Substituted triazoles and methods relating thereto
Substituted 1,2,3-triazole compounds are disclosed which have utility in the treatment of a variety of neurological disorders. The compounds provided herein have the general structure: wherein R 1 , R 2 , R 3 and n are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound provided herein in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for treating neurological disorders in a subject in need thereof.
1. A compound having the following structure (A):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, —C(═O)OR 4 , —C(═O)—C 1-6 alkanediyl-NH 2 , C(═O)NR 5 R 5 , or —C(═O)R 6 , wherein said C 1-6 alkanediyl is optionally substituted with a group selected from —NH—C(═NH)NH 2 , —CO 2 H, —CO 2 CH 3 , —SH, —C(═O)NH 2 , —NH 2 , —SCH 3 , phenyl, —OH, —OC 1-4 alkyl, 4-hydroxy-phenyl, imidazolyl, cyclohexyl, and indolyl;
R 3 at each occurrence is Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl;
R 4 at each occurrence is C 1-4 alkyl;
R 5 at each occurrence is independently H or C 1-4 alkyl;
R 6 is 5-6 member nonaromatic heterocycle, or 5-6 member heterocycleC 1-4 alkyl wherein 5-6 member heterocycleC 1-4 alkyl is optionally substituted with OH, Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl; and
n is 0-3.
2. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n is 1.
3. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n is 2.
4. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is H.
5. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
6. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, —C(═O)OR 4 , —C(═O)NR 5 R 5 , or —C(═O)R 6 .
7. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 2 is —C(═O)—C 1-6 alkanediyl-NH 2 , optionally substituted with a group selected from —NH—C(═NH)NH 2 , —CO 2 H, —CO 2 CH 3 , —SH, —C(═O)NH 2 , —NH 2 , —SCH 3 , phenyl, —OH, —OC 1-4 alkyl, 4-hydroxy-phenyl, cyclohexyl, imidazolyl, and indolyl.
8. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
9. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 3 is Cl, F, or trifluoromethyl.
10. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 3 is C 1-4 alkyl or —OC 1-4 alkyl.
11. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n=1 or 2 and R 3 is F.
12. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 6 is a 5-6 member nonaromatic heterocycle.
13. The compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R 6 is a 5-6 member heterocycleC 1-4 alkyl wherein 5-6 member heterocycleC 1-4 alkyl is optionally substituted with OH, Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl.
14. A compound, which is
(2S)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide;
(3S)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide;
(3R)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-methoxypropanamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-hydroxypropanamide;
N-[1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-3-pyridin-3-yl-propionamide;
3-(3-chlorophenyl)-N-{1-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}propanamide;
(2S)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-2-(2-oxopyrrolidin-1-yl)butanamide;
[1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-dimethyl-amine;
[1-benzyl-1H-[1,2,3]triazol-4-yl]-dimethyl-amine;
1-[(2,6-difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazol-4-amine;
1-[(2,6-difluorophenyl)methyl]-N-ethyl-1H-1,2,3-triazol-4-amine; or
2-({1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}amino)ethan-1-ol;
or a solvate, or pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein the compound is (2S)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide, or a solvate, or pharmaceutically acceptable salt thereof.
16. The compound of claim 14 , wherein the compound is (3R)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide, or a solvate, or pharmaceutically acceptable salt thereof.
17. The compound of claim 14 , wherein the compound is [1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-dimethyl-amine, or a solvate, or pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
19. A method for treating a neurological condition of a subject having said neurological condition, wherein the condition is essential tremor, epilepsy, status epilepticus, or nerve agent exposure, comprising administering to the subject an effective amount of a compound of claim 1 , or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.
20. A method for treating a neurological condition of a subject having said neurological condition, wherein the condition is essential tremor, epilepsy, status epilepticus, or nerve agent exposure, comprising administering to the subject an effective amount of a pharmaceutical composition of claim 18 .
21. The method of claim 20 , wherein the condition is essential tremor.
22. The compound of claim 14 , wherein the compound is 1-[(2,6-difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazol-4-amine, or a solvate, or pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 14 , or a solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.