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CN-121986086-A - Ionizable lipids and lipid nanoparticles for RNA delivery

CN121986086ACN 121986086 ACN121986086 ACN 121986086ACN-121986086-A

Abstract

Provided herein are novel ionizable cationic lipid compounds that are capable of assembling with other helper lipids such as phospholipids, structural lipids, and polymer conjugated lipids capable of reducing aggregation to form lipid nanoparticles for delivery of therapeutic RNAs both in vitro and in vivo. These compounds contain thiourea groups (-NRc-C (S) -NRd-) in the linker between the lipid group and the head group.

Inventors

  • DONG HE
  • ZHAO YIMING
  • LU YU

Assignees

  • 广州百济神州生物制药有限公司

Dates

Publication Date
20260505
Application Date
20241011
Priority Date
20231013

Claims (20)

  1. 1. A compound of formula (I): (I) Or a pharmaceutically acceptable salt thereof or a stereoisomer, tautomer or geometric isomer thereof, R H is-N (R 1 R 2 ), cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one, two, or three substituents R Ha ; r Ha is C 1-12 alkyl, OR-OH, wherein the C 1-12 alkyl is independently unsubstituted OR substituted with F, -OR, -CO 2 R, -SR, OR-C 1-6 alkyl; R 1 and R 2 are each independently H or C 1-12 alkyl, or R 1 and R 2 form, with the nitrogen atom to which they are attached, a 4-to 9-membered heterocyclyl group containing 0 or 1 heteroatom selected from oxygen, nitrogen or sulfur, or a 5-to 9-membered heteroaryl group containing 0,1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, and Each R a is independently selected from H or C 1-6 alkyl; Each R b is independently selected from H or C 1-6 alkyl; m is an integer ranging from 1 to 15; R c and R d are each independently selected from H or C 1-6 alkyl, each of said C 1-6 alkyl being independently substituted with one, two or three R M ; M 1 and M 2 are each independently a single bond, C 1-18 alkylene or C 2-18 alkenylene, wherein one or two methylene units of the C 1-18 alkylene or C 2-18 alkenylene are optionally and independently replaced by L m1 or L m2 , wherein each of the C 1-18 alkylene or C 2-18 alkenylene is independently unsubstituted or substituted by one, two or three R M ; L 1 and L 2 are independently selected from the group consisting of single bond 、-C(=O)O-、-OC(=O)O-、-OC(=O)C(=O)O-、-C(=O)S-、-C(=S)O-、-C(=S)S-、-OC(=O)-、-OC(=S)-、-SC(=O)-、-SC(=S)-、-C(=O)-、-C(=S)-、-O-、-S-、-NR L -、-C(=O)NR L -、-C(=S)NR L -、-NR L C(=O)-、-NR L C(=S)-、-NR L C(=O)NR L -、-NR L C(=S)NR L -、-OC(=O)NR L -、-OC(=S)NR L -、-SC(=S)NR L -、-SC(=O)NR L -、-NR L C(=O)O-、-NR L C(=S)O-、-NR L C(=S)S-、-NR L C(=O)S-、-CH(OH)-、-CH(SH)-、-P(=O)(OR L )O-、-S(O)-、-S(O) 2 -、-S-S-、 cycloalkylene, arylene, heteroaryl, and heterocyclylene; R L is H or C 1-12 alkyl, and T 1 and