Poly(ethylene glycol) containing chemically disparate endgroups

• US 20080207913A1
• Filed: 04/27/2007
• Published: 08/28/2008
• Est. Priority Date: 04/27/2006
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin N.
• Granted Patent: US 7,560,588 B2
• Time in Patent Office: Days
• US Class Current: 548/237
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: C07C 217/08 the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 217/84 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 247/04 being saturated
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 263/14 with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 311/88 Nitrogen atoms
• CPC Class Codes: C07D 317/22 etherified
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/42 Halides thereof
• CPC Class Codes: C07F 9/65502 the oxygen atom being part of a three-membered ring
• CPC Class Codes: C07F 9/65505 Phosphonic acids containing oxirane groups; esters thereof
• CPC Class Codes: C07F 9/6552 the oxygen atom being part of a six-membered ring
• CPC Class Codes: C08G 2650/48 containing fluorine, e.g. perfluropolyethers
• CPC Class Codes: C08G 65/2612 : containing aromatic or arylaliphatic hydroxyl groups
• CPC Class Codes: C08G 65/2627 : containing aromatic or arylaliphatic amine groups
• CPC Class Codes: C08G 65/263 : containing heterocyclic amine groups
• CPC Class Codes: C08G 65/325 : containing nitrogen
• CPC Class Codes: C08G 65/329 : with organic compounds
• CPC Class Codes: C08G 65/3322 : acyclic
• CPC Class Codes: C08G 65/33303 : containing amino group
• CPC Class Codes: C08G 65/33337 : cyclic
• CPC Class Codes: C08G 65/33396 : having oxygen in addition to nitrogen
• CPC Class Codes: C08G 65/3353 : containing oxygen in addition to phosphorus
• CPC Class Codes: C08G 65/336 : containing silicon
• CPC Class Codes: C08G 65/337 : containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08G 65/4006 : (I) or (II) containing elements other than carbon, oxygen, hydrogen or halogen as leaving group (X)
• CPC Class Codes: C08L 2203/02 : for biomedical use

Abstract

The present invention provides bifunctional polymers, methods of preparing the same, and intermediates thereto. These compounds are useful in a variety of applications including the PEGylation of biologically active molecules. The invention also provides methods of using said compounds and compositions thereof.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein:

R¹ is hydrogen, halogen, NO₂, CN, N₃, —

N═

C═

O, —

CH═

NN(R)₂, —

P(O)(OH)₂, —

P(O)(Cl)₂, a 9-30 membered crown ether, or a detectable moiety;

L¹ and L² are independently —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

; and

R² is —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, N₃, an epoxide ring, a crown ether, a detectable moiety, —

P(O)(OH)₂, or —

P(O)(Cl)₂, or a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

3. The compound according to claim 2, wherein R² is —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, N₃, an epoxide ring, a crown ether, a detectable moiety, —

P(O)(OH)₂, —

P(O)(Cl)₂, or a phenyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH-—

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

4. The compound according to claim 2, wherein either of R¹ or R² is a detectable moiety selected from

15. The compound according to any of claims 1, 5, and 10, wherein said compound has a PDI of about 1.0 to about 1.2.

16. The compound according to claim 15, wherein said compound has a PDI of about 1.02 to about 1.05.

26. A method of PEGylating a moiety selected from a primary or secondary label, a dye, or another detectable moiety, a biomolecule, a protein therapeutic, a small molecule drug, a virus, a therapeutic carrier, a cell, or a surface, comprising the step of linking the compound according to any of claims 1, 5, 10, 17, 21, or 25 to said moiety either covalently or ionically.

5. A compound of formula I:

6. The compound according to claim 5, wherein:

L¹ and L² are independently —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

; and

R² is —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, N₃, an epoxide ring, a crown ether, a detectable moiety, —

P(O)(OH)₂, or —

P(O)(Cl)₂, or a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

7. The compound according to claim 6, wherein R² is a detectable moiety selected from

8. The compound according to claim 5, wherein R² is —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, N₃, an epoxide ring, a crown ether, a detectable moiety, —

P(O)(OH)₂, —

P(O)(Cl)₂ or a phenyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

9. The compound according to claim 8, wherein L¹ and L² are independently —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

.

10. A compound of formula I:

11. The compound according to claim 10, wherein R¹ is an optionally substituted ring selected from phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl.

12. The compound according to claim 11, wherein R¹ is a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

13. The compound according to claim 12, wherein:

L¹ and L² are independently —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

; and

R² is —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, N₃, an epoxide ring, a crown ether, a detectable moiety, —

P(O)(OH)₂, or —

P(O)(Cl)₂, or a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

14. The compound according to claim 13, wherein R² is a detectable moiety selected from

17. A compound of formula IIa:

18. The compound according to claim 17, wherein R^x is an aliphatic group optionally substituted with any of Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH₂, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O)(C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

19. The compound according to claim 17, wherein R^x is a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

20. The compound according to claim 17, wherein L^x is —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

.

21. A compound of formula IIb:

22. The compound according to claim 21, wherein R^x is an aliphatic group optionally substituted with any of Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH₂, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O)(C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

23. The compound according to claim 21, wherein R^x is a phenyl, pyridyl, naphthyl, pyrenyl, triazolyl, imidazolyl, phthalimide, tetrazolyl, furanyl, or pyranyl ring optionally substituted with CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

24. The compound according to claim 21, wherein L^x is —

O—

, —

S—

, —

NH—

, —

C(O)O—

, -Cy-, —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, or —

OCH₂CH₂NHNH—

.

25. A compound selected from any of the following formulae:

27. A compound selected from any of those set forth in Tables 1 through 25.