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CN-121971633-A - Compounds comprising nucleic acids and half-life extending motifs

CN121971633ACN 121971633 ACN121971633 ACN 121971633ACN-121971633-A

Abstract

Disclosed herein are compounds comprising nucleic acid (a), their preparation and their use.

Inventors

  • A. T. Suko
  • C. Arleson
  • F. C. Tooch

Assignees

  • 诺华股份有限公司

Dates

Publication Date
20260505
Application Date
20201125
Priority Date
20191126

Claims (20)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, (HLEM) z -A(I), Wherein: (A) Is a single-stranded oligonucleotide or a double-stranded oligonucleotide covalently bonded to a half-life extending motif (HLEM), Wherein the double stranded oligonucleotide is a small interfering RNA comprising: a) An antisense strand and a sense strand, wherein the antisense strand and sense strand are 17 to 25 nucleotides in length; b) One or more modified nucleotides comprising a modified sugar moiety comprising a2 '-modification selected from the group consisting of a 2' -O-methyl modification, a2 '-O-methoxyethyl modification, a 2' -fluoro modification, and a2 '-deoxy-2' -fluoro modification; And C) One or more modified internucleotide linkages selected from the group consisting of phosphorothioate linkages, phosphoramide linkages, and phosphodiamide linkages; Wherein the single stranded oligonucleotide is a small interfering RNA comprising: a) 15 to 25 nucleotides in length, B) One or more modified nucleotides comprising a modified sugar moiety comprising a2 '-modification selected from the group consisting of a 2' -O-methyl modification, a2 '-O-methoxyethyl modification, a 2' -fluoro modification, and a2 '-deoxy-2' -fluoro modification; And C) One or more modified internucleotide linkages selected from the group consisting of phosphorothioate linkages and phosphorodiamidate linkages; z is 1; wherein the half-life extending motif is represented by formula (III): (III), Wherein: k is 1; L 2 is unsubstituted C 2 -C 22 alkylene, And A) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A is-OPO 2 -O-or-O-P (O) (S) -O-; L 1B is-L 10 -NH-C (O) -or-L 10 -C (O) -NH-, wherein L 10 is hydroxymethyl-substituted C 1 -C 20 alkylene or unsubstituted C 1 -C 20 alkylene; L 1C is a bond or R 1C -substituted C 1 -C 10 alkylene; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or oxy-substituted or unsubstituted 5 to 8 membered heteroalkylene; L 1E is a bond, -NHC (O) -or-C (O) NH-; r 1C is-NHC (O) -L 2C -R 8C ; l 2C is a bond or unsubstituted C 2 -C 22 alkylene, an R 8C is hydrogen, C 1 -C 3 alkyl or-COOH; Or (b) B) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: l 1A is-OPO 2 -O-or-O-P (O) (S) -O; L 1B is hydroxymethyl-substituted C 1 -C 20 alkylene, unsubstituted C 1 -C 20 alkylene or unsubstituted 2 to 20 membered heteroalkylene; L 1C is-N (R 20 )-、-N(R 20 )C(O)-、-C(O)N(R 21 ) -or-OPO 2 -O-; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or R 1D -substituted C 1 -C 10 alkylene; L 1E is a bond, -NHC (O) -or-C (O) NH-; r 1D is independently-NHC (O) -L 2D -R 8D ; L 2D is a bond or unsubstituted C 2 -C 22 alkylene; R 8D is hydrogen, C 1 -C 3 alkyl or-COOH, and Each of R 20 、R 21 and R 22 is hydrogen or unsubstituted C 1 -C 10 alkyl; Or (b) C) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A -L 1B -is Or (b) ; L 1C is R 1C -substituted C 1 -C 10 alkylene; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or oxy-substituted or unsubstituted 5 to 8 membered heteroalkylene; L 1E is-N (R 20 ) C (O) -or-C (O) N (R 21 ) -; Each of R 20 and R 21 is hydrogen or unsubstituted C 1 -C 10 alkyl; R 1C is-NHC (O) -L 2C -R 8C ; l 2C is a bond or unsubstituted C 10 -C 22 alkylene, an R 8C is hydrogen, C 1 -C 3 alkyl or-COOH; Or (b) D) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A -L 1B -is Or (b) And (2) and -L 1C -L 1D -L 1E -is 、 Or (b) 。