T 2 are each independently C 1-24 alkyl, C 2-24 alkenyl or C 2-24 alkynyl, wherein one or two methylene units of said C 1-24 alkyl, C 2-24 alkenyl or C 2-24 alkynyl are optionally and independently replaced by L m1 or L m2 , wherein each of said C 1-12 alkylene or C 2-12 alkenylene is independently substituted by one, two or three R M ; L m1 and L m2 are independently selected from the group consisting of single bond 、-C(=O)O-、-OC(=O)O-、-OC(=O)C(=O)O-、-C(=O)S-、-C(=S)O-、-C(=S)S-、-OC(=O)-、-OC(=S)-、-SC(=O)-、-SC(=S)-、-C(=O)-、-C(=S)-、-O-、-S-、-NR mL -、-C(=O)NR mL -、-C(=S)NR L -、-NR mL C(=O)-、-NR mL C(=S)-、-NR mL C(=O)NR mL -、-NR mL C(=S)NR mL -、-OC(=O)NR mL -、-OC(=S)NR mL -、-SC(=S)NR mL -、-SC(=O)NR mL -、-NR mL C(=O)O-、-NR mL C(=S)O-、-NR mL C(=S)S-、-NR mL C(=O)S-、-CH(OH)-、-CH(SH)-、-P(=O)(OR mL )O-、-S(O)-、-S(O) 2 -、-S-S-、 cycloalkylene, arylene, heteroaryl, and heterocyclylene; R mL is H or C 1-12 alkyl; R M is F, -OR, -CO 2 R、-SR、-C 1-6 alkyl, cycloalkyl, OR heterocyclyl; R is hydrogen, or C 1-6 alkyl optionally substituted with one, two or three substituents selected from F, cycloalkyl, or heterocyclyl.
  2. 2. The compound of claim 1, wherein R H is-N (R 1 R 2 ).
  3. 3. A compound according to claim 1 or claim 2, wherein R H is-N (R 1 R 2 ), and R 1 and R 2 are each independently H or C 1-4 alkyl; Preferably R 1 and R 2 are each independently methyl or ethyl; More preferably R 1 and R 2 are each independently methyl, or R H is-N (R 1 R 2 ), and R 1 and R 2 form, with the nitrogen atom to which they are attached, a 4-to 8-membered heterocyclyl containing 0 or 1 heteroatom selected from oxygen, nitrogen or sulfur; Preferably R H is-N (R 1 R 2 ), and R 1 and R 2 form, with the nitrogen atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered heterocyclyl; more preferably R H is-N (R 1 R 2 ), and R 1 and R 2 form with the nitrogen atom to which they are attached 、 、 、 Or (b) ; R H is-N (R 1 R 2 ) and R 1 and R 2 form, with the nitrogen atom to which they are attached, a 5-to 8-membered heteroaryl group containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur; Preferably R H is-N (R 1 R 2 ), and R 1 and R 2 form a 5-, 6-, 7-, or 8-membered heteroaryl group with the nitrogen atom to which they are attached; more preferably R H is-N (R 1 R 2 ), and R 1 and R 2 form with the nitrogen atom to which they are attached 。
  4. 4. The compound of any one of claims 1-3, wherein R a and R b are each H, or m is 2 or 3, and R a and R b are each H.
