Cyclooctynes for click chemistry
Provided herein are dibenzocyclooctyne compounds useful as reagents in 1,3-dipolar cycloaddition reactions, and methods for their preparation.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 groups;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 , —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 ; —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , or —C 1-6 alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2;
X 1 is N or CH; and
X 2 is N + or C;
provided that when X 1 is N, X 2 is C; or when X 1 is CH, X 2 is N + .
2. The compound of claim 1 , having a structure according to formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 group;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 , —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 , —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , —C 1-6 alkyl;
n is 0, 1, or 2; and
p is 0, 1, or 2.
3. The compound of claim 2 , wherein R 3 and R 4 are H.
4. The compound of claim 2 , wherein R 1 and R 2 are F, Cl, Br, I, OTf, or B(OH) 2 .
5. The compound of claim 2 , wherein R 1 and R 2 are Cl.
6. The compound of claim 2 , wherein n is 1 and p is 0.
7. The compound of claim 1 , having a structure according to formula (Ib):
or a pharmaceutically acceptable salt thereof,
wherein R 1 is, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 or —C 1-6 -alkyl; and
n is 0, 1, or 2.
8. The compound of claim 1 , wherein the compound of formula (I) is:
or a pharmaceutically acceptable salt thereof.