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1A is-OPO 2 -O-.
  3. 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L 1B is-L 10 -NH-C (O) -or-L 10 -C (O) -NH-, wherein L 10 is hydroxymethyl-substituted C 1 -C 8 alkylene or unsubstituted C 1 -C 8 alkylene.
  4. 4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L 1B is Or (b) 。
  5. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein-L 1A -L 1B -is 、 、 、 Or (b) 。
  6. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein-L 1A -L 1B -is-OPO 2 -O-L 10 -NH-C (O) -, wherein L 10 is hydroxymethyl-substituted C 1 -C 12 alkylene or unsubstituted C 1 -C 12 alkylene.
  7. 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -L 1A -L 1B -is Or (b) And is attached to the 3' carbon of the oligonucleotide, or Or-L 1A -L 1B -is Or (b) And is attached to the 5' carbon of the oligonucleotide.
  8. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  9. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the half-life extending motif (HLEM) is ; ; ; ; ; ; ; Either (or) or (b) 。
  10. 10. A compound of formula (II): (HLEM) z -A-(UM) t (II), Wherein: (A) For a single-stranded oligonucleotide or double-stranded oligonucleotide covalently bonded to a half-life extending motif (HLEM) and an Uptake Motif (UM), Wherein the double stranded oligonucleotide is a small interfering RNA comprising: a) An antisense strand and a sense strand, wherein the antisense strand and the sense strand are 17 to 25 nucleotides in length; b) One or more modified nucleotides comprising a modified sugar moiety comprising a2 '-modification selected from the group consisting of a 2' -O-methyl modification, a2 '-O-methoxyethyl modification, a 2' -fluoro modification, and a2 '-deoxy-2' -fluoro modification; And C) One or more modified internucleotide linkages selected from the group consisting of phosphorothioate linkages and phosphorodiamidate linkages; Wherein the single stranded oligonucleotide is a single stranded small interfering RNA comprising: d) 15 to 25 nucleotides in length, E) One or more modified nucleotides comprising a modified sugar moiety comprising a2 '-modification selected from the group consisting of a 2' -O-methyl modification, a2 '-O-methoxyethyl modification, a 2' -fluoro modification, and a2 '-deoxy-2' -fluoro modification; And F) One or more modified internucleotide linkages selected from the group consisting of phosphorothioate linkages, phosphoramide linkages, and phosphodiamide linkages; t is 1; z is 1; wherein the half-life extending motif has the structure of formula (III): (III) Wherein: k is 1; L 2 is unsubstituted C 2 -C 22 alkylene, And A) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A is-OPO 2 -O-or-O-P (O) (S) -O-; L 1B is-L 10 -NH-C (O) -or-L 10 -C (O) -NH-, wherein L 10 is hydroxymethyl-substituted C 1 -C 20 alkylene or unsubstituted C 1 -C 20 alkylene; L 1C is a bond or R 1C -substituted C 1 -C 10 alkylene; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or oxy-substituted or unsubstituted 5 to 8 membered heteroalkylene; L 1E is a bond, -NHC (O) -or-C (O) NH-; R 1C is independently-NHC (O) -L 2C -R 8C ; l 2C is a bond or unsubstituted C 2 -C 22 alkylene, an R 8C is hydrogen, C 1 -C 3 alkyl or-COOH; Or (b) B) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: l 1A is-OPO 2 -O-or-O-P (O) (S) -O; L 1B is hydroxymethyl-substituted C 1 -C 20 alkylene, unsubstituted C 1 -C 20 alkylene or unsubstituted 2 to 20 membered heteroalkylene; L 1C is-N (R 20 )-、-N(R 20 )C(O)-、-C(O)N(R 21 ) -or-OPO 2 -O-; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or R 1D -substituted C 1 -C 10 alkylene; L 1E is a bond, -NHC (O) -or-C (O) NH-; R 1D is independently-NHC (O) -L 2D -R 8D ; L 2D is a bond or unsubstituted C 2 -C 22 alkylene; R 8D is hydrogen, C 1 -C 3 alkyl or-COOH, and Each of R 20 、R 21 and R 22 is hydrogen or unsubstituted C 1 -C 10 alkyl; Or (b) C) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A -L 1B -is Or (b) ; L 1C is R 1C -substituted C 1 -C 10 alkylene; L 1D is a bond, unsubstituted C 1 -C 20 alkylene, or oxy-substituted or unsubstituted 5 to 8 membered heteroalkylene; L 1E is-N (R 20 ) C (O) -or-C (O) N (R 21 ) -; Each of R 20 and R 21 is hydrogen or unsubstituted C 1 -C 10 alkyl; R 1C is-NHC (O) -L 2C -R 8C ; l 2C is a bond or unsubstituted C 10 -C 22 alkylene, an R 8C is hydrogen, C 1 -C 3 alkyl or-COOH; Or (b) D) L 1 is-L 1A -L 1B -L 1C -L 1D -L 1E -, wherein: L 1A -L 1B -is Or (b) And (2) and -L 1C -L 1D -L 1E -is 、 Or (b) ; Wherein the uptake motif has the structure of formula (IV): (IV), Wherein: L 3 is-OPO 2 -O-or-O-P (O) (S) -O-; L 4 is-L 7 -NH-C (O) -or-L 7 -C (O) -NH-, wherein L 7 is hydroxymethyl-substituted C 1 -C 20 alkylene or unsubstituted C 1 -C 20 alkylene, or oxy-substituted 2-to 20-membered heteroalkylene or unsubstituted 2-to 20-membered heteroalkylene; L 5 is-L 5A -L 5B -L 5C -L 5D -L 5E -, wherein: l 5A is a bond or unsubstituted C 1 -C 20 alkylene; l 5B is a bond or unsubstituted phenylene; L 5C is a bond, unsubstituted C 1 -C 20 alkylene, unsubstituted C 2 -C 20 alkynylene or unsubstituted phenylene; L 5D is a bond or unsubstituted C 1 -C 20 alkylene; L 5E is-NHC (O) -; L 6 is-NHC (O) -; R 1 and R 2 are unsubstituted C 1 -C 25 alkyl, wherein at least one of R 1 and R 2 is unsubstituted C 9 -C 19 alkyl, and R 3 is hydrogen.
  11. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein L 3 is-OPO 2 -O-.
  12. 12. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, wherein L 4 is-L 7 -NH-C (O) -or-L 7 -C (O) -NH-, wherein hydroxymethyl-substituted C 1 -C 20 alkylene or unsubstituted C 1 -C 20 alkylene.
  13. 13. The compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein L 4 is Or (b) 。
  14. 14. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein-L 3 -L 4 -is-OPO 2 -O-L 7 -NH-C (O) -, wherein L 7 is hydroxymethyl-substituted C 5 -C 8 alkylene or unsubstituted C 5 -C 8 alkylene.
  15. 15. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein-L 3 -L 4 -is 、 Or (b) 。
  16. 16. The compound according to any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein L 5 is-NHC (O) -, 、 、 、 Or (b) 。
  17. 17. A compound according to any one of claims 10 to 16, or a pharmaceutically acceptable salt thereof, wherein L 5A is a bond or unsubstituted C 1 -C 8 alkylene; l 5B is a bond, -NHC (O) -or unsubstituted phenylene; L 5C is a bond, unsubstituted C 2 -C 8 alkynylene, or unsubstituted phenylene; L 5D is a bond or unsubstituted C 1 -C 8 alkylene, and L 5E is-NHC (O) -.
  18. 18. The compound according to any one of claims 10 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 1 -C 17 alkyl.
  19. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 13 -C 17 alkyl.
  20. 20. The compound according to any one of claims 10 to 19, or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted C 13 -C 17 alkyl.

