-aminopiperidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(3R)-3-aminopyrrolidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(3S)-3-aminopiperidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(2,7-diazaspiro[4.4]non-2-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(1,7-diazaspiro[4.5]dec-7-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(1,6-diazaspiro[3.5]non-1-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-{[4-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)butyl]amino}-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-{[4-(4-aminoazepan-1-yl)butyl]amino}-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-{[4-(3-aminoazetidin-1-yl)butyl]amino}-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[4-(aminomethyl)-4-phenylpiperidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[3-(aminomethyl)piperidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[3-(aminomethyl)pyrrolidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-(octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-{[4-(4-aminopiperidin-1-yl)butyl]amino}-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[3-(aminomethyl)-3-phenylpyrrolidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-({4-[3-(aminomethyl)azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(3,9-diazabicyclo[4.2.1]non-3-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-(1,4-diazepan-1-yl)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

(R)-5-chloro-2-fluoro-4-((4-((isoindolin-1-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((4-((isoindolin-1-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-((4-((isoindolin-1-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

4-((4-((2-(aminomethyl)benzyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-((((1S,3R)-3-(((S)-pyrrolidin-2-ylmethyl)amino)cyclohexyl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-((((1R,3S)-3-(((S)-pyrrolidin-2-ylmethyl)amino)cyclohexyl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-[({(3aR,5R, 6aS)-2-[(2S)-pyrrolidin-2-ylmethyl]octahydro-cyclopenta[c]pyrrol-5-yl}methyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(5-phenyl-4-{[(2S)-pyrrolidin-2-ylmethyl]amino}pentyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-yl-3-(trifluoromethyl)benzenesulfonamide;

2,5-difluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 3-chloro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

3-chloro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]benzenesulfonamide;

(S)-5-chloro-4-((4-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)butyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2S,5R)-5-phenylpyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2S,4S)-4-phenylpyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2S,4S)-4-phenoxypyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2 S, 3R)-3-phenylpyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-({[(2S,4R)-4-cyanopyrrolidin-2-yl]methyl}amino)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2R,4S)-4-phenylpyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2S,4R)-4-phenylpyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(5-phenylpiperidin-2-yl)methyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-{[4-({[(2R)-4,4-difluoropyrrolidin-2-yl]methyl}amino)butyl]amino}-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({[(2S,4R)-4-methoxypyrrolidin-2-yl]methyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-((5-((pyrrolidin-2-ylmethyl)amino)pentyl)-amino)benzenesulfonamide;

5-chloro-2-fluoro-4-({5-[(piperidin-2-ylmethyl)-amino]pentyl}amino)-N-1,3-thiazol-2-yl-benzenesulfonamide;

5-chloro-2-fluoro-4-({5-[(piperidin-3-ylmethyl)-amino]-pentyl}amino)-N-1,3-thiazol-2-yl-benzenesulfonamide;

4-[(5-{[(2R)-2-aminopropyl]-amino}pentyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-yl-benzenesulfonamide;

4-({5-[(azetidin-2-ylmethyl)amino]-pentyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-yl-benzenesulfonamide;

5-chloro-2-fluoro-4-((2-phenyl-4-(((S)-pyrrolidin-2-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

5-chloro-4-[(2,2-difluoro-4-{[(2R)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-4-[(2,2-difluoro-4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide,

4-({4-[(2R)-2-(aminomethyl)azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;

5-chloro-2-fluoro-4-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]butyl}-amino)-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[2-(tricyclo[3.3.1.1˜

3,7˜

]dec-2-ylamino)-ethyl]amino}butyl)amino]benzene-sulfonamide;

4-({4-[(2R)-2-(aminomethyl)azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;

4-({4-[(2S)-2-(aminomethyl)azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-({4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]butyl}amino)benzene-sulfonamide;

5-chloro-2-fluoro-4-({4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-butyl}amino)-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;

4-((4-(3-(aminomethyl)azetidin-1-yl)butyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-{[4-(3-aminoazetidin-1-yl)-butyl]amino}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;

5-cyano-2-fluoro-4-({4-[(3R)-pyrrolidin-3-ylamino]-butyl}amino)-N-1,3-thiazol-2-yl-benzenesulfonamide;

5-cyano-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-({4-[(3R)-pyrrolidin-3-yl-amino]butyl}amino)benzene-sulfonamide;

4-({4-[(1S,4R)-2-azabicyclo[2.2.1]hept-6-yl-amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;

2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-5-methyl-4-({4-[(3R)-pyrrolidin-3-ylamino]-butyl}amino)benzene-sulfonamide;

5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-({4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]butyl}amino)benzene-sulfonamide;

5-cyano-2-fluoro-4-({4-[(3R)-pyrrolidin-3-yl-amino]butyl}amino)-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;

4-({4-[(3-amino-2-fluoro-propyl)amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-benzenesulfonamide;

2,5-difluoro-4-[(4-{[2-(methylamino)ethyl]amino}-butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;

5-chloro-2-fluoro-4-[(4-{[2-(methylamino)ethyl]amino}-butyl)amino]-N-(4-methyl-1,3-thiazol-2-yl)benzene-sulfonamide (R) 4-({4-[2-(aminomethyl)-azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;

(S) 4-({4-[2-(aminomethyl)-azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;

4-({4-[2-(aminomethyl)-azetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;

or

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-({4-[(3R)-3-(methylamino)-pyrrolidin-1-yl]butyl}-amino)-benzenesulfonamide,

or a pharmaceutically acceptable salt of any thereof.