JPWO2021055849A5

JPWO2021055849A5 -

Info

Publication number: JPWO2021055849A5
Application number: JP2022518190A
Authority: JP
Publication date: 2023-09-26

Claims

Formula (A-1):

or its N-oxide , or a salt thereof, in the formula:
The R' ^branch is

And;

indicates the joining point;
wherein R ^aα and R ^aβ are each independently selected from the group consisting of H and C _1-2 alkyl, and at least one of R ^aα and R ^aβ is C ₁ or C ₂ alkyl;
R' is selected from the group consisting of C _1-18 alkyl and C _2-18 alkenyl;
R ² and R ³ are each independently selected from the group consisting of C _1-14 alkyl and C _2-14 alkenyl;
R ⁴ is -(CH ₂ ) _n Q, n is independently selected from 1, 2, 3, 4, and 5, and Q is NRS(O) ₂ R ^SX and

and A is a 3- to 14-membered heterocycle containing one or more heteroatoms selected from N, O, and S; a is 1, 2, 3, or 4;

indicates the joining point;
R is selected from H and C _1-3 alkyl;
R ^SX is C _3-8 carbocycle, 3-14 membered heterocycle containing one or more heteroatoms selected from N, O and S, C _1-6 alkyl, C _2-6 alkenyl, ( C _1-3 alkoxy) C _1-3 alkyl, (CH ₂ ) _p1 O(CH ₂ ) _p2 R ^SX1 , and (CH ₂ ) _p1 R ^SX1 , and the carbocycle and heterocycle are oxo, C ₁ optionally substituted with one or more groups selected from _-6 alkyl, and (C _1-3 alkoxy)C _1-3 alkyl;
R ^SX1 is selected from C(O)NR ¹⁴ R ¹⁴ ', a C _3-8 carbocycle, and a 3- to 14-membered heterocycle containing one or more heteroatoms selected from N, O and S; , the carbocycle and the heterocycle are oxo, halo, C _1-3 alkyl, (C _1-3 alkoxy)C _1-3 alkyl, C _1-6 alkylamino, di-(C _1-6 alkyl)amino, respectively. , and optionally substituted with one or more groups selected from _NH2 ;
Each R ¹³ is OH, oxo, halo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylamino, di-(C _1-6 alkyl)amino, NH ₂ , selected from the group consisting of C(O) _NH2 , CN, and _NO2 ;
R ¹⁴ and R ¹⁴ ' are each independently selected from the group consisting of H and C _1-6 alkyl;
p ₁ is selected from 1, 2, 3, 4, and 5;
A compound or an N-oxide thereof, or a salt thereof, wherein p ₂ is selected from 1, 2, 3, 4, and 5.

Structure below:

2. A compound according to claim 1, having one of:

3. A compound according to claim 1 or 2 , wherein n is 3.

^3. A compound according to claim 1 or 2 , wherein Q is NRS(O) _2RSX .

3. A compound according to claim 1 or 2 , wherein R is H.

3. A compound according to claim 1 or 2 , wherein R ^SX is selected from C _3-6 carbocycle and C _1-3 alkyl.

3. A compound according to claim 1 or 2 , wherein R ^SX is ethyl.

3. A compound according to claim 1 or 2 , wherein R ^SX is cyclopropyl.

3. The compound according to claim 1 or 2 , wherein R ^SX is ( _CH2 ) _p1 R ^SX1 .

3. A compound according to claim 1 or 2, wherein p ₁ is 1 and R ^SX1 is 6-membered heterocycloalkyl, 5-membered heteroaryl, or phenyl.

3. A compound according to claim 1 or 2 , wherein R ^SX1 is a 5-membered heteroaryl.

3. A compound according to claim 1 or 2 , wherein R ^SX1 is oxazurole or isoxazole.

Q is

The compound according to claim 1 or 2 , which is

3. A compound according to claim 1 or 2 , wherein A is a 5-membered heteroaryl.

3. A compound according to claim 1 or 2 , wherein A is thiadiazole.

3. A compound according to claim 1 or 2 , wherein each R ¹³ is selected from the group consisting of oxo, C _1-6 alkylamino, di-(C _1-6 alkyl)amino, and NH ₂ .

R ⁴ is

The compound according to claim 1 or 2 , which is

below:

or a pharmaceutically acceptable salt thereof .

Empty lipid nanoparticles (empty LNPs) comprising a compound according to claim 1 or 2 , a phospholipid, a structured lipid, and a PEG lipid.

(a) about 40 mole% to about 60 mole% of the compound, about 0 mole% to about 20 mole% phospholipids, about 30 mole% to about 50 mole% structured lipids, and about 0 mole% to about 5 mole%; Contains mol% PEG lipid,
(b) The phospholipid is 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero -3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl- sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl- sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero- 3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1 , 2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2 - didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and their selected from the group consisting of a mixture;
(c) the structured lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, and mixtures thereof;
(d) the PEG lipid is selected from the group consisting of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, and mixtures thereof; and /or
(e) The PEG lipid is PEG _2k -DMG and PEG-1:

and mixtures thereof,
Empty LNP according to claim 19 .

Loaded lipid nanoparticles (loaded LNPs) comprising empty LNPs according to claim 19 and one or more therapeutic and/or prophylactic agents.

22. The loaded LNP of claim 21 , wherein the one or more therapeutic and/or prophylactic agents are nucleic acids.

The nucleic acid is RNA, and the RNA is short interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), RNA interference (RNAi) molecule, micro RNA (miRNA), antagomir, antisense RNA, ribozyme, dicer substrate RNA ( 23. The loaded LNP of claim 22 , wherein the loaded LNP is selected from the group consisting of small hairpin RNA (shRNA), messenger RNA (mRNA), and mixtures thereof.

24. The loaded LNP of claim 23 , wherein the RNA is mRNA.

A pharmaceutical composition comprising the loaded LNPs of claim 21 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition for delivering a therapeutic and/or prophylactic agent to cells within a subject , comprising the loaded LNP of claim 21 .

22. A pharmaceutical composition for specifically delivering a therapeutic and/or prophylactic agent to an organ of interest , comprising a loaded LNP according to claim 21 .

22. A pharmaceutical composition for producing a polypeptide of interest in cells within a subject , the composition comprising the loaded LNP of claim 21 .

22. A pharmaceutical composition for treating a disease or disorder in a subject in need thereof , comprising a loaded LNP according to claim 21 .