Description

Compounds comprising nucleic acids and half-life extending motifs The applicant submitted, on 25.11.2020, PCT application PCT/US2020/062358 entitled "compound comprising a nucleic acid and a half-life extending motif", which entered the national stage of china on 21.2022, application number 202080094151.1. The application is a divisional application of the China application. Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application No. 62/940,835 filed on 11.26 2019, which is incorporated herein by reference in its entirety for all purposes. References to "sequence Listing", tables, or computer program List appendix submitted as ASCII files A sequence listing written in file DTX-003-01wo_st25.txt created on 11/23/2020, size 1,174 bytes, machine format IBM-PC, using MS Windows operating system is incorporated herein by reference. Technical Field The present disclosure relates to the field of biologically active compounds comprising nucleic acids. More specifically, the disclosure relates to compounds comprising nucleic acids, their preparation and their use. Background Delivering therapeutic nucleic acids into cells remains a challenging area of research. Thus, there is a need for improved nucleic acid compounds and strategies for introducing such compounds into cells. Disclosure of Invention Provided herein, inter alia, are compounds or compounds comprising a nucleic acid (a) covalently bonded to a half-life extending motif (HLEM). In one aspect, compounds having the following formula (I) are provided: (HLEM) z -A (I). z is an integer from 1 to 5. In embodiments, the half-life extending motif has the following structure: (III). k is an integer from 1 to 5. L 1 is independently a covalent linker. L 2 is independently unsubstituted alkylene. In embodiments, the nucleic acid is covalently bound to an Uptake Motif (UM). In embodiments, the compound has formula (II): (HLEM) z-A-(UM)t (II). t is an integer from 1 to 5. In embodiments, the uptake motif independently has the following structure: (IV)。 L 3 and L 4 are independently bond 、-N(R23)-、-O-、-S-、-C(O)-、-N(R23)C(O)-、-C(O)N(R24)-、-N(R23)C(O)N(R24)-、-C(O)O-、-OC(O)-、-N(R23)C(O)O-、-OC(O)N(R24)-、-OPO2-O-、-O-P(O)(S)-O-、-O-P(O)(R25)-O-、-O-P(S)(R25)-O-、-O-P(O)(NR23R24)-N-、-O-P(S)(NR23R24)-N-、-O-P(O)(NR23R24)-O-、-O-P(S)(NR23R24)-O-、-P(O)(NR23R24)-N-、-P(S)(NR23R24)-N-、-P(O)(NR23R24)-O-、-P(S)(NR23R24)-O-、-S-S-、 substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each R 23、R24 and R 25 is independently hydrogen or unsubstituted C 1-C10 alkyl. L 5 is-L 5A-L5B-L5C-L5D-L5E-.L6 is -L6A-L6B-L6C-L6D-L6E-.L5A、L5B、L5C、L5D、L5E、L6A、L6B、L6C、L6D and L 6E are independently a bond-NH-, -O-, -S-, -C (O) -, -NHC (O) -, -NHC (O) NH-, -C (O) O-, -OC (O) -, -C (O) NH-, substituted or unsubstituted alkylene a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene. R 1 and R 2 are independently unsubstituted C 1-C25 alkyl, wherein at least one of R 1 and R 2 is unsubstituted C 9-C19 alkyl. R 3 is hydrogen 、-NH2、-OH、-SH、-C(O)H、-C(O)NH2、-NHC(O)H、-NHC(O)OH、-NHC(O)NH2、-C(O)OH、-OC(O)H、-N3、 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one aspect, a method is provided comprising contacting a cell with a compound as described herein or a compound comprising a nucleic acid (a). In one aspect, there is provided a method comprising administering a compound as described herein or a compound comprising a nucleic acid (a) to a subject. In one aspect, there is provided a compound or a compound comprising a nucleic acid (a) for use in therapy as described herein. In one aspect, a method of introducing a nucleic acid into a cell in a subject is provided. The method comprises administering to the subject a compound comprising a nucleic acid (a) as described herein. In one aspect, there is provided a cell comprising a compound comprising a nucleic acid (a) as described herein. In one aspect, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable excipient and a compound comprising nucleic acid (a) as described herein. Other aspects are disclosed below. Drawings FIG. 1A illustrates a structure of DT-000137 according to an example embodiment. FIG. 1B illustrates the structure of DT-000146 according to an example embodiment. FIG. 1C illustrates the structure of DT-000347 according to an example embodiment. FIG. 1D illustrates the structure of