Chemical crosslinkers and compositions thereof

1. A compound of Formula (I):

or a salt thereof, wherein:

A 1 is a moiety selected from Formula (A 1 a1), Formula (A 1 a2), Formula (A 1 a3), Formula (A 1 a4), Formula (A 1 b1), Formula (A 1 b3), Formula (A 1 b4), Formula (A 1 c1), Formula (A 1 c2), Formula (A 1 c3), Formula (A 1 d1), Formula (A 1 d2), Formula (A 1 d3), Formula (A 1 d4), Formula (A 1 d5), Formula (A 1 d6), Formula (A 1 d7), Formula (A 1 d8), Formula (A 1 e1), Formula (A 1 e2), Formula (A 1 f1), Formula (A 1 f2), Formula (A 1 f3), Formula (A 1 f4), and Formula (A 1 f5):

wherein:

each R 8 and R 9 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and phenyl;

each E is selected from F, Cl, Br, and I; and

each L 2 is selected from hydroxysuccinimidyl, phenol yl, substituted phenol yl, hydroxybenzotriazolyl, F, Cl, Br, N-hydroxysuccinimidyl, sulfo-N-hydroxysuccinimidyl, 4-nitrophenol-yl, pentafluorophenol-yl, 4-methylsulfonylphenol-yl, hydroxybenzotriazolyl, 1-hydroxy-7-azabenzotriazolyl, trichlorophenol-yl, and imidazolyl;

X 1 and X 3 are independently selected from a covalent bond, C 1-20 alkanediyl, substituted C 1-20 alkanediyl, C 1-20 heteroalkanediyl, substituted C 1-20 heteroalkanediyl, C 3-12 cycloalkanediyl, substituted C 3-12 cycloalkanediyl, C 3-12 heterocycloalkanediyl, substituted C 3-12 heterocycloalkanediyl, C 4-20 alkanecycloalkanediyl, substituted C 4-20 alkanecycloalkanediyl, C 4-20 heteroalkanecycloalkanediyl, substituted C 4-20 heteroalkanecycloalkanediyl, C 6-20 arenediyl, substituted C 6-20 arenediyl, C 6-20 heteroarenediyl, substituted C 6-20 heteroarenediyl, C 7-20 alkanearenediyl, substituted C 7-20 alkanearenediyl, C 6-20 heteroalkanearenediyl, substituted C 6-20 heteroalkanearenediyl, and —(CH 2 ) n1 —(CH 2 —CH 2 —O) n2 —(CH 2 )— 3 —, wherein:

each n1 and n3 is independently an integer selected from 0 to 5; and

each n2 is independently an integer selected from 1 to 25;

X 2 is selected from a covalent bond, —O—, —S—, —NH—, —N═, —N═N—, —N═CH—, —SO—, —SO 2 —,—SO 2 NH—, —SS—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)S—, —C(O)NH—N═, —OP(O)OH)O—, —OC(O)O—, —OC(O)NH—, —NHC(O)NH—, and —NHC(S)NH—;

R 1 and R 2 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 6-10 aryl, substituted C 6-10 aryl, C 6-10 heteroaryl, and substituted C 6-10 heteroaryl; and

L 1 is selected from F, Cl, Br, N-hydroxysuccinimidyl, sulfo-N-hydroxysuccinimidyl, 4-nitrophenol-yl, pentafluorophenol-yl, 4-methylsulfonylphenol-yl, hydroxybenzotriazolyl, 1-hydroxy-7-azabenzotriazolyl, trichlorophenol-yl, and imidazolyl;

provided that compounds falling within the following scopes of the Formula (I) are excluded:

(1) A 1 is (A 1b 3), X 2 is a covalent bond, one of R 1 and R 2 is hydrogen and the other is substituted C 1-6 alkyl, L 1 is 4-nitrophenol-yl, X 1 is substituted C 1-20 alkanediyl and X 3 is a covalent bond;

(2) A 1 is (A 1 a2), R 8 is hydrogen, X 2 is a covalent bond, R 1 and R 2 are hydrogen, L 1 is 4-nitrophenol-yl, X 3 is substituted C 1-20 alkanediyl and X 1 is a covalent bond;

(3) A 1 is (A 1 b1), L2 is Cl, R 1 and R 2 are hydrogen, L 1 is Cl, X 2 is a covalent bond, X 3 is C 1-20 alkanediyl, and X 1 is substituted C 1-20 heteroalkanediyl;

(4) A 1 is (A 1 a3), E is F, one of R 1 and R 2 is hydrogen and the other is substituted C 1-6 alkyl, L 1 is Cl, X 3 is a covalent bond, X 2 is —O— and X 1 is substituted C 4-20 heteroalkanecycloalkanediyl; and

(5) A 1 is (A 1 b1), L 2 is Cl, R 1 and R 2 are hydrogen, L is Cl, X 3 is C 6-20 arenediyl, X 2 is —C(O)—, and X 1 is C 1-20 heteroalkanediyl.