  5. 5. A compound according to any one of claims 1 to 3 wherein - (CR a R b ) m -part is -(CH 2 -CR a R b )-、-(CR a R b -CH 2 )-、-(CH 2 -CH 2 -CR a R b )-、-(CH 2 -CR a R b -CH 2 )- or- (CR a R b -CH 2 -CH 2 ) -, wherein R a and R b are H or C 1-6 alkyl, and R a and R b are not both H, or The- (CR a R b ) m -part is -(CH 2 -CR a R b )-、-(CR a R b -CH 2 )-、-(CH 2 -CH 2 -CR a R b )-、-(CH 2 -CR a R b -CH 2 )- or- (CR a R b -CH 2 -CH 2 ) -, where R a and R b are H or C 1-6 alkyl, or The- (CR a R b ) m -part is -(CH 2 -CR a R b )-、-(CR a R b -CH 2 )-、-(CH 2 -CH 2 -CR a R b )-、-(CH 2 -CR a R b -CH 2 )- or- (CR a R b -CH 2 -CH 2 ) -, where R a and R b are H, methyl or ethyl, or The- (CR a R b ) m -part is -(CH 2 -CR a R b )-、-(CR a R b -CH 2 )-、-(CH 2 -CH 2 -CR a R b )-、-(CH 2 -CR a R b -CH 2 )- or- (CR a R b -CH 2 -CH 2 ) -, where R a and R b are H or methyl.
  6. 6. The compound of any one of claims 1-5, wherein R c is H or C 1-4 alkyl, preferably R c is H, methyl, or ethyl.
  7. 7. The compound of any one of claims 1-6, wherein R d is H or C 1-4 alkyl, preferably R d is H, methyl, or ethyl.
  8. 8. The compound of any one of claims 1-7, wherein M 1 and M 2 are each independently C 4-12 alkylene or C 4-12 alkenylene; Preferably M 1 and M 2 are each independently C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 Alkylene, C 8 Alkylene, C 9 Alkylene, C 10 Alkylene, C 11 Alkylene, C 12 Alkylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, C 12 alkenylene, C 5 Alkenylene, C 6 Alkenylene, C 7 Alkenylene, C 8 Alkenylene, C 9 Alkenylene, C 10 Alkenylene, C 11 Alkenylene, or C 12 Alkenylene.
  9. 9. The compound of any one of claims 1-8, wherein L 1 and L 2 are independently selected from single bond 、-C(=O)O-、-C(=O)S-、-C(=S)O-、-C(=S)S-、-OC(=O)-、-OC(=S)-、-SC(=O)-、-SC(=S)-、-C(=O)-、-C(=S)-、-O-、-S-、-OC(=O)O-、-OC(=O)C(=O)O-、-P(=O)(OR L )O-、 or-S-S-, preferably L 1 and L 2 are independently single bonds.
  10. 10. The compound of claim 1, wherein L 1 and L 2 are independently-C (=o) O-or-OC (=o) -.
  11. 11. The compound of any one of claims 1-10, wherein T 1 and T 2 are each independently C 6-12 alkyl or C 6-12 alkenyl; Preferably T 1 and T 2 are each independently C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 6 dienyl, C 7 dienyl, C 8 dienyl, C 9 dienyl, C 10 Alkenyl, C 11 Alkenyl, or C 12 Alkenyl.
  12. 12. The compound of any one of claims 1 to 10, wherein T 1 and T 2 are each independently , Wherein the method comprises the steps of R A and R B are each independently selected from H or C 1-6 alkyl; p is an integer ranging from 0 to 12; t a1 is H or C 1-6 alkyl; T a2 and T a3 are each independently C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl; provided that the variables R A 、R B 、p、T a1 、T a2 and T a3 are each selected such that T 1 and T 2 are each independently C 6-24 alkyl, C 6-24 alkenyl, or C 6-24 alkynyl.
  13. 13. The compound of claim 12, wherein p is 0.
  14. 14. The compound of claim 12, wherein p is 1.
