Lipid compounds, lipid nanoparticle compositions and use thereof with polyribonucleotides

Abstract

This disclosure relates to lipid compounds and lipid nanoparticles (LNPs) prepared therefrom that are particularly effective in delivery of circular polyribonucleotides. Methods of use of the lipid compounds and LNPs, e.g., for circular RNA delivery, are also provided.

Description

Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 LIPID COMPOUNDS, LIPID NANOPARTICLE COMPOSITIONS AND USE THEREOF WITH POLYRIBONUCLEOTIDES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application No.63 / 744,106, filed January 10, 2025, and U. S. Provisional Patent Application No. 63 / 900,184 filed October 16, 2025, each of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Lipid nanoparticles (LNPs) are typically spherical vesicles composed of lipid compounds. LNPs recently have been demonstrated to be effective delivery systems for mRNA therapeutics, for example, in vaccines.

[0003] Certain circular polyribonucleotides are ubiquitously present in human tissues and cells, including tissues and cells of healthy individuals. While circular RNA constructs also are being developed as therapeutics, LNPs used for delivery of mRNA therapeutics may not be suitable or optimal for delivery of circular RNA therapeutics.SUMMARY

[0004] The present disclosure described herein includes novel lipid compounds, as well as LNPs and other lipid carriers incorporating the lipid compounds. The lipid compounds and lipid carriers of the disclosure are particularly suitable for and effective in delivery of polyribonucleotides. Thus, the disclosure includes use of the lipid compounds and lipid carriers in methods for delivery of nucleic acid cargos, such as delivery of coding and non-coding RNAs, into cells.

[0005] In some embodiments the disclosure relates to a compound or pharmaceutically acceptable salt thereof, of formula (I),(CH2)n-L2-R2R1-L - (CH2)p- N(CH2)n-L2-R2(I).whereinR1is C6-10 aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io aryl, 5- to 10-membered heterocyclyl ring or 5- to 10- membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, Cs-Cis alkenyl, N(Cs-Ci6 alkyl)2, CH(C4-Ci2 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alky l;Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 each R3is independently halogen, OH, oxo, SH, thioxo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with Ci- 6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl;each RBis independently C1-6 alkyl or C1-6 alkoxy;each Rcis independently H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;each REis independently C1-6 alkyl or a 5-membered heteroaryl wherein the 5- membered heteroaryl is optionally substituted with C1-6 alkyl;L1is C(O)N(H), C(O)O, or N(H);each L2is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3, 4, 5, or 6; andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0006] In some aspects, each R2is independently

[0007] In some embodiments the disclosure relates to a compound or pharmaceutically acceptable salt thereof, selected from Table A.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0008] In some embodiments, the disclosure relates to a nanoparticle composition comprising a lipid compound or pharmaceutically acceptable salt thereof the disclosure.

[0009] In some aspects, nanoparticle composition further comprises a lipid carrier.

[0010] In some aspects, the lipid carrier comprises a cationic lipid, a non-cationic lipid, a sterol, and a PEG-modified lipid. In some aspects, the lipid carrier comprises a natural lipid.

[0011] In some aspects, the nanoparticle further comprises a therapeutic and / or prophylactic agent.

[0012] In some embodiments, the disclosure relates to a pharmaceutical composition comprising the compound of the disclosure, or a nanoparticle composition of the disclosure, and a pharmaceutically acceptable carrier.

[0013] In some aspects, the pharmaceutical composition further comprises a therapeutic agent. In some aspects, the pharmaceutical composition further comprises a prophylactic agent.

[0014] In some aspects, the therapeutic agent is a nucleic acid. In some aspects, the nucleic acid is an RNA or DNA. In some aspects, the DNA or RNA is linear, circular, single stranded, or double stranded. In some aspects, the RNA is a mRNA or a circular RNA. In some aspects, the RNA is a circular RNA. In some aspects, the therapeutic agent is a protein or small molecule drug.

[0015] In some embodiments the disclosure relates to a pharmaceutical composition, wherein the pharmaceutical composition is a vaccine.

[0016] In some embodiments the disclosure relates to a method of treating a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the nanoparticle composition of the disclosure or pharmaceutical composition of the disclosure.

[0017] In some embodiments the disclosure relates to a method of preventing a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the nanoparticle composition of the disclosure or pharmaceutical composition of the disclosure.

[0018] One embodiment of the present disclosure includes a process for preparing a compound of the present disclosure. One embodiment of the present disclosure includes a compound obtained by a process of the present disclosure.

[0019] One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments may be combined in any way or combination.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0020] One or more aspects and embodiments may be incorporated in a different orientation although not specifically described. That is, all aspects and embodiments may be combined in any orientation or combination.DETAILED DESCRIPTION

[0021] The present disclosure is directed to compounds and salts thereof, compositions and methods.

[0022] This present disclosure is directed, at least in part, to lipid compounds and compositions, such as LNPs, prepared therefrom. Methods of making and using the lipid earners using the lipid compounds of the disclosure including, for example, encapsulating circular polyribonucleotides in a lipid carrier, are also provided.Definition of Terms

[0023] When describing the compounds, compositions, methods and processes of this disclosure, the following terms have the following meanings, unless otherwise indicated.

[0024] It is noted that, as used in this specification and the intended claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds.

[0025] The term "alkyl," as used herein, refers to a saturated, straight, or branched hydrocarbon chain radical having one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like. In certain embodiments, the alkyl is methyl. In certain embodiments, the alkyd is ethyl. In other embodiments the alkyl is penty l. In yet other embodiments, the alkyl is hexyl.

[0026] In some instances, the number of carbon atoms in a moiety is indicated by the prefix " Cx-Cy" or " Cx-y", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, " Ci-Ce alkyl" or " Ci-6 alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms and " C1-C3 alkyl" or " C1-3 alkyd" means an alkyd substituent containing from 1 to 3 carbon atoms. Additionally, " C1-C4 alkyl" or " Ci-4 alkyl" means an alkyl substituent containing from 1 to 4 carbon atoms.

[0027] As used herein, the term '‘halo” or “halogen” means F, Cl, Br or I.

[0028] As used herein, the term “alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl group having the specified number of carbon atoms. For example, a “Ci-Cs alkoxy” group is a radical of the formula -ORa where Ra is an alkyl group having the between one and six carbon atoms.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0029] As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a “Ci-Ce haloalky l” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.

[0030] As used herein, the term '‘haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.

[0031] As used herein, the term “heterocyclyl” refers to a stable, non-aromatic, mono-, bi-, or tricyclic (fused, bridged, or spiro) radical in which one or more ring atoms is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S), which has the specified number of ring atoms, and which is attached to the rest of the molecule by a single bond. Heterocyclic rings may be saturated, or may contain one or more double or triple bonds. In some embodiments, the “heterocyclyl” group has the indicated number of ring members, in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl includes a total of 6 ring members, at least one of which is a heteroatom (e.g.. a heteroatom independently selected fromN, O. P, and S).

[0032] As used herein, the term “heteroaryl” refers to a stable mono-, bi-, or tricyclic ring radical having the specified number of ring atoms, wherein at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatoms independently selected from N, O, P, and S). In some embodiments, each ring in the system contains 5 to 7 ring members. For example, a 6-membered heteroaryl includes a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O, and P. The term “heteroaryl” may be used interchangeably with the term “heteroary l ring” or the term “heteroaromatic”.

[0033] Tautomers are defined as two or more compounds that differ by the position of a single hydrogen atom. Typically, compounds that demonstrate tautomerism readily interconvert between the two or more tautomeric forms. Examples of tautomerism include, but are not limited to, the keto and enol forms of ketone-containing compounds, the amide and imidic acid forms of compounds containing an amide bond, as well as the hydroxy pyridine and pyridone forms of compounds containing a hydroxy-substituted pyridine ring. Additional examples of tautomerism include rings such as in:Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0034] " Pharmaceutically acceptable" carrier, diluent, or excipient is a carrier, diluent, or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0035] " Pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio.

[0036] As used herein, the term "effective amount," "effective concentration," or "concentration effective to" refers to an amount of a lipid-based carrier (or lipid nanoformulation), a liposome, a lipid nanoparticle (LNP), or nucleic acid composition, sufficient to effect the recited result or to reach a target level (e.g., a predetermined or threshold level) in or on a target organism.

[0037] The term "subject," as used herein, refers to a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0038] As used herein, the term “circRNA” or “circular RNA”, or “eRN A™7’ or “circular polyribonucleotide” are used interchangeably and mean a polyribonucleotide molecule that has a structure having no free ends (i.e., no free 3’ and / or 5’ ends), for example a polyribonucleotide molecule that forms a circular or end-less structure through covalent or non-covalent bonds.

[0039] As used herein, the term "reporter gene" refers to a polynucleotide that encodes a molecule that may be detected readily, either directly or by its effect on the host cell (phenotype). Exemplary reporter genes encode enz mes, luminescent or fluorescent proteins, antigenic epitopes (for example HiBit Tags), mRNA of distinct sequences, and the like.

[0040] As used herein, the term "cell-penetrating agent" refers to agents that alter properties (e.g., permeability) of the cell wall, extracellular matrix, or cell membrane of a cell (e.g., an animal cell, a plant cell, a bacterial cell, or a fungal cell) in a manner that promotes increased cell uptake relative to a cell that has not been contacted with the agent.Compounds

[0041] The present disclosure provides compounds having chemical structures as described herein. In one embodiment, the compounds of the present disclosure are represented by formula (I), or pharmaceutically acceptable salts thereof:(CH2)n-L2-R2R1-L -(CH2)P-N(CH2)n- L2-R2(1).whereinAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 R1is Ce-io aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io ary l. 5- to 10-membered heterocyclyl ring or 5- to 10- membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, Cs-Cis alkenyl, N(Cs-Ci6 alkyl)2, CH(C4-Ci2 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl;each R3is independently halogen, OH, oxo, SH, thioxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalky 1, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with Ci- 6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl;each RBis independently C1-6 alkyl or C1-6 alkoxy;each Rcis independently H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;each REis independently C1-6 alkyl or a 5-membered heteroaryl wherein the 5- membered heteroaryl is optionally substituted with C1-6 alkyl;L1is C(O)N(H), C(O)O, or N(H);each L2is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3, 4, 5, or 6; andeach n is independently 1, 2, 3. 4, 5, 6. 7, or 8.

[0042] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Li is C(O)N(H), C(O)O, orN(H). In some embodiments, Li is C(O)N(H). In some embodiments, Li is C(O)O. In some embodiments, Li is N(H).

[0043] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each L2is independently selected from the group consisting of absent, C(CHs)2C(O)O, C(O)O, and OC(O)O. In some embodiments, at least one L2is absent. In some embodiments, at least one L2is C(CH3)2C(O)O. In some embodiments, at least one L2is C(O)O. In some embodiments, at least one L2is OC(O)O.

[0044] In some embodiments, at least one L2is C(CH3)2C(O)O and at least one L2is absent. In some embodiments, at least one L2is C(CH3)2C(O)O and at least one L2is C(CH3)2C(O)O. In some embodiments, at least one L2is C(CH3)2C(O)O and at least one L2is C(O)O. In some embodiments, at least one L2is C(CH3)2C(O)O and at least one L2is OC(O)O.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0045] In some embodiments, at least one L2 is C(O)O and at least one L2 is C(CH3)2C(O)O.

[0046] In one embodiment, the compounds of formula (I) may be of formula (I- A), or pharmaceutically acceptable salts thereof:0 (I-A).

[0047] In one embodiment, the compounds of formula (I) may be of formula (I-B), or pharmaceutically acceptable salts thereof:

[0048] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of Ce-10 ary l, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io aryl, 5- to 10-membered heterocyclyl ring and 5- to 10-membered heteroaiyl ring are optionally substituted with one to four R3. In some embodiments. R1is Cs-io aryl optionally substituted with one to four R3. In some embodiments, R1is a 5- to 10-membered heterocyclyl ring optionally substituted with one to four R3. In some embodiments, Ri is a 5- to 10-membered heteroaryl ring optionally substituted with one to four R3.

[0049] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one to four R3. In some aspects, when R1is a 5-membered heteroar l ring, each R3is independently selected from oxo, OH, halo, C1-6 alkoxy, C3-6 cycloalkyl, C(O)N(Rc)2, S(O)2N(RA)2or phenyl optionally substituted with one to two RB. In some aspects, when R1is a 5-membered heteroaryl ring, each R3is independently selected from oxo. OH, Cl, CH3, CH2CH2CH3, cyclpropyl, C(O)N(H)2, C(O)N(H)CH3, C(O)N(H)(CH2)2CH3, OCH2CH3, S(O)2N(H)2, S(O)2N(H)CHS, S(O)2N(H)- 1-methyl-lH-pyrazole, or phenyl optionally substituted with OCH3.

[0050] In other aspects, R1is selected from the group consisting of pyrazole. isoxazole, thiophene, thiazole, or thiadiazole wherein the pyrazole, imidazole, triazole, isoxazole, thiophene, thiazole, and thiadiazole are optionally substituted with one R3. In some aspects, R1is pyrazole optionally substituted with one to two R3. In some aspects, R1is imidazole optionallyAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 substituted with one to two R3. In some aspects, R1is triazole optionally substituted with one to two R3. In some aspects, R1is isoxazole optionally substituted with one to two R3. In some aspects, R1is thiophene optionally substituted with one to two R3. In some aspects, R1is thiazole optionally substituted with one to two R3. In further aspects, R1is selected from the group consisting of:Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1. In some aspectsR1is

[0051] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a Ce-io aryl optionally substituted with one to four R3. In some aspects, R1is a phenyl ring. In some aspects, when R1is a phenyl ring, each R3is independently selected from halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, C(O)N(Rc)2, N(RD)C(O)-RE, S(O)2RB, and S(O)2N(RA)2. In some aspects, when R1is a phenyl ring, each R3is independently selected from F, OH, OCH3, OCF2CHF2, C1-6 haloalkoxy, C(O)N(H)CH3, N(H)C(O)-CH3, N(H)C(O)-furyl, S(O)2CHs, S(O)2N(H)2, S(O)2N(H)CH3, S(O)2N(CH3)2, S(O)2N(H)CH(CH3)2, S(O)2N(H)CH2CH3, S(O)2N(H)-cycloproyl, S(O)2N(H)-oxetane, and S(O)2N(H)- azepane. In further aspects, R1is selected from the group consisting of:

[0052] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heteroaryl ring optionally substituted with one to four R3. In some aspects, when R1is a 6-membered heteroaryl ring, each R3is independently selected from OH, C1-6 alkyl, S-C1-6 alkyl, S(O)2N(RA)2. In some aspects, when R1is a 6-membered heteroaryl ring, each R3is independently selected from OH, CH3,Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 SCHs, and S(0)2N(H)CH?. In other aspects, R1is selected from the group consisting of pyrimidine and pyridine wherein the pyrimidine and pyridine optionally substituted with one to two R3. In further aspects, R1is selected from the group consisting of:

[0053] In some aspects R1is selected from the group consisting of:

[0054] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 8-membered heteroaryl optionally substituted with one to four R3. In some aspects, R1is 1H-imidazo[1,2-b]pyrazole. In some aspects, R1is

[0055] In some embodiments, the disclosure relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heteroaryl optionally substituted with one to four R3. In some aspects, when R1is a 9-membered heteroaryl, each R3is independently selected from halo, OH, and C1-6alkyl. In some aspects, when R1is a 9-membered heteroaryl, each R3is independently selected from F, OH, and CH3.

[0056] In some aspects, R1is selected from the group consisting of pyrazolo[1,5-a]pyrazine, 1H-pyrazolo[3,4-b]pyridine, imidazo[1,5-a]pyrazine, and 1H-indole wherein the pyrazolo[1,5-a]pyrazine, 1H-pyrazolo[3,4-b]pyridine, imidazo[1,5-a]pyrazine, and 1H-indole are optionally substituted with one to two R3. In further aspects, R1is selected from the group consisting of:Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0057] In some aspects, R1is selected from the group consisting of

[0058] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heteroaryl ring optionally substituted with one to four R3. In some aspects, when R1is a 10-membered heteroaryl ring, each R3is independently selected from halo, OH, or N(RC)2. In some aspects, when R1is a 10-membered heteroaryl ring, each R3is independently selected from Cl, OH, or N(H)2.

[0059] In some aspects, R1is a quinoline optionally substituted with one R3. In some aspects, R1is selected from the group consisting of:H

[0060] In some aspects, R1is.

[0061] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heterocyclyl optionally substituted with one to four R3. In some aspects, R1is pyrrolidine or imidazolidine, wherein the pyrrolidine or imidazolidine are optionally substituted with one R3.

[0062] In some aspects, when R1is a 5-membered heterocyclyl ring, each R3is independently selected from oxo or OH. In some aspects, R1is selected from the group consisting of:Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0063] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is an 8-membered heterocyclyl optionally substituted with one to four R3. In some aspects, R1is 3,5-dihydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide optionally substituted with one R3. In some aspects, R1is

[0064] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heterocyclyl optionally substituted with one to four R3. In some aspects, when R1is a 9-membered heterocyclyl, each R3is independently selected from Ci-6 alkyl, oxo, or OH. In some aspects, when R1is a 9-membered heterocyclyl, each R3is independently selected from CH3, oxo, or OH.

[0065] In some aspects, R1is selected from the group consisting of a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 6,7-dihydropyrazolo[1,5-a]pyrazine, 2,3-dihydro-1H-imidazo[4,5-b]pyridine, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, and 3H-imidazo[4,5-b]pyridine, wherein 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 6,7-dihydropyrazolo[1,5-a]pyrazine, 2,3-dihydro-1H-imidazo[4,5-b]pyridine, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, and 3H-imidazo[4,5-b]pyridine are optionally substituted with one R3. In further aspects, R1is selected from the group consisting of

[0066] In some aspects, R1is

[0067] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heterocyclyl optionally substituted with one to four R3. In some aspects, when R1is a 10-membered heterocyclyl, each R3is independently selected oxo, C1-6 alkyl, or C1-6 alkoxy. In some aspects, when R1is a 10-membered heterocyclyl, each R3is independently selected oxo, CH3, or OCH3.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0068] In some aspects, R1is selected from the group consisting of a 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine, 7,8-dihydro-6H-pyrazolo[1,5-a][1,4]diazepine, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine, 1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 1,2-dihydropyrido[2,3-d]pyrimidine, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine, and 4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepine, wherein the 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine, 7,8-dihydro-6H-pyrazolo[1,5-a][1,4]diazepine, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine, 1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 1,2-dihydropyrido[2,3-d]pyrimidine, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine, or 4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diazepine are optionally substituted with one to three R3. In further aspects, R1is selected from the group consisting of:

[0070] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2is selected from the group consisting of a C10-C20 alkyl, C8-C18 alkenyl, N(C8-C16 alkyl)2, CH(C4-C12 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl. In some embodiments, at least one R2is a C10-C20alkyl. In some embodiments, at least one R2is a Cs-Cis alkenyl. In some embodiments, at least one R2is a N(Cs-Ci6 alkyl)2. In some embodiments, at least one R2is a CH(C4-Ci2Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 alkoxy )2. In some embodiments, at least one R2is a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl.

[0071] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2is selected from the group consistingatleast one R2is a N(C8-12alkyl)2. In some embodiments, at least oneR2is. In some embodiments, at least one R2is0In some embodiments, at least oneIn some embodiments, at least one R2isIn some embodiments, at least one R2is. In some embodiments, at least one R2isIn some embodiments, at least one R2is. In someembodiments, at least one R2isIn some embodiments, at least one R2is [image]. In some embodiments, at least one R2isIn some embodiments, at least one R2isAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1In some embodiments, at least one R2isIn some embodiments, at least one R2isatleast one R2is. In some embodiments, R2are the same. In some embodiments, R2are different.

