Antidotes to Cyanide Poisoning

1 . A method of treating or preventing cyanide poisoning, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 6-10 aryl;

R 2 is selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 6-10 aryl; or

R 1 and R 2 together form a group selected from C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene;

n is an integer selected from 1, 2, 3, 4, and 5;

each L is a ligand independently selected from halogen, NR c1 R d1 , NR c1 R d1 R e1 , C 2-12 alkene, OR a1 , H 2 O, HOR 3 , NC—R 3 , P(R a1 ) 3 , S(O) 2 R 1 R 2 , SR 1 R 2 , and 5-10 membered heteroaryl; or

any two L together form a bidentate ligand selected from C 4-12 alkyldiene, 12-16 membered fused heteroaryl, and bis (5-10 membered heteroaryl);

each R a1 is independently selected from H, C 1-6 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 6-10 aryl;

each R c1 , R d1 , and R e1 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-10 cycloalkyl; or

any two R c1 together form a group selected from C 1-3 alkylene, C 2-4 alkenylene, and C 3-10 cycloalkylene; and

R 3 is selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 6-10 aryl.

2 . The method of claim 1 , wherein the compound of Formula (I) has formula:

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein the compound of Formula (I) has formula:

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein the compound of Formula (I) has formula:

or a pharmaceutically acceptable salt thereof.

5 . The method of claim 1 , wherein:

R 1 and R 2 are each independently C 1-3 alkyl,

n is an integer selected from 1,3, and 5;

each L is independently selected from halogen, NR c1 R d1 R e1 , C 2 -12 alkene, NC—R 3 , P(R a1 ) 3 , S(O) 2 R 1 R 2 , SR 1 R 2 , and 5-10 membered heteroaryl; or

any two L together form a bidentate ligand selected from C 4-12 alkyldiene, 12-16 membered fused heteroaryl, and bis (5-10 membered heteroaryl);

each R a1 is independently selected from C 1-6 alkyl and C 6-10 aryl;

each R c1 , R d1 , and R e1 is independently selected from H, C 1-3 alkyl, and C 3-10 cycloalkyl; or

any two R c1 together form a group selected from C 1-3 alkylene and C 3-10 cycloalkylene; and

R 3 is selected from C 1-3 alkyl and C 6-10 aryl.

6 . The method of claim 1 , wherein:

R 1 and R 2 are each independently C 1-3 alkyl,

n is an integer selected from 1,3, and 5;

each L is independently selected from halogen, NR c1 R d1 R e1 , S(O) 2 R 1 R 2 , and SR 1 R 2 ; and

each R c1 , R d1 , and R e1 is independently selected from H and C 1-3 alkyl.

7 . The method of claim 1 , wherein the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

9 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

10 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

11 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

12 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

13 . The method of claim 7 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

14 . The method of claim 1 , wherein the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

15 . The method of claim 1 , wherein the pharmaceutical composition is suitable for administration by an intramuscular injection.

16 . The method of claim 1 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent useful in treating or preventing cyanide poisoning, or a pharmaceutically acceptable salt thereof.

17 . The method of claim 16 , wherein the additional therapeutic agent is selected from: hydroxocobalamin, methemoglobin, riboflavin, methotrexate, sulfanegen, 3-mercaptopyruvic acid (3-MP), amyl nitrite, sodium nitrite, sodium thiosulfate, 4-dimethylaminophenol (4-DMAP), dicobalt edetate, glucose, and oxygen therapy.

18 . The method of claim 1 , further comprising administering to the subject a pharmaceutical composition comprising at least one additional therapeutic agent useful in treating or preventing cyanide poisoning, or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprising the additional therapeutic agent, or a pharmaceutically acceptable salt thereof, are administered to the subject in separate dosage forms.

20 . The method of claim 18 , wherein the additional therapeutic agent is selected from: hydroxocobalamin, methemoglobin, riboflavin, methotrexate, sulfanegen, 3-mercaptopyruvic acid (3-MP), amyl nitrite, sodium nitrite, sodium thiosulfate, 4-dimethylaminophenol (4-DMAP), dicobalt edetate, glucose, and oxygen therapy.