  15. 15. The compound of any one of claims 12-14, wherein T a1 is H and T a2 and T a3 are each independently C 4-12 alkyl or C 4-12 alkenyl, or T a1 is H and T a2 and T a3 are each independently C 4-12 alkyl or C 4-12 alkadienyl, or T a1 is H, T a2 is C 3-12 alkyl and T a3 is C 3-12 alkenyl, or T a1 is H, T a2 is C 3-12 alkyl, and T a3 is C 3-12 alkadienyl.
  16. 16. The compound of any one of claims 1-15, wherein M 1 and M 2 are each independently C 3-12 alkylene or C 3-12 alkenylene, L 1 and L 2 are each independently a single bond, and T 1 and T 2 are each independently C 6-12 alkyl or C 6-12 alkenyl; Preferably M 1 and M 2 are each independently C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 Alkylene, C 8 Alkylene, C 9 Alkylene, C 10 Alkylene, C 11 Alkylene, C 12 Alkylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, C 12 alkenylene, C 5 Alkenylene, C 6 Alkenylene, C 7 Alkenylene, C 8 Alkenylene, C 9 Alkenylene, C 10 Alkenylene, C 11 Alkenylene, or C 12 Alkenylene, and T 1 and T 2 are each independently C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 6 alkadienyl, C 7 alkadienyl, C 8 Alkenyl, C 9 Alkenyl, C 10 Alkenyl, C 11 Aldienyl, or C 12 Aldienyl.
  17. 17. The compound of any one of claims 1-15, wherein M 1 and M 2 are each independently C 3-12 alkylene or C 3-12 alkenylene, L 1 and L 2 are each independently-C (=O) O-or-OC (=O) -, and T 1 and T 2 are each independently C 6-12 alkyl or C 6-12 alkenyl; Preferably M 1 and M 2 are each independently C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 Alkylene, C 8 Alkylene, C 9 Alkylene, C 10 Alkylene, C 11 Alkylene, C 12 Alkylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, C 12 alkenylene, C 5 Alkenylene, C 6 Alkenylene, C 7 Alkenylene, C 8 Alkenylene, C 9 Alkenylene, C 10 Alkenylene, C 11 Alkenylene, or C 12 Alkenylene, and T 1 and T 2 are each independently C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 6 alkadienyl, C 7 alkadienyl, C 8 Alkenyl, C 9 Alkenyl, C 10 Alkenyl, C 11 Aldienyl, or C 12 Aldienyl.
  18. 18. The compound of any one of claims 1-15, wherein M 1 and M 2 are each independently C 4-12 alkylene or C 4-12 alkenylene, L 1 and L 2 are each independently-C (=O) O-or-OC (=O) -, and T 1 and T 2 are each independently 。
  19. 19. The compound of any one of claim 1 to 15, wherein the moiety-M 2 -L 2 -T 2 or-M 1 -L 1 -T 1 is decyl, undecyl, dodecyl, tridecyl, tetradecyl, heptadecyl, octadecyl, decenyl, decyldienyl, undecenyl, undecyldienyl, dodecenyl, tridecyl, tridecenyl, tetradecenyl, tetradecdienyl, heptadecenyl, octadecenyl, or octadecenyl.
  20. 20. The compound of any one of claims 1-15, wherein the moiety-M 2 -L 2 -T 2 or-M 1 -L 1 -T 1 is decan-2-yl, undecan-3-yl, dodecan-4-yl, tridecane-5-yl, tetradecan-6-yl, 2-methylundecan-3-yl, 2-methyldecan-2-yl, 3-methylundecan-3-yl, 4-methyldodecan-4-yl, or heptadecan-9-yl.