[0072] In some embodiments, one R2isand one R2is. In some embodiments, one R2isIn some embodiments, one R2is and one R2is. In some embodiments, one R2is

[0073] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is unsubstituted. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R3is selected from the group consisting of halogen. OH, oxo, SH, thioxo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB. In some embodiments, at least one R3is halogen. In some embodiments, at least one R3is OH. In some embodiments, at least one R3is oxo. In some embodiments, at least one R3is SH. In some embodiments, at least one R3is thioxo. In some embodiments, at least one R3is C1-6 alkyl. In some embodiments, at least one R3is C1-6 alkoxy. In some embodiments, at least one R3is C1-6 haloalkoxy. In some embodiments, at least one R3is C3-6cycloalkyl. In some embodiments, at least one R3is C1-6 haloalkyl, C(O)N(RC)2. In some embodiments, at least one R3is N(RD)C(O)-RE. In some embodiments, at least one R3is N(RC)2.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 In some embodiments, at least one R3is S(O)2RBIn some embodiments, at least one R3is S(O)2N(RA)2. In some embodiments, at least one R3is S-Ci-6 alkyl. In some embodiments, at least one R3is phenyl wherein the phenyl is optionally substituted with one to two RB.

[0074] In some embodiments, at least one R3is F. In some embodiments, at least one R3is Cl. In some embodiments, at least one R3is CH3. In some embodiments, at least one R3is cyclopropyl. In some embodiments, at least one R3is OCH3. In some embodiments, at least one R3is OCH2CH3. In some embodiments, at least one R3is OCF2CHF2. In some embodiments, at least one R3is SCH3. In some embodiments, at least one R3is phenyl. In some embodiments, at least one R3is phenyl-OCH3. In some embodiments, at least one R3is C(O)NH2. In some embodiments, at least one R3is N(H)C(O)-CH3. In some embodiments, at least one R3is SO2CH3. In some embodiments, at least one R3is N(H)C(O)-furan. In some embodiments, at least one R3is SO2NH2. In some embodiments, at least one R3is SO2NHCH3. In some embodiments, at least one R3is SO2NHCH(CH3)2. In some embodiments, at least one R3is SO2NH-cyclopropyl. In some embodiments, at least one R3is SO2NH-oxetane. In some embodiments, at least one R3is SO2NH-1 -methyl pyrazole. In some embodiments, at least one R3is SO2-azepane. In some embodiments, at least one R3is SCH3.

[0075] In some embodiments, at least two R3are Cl. In some embodiments, at least two R3are F. In some embodiments, at least two R3are CH3. In some embodiments, at least two R3are OCH3

[0076] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl. In some embodiments, at least one RAis H, C1-6alkyl. In some embodiments, at least one RAis C3-6 cycloalkyl. In some embodiments, at least one RAis 4-6 membered heterocyclyl. In some embodiments, at least one RAis a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl. In some embodiments, two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

[0077] In some embodiments, one RAis H and one RAis H. In some embodiments, one RAis H and one RAis CH3. In some embodiments, one RAis CH3 and one RAis CH3. In some embodiments, one RAis H and one RAis CH(CH3)2. In some embodiments, one RAis H and one RAis cyclopropyl. In some embodiments, one RAis H and one RAis pyrazole. In some embodiments, one RAis H and one RAis 1 -methyl- IH-pyrazole. In some embodiments, one RAAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 is H and one RAis oxetane. In some embodiments, two RAtogether with the nitrogen to which they are attached form an azepane ring. In some embodiments, each RAis the same. In some embodiments, each RAis different.

[0078] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of C1-6 alkyl and Ci-6 alkoxy. In some embodiments, at least one RBis Ci-6 alkyl. In some embodiments, at least one RBis Ci-6 alkoxy. In some embodiments, at least one RBis OCH3. In some embodiments, at least one RBis CH3. In some embodiments, two RBare CH3.

[0079] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkoxy. In some embodiments, at least one Rcis H. In some embodiments, at least one Rcis C1-6 alkyl. In some embodiments, at least one Rcis C3-6 cycloalkyl. In some embodiments, at least one Rcis C1-6 alkoxy. In some embodiments, one Rcis H and one Rcis H. In some embodiments, each Rcis the same. In some embodiments, each Rcis different.

[0080] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from the group consisting of H and C1-6 alkyl. In some embodiments, RDis H. In some embodiments, RDis C1-6 alkyd. In some embodiments, RDis CH3.

[0081] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each REis independently selected from the group consisting of C1-6 alkyl and a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl. In some embodiments, REis C1-6 alkyl. In some embodiments, REis a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6alkyl. In some embodiments. REis a 5-membered heteroaryl. In some embodiments, REis a 5-membered heteroaryl is optionally substituted with one C1-6 alkyl.

[0082] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0083] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each n is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, at least one n is 1. In some embodiments, at least one n is 2. In some embodiments, at least one n is 3. In some embodiments, at least one n is 4. In someAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 embodiments, at least one n is 5. In some embodiments, n is 6. In some embodiments, at least one n is 7. In some embodiments, at least one n is 8. In some embodiments, each n is the same. In some embodiments, each n is different. In some embodiments, one n is 6 and one n is 6.

[0084] In one embodiment, the compounds of the present disclosure are represented by formula (II), or pharmaceutically acceptable salts thereof:(CH2)n-L2-R2R1-L -(CH2)p-N(CH2)n-L2-R2(n).whereinR1is Ce-io aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io aryl, 5- to 10-membered heterocyclyl ring or 5- to 10- membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, Cs-Ci6 alkenyl, N(Cs-Ci6 alkyl)2, CH(C4-Ci2 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl;each R3is independently halogen, OH, oxo, SH, thioxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, C1-6haloalkyl, C(O)N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with Ci- 6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl;each RBis independently C1-6alkyl or C1-6alkoxy;each Rcis independently H, C1-6 alkyl. C3-6 cycloalkyl, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;each REis independently C1-6alkyl or a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6alkyl;L1is C(O)N(H), C(O)O, or N(H);each L2is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3, 4, 5, or 6; andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0085] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of Ce-10 aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io ary l. 5- to 10-membered heterocyclyl ring and 5- to 10-membered heteroaryl ring areAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 optionally substituted with one to four R3. In some embodiments, R1is Ce-io aryl optionally substituted with one to four R3. In some embodiments, R1is a 5- to 10-membered heterocyclyl ring optionally substituted with one to four R3. In some embodiments, Ri is a 5- to 10-membered heteroaryl ring optionally substituted with one to four R3.

[0086] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one to four R3. In some aspects, when R1is a 5-membered heteroaryl ring, each R3is independently selected from Ci-6 alkoxy, C3-6 cycloalkyl C(O)N(Rc)2, S(O)2N(RA)2or phenyl optionally substituted with one to two RB.

[0087] In other aspects, R1is selected from the group consisting of pyrazole, isoxazole, thiophene, thiazole, or thiadiazole wherein the pyrazole, isoxazole, thiophene, thiazole, and thiadiazole are optionally substituted with one R3. In some aspects, R1is pyrazole optionally substituted with one R3. In some aspects, R1is isoxazole optionally substituted with one R3. In some aspects, R1is thiophene optionally substituted with one R3. In some aspects, R1is thiazole optionally substituted with one R3. In further aspects, R1is selected from the group consisting

[0088] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a Ce-io aryl optionally substituted with one to four R3. In some aspects, R1is a phenyl ring. In some aspects, when R1is a phenyl ring.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 each R3is independently selected from halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and S(O)2N(RA)2. In further aspects, R1is selected from the group consisting of:

[0089] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heteroaryl ring optionally substituted with one to four F. In some aspects, when R1is a 6-membered heteroaryl ring, each R3is independently selected from OH, Ci-6 alkyl, and S-Ci-6 alkyl.

[0090] In other aspects, R1is selected from the group consisting of pyrimidine and pyridine wherein the pyrimidine and pyridine optionally substituted with one to two R3. In further aspects, R1is selected from the group consisting of:HO HO

[0091] In some aspects R1is selected from the group consisting of:Attomey Docket 96676-435728 | Client Ref: SBM24-112WO1

[0092] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heteroaryl optionally substituted with one to four R3. In some aspects, when R1is a 9-membered heteroaryl, each R3is independently selected from halo, OH, and C1-6 alkyl.

[0093] In some aspects, R1is selected from the group consisting of pyrazolo[l,5-a]pyrazine, 1H-pyrazolo[3,4-b]pyridine, and IH-indole wherein the pyrazolo[l,5-a]pyrazine, lH-pyrazolo[3,4-b]pyridine, and IH-indole are optionally substituted with one to two R3. In further aspects, R1is selected from the group consisting of:

[0094] In some aspects, R1is

[0095] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heteroaryl ring optionally substituted with one to four R3. In some aspects, when R1is a 10-membered heteroaryl ring, each R3is independently selected from halo or OH.

[0096] In some aspects, R1is a quinoline optionally substituted with one R3. In some aspects, R1is selected from the group consisting of:

[0097] In some aspects, R1is.

[0098] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heterocyclyl optionally substituted with one to four R3. In some aspects, when R1is a 9-membered heterocyclyl, each R3is independently selected oxo or OH.

[0099] In some aspects, R1is selected from the group consisting of a 4, 5, 6, 7-tetrahydropyrazolo[l,5-a]pyrazine, 6,7-dihydropyrazolo[l,5-a]pyrazine, 2,3 -dihydro- 1H-imidazo[4,5-b]pyridine, and 3H-imidazo[4,5-b]pyridine, wherein 4, 5,6.7-tetrahydropyrazolo[l,5-a]pyrazine, 6,7-dihydropyrazolo[l,5-a]pyrazine, 2,3 -dihydro- 1H-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 imidazo[4,5-b]pyridine, and 3H-imidazo[4,5-b]pyridine are optionally substituted with one R3. In further aspects, R1is selected from the group consisting of:

[0101] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heterocyclyl optionally substituted with one to four R3. In some aspects, when R1is a 10-membered heterocyclyl, each R3is independently selected oxo, Ci-6 alkyl, or Ci-6 alkoxy.

[0102] In some aspects, R1is selected from the group consisting of a 5.6.7.8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine, 7,8-dihydro-6H-pyrazolo[l,5-a][l,4]diazepine, 5, 6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine, l,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 1,2-dihydropyrido[2,3-d]pyrimidine, 3,4-dihydro-2H-benzo[b] [l,4]oxazine, 2H-benzo[b][ 1,4] oxazine, 2,3,4,5-tetrahydro-lH-pyrrolo[l,2-a][l,4]diazepine, and 4,5-dihydro-3H-pyrrolo[l,2-a][l,4]diazepine, wherein the 5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][I,4]diazepine, 7,8-dihydro-6H-pyrazolo[l,5-a][l,4]diazepine, 5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a] [ 1,4] diazepine, l,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, l,2-dihydropyrido[2,3-d]pyrimidine, 3,4-dihydro-2H-benzo[b][1.4]oxazine, 2H-benzo[b][ 1,4] oxazine, 2,3,4,5-tetrahydro-lH-pyrrolo[l,2-a][ 1,4] diazepine, or 4, 5-dihydro-3H-pyrrolo[l,2-a][ 1.4] diazepine are optionally substituted with one to three R3. In further aspects, R1is selected from the group consisting of:Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0104] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R2is selected from the group consisting of a C10-C20 alkyl, Cs-Ci6 alkenyl, N(Cs-Ci6 alkyl)2. CH(C4-Ci2 alkoxy )2. or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl. In some embodiments, at least one R2is a C10-C20 alkyl. In some embodiments, at least one R2is a C8-C16 alkenyl. In some embodiments, at least one R2is a N(Cs-Ci6 alkyl)2. In some embodiments, at least one R2is a CH(C4-Ci2 alkoxy )2. In some embodiments, at least one R2is a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl.

[0105] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R2is selected from the group consistingAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1some embodiments, at least oneR2is In some embodiments, at leastIn some embodiments, at least one R2is. In some embodiments, at least one R2is"'h-. In some embodiments, atleast one R2is In some embodiments, at least one R2isIn some embodiments, at least one R2is some embodiments, at least one R2is. In some embodiments, at least one R2isIn some embodiments, at least one R2isIn some embodiments, at least one R2isIn some embodiments, at least one R2is. In some embodiments, atleast one R2is. In some embodiments, R2are the same. In some embodiments, R2are different.

[0106] In some embodiments, one R2isand one R2is. In some embodiments, one R2is andAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 O'O'. In some embodiments, one R2is and oneR2is.

[0107] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is unsubstituted. In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R3is selected from the group consisting of halogen, OH, oxo, SH, thioxo, C1-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalky 1, C(O)N(Rc)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB. In some embodiments, at least one R3is halogen. In some embodiments, at least one R3is OH. In some embodiments, at least one R3is oxo. In some embodiments, at least one R3is SH. In some embodiments, at least one R3is thioxo. In some embodiments, at least one R3is C1-6 alky l. In some embodiments, at least one R3is C1-6 alkoxy. In some embodiments, at least one R3is C1-6 haloalkoxy. In some embodiments, at least one R3is C3-6 cycloalkyl. In some embodiments, at least one R3is C1-6 haloalkyl, C(O)N(RC)2. In some embodiments, at least one R3is N(RD)C(O)-RE. In some embodiments, at least one R3is S(O)2RB. In some embodiments, at least one R3is S(O)2N(RA)2. In some embodiments, at least one R3is S-C1-6 alkyl. In some embodiments, at least one R3is phenyl wherein the phenyl is optionally substituted with one to two RB.

[0108] In some embodiments, at least one R3is F. In some embodiments, at least one R3is Cl. In some embodiments, at least one R3is CH3. In some embodiments, at least one R3is cyclopropyl. In some embodiments, at least one R3is OCH3. In some embodiments, at least one R3is OCH2CH3. In some embodiments, at least one R3is OCF2CHF2. In some embodiments, at least one R3is SCH3. In some embodiments, at least one R3is phenyl. In some embodiments, at least one R3is phenyl-OCH3. In some embodiments, at least one R3is C(O)NH2. In some embodiments, at least one R3is N(H)C(O)-CH3. In some embodiments, at least one R3is SO2CH3. In some embodiments, at least one R3is N(H)C(O)-furan. In some embodiments, at least one R3is SO2NH2. In some embodiments, at least one R3is SO2NHCH3. In some embodiments, at least one R3is SO2NHCH(CH3)2In some embodiments, at least one R3is SO2NH-cyclopropyl. In some embodiments, at least one R3is SO2NH-oxetane. In some embodiments, at least one R3is SO2NH-1-methyl pyrazole. In some embodiments, at least one R3is SO2-azepane. In some embodiments, at least one R3is SCH3.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0109] In some embodiments, at least two R3are Cl. In some embodiments, at least two R3are F. In some embodiments, at least two R3are CH3. In some embodiments, at least two R3are OCH3.

[0110] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl. In some embodiments, at least one RAis H, C1-6 alkyl. In some embodiments, at least one RAis C3-6 cycloalkyl. In some embodiments, at least one RAis 4-6 membered heterocyclyl. In some embodiments, at least one RAis a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl. In some embodiments, two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl.

[0111] In some embodiments, one RAis H and one RAis H. In some embodiments, one RAis H and one RAis CH3. In some embodiments, one RAis CH3 and one RAis CH3. In some embodiments, one RAis H and one RAis CH(CH3)2. In some embodiments, one RAis H and one RAis cyclopropyl. In some embodiments, one RAis H and one RAis pyrazole. In some embodiments, one RAis H and one RAis 1 -methyl- IH-pyrazole. In some embodiments, one RAis H and one RAis oxetane. In some embodiments, two RAtogether with the nitrogen to which they are attached form an azepane ring. In some embodiments, each RAis the same. In some embodiments, each RAis different.

[0112] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy. In some embodiments, at least one RBis C1-6 alkyl. In some embodiments, at least one RBis C1-6 alkoxy. In some embodiments, at least one RBis OCH3. In some embodiments, at least one RBis CH3. In some embodiments, two RBare CH3.

[0113] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkoxy. In some embodiments, at least one Rcis H. In some embodiments, at least one Rcis C1-6 alkyl. In some embodiments, at least one Rcis C3-6 cycloalkyl. In some embodiments, at least one Rcis C1-6 alkoxy. In some embodiments, one Rcis H and one Rcis H. In some embodiments, each Rcis the same. In some embodiments, each Rcis different.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0114] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from the group consisting of H and Ci-6 alkyl. In some embodiments, RDis H. In some embodiments, RDis Ci-6 alkyl. In some embodiments, RDis CH3.

[0115] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each REis independently selected from the group consisting of C1-6 alkyl and a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl. In some embodiments, REis C1-6 alkyl. In some embodiments, REis a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl. In some embodiments, REis a 5-membered heteroaryl. In some embodiments, REis a 5-membered heteroaryl is optionally substituted with one C1-6 alkyl.

[0116] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Li is C(O)N(H), C(O)O, or N(H). In some embodiments, Li is C(O)N(H). In some embodiments, Li is C(O)O. In some embodiments, Li is N(H).

[0117] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each L2 is independently selected from the group consisting of absent, C(CH3)2C(O)O, C(O)O. and OC(O)O. In some embodiments, at least one L2 is absent. In some embodiments, at least one L2 is C(CH3)2C(O)O. In some embodiments, at least one L2 is C(O)O. In some embodiments, at least one L2 is OC(O)O.

[0118] In some embodiments, at least one L2 is C(CH3)2C(O)O and at least one L2 is absent. In some embodiments, at least one L2 is C(CH3)2C(O)O and at least one L2 is C(CH3)2C(O)O. In some embodiments, at least one L2 is C(CH3)2C(O)O and at least one L2 is C(O)O. In some embodiments, at least one L2 is C(CHs)2C(O)O and at least one L2 is OC(O)O.

[0119] In some embodiments, at least one L2 is C(O)O and at least one L2 is C(CH3)2C(O)O.

[0120] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein p is I, 2, 3. 4. 5, or 6. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0121] In some embodiments, the disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each n is independently 1, 2, 3. 4, 5, 6. 7, or 8. In some embodiments, at least one n is 1. In some embodiments, at least one n is 2. In some embodiments, at least one n is 3. In some embodiments, at least one n is 4. In some embodiments, at least one n is 5. In some embodiments, n is 6. In some embodiments, at leastAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 one n is 7. In some embodiments, at least one n is 8. In some embodiments, each n is the same. In some embodiments, each n is different. In some embodiments, one n is 6 and one n is 6.

[0122] In one embodiment, the compounds of the present disclosure are represented by formula (II-A), or pharmaceutically acceptable salts thereof:,0HN— (CH2)p— N'YCH fxdr0"R20(II-A);whereinR1is C6-10 aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io aryl, 5- to 10-membered heterocyclyl ring and 5- to 10-membered heteroary l ring are optionally substituted with one to four R3;each R2is independently aCn-is alky l; a C(0-Cs-i2 alkyl)2, aN(Cs-i2 alky 1)2,each R3is independently selected from halo, OH, oxo, Ci-6 alky l, Ci-6 alkoxy, Ci-6 haloalky 1, C 1-6 haloalkoxy, C3-6 cycloalkyl, C(0)N(Rc)2, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, or 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, ortwo RAtogether with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl;each RBis independently C1-6 alkyl or C1-6 alkoxy;Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 each Rcis independently H, Ci-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy;p is 1, 2, 3, 4, 5, or 6; andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0123] In some embodiments, the disclosure relates to a compound of formula (II- A), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of Ce- 10 aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io ary l. 5- to 10-membered heterocyclyl ring and 5- to 10-membered heteroaryl ring are optionally substituted with one to four R3. In some embodiments, R1is C6-10 ar l optionally substituted with one to four R3. In some embodiments, R1is a 5- to 10-membered heterocyclyl ring optionally substituted with one to four R3. In some embodiments, Ri is a 5- to 10-membered heteroaryl ring optionally substituted with one to four R3.