2. The compound of claim 1 , wherein A 1 is a moiety selected from Formula (A 1 a1-1), Formula (A 1 a2-1), Formula (A 1 a3-1), Formula (A 1 a4), Formula (A 1 b1-1), Formula (A 1 b3), Formula (A 1 b4), Formula (A 1 c1), Formula (A 1 c2), Formula (A 1 c3), Formula (A 1 d1), Formula (A 1 d2), Formula (A 1 d3), Formula (A 1 e1), Formula (A 1 e2), Formula (A 1 f1), Formula (A 1 f3), Formula (A 1 f4), and Formula (A 1 f5):

3. The compound of claim 1 , wherein X′ is selected from a covalent bond, methane-diyl, ethane-diyl, propane-diyl, butane-diyl, pentane-diyl, hexane-diyl, cyclopropane-diyl, cyclobutane-diyl, cyclopentane-diyl, cyclohexane-diyl, methylcyclohexane-diyl, benzene-diyl, methylbenzene-diyl, ethylbenzene-diyl, propylbenzene-diyl, butylbenzene-diyl, and —(CH 2 ) n1 —(CH 2 —CH 2 —O) 1 —(CH 2 )— 3 —, wherein each n1 and n3 is independently an integer selected from 0 to 5 and n2 is an integer selected from 1 to 25.

4. The compound of claim 1 , wherein X 2 is selected from a covalent bond, —O—, —S—, —SO—, —SO 2 —, —SO 2 NH—, —SS—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)NH—N═, —OC(O)NH—, and —NHC(O)NH—.

5. The compound of claim 1 , wherein X 3 is selected from a covalent bond, methane-diyl, ethane-diyl, propane-diyl, butane-diyl, pentane-diyl, hexane-diyl, cyclopropane-diyl, cyclobutane-diyl, cyclopentane-diyl, cyclohexane-diyl, methylcyclohexane-diyl, benzene-diyl, methylbenzene-diyl, ethylbenzene-diyl, propylbenzene-diyl, butylbenzene-diyl, and —(CH 2 ) n1 —(CH 2 —CH 2 —O) n2 —(CH 2 ) n3 —, wherein each n1 and n3 is independently an integer selected from 0 to 5 and n2 is an integer selected from 1 to 25.

6. The compound of claim 1 , wherein R 1 and R 2 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, and phenyl.

7. The compound of claim 1 , wherein L 1 is selected from Cl, N-hydroxysuccinimidyl, sulfo-N-hydroxysuccinimidyl, 4-nitrophenol-yl, and pentafluorophenol-yl.

8. The compound of claim 1 , wherein the compound is selected from (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-(2,5-dioxopyrrol-1-yl)acetate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 3-(2,5-dioxopyrrol-1-yl)propanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-(2,5-dioxopyrrol-1-yl)butanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 5-(2,5-dioxopyrrol-1-yl)pentanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-(2,5-dioxopyrrol-1-yl)hexanoate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 6-(2,5-dioxopyrrol-1-yl)hexanoate; [1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxy-2-methyl-propyl] 6-(2,5-dioxopyrrol-1-yl)hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[6-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]hexanoylamino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarboxylate; [1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxy-2-methyl-propyl] 4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarboxylate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 3-(2,5-dioxopyrrol-1-yl)benzoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-(2,5-dioxopyrrol-1-yl)benzoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoate; O4-(2,5-dioxopyrrolidin-1-yl) O1-[(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl] butanedioate; (4-nitrophenoxy)carbonyloxymethyl 5-[(4S)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 5-(5-methyl-2-oxo-imidazolidin-4-yl)pentanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[5-(5-methyl-2-oxo-imidazolidin-4-yl)pentanoylamino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 5-[(4S)-2,5,5-trioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[5-[(4S)-2,5,5-trioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-methylprop-2-enoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-(2-methylprop-2-enoylamino)hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl prop-2-ynoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-(prop-2-ynoylamino)hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 3-(3-methyldiazirin-3-yl)propanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[3-(3-methyldiazirin-3-yl)propanoylamino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-(7-oxofuro[3,2-g]chromen-9-yl)oxybutanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-vinyl sulfonylacetate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[(2-vinylsulfonylacetyl)amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[(2-bromoacetyl)amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-azidohexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-(6-azidohexanoylamino)hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-azidobenzoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[(4-azidobenzoyl)amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-azido-2-nitro-benzoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[(4-azido-2-nitro-benzoyl)amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 4-azido-2-hydroxy-benzoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[(4-azido-2-hydroxy-benzoyl)amino]hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-(7-azido-4-methyl-2-oxo-chromen-3-yl)acetate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 6-[[2-(7-azido-4-methyl-2-oxo-chromen-3-yl)acetyl]amino] hexanoate; (4-nitrophenoxy)carbonyloxymethyl 6-(2,5-dioxopyrrol-1-yl)hexanoate; (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 3-[2-[2-(2,5-dioxopyrrol-1-yl)ethoxy]ethoxy]propanoate; O4-(2,5-dioxopyrrolidin-1-yl) O1-[(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl] butanedioate; (4-nitrophenoxy)carbonyloxymethyl 5-(5-methyl-2-oxo-imidazolidin-4-yl)pentanoate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[(prop-2-ynoylamino)methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[3-(3-methyldiazirin-3-yl)propanoylamino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[4-(7-oxofuro[3,2-g]chromen-9-yl)oxybutanoylamino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[(2-vinylsulfonylacetyl)amino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[(2-bromoacetyl)amino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[(6-azidohexanoylamino)methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[(4-azidobenzoyl)amino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[[2-(7-azido-4-methyl-2-oxo-chromen-3-yl)acetyl]amino]methyl]cyclohexanecarboxylate; 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[5-(5-methyl-2-oxo-imidazolidin-4-yl)pentanoylamino]methyl]cyclohexanecarboxylate; and 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[[5-[(4S)-2,5,5-trioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]methyl]cyclohexanecarboxylate; or a salt of any of the foregoing.

9. The compound 1-(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxyethyl 4-[(3-methylbut-2-enoylamino)methyl]cyclohexanecarboxylate.