Description

Ionizable lipids and lipid nanoparticles for RNA delivery Technical Field Provided herein is a novel ionizable cationic lipid compound that can be assembled with other helper lipids such as phospholipids, structural lipids, and polymer conjugated lipids capable of reducing aggregation to form lipid nanoparticles for the delivery of therapeutic and/or prophylactic nucleic acids (e.g., RNA) in vitro and in vivo. Background Lipid nanoparticle compositions (including cationic and/or ionizable lipids, phospholipids, PEG lipids, and structural lipids) have proven effective as transport carriers for delivering biologically active substances, including small molecule drugs, proteins, and nucleic acids, into cells and/or intracellular compartments. However, efficient targeted delivery of nucleic acids remains a continuing medical challenge due to the inherent instability of nucleic acids and the limited ability to penetrate cell membranes, which impedes delivery of nucleic acids to cells. Thus, there is a need to develop novel ionizable lipids with improved safety, efficacy, and specificity in nucleic acid delivery. Disclosure of Invention Provided herein is a novel ionizable cationic lipid compound or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or geometric isomer thereof, that can be used alone or in combination with other lipid components such as other helper lipids, such as phospholipids, structural lipids, and polymer conjugated lipids, to form Lipid Nanoparticles (LNPs) for delivering therapeutic and/or prophylactic agents (e.g., therapeutic nucleic acids). Also provided herein is a method for delivering nucleic acids (such as antisense oligonucleotides, small interfering RNAs and/or messenger RNAs) through lipid nanoparticles comprising ionizable cationic lipid compounds and a method for treating and preventing various diseases or disorders using such lipid nanoparticles. The embodiments include the following aspects: In some embodiments, provided herein is a compound of formula (I): (I) Or a pharmaceutically acceptable salt thereof or a stereoisomer, tautomer or geometric isomer thereof, R H is-N (R 1R2), cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of the cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one, two, or three substituents R Ha; r Ha is C 1-12 alkyl, OR-OH, wherein the C 1-12 alkyl is independently unsubstituted OR substituted with F, -OR, -CO 2 R, -SR, OR-C 1-6 alkyl; R 1 and R 2 are each independently H or C 1-12 alkyl, or R 1 and R 2 form, with the nitrogen atom to which they are attached, a 4-to 9-membered heterocyclyl group containing 0 or 1 heteroatom selected from oxygen, nitrogen or sulfur, or a 5-to 9-membered heteroaryl group containing 0,1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, and Each R a is independently selected from H or C 1-6 alkyl; Each R b is independently selected from H or C 1-6 alkyl; m is an integer ranging from 1 to 15; R c and R d are each independently selected from H or C 1-6 alkyl, each of said C 1-6 alkyl being independently substituted with one, two or three R M; M 1 and M 2 are each independently a single bond, C 1-18 alkylene or C 2-18 alkenylene, wherein one or two methylene units of the C 1-18 alkylene or C 2-18 alkenylene are optionally and independently replaced by L m1 or L m2, wherein each of the C 1-18 alkylene or C 2-18 alkenylene is independently unsubstituted or substituted by one, two or three R M; L 1 and L 2 are independently selected from the group consisting of single bond 、-C(=O)O-、-OC(=O)O-、-OC(=O)C(=O)O-、-C(=O)S-、-C(=S)O-、-C(=S)S-、-OC(=O)-、-OC(=S)-、-SC(=O)-、-SC(=S)-、-C(=O)-、-C(=S)-、-O-、-S-、-NRL-、-C(=O)NRL-、-C(=S)NRL-、-NRLC(=O)-、-NRLC(=S)-、-NRLC(=O)NRL-、-NRLC(=S)NRL-、-OC(=O)NRL-、-OC(=S)NRL-、-SC(=S)NRL-、-SC(=O)NRL-、-NRLC(=O)O-、-NRLC(=S)O-、-NRLC(=S)S-、-NRLC(=O)S-、-CH(OH)-、-CH(SH)-、-P(=O)(ORL)O-、-S(O)-、-S(O)2-、-S-S-、 cycloalkylene, arylene, heteroaryl, and heterocyclylene; R L is H or C 1-12 alkyl, and T 1 and T 2 are each independently C 1-24 alkyl, C 2-24 alkenyl or C 2-24 alkynyl, wherein one or two methylene units of said C 1-24 alkyl, C 2-24 alkenyl or C 2-24 alkynyl are optionally and independently replaced by L m1 or L m2, wherein each of said C 1-24 alkyl, C 2-24 alkenyl or C 2-24 alkynyl is independently substituted by one, two or three R M; L m1 and L m2 are independently selected from the group consisting of single bond 、-C(=O)O-、-OC(=O)O-、-OC(=O)C(=O)O-、-C(=O)S-、-C(=S)O-、-C(=S)S-、-OC(=O)-、-OC(=S)-、-SC(=O)-、-SC(=S)-、-C(=O)-、-C(=S)-、-O-、-S-、-NRmL-、-C(=O)NRmL-、-C(=S)NRL-、-NRmLC(=O)-、-NRmLC(=S)-、-NRmLC(=O)NRmL-、-NRmLC(=S)NRmL-、-OC(=O)NRmL-、-OC(=S)NRmL-、-SC(=S)NRmL-、-SC(=O)NRmL-、-NRmLC(=O)O-、-NRmLC(=S)O-、-NRmLC(=S)S-、-NRmLC(=O)S-、-CH(OH)-、-CH(SH)-、-P(=O)(ORmL)O-、-S(O)-、-S(O)2-、-S-S-、 cycloalkylene, arylene, heteroaryl, and heterocyclylene; R mL is H or C 1-12 alkyl, R M is F, -OR, -CO 2R、-SR、-C1-6 alkyl, cycloalkyl, OR heterocyclyl;