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CN-122003427-A - Targeted delivery ligands

CN122003427ACN 122003427 ACN122003427 ACN 122003427ACN-122003427-A

Abstract

The present invention provides a targeted delivery ligand, wherein the targeted delivery ligand comprises a conjugate group represented by formula (X), or an isotopic variant, tautomer, stereoisomer, or mixture thereof, and a nucleic acid molecule comprising the targeted delivery ligand.

Inventors

  • CHEN BO
  • XU JIANYAN
  • MIAO YU
  • ZHAN QINGMING
  • TENG GANG
  • ZHANG HAIFAN
  • WANG LEI

Assignees

  • 成都新泽利医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241018
Priority Date
20231020

Claims (20)

  1. A delivery ligand, wherein the delivery ligand comprises a conjugate group of formula (X), or an isotopic variant, tautomer, stereoisomer, or mixture thereof: Wherein, the The R is through Is connected with biological molecules; Each W is independently selected from H, D, W 0 is selected from the group consisting of bond 、-OCH 2 -、-OCH 2 CH 2 -、-OCH 2 OCH 2 -、-OCH 2 CH 2 CH 2 -、-OCH 2 CH 2 CH 2 CH 2 -、-CH 2 OCH 2 CH 2 CH 2 -、-CH 2 CH 2 OCH 2 CH 2 -、-CH 2 CH 2 CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 CH 2 O-、C 1-6 alkylene, C 1-6 haloalkylene, C 1-6 alkenylene, or C 1-6 alkynylene, optionally deuterated, up to complete deuteration; W 1 is selected from the group consisting of a bond, -O-L 1 -、-C(O)-、-C(O)-L 1 -, -C (O) O-, or-C (O) O-L 1 -, which is optionally deuterated until fully deuterated; L 1 is- (CR a R b ) m -, 1,2, 3,4 or 5 of CR a R b in said L 1 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR a -; Each R a and R b is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R a 、R b on any one or more of the carbon atoms in L 1 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; W 2 is selected from-L 2 -NH-、-L 2 -O-、-L 2 -C (O) -or-L 2 -OC (O) -, which is optionally deuterated until fully deuterated; L 2 is- (CR c R d ) n -, 1,2, 3,4 or 5 of CR c R d in said L 2 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR c -; each R c and R d is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R c 、R d on any one or more of the carbon atoms in L 2 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; w 3 is selected from-L 3 -C(O)NH-、-L 3 -NHC(O)-、-L 3 -OC (O) NH-or-L 3 -NHC (O) O-, which is optionally deuterated until fully deuterated; l 3 is- (CR e R f ) h -, 1,2, 3,4 or 5 of CR e R f in said L 3 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR e -; each R e and R f is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R e 、R f on any one or more of the carbon atoms in L 3 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; W 4 is selected from -L 4 -NHC(O)-、-L 4 -NHC(O)-(CH 2 ) 1-6 -、-L 4 -NHC(O)O-、-L 4 -NHC(O)O-(CH 2 ) 1-6 -、-L 4 -C(O)NH-、-L 4 -C(O)NH-(CH 2 ) 1-6 -、-L 4 -OC(O)NH- or-L 4 -OC(O)NH-(CH 2 ) 1-6 -, which is optionally deuterated until fully deuterated; L 4 is selected from -(CR g R h ) k -、-(CR g R h ) 1-6 -(OCR g R h -CR g R h ) k - or- (CR g R h ) 1-6 -(NH-CR g R h -CR g R h ) k -, 1,2,3, 4 or 5 of CR g R h not adjacent in said L 4 may be replaced by a heteroatom selected from-O-, -S-and-NR g -; Each R g and R h is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R g 、R h on any one or more of the carbon atoms in L 4 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; m, n, h and k are independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9 or 10; L 5 is selected from the group consisting of a bond, C 1-6 alkylene, C 1-6 alkenylene, or-C 1-6 alkylene-O-C 1-6 alkylene-, which is optionally deuterated until fully deuterated; a is selected from a bond, -C (O) -or-NHC (O) -; T is- (CR i R j ) q -, where 1,2,3,4 or 5 of said non-adjacent CR i R j ' S may be replaced by a heteroatom selected from the group consisting of-O-, -S-and-NR i -, T is optionally deuterated until fully deuterated; each R i and R j is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R i 、R j on any one or more of the carbon atoms in T together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl; q is selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; B is selected from -C(O)-(CR k R m ) 0-6 -、-NH-(CR k R m ) 0-6 -、-OC(O)-(CR k R m ) 0-6 -、-NHC(O)-(CR k R m ) 0-6 - or-C (O) NH- (CR k