Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR

1. A compound of Formula (A)

wherein

R 1 is —Z—X—Y wherein X is a linker of any of structures L1-L10

each Q is independently absent or is C(O), C(O)—NR 4 , NR 4 —C(O), O—C(O)—NR 4 , NR 4 —C(O)—O, —CH 2 —, a heteroaryl, or a heteroatom group selected from O, S, S—S, S(O), S(O) 2 , and NR 4 , wherein at least two carbon atoms separate the heteroatom groups O, S, S—S, S(O), S(O) 2 and NR 4 from any other heteroatom group;

each T is independently absent or is alkylene, alkenylene, or alkynylene, wherein one or more —CH 2 — groups of the alkylene, alkenylene, or alkynylene may each independently be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— wherein the heteroatom groups are separated by at least 2 carbon atoms;

Y is a Cas9 ribonucleoprotein, cas9 protein, or plasmid, and

Z is absent or is —C≡C—, —CH═CH—, —CH 2 —, —CH 2 —O—, —C(O)—N(R 4 )—, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —S(O) 2 —N(R 4 )—, —C(O)—O—, —CH 2 —N(R 4 )—, —CH 2- N(R 4 )—C(O)—, —CH 2 —N(R 4 )—S(O) 2 —, —CH 2 —N(R 4 )—C(O)—O—, —CH 2 —N(R 4 )—C(O)—N(R 4 )—, —CH 2 —O—C(O)—, —CH 2 —O—C(O)—N(R 4 )—, —CH 2 —O—C(O)—O—, or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with R 5 ;

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein if n is greater than 1, each T and each Q of each (T-Q-T-Q) is independently selected;

R 2 is —OH, —N 3 , —N(R 3 ) 2 , —N(R 3 )—C(O)—R 3 , —N(R 3 )—C(O)—N(R 3 ) 2 , —N(R 3 )—C(O)—OR 3 , tetrazole, or triazole, wherein the tetrazole and triazole are optionally substituted with R 3 ;

each R 3 is independently —H, —(C 1 -C 5 )alkyl, halo-substituted (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein a —CH 2 — group of the alkyl or cycloalkyl may be replaced with a heteroatom group selected from —O—, —S—, and —N(R 4 )— and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and

each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 )2, —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms;

each R 5 is independently —H, (C 3 -C 20 )cycloalkyl or (C 1 -C 20 )alkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with one to six halo atoms;

or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (A)

wherein

R 1 is Z—X—Y, —Z—Y, —X—Y, —X, —Y, or —Z—X wherein X is a linker of any of structures L1-L10

each Q is independently absent or is C(O), C(O)—NR 4 , NR 4 —C(O), O—C(O)—NR 4 , NR 4 —C(O)—O, —CH 2 —, a heteroaryl, or a heteroatom group selected from O, S, S—S, S(O), S(O) 2 , and NR 4 , wherein at least two carbon atoms separate the heteroatom groups O, S, S—S, S(O), S(O) 2 and NR 4 from any other heteroatom group;

wherein each T is independently absent or is alkylene, alkenylene, or alkynylene, wherein one or more —CH 2 — groups of the alkylene, alkenylene, or alkynylene may each independently be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— wherein the heteroatom groups are separated by at least 2 carbon atoms;

Y is [R 6 ,] a Cas9 ribonucleoprotein, cas9 protein, or plasmid;

Z is —C≡C—, —CH═CH—, —CH 2 —, —CH 2 —O—, —C(O)—N(R 4 )—, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —S(O) 2 —N(R 4 )—, —C(O)—O—, —CH 2 —N(R 4 )—, —CH 2- N(R 4 )—C(O)—, —CH 2 —N(R 4 )—S(O) 2 —, —CH 2 —N(R 4 )—C(O)—O—, —CH 2 —N(R 4 )—C(O)—N(R 4 )—, —CH 2 —O—C(O)—, —CH 2 —O—C(O)—N(R 4 )—, —CH 2 —O—C(O)—O—, or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with R 5 ;

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein if n is greater than 1, each T and each Q of each (T-Q-T-Q) is independently selected;

R 2 is —OH, —N 3 , —N(R 3 ) 2 , —N(R 3 )—C(O)—R 3 , —N(R 3 )—C(O)—N(R 3 ) 2 , —N(R 3 )—C(O)—OR 3 , —N(R 3 )—S(O) 2 —R 3 , tetrazole, or triazole, wherein the tetrazole and triazole are optionally substituted with R 3

each R 3 is independently —H, —(C 1 -C 5 )alkyl, halo-substituted (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein one or more —CH 2 — groups of the alkyl or cycloalkyl may each be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms;

each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 )2, —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms;

each R 5 is independently —H, (C 3 -C 20 )cycloalkyl or (C 1 -C 60 )alkyl wherein one to six —CH 2 — groups of the cycloalkyl or one to 20 —CH 2 — groups of the alkyl may each be replaced with heteroatoms independently selected from —O—, —S—, and —N(R 4 )— wherein the heteroatoms are separated by at least two carbon atoms, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is —X—Y and R 2 is —NH—C(O)—CH 3 .

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is capable of binding to a receptor present on a hepatocyte.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the receptor present on a hepatocyte is an asialoglycoprotein receptor.

6. A pharmaceutical composition comprising (i) a compound of claim 5 ; or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient, diluent, or carrier.

7. The composition of claim 6 wherein said compound or said therapeutically acceptable salt thereof is present in a therapeutically effective amount.