[0124] In some embodiments, the disclosure relates to a compound of formula (II- A), or a pharmaceutically acceptable salt thereof, wherein each R2is selected from the group consistingleast one R2is a Cn-is alkyl. In some embodiments, at least one R2is a C(O-Cs-i2 alkyl)2. In some embodiments, at least one R2is aN(Cs-i2 alkyl)2. In some embodiments, at least one R2isOembodiments, at least one R2isjn someembodiments, at least oneR2is. In some embodiments, at least one R2isInAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1some embodiments, at least one R2isIn some embodiments, at least oneIn some embodiments, at least one R2is In some embodiments, at least one R2isIn some embodiments, at least one R2isIn some embodiments, at least one R2is. In some embodiments, atleast one R2is. In some embodiments, R2are the same. In some embodiments, R2are different.

[0125] In some embodiments, one R2isand one R2is

[0126] In some embodiments, the disclosure relates to a compound of formula (II- A), or a pharmaceutically acceptable salt thereof, wherein each R3is selected from the group consisting of halogen, OH, oxo, Ci-e alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C3-6 cycloalkyl, C(O)N(RC)2, S(O)2N(RA)2, S-C1-6 alkyl and phenyl wherein the phenyl is optionally substituted with one to two C1-6 alkyl and C1-6 alkoxy. In some embodiments, at least one R3is halo. In some embodiments, at least one R3is OH. In some embodiments, at least one R3is oxo. In some embodiments, at least one R3is C1-6 alkyl. In some embodiments, at least one R3is C1-6 alkoxy. In some embodiments, at least one R3is C1-6 haloalkyl. In some embodiments, at least one R3is C1-6 haloalkoxy. In some embodiments, at least one R3is C3-6cycloalkyl. In some embodiments, at least one R3is C(O)N(Rc)2. In some embodiments, at least one R3is S(O)2N(RA)2. In some embodiments, at least one R3is S-C1-6 alkyl. In some embodiments, at least one R3is phenyl wherein the phenyl is optionally substituted with one to two RB.

[0127] In some embodiments, at least one R3is F. In some embodiments, at least one R3is Cl. In some embodiments, at least one R3is CH3. In some embodiments, at least one R3is cyclopropyl. In some embodiments, at least one R3is OCH3. In some embodiments, at least one R3is OCH2CH3. In some embodiments, at least one R3is OCF2CHF2. In some embodiments, at least one R3is SCH3. In some embodiments, at least one R3is phenyl. In some embodiments, atAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 least one R3is phenyl-OCH3. In some embodiments, at least one R3is C(O)NH2. In some embodiments, at least one R3is SO2NH2. In some embodiments, at least one R3is SO2NHCH3 In some embodiments, at least one R3is SO2NHCH(CH3)2. In some embodiments, at least one R3is SO2NH-cyclopropyl. In some embodiments, at least one R3is SO2NH-I -methyl pyrazole. In some embodiments, at least one R3is SO2-azepane.

[0128] In some embodiments, the disclosure relates to a compound of formula (II- A), or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, 5-membered heteroaryl wherein the 5-membered heteroaryl are optionally substituted with C1-6 alkyl, and two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl. In some embodiments, at least one RAis C1-6 alkyl. In some embodiments, at least one RAis C3-6 cycloalkyl. In some embodiments, at least one RAis 5-membered heteroaryl optionally substituted with C1-6 alkyl. In some embodiments, two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl.

[0129] In some embodiments, one RAis H and one RAis H. In some embodiments, one RAis H and one RAis CH3. In some embodiments, one RAis H and one RAis CH(CH3)2. In some embodiments, one RAis H and one RAis cyclopropyl. In some embodiments, one RAis H and one RAis pyrazole. In some embodiments, one RAis H and one RAis 1 -methyl- IH-pyrazole. In some embodiments, two RAtogether with the nitrogen to which they are attached form an azepane ring. In some embodiments, each RAis the same. In some embodiments, each RAis different.

[0130] In some embodiments, the disclosure relates to a compound of formula (II- A), or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of C1-6 alky l and C1-6 alkoxy. In some embodiments, at least one RBis C1-6 alky-1. In some embodiments, at least one RBis C1-6 alkoxy. In some embodiments, at least one RBis OCH3.

[0131] In some embodiments, the disclosure relates to a compound of formula (II-A), or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkoxy. In some embodiments, at least one Rcis H. In some embodiments, at least one Rcis C1-6 alkyl. In some embodiments, at least one Rcis C3-6 cycloalkyl. In some embodiments, at least one Rcis C1-6 alkoxy. In some embodiments, one Rcis H and one Rcis H. In some embodiments, each Rcis the same. In some embodiments, each Rcis different.

[0132] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, 3, 4. 5, or 6. In some embodiments, pAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0133] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each n is independently 1, 2, 3. 4, 5, 6, 7, or 8. In some embodiments, at least one n is 1. In some embodiments, at least one n is 2. In some embodiments, at least one n is 3. In some embodiments, at least one n is 4. In some embodiments, at least one n is 5. In some embodiments, n is 6. In some embodiments, at least one n is 7. In some embodiments, at least one n is 8. In some embodiments, each n is the same. In some embodiments, each n is different. In some embodiments, one n is 6 and one n is 6.

[0134] In some embodiments, one R2is andoneR2js' p js4; andeach n is 6.

[0135] The present disclosure provides compounds that are lipids which may form lipid nanoparticles. Without intending to be bound by theory, lipid nanoparticles are typically spherical vesicles composed of lipid compounds which encapsulate a compound of interest and aid in delivery of the compound to specific tissues.

[0136] In the following descriptions and embodiments, references to specific substituents only correspond to formula numbers in which those specific substituents are present or appear.Lipid Compositions

[0137] In another aspect, the present disclosure provides compositions comprising a lipid compound of the disclosure and a lipid carrier. Non-limiting examples of lipid carriers include lipid vesicles, liposomes and lipid nanoparticles (LNPs). As used herein, a “lipid vesicle” refers to a closed structure organized in lipid bilayers with an internal (e.g, aqueous) compartment. As used herein, a “liposome” refers to a spherical-shaped vesicle composed of one or more lipid bilayers, which closely resembles the structure of cell membranes. As used herein, a “lipid nanoparticle” or “LNP” refers to spherical vesicles made of ionizable lipids, typically that are positively charged at low pH (thus enabling complexation with RNA) and neutral at physiological pH (thus reducing potential side effects) and that are taken up by cells via, endocytosis. In addition to the ionizable lipid, LNPs typically contain additional components, as described in further detail below.

[0138] Lipid carriers, including lipid vesicles, liposomes and LNPs may be prepared using the lipid compounds of the disclosure according to standard methodologies well established in the art.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Lipid Nanoformulations / Lipid-based carriers

[0139] In some embodiments, compounds described herein are formulated into a lipid-based carrier (or lipid nanoformulation). In some embodiments, the lipid-based carrier (or lipid nanoformulation) is a liposome or a lipid nanoparticle (LNP). In one embodiment, the lipid-based carrier is an LNP. In one embodiment, the lipid-based carrier is an LNP composed of natural or synthetic lipids.

[0140] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises a cationic lipid (e.g., an ionizable lipid), a non-cationic lipid (e.g., phospholipid), a sterol (e.g., cholesterol), and a PEG-modified lipid. In some embodiments, the lipid-based carrier (or lipid nanoformulation) contains one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0141] All above descriptions and all above embodiments discussed relating to the aspects of the lipid compounds, including the compounds covered by formula (I), are all applicable to aspects of the disclosure relating to the lipid-based carriers (or a lipid nanoformulation).

[0142] As described herein, suitable compounds to be used in the lipid-based carrier (or lipid nanoformulation) include all the isomers and isotopes of the compounds described above, as well as all the pharmaceutically acceptable salts, solvates, or hydrates thereof, and all crystal forms, crystal form mixtures, and anhydrides or hydrates.

[0143] In addition to one or more compounds described herein, the lipid-based carrier (or lipid nanoformulation) may further include a second lipid. In some embodiments, the second lipid is a cationic lipid, a non-cationic (e.g., neutral, anionic, or zwitterionic) lipid, or an ionizable lipid.

[0144] The lipid-based carrier (or lipid nanoformulation) may contain positively charged (cationic) lipids, neutral lipids, negatively charged (anionic) lipids, or a combination thereof.

[0145] One or more naturally occurring and / or synthetic lipid compounds may be used in the preparation of the lipid-based carrier (or lipid nanoformulation).

[0146] As described herein, a lipid-based carrier (or lipid nanoformulation) may be a lipid particle that has a complexity characterized by comprising a wide variety of lipids, including both synthetic lipids or lipids extracted from one or more natural sources (such as plants or bacteria). Natural lipids may be derived from a variety of arthropod, fungi, plant, archaea, or bacteria, or one or more parts thereof (e.g., segments, organs, eggs, spores, mycelium, tissue, membrane or cell wall). For example, natural lipids may be produced from organs / structures / tissues / cell cultures (e.g., body segments, appendages, organs, eggs, exoskeleton, embryos, spores, mycelium, hyphae, thallus, suspension cultures, cell walls, inner or outer membranes, gametophytes, sporophytes, polymerases, glycerol-ether lipids, metabolic products, flagella, pili, ribosomes or organelles) or progeny of same. The source may be at anyAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 stage of development. In some embodiments, the natural lipids are extracted from a plant source, such as lemon or soy. In some embodiments, the natural lipids are derived from an insect or fungi (e.g. cricket, yeast, or mushroom). In some embodiments, the natural lipids are produced from a bacteria or archaea (e.g. E. coli or Salmonella typhimurium). In some embodiments, the natural lipids are produced from an algae (e.g. kelp or chlorella). In some embodiments, the natural lipids are produced from an animal organ (e g. brain or blood).

[0147] In some embodiments, the lipid-based carrier (or lipid nanoformulation) may comprise between 10% w / w and 99% w / w lipids derived from a lipid structure from one or more natural sources, e.g.. it may contain at least 10% w / w, at least 20% w / w, at least 30% w / w, at least 40% w / w, at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, or about 99% w / w lipids derived from a lipid structure from one or more natural sources.

[0148] In some embodiments, the lipid-based earner (or lipid nanoformulation) comprises natural lipids from multiple sources. In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises natural lipids extracted from one source (i.e. plant, bacteria) as well as a natural lipid from a second source (i.e. a different plant, bacteria). In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises natural lipids extracted from a plant source and a natural sterol lipid extracted from a different plant source that is added to the lipid particle formulation. In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises natural lipids extracted from a plant source and a natural lipid extracted from a second bacterial source.

[0149] In some embodiments, the lipid-based earner is a modified natural nanoparticle. As used herein, the term "modified natural particle" refers to a natural lipid nanoparticles composition including both naturally derived lipids and one or more synthetically derived lipids such as formulas (I) to (VI). In some embodiments, modified natural nanoparticles may include ionizable lipids, non-cationic lipids, sterols, and PEGylated lipids. In some embodiments, the modified lipid nanoparticle may comprise the natural lipids used in combination with a synthetic lipid as described herein.

[0150] In some embodiments, the modified natural nanoparticle is composed of lipids from a natural source selected from a plant, bacteria, animal, insect, archaea, or fungi. In some embodiments, the natural lipids are extracted from a plant source, such as lemon, soy, or algae. In some embodiments, the natural lipids are extracted from a bacteria source, such as E. coli or Salmonella typhimurium. In some embodiments, the modified natural nanoparticle may contain 3-1000 lipids extracted from one or more natural (e.g., plant, bacteria) sources. In some embodiments, the modified natural nanoparticle contains at least 10 natural lipids belonging toAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 one or more of the classes selected from the group consisting of fatty acyls (FA), fatty acyl conjugates, phospholipids, glycerolipids, glycolipids, glycerophospholipids, sphingolipids, waxes, and sterol.

[0151] A modified natural nanoparticle may comprise between 10% and 99.99% lipids derived from the lipid structure from the natural source (e.g., lemon, soy, algae. E. coli or Salmonella typhimurium), e.g., may contain at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 99.99% lipids derived from the lipid structure from the natural source. A modified natural nanoparticle may comprise all or a fraction of the lipid species present in the lipid structure from the natural source, e.g., it may contain at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 99.99% of the lipid species present in the lipid structure from the natural source. A modified natural nanoparticle may comprise reduced or minimized residual dsDNA or protein matter endogenous to the one or more natural (i.e. plant, bacteria) sources, e.g., it may contain 0% w / w, less than 1% w / w, less than 5% w / w, less than 10% w / w, less than 15% w / w, less than 20% w / w, less than 30% w / w, less than 40% w / w, or less than 50% w / w of the dsRNA or protein matter endogenous to the one or more natural (e.g., plant, bacteria) sources.

[0152] Modified natural nanoparticles may comprise additional components and / or possess beneficial properties for use such as a cell-penetrating agent. In some embodiments, a modified natural lipid nanoparticle may include a natural cell -penetrating agent that may be capable of increasing delivery of one or more polynucleotides by the lipid formulation (e.g. lipid nanoparticle or natural nanoparticle) to a cell, and / or may be capable of increasing loading (e.g., loading efficiency or loading capacity) of a polynucleotide.

[0153] To improve selectivity for target cells and, thus therapeutic efficacy, lipid nanoparticles may be functionalized with targeting moieties. Targeting moieties may comprise a variety of molecules, including but not limited to, antibodies, peptides, integrin ligands, glucose, transferrin, or folic acid. Incorporating a reactive functional group, for example, an LNP modified by the inclusion of PEG lipids with reactive functional groups on the surface of LNPs may enable attachment of such targeting moieties to the LNP itself. For example, conjugation of antibodies to nanoparticles may be achieved through a variety of different methods, including but not limited to ionic adsorption (non-covalent attachment), covalent binding (including carbodiimide chemistry, maleimide chemistry and click-chemistry) or through the use of adapter molecules such as biotin. One such example includes the incorporation of a reactive chemistry handle such as DSPE-PEG 2000 Maleimide onto the surface of LNPs to facilitate conjugation of antibodies to the LNP via maleimide chemistry.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0154] Any appropriate targeting moiety is contemplated herein and may be conjugated to the lipid nanoparticles using any appropriate chemistry.

[0155] More embodiments of natural lipids, complex lipid particles, and methods of producing and delivering natural nanoparticles may be found in PCT Application No.PCT / US2023 / 021094, filed on May 5. 2023, PCT Application No. PCT / US24 / 25134, filed on April 18, 2024, and PCT Application No. PCT / US24 / 25270, filed on April 18, 2024, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the modified natural nanoparticle is plant-based, e.g. as described in International Patent Publication Nos. WO2011 / 097480, WO2013 / 070324. WO2017 / 004526, W02020 / 041784, W02021 / 041301, WO2023 / 069498, W02023 / 122080, or WO2024 / 102434. In some embodiments, the modified natural nanoparticle is bacteria-derived, e.g. as described in International Patent Publication Nos. WO2023 / 096858.Ionizable Lipids

[0156] In addition, to the above, in some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises one or more ionizable lipids. As used herein, '‘ionizable lipid’7refers to an amphiphilic molecule (e.g. a lipid) containing a group (e.g. a head group) that may be ionized, e.g. dissociated to produce one or more electrically charged species, under a given condition (e.g. pH).

[0157] More embodiments of ionizable lipids may be found in PCT Application No.PCT / US24 / 25134, filed on April 18, 2024, and PCT Application No. PCT / US24 / 25270, filed on April 18, 2024, the contents of which are incorporated herein by reference in their entirety. Other embodiments of ionizable lipids may be found in PCT Application No. PCT / US22 / 50725, filed on November 22, 2022, PCT Application No. PCT / US23 / 16300, filed on March 24, 2023, PCT Application No. PCT / US22 / 50111, filed on November 16, 2022, and PCT Application No. PCT / US23 / 31669, filed on August 31, 2023, the contents of which are incorporated herein by reference in their entirety. It has been surprisingly found that ionizable lipids comprising alkyl chains with multiple sites of unsaturation, e.g., at least two or three sites of unsaturation, are particularly useful for forming lipid particles with increased membrane fluidity. A number of ionizable lipids and related analogs, suitable for use herein, have been described in U. S. Patent Publication Nos. 20060083780 and 20060240554; U. S. Pat. Nos. 5,208,036; 5,264,618;5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication No. WO 96 / 10390, the disclosures of which are herein incorporated by reference in their entirety for all purposes.

[0158] In some embodiments, ionizable lipids are ionizable such that they may dissociate to exist in a positively charged form depending on pH (e.g. a cationic lipid as defined below). The ionization of an ionizable lipid affects the surface charge of a lipid modified comprising theAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 ionizable lipid under different pH conditions. The surface charge of the lipid nanoparticle in turn may influence its plasma protein absorption, blood clearance, and tissue distribution (Semple, S. C., et al., Adv. Drug Deliv Rev 32:3-17 (1998)) as well as its ability to form endosomolytic non-bilayer structures (Hafez, I. M., et al., Gene Ther 8: 1188-1196 (2001)) that may influence the intracellular delivery of nucleic acids.

[0159] In some embodiments, ionizable lipids are those that are generally neutral, e.g., at physiological pH (e.g., pH about 7), but may cany' net charge(s) at an acidic pH or basic pH. In one embodiment, ionizable lipids are those that are generally neutral at pH about 7, but may carry net charge(s) at an acidic pH. In one embodiment, ionizable lipids are those that are generally neutral at pH about 7, but may carry net charge(s) at a basic pH.

[0160] In some embodiments, ionizable lipids do not include those cationic lipids or anionic lipids that generally carry net charge(s) at physiological pH (e.g., pH about 7).Cationic Lipids (Positively Charged)

[0161] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises one or more cationic lipids, e.g., a cationic lipid that may exist in a positively charged or neutral form depending on pH, or an amine-containing lipid that may be readily protonated. In some embodiments, the cationic lipid is a lipid capable of being positively charged, e.g., under physiological conditions. Exemplary' cationic lipids include one or more amine group(s) which bear the positive charge. Examples of positively charged (cationic) lipids include, but are not limited to, N, N'-dimethyl-N, N'-dioctacyl ammonium bromide (DDAB) and chloride DDAC), N-(l-(2,3-dioleyloxy)propyl)-N, N, N-trimethylammonium chloride (DOTMA), 3P-[N-(N', N'-dimethylaminoethyl)carbamoyl) cholesterol (DC-chol), 1,2-dioleoyloxy-3-[trimethylammonio] -propane (DOTAP), l,2-dioctadecyloxy-3-[trimethylammonio] -propane (DSTAP), and 1.2-dioleoyloxypropyl-3-dimethyl-hydroxy ethyl ammonium chloride (DORI). N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-dimethyl-2,3-dioleyloxypropylamine (DODMA), 1,2-Dioleoyl-3-Dimethylammonium-propane (DODAP), 1,2-Dioleoylcarbamyl-3-Dimethy lammonium-propane (DOCDAP), 1,2-Dilineoyi-3 -Dimethylammonium-propane (DLINDAP). 3-Dimethylammo-2-(Cholest-5-en-3-beta-oxybutyl-4-oxy)-l -(cis.cis-9, 12- octadecadienoxy (propane (CLinDMA), 2-[5'-(cholest-5-en-3-beta-oxy)-3'-oxapentoxy)-3-dimethyl-l-(cis, cis-9',12'-octadecadienoxy (propane (CpLin DMA), N,N-Dimethyl-3,4-dioleyloxybenzylamine (DMOBA), and the cationic lipids described in Martin et al., Current Pharmaceutical Design, pages 1-394, which is herein incorporated by reference in its entirety. In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises more than one cationic lipid.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0162] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises a cationic lipid having an effective pKa over 6.0. In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a second cationic lipid having a different effective pKa (e.g., greater than the first effective pKa) than the first cationic lipid.