R m ) 0-6 -, 1,2 or 3 CR k R m not adjacent in said B may be replaced by heteroatoms selected from-O-, -S-and-NR k -, said B optionally being deuterated until fully deuterated; Each R k and R m is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R k 、R m on any one or more of carbon atoms in B together with the same or different carbon atom to which they are attached form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl; p is selected from a bond or 1 to 3 amino acid residues; R is selected from Ring S is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; R 1 is selected from hydroxyl-containing groups such as-OR 0 、-C 1-6 alkylene-OR 0 、-C 1-6 alkenylene-OR 0 OR-C 1-6 alkynylene-OR 0 , wherein R 0 is H, D, a hydroxyl protecting group, OR a solid support; The hydroxyl protecting group is selected from Trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), methoxymethyl (MOM), phenoxymethyl (BOM), 2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzyloxymethyl (PMO), -C (O) 86C (Fmoc), DMT 4 '-Dimethoxy (DMT) or (DMT) 4' -dimethoxy (O) 4, DMT '-DMT (O) or (DMT) 4' -dimethoxy (O) 4, 3R; R 2 and R 3 are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R 2 、R 3 together with the same carbon atom to which they are attached form C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the ring formed by R 2 、R 3 and both optionally being deuterated until fully deuterated; R 4 is selected from H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, R 4 is optionally deuterated until fully deuterated; Z is O, NH or CH 2 ; r and R # are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; x, y are independently selected from 0, 1, 2, 3, 4 or 5; Each of the above W, A, T, B, P and R is optionally further substituted with 1,2, 3,4,5, 6,7, 8 or more substituents selected from H, D, OH, CN, NH 2 、NO 2 , oxo, thioxo, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; provided that when R is When at least one of R a and R b 、R c and R d 、R e and R f 、R g and R h 、R i and R j 、R k and R m forms a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group with the same or different carbon atoms to which they are attached.
  2. The delivery ligand of claim 1, wherein at least one group of R a and R b 、R c and R d 、R e and R f 、R g and R h 、R i and R j 、R k and R m , together with the same or different carbon atoms to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  3. The delivery ligand of claim 1 or 2, wherein R a 、R b on any one or more carbon atoms in L 1 , together with the same carbon atom to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  4. A delivery ligand according to any one of claims 1 to 3 wherein R c 、R d on any one or more carbon atoms in L 2 together with the same carbon atom to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or 3-7 membered heterocyclyl.
  5. The delivery ligand of any one of claims 1-4, wherein R e 、R f on any one or more carbon atoms in L 3 , taken together with the same carbon atom to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  6. The delivery ligand of any one of claims 1-5, wherein R g 、R h on any one or more carbon atoms in L 4 , together with the same carbon atom to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  7. The delivery ligand of any one of claims 1-6, wherein R i 、R j on any one or more carbon atoms in T, taken together with the same carbon atom to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  8. The delivery ligand of any one of claims 1-7, wherein R k 、R m on any one or more carbon atoms in B, together with the same carbon atom to which they are attached, form a C 3-10 cycloalkyl, a 3-10 membered heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl, preferably a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl.
  9. The delivery ligand of any one of claims 1-8, wherein R is selected from the group consisting of Wherein ring S, R 1 、R 2 、R 3 、R 4 , Z, R, r#, x and y are as defined in any one of claims 1 to 8; Preferably, R is selected from Wherein ring S, R 1 、R 2 、R 3 、R 4 , Z, R, r#, x and y are as defined in any one of claims 1 to 8; more preferably, R is selected from More preferably, R is selected from * Represents a chiral center, independently selected from the (S) or (R) configurations, or mixtures thereof.
  10. The delivery ligand of any one of claim 1 to 9, wherein, W 0 is selected from-OCH 2 -、-OCH 2 CH 2 -、-OCH 2 CH 2 CH 2 -or-OCH 2 CH 2 CH 2 CH 2 -; W 1 is selected from the group consisting of a bond, -O-L 1 -、-C(O)-L 1 -, or-C (O) -; W 2 is selected from-L 2 -NH-or-L 2 -O-; W 3 is selected from-L 3 -C (O) NH-or-L 3 -NHC (O) -; W 4 is selected from-L 4 -NHC(O)-、-L 4 -NHC(O)-(CH 2 ) 1-6 -、-L 4 -C (O) NH-or-L 4 -C(O)NH-(CH 2 ) 1-6 -; Preferably, the method comprises the steps of, W 0 is-OCH 2 -; W 1 is selected from the group consisting of a bond, -C (O) -L 1 -, or-C (O) -; W 2 is selected from-L 2 -NH-; W 3 is-L 3 -C (O) NH-; W 4 is selected from-L 4 -NHC (O) -or-L 4 -NHC(O)-(CH 2 ) 1-6 -.
  11. The delivery ligand of any one of claim 1 to 10, wherein, The R is through Is connected with biological molecules; Each W is independently selected from H, D, L 1 is- (CR a R b ) m -; Each R a and R b is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R a 、R b on any one or more carbon atoms in L 1 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 2 is- (CR c R d ) n -; Each R c and R d is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R c 、R d on any one or more carbon atoms in L 2 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 3 is- (CR e R f ) h -; Each R e and R f is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R e 、R f on any one or more carbon atoms in L 3 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 4 is- (CR g R h ) 1-6 -(OCR g R h -CR g R h ) k -; Each R g and R h is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R g 、R h on any one or more carbon atoms in L 4 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; m, n, h and k are independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; L 5 is selected from the group consisting of a bond, C 1-6 alkylene, C 1-6 alkenylene, or-C 1-6 alkylene-O-C 1-6 alkylene-; a is selected from-C (O) -or-NHC (O) -; T is- (CR i R j ) q -; Each R i and R j is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R i 、R j on any one or more carbon atoms of T together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; q is selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; B is -C(O)-(CR k R m ) 0-6 -、-NH-(CR k R m ) 0-6 -、-OC(O)-(CR k R m ) 0-6 -、-NHC(O)-(CR k R m ) 0-6 - or-C (O) NH- (CR k R m ) 0-6 -; Each R k and R m is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R k 、R m on any one or more carbon atoms of B together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; p is selected from a bond or 1 to 3 amino acid residues; R is selected from Ring S is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; R 1 is selected from-OR 0 、-CH 2 OR 0 OR-CH 2 CH 2 OR 0 , wherein R 0 is H, D, a hydroxyl protecting group OR a solid support; The hydroxyl protecting group is selected from Trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), methoxymethyl (MOM), phenoxymethyl (BOM), 2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzyloxymethyl (PMO), -C (O) 86C (Fmoc), DMT 4 '-Dimethoxy (DMT) or (DMT) 4' -dimethoxy (O) 4, DMT '-DMT (O) or (DMT) 4' -dimethoxy (O) 4, 3R; R 2 and R 3 are independently selected from H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R 2 、R 3 together with the carbon atom to which they are attached form C 3-7 cycloalkyl or 3-7 membered heterocyclyl; R 4 is selected from H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; Z is O, NH or CH 2 ; R and R # are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; x, y are independently selected from 0, 1, 2, 3, 4 or 5; provided that when R is When at least one group of R a and R b 、R c and R d 、R e and R f 、R g and R h 、R i and R j 、R k and R m forms a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group.
  12. The delivery ligand of any one of claim 1 to 11, wherein, the conjugate group is selected from the group consisting of formula (I), formula (I-1), formula (I-2), formula (I '-1), formula (I' -2), formula (II-1), formula (II-2), formula (II '-1), formula (II' -2), formula (III-1), formula (III-2), formula (III-3), formula (III-4), formula (III-5), formula (III-6) formula (III '), formula (III' -1), formula (III '-2), formula (III' -3), formula (III '-4), formula (III' -5), formula (III '-6), formula (IV-1), formula (IV-2), formula (IV' -1), formula (IV '-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4), formula (V' -1), A structure represented by formula (V ' -2), formula (V ' -3) or formula (V ' -4), or an isotopic variant, tautomer, stereoisomer, or mixture thereof: wherein, represents a chiral center, independently selected from (S) or (R) configurations, or mixtures thereof; each variable being as defined in any one of claims 1 to 11.
