Trapping reagents for reactive metabolites screening
The present invention provides compounds of Formula (I) and (II): wherein R 1 , R 2 , R 4 , R 5 , R 6 , X and n are as defined herein, and wherein R 3 is hydrogen or a sulfur protecting group. Compounds of Formula (I) and (II), wherein R 3 is hydrogen, may be useful in methods for detecting a reactive metabolite in a sample, e.g., wherein the metabolite is generated from the metabolism of a test compound, and wherein the metabolite and the compound of Formula (I) or (II) react to form a detectable adduct, e.g., detectable by mass spectrometry.
1. A compound of Formula (I):
wherein:
R 1 is hydrogen;
R 2 is —C(═O)R A , —C(═O)OR A , or —C(═O)NHR A , wherein R A is a group of formula:
wherein
p is 0, 1, or 2;
m is 1, 2, 3, 4, or 5; and
R 7 is halogen;
R 3 is hydrogen or a sulfur protecting group;
each instance of R 4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, or two R 4 groups are joined to form a substituted or unsubstituted heterocyclic ring;
n is 1, 2, 3, 4, 5, or 6; and
X − is a counteranion.
2. The compound of claim 1 , wherein R 7 is bromo or fluoro.
3. The compound of claim 1 , wherein R 3 is hydrogen.
4. The compound of claim 1 , wherein each instance of R 4 is independently substituted or unsubstituted alkyl.
5. The compound of claim 4 , wherein each instance of R 4 is independently substituted or unsubstituted C 1-6 alkyl.
6. The compound of claim 5 , wherein each instance of R 4 is —CH 3 .
7. The compound of claim 1 , wherein n is 2.
8. The compound of claim 1 , wherein X − is a chloride counteranion.
9. The compound of claim 1 of Formula (I-a) or Formula (I-b):
10. A compound of Formula (II):
wherein:
each instance of R 1 and R 2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R A , —C(═O)OR A , —C(═O)N(R A ) 2 , or an amino protecting group, or R 1 and R 2 are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring;
R 3 is hydrogen or a sulfur protecting group;
R 5 and R 6 are independently selected from —OR B , —N(R B ) 2 , and a group of formula (i):
provided at least one of R 5 and R 6 is a group of formula (i);
each instance of R B is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R B groups are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R 4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, or two R 4 groups are joined to form a substituted or unsubstituted heterocyclic ring;
n is 1, 2, 3, 4, 5, or 6; and
X − is a counteranion.
11. The compound of claim 10 , wherein R B is a group of formula:
wherein p is 0, 1, or 2; m is 1, 2, 3, 4, or 5; and R 7 is halogen.
12. The compound of claim 11 , wherein R 7 is bromo or fluoro.
13. The compound of claim 11 , wherein m is 5 and R 7 is fluoro.
14. The compound of claim 10 of Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), or Formula (II-g):
15. The compound of claim 10 , wherein the compound is selected from the group consisting of:
16. A compound of Formula (I-c):
each instance of R 1 and R 2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R A , —C(═O)OR A , —C(═O)N(R A ) 2 , or an amino protecting group, or R 1 and R 2 are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring;
R 3 is hydrogen or a sulfur protecting group; and
X − is a counteranion.
17. The compound of claim 16 , wherein the compound is selected from the group consisting of: