Cyclooctenes for bioorthogonol reactions

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

each X is independently CH 2 or O;

R 1 is (CH 2 —CH 2 —O) n R 2 ;

R 2 is selected from the group consisting of H, C 1-6 alkyl, and an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester; and

n is an integer from 1 to 20.

2. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula IA:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (CH 2 —CH 2 —O) n R 2 ;

R 2 is selected from the group consisting of H, C 1-6 alkyl, or an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester; and

n is an integer from 1 to 20.

3. The compound of claim 1 , wherein R 2 is selected from H and C 1-6 alkyl.

4. The compound of claim 1 , wherein R 2 is an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester.

5. The compound of claim 4 , wherein R 2 is an NHS ester which is an NHS carbamate.

6. The compound of claim 5 , wherein the NHS carbamate is N,N′-disuccinimidyl carbonate.

7. The compound of claim 1 , wherein n is 1.

8. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. A compound of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 —CH 2 —O) n R 5 ;

R 4 is selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 —CH 2 —O) n R 5 ;

wherein one of R 3 and R 4 is —(CH 2 —CH 2 —O) n R 5 ;

R 5 is selected from the group consisting of H, C 1-6 alkyl, and an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester; and

n is an integer from 1 to 20.

10. The compound of claim 9 , wherein R 3 is H.

11. The compound of claim 9 , wherein R 5 is a C 1-6 alkyl.

12. The compound of claim 9 , wherein R 5 is an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester.

13. The compound of claim 12 , wherein R 5 is an NHS ester which is an NHS carbamate.

14. The compound of claim 13 , wherein the NHS carbamate is N,N′-disuccinimidyl carbonate.

15. The compound of claim 9 , wherein n is 3.

16. The compound of claim 9 , wherein the compound of Formula II is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A compound of Formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or NR 6 ;

Z is O or NR 6 ;

wherein one of Y and Z is O, and the other is NR 6 ;

R 6 is —(CH 2 ) m —(CH 2 —CH 2 —O) n R 7 ;

R 7 is selected from the group consisting of H, C 1-6 alkyl, and an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester;

m is an integer from 1 to 20; and

n is an integer from 1 to 20.

18. The compound of claim 17 , wherein R 7 is a H.

19. The compound of claim 17 , wherein R 7 is an amine-reactive crosslinking group selected from the group consisting of an isothiocyanate, an isocyanate, an acyl azide, an NHS ester, a sulfonyl chloride, an aldehyde, a glyoxal, an epoxide, an oxirane, a carbonate, an aryl halide, an imidoester, a carbodiimide, an anhydride, a hydrazine, a hydrazide, a hydroxyl amine, and a fluorophenyl ester.

20. The compound of claim 19 , wherein R 7 is an NHS ester which is an NHS carbamate.

21. The compound of claim 20 , wherein the NHS carbamate is N,N′-disuccinimidyl carbonate.

22. The compound of claim 17 , wherein n is 1.

23. The compound of claim 17 , wherein m is 2.

24. The compound of claim 17 , wherein the compound of Formula III is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.