  13. The delivery ligand of any one of claims 1-12, wherein said conjugate group is selected from the group consisting of a structure as shown in formula (I-1), formula (I ' -1), formula (II ' -1), formula (III-2), formula (III-5), formula (III-6), formula (III ' -2), formula (III ' -5), formula (III ' -6), formula (IV-1), formula (IV-2), formula (IV ' -1), formula (IV ' -2), formula (V-1), formula (V-4), formula (V ' -1), or formula (V ' -4), or isotopic variants, tautomers, stereoisomers, or mixtures thereof: Wherein, the * Represents a chiral center independently selected from the (S) or (R) configurations, or mixtures thereof; Each W is independently selected from H, L 1 is- (CR a R b ) m -, 1,2, 3,4 or 5 of CR a R b in said L 1 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR a -; each R a and R b is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R a 、R b on any one or more of the carbon atoms in L 1 together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 3-10 membered heterocyclyl; L 2 is- (CR c R d ) n -, 1,2, 3,4 or 5 of CR c R d in said L 2 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR c -; each R c and R d is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R c 、R d on any one or more of the carbon atoms in L 2 together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 3-10 membered heterocyclyl; l 3 is- (CR e R f ) h -, 1,2, 3,4 or 5 of CR e R f in said L 3 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR e -; each R e and R f is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R e 、R f on any one or more of the carbon atoms in L 3 together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 3-10 membered heterocyclyl; L 4 is selected from -(CR g R h ) k -、-(CR g R h ) 1-6 -(OCR g R h -CR g R h ) k - or- (CR g R h ) 1-6 -(NH-CR g R h -CR g R h ) k -, 1,2,3, 4 or 5 of CR g R h not adjacent in said L 4 may be replaced by a heteroatom selected from-O-, -S-and-NR g -; Each R g and R h is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R g 、R h on any one or more of the carbon atoms in L 4 together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 3-10 membered heterocyclyl; m, n, h and k are independently selected from 1,2, 3, 4, 5, 6, 7, 8, 9 or 10; L 5 is selected from the group consisting of a bond, C 1-6 alkylene, C 1-6 alkenylene, or-C 1-6 alkylene-O-C 1-6 alkylene-; a is selected from-C (O) -or-NHC (O) -; T is- (CR i R j ) q -, where 1,2, 3,4 or 5 CR i R j that are not adjacent in the T may be replaced by a heteroatom selected from the group consisting of-O-, -S-, and-NR i -; each R i and R j is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R i 、R j on any one or more of the carbon atoms in T together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 3-10 membered heterocyclyl; q is selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; B is selected from -C(O)-(CR k R m ) 0-6 -、-NH-(CR k R m ) 0-6 -、-OC(O)-(CR k R m ) 0-6 -、-NHC(O)-(CR k R m ) 0-6 - or-C (O) NH- (CR k R m ) 0-6 -, 1,2, 3,4 or 5 CR k R m not adjacent in said B may be replaced by a heteroatom selected from-O-, -S-and-NR i -; Each R k and R m is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl or C 1-6 alkynyl, or R k 、R m on CR k R m together with the carbon atom to which they are attached form a C 3-10 cycloalkyl or a 3-to 10-membered heterocyclyl; p is selected from a bond or 1 to 3 amino acid residues; L 1 -L 5 , T and B are optionally deuterated until fully deuterated; Provided that when the conjugate group is of formula (I), at least one group of R a and R b 、R c and R d 、R e and R f 、R g and R h 、R i and R j 、R k and R m forms a C 3-10 cycloalkyl or 3-10 membered heterocyclyl group with the carbon atom to which they are attached.
  14. The delivery ligand of claim 13, wherein, L 1 is- (CR a R b ) m -; Each R a and R b is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R a 、R b on any one or more carbon atoms in L 1 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 2 is- (CR c R d ) n -; Each R c and R d is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R c 、R d on any one or more carbon atoms in L 2 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 3 is- (CR e R f ) h -; Each R e and R f is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R e 、R f on any one or more carbon atoms in L 3 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; L 4 is- (CR g R h ) 1-6 -(OCR g R h -CR g R h ) k -; Each R g and R h is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R g 、R h on any one or more carbon atoms in L 4 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; m, n, h and k are independently selected from 1,2,3,4 or 5; L 5 is selected from a bond, C 1-6 alkylene, or-C 1-4 alkylene-O-C 1-4 alkylene-; a is selected from-C (O) -or-NHC (O) -; T is- (CR i R j ) q -; Each R i and R j is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R i 、R j on any one or more carbon atoms of T together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; q is selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; B is -C(O)-(CR k R m ) 0-6 -、-NH-(CR k R m ) 0-6 -、-OC(O)-(CR k R m ) 0-6 -、-NHC(O)-(CR k R m ) 0-6 - or-C (O) NH- (CR k R m ) 0-6 -; Each R k and R m is independently H, D, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, or R k 、R m on any one or more carbon atoms of B together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; P is selected from a bond or 1 amino acid residue.
  15. The delivery ligand of claim 13 or 14, wherein, L 1 is- (CR a R b ) m -; each R a and R b is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R a 、R b on any one or more of the carbon atoms in L 1 together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; m is selected from 1, 2, 3 or 4; L 2 is- (CR c R d ) n -; Each R c and R d is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R c 、R d on any one or more of the carbon atoms in L 2 together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; n is selected from 1, 2, 3 or 4; L 3 is- (CR e R f ) h -; Each R e and R f is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R e 、R f on any one or more of the carbon atoms in L 3 together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; h is selected from 2, 3, 4 or 5; L 4 is- (CR g R h ) 1-6 -(OCR g R h -CR g R h ) k -; Each R g and R h is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R g 、R h on any one or more of the carbon atoms in L 4 together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; k is selected from 1, 2, 3 or 4; L 5 is selected from a bond, C 1-6 alkylene, or-C 1-4 alkylene-O-C 1-4 alkylene-; a is selected from-C (O) -or-NHC (O) -; T is- (CR i R j ) q -; Each R i and R j is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R i 、R j on any one or more of the carbon atoms in T together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; q is selected from 5, 6, 7, 8, 9, 10, 11 or 12; B is selected from-C (O) -, -OC (O) -, -NH-, -NHC (O) -, -C (O) - (CR k R m ) 0-4 -, or-C (O) NH- (CR k R m ) 0-4 -; each R k and R m is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl, or R k 、R m on any one or more of the carbon atoms of B together with the carbon atoms to which they are attached form C 3-7 cycloalkyl; P is selected from a bond or 1 amino acid residue.
  16. The delivery ligand of any one of claim 13-15, wherein, L 1 is- (CR a R b ) m -; each R a and R b is independently H or C 1-4 alkyl, or R a 、R b on any one or more carbon atoms in L 1 together with the carbon atoms to which they are attached form C 3-5 cycloalkyl; m is selected from 1, 2 or 3; L 2 is- (CR c R d ) n -; Each R c and R d is independently H or C 1-4 alkyl, or R c 、R d on any one or more carbon atoms in L 2 together with the carbon atoms to which they are attached form C 3-5 cycloalkyl; n is selected from 2, 3 or 4; L 3 is- (CR e R f ) h -; Each R e and R f is independently H or C 1-4 alkyl, or R e 、R f on any one or more carbon atoms in L 3 together with the carbon atoms to which they are attached form C 3-5 cycloalkyl; h is selected from 3, 4 or 5; L 4 is- (CR g R h ) 1-6 -(OCR g R h -CR g R h ) k -; Each R g and R h is independently H or C 1-4 alkyl, or R g 、R h on any one or more carbon atoms in L 4 together with the carbon atoms to which they are attached form C 3-5 cycloalkyl; k is selected from 2, 3 or 4; L 5 is selected from a bond, - (CH 2 ) 1-4 -, or- (CH 2 ) 1-2 O(CH 2 ) 1-2 -; a is selected from-C (O) -or-NHC (O) -; T is- (CR i R j ) q -; Each R i and R j is independently H or C 1-4 alkyl, or R i 、R j on any one or more of the carbon atoms in T, together with the carbon atoms to which they are attached, form C 3-5 cycloalkyl; q is selected from 5, 6, 7, 8, 9 or 10; B is selected from-C (O) -, -C (O) NH-, or-C (O) NH- (CR k R m ) 1-3 -; Each R k and R m is independently H or C 1-4 alkyl, or R k 、R m on any one or more of the carbon atoms in B together with the carbon atoms to which they are attached form cyclopropyl; p is selected from the group consisting of a bond, -Cit-, -Arg-or-Phe-.
  17. The delivery ligand of any one of claim 13-16, wherein, L 1 is- (CR a R b ) 2 -, preferably-CH 2 CH 2 -or Each R a and R b is independently H, or R a 、R b on any one or more carbon atoms in L 1 together with the carbon atoms to which they are attached form cyclopropyl; L 2 is- (CR c R d ) 3 -, preferably-CH 2 CH 2 CH 2 -), Each R c and R d is independently H, or R c 、R d on any one or more carbon atoms in L 2 together with the carbon atoms to which they are attached form cyclopropyl; L 3 is- (CR e R f ) 4 -, preferably-CH 2 CH 2 CH 2 CH 2 -or Each R e and R f is independently H, or R e 、R f on any one or more carbon atoms in L 3 together with the carbon atoms to which they are attached form cyclopropyl; L 4 is- (CR g R h ) 2 -(OCR g R h -CR g R h ) 2 -preferably Each R g and R h is independently H, or R g 、R h on any one or more carbon atoms in L 4 together with the carbon atoms to which they are attached form cyclopropyl; A is-C (O) -or-NHC (O) -; L 5 is selected from the group consisting of a bond, -CH 2 CH 2 -, or-CH 2 OCH 2 -; T is- (CR i R j ) 7-10 -; Each R i and R j is independently H, or R i 、R j on any one or more of the carbon atoms of T, together with the carbon atoms to which they are attached, form cyclopropyl; B is selected from-C (O) -, -C (O) NH-or-C (O) NH-CR k R m -; R k and R m are independently H, or R k 、R m on any one or more of the carbon atoms of B together with the carbon atoms to which they are attached form cyclopropyl; p is selected from the group consisting of a bond, -Cit-, or-Phe-.
  18. The delivery ligand of any one of claim 1 to 17, wherein, Each W is the same or different and is independently selected from H, A is-NHC (O) -; T is selected from B is selected from-C (O) -, P is selected from a chemical bond,
  19. The delivery ligand of any one of claim 1-18, wherein, the conjugate group is selected from the group consisting of formula (VI), formula (VI-1), formula (VI-2), formula (VI ' -1), formula (VI ' -2), formula (VII-1), formula (VII-2), formula (VII ' -1), formula (VII ' -2), formula (VIII-1), formula (VIII-2), formula (VIII-3) a structure represented by formula (VIII-4), formula (VIII '), formula (VIII-5), formula (VIII-6), formula (VIII ' -1), formula (VIII ' -2), formula (VIII ' -3), formula (VIII ' -4), formula (VIII ' -5), formula (VIII ' -6), formula (IX-1), formula (IX-2), formula (IX ' -1) or formula (IX ' -2), or an isotopic variant, tautomer, stereoisomer, or mixture thereof: wherein the variables are as defined in any one of claims 1 to 18.
  20. The delivery ligand of any one of claims 1-18, wherein said conjugate group is selected from the group consisting of structures represented by formula (VI-1) or formula (VI' -1), or isotopic variants, tautomers, stereoisomers, or mixtures thereof: Each W is independently selected from H, L 1 、L 2 、L 3 、L 4 、L 5 , A, B, T and P are as defined in any one of claims 1 to 18; Provided that at least one group of R a and R b 、R c and R d 、R e and R f 、R g and R h 、R i and R j 、R k and R m forms a ring with the carbon atoms to which they are attached; R 1 is selected from-OR 0 、-CH 2 OR 0 OR-CH 2 CH 2 OR 0 , wherein R 0 is H, D, a hydroxyl protecting group OR a solid support; The hydroxyl protecting group is preferably-C (O) CH 2 CH 2 C (O) OH or 4,4' -Dimethoxytrityl (DMTR); r is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; x is selected from 0, 1, 2, 3, 4, 5 or 6; Preferably, the method comprises the steps of, R 1 is-OR 0 , wherein R 0 is H OR a hydroxy protecting group, preferably H; The hydroxyl protecting group is preferably-C (O) CH 2 CH 2 C (O) OH; R is selected from H or C 1-6 alkyl; x is selected from 0, 1, 2, 3 or 4; More preferably, the process is carried out, R 1 is OH; R is selected from H or C 1-4 alkyl, preferably H; x is 0, 1, 2 or 3.

Description

Targeted delivery ligands The present invention claims priority from chinese patent application No. c 202311369031.X, 10/20 of 2023, incorporated herein by reference in its entirety as part of the present disclosure. Technical Field The present invention is in the field of medicine, in particular to nucleic acid molecules comprising a targeted delivery ligand and containing the targeted delivery ligand. Background Liver is the largest metabolic organ of human body, and participates in synthesis and metabolism of various chemical substances in the body, and liver function abnormality can cause a series of liver-related diseases including cancer, metabolic diseases and the like. Liver targeting has been a focus of research in the treatment of liver-related diseases. siRNA interference (RNAi) therapy has been discovered since 1998 as a promising candidate therapy for a variety of diseases. However, since siRNA is a relatively polyanionic molecule, it is difficult for these molecules to enter cells through a passive diffusion mechanism. Furthermore, delivery of siRNA to tissues and cells in vivo remains the biggest challenge in its clinical application due to rapid digestion of siRNA in plasma, clearance in the kidneys, limited penetration through capillary endothelium and low cellular uptake efficiency. GalNAc (N-acetylgalactosamine) is a high affinity targeting ligand for asialoglycoprotein receptor (ASGPR). ASGPR is an ideal receptor for active targeting, which is specifically expressed on the surface of liver cells and enters cells to form endosomes through endocytosis after being combined with GalNAc, so that a sufficient amount of nucleic acid medicine is brought into the cells to realize liver targeting delivery of the nucleic acid medicine. N-acetylgalactosamine (GalNAc) is capable of specifically binding to asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes. Thus, there is a need in the art for GalNAc-containing targeted delivery ligands. Disclosure of Invention The present invention provides a novel targeted delivery ligand containing N-acetylgalactosamine. In one aspect, the present invention provides a delivery ligand, wherein the delivery ligand comprises a conjugate group represented by formula (X), or an isotopic variant, tautomer, stereoisomer, or mixture thereof: Wherein, the The R is throughIs connected with biological molecules; Each W is independently selected from H, D, W 0 is selected from the group consisting of bond 、-OCH2-、-OCH2CH2-、-OCH2OCH2-、-OCH2CH2CH2-、-OCH2CH2CH2CH2-、-CH2OCH2CH2CH2-、-CH2CH2OCH2CH2-、-CH2CH2CH2OCH2-、-CH2CH2OCH2CH2O-、C1-6 alkylene, C 1-6 haloalkylene, C 1-6 alkenylene, or C 1-6 alkynylene, optionally deuterated, up to complete deuteration; W 1 is selected from the group consisting of a bond, -O-L 1-、-C(O)-、-C(O)-L1 -, -C (O) O-, or-C (O) O-L 1 -, which is optionally deuterated until fully deuterated; L 1 is- (CR aRb)m -, 1,2, 3,4 or 5 of CR aRb in said L 1 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR a -; Each R a and R b is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R a、Rb on any one or more of the carbon atoms in L 1 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; W 2 is selected from-L 2-NH-、-L2-O-、-L2 -C (O) -or-L 2 -OC (O) -, which is optionally deuterated until fully deuterated; L 2 is- (CR cRd)n -, 1,2, 3,4 or 5 of CR cRd in said L 2 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR c -; each R c and R d is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R c、Rd on any one or more of the carbon atoms in L 2 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; w 3 is selected from-L 3-C(O)NH-、-L3-NHC(O)-、-L3 -OC (O) NH-or-L 3 -NHC (O) O-, which is optionally deuterated until fully deuterated; l 3 is- (CR eRf)h -, 1,2, 3,4 or 5 of CR eRf in said L 3 that are not adjacent may be replaced by a heteroatom selected from-O-, -S-and-NR e -; each R e and R f is independently H, D, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, or C 1-6 alkynyl, or R e、Rf on any one or more of the carbon atoms in L 3 taken together with the same or different carbon atoms to which they are attached form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; W 4 is selected from -L4-NHC(O)-、-L4-NHC(O)-(CH2)1-6-、-L4-NHC(O)O-、-L4-NHC(O)O-(CH2)1-6-、-L4-C(O)NH-、-L4-C(O)NH-(CH2)1-6-、-L4-OC(O)NH- or-L 4-OC(O)NH-(CH2)1-6 -, which is optionally deuterated until fully deuterated; L 4 is selected from -(CRgRh)k-、-(CRgRh)1-6-(OCRgRh-CRgRh)k- or- (CR gRh)1-6-(NH-CRgRh-CRgRh)k -, 1,2,3, 4 o