US 10,519,147 B2Granted

Diamino-alkylamino-linked arylsulfonamide compounds with selective activity in voltage-gated sodium channels

AssigneeMerck Sharp & Dohme Corp.

InventorsThomas J. Greshock, James Mulhearn, Liangqin Guo, Ting Zhang, Deping Wang, Ronald M. Kim, Mark E. Layton, Michael J. Kelly, III, Rajan Anand, Philippe Nantermet, Tianying Jian, Anthony J. Roecker, Walter Won, Gang Zhou

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Abstract

Disclosed are compounds of Formula A, or a salt thereof, where Q, X, R1 and R2 are as defined herein, which compounds have properties for inhibiting Nav 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 pain (acute, post-operative, neuropathic), or cough or itch disorders using the same.

Claims18

Dependent claims

A compound of Formula A:

or a pharmaceutically acceptable salt thereof,
wherein:
R1 is —Cl, —Br, or —F;
R2 is —H or —CH3;
X is:
—N═;
or
—C(R3)═, wherein R3 is:
(i) —H;
(ii) —Cl;
or (iii) —F;
and
Q is:
(a) a moiety of the formula:
wherein one of R5a is NH2 and the others are —H;
or
(b) a moiety of the formula:
(c) a moiety of the formula:
wherein
D1 is a linear- or branched-alkyl, or a geminal-cycloalkyl moiety of up to 6 carbon atoms;
and
R6 is optionally present as a single substituent and is linear or branched alkyl of up to 4 carbon atoms, which is optionally substituted on one or more carbon atoms thereof with one or more —F;
or
(d) R4—NH-D2-, wherein R4 is —H, lower alkyl, or lower cycloalkyl and D2 is a linear alkyl of at least two up to 6 carbon atoms, a branched-alkyl of up to 6 carbon atoms, or a geminal-cycloalkyl moiety of up to 8 carbon atoms.

21 more elements

A compound which is:

5-chloro-2-fluoro-4-[(4-{[(2S)-piperidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2R)-piperidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1S,2S)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-amino-1,1-dimethylethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-aminoethyl)(methyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-{[4-({(1S)-1-[(2S)-pyrrolidin-2-yl]ethyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1S,2R)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1R,2S)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-aminoethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-({4-[(3R)-pyrrolidin-3-ylamino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-({4-[(3S)-pyrrolidin-3-ylamino]butyl}-amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;
N1-(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N4—((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
(R) N1-(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N4—((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
(S) N-(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N4—((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
4-((4-((azetidin-3-ylmethyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[2-(methylamino)ethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
(R)-5-chloro-2-fluoro-4-((4-((pyrrolidin-2-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
2,5-difluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]benzenesulfonamide;
5-bromo-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-4-{[4-({[(2S,4S)-4-methylpyrrolidin-2-yl]methyl}amino)butyl]amino 1-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-{[4-(1[(2S,5S)-5-methylpyrrolidin-2-yl]methyl}amino)butyl]amino 1-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-N-1,3-thiazol-2-yl-4-{[4-(1[(2S,4S)-4-(trifluoromethyl)pyrrolidin-2-yl]methyl 1 amino)butyl]amino}benzenesulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclo-pentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
4-[(4-{[(2R)-azetidin-2-ylmethyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzene-sulfonamide;
4-[(4-{[(2S)-azetidin-2-ylmethyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
4-[(4-{[(2S)-2-aminopropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{[4-(azetidin-3-ylamino)butyl]-amino}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2R)-piperidin-2-ylmethyl]amino}butyl)amino]benzene-sulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclopentyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;
4-[(4-{[(2R)-2-aminopropyl]amino}-butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;
4-[(4-{[(1R)-2-amino-1-methylethyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclopentyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(2S)-2-aminopropyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-[(2R)-pyrrolidin-2-yl-methyl]amino-butyl)-amino]benzenesulfonamide;
5-chloro-2-fluoro-4-{[4-({2-[(2R)-pyrrolidin-2-yl]ethyl}-amino)-butyl]-amino}-N-1,3-thiazol-2-yl-benzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2R)-piperidin-2-yl-methyl]amino}butyl)-amino]-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2R)-piperidin-2-yl-methyl]amino}butyl)-amino]benzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2R)-pyrrolidin-2-yl-methyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({2-[(2R)-pyrrolidin-2yl]-ethyl}amino)butyl]-amino}benzenesulfonamide;
5-chloro-2-fluoro-4-({4-[(3R)-pyrrolidin-3-ylamino]-butyl}amino)-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
5-chloro-2-fluoro-4-{[4-({2-[(2R)-pyrrolidin-2-yl]ethyl}-amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
5-chloro-2-fluoro-4-{[4-({2-[(2S)-pyrrolidin-2-yl]ethyl}-amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
4-{[4-(azetidin-3-ylamino)-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-({2-[(2S)-pyrrolidin-2-yl]ethyl}amino)butyl]amino}benzenesulfonamide;
4-[(4-{[(1R)-3-amino-1-methylpropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-benzenesulfonamide;
4-[(4-{[(1R)-3-amino-1-methylpropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;
4-({4-[(3-amino-1,1-dimethylpropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[3-(methylamino)-propyl]amino}butyl)amino]-benzenesulfonamide;
4-[(4-{[(1R)-3-amino-1-methylpropyl]amino}butyl)-amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
4-[(4-{[(3R)-3-amino-butyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;
4-({4-[(3-aminopropyl)-amino]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
4-({4-[(2-aminoethyl)-amino]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
4-[(4-{[(3R)-3-aminobutyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzene-sulfonamide;
4-({4-[(3-aminopropyl)amino]-butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;
5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-({4-[(3R)-pyrrolidin-3-yl-amino]butyl}amino)benzene-sulfonamide;
5-bromo-2-fluoro-4-({4-[(3R)-pyrrolidin-3-ylamino]-butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-{[4-(azepan-3-ylamino)-butyl]amino}-5-chloro-2-fluoro-N-1,3-thiazol-2-yl-benzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[2-(methylamino)ethyl]amino}-butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluoro-4-[(4-{[2-(methylamino)ethyl]-amino}butyl)amino]benzene-sulfonamide;
5-bromo-2-fluoro-4-[(4-{[2-(methylamino)ethyl]amino}-butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-bromo-2-fluoro-4-[(4-{[3-(methylamino)propyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[3-(methylamino)-propyl]amino}butyl)amino]-benzenesulfonamide;
4-({4-[(2-aminoethyl)-amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzene-sulfonamide;
5-chloro-2-fluoro-4-{[4-({3-[(2-fluoroethyl)amino]-propyl}amino)butyl]amino}-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
4-[(4-{[(1R)-2-amino-1-methylethyl]amino}butyl)-amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-benzenesulfonamide;
4-[(4-{[(1R)-2-amino-1-methylethyl]amino}butyl)-amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
4-({4-[(2-amino-1,1-dimethylethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[1-(aminomethyl)cyclobutyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(1-aminocyclopropyl)methyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(1R,2S)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2R)-2-(methylamino)propyl]-amino}butyl)amino]benzenesulfonamide;
4-[(4-{[(1 S)-2-amino-1-methylethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(1 S)-2-amino-1-methylethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-[(4-{[(1 S)-2-amino-1-methylethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1-aminocyclobutyl)methyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(1S,2S)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-[(4-{[(1S,2S)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(1S,2S)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(2R)-azetidin-2-ylmethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;
4-[(4-{[(2S)-azetidin-2-ylmethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(2R)-azetidin-2-ylmethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(2S)-azetidin-2-ylmethyl]amino}butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-[(4-{[(2R)-azetidin-2-ylmethyl]amino}butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-[4-[[(1R)-3-amino-1-methyl-propyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(2S)-2-aminopropyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[(2-aminocyclobutyl)amino]butylamino]-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((4-(((1R,2R)-2-aminocyclobutyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((4-(((1S,2S)-2-aminocyclobutyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((4-(((S)-2-((R)-1-aminoethyl)-4-methylpentyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
4-((4-(((S)-2-((R)-1-aminoethyl)-4-methylpentyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(1R,2R)-2-aminocyclopentyl]amino]butylamino]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-(2-aminoethylamino)butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[(1-aminocyclopropyl)methylamino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-bromo-2-fluoro-4-[4-[2-(methylamino)ethylamino]butylamino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-bromo-2-fluoro-4-[4-[3-(methylamino)propylamino]butylamino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-bromo-4-[4-[2-(ethylamino)ethylamino]butylamino]-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(1S,2R)-2-aminocyclopentyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(1R,2R)-2-aminocyclopentyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(1S,3S)-3-aminocyclopentyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-bromo-2-fluoro-4[4-[(3-methylpyrrolidin-3-yl)amino]butylamino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-(3-aminopropylamino)butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[1-(aminomethyl)cyclopropyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-[4-[[(2R)-2-aminopropyl]amino]butylamino]-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
(S)-5-bromo-2-fluoro-4-((4-(pyrrolidin-3-ylamino)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
or
4-[(4-{[(1R)-2-amino-1-methylethyl]amino}butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,
or a pharmaceutically acceptable salt of any thereof.

109 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/061,815Filed 15 Dec 2016 · us provisional application
Priority: 18 Dec 2015
Published: US 2018/0362518 A120 Dec 2018
Granted: 31 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 11/14
Drugs for disorders of the respiratory system: antitussive agents
A61P 17/04
Drugs for dermatological disorders: antipruritics

Family

Application62/269,648Us provisional application · filed 18 Dec 2015
Application62/417,040Us provisional application · filed 3 Nov 2016
Application62/422,182Us provisional application · filed 15 Nov 2016
US 2018/0362518 A1Pre-grant publication · published 20 Dec 2018
US 10,519,147 B2This patent

From the US filing history. Foreign family members aren’t listed.