# US 2025/0367129 A1 · Lipid Compounds and Uses Thereof

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- Number: US 2025/0367129 A1
- Document ID: US20250367129A1
- Status: Published application
- Kind: A1
- Application number: 19/125,013
- Filed: 2023-11-01
- Published: 2025-12-04
- Earliest claimed: 2022-11-04
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Matthew Frank Brown; Daniel Paul Canterbury; Ye Che; Wenhua Jiao; Roger Hochoon Pak; Mark Edward Schnute
- Web page: https://patentgrep.com/patent/US20250367129A1

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- C07D 209/54: Spiro-condensed
- C07D 221/20: Spiro-condensed ring systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/10: Spiro-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds are provided having the following structure: (I) or a pharmaceutically acceptable salt, N-oxide, tautomer or stereoisomer thereof, wherein R1, G1, W and m, n, o and p are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a nucleic acid, compositions comprising the compounds and methods for their use and preparation are also provided.

## Claims

### Claim 1

A compound of Formula (I)
or a pharmaceutically acceptable salt, N-oxide, tautomer, or stereoisomer thereof, wherein
m, n, o, and p are each independently 1-3;
G1 is C1-12alkylene or C2-12alkenylene;
R1 is —N(R2)R3, —OR4, CN, —N(R4)(heteroaryl), —O(CH2)qOH, —(OCH2CH2)rOH, —OC(═O)R5, —N(R4)C(═O)R5, —N(R4)S(O)2R5, —N(R4)C(═O)N(R2)R3, —OC(═O)N(R2)R3, —N(R4)C(═O)OR5, —N(R4)C(═S)N(R2)R3, —N(R4)C(═NR6)N(R2)R3, or
R2 and R3 are each independently H, C1-6alkyl, C3-8cycloalkyl, or aryl; or R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R4 is H, C1-6alkyl or C3-8cycloalkyl;
R5 is C1-6alkyl or C3-8cycloalkyl optionally substituted by C1-6alkyl;
R6 is H, CN, NO2, C1-6alkyl, OR5, S(O)2R5, or S O)2N(R2)R3;
q is 2-6;
r is 1-6;
W is
X is N or CH;
G2 and G3 are each independently C1-12alkylene or C2-12alkenylene;
L1 and L2 are each independently —C(═O)OR7, —OC(═O)R7, —OC(═O)(CH2)rC(═O)OR7, —OC(═O)(CH2)rOC(═O)R7, —OC(═O)N(R4)R7, —N(R4)C(═O)OR7, —N(R4)C(═O)N(R4)R7, —OC(═O)OR7, or —S—SR7; and
R7 is C6-24alkyl, C6-24alkenyl, or C6-24alkynyl where each is optionally substituted by F, C1-6alkoxy, C3-8cycloalkyl, or C3-8cycloalkenyl, wherein the R7 of L1 and L2 may be the same or different.

### Claim at position 2

2-4. (canceled)

### Claim 5 (depends on 1)

The compound of claim 1, wherein
G1 is C1-12alkylene;
R1 is —OH or
R2 and R3 are each independently H, C1-6alkyl, or C3-8cycloalkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R4 is H, C1-6alkyl or C3-8cycloalkyl;
G2 and G3 are each independently C1-12alkylene;
L1 and L2 are each —OC(═O)R1; and
R7 is C6-24alkyl, C6-24alkenyl, or C6-24alkynyl wherein each is optionally substituted by F, C1-6alkoxy, C3-8cycloalkyl, or C3-8cycloalkenyl, wherein the R7 of L1 and L2 may be the same or different.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R7 has the following structure:

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is OH.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is

### Claim 9 (depends on 1)

The compound of claim 1, wherein G1 is C2-C5 alkylene.

### Claim 10 (depends on 1)

The compound of claim 1, wherein G1 is C3-C5 alkylene.

### Claim 11 (depends on 1)

The compound of claim 1 selected from the group consisting of:
(3-(4-hydroxybutyl)-3-azaspiro[5.5]undecane-9,9-diyl)bis(methylene) bis(2-heptylnonanoate);
2-(3-(4-hydroxybutyl)-3-azaspiro[5.5]undecan-9-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-cyclobutyldecanoate);
2-(9-(5-hydroxypentyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-hexyldecanoate);
3-((2-hexyldecanoyl)oxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl palmitate;
2-(9-(3-((2-(methylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)propyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(3-(1-methylcyclopropane-1-carboxamido)propyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(9-(3-hydroxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(3-(ethylsulfonamido)propyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[4.4]nonan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(8-(4-hydroxybutyl)-2,8-diazaspiro[4.5]decan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
3-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)pentane-1,5-diyl bis(2-hexyldecanoate);
2-(7-(5-hydroxypentyl)-2,7-diazaspiro[4.4]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(2-(5-hydroxypentyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(7-(5-hydroxypentyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)pentane-1,5-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-7-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(5-hydroxypentan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-octyldecanoate);
2-(9-(5-hydroxypentyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptyldecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-butyldecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(3-hexylundecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-pentyldecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-(cyclobutylmethyl)decanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptyltetradecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-(cyclopentylmethyl)decanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[4.4]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-(cyclopent-3-en-1-ylmethyl)decanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-(2-cyclobutylethyl)decanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-(cyclohexylmethyl)decanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(4,5-dibutylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(3,3-dibutylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(4-heptylundecanoate);
2-(7-(5-hydroxypentyl)-2,7-diazaspiro[4.4]nonan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
3-(decanoyloxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl 2-hexyldecanoate;
3-((2-hexyldecanoyl)oxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl (Z)-dodec-5-enoate;
3-((2-(cyclobutylmethyl)decanoyl)oxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl 2-hexyldecanoate;
3-((2-hexyldecanoyl)oxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl 2-butylundecanoate;
3-((4,5-dibutylnonanoyl)oxy)-2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl palmitate;
3-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)pentane-1,5-diyl bis(2-heptylnonanoate);
2-(2-(5-hydroxypentyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(7-(5-hydroxypentyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-7-yl)propane-1,3-diyl bis(2-hexyldecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(2-hydroxyethyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(7R,8R)-2-(3-hydroxypropyl)-2-azaspiro[4.4]nonane-7,8-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(3-hydroxypropyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(3-((2-(methylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)propyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(5-hydroxypentyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
(2S,3S)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-octyldecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptyltetradecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-hexyldecanoate);
rac-O,O′-((2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl) di(pentadecan-8-yl) Disuccinate;
rac-O′1,O1-((2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl) 7,7′-di(pentadecan-8-yl) di(heptanedioate);
rac-(((2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl)bis(oxy))bis(6-oxohexane-6,1-diyl) bis(2-heptylnonanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-pentyldecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptyldecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-hexylundecanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-hexylnonanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-butyldecanoate);
rac-(2R,3R)-3-((2-ethylnonanoyl)oxy)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decan-2-yl 2-hexyldecanoate; and
bis(3-pentyloctyl) 3-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)pentanedioate;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 selected from the group consisting of;
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(2-(4-hydroxybutyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(9-(5-hydroxypentyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
rac-(2R,3R)-8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,8-diazaspiro[4.5]decan-8-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(9-(3-hydroxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(2-heptylnonanoate);
2-(9-(4-hydroxybutyl)-3,9-diazaspiro[5.5]undecan-3-yl)propane-1,3-diyl bis(3-hexylundecanoate);
2-(7-(4-hydroxybutyl)-2,7-diazaspiro[4.4]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(7-(5-hydroxypentyl)-2,7-diazaspiro[3.5]nonan-2-yl)propane-1,3-diyl bis(2-hexyldecanoate);
2-(2-(4-hydroxybutyl)-2,7-diazaspiro[3.5]nonan-7-yl)propane-1,3-diyl bis(2-hexyldecanoate); and
rac-(2R,3R)-8-(5-hydroxypentyl)-8-azaspiro[4.5]decane-2,3-diyl bis(2-heptylnonanoate);
or a pharmaceutically acceptable salt thereof.

### Claim at position 11

13-40. (canceled)

### Claim 41 (depends on 1)

A pharmaceutical composition comprising a nucleic acid, at least one pharmaceutically acceptable excipient, and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 41)

The pharmaceutical composition of claim 41, wherein the pharmaceutically acceptable excipient is selected from the group consisting of neutral lipids, steroids and polymer conjugated lipids.

### Claim 43 (depends on 42)

The pharmaceutical composition of claim 42, wherein the pharmaceutical composition comprises 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phophatidylethanolamines such as 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelins (SM), or a combination thereof.

### Claim 44 (depends on 42)

The pharmaceutical composition of claim 42, wherein the steroid is cholesterol.

### Claim 45 (depends on 42)

The pharmaceutical composition of claim 42, wherein the polymer conjugated lipid is a pegylated lipid.

### Claim 46 (depends on 45)

The pharmaceutical composition of claim 45, wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer, PEG-DMG, 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159) or a PEG dialkyoxypropylcarbamate.

### Claim 47 (depends on 41)

The pharmaceutical composition of claim 41, wherein the nucleic acid is RNA.

### Claim 48 (depends on 47)

The pharmaceutical composition of claim 47, wherein the RNA is messenger RNA.

### Claim 49

(canceled)

### Claim 50 (depends on 41)

A method for administering a nucleic acid to a subject in need thereof, the method comprising preparing or providing the pharmaceutical composition of claim 41, and administering the pharmaceutical composition to the subject.

### Claim at position 22

51-53. (canceled)