[0163] In some embodiments, cationic lipids that may be used in the lipid-based earner (or lipid nanoformulation) include, for example those described in Table 4 of WO 2019 / 217941, which is incorporated by reference.

[0164] In some embodiments, the cationic lipid is an ionizable lipid (e.g., a lipid that is protonated at low pH, but that remains neutral at physiological pH). In some embodiments, the lipid-based carrier (or lipid nanoformulation) may comprise one or more additional ionizable lipids, different than the ionizable lipids described herein. Exemplary ionizable cationic lipids include, but are not limited to,(LP01),(SM-086),(ALC-0315).(Lipid 10),(Lipid A9), and(DLin-MC3-DMA),(see WO 2017 / 004143A1, which is incorporated herein by reference in its entirety).Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0165] In some embodiments, the lipid-based earner (or lipid nanoformulation) further comprises one or more cationic lipid compounds described by WO 2021 / 113777 (e.g, a lipid of Formula (3) such as a lipid of Table 3 of WO 2021 / 113777), which is incorporated herein by reference in its entirety.

[0166] In one embodiment, the ionizable cationic lipid is a lipid disclosed in Hou, X., et al. Nat Rev Mater 6, 1078-1094 (2021). (See also https: / / doi.org / 10.1038 / s41578-021-00358-0 (e.g., L319, C12-200, and DLin-MC3-DMA) which is incorporated by reference herein in its entirety).

[0167] Examples of other ionizable cationic lipids that may be used in lipid-based carrier (or lipid nanoformulation) include, without limitation, one or more of the following formulas: X of US 2016 / 0311759; I of US 20150376115 or in US 2016 / 0376224; Compound 5 or Compound 6 in US 2016 / 0376224; I, IA, or II of US 9,867,888; I, II or III of US 2016 / 0151284; I, IA, II, or IIA of US 2017 / 0210967; I-c of US 2015 / 0140070; A of US 2013 / 0178541; I of US 2013 / 0303587 or US 2013 / 0123338; I of US 2015 / 0141678; II. Ill, IV, or V of US 2015 / 0239926; I of US 2017 / 0119904; I or II of WO 2017 / 117528; A of US 2012 / 0149894; A of US 2015 / 0057373; A of WO 2013 / 116126; A of US 2013 / 0090372; A of US 2013 / 0274523; A of US 2013 / 0274504; A of US 2013 / 0053572; A of WO 2013 / 016058; A of WO 2012 / 162210; I of US 2008 / 042973; I. II, III, or IV of US 2012 / 0128767; I or II of US 2014 / 0200257; I, II, or III of US 2015 / 0203446; I or III of US 2015 / 0005363; I, IA, IB, IC, ID, II, IIA, IIB, IIC, IID, or III-XXIV of US 2014 / 0308304; of US 2013 / 0338210; I, II, III, or IV of WO 2009 / 132131; A of US 2012 / 0101147; I or XXXV of US 2012 / 0027796; XIV or XVII of US 2012 / 0058144; of US 2013 / 0323269; I of US 2011 / 0117125; I, II, or III of US 2011 / 0256175; I, II, III, IV, V, VI, VII, VIII, IX, X. XI. XII of US 2012 / 0202871; I, II, III, IV, V, VI, VII, VIII, X, XII, XIII, XIV, XV, or XVI of US 2011 / 0076335; I or II of US 2006 / 008378; I of WO2015 / 074085 (e.g, ATX-002); I of US 2013 / 0123338; I or X-A-Y-Z of US 2015 / 0064242; XVI, XVII, or XVIII of US 2013 / 0022649; I, II, or III of US 2013 / 0116307; I, II, or III of US 2013 / 0116307; I or II of US 2010 / 0062967; I-X of US 2013 / 0189351; I of US 2014 / 0039032; V of US 2018 / 0028664; I of US 2016 / 0317458; I of US 2013 / 0195920; 5, 6. or 10 of US 10,221,127; III-3 of WO 2018 / 081480; 1-5 or 1-8 of WO 2020 / 081938; I of WO 2015 / 199952 (e.g., compound 6 or 22) and Table 1 therein; 18 or 25 of US 9,867,888; A of US 2019 / 0136231; II of WO 2020 / 219876; 1 of US 2012 / 0027803; OF-02 of US 2019 / 0240349; 23 of US 10,086,013; cKK-E12 / A6 of Miao et al (2020); C12-200 of WO 2010 / 053572; 7C1 of Dahlman et al (2017); 304-013 or 503-013 of Whitehead et al; TS-P4C2 of U S9, 708, 628; I of WO 2020 / 106946; I of WO 2020 / 106946; (1), (2), (3), or (4) of WO 2021 / 113777; and any one of Tables 1-16 of WO 2021 / 113777, all of which are incorporated herein by reference in their entirety.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0168] In some embodiments, the lipid-based earner (or lipid nanoformulation) further includes biodegradable ionizable cationic lipids, for instance, (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3- ((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z.12Z)-octadeca-9,12-dienoate). See, e.g., lipids of WO 2019 / 067992, WO 2017 / 173054, WO 2015 / 095340, and WO 2014 / 136086, which are incorporated herein by reference in their entirety.Non-Cationic Lipids (e.g., Phospholipids)

[0169] In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises one or more non-cationic lipids. In some embodiments, the non-cationic lipid is a phospholipid. In some embodiments, the non-cationic lipid is a phospholipid substitute or replacement. In some embodiments, the non-cationic lipid is a negatively charged (anionic) lipid. In some embodiments, the non-cationic lipid is a neutral lipid.

[0170] Exemplary non-cationic lipids include, but are not limited to, distearoyl-sn-glycero-phosphoethanolamine, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), monomethylphosphatidylethanolamine (such as 16-O-monomethyl PE), dimethyl- phosphatidylethanolamine (such as 16-O-dimethyl PE), 18-1 -trans PE, l-stearoyl-2-oleoyl-phosphatidy ethanolamine (SOPE), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoylphosphatidylserine (DOPS), sphingomyelin (SM), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dierucoylphosphatidylcholine (DEPC), palmitoyloleyolphosphatidylglycerol (POPG), dielaidoyl-phosphatidylethanolamine (DEPE), 1,2-dilauroyl- sn-glycero-3-phosphocholine (DLPC), Sodium 1,2- ditetradecanoyl-sn-glycero-3-phosphate (DMPA), phosphatidylcholine (lecithin), phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. It is understood that other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids may also be used. The acyl groups in these lipids are preferably acyl groupsAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. Additional exemplary lipids, in certain embodiments, include, without limitation, those described in Kim et al. (2020) dx.doi.org / 10.1021 / acs.nanolett.0c01386, which is incorporated herein by reference. Such lipids include, in some embodiments, plant lipids found to improve liver transfection with mRNA (e.g.. DGTS).

[0171] In some embodiments, the lipid-based carrier (or lipid nanoformulation) may comprise a combination of distearoylphosphatidylcholine / cholesterol, dipalmitoylphosphatidylcholine / cholesterol, dimyrystoylphosphatidylcholine / cholesterol, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) / cholesterol, or egg sphingomyelin / cholesterol.

[0172] Other examples of suitable non-cationic lipids include, without limitation, nonphosphorous lipids such as, e.g., stearylamine. dodecylamine, hexadecylamine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, amphoteric acry lic polymers, triethanolamine-lauryl sulfate, alkyl-aryl sulfate polyethyloxylated fatty acid amides, dioctadecyl dimethyl ammonium bromide, ceramide, sphingomyelin, and the like. Other noncationic lipids are described in WO 2017 / 099823 or US 2018 / 0028664, which are incorporated herein by reference in their entirety.

[0173] In one embodiment, the lipid-based carrier (or lipid nanoformulation) further comprises one or more non-cationic lipid that is oleic acid or a compound of Formula I. II, or IV of US 2018 / 0028664, which is incorporated herein by reference in its entirety. The non-cationic lipid content may be, for example, 0-30% (mol) of the total lipid components present. In some embodiments, the non-cationic lipid content is 5-20% (mol) or 10-15% (mol) of the total lipid components present.

[0174] In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a neutral lipid, and the molar ratio of an ionizable lipid to a neutral lipid ranges from about 2:1 to about 8:1 (e.g., about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1).

[0175] In some embodiments, the lipid-based carrier (or lipid nanoformulation) does not include any phospholipids.

[0176] In some embodiments, the lipid-based carrier (or lipid nanoformulation) may further include one or more phospholipids, and optionally one or more additional molecules of similar molecular shape and dimensions having both a hydrophobic moiety and a hydrophilic moiety (e.g., cholesterol).Sterols

[0177] The lipid-based carrier (or lipid nanoformulation) described herein may further comprise one or more sterols. As used herein, the term '‘sterol” refers to sterols (e.g., cholesterol) and also to lipids containing sterol moieties.Attomey Docket 96676-435728 | Client Ref: SBM24-112WO1

[0178] Incorporation of sterols in the lipid nanoparticle may help mitigate aggregation of other lipids in the particle. Sterols may be selected from the group including but not limited to, cholesterol or cholesterol derivative, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha-tocopherol, hopanoids, phytosterols, steroids, and mixtures thereof. In certain embodiments, the sterol is a steroid. In certain embodiments, the sterol is cholesterol. In certain embodiments, the sterol is an analog of cholesterol. In certain embodiments, the sterol is alpha-tocopherol.

[0179] In some embodiments, sterols may be incorporated into the lipid-based carrier at molar ratios ranging from about 0.1 to 1.0 (cholesterol phospholipid).

[0180] In some embodiments, sterols, when present, may include one or more of cholesterol or cholesterol derivatives, such as those described in WO 2009 / 127060 or US 2010 / 0130588, which are incorporated herein by reference in their entirety. Additional exemplary sterols include phytosterols, including those described in Eygeris et al. (2020). Nano Lett.2020;20(6):4543-4549, incorporated herein by reference.

[0181] In some embodiments, the sterol is a cholesterol derivative. Non-limiting examples of cholesterol derivatives include polar analogues such as 5a-cholestanol, 53-coprostanol, cholesteryl-(2’-hydroxy)-ethyl ether, cholesteryl-(4'- hydroxy )-butyl ether, and 6-ketocholestanol; non-polar analogues such as 5a-cholestane, cholestenone, 5a-cholestanone, 5p-cholestanone, and cholesteryl decanoate; and mixtures thereof. In some embodiments, the cholesterol derivative is a polar analogue, e.g., cholesteryl-(4'-hydroxy)-butyl ether. Exemplary cholesterol derivatives are described in WO 2009 / 127060 and US 2010 / 0130588, each of which is incorporated herein by reference in its entirety.

[0182] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises a sterol that is a natural sterol.

[0183] In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises sterol in an amount of 0-50 mol% (e.g., 0-10 mol %, 10-20 mol %, 20-50 mol%, 20-30 mol %, 30-40 mol %. or 40-50 mol %) of the total lipid components.Polymers and Polyethylene Glycol (PEG) - Lipids

[0184] In some embodiments, the lipid-based carrier (or lipid nanoformulation) may include one or more polymers or co-polymers, e.g., poly(lactic-co-glycolic acid) (PFAG) nanoparticles.

[0185] In some embodiments, the lipid-based carrier (or lipid nanoformulation) may include one or more polyethylene glycol (PEG) lipid. Examples of useful PEG-lipids include, but are not limited to, l,2-Diacyl-sn-Glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-350] (mPEG350 PE); 1,2-Diacyl-sn- Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-550] (mPEG 550 PE); 1,2- Diacyl-sn-Glycero-3-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-750] (mPEG 750 PE); 1,2-Diacyl-sn-Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-1000] (mPEG 1000 PE); l,2-Diacyl-sn-Glycero-3-Phosphoethanolamine-N-[Methoxy(Poly ethylene glycol)-2000] (mPEG 2000 PE); l,2-Diacyl-sn-Glycero-3-Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)-3000] (mPEG 3000 PE); l,2-Diacyl-sn-Glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000] (mPEG 5000 PE); N-Acyl- Sphingosine- 1-[Succinyl(Methoxy Polyethylene Glycol) 750] (mPEG 750 Ceramide); N-Acyl- Sphingosine- 1-[Succinyl(Methoxy Polyethylene Glycol) 2000] (mPEG 2000 Ceramide); and N- Acyl-Sphingosine-l-[Succinyl(Methoxy Polyethylene Glycol) 5000] (mPEG 5000 Ceramide). In some embodiments, the PEG lipid is a polyethyleneglycol-diacylglycerol (i.e., polyethyleneglycol diacylglycerol (PEG-DAG), PEG-chol esterol, or PEG-DMB) conjugate.

[0186] In some embodiments, the lipid-based carrier (or nanoformulation) includes one or more conjugated lipids (such as PEG-conjugated lipids or lipids conjugated to polymers described in Table 5 of WO 2019 / 217941, which is incorporated herein by reference in its entirety). In some embodiments, the one or more conjugated lipids is formulated with one or more ionic lipids (e.g., non-cationic lipid such as a neutral or anionic, or zwitterionic lipid); and one or more sterols (e.g., cholesterol).

[0187] The PEG conjugate may comprise a PEG-dilaurylglycerol (C12), a PEG-dimyristylglycerol (C14), a PEG-dipalmitoylglycerol (C16), a PEG-disterylglycerol (Cl 8), PEG-dilaurylglycamide (Cl 2), PEG-dimyristylglycamide (Cl 4), PEG-dipalmitoylglycamide (Cl 6), and PEG-disterylglycamide (Cl 8).

[0188] In some embodiments, conjugated lipids, when present, may include one or more of PEG-diacylglycerol (DAG) (such as l-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), a pegylated phosphatidylethanolamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) (such as 4-0-(2',3'-di(tetradecanoyloxy)propyl-l-0-(w-methoxy(poly ethoxy )ethyl) butanedioate (PEG-S-DMG)), PEG dialkoxypropylcarbam, N-(carbonyl-methoxypolyethylene glycol 2000)- 1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, and those described in Table 2 of WO 2019 / 051289 (which is herein incorporated by reference in its entirety ), and combinations of the foregoing.

[0189] Additional exemplary PEG-lipid conjugates are described, for example, in US 5,885.613, US 6,287,591, US 2003 / 0077829, US 2003 / 0077829, US 2005 / 0175682, US 2008 / 0020058, US 2011 / 0117125, US 2010 / 0130588, US 2016 / 0376224, US 2017 / 0119904, US 2018 / 0028664, and WO 2017 / 099823, all of which are incorporated herein by reference in their entirety.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0190] In some embodiments, the PEG-lipid is a compound of Formula III, III-a-1, III-a-2, Ill-b-1, III-b-2, or V of US 2018 / 0028664, which is incorporated herein by reference in its entirety. In some embodiments, the PEG-lipid is of Formula II of US 2015 / 0376115 or US 2016 / 0376224. both of which are incorporated herein by reference in their entirety. In some embodiments, the PEG-DAA conjugate may be, for example. PEG-dilauryloxypropyl, PEG-dimyristyloxypropyl, PEG-dipalmityloxypropyl, or PEG-distearyloxypropyl. In some embodiments, the PEG-lipid includes one of the following:0

[0191] In some embodiments, lipids conjugated with a molecule other than a PEG may also be used in place of PEG-lipid. For example, polyoxazoline (POZ)-lipid conjugates, polyamidelipid conjugates (such as ATTA-lipid conjugates), and cationic-polymer lipid (GPL) conjugates may be used in place of or in addition to the PEG-lipid.

[0192] Exemplary conjugated lipids, e.g., PEG-hpids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids, include those described in Table 2 of WO2019 / 051289A9, which is incorporated herein by reference in its entirety.

[0193] In some embodiments, the conjugated lipid (e.g., the PEGylated lipid) may be present in an amount of 0-20 mol% of the total lipid components present in the lipid-based carrier (or lipid nanoformulation). In some embodiments, the conjugated lipid (e g., the PEGylated lipid) content is 0.5-10 mol% or 2-5 mol% of the total lipid components.

[0194] When needed, the lipid-based carrier (or lipid nanoformulation) described herein may be coated with a polymer layer to enhance stability in vivo (e.g., sterically stabilized LNPs).

[0195] Examples of suitable polymers include, but are not limited to, poly(ethylene glycol), which may form a hydrophilic surface layer that improves the circulation half-life of liposomes and enhances the amount of lipid nanoformulations (e.g., liposomes or LNPs) that reach therapeutic targets. See, e.g.. Working et al. J Pharmacol Exp Ther, 289: 1128-1133 (1999); Gabizon et al., J Controlled Release 53: 275-279 (1998); Adlakha Hutcheon et al., NatAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Biotechnol 17: 775-779 (1999); and Koning et al., Biochim Biophys Acta 1420: 153-167 (1999), which are incorporated herein by reference in their entirety.Percentages of Lipid Nanoformulation Components

[0196] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises one of more of the compounds described herein, optionally a non-cationic lipid (e.g, a phospholipid), a sterol, a neutral lipid, and optionally conjugated lipid (e.g, a PEGylated lipid) that inhibits aggregation of particles. In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes). The amounts of these molecules may be varied independently and to achieve desired properties. For example, in some embodiments, the ionizable lipid including the lipid compounds described herein is present in an amount from about 20 mol% to about 100 mol% (e.g, 20-90 mol%, 20-80 mol%, 20-70 mol%, 25-100 mol%, 30-70 mol%, 30-60 mol%, 30-40 mol%, 40-50 mol%, or 50-90 mol%) of the total lipid components; a non-cationic lipid (e.g.. phospholipid) is present in an amount from about 0 mol% to about 50 mol% (e.g., 0-40 mol%, 0-30 mol%, 5-50 mol%, 5-40 mol%, 5-30 mol%, or 5-10 mol%) of the total lipid components, a conjugated lipid (e.g., a PEGylated lipid) in an amount from about 0.5 mol% to about 20 mol% (e.g, 1-10 mol% or 5-10%) of the total lipid components, and a sterol in an amount from about 0 mol % to about 60 mol% (e.g, 0-50 mol%, 10-60 mol%, 10-50 mol%, 15-60 mol%, 15-50 mol%, 20-50 mol%, 20-40 mol%) of the total lipid components, provided that the total mol% of the lipid component does not exceed 100%. In some embodiments, the ionizable lipid including the lipid compounds described herein is present in an amount from about 20 mol% to about 100 mol% (e.g, 20-90 mol%, 20-80 mol%, 20-70 mol%, 25-100 mol%, 30-70 mol%, 30-60 mol%, 30-40 mol%, 40-50 mol%, or 50-90 mol%) of the total lipid components; a non-cationic lipid (e.g., phospholipid) and / or naturally derived non-cationic lipid is present in an amount from about 0 mol% to about 50 mol% (e.g, 0-40 mol%, 0-30 mol%, 5-50 mol%, 5-40 mol%, 5-30 mol%, or 5-10 mol%) of the total lipid components, a conjugated lipid (e.g, a PEGylated lipid) in an amount from about 0.5 mol% to about 20 mol% (e.g, 1-10 mol% or 5-10%) of the total lipid components, and a sterol including naturally derived sterol in an amount from about 0 mol % to about 60 mol% (e.g, 0-50 mol%, 10-60 mol%, 10-50 mol%, 15-60 mol%, 15-50 mol%, 20-50 mol%, 20-40 mol%) of the total lipid components, provided that the total mol% of the lipid component does not exceed 100%.

[0197] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein, about 0-50Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 mol% phospholipid, about 0-50 mol% sterol, and about 0-10 mol% PEGylated lipid. In some embodiments, the lipid-based carrier comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA). or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes etc.) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein, about 0-50 mol% phospholipid, about 0-50 mol% sterol, and about 0-10 mol% PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.

[0198] In one embodiment, the lipid-based carrier (or lipid nanoformulation) comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein; about 0-40 mol% phospholipid e.g., DSPC), about 0-50 mol% sterol (e.g., cholesterol), and about 0-10 mol% PEGylated lipid.

