ALPHA-V BETA-6 (avb6) INTEGRIN LIGANDS FOR EXTRAHEPATIC DELIVERY

1 . A compound comprising an av 6 integrin targeting ligand, wherein the compound is of Formula (X):

or a salt thereof, wherein:

Y is O, N(H), S, or CH 2 ;

R 1 is hydrogen or C 1-6 alkyl;

R Y is

 wherein

m is 0, 1, 2, 3, or 4; and

each R 2 is independently R, or two R 2 groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4-8 membered ring that is optionally substituted by 1, 2, 3 or 4 groups independently selected from the group consisting of R and a nitrogen protecting group;

and

R L is —N(R 3 )(R 4 ), —O(R 5 ), —S(R 5 ), or —R 5 , wherein

(i) R 3 is hydrogen or C 1-6 alkyl and R 4 is R 5 ; or

(ii) R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 4-8 membered monocyclic heterocyclyl group that is substituted with R 5 ;

and

R 5 is -L-ZZ-L′-R T wherein

L and L′ are independently -L 1 -[G-L 2 ] q -G-L 3 -, wherein

* is the bond to ZZ;

q is 0_or an integer selected from 1-25;

L 1 is a bond or -B-A-;

each L 2 is independently -A-B-A-;

L 3 is a bond or -A-B-A-;

each G is independently -D-E-F-, wherein D, E, and F are each independently a bond, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups;

each A is independently a bond, —O—, —S—, or —N(R N )—;

each B is independently a bond, CH 2 , C(O), C(S), C(NR N ), S(O) S(O) 2 , P(O)(OH), P(S)(OH), or P(S)(SH);

each R N is independently hydrogen or C 1-6 alkyl, or two R N within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl;

and

ZZ is -A′-B′-A′- or a linking group formed by a reactive pair, wherein

each A′ is independently a bond, —O—, —S—, or —N(R N3 )—;

each B′ is independently a bond, CH 2 , C(O), C(S), C(NR N3 ), —C═N—, S(O), S(O) 2 , P(O)(OH), P(S)(OH), or P(S)(SH); and

each R N3 is independently hydrogen or C 1-6 alkyl, or two R N3 within the -A′-B′-A′- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl;

R T is -G 0 -OR T1 , wherein

G 0 is absent or -D 0 -E U -F 0 -, wherein Do, E 0 , and F 0 are independently a bond, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R substituents;

and

R T1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, -L K -S S , or -L L -oligonucleotide, wherein

L K is a support linking group;

L L is an oligonucleotide linking group; and

S S is a solid support, —OR SS or —N(R SS ) 2 , or hydrogen, wherein

each R SS is independently hydrogen or C 1-6 alkyl.

and

each R is independently selected from the group consisting of R′, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkylC 1-6 alkyl, heterocyclylC 1-6 alkyl, aryl C 1-6 alkyl, heteroarylC 1-6 alkyl, each of which, other than R′, is optionally substituted with 1, 2, or 3 R′ groups, wherein

each R′ is independently halogen, cyano, azido, nitro, —N(R b ) 2 , —O(R a ), —S(R 0 ), —C(O)OR 0 ,

C(O)R 0 , —C(O)N(R 0 ) 2 , —C(NR 0 )OR 0 , —C(NR 0 )R 0 , —C(NR 0 )N(R 0 ) 2 , —C(S)OR 0 , —C(S)R 0 , —C(S)N(R 0 ) 2 , —S(O) 2 R 0 , —S(O) 2 OR 0 , —S(O) 2 N(R 0 ) 2 , —N(R 0 )C(O)OR 0 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)N(R 0 ) 2 , —N(R 0 )S(O) 2 R 0 , —N(R 0 )S(O) 2 OR 0 , —N(R 0 )S(O) 2 N(R 0 ) 2 , —OC(O)OR 0 , —OC(O)R 0 , —OC(O)N(R 0 ) 2 , —OS(O) 2 R 0 , —OS(O) 2 OR 0 , —OS(O) 2 N(R 0 ) 2 , or —SC(O)R 0 , wherein

each R 0 is independently hydrogen or C 1-6 alkyl; each R a is independently hydrogen, C 1-6 alkyl, or a hydroxyl protecting group; and each R b is independently hydrogen, C 1-6 alkyl, or a nitrogen protecting group,

provided that in each -D-E-F- group at least one of D, E, and F is not a bond; and R L is not N-morpholinyl.

