US 12,246,008 B2Granted

4-amino or 4-alkoxy-substituted aryl sulfonamide compounds with selective activity in voltage-gated sodium channels

AssigneeMerck Sharp & Dohme Corp.

InventorsChristopher J. Bungard, Helen Y. Chen, Jason M. Cox, Liangqin Guo, Michael J. Kelly, III, Ronald M. Kim, Mark E. Layton, Hong Liu, Jian Liu, Mehul F. Patel, James J. Perkins, Deping Wang, Walter Won, Younong Yu, Ting Zhang

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Abstract

Disclosed are compounds of Formula (I), Formula (II), or a salt thereof: Formula (I) Formula (II) 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 (I), Formula (II) or their salts, and methods of treating pain disorders, cough, and itch using the same.

Claims17

Dependent claims

A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

wherein:
X is selected from the group consisting of thiadiazolyl, pyridyl, thiazolyl, and pyrimidinyl, said thiadiazolyl, pyridyl, thiazolyl, and pyrimidinyl, optionally substituted with 1 to 3 groups selected from halogen and C1-6 alkyl;
Y is phenyl;
Z is selected from NH and O;
R1 is selected from C1-6 alkyl and (CH2)nC3-6 cycloalkyl;
R2 and R3 are independently selected from the group consisting of hydrogen, halogen, OC1-6 alkyl, C1-6 alkyl, C3-10 heteroaryl, CN, C1-3 haloalkyl, and (CH2)nOH;
R4 is selected from the group consisting of CHR5NR2, CH2NHCH(C1-6 alkyl)2, CH2R5, CH2N(R5)CH2CHRNR2, CH2CH(R5)(CH2)pNR2, and (CH2)nC(R)2(CHR)pNRR7,
R5 is selected from the group consisting of C1-6 alkyl, (CH2)nC6-10 aryl, C3-6 cycloalkyl, (CH2)nC3-10 heterocyclyl, and OC1-6 alkyl, said alkyl, aryl, cycloalkyl and heterocyclyl optionally substituted with 1 to 3 groups of halogen, CF3, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)pNR2;
R is hydrogen or C1-6 alkyl, or two adjacent R groups can combine with the carbon atom to which they are attached to form C3-6 cycloalkyl optionally substituted with 1 to 3 groups of halogen or C1-6 alkyl;
R6 is NHR;
R7 is hydrogen or C1-6 alkyl,
R9 is hydrogen or halogen;
p is 0, 1, or 2, and
n is 0, 1, 2, 3, or 4.

11 more elements

A compound which is:

4-(((2S)-4-amino-2-((R)-1-aminoethyl)-5,5,5-trifluoropentyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((5-amino-2-((R)-1-aminoethyl)-4,4-dimethylpentyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)-4-((((5R,6S)-5,8,8-trimethyl-1,4-diazonan-6-yl)methyl)amino)benzenesulfonamide;
4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2R,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((4,4-dimethylpyrrolidin-2-yl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-4-amino-2-((R)-1-aminoethyl)-4-(1-methylcyclopropyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-6-amino-2-((R)-1-aminoethyl)-4-cyclopropylhexyl)amino)-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)pentyl)amino)-2,3,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-2-((2-azaspiro[3.4]octan-5-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-amino-2-methylpropyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-amino(cyclopropyl)methyl)-4,4-dimethylhexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-amino-2-cyclopropylethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S,3R)-3-amino-2-(((1S,2S)-2-(aminomethyl)cyclopropyl)methyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-(amino(cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((isopropylamino)methyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((((R)-2-aminopropyl)(isopropyl)amino)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-2-fluoro-N-(1,2,4-thiadiazol-5-yl)-5-(thiazol-2-yl)benzenesulfonamide;
2-((2R,3R)-2,7-diamino-5,5-dimethylheptan-3-yl)-7-fluoro-N-(1,2,4-thiadiazol-5-yl)chromane-6-sulfonamide;
4-(((2S,3R)-3-amino-2-((1-(2-(dimethylamino)ethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((2-(aminomethyl)cyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((2-(aminomethyl)-1-methylcyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((1-(2-aminoethyl)-3,3-difluorocyclobutyl)methyl)butyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((2-(2-aminoethyl)cyclohexyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-cyano-2-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-2-((5-azaspiro[2.4]heptan-6-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((1-(aminomethyl)cyclobutyl)methyl)butyl)amino)-2-fluoro-5-methoxy-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((4,4-dimethylpyrrolidin-3-yl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-2-fluoro-5-(oxazol-2-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-4-amino-2-((R)-1-aminoethyl)-4-cyclopropylbutyl)amino)-2-fluoro-5-(hydroxymethyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-5-amino-2-((R)-1-aminoethyl)-4-methoxypentyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-4-amino-2-((R)-1-aminoethyl)hexyl)amino)-2-fluoro-5-methoxy-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S)-4-amino-2-((R)-1-aminoethyl)-6,6,6-trifluorohexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-((1-aminocyclobutyl)methyl)butyl)amino)-3-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((2-((R)-1-aminoethyl)-4-(aminomethyl)hexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-(((1R,2S)-2-(aminomethyl)-1-methylcyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-(((1S,2R)-2-(aminomethyl)-1-methylcyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,3-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-(morpholin-3-ylmethyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((2S,3R)-3-amino-2-((1-aminocyclobutyl)methyl)butyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;
4-(((S)-4-amino-2-((R)-1-aminoethyl)-4-methylpentyl)amino)-5-chloro-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide;
4-(((S)-4-amino-2-((R)-1-aminoethyl)-4-methylpentyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-5-methylbenzenesulfonamide;
4-((4-amino-2-((R)-1-aminoethyl)-5-methylhexyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-3-amino-2-(pyrrolidin-1-ylmethyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-(((3R)-2-(((1R,3R,4S)-2-azabicyclo[2.2.1] heptan-3-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
or a pharmaceutically acceptable salt of any thereof.

47 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/296,601Filed 2 Dec 2019 · us provisional application
Priority: 5 Dec 2018
Published: US 2022/0000844 A16 Jan 2022
Granted: 11 Mar 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles
A61K 31/167
Having aromatic rings, e.g. colchicine, atenolol, progabide: having the nitrogen of a carboxamide group directly attached to the aromatic ring,…
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…