[0199] In some embodiments, the lipid-based carrier comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzy mes, etc.) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein; about 0-40 mol% phospholipid (e.g., DSPC), about 0-50 mol% sterol (e.g., cholesterol), and about 0-10 mol% PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.

[0200] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises about 30-60 mol% (e.g., about 35-55 mol%, or about 40-50 mol%) of the ionizable lipid including the lipid compounds described herein, about 0-30 mol% (e.g., 5-25 mol%, or 10-20 mol%) phospholipid, about 15-50 mol% (e.g, 18.5-48.5 mol%, or 30-40 mol%) sterol, and about 0-10 mol% (e.g., 1-5 mol%. or 1.5-2.5 mol%) PEGylated lipid.

[0201] In some embodiments, the lipid-based carrier comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzy mes, etc.) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 30-60 mol% (e.g.. about 35-55 mol%, or about 40-50 mol%) of the ionizable lipid including the lipid compounds described herein, about 0-30 mol% (e.g., 5-25 mol%, or 10-20 mol%) phospholipid, about 15-50 mol% (e.g., 18.5-48.5 mol%, or 30-40 mol%) sterol, and about 0-10 mol% (e.g., 1-5 mol%, or 1.5-2.5 mol%)Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.

[0202] In some embodiments, molar ratios of ionizable lipid / sterol / phospholipid (or another lipid) / PEG-lipid / additional components is varied in the following ranges: ionizable lipid (25-100%); phospholipid (DSPC) (0-40%); sterol (0-50%); and PEG lipid (0-5%).

[0203] In some embodiments, the lipid-based carrier comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes, etc.) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises molar ratios of ionizable lipid / sterol / phospholipid (or another lipid) / PEG-lipid / additional components in the following ranges: ionizable lipid (25-100%); phospholipid (DSPC) (0-40%); sterol (0-50%); and PEG lipid (0-5%). In some embodiments, the encapsulation efficiency of the pay load may be at least 70%.

[0204] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises, by mol% or wt% of the total lipid components, 50-75% ionizable lipid (including the lipid compound as described herein), 20-40% sterol (e.g., cholesterol or derivative), 0 to 10% non-cationic-lipid, and 1-10% conjugated lipid (e.g., the PEGylated lipid).

[0205] In some embodiments, the lipid-based carrier comprises a payload (e.g., small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes, etc.) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises, by mol% or wt% of the total lipid components, 50-75% ionizable lipid (including the lipid compound as described herein), 20-40% sterol (e.g, cholesterol or derivative), 0 to 10% non-cationic-lipid, and 1-10% conjugated lipid (e.g., the PEGylated lipid). In some embodiments, the encapsulation efficiency of the payload may be at least 70%.

[0206] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises (i) small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes; (ii) a cationic lipid comprising from 50 mol% to 65 mol% of the total lipid present in the lipid-based carrier; (iii) a non-cationic lipid comprising a mixture of a phospholipid and a cholesterol derivative thereof, wherein the phospholipid comprises from 3 mol% to 15 mol% of the total lipid present in the lipid-based carrier and the cholesterol or derivative thereof comprises from 30 mol% to 40 mol% of the totalAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 lipid present in the lipid-based carrier; and (iv) a conjugated lipid comprising 0.5 mol% to 2 mol% of the total lipid present in the particle.

[0207] In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises (i) small molecule therapies, nucleic acids, such as DNA and / or RNA, including mRNA, siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes; (ii) a cationic lipid comprising from 50 mol % to 85 mol % of the total lipid present in the lipid-based carrier; (iii) a noncationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the lipid-based carrier; and (iv) a conjugated lipid comprising from 0.5 mol % to 2 mol % of the total lipid present in the lipid-based carrier.

[0208] In some embodiments, the lipid compound described herein is a component of the lipid-based carrier (or lipid nanoformulation) and comprises from 10 mol% to 95 mol%, from 10 mol% to 90 mol%, from 10 mol% to 80 mol%, from 10 mol% to 70 mol%. from 10 mol% to 60 mol%, from 20 mol% to 55 mol%, from 20 mol% to 45 mol%, 20 mol% to 40 mol%, from 25 mol% to 50 mol%, from 25 mol% to 45 mol%, from 30 mol% to 50 mol%, from 30 mol% to 45 mol%, from 30 mol% to 40 mol%, from 35 mol% to 45 mol%, or from 37 mol% to 42 mol% (or any fraction of these ranges) of the total lipid components.

[0209] In some embodiments, where the lipid-based carrier (or lipid nanoformulation) contains a mixture of phospholipid and sterol (e g. cholesterol or derivative), the mixture may be present up to 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol% of the total lipid components.

[0210] In some embodiments, the phospholipid component in the mixture may be present from 2 mol% to 20 mol%. from 2 mol% to 15 mol%, from 2 mol% to 12 mol%, from 4 mol% to 15 mol%, from 4 mol% to 10 mol%, from 5 mol% to 10 mol%, (or any fraction of these ranges) of the total lipid components. In some embodiments, the lipid-based carrier (or lipid nanoformulation) is phospholipid-free.

[0211] In some embodiments, the sterol component (e.g. cholesterol or derivative) in the mixture may comprise from 25 mol% to 45 mol%, from 25 mol% to 40 mol%. from 25 mol% to 35 mol%, from 25 mol% to 30 mol%, from 30 mol% to 45 mol%, from 30 mol% to 40 mol%, from 30 mol% to 35 mol%, from 35 mol% to 40 mol%, from 27 mol% to 37 mol%, or from 27 mol% to 35 mol% (or any fraction of these ranges) of the total lipid components.

[0212] In some embodiments, where the lipid-based carrier (or lipid nanoformulation) is phospholipid-free, the sterol component (e.g. cholesterol or derivative) may be present up to 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol% of the total lipid components. For instance, the sterol component (e.g. cholesterol or derivative) may be present from 25 mol% to 65 mol%, from 25 mol% to 60 mol%. from 25 mol% to 55 mol%,Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 from 25 mol% to 50 mol%, from 25 mol% to 45 mol%, from 25 mol% to 40 mol%, from 30 mol% to 45 mol%, from 30 mol% to 40 mol%, from 35 mol% to 45 mol%, from 30 mol% to 35 mol%, or from 35 mol% to 40 mol% (or any fraction thereof or range therein) of the total lipid components.

[0213] In some embodiments, the non-ionizable lipid components in the lipid-based carrier (or lipid nanoformulation) may be present from 5 mol% to 90 mol%, from 10 mol% to 85 mol%, or from 20 mol% to 80 mol% (or any fraction of these ranges) of the total lipid components.

[0214] The ratio of total lipid components to the pay load (e.g, an encapsulated therapeutic agent such as nucleic acids, such as DNA and / or RNA including mRNA. siRNA, microRNA, circular RNA (circRNA), or shRNA; modified nucleic acids; peptide therapies and / or proteins therapies, including antibodies and / or enzymes or small molecule therapies may be varied as desired. For example, the total lipid components to the payload (mass or weight) ratio may be from about 10: 1 to about 30: 1. In some embodiments, the total lipid components to the payload ratio (mass / mass ratio; w / w ratio) may be in the range of from about 1: 1 to about 25:1, from about 10:1 to about 14:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5: 1 to about 9: 1, or about 6: 1 to about 9:1. The amounts of total lipid components and the payload may be adjusted to provide a desired N / P ratio, for example, N / P ratio of 3, 4, 5, 6, 7, 8, 9, 10, 11. 12. 13. 14. 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. 28. 29. 30. or higher. Generally, the lipid-based carrier (or lipid nanoformulation’s) overall lipid content may range from about 5 mg / ml to about 30 mg / mL. Nitrogen:phosphate ratios (N: P ratio) is evaluated at values between 0.1 and 100.

[0215] In some embodiments, the RNA and particle composition has an N: P ratio of at least 3. for instance, an N: P ratio of 3 to 100, 3 to 50, 3 to 30, 3 to 20, 3 to 15, 3 to 12, 6 to 30, 6 to 20, 6 to 15, or 6 to 12.

[0216] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 50: 10:38.5: 1.5. In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, cholesterol and a PEG-ylated lipid in a molar ratio of 60:38.5:1.5.

[0217] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 35:20:42.5:2.5, 35:50:12.5:2.5, 50:20:28.5:1.5, or 45:20:33.5:1.5 depending on the natural source and the ionizable lipid used. In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 35:20:42.5:2.5. In someAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 35:50:12.5:2.5. In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 50:20:28.5: 1.5. In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes the ionizable lipid compound as described herein, phospholipid, cholesterol, and a PEG-ylated lipid in a molar ratio of 45:20:33.5:1.5.

[0218] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes 20 mol% - 50 mol% of the ionizable lipid as described herein, 5 mol% - 60 mol% of the natural lipids, 7 mol% - 50 mol% of the sterol, and 0.5 mol% - 3 mol% of the polyethylene glycol (PEG)-lipid.

[0219] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes 0 mol% - 90 mol% ionizable lipid as described herein, 0 mol% - 90 mol% natural lipids, 0 mol% -10 mol% sterol and 0 mol% - 10 mol% PEG lipids.

[0220] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes 0 mol% - 90 mol% ionizable lipid as described herein, 0 mol% - 90 mol% non-cationic lipid, 0 mol% - 90 mol% natural lipids, 0 mol% - 10 mol% sterol and 0 mol% - 10 mol% PEG lipids.

[0221] In some embodiments, the lipid-based carrier (or lipid nanoformulation) includes 0 mol% - 90 mol% ionizable lipid as described herein, 0 mol% - 90 mol% natural lipids, and 5 mol% - 10 mol% PEG lipids.Properties of Lipid Nanoformulations

[0222] In some embodiments, the average particle diameter of the lipid-based carrier (or lipid nanoformulation) may be between 10s of nm and 100s of nm, e.g., measured by dynamic light scattering (DLS). In some embodiments, the average particle diameter of the lipid-based carrier (or lipid nanoformulation) ranges from about 1 mm to about 500 mm, from about 5 mm to about 200 mm, from about 10 mm to about 100 mm, from about 20 mm to about 80 min. from about 25 mm to about 60 mm, from about 30 mm to about 55 mm, from about 35 mm to about 50 mm, from about 38 mm to about 42 mm, from about 40 nm to about 150 nm (such as about 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm. 135 nm, 140 nm. 145 nm, or 150 nm). from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, from about 50 nm to about 60 nm, from about 60 nm to about 100 nm, from about 60 nm to about 90 nm, from about 60 nm to about 80 nm, from about 60 nm to about 70 nm, from about 70 nm to about 100 nm, from about 70 nm to about 90 nm,Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 from about 70 nm to about 80 nm, from about 80 nm to about 100 nm, from about 80 nm to about 90 nm, or from about 90 nm to about 100 nm.

[0223] In some embodiments, the nanoparticle has a size of less than about 200 nm.

[0224] The lipid-based carrier or lipid nanoformulation (e.g., liposome or LNP) may, in some instances, be relatively homogenous. A polydispersity index (PDI) may be used to indicate the homogeneity of a lipid nanoformulation (e.g., liposome or LNP), e.g., the particle size distribution of the liposome or LNP. A small (e.g., less than 0.3) PDI generally indicates a narrow particle size distribution. A lipid-based carrier or lipid nanoformulation (e.g., liposome or LNP) may have a PDI from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05. 0.06.0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the PDI of the lipid-based carrier or lipid nanoformulation (e.g., liposome or LNP) may be from about 0.10 to about 0.20.

[0225] The zeta potential of a lipid-based carrier or a lipid nanoformulation (e.g., liposome or LNP) may be used to indicate the electrokinetic potential of the composition. In some embodiments, the zeta potential may describe the surface charge of a liposome or LNP. Lipid nanoformulations (e.g., liposomes or LNP) with relatively low charges, positive or negative, are generally desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a liposome or LNP may be from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about -10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV. from about -5 mV to about 0 mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV.

[0226] The efficiency of encapsulation of a payload such as a protein and / or nucleic acid, describes the amount of protein and / or nucleic acid that is encapsulated or otherwise associated with a lipid nanoformulation (e g., liposome or LNP) after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., at least 70%. 80%. 90%.95%, close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of protein or nucleic acid in a solution containing the liposome or LNP before and after breaking up the liposome or LNP with one or more organic solvents or detergents. An anion exchange resin may be used to measure the amount of free protein or nucleic acid (e.g., RNA) in a solution. Fluorescence may be used to measure the amount of free protein and / or nucleic acid (e.g., RNA) in a solution. For the lipid-based carrier (or lipidAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 nanoformulation) described herein, the encapsulation efficiency of a protein and / or nucleic acid may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 70%. In some embodiments, the encapsulation efficiency may be at least 80%. In some embodiments, the encapsulation efficiency may be at least 90%. In some embodiments, the encapsulation efficiency may be at least 95%.

[0227] The lipid carrier or lipid nanoformulation may optionally include one or more coatings. In some embodiments, the lipid carrier or lipid nanoformulation (e.g, liposome or LNP) may be formulated in a capsule, film, or tablet having a coating. A capsule, film, or tablet including a composition described herein may have any useful size, tensile strength, hardness, or density.

[0228] Additional exemplary lipids, formulations, methods, and characterization of a lipid carrier or lipid nanoformulation (e.g., liposome or LNP) are taught by WO 2020 / 061457 and WO 2021 / 113777, which are incorporated herein by reference in their entirety. Further exemplary lipids, formulations, methods, and characterization of LNPs are taught by Hou et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater (2021). doi.org / 10.1038 / s41578-021-00358-0, which is incorporated herein by reference in its entirety (see, for example, exemplary' lipids and lipid derivatives of Figure 2 of Hou et al.).

[0229] In some embodiments, in vitro or ex vivo cell lipofections are performed using Lipofectamine MessengerMax (Thermo Fisher) or TransIT-mRNA Transfection Reagent (Minis Bio). In certain embodiments, LNPs are formulated using the GenVoy ILM ionizable lipid mix (Precision NanoSystems). In certain embodiments, LNPs are formulated using 2,2-dilinoleyl-4-dimethylaminoethyl-[ 1, 3] -dioxolane (DLin-KC2-DMA) or dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA or MC3), the formulation and in vivo use of which are taught in Jayaraman et al. Angew Chem Int Ed Engl 51(34):8529-8533 (2012), incorporated herein by reference in its entirety'.

[0230] Lipid nanoformulations (e.g., liposome or LNP) optimized for the delivery of CRISPR-Cas systems, e.g., Cas9-gRNA RNP, gRNA, Cas9 mRNA, are described in WO 2019067992 and WO 2019067910, which are incorporated by reference in their entirety.

[0231] Additional specific lipid nanoformulations (e.g., liposome or LNP) useful for delivery of nucleic acid effector molecules are described in US 8158601 and US 8168775, which are incorporated by reference in their entirety.

[0232] A variety of methods may be used for preparing the lipid carrier or lipid nanoformulation (e.g., liposomes or LNPs) described herein. Such methods are known in the art or disclosed herein, for example, the methods described in Lichtenberg and Barenholz in Methods of Biochemical Analysis, 33:337-462 (1988), which is incorporated herein by reference in itsAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 entirety. See also Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980); U. S. Patent Nos. 4,235,871; 4,501,728; and 4,837,028; Liposomes, Marc J. Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1; and Hope, et al., Chem. Phys. Lip. 40:89 (1986), which are incorporated herein by reference in their entirety. Small unilamellar vesicles (SUV, size <100 nm) may be prepared by a combination of standard methods of thin-film hydration and repeated extrusion.

[0233] Techniques for sizing the lipid carrier or lipid nanoformulations (e.g., liposomes or LNPs) to a desired size are well-known to one skilled in the art. See, e.g., U. S. Patent No. 4,737,323, and Hope et al., Biochim. Biophys. Acta, 812: 55-65, which are incorporated by reference in their entirety. Sonicating a lipid nanoformulation (e.g., liposome or LNP) suspension either by bath or probe sonication produces a progressive size reduction down to small unilamellar vesicles less than about 50 nm in size. Homogenization or microfluidization are other methods which rely on shearing energy' to fragment large lipid nanoformulations (e.g., liposomes or LNPs) into smaller ones. In a typical homogenization procedure, multilamellar vesicles are recirculated through a standard emulsion homogenizer until selected lipid nanoformulation (e.g., liposome or LNP) sizes, typically between about 100 and 500 nm, are observed. In both methods, the particle size distribution may be monitored by conventional laser-beam particle size discrimination.

[0234] Extrusion of lipid nanoformulations (e.g., liposomes or LNPs) through a small-pore polycarbonate membrane or an asymmetric ceramic membrane is a very effective method for reducing liposome or LNP sizes to a relatively well- defined size distribution. Typically, the suspension is cycled through the membrane one or more times until the desired liposome or LNP size distribution is achieved. The lipid-based carrier or lipid nanoformulations may be extruded through successively smaller-pore membranes, to achieve a gradual reduction in liposome or LNP size.

[0235] Any of the lipid-based carrier or lipid nanoformulations described herein may be analyzed by methods well-known to one skilled in the art to determine its physical and / or chemical features. For example, a phosphate assay may be used to determine the concentration of the lipid nanoformulations. One phosphate assay is based on the interaction between molybdate and malachite green dye. The main principle involves the reaction of inorganic phosphate with molybdate to form a colorless unreduced phosphomolybdate complex which is converted to a blue colored complex when reduced under acidic conditions. Phosphomolybdate gives 20 or 30 times more color when complexed with malachite green. The final product, reduced green soluble complex is measured by its absorbance at 620 nm and is a direct measure of inorganic phosphate in solution.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0236] In some embodiments, the lipid-based carrier or lipid nanoformulations disclosed herein are tested for particle size, lipid concentration, and active agent encapsulation.

[0237] All references and publications cited herein are hereby incorporated by reference.Exemplary compounds

[0238] Exemplary compounds described in the disclosure and in pharmaceutical compositions of the disclosure include but are not limited to the compounds listed in Table 1.Pharmaceutically acceptable salts of the compounds listed in Table 1 are also useful in the method of the disclosure and in pharmaceutical compositions of the disclosure.Table 1: Exemplary Lipid CompoundsEx: Structure1N AA 0HN^ JAY02 ci o\= / HN^03 F\ / =\ / P°Y M o\ _0AN04 / =\ pN / M 0AN HN^HO7A^0Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1Additional Embodiments of the Disclosure

[0239] One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments may be combined in any way or combination.

[0240] Embodiment 1: A compound of formula (II)z(CH2)n-L2-R2R1-L -(CH2)P-N\(CH2)n-L2-R2(II),or a pharmaceutically acceptable salt thereof, wherein:R1is Ce-io aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io and, 5- to 10-membered heterocyclyl ring or 5- to 10-membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, Cs-Ci6 alkenyl, N(Cs-Ci6 alkyl)2, CH(C4-Ci2 alkoxy )2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl;each R3is independently halogen, OH, oxo, SH, thioxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5 -membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl optionally substituted with C1-6 alkyl:each RBis independently C1-6 alkyl or C1-6 alkoxy;each Rcis independently H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 each REis independently Ci-6 alkyl or a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with Ci-6 alkyl;Li is C(O)N(H), C(O)O, or N(H);each L2 is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3. 4. 5, or 6: andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0241] Embodiment 2: The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyeach R3is independently halogen, OH, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl. C(O)N(Rc)2. S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, or 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl;Li is C(O)N(H); andeach L2is C(CH3)2C(O)O.

[0242] Embodiment s: The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (II-A):Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0243] Embodiment 4: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl optionally substituted with one to four R3.

[0244] Embodiment 5: The compound of any of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:each R3is independently halogen, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, N(RD)C(O)-RE, S(O)2RB, or S(O)2N(RA)2, optionally wherein each R3is independently halogen, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, or S(O)2N(RA)2;each RAis independently H, Ci-6 alkyl. C3-6 cycloalkyl, a 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl, optionally wherein each RAis independently H, C1-6 alkyl, C3-6 cycloalky l, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl; andeach RBis independently C1-6 alkyl.