2 . The compound of claim 1 , wherein R Y is;

wherein p is 0, 1, 2, 3 or 4; and each R 21 is independently selected from the group consisting of an R and a nitrogen protecting group;

wherein R P is a nitrogen protecting group; or

wherein R P is a nitrogen protecting group.

3 - 5 . (canceled)

6 . The compound of claim 1 , wherein -L′-R T is:

wherein * is the bond to ZZ; and L 1 is a bond, C(O), C(S), S(O) 2 , P(O)(OH), or P(S)(OH), or

wherein* is the bond to ZZ;

L 1 is a bond, C(O), C(S), S(O) 2 , P(O)(OH), or P(S)(OH); and

R is —O(R a ) or —C 1-6 alkyl-O(R a ), wherein R a is hydrogen or a hydroxyl protecting group.

7 . (canceled)

8 . The compound of claim 1 , wherein —R L is:

wherein R P3 is hydrogen or a hydroxyl protecting group; or

9 . (canceled)

10 . The compound of claim 8 , wherein R P3 is an optionally substituted trityl group.

11 . The compound of claim 1 , wherein -L′- is:

(i) -L 1 -G-L 3 -*, wherein * is the bond to ZZ; or

(ii) —C(O)—C 2-30 alkyl-*.

12 . (canceled)

13 . The compound of claim 1 represented by the following formula:

14 . The compound of claim 1 , wherein L is:

(i) -L 1 -[G-L 2 ] q -G-L 3 -*, wherein q is 0, 1, 2, 3, 4, or 5;

(ii) -L 1 -G-*, wherein * is the bond to ZZ;

G is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups;

L 1 is -B-A-, wherein,

A is a bond, —O—, —S—, or —N(R N )—, wherein each R N is independently hydrogen or C 1-6 alkyl; and

B is a bond, C(O), C(S), S(O) 2 , P(O)(OH), or P(S)(OH);

wherein * is the bond to ZZ; k is an integer from 1 to 10; L 1 is bond, C(O), C(S), C(NR N ), S(O) 2 , P(O)(OH), or P(S)(OH); and R N is hydrogen or C 1-6 alkyl;

(iv) a group selected from:

wherein * is the bond to ZZ; t is an integer from 0 to 10;

wherein * is the bond to ZZ, t is an integer from 0 to 10; a is an integer from 1 to 3 and s and s′ are each independently an integer from 1 to 24;

wherein * is the bond to ZZ; a is 1, 2 or 3; and each s, s′, and s″ independently is an integer from 1 to 24;

wherein * is the bond to ZZ; and s, s′, and s″ are independently is an integer from 1 to 24;

wherein * is the bond to ZZ and each s, s′, and s″ independently is an integer from 1 to 24; and

wherein * is the bond to ZZ; s and k are independently is an integer from 1 to 20; and w is an integer from 1 to 10;

wherein * is the bond to ZZ and w is an integer from 1 to 20; or

wherein * is the bond to ZZ; k is an integer from 1 to 10.

15 - 19 . (canceled)

20 . The compound of claim 1 , wherein ZZ:

(i) comprises a group selected from the group consisting of:

(ii) is -A′-B′-A′-, wherein

each A′ is independently a bond, —O—, —S—, or —N(R N3 )—, wherein R N3 is independently hydrogen or C 1-6 alkyl and

each B′ is independently CH 2 , C(O), C(S), S(O) 2 , P(O)(OH), or P(S)(OH);

(iii) is -A′-B′- or -B′-A′- wherein

each A′ is independently —O— or —N(R N3 )—, wherein R N3 is independently hydrogen or C 1-6 alkyl.

each B′ is independently CH 2 , C(O), S(O) 2 , P(O)(OH), or P(S)(OH); and

each R N3 is independently hydrogen or C 1-6 alkyl;

(iv) is —CH 2 O—, —OCH 2 —, —S—S—, —C═N—, —C═N—O—, —C═N—N(R N3 )—, —N═C—, —O—N═C—, —N(R N3 )—N═C—, —C(O)N(R N3 )—, —N(R N3 )C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R N3 )—, —N(R N3 )C(O)O—, —N(R N3 )C(O)N(R N3 )—, —S(O) 2 N(R N3 )—, —N(R N3 )S(O) 2 —, —OP(O)(OH)O—, —OP(S)(OH)O—, —OP(O)(OH)—, —OP(S)(OH)—, —P(O)(OH)O—, or —P(S)(OH)O—. wherein R N3 is independently hydrogen or C 1-6 alkyl;

(iv) is —C(O)N(R N3 )— or —N(R N3 )C(O)—, wherein R N3 is independently hydrogen or C 1-6 alkyl; or

(v) is —OP(O)(OH)O—, —OP(S)(OH)O—, —OP(O)(OH)—, —OP(S)(OH)—, —P(O)(OH)O—, or —P(S)(OH)O—.

21 - 25 . (canceled)

26 . The compound of claim 1 , wherein R T1 is -L L -oligonucleotide, wherein L L is a divalent linker that connects to the 3′-end of the oligonucleotide, the 5′-end of the oligonucleotide, or an internal 2′- or 3′ position on an internal nucleotide.

27 . The compound of claim 26 , wherein L L connects to an oxygen atom on a nucleoside, and is P(O)(OH)—, —P(S)(OH)—, or —P(S)(SH).

28 . The compound of claim 27 , wherein L L is P(O)(OH)— or P(S)(OH)—.

29 . (canceled)

30 . The compound of claim 1 , wherein R T is R T1 , wherein R T1 is -L L -oligonucleotide, wherein L L connects to an oxygen atom on a nucleoside of the oligonucleotide, LL is a bond, and the nucleoside is of Formula (X-f),

wherein B is an optionally modified nucleobase and * represents the bond to ZZ.

31 . The compound of claim 30 , wherein -L′- is —C 4-10 alkyl-*, wherein * is the bond to ZZ, or

wherein the nucleoside is of a formula selected from the group consisting of

wherein

B is an optionally modified nucleobase;

each n is independently 0 or an integer selected from 1-10; and

each m is independently integer selected from 1-20.

32 . (canceled)

33 . The compound of claim 1 , wherein R T1 is -L L -oligonucleotide and is conjugated at the 5′-end of the oligonucleotide.

34 . The compound of claim 33 , represented by the following formula:

wherein Y′ is O or S.

35 . The compound of claim 1 , wherein R T1 is -L L -oligonucleotide and is conjugated at the 3′-end of the oligonucleotide.

36 . The compound of claim 35 , having represented by the following formula:

(i)

wherein Y is O or Si

(ii)

wherein Y′ is O or S, R 1 is hydrogen or C 1-6 alkyl, and R P is hydrogen or a nitrogen protecting group;

(iii)

wherein Y′ is O or S, R 1 is hydrogen or C 1-6 alkyl, and R P is hydrogen or a nitrogen protecting group;

(iv)

wherein Y′ is O or S, R 1 is hydrogen or C 1-6 alkyl, and R P is hydrogen or a nitrogen protecting group;

(v)

wherein each m is independently an integer selected from 1-10; Y′ is O or S, R 1 is hydrogen or C 1-6 alkyl, and R P is hydrogen or a nitrogen protecting group;

(vi)

wherein Y′ is O or S, R 1 is hydrogen or C 1-6 alkyl, and R P is hydrogen or a nitrogen protecting group.

37 - 41 . (canceled)

42 . The compound of claim 36 , wherein in (vi), R P is hydrogen and R 1 is hydrogen; and/or wherein Y′ is O or S.

43 - 44 . (canceled)

45 . A compound comprising a αvβ6 integrin targeting ligand, wherein the compound is of Formula (XV):

or a salt thereof, wherein

x is 2, 3, 4, 5, 6, 7, or 8;

T is a divalent linking group;

Δ is a branching group;

each ZZ is independently -A′-B′-A′- or a linking group formed by a first reactive pair,

wherein

each A′ is independently a bond, —O—, —S—, or —N(R N3 )—;

each B′ is independently a bond, CH 2 , C(O), C(S), C(NR N3 ), —C═N—, S(O), S(O) 2 , P(O)(OH), P(S)(OH), or P(S)(SH); and

each R N3 is independently hydrogen or C 1-6 alkyl, or two R N3 within the -A′-B′-A′- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl;

Z 0 is a member of a second reactive pair; and

R T is -G 0 -OR T1 , wherein

G 0 is -D 0 -E U -F 0 -, wherein

D 0 , E 0 , and F 0 are independently a bond, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; and

R T1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, or -L K -S S , or -L L -oligonucleotide, wherein

 L K is a support linking group;

 S S is a solid support, —OR SS or —N(R SS ) 2 , or hydrogen, wherein

 each R SS is independently hydrogen or C 1-6 alkyl; and

L L is an oligonucleotide linking group; and each Φ is a compound of the Formula (XII),

wherein:

Y is O, N(H), S, or CH 2 ;

R 1 is hydrogen or C 1-6 alkyl;

R Y is

 wherein

m is 0, 1, 2, 3, or 4; and

each R 2 is independently R, or two R 2 groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4-8 membered ring that is optionally substituted by 1, 2, 3 or 4 groups independently selected from the group consisting of R and a nitrogen protecting group;

and

R L is —N(R 3 )(R 4 ), —O(R 5 ), —S(R 5 ), or —R 5 , wherein

(i) R 3 is hydrogen or C 1-6 alkyl and R 4 is R 5 ; or

(ii) R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 4-8 membered monocyclic heterocyclyl group that is substituted with R 5 ;

and

R 5 is -L-* wherein L is -L 1 -[G-L 2 ] q -G-L 3 -*,

* is the bond to a ZZ; and

q is 0 or an integer selected from 1-25;

L 1 is a bond or -B-A-;

each L 2 is independently -A-B-A-;

L 3 is a bond or -A-B-A-;

each G is independently -D-E-F-, wherein

D, E, and F are independently a bond, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups;

each A is independently a bond, —O—, —S—, or —N(R N )—;

each B is independently a bond, CH 2 , C(O), C(S), C(NR N ), S(O), S(O) 2 , P(O)(OH), P(S)(OH), or P(S)(SH);

each R N is independently hydrogen or C 1-6 alkyl, or two R N within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

46 - 109 . (canceled)

110 . A dsRNA agent for inhibiting the expression of a target gene, comprising the compound comprising an αvβ6 integrin targeting ligand of claim 1 .

111 . The dsRNA agent of claim 110 , wherein the αvβ6 integrin targeting ligand is conjugated to the sense strand.

112 . The dsRNA agent of claim 111 , wherein the αvβ6 integrin targeting ligand;

(i) is conjugated to the 3′-end of the sense strand;

(ii) is conjugated to the 5′-end of the sense strand;

(iii) is conjugated to both the 5′-end and the 3′-end of the sense strand; or

(iv) is conjugated to the an internal position of the sense strand.

113 - 115 . (canceled)

116 . The dsRNA agent of claim 110 , wherein the αvβ6 integrin targeting ligand is conjugated to the antisense strand.

117 . The dsRNA agent of claim 116 , wherein the αvβ6 integrin targeting ligand;

(i) is conjugated to the 3′ end antisense strand; or

(ii) is conjugated to an internal position of antisense strand.

118 . (canceled)

119 . The dsRNA agent of claim 110 , wherein the target gene is selected from the group consisting of adrenoceptor beta 1 (ADRB1); calcium voltage-gated channel subunit alpha1 C (CACNA1C); calcium voltage-gated channel subunit alpha1 G (CACNA1G) (T type calcium cchannel); angiotensin II receptor type 1 (AGTR1); Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 1 (HCN1); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 3 (HCN3); Potassium Voltage-Gated Channel Subfamily A Member 5 (KCNA5); Potassium Inwardly Rectifying Channel Subfamily J Member 3 (KCNJ3); Potassium Inwardly Rectifying Channel Subfamily J Member 4 (KCNJ4); phospholamban (PLN); calcium/calmodulin dependent protein kinase II delta (CAMK2D); and Phosphodiesterase 1 (PDE1); myostatin (MSTN); Cholinergic Receptor Nicotinic Alpha 1 Subunit (CHRNA1); Cholinergic Receptor Nicotinic Beta 1 Subunit (CHRNB1); Cholinergic Receptor Nicotinic Delta Subunit (CHRND); Cholinergic Receptor Nicotinic Epsilon Subunit (CHRNE); Cholinergic Receptor Nicotinic Gamma Subunit (CHRNG); Collagen Type XIII Alpha 1 Chain (COL13A1); Docking Protein 7 (DOK7); LDL Receptor Related Protein 4 (LRP4); Muscle Associated Receptor Tyrosine Kinase (MUSK); Receptor Associated Protein Of The Synapse (RAPSN); Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A); Double Homeobox 4 (DUX4); dystrophy myotonic protein kinase (DMPK); glycogen synthase 1 (GYS1); survival of motor neuron 1 (SMN1), and alpha-glucosidase (GAA).

120 . A cell containing the dsRNA agent of claim 110 .

121 . A pharmaceutical composition for inhibiting expression of the target gene, comprising the dsRNA agent of claim 110 .

122 . A method of inhibiting expression of a target gene in a skeletal muscle cell and/or a cardiac muscle cell, comprising contacting the cell with the dsRNA agent of claim 110 , thereby inhibiting expression of the target gene in the skeletal muscle cell and/or the cardiac muscle cell.

123 . The method of claim 122 , wherein the cell is within a subject.

124 . The method of claim 123 , wherein the subject is a human.

125 . A method of treating a subject having a skeletal muscle disorder and/or a cardiac muscle disorder, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 110 , thereby treating the subject.

126 . The method of claim 125 , wherein the skeletal muscle disorder and/or cardiac muscle disorder is selected from the group consisting of myostatin-related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, spasticity, obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmia, and congestive heart failure (CHF).

127 . A method of inhibiting expression of a target gene in a lung cell, comprising contacting the cell with the dsRNA agent of claim 110 , thereby inhibiting expression of the target gene in the lung cell.

128 . The method of claim 127 , wherein the cell is within a subject.

129 . The method of claim 128 , wherein the subject is a human.

130 . A method of treating a subject having a lung disorder, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 110 , thereby treating the subject.

131 . The method of claim 130 , wherein the lung disorder is selected from the group consisting of idiopathic pulmonary fibrosis, asthma, asthma and chronic rhinosinusitis, nasal polyps and chronic rhinosinusitis.

132 . The method of claim 122 , wherein the dsRNA agent is administered to the subject subcutaneously, intramuscularly, intravenously or via inhalation.

133 - 135 . (canceled)

136 . An RNA-induced silencing complex (RISC) comprising an antisense strand of any of the dsRNA agents of claim 110 .