Benzoxazolinone compounds with selective activity in voltage-gated sodium channels
View Patent ↗Disclosed are compounds of Formula A: Formula A, or a salt thereof, wherein “Het”, R a , and R b are defined herein, which 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 neuropathic pain disorders using the same.
1. A compound of the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
one of R 1 and R 2 is —H and the other is:
(i) —H;
(ii) —C 1-8 alkyl, wherein the alkyl moiety is optionally substituted with a C 3-6 cycloalkyl moiety;
R a is —H, C 1-6 alkyl, C 1-6 alkoxy, —CN or halogen;
one of R G1 and R G3 is —H and the other is —H or Halogen; and
R 4 , R 5 , and R 6 are independently:
(i) —H;
(ii) halogen;
(iii) linear C 1-8 -alkyl, C 3-8 -branched alkyl, C 3-8 -cycloalkyl, C 2-8 alkenyl, or C 2-6 alkynyl, as these moieties are defined herein, which substituents may optionally be substituted by one or more moieties which are:
(a) halogen;
(b) hydroxyl;
(c) C 3-6 -cycloalkyl substituted with an amino-moiety;
(d);
(e) (R aa ) 2 N-(J)-, wherein R aa is:
(1) independently for each occurrence —H or is C 1-6 -linear alkyl or C 3-6 -cycloalkyl;
(2) and wherein “J” is a moiety of the structure:
wherein “p” is an integer of 1 to 4 and “q” is an integer of 0 to 5;
(f) —N(R ab ) 2 , wherein R ab is: (1) independently for each occurrence —H or is C 1-6 -linear alkyl or is C 3-6 -cycloalkyl, which is optionally bonded to the ring through —S(O 2 )— or —C(O)— moiety;
(iv).
2. A compound of claim 1 , or a salt thereof, wherein:
R G1 and R G3 are selected to provide a moiety of Formula CA or CB:
and
one of R 4 , R 5 , and R 6 are —H, and the other two are independently for each occurrence:
(a) —H;
(b) halogen;
(c) C 1-8 -alkyl, C 2-8 alkenyl, or C 2-6 alkynyl, which substituents may optionally be substituted by one or more moieties which are:
(i) halogen;
(ii) hydroxyl;
(iii) (R aa ) 2 N-(J)-, wherein R aa is: (1) independently for each occurrence: —H; —SO 2 C 1-8 -alkyl; —SO 2 -aryl; —(O═C)C 1-8 -alkyl; C 1-6 -linear alkyl-; or C 3-6 -cycloalkyl-, and when R aa is selected to be an alkyl moiety it may be optionally substituted with one or more fluorine substituents, and wherein “J” is a moiety of the structure:
where “p” is an integer of 1 to 4 and “q” is an integer of 0 to 5;
(iv) —N(R ab ) 2 , wherein R ab is: (1) independently for each occurrence: —H; —SO 2 C 1-8 -alkyl; —SO 2 -aryl; —(O═C)C 1-8 -alkyl; C 1-6 -linear alkyl; or C 3-6 -cycloalkyl and is optionally bonded to the ring through —S(O 2 )— or —C(O)— moiety; or
(v) C 1-6 -alkoxy;
(d).
3. A compound of claim 1 , or a salt thereof, wherein R 6 is —H.
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
3-{(1R)-1-[2-(4-aminocyclohex-1-en-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(3-aminoprop-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-{[(1R,2R)-2-aminocyclohexyl]ethynyl}phenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(3-amino-4-hydroxybut-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-{[(1R,2S)-2-aminocyclohexyl]ethynyl}phenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{2-[(1-aminocyclohexyl)ethynyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(4-amino-4-methylpent-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{2-[3-(dimethylamino)prop-1-yn-1-yl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(aminomethyl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{2-[(dimethylamino)methyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-bromo-3-methylphenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(aminomethyl)phenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-bromophenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(3-bromophenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(3-bromophenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(3-bromo-2-methylphenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-bromo-3-methylphenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-bromophenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(3-bromo-2-methylphenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(aminomethyl)-3-methylphenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(aminomethyl)-3-methylphenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(aminomethyl)phenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(aminomethyl)-2-methylphenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(aminomethyl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[(dimethylamino)methyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[(tert-butylamino)methyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(2-aminoethyl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(2-aminoethyl)-2-methylphenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-amino-3-methylbut-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
5-fluoro-N-(6-fluoropyridin-2-yl)-3-[(1R)-1-{3-[3-(methylamino)prop-1-yn-1-yl]phenyl}ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[3-(dimethylamino)prop-1-yn-1-yl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[(1-aminocyclohexyl)ethynyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminobut-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[3-(cyclohexylamino)prop-1-yn-1-yl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[(1-aminocyclopropyl)ethynyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[3-(diethylamino)prop-1-yn-1-yl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(3-{[(1S,2S)-2-aminocyclohexyl]ethynyl}phenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-{3-[(2-aminocyclopentyl)ethynyl]phenyl}ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminoprop-1-yn-1-yl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminoprop-1-yn-1-yl)-2-methylphenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminoprop-1-yn-1-yl)phenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminoprop-1-yn-1-yl)-2-methylphenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-{[(1S,2S)-2-aminocyclohexyl]ethynyl}-3-methylphenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-{[(1R,2R)-2-aminocyclohexyl]ethynyl}-3-methylphenyl)ethyl]-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-[(1R)-1-(2-{[(1S,2S)-2-aminocyclohexyl]ethynyl}-3-methylphenyl)ethyl]-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-aminopropyl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-amino-propyl)phenyl]ethyl}-N-(6-fluoropyridin-2-yl)-5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[3-(3-amino-propyl)-2-methylphenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide;
3-{(1R)-1-[2-(2-aminoethyl)phenyl]ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide; or
3-{(1R)-1-[2-(2-aminoethyl)-3-methylphenyl]-ethyl}-5-fluoro-N-(6-fluoropyridin-2-yl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide.
5. A pharmaceutical composition comprising at least one compound of claim 4 or a pharmaceutically acceptable salt thereof, and at least one excipient.