[0245] Embodiment 6: The compound of any of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein one R3is OCH3, and one R3is S(O)2N(RA)2.

[0246] Embodiment 7: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heteroaryl or a 6-membered heterocyclyl wherein the 6-membered heteroaryl or 6-membered heterocyclyl is optionally substituted with one to four R3, optionally wherein:.R1is a 6-membered heteroaryl optionally substituted with one to four R3; or R1is a 6-membered heterocyclyl optionally substituted with one to four R3.

[0247] Embodiment 8: The compound of any of Embodiments 1 to 3 and 7, or a pharmaceutically acceptable salt thereof, wherein each R3is independently OH, oxo, SH, thioxo, C1-6 alkyl, or S-C1-6 alkyl, optionally wherein each R3is independently OH, C1-6 alkyl, or S-C1-6 alkyl.

[0248] Embodiment 9: The compound of any of Embodiments 1 to 3, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein R1is a pyrimidine or pyridine wherein the pyrimidine or pyridine is optionally substituted with one to two R3.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0249] Embodiment 10: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one to four R3.

[0250] Embodiment 11: The compound of any of Embodiments 1 to 3 and 9. or a pharmaceutically acceptable salt thereof, wherein:each R3is independently halogen, OH, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, C(O)NH2, S(O)2N(RA)2, or phenyl wherein the phenyl is optionally substituted with one to two RB, optionally wherein each R3is independently C1-6 alkoxy, C3-6 cycloalkyl, C(O)NH2, S(O)2N(RA)2, or phenyl wherein the phenyl is optionally substituted with one to two RB; each RAis independently H, C1-6 alkyl, or a 5-membered heteroaryl wherein the 5- membered heteroaryl is optionally substituted with C1-6 alkyl, optionally wherein each RAis independently H or 5-membered heteroary l wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl; andeach RBis independently C1-6 alkoxy.

[0251] Embodiment 12: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is selected from a pyrrole, pyrazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole wherein the pyrrole, pyrazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole is optionally substituted with one R3, optionally wherein R1is selected from a pyrazole, isoxazole, thiophene, or thiazole wherein the pyrazole, isoxazole, thiophene, or thiazole is optionally substituted with one R3.

[0252] Embodiment 13: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heteroar l optionally substituted with one to four R3.

[0253] Embodiment 14: The compound of any of Embodiments 1 to 3, and 13, or a pharmaceutically acceptable salt thereof, wherein each R3is independently halogen, OH, or C1-6 alkyl.

[0254] Embodiment 15: The compound of any of Embodiments 1 to 3. or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heteroaryl optionally substituted with one to four R3.

[0255] Embodiment 16: The compound of any of Embodiments 1 to 3, and 15, or a pharmaceutically acceptable salt thereof, wherein each R3is independently halogen or OH, optionally wherein each R3is independently halogen.

[0256] Embodiment 17: The compound of any of Embodiments 1 to 3, 15, and 16, or a pharmaceutically acceptable salt thereof, wherein R1is a quinoline optionally substituted with one R3.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0257] Embodiment 18: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heterocyclyl optionally substituted with one to four R3.

[0258] Embodiment 19: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heterocyclyl optionally substituted with one to four R3.

[0259] Embodiment 20: The compound of any of Embodiments 1 to 3, 4, 7, 9, 12, 13, 15, 17, 18, and 19, or a pharmaceutically acceptable salt thereof, wherein each R3is independently oxo, Ci-6 alkyl, or Ci-6 alkoxy.

[0260] Embodiment 21: The compound of any of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyp is 4; andeach n is 6.

[0261] Embodiment 22: The compound of any of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyeach n is 6 or 7.

[0262] Embodiment 23: The compound of Embodiment 1, wherein the compound is selected from Table A, or a pharmaceutically acceptable salt thereof.

[0263] Embodiment 24: A nanoparticle composition comprising a lipid compound of any of Embodiments 1 to 23, or a pharmaceutically acceptable salt thereof.

[0264] Embodiment 25: The nanoparticle composition of Embodiment 24, further comprising a lipid carrier.

[0265] Embodiment 26: The nanoparticle composition of Embodiment 25, wherein the lipid carrier comprises a cationic lipid, a non-cationic lipid, a sterol, and a PEG-modified lipid.

[0266] Embodiment 27: The nanoparticle composition of Embodiment 25 or 26, wherein the lipid carrier comprises a natural lipid.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0267] Embodiment 28: The nanoparticle composition of any of Embodiments 24 to 27, further comprising a therapeutic and / or prophylactic agent.

[0268] Embodiment 29: A pharmaceutical composition comprising (a) the compound of any of Embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, or (b) the nanoparticle composition of any of Embodiments 24 to 28. and a pharmaceutically acceptable carrier.

[0269] Embodiment 30: The pharmaceutical composition of Embodiment 29, further comprising a therapeutic agent.

[0270] Embodiment 31: The pharmaceutical composition of Embodiment 29 or 30, further comprising a prophylactic agent.

[0271] Embodiment 32: The pharmaceutical composition of Embodiment 29 or 30, wherein the therapeutic agent is a nucleic acid.

[0272] Embodiment 33: The pharmaceutical composition of Embodiment 32, wherein the nucleic acid is an RNA or DNA.

[0273] Embodiment 34: The pharmaceutical composition of Embodiment 33, wherein the DNA or RNA is linear, circular, single stranded, or double stranded.

[0274] Embodiment 35: The pharmaceutical composition of Embodiment 34, wherein the RNA is an mRNA or a circular RNA.

[0275] Embodiment 36: The pharmaceutical composition of Embodiment 35, wherein the RNA is a circular RNA.

[0276] Embodiment 37: The pharmaceutical composition of Embodiment 30, wherein the therapeutic agent is a protein or small molecule drug.

[0277] Embodiment 38: The pharmaceutical composition of any of Embodiments 29 to 31, wherein the pharmaceutical composition is a vaccine.

[0278] Embodiment 39: A method of treating a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the nanoparticle composition of any of Embodiments 24 to 28 or the pharmaceutical composition of any of claims 29 to 38.

[0279] Embodiment 40: A method of preventing a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a prophylactically effective amount of the nanoparticle composition of any of Embodiments 24 to 28 or the pharmaceutical composition of any of Embodiments 29 to 38.

[0280] Embodiment 41: A compound of formula (I) / (CH2)n-L2-R2R1-L!-(CH2)p-N(CH2)n- L2-R2(i)Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 or a pharmaceutically acceptable salt thereof, wherein:R1is C6-10 aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the C6-10 aryl, 5- to 10-membered heterocyclyl ring or 5- to 10-membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, C8-C18 alkenyl, N(C8-C16 alkyl)2, CH(C4-C12 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl;each R3is independently halogen, OH, oxo, SH, thioxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RF, S(O)2RB. S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroary l wherein the 5 -membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl optionally substituted with C1-6 alkyl;each RBis independently C1-6 alkyl or C1-6 alkoxy;each Rcis independently H, C1-6 alkyl, C3-6 cycloalky l, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;each REis independently C1-6 alkyl or a 5-membered heteroaryl wherein the 5-membered heteroary l is optionally substituted with C1-6 alkyl;Li is C(O)N(H), C(O)O, or N(H);each L2 is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3, 4. 5, or 6; andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0281] Embodiment 42: The compound of Embodiment 41, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0282] Embodiment 43: The compound of Embodiment 41 or 42 or a pharmaceutically acceptable salt thereof, wherein:each R3is independently halogen, OH, oxo, SH, thioxo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB; optionally wherein R3is independently OH, oxo, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C(O)N(Rc)2, S(O)2N(RA)2,each RAis independently H, C1-6 alkyd, C3-6 cycloalkyl, or 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl;Li is C(O)N(H); andeach L2is C(CH3)2C(O)O or C(O)O.

[0283] Embodiment 44: The compound of Embodiment 41, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has formula (I-A):Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 oHN— (CH2)P— N0(I-A).

[0284] Embodiment 45: The compound of Embodiment 41, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has formula (I-B):(I B)

[0285] Embodiment 46: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl optionally substituted with one to four R3.

[0286] Embodiment 47: The compound of any of Embodiments 40 to 46, or a pharmaceutically acceptable salt thereof, wherein:each R3is independently halogen, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, C(O)N(Rc)2, N(RD)C(O)-RE, S(O)2RB, or S(O)2N(RA)2, optionally wherein each R3is independently halogen, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, or S(O)2N(RA)2;each RAis independently H, Ci-6 alkyl, C3-6 cycloalkyl, a 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl. optionally wherein each RAis independently H. C1-6 alkyl, C3-6 cycloalky 1, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl; andeach RBis independently C1-6 alkyl.

[0287] Embodiment 48: The compound of any of Embodiments 41 to 47, or a pharmaceutically acceptable salt thereof, wherein one R3is OCH3, and one R3is S(O)2N(RA)2.

[0288] Embodiment 49: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered hctcroaryl or a 6-membered heterocyclyl wherein the 6-membered heteroaryl or 6-membered heterocyclyl is optionally substituted with one to four R3, optionally wherein:.R1is a 6-membered heteroaryl optionally substituted with one to four R3; or R1is a 6-membered heterocyclyl optionally substituted with one to four R3.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0289] Embodiment 49: The compound of any of Embodiments 41 to 45 and 49, or a pharmaceutically acceptable salt thereof, wherein each R3is independently OH, oxo, SH, thioxo, Ci-6 alkyl, or S-Ci-6 alkyl, optionally wherein each R3is independently OH, Ci-6 alkyl, or S-Ci-6 alkyl.

[0290] Embodiment 51: The compound of any of Embodiments 41 to 45, 49, and 50, or a pharmaceutically acceptable salt thereof, wherein R1is a pyrimidine or pyridine wherein the pyrimidine or pyridine is optionally substituted with one to two R3.

[0291] Embodiment 52: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one to four R3.

[0292] Embodiment 53: The compound of any of Embodiments 41 to 45 and 52, or a pharmaceutically acceptable salt thereof, wherein:each R3is independently halogen, OH, oxo, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, C(O)NH2, S(O)2N(RA)2, or phenyl wherein the phenyl is optionally substituted with one to two RB, optionally wherein each R3is independently C1-6 alkoxy, C3-6 cycloalkyl, C(O)NH2, S(O)2N(RA)2, or phenyl wherein the phenyl is optionally substituted with one to two RB; each RAis independently H, C1-6 alkyl, or a 5-membered heteroaryl wherein the 5- membered heteroaryl is optionally substituted with C1-6 alkyl, optionally wherein each RAis independently H or 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl; andeach RBis independently C1-6 alkoxy.

[0293] Embodiment 54: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is selected from a pyrrole, pyrazole, imidazole, triazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole wherein the pyrrole, pyrazole, imidazole, triazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole is optionally substituted with one R3, optionally wherein R1is selected from a pyrazole, imidazole, isoxazole, thiophene, or thiazole wherein the pyrazole. isoxazole, thiophene, or thiazole is optionally substituted with one R3.

[0294] Embodiment 55: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heteroary 1 optionally substituted with one to four R3.

[0295] Embodiment 56: The compound of any of Embodiments 41 to 45, and 55, or a pharmaceutically acceptable salt thereof, wherein each R3is independently halogen, OH, or C1-6 alkyl.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0296] Embodiment 57: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heteroaryl optionally substituted with one to four R3.

[0297] Embodiment 58: The compound of any of Embodiments 41 to 45, and 57, or a pharmaceutically acceptable salt thereof, wherein each R3is independently halogen, OH. or N(RC)2optionally wherein each R3is independently halogen.

[0298] Embodiment 59: The compound of any of Embodiments 41 to 42, 57, and 58, or a pharmaceutically acceptable salt thereof, wherein R1is a quinoline optionally substituted with one R3.

[0299] Embodiment 60: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heterocyclyl optionally substituted with one to four R3.

[0300] Embodiment 61: The compound of any of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heterocyclyl optionally substituted with one to four R3.

[0301] Embodiment 62: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is and 8-membered heteroaryl optionally substituted with one R3.

[0302] Embodiment 63: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is and 5-membered heterocyclyl optionally substituted with one R3, optionally wherein R3is independently oxo or OH.

[0303] Embodiment 64: The compound of any of Embodiments 41 to 45, or a pharmaceutically acceptable salt thereof, wherein R1is and 8-membered heterocyclyl optionally substituted with one R3.

[0304] Embodiment 65: The compound of any of Embodiments 41 to 64, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyp is 4; andeach n is 6.

[0305] Embodiment 66: The compound of any of Embodiments 41 to 64, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1each n is 6 or 7.

[0306] Embodiment 67: The compound of Embodiment 41, wherein the compound is selected from Table A, or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 68: A nanoparticle composition comprising a lipid compound of any of Embodiments 41 to 67, or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 69: The nanoparticle composition of Embodiment 67, further comprising a lipid carrier.

[0309] Embodiment 70: The nanoparticle composition of Embodiment 69, wherein the lipid carrier comprises a cationic lipid, a non-cationic lipid, a sterol, and a PEG-modified lipid.

[0310] Embodiment 71: The nanoparticle composition of Embodiment 69 or 70, wherein the lipid carrier comprises a natural lipid.

[0311] Embodiment 72: The nanoparticle composition of any of Embodiments 68 to 71, further comprising a therapeutic and / or prophylactic agent.

[0312] Embodiment 73: A pharmaceutical composition comprising (a) the compound of any of Embodiments 41 to 67, or a pharmaceutically acceptable salt thereof, or (b) the nanoparticle composition of any of Embodiments 68 to 72, and a pharmaceutically acceptable carrier.

[0313] Embodiment 74: The pharmaceutical composition of Embodiment 73, further comprising a therapeutic agent.

[0314] Embodiment 75: The pharmaceutical composition of Embodiment 73 or 74, further comprising a prophylactic agent.

[0315] Embodiment 76: The pharmaceutical composition of Embodiment 73 or 74, wherein the therapeutic agent is a nucleic acid.

[0316] Embodiment 77: The pharmaceutical composition of Embodiment 76, wherein the nucleic acid is an RNA or DNA.

[0317] Embodiment 78: The pharmaceutical composition of Embodiment 77, wherein the DNA or RNA is linear, circular, single stranded, or double stranded.

[0318] Embodiment 79: The pharmaceutical composition of Embodiment 78, wherein the RNA is an mRNA or a circular RNA.

[0319] Embodiment 80: The pharmaceutical composition of Embodiment 79, wherein the RNA is a circular RNA.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0320] Embodiment 81: The pharmaceutical composition of Embodiment 74, wherein the therapeutic agent is a protein or small molecule drug.

[0321] Embodiment 82: The pharmaceutical composition of any of Embodiments 73 to 81, wherein the pharmaceutical composition is a vaccine.

[0322] Embodiment 83: A method of treating a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the nanoparticle composition of any of Embodiments 68 to 72 or the pharmaceutical composition of any of claims 73 to 82.

[0323] Embodiment 84: A method of preventing a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a prophylactically effective amount of the nanoparticle composition of any of Embodiments 68 to 72 or the pharmaceutical composition of any of Embodiments 73 to 82.

[0324] The above compounds and others within the scope of this disclosure may be made and tested for activity using the following procedures.

[0325] Reagents and solvents used below may be obtained from commercial sources such as Sigma- Aldrich Chemical Co. (St. Louis, Missouri, USA).JH NMR were recorded on an NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; quin, quintlet; m. multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge. A single m / e value is reported for the M+H (or, as noted, M-H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1EXAMPLESExample 1:_heptadecan-9-yl 8-((7,7-dimethyl-8-oxo-8-(undecyloxy)octyl)(4-(quinoline-4-carboxamido)butyl)amino)-2,2-dimethyloctanoateBrBr stepl BrZC10H21 (COCI)2, DMF 6 DCM, 25 °C, 2 h TEA, DMAP, DCM step 3 25 °C, 8 h step 4 O OHC10H21 C7H-15 ) C7H15 BocHN 14 TEA, DMAP, DCM K2CO3, KI, ACN 25 °C, 8 h 8 50 °C, 8 h step 6 step 5 NH2BocHN NH\ C7H15C7H,57K2CO3, KI, ACN O 80 °C, 8 h step 7 C1OH21TFA, DCM - ► 25 °C, 2 h step 8Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1EDCI, DMAP, DCM25 °C, 8 hstep 9

[0326] Step 1: Solution 1: {tert-butyl 2-methylpropanoate, 1 eq, 250 g} and {1.6-di bromohexane, 1.5 eq, 634.402 g} in {THF, 2500 mL}. Solution 2: {LDA, 1.5eq, 278.551 g}. The solution 1 was pumped by Pump 1 {SI, Pl, 57.541 mL / min} to flow reactor 1 {FLR1, PF A, Dynamic mixer, 1.5mL, 25 °C}. {FLR1, PF A, Coils reactor, 6.350 (1 / 4) mm, 119.521 mL, 25 °C}. The solution 2 was pumped by Pump 2 {S2, P2, 43.31 mL / min} to flow reactor 1 {FLR1, PF A. Dynamic mixer, 1.5 mL. 25 °C}. {FLR1, PF A, Coils reactor, 6.350 (1 / 4) mm, 119.521 mL, 25 °C}. The residence time of flow reactor 1 was {FLR1, 1.2 min}. The mixture was collected with a bottle (2 L aq. NH4Cl). The Pump 1 and Pump 2 was started at the same time. The reaction mixture was collected after running FLR1, 1.2 min. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / 0 to 50 / 1) to give compound tert-butyl 8-bromo-2, 2-dimethyl-octanoate (280 g, 911.26 mmol, 50.91% yield) as colorless oil.

[0327] 'H NMR (400 MHz, CDCh), 3.41 (t, J=7.2 Hz, 2H), 1.83-1.87 (m, 2H), 1.41-1.57 (m, 13H), 1.26-1.30 (m, 4H), 1.11 (s, 6H).

[0328] Step 2: To a solution of tert-butyl 8-bromo-2, 2-dimethyl-octanoate (280 g. 911.26 mmol, 1 eq) in DCM (800 mL) was added TFA (1.23 kg, 10.77 mol, 800 mL, 11.82 eq). The mixture was stirred at 25 °C for 2 hours. Remove the DCM on a rotary evaporator then the mixture was adjusted to pH 8 with NaHCCh and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 50 / 1) to give a compound 8-bromo-2, 2-dimethyl-octanoic acid (140 g, 358.34 mmol, 30.00% yield) as yellow oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0329] Step 3: To a solution of 8-bromo-2,2-dimethyl-octanoic acid (70 g, 278.71 mmol, 1 eq) in DCM (700 mL) was added (COC1)2(106.13 g, 836.12 mmol, 73.19 mL, 3 eq) and DMF (407.43 mg, 5.57 mmol, 428.88 pL, 0.02 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to get a compound 8-bromo-2,2-dimethyl-octanoyl chloride (75 g, crude) as yellow oil.

[0330] Step 4: A mixture of 8-bromo-2,2-dimethyl-octanoyl chloride (75 g, 278.18 mmol, 1 eq), undecan-l-ol (52.73 g, 306.00 mmol, 1.1 eq), TEA (140.75 g, 1.39 mol, 193.60 mL, 5 eq), DMAP (6.80 g, 55.64 mmol, 0.2 eq) in DCM (1000 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2atmosphere. The mixture was poured into water (500 mL) and extracted with Ethyl acetate (500 mL*3). The combined organic layers were washed with brine (500 mL*2) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 50 / 1) to give acompound undecyl 8-bromo-2,2-dimethyl-octanoate (70 g, 88.05 mmol, 31.88% yield) as yellow oil.

[0331] Step 5: A mixture of undecyl 8-bromo-2,2-dimethyl-octanoate (25 g, 61.66 mmol, 1 eq), tert-butyl N-(4-aminobutyl) carbamate (46.43 g, 246.64 mmol, 4 eq), K2COs (17.04 g, 123.32 mmol, 2 eq), KI (5.12 g, 30.83 mmol, 0.5 eq) in ACN (500 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 50 °C for 8 hours under N2atmosphere. The mixture was poured into water (500 mL) and extracted with Ethyl acetate (500 mL*3). The combined organic layers were washed with brine (300 mL*3) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) to give a compound undecyl 8-[4-(tert-butoxycarbonylamino)butylamino]-2,2-dimethyl-octanoate (18 g, 32.99 mmol, 49.76% yield) as yellow oil.

[0332] 'H NMR (400 MHz, CDCh), 4.04 (t, J=6.4 Hz, 2H), 3.12-3.13 (m, 2H), 2.55-2.63 (m, 4H), 1.53-1.98 (m. 2H), 1.50-1.52 (m. 18H), 1.44-1.48 (m, 21H). 1.27 (s. 6H), 0.99-1.15 (m. 3H).

[0333] Step 6: A mixture of 8-bromo-2,2-dimethyl-octanoyl chloride (53 g, 196.58 mmol, 1 eq), heptadecan-9-ol (55.46 g, 216.24 mmol, 1.1 eq), TEA (99.46 g, 982.92 mmol, 136.81 mL, 5 eq), DMAP (4.80 g, 39.32 mmol, 0.2 eq) in DCM (1000 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2atmosphere. The mixture was poured into water (500 mL) and extracted with Ethyl acetate (500 mL*3). The combined organic layers were washed with brine (500 mL* 2) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 50 / 1) to give a compound 1-octylnonyl 8-bromo-2,2-dimethyl-octanoate (37 g, 75.57 mmol, 38.54% yield) as yellow oil.

[0334] Step 7: A mixture of undecyl 8-[4-(tert-butoxycarbonylamino)butylamino]-2,2-dimethyl-octanoate (1 g, 1.95 mmol. 1 eq), 1-octylnonyl 8-bromo-2,2-dimethyl-octanoate (1.05 g, 2.15 mmol, 1.1 eq), K₂CO₃ (539.02 mg, 3.90 mmol, 2 eq), KJ (161.86 mg, 975.03 pmol, 0.5 eq) in ACN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 8 hours under N2 atmosphere. The mixture was poured into water (20 mL) and extracted with Ethyl acetate (20 mL*3). The combined organic layers were washed with brine (50 mL*2) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=100 / l to 1 / 1) to give a compound undecyl 8-[4-(tert-butoxycarbonylamino)butyl-[7,7-dimethyl-8-(1-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (900 mg, 761.80 pmol, 39.00% yield) as yellow oil.

[0335] H NMR (400 MHz, CDCh), 5.06-5.07 (m, 1H), 4.82-4.85 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.11-3.12 (m, 2H), 2.36-2.38 (m, 6H), 1.52-1.63 (m, 17H), 1.41-1.48 (m, 6H), 1.26-1.36 (m, 56H), 1.16 (s, 12H), 0.88 (t, J 6.8 Hz, 9H).

[0336] Step 8: To a solution of undecyl 8-[4-(tert-butoxycarbonylamino)butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.9 g, 976.66 pmol, 1 eq) in DCM (4 mL) was added TFA (2.76 g, 24.23 mmol, 1.80 mL, 24.81 eq). The mixture was stirred at 25 °C for 2 hours. Remove the DCM on a rotary evaporator then the mixture was adjusted to pH 8 with NaHCCL and extracted with EtOAc (5 mL*2). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a compound undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (780 mg, 892.63 pmol, 91.40% yield) as yellow oil.

[0337] Step 9: A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (260 mg, 316.54 pmol, 1 eq), quinoline-4-carboxylic acid (60.30 mg. 348.19 pmol. 1.1 eq), DMAP (19.34 mg, 158.27 pmol, 0.5 eq), EDCI (121.36 mg, 633.07 pmol, 2 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture w as stirred at 25 °C for 8 hours under N2 atmosphere. The mixture was poured into water (5 mL) then extracted with Ethyl acetate (5 mL*3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / ltol / l) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(quinoline-4-carbonyl amino)butyl]amino]-2,2-dimethyl-octanoate (110 mg, 110.39 pmol, 34.87% yield, 98% purity) as yellow oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0338] H NMR (400 MHz, CDCh), 8.93 (d, J=4.4 Hz, 1H), 8.15-8.24 (m, 2H), 7.76-7.89 (m, 1H), 7.73-7.75 (m, 1H), 7.60-7.62 (m, 1H), 7.43-7.72 (m, 1H), 4.77-4.83 (m, 1H), 4.02 ((t, J=6.4 Hz, 2H), 3.53-3.57 (m, 2H), 2.19-2.45 (m, 6H), 1.61-1.74 (m, 2H), 1.47-1.61 (m, 4H), 1.27-1.44 (m, 8H), 1.14-1.35 (m, 68H), 0.86-0.89 (m, 9H). (M+H+): 976.9.

[0339] LCMS-CAD: (M+H+): 976.9 @ 10.921 min

[0340] LCMS-ELSD: (M+H+): 976.8 @ 11.184 minExample 2: undecyl 8-[4-[(7-chloroquinoline-4-carbonyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoateEDCI, DMAP, DCM, 25 °C, 8 h

[0341] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (260 mg, 316.54 pmol, 1 eq), 7-chloroquinoline-4-carboxylic acid (72.29 mg. 348.19 pmol, 1.1 eq), EDCI (121.36 mg, 633.07 pmol, 2 eq), DMAP (19.34 mg. 158.27 pmol. 0.5 eq) in DCM (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The mixture was poured into water (2 mL) then extracted with Ethyl acetate (2 mL*3). The combined organic layers were washed with brine (5 mL) and dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 1 / 1) and prep-HPLC column: Welch Ultimate XB NH2 lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 0%-30% B over 10.0 min. The mixture was diluted with brine 100 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated underAttomey Docket 96676-435728 | Client Ref: SBM24-112WO1 N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexanephase was concentrated under N2 atmosphere to give compound undecyl 8-[4-[(7-chloroquinoline-4-carbonyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2.2-dimethyl-octanoate (64 mg, 62.04 pmol, 40.46% yield, 98% purity) as yellow oil.

[0342] 'H NMR (400 MHz, CDCh), 8.93-8.94 (m, 1H), 8.21-8.23 (m, 1H), 8.13-8.14 (m, 1H), 8.06-8.08 (m, 1H), 7.54-7.56 (m, 1H), 7.27-7.43 (m, 1H), 4.80-4.83 (m, 1 H), 4.02 (t, J=6.8 Hz, 2H), 3.56-3.51 (m, 2H), 2.21-2.50 (m, 6H), 1.50-1.74 (m, 2H), 1.47-1.48 (m, 4H), 1.44-1.47 (m, 6H), 1.25-1.26 (m. 42H), 1.10-1.14 (m, 28H), 0.89-0.86 (m, 9H). (M+H+): 1010.9.

[0343] LCMS-CAD (M+H+): 1010.9 @ 11.848 min.

[0344] LCMS-ELSD: (M+H+): 1010.9 @ 11.843 min.Example 3: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3-fluoro-4-methoxy-benzoyl)amino]butyl]amino]-2,2-dimethyl-octanoate

[0345] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g. 365.23 pmol, 1 eq), 3-fluoro-4-methoxy-benzoyl chloride (68.88 mg, 365.23 pmol, 1 eq) in DCM (5 mL) was added TEA (73.92 mg, 730.47 pmol, 101.67 pL, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 hr. The combined organic phase was diluted with EtOAc 20 mL and washed with water 60 mL (20 mL*3) and brine 40 mL (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh.Petroleum ether / Ethyl acetate / NH3. H2O=l / l / 0 to 0 / 1 / 0.1) to give a compound undecyl 8-[[7,7-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3-fluoro-4-methoxy-benzoyl)amino] butyl] amino] -2.2-dimethyl-octanoate (72 mg, 72.48 pmol, 20.67% yield, 98% purity) as colorless oil.

[0346] 'H NMR (400 MHz, CDCh), 7.53-7.56 (m, 2H), 6.95-7.00 (m, 2H), 4.81-4.84 (m, 1H), 4.04 (t. J=6.4 Hz, 2H). 3.93 (s. 3H), 3.42-3.47 (m. 2H), 2.38-2.49 (m. 6H), 1.66-1.68 (m. 6H), 1.50-1.52 (m, 8H), 1.40-1.42 (m, 4H), 1.17-1.27 (m, 52H), 1.15 (s, 12H), 0.86-0.90 (m, 9H). (M+H+): 973.9.

[0347] LCMS-CAD: (M+H+): 973.9 @ 11.726 min.

[0348] LCMS-ELSD: (M+H+): 973.9 @ 11.710 min.Example 4: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(2-oxo-lH-pyrimidine-4-carbonyl)amino] butyl] amino] -2, 2-dimethyl-octanoate / =\ O HN < OH2ONMM, THF, 0-25 °C, 8 h

[0349] To a solution of 2-oxo-lH-pyrimidine-4-carboxylic acid (7.75 mg, 55.34 pmol, 1 eq) in THF (2 mL) was added 4-methyl morpholine (11.19 mg, 110.68 pmol, 12.17 pL, 2 eq) and isobutyl carbonochloridate (7.94 mg, 58.11 pmol. 7.60 pL, 1.05 eq). The mixture was stirred at 25 °C for 30 min. Then the mixture was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-( I -octylnonoxy)-8-oxo-octyl |amino|-2.2-dimethyl-octanoate (50 mg, 60.87 pmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 7.5 hours. The mixture was poured into water (5 mL) then extracted with Ethyl acetate (5 mL*2). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC column: X-Select CSH Phenyl-Hexyl 100*30 5u; mobile phase: [H2O(0.1%TFA)-ACN: THF=1: 1 ]; gradient: 55%-90% B over 16.0 min. TheAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 mixture was diluted with brine 50 mL and extracted with EtOAc 30 rnL (10 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 30 mL (10 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 10 mL and washed with ACN 20 mL (10 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(2-oxo-lH-pyrimidine-4-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate (18 mg, 19.08 pmol, 36.00% yield, 100% purity) as yellow oil.

[0350] H NMR (400 MHz, CDCh), 8.07 (s, 1H), 7.14 (s, 1H), 4.81-4.82 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.35-3.51 (m, 2H), 2.51-2.69 (m, 4H), 1.91-2.25 (m, 10H), 1.61-1.59 (m, 12H), 1.18-1.35 (m, 50H), 1.14 (s, 12H), 0.89-0.86 (m, 9H). (M+H+): 943.8.

[0351] LCMS-CAD: (M+H+): 943.8 @ 11.231 min.

[0352] LCMS-ELSD: (M+H+): 944.0 @ 11.024 min.Example 5: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[5-(4-methoxyphenyl)-lH-pyrazole-4-carbonyl] amino] butyl ]amino]-2,2-dimethyl-octanoate50 °C, 8 hAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0353] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq), 5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (79.70 mg, 365.23 pmol, 1 eq) in DMF (3 mL) was added EDCI (105.02 mg, 547.85 pmol, 1.5 eq), HOBt (49.35 mg, 365.23 pmol, 1 eq), TEA (36.96 mg, 365.23 pmol, 50.84 pL, 1 eq). The mixture was stirred at 50 °C for 8 hrs. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=l / 0) and prep-HPLC (column: Welch Ultimate XB NEL lOu 100*30mm;mobile phase: [Heptane-THF: ACN=2:l];gradient:10%-50% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[5-(4-methoxyphenyl)-lH-pyrazole-4-carbonyl] amino]butyl]amino]-2.2-dimethyl-octanoate (16 mg, 15.51 pmol. 79.20% yield, 98% purity) as yellow oil.

[0354] 'H NMR (400 MHz, CDCh), 8.34 (brs, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.35 (brs, 1H), 6.90 (d, 1 8.4 Hz, 2H), 6.76 (brs, 1H), 4.73-4.89 (m, 1H), 4.03 (t, >6.8 Hz, 2H), 3.73-3.86 (m, 3H), 3.39 (d, J=4.8 Hz, 2H), 2.82-3.13 (m, 6H), 1.65-1.90 (m, 16H), 1.23-1.36 (m, 54H), 1.14 (s, 12H), 0.85-0.91 (m, 9H). (M+H ): 1021.8

[0355] LCMS-CAD: (M+H+): 1021.8 @ 11.690 min.

[0356] LCMS-ELSD: (M+H+): 1021.9 @ 11.696 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 6: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(6-fluoro-lH-indole-3-carbonyl)amino] butyl] amino] -2,2-dimethyl-octanoate

[0357] Step 1: A solution of 6-fluoro-lH-indole-3-carboxylic acid (0.13 g, 602.94 pmol, 1 eq, HC1) in DCM (10 mL) was added thionylchloride (286.93 mg, 2.41 mmol, 175.17 pL, 4 eq). The mixture was degassed and purged with N2 for 3 times, and stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a compound 6-fluoro-lH-indole-3-carbonyl chloride (0.11 g, crude) as yellow oil.

[0358] Step 2: To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq), TEA (147.83 mg, 1.46 mmol, 203.34 pL, 4 eq) in DCM (5 mL) was added 6-fluoro-lH-indole-3-carbonyl chloride (108.25 mg, 547.85 pmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 3 hrs. The combined organic phase was diluted with EtOAc 20 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / l to 1 / 1, 3% NH3 H2O) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u;mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l]; gradient:40%-75% B over 16.0 min). The mixture was diluted with brine 60 mL and extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried over Na₂SO₄, filteredAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 30 mL (10 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 10 mL and washed with ACN 20 mL (10 mL*2). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was purified by prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm;mobile phase: [Heptane-EtOH];gradient:0%-30% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(6-fluoro-lH-indole-3-carbonyl)amino]butyl] amino] -2.2-dimethyl-octanoate (27 mg, 27.48 pmol. 54.00% yield, 100% purity) as yellow oil.

[0359] 'H NMR (400 MHz, CDCh), 9.20 (brs, 1H), 7.98-8.12 (m, 1H), 7.76 (brs, 1H), 6.92-7,15 (m, 2H), 6.65 (brs, 1H), 4.78-4.92 (m, 1H), 4.05 (t, J=6.8 Hz, 2H), 3.45-3.57 (m, 2H), 2.35-2.60 (m, 6H), 1.45-1.65 (m, 16H), 1.18-1.40 (m, 54H), 1.16 (s, 12H), 0.82-0.90 (m, 9H).(M+H ): 982.8.

[0360] LCMS-CAD: (M+H+): 982.8 @ 12.094 min.

[0361] LCMS-ELSD: (M+H+): 982.8 @ 12.106 min.Example 7: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(2-oxo-lH-pyridine-4-carbonyl)amino] butyl] amino]-2,2-dimethyl-octanoate1. (COCI)2, DMF, DCM, 0 °C, 2 h 2. TEA, DMAP, DMF, 25 °C, 8 h

[0362] To a solution of 2-oxo-lH-pyridine-4-carboxylic acid (600 mg, 4.31 mmol,1 eq) in DCM (6 mL) was added DMF (315.27 mg, 4.31 mmol, 331.86 pL, 1 eq) and oxalyl dichloride (656.95 mg, 5.18 mmol, 453.07 pL, 1.2 eq). The mixture was stirred at 0 °C for 2 hrs.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 The reaction mixture was concentrated under reduced pressure to give compound 2-oxo-lH-pyridine-4-carbonyl chloride (679 mg, crude) as yellow oil. To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (435.76 mg, 530.51 pmol, 1 eq) in DMF (5 mL) was added TEA (536.83 mg, 5.31 mmol, 738.41 pL. 10 eq) and DMAP (32.41 mg. 265.26 pmol. 0.5 eq) and 2-oxo-lH-pyridine-4-carboxylic acid (73.80 mg, 530.51 pmol, 1 eq). The mixture was stirred at 25 °C for 8 hrs. The reaction mixture was quenched by addition H2O 10 mL at 0 °C, and then extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.05%TFA-ACN: THF=l:l];gradient:55%-90% B over 14.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase w as concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(2-oxo-lH-pyridine-4-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate (135 mg, 143.24 pmol, 54.00% yield, 100% purity) as yellow oil.

[0363] 'll NMR (400 MHz, CDCh), 8.31-9.34 (m, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.72 (d, J=6.8Hz, 1H), 4.81-4.84 (m, 1H), 4.04 (t, J=6.8Hz, 2H), 3.46-3.48 (m, 2H), 2.53-2.60 (m, 6H), 1.57-1.62 (m, 6H), 1.49-1.50 (m, 12H), 1.21-1.38 (m, 52H), 1.14 (s, 12H), 0.86-0.89 (m, 9H)(M+H+): 942.9.

[0364] LCMS-CAD: (M+H+): 942.9 @ 11.721 min.

[0365] LCMS-ELSD: (M+H+): 942.9 @ 10.781 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 8: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(l-oxo-2,3,4,5-tetrahydropyrrolo [ 1,2-a] [1,4] diazepine-8-carbonyl)amino] butyl] amino] -2,2-dimethyl-octanoate

[0366] To a solution ofl-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carboxylic acid (496.47 mg, 2.56 mmol, 3 eq), HATU (324.04 mg, 852.21 pmol, 1 eq), DIEA (220.28 mg, 1.70 mmol, 296.88 pL, 2 eq) in DMF (7 mL) was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.7 g, 852.21 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hrs. The combined organic phase was diluted with EtOAc 20 mL and washed with water 30 mL (10 mL*3) and brine 20 mL (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / 0 to 1 / 1.3% NEL THF) and prep-MPLC (column: Welch Ultimate XB NFL lOu 100*30mm;mobile phase:[Heptane-EtOH] gradient: 0%-30% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[( 1 -oxo-2,3,4,5-tetrahydropyrrolo[ 1.2-a] [ 1,4] diazepine-8-carbonyl)amino]butyl]amino] -2.2-dimethyl-octanoate (0.42 g, 416.82 pmol, 59.40% yield, 100% purity) as yellow oil.

[0367] 'H NMR (400 MHz, CDCh), 7.36 (brs, 1H), 7.04 (brs, 1H), 6.20 (brs, 1H), 5.90 (brs, 1H), 4.72-4.95 (m, 1H), 3.96-4.28 (m, 4H), 3.25-3.49 (m, 4H), 2.03-2.67 (m, 8H), 1.55-1.60 (m, 4H), 1.39-1.54 (m, 14H), 1.20-1.32 (m, 52H), 1.15 (s. 12H), 0.85-0.91 (m, 9H). (M+H+): 997.8.

[0368] LCMS-CAD: (M+H+): 997.8 @ 11.267 min.

[0369] LCMS-ELSD: (M+H+): 997.9 @ 11.370 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 9: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[4-(l, 1,2,2-tetrafluoroethoxy)benzoyl]amino]butyl]amino]-2,2-dimethyl-octanoate0~25 °C, 3 h

[0370] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.7 g. 852.21 pmol, 1 eq), 4-(l, 1,2,2-tetrafluoroethoxy)benzoic acid (202.94 mg, 852.21 umol. 1 eq), HATU (324.04 mg, 852.21 pmol, 1 eq), DIEA (220.28 mg, 1.70 mmol, 296.88 pL, 2 eq) in DMF (10 mL) at 0 °C, and then the mixture was stirred at 25 °C for 3 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / 0 to 0 / 1) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm;mobile phase: [Heptane-EtOEI];gradient:5%-30% B over 10.0 min) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[4-(l.l,2,2-tetrafluoroethoxy)benzoyl]amino]butyl]amino]-2,2-dimethyl-octanoate (0.11 g, 104.56 pmol, 36.30% yield, 99% purity) as colorless oil.

[0371] H NMR (400 MHz, CDCh) 7.84 (s, 2H), 7.34-7.35 (m, 1H), 7.18-7.19 (m, 1H), 5.78-6.09 (m, 1H), 4.78-4.81 (m, 1H), 4.01-4.09 (t, J=6.8 Hz, 2H), 3.49-3.51 (m, 2H), 2.31-2.71 (m, 6H), 1.56-1.71 (m, 10H), 1.35-1.46 (m, 5H), 1.14-1.32 (m, 55H), 1.07 (s, 12H), 0.61-0.69 (m, 9H), (M+H+): 1041.9.

[0372] LCMS-CAD: (M+H+): 1041.9 @ 12.383 min.

[0373] LCMS-ELSD: (M+H+): 1041.9 @ 12.352 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 10: undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(6-methyl-4-methylsulfanyl-2-oxo-lH-pyrimidine-5-carbonyl) amino] butyl] amino] -2, 2-dimethyl-octanoateHATU, DIPEA, DMF, 25 °C, 8 h

[0374] A mixture of 6-methyl-4-methylsulfanyl-2-oxo-lH-pyrimidine-5-carboxylic acid (219.38 mg, 1.10 mmol, 1 eq), undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.9 g, 1.10 mmol, 1 eq), HATU (499.94 mg, 1.31 mmol, 1.2 eq), DIEA (424.83 mg, 3.29 mmol, 572.55 pL. 3 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The mixture was poured into water (10 mL) then extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate=10 / 0 to 0 / 1), prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-EtOH]; gradient: 5%-80% B over 10.0 min) and column chromatography (SiCh, Petroleum ether: Ethyl acetate=10 / 0 to 0 / 1) to give a compound undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]- [4- [(6-methyl-4-methylsulfanyl-2-oxo-lH-pyrimidine-5 -carbonyl) amino] butyl] amino] -2, 2-dimethyl-octanoate (61 mg, 60.17 pmol, 5.49% yield, 99% purity) as colorless oil.

[0375] 'H NMR (400 MHz, CDCh), 7.51-7.52 (m, 1H), 4.80-4.83 (m, 1H), 4.02 (t, J=6.8 Hz, 2H), 3.41-3.45 (m, 2H), 2.54 (s, 3H), 2.31-2.45 (m, 9H), 1.61-1.62 (m, 6H), 1.49-1.59 (m, 8H), 1.21-1.45 (m, 56H), 1.14 (s, 12H). 0.86-0.88 (m, 9H). (M+H+): 1003.8.

[0376] LCMS-CAD: (M+H+): 1003.8 @ 11.349 min.

[0377] LCMS-ELSD: (M+H+): 1003.8 @ 11.357 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 11: undecyl 8-[4-[(3-cyclopropyl-lH-pyrazole-4-carbonyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate

[0378] To a solution of 3-cyclopropyl-1H-pyrazole-4-carboxylic acid (240.81 mg, 1.58 mmol, 1 eq) in DCM (13 rnL) was added EDCI (394.42 mg, 2.06 mmol, 1.3 eq), HOBt (299.40 mg, 2.22 mmol, 1.4 eq), undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.3 g, 1.58 mmol, 1 eq) and TEA (320.30 mg, 3.17 mmol, 440.58 pL. 2 eq). The mixture was stirred at 25 °C for 8 hours. The mixture was poured into water (20 mL) then extracted with DCM (20 mL*2). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue w as purified by column chromatography (SiCh, Petroleum ether: Ethyl acetate=10 / 0 to 0 / 1) and prep-HPLC (column: WePure Biotech Phenyl-Hexyl 250*70 7u; mobile phase: [H2O (0.1% TFA)-ACN: THF=1: 1J; gradient: 60%-80% B over 20.0 mm). The mixture was diluted with brine 100 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2atmosphere to give a compound undecyl 8-[4-[(3-cyclopropyl-lH-pyrazole-4-carbonyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (269 mg, 281.52 pmol, 17.79% yield, 100% purity) as colorless oil.

[0379] H NMR (400 MHz, CDCh), 7.86 (s, 1H), 6.48-6.51 (m, 1H), 4.82-4.85 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.42-3.47 (m, 2H), 2.30-2.44 (m, 7H), 1.61-1.63(m, 8H), 1.50-1.60 (m, 6H),Attomey Docket 96676-435728 | Client Ref: SBM24-112WO1 1.23-1.26 (m, 4H), 1.15-1.23 ( m, 52H), 1.15 (s, 12H), 0.89-1.15 (m, 2H), 0.86-0.88 (m, 11H). (M+H+): 955.8.

[0380] LCMS-CAD: (M+H+): 955.8 @ 11.648 min.

[0381] LCMS-ELSD: (M+H+): 955.8 @ 11.660 min.Example 12: undecyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-[7,7-dimethyl-8- (l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate

[0382] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.6 g, 730.47 pmol, 1 eq), 3-carbamoylisoxazole-5-carboxylic acid (171.04 mg, 1.10 mmol. 1.5 eq), EDCI (280.06 mg, 1.46 mmol, 2 eq), DMAP (17.85 mg, 146.09 pmol, 0.2 eq) in DMF (6 mL). The mixture was stirred at 50 °C for 3 hrs. The combined organic phase was diluted with EtOAc 20 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4. fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=20 / l to 1 / 1, 3% NH3 H2O) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm;mobile phase: [Heptane-EtOH];gradient:0%-30% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound undecyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2, 2-dimethyLoctanoate (53 mg, 54.69 pmol, 34.98% yield, 99% purity) as yellow oil.

[0383] 'H NMR (400 MHz, CDCh), 8.51 (brs, 1H), 7.26-7.30 (m, 1H), 6.82 (brs, 1H), 5.68 (brs, 1H), 4.79-4.85 (m, 1H), 4.04 (t, J=6.8 Hz, 2H), 3.38-3.52 (m, 2H), 2.22-2.64 (m, 6H), 1.60-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 1.75 (m, 6H), 1.38-1.53 (m, 12H), 1.21-1.32 (m, 52H), 1.15 (s, 12H), 0.86-0.91 (m, 9H).(M+H+): 959.8.

[0384] LCMS-CAD: (M+H+): 959.8 @ 11.480 min.

[0385] LCMS-ELSD: (M+H+): 959.8 @ 11.493 min.Example 13: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(4-oxo-5H-pyrazolo[l,5-a]pyrazine-3-carbonyl)amino]butyl]amino] -2,2-dimethyl-octanoate

[0386] To a solution of 4-oxo-5H-pyrazolo[l,5-a]pyrazine-3-carboxylic acid (191.91 mg, 1.07 mmol, 1.1 eq), HATU (370.33 mg, 973.96 pmol, 1 eq), DIEA (251.75 mg, 1.95 mmol. 339.29 pL, 2 eq) in DMF (8 mL) was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.8 g, 973.96 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hrs. The combined organic phase was diluted with EtOAc 20 mL and washed with water 30 mL (10 mL*3) and brine 20 mL (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 1 / 1,3% NFL THF) and prep-MPLC (column: Welch Ultimate XB NEE lOu 100*30mm;mobile phase: [Heptane- EtOH] gradient: 0%-30% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound undecyl 8-[[7.7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(4-oxo-5H-pyrazolo[l,5-a]pyrazine-3-carbonyl)amino]butyl]amino] -2,2-dimethyl-octanoate (314 mg, 316.39 pmol, 62.17% yield, 99% purity) as yellow oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0387] H NMR (400 MHz, CDCh), 9.96-10.09 (m, 1H), 8.45 (brs, 1H), 7.24-7.30 (m, 1H), 6.84-6.94 (m, 1H), 4.76-4.92 (m, 1H), 4.06 (t, J=6.8 Hz, 2H), 3.36-3.57 (m, 2H), 2.30-2.60 (m, 6H), 1.48-1.71 (m, 14H), 1.20-1.47 (m, 56H), 1.17 (s, 12H), 0.83-0.94 (m, 9H). (M+H+): 982.8.

[0388] LCMS-CAD: (M+H+): 982.8 @ 11.614 min.

[0389] LCMS-ELSD: (M+H+): 982.8 @ 11.621 min.Example 14: 4-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(7,7-dimethyl-8-oxo-8-undecoxy-octyl)amino] butyl 2-oxo-lH-pyridine-4-carboxylate

[0390] Step 1: To a solution of 1-octylnonyl 8-bromo-2, 2-dimethyl-octanoate (5 g, 10.21 mmol, 1 eq) in EtOH (60 mL) was added 4-aminobutan-l-ol (18.21 g, 204.24 mmol, 18.96 mL, 20 eq). The mixture was stirred at 50 °C for 8 hours. The reaction mixture was quenched by addition H2O 20 mL at 0 °C, and then extracted with EtOAc 30 mL (10 mL*3). The combinedAttomey Docket 96676-435728 | Client Ref: SBM24-112WO1 organic layers were dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) to give a compound 1-octylnonyl 8-(4-hydro\ybutylamino)-2. 2-dimethyl-octanoate (4 g, 7.63 mmol. 74.74% yield) as yellow oil.

[0391] 'H NMR (400 MHz. CDCh), 4.81-4.84 (m. 1H), 3.56-3.58 (m. 2H), 2.58-2.66 (m. 4H), 1.61-1.68 (m, 4H), 1.47-1.51 (m, 8H), 1.25-1.29 (tn, 30H), 1.14 (s, 6H), 0.88 (t, J=6.8 Hz, 6H).

[0392] Step 2: To a solution oP I -octylnonyl 8-(4-hydroxybutylamino)-2, 2-dimethyl-octanoate (4.5 g, 9.04 mmol, 1 eq) in DMF (40 mb) was added K2CO3 (3.75 g, 27.12 mmol, 3 eq) and KI (1.50 g, 9.04 mmol, 1 eq) and undecyl 8-bromo-2, 2-dimethyl-octanoate (3.66 g, 9.04 mmol. 1 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was quenched by addition H2O 40 mL at 0 °C, and then extracted with EtOAc 150 mL (50 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i O2. Petroleum ether / Ethyl acetate=20 / l to 0 / 1) to give a compound undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(4-hydroxybutyl) amino] -2, 2-dimethyl-octanoate (4 g, 4.86 mmol, 53.81% yield) as yellow oil.

[0393] 'H NMR (400 MHz, CDCh), 4.81-4.84 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.55-3.65 (m, 2H), 2.30-2.58 (m. 6H), 1.61-1.64 (m. 6H), 1.48-1.55 (m. 10H), 1.43-1.47 (m, 2H), 1.21-1.35 (m, 54H), 1.15 (s, 12H), 0.87-0.90 (m, 9H).

[0394] Step 3: To a solution of undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(4-hydroxy butyl) amino] -2, 2-dimethyl-octanoate (500 mg, 608.00 pmol, 1 eq) in DCM (5 mL) was added HOBt (106.80 mg, 790.39 pmol, 1.3 eq), EDCI (139.86 mg, 729.60 pmol. 1.2 eq) and 2-hydroxypyridine-4-carboxylic acid (253.73 mg, 1.82 mmol, 3 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition H2O 10 mL at 0 °C, and then extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) and purified by prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u;mobile phase: [H2O ( 0.05%TFA) -ACN: THF=l:l];gradient:55%-85% B over 16.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue w as diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase w as concentrated under N2 atmosphere to give a compound 4-[[7,7-dimethyl-8-(l-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 octylnonoxy)-8-oxo-octyl]-(7,7-dimethyl-8-oxo-8-undecoxy-octyl)amino] butyl 2-oxo-lH-pyridine-4-carboxylate (150 mg, 155.81 pmol, 49.00% yield, 98% purity) as yellow oil.

[0395] 'H NMR (400 MHz, CDCh), 7.42 (d, J=6.8 Hz, 1H), 7.22 (s, 1H), 6.77-6.79 (m, 1H), 4.82-4.85 (m, 1H), 4.33 (t, J=6.4 Hz, 2H), 4.04 (t, J=6.8 Hz, 2H), 2.37-2.44 (m, 6H), 1.63-1.76 (m. 2H), 1.49-1.61 (m. 16H), 1.21-1.35 (m, 52H). 1.15 (s, 12H), 0.86-0.89 (m, 9H). (M+H+): 943.8.

[0396] LCMS-CAD: (M+H+): 943.8 @ 11.508 min.

[0397] LCMS-ELSD: (M+H+): 943.8 @ 11.512 min.Example 15: undecyl 8-[[7,7-dimethyl-8-(l-octyInonoxy)-8-oxo-octyI]-[4-[(5-sulfamoylthiophene-3-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate

[0398] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq) and 5-sulfamoylthiophene-3-carboxylic acid (75.69 mg, 365.23 pmol, 1 eq) in DCM (3 rnL) was added EDCI (140.03 mg, 730.47 pmol, 2 eq) and DMAP (8.92 mg, 73.05 pmol, 0.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition water 60 mL at 25 °C, and then extracted with EtOAc 60 mL (30 mL*2). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.1% TFA)-ACN: THF=1:1]; gradient:45%-80% B over 16.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 90 rnL (30 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN andAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 TEA 60 mL (20 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(5-sulfamoylthiophene-3-carbonyl)amino]butyl] amino] -2.2-dimethyl-octanoate (110 mg. 108.85 pmol, 29.80% yield, 100% purity) as colorless oil.

[0399] 'H NMR (400 MHz, CDCh), 8.07 (s, 1 H), 7.95 (s, 1H), 7.46 (t, J=4.8 Hz, 1H), 4.78-4.84 (m, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.39-3.44 (m, 2H), 2.40-2.48 (m, 6H), 1.25-1.65 (m, 70H), 1.45 (s, 12H), 0.75-0.90 (m, 9H). (M+H+): 1010.8.

[0400] LCMS-CAD: (M+H+): 1010.8 @ 11.192 min.

[0401] LCMS-ELSD: (M+H+): 1010.9 @ 11.187 min.Example 16:_4-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(7, 7-dimethyl-8-oxo-8-undecoxy-octyl) amino] butyl 5-ethoxy-lH-pyrazole-3-carboxylate

[0402] To a solution of undecyl 8-[[7.7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(4-hydroxybutyl) amino]-2,2-dimethyl-octanoate (500 mg, 608.00 pmol, 1 eq) in DCM (5 mL) was added HATU (231.18 mg, 608.00 pmol, 1 eq) and DIEA (235.74 mg, 1.82 mmol, 317.70 pL, 3 eq) and 5-ethoxy-lH-pyrazole-3-carboxylic acid (189.86 mg, 1.22 mmol, 2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition H2O 40 mL at 0 °C, and then extracted with EtOAc 150 mL (50 mL*3). The combined organic layers were dned over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1), p-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-30% B over 10.0 min) and prep-HPLC (column: X-Select CSHAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.1% TFA)-ACN: THF=1:1]; gradient: 50%-90% B over 16.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 90 rnL (30 mL*3). The combined organic layers were dried over Na₂SO₄, fdtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-(7, 7-dimethyl-8-oxo-8-undecoxy-octyl) amino] butyl 5-ethoxy-lH-pyrazole-3-carboxylate (15 mg, 15.46 pmol, 21.21% yield. 99% purity) as yellow oil.

[0403] 'H NMR (400 MHz, CDCh), 6.21 (s, 1 H), 4.83-4.95 (m, 1H), 4.03-4.34 (m, 6H), 2.38-2.51 (m, 6H), 1.75-1.77 (m, 2H), 1.50-1.70 (m, 12H), 1.40-1.42 (m, 7H), 1.25-1.39 (m, 52H), 1.15 (s, 12H), 0.86-0.89 (m, 9H). (M+H+): 960.8.

[0404] LCMS-CAD: (M+H+): 960.8 @ 12.128 min.

[0405] LCMS-ELSD: (M+H+): 960.9 @ 11.657 min.Example 17: undecyl 8- [[7, 7- dimethyl- 8-(l- octylnonoxy)-8- oxo- octyl] - [4- [[4- methoxy-3-(methylsulfamoyl) benzoyl] amino] butyl] amino]-2, 2-dimethyl-octanoate

[0406] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.7 g, 852.21 pmol. 1 eq), 4-methoxy-3-(methylsulfamoyl)benzoic acid (271.71 mg, 1.11 mmol, 1.3 eq), DMAP (104.11 mg. 852.21 pmol, 1 eq), EDCI (653.48 mg, 3.41 mmol, 4 eq) and TEA (86.23 mg, 852.21 pmol, 118.62 pL,Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 1 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The reaction mixture was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=5 / l to 0 / 1) and p-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-30% B over 10.0 min) to give a compound undecyl 8-[[7, 7- dimethyl-8-(l- octylnono\y)-8- oxo- octyl] - [4- [[4- methoxy-3-(methylsulfamoyl) benzoyl] amino] butyl] amino]-2, 2-dimethyl-octanoate (150 mg. 140.18 pmol, 16.45% yield, 98% purity) as colorless oil.

[0407] 'H NMR (400 MHz, CDCh), 8.16-8.22 (m, 2H), 7.01-7.13 (m, 2H), 4.80-4.84 (m, 2H), 4.02-4.05 (m, 5H), 3.44-3.48 (m, 2H), 2.43-2.63 (m, 9H), 1.59-1.66 (m, 4H), 1.51-1.58 (m, 8H), 1.41-1.49 (m, 4H), 1.26-1.40 (m, 54H), 1.15 (s, 12H). 0.86-0.89 (m, 9H). (M+H+): 1048.9.

[0408] LCMS-CAD: (M+H+): 1048.9 @ 11.279 min.

[0409] LCMS-ELSD: (M+H+): 1048.9 @ 11.267 min.Example 18: undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3-fluoro-4-hydroxy- benzoyl) amino] buty 1] amino]-2, 2-dimethyl-octanoate

[0410] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2, 2-dimethyl-octanoate (0.5 g. 608.72 pmol, 1 eq), 3-fluoro-4-hydroxy-benzoic acid (95.03 mg, 608.72 pmol, 1 eq), HOBt (115.15 mg, 852.21 pmol, 1.4 eq), EDCI (151.70 mg, 791.34 pmol. 1.3 eq) and TEA (123.19 mg, 1.22 mmol, 169.45 pL. 2 eq) in DCM (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 hours under N2 atmosphere. The mixture was poured into water (10 mL) then extracted with Ethyl acetate (10 mL*2). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=10 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.05% TFA-ACN: THF=1:1)]; gradient: 45%-85% B over 16.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecy l 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3-fluoro-4-hydroxy -benzoyl) amino] butyl] amino]-2,2-dimethyl-octanoate (23 mg, 23.73 pmol, 7.59% yield, 99% purity) as yellow oil.

[0411] 'H NMR (400 MHz, CDC13), 7.52-7.55 (m, 1H), 7.38-7.39 (m, 1H), 7.00-7.05 (m, 1H), 6.92 (t, 8.4 Hz, 1H), 4.82-4.85 (m, 1H), 4.04 (t, 8.4 Hz, 2H), 3.44-3.45 (m, 2H), 2.45-2.52 (m, 6H), 1.48-1.66 (m, 18H), 1.23-1.47 (m, 52H), 1.15 (s, 12H), 0.86-0.89 (m. 9H). (M+H+): 959.8.

[0412] LCMS-CAD: (M+H+): 959.8 @ 11.789 min.

[0413] LCMS-ELSD: (M+H+): 959.9 @ 11.308 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 19: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(l-methyl-2,4-dioxo-pyrido[2,3-d]pyrimidine-7-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate

[0414] To a solution of undecyl 8-[4-aminobutyl-[7,7- dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino]-2,2-dimethyloctanoate(500 mg, 608.72 pmol, 1 eq) and l-methyl-2,4-dioxo-pyrido [2,3-d]pyrimidine-7-carboxylic acid (161.56 mg, 730.47 pmol, 1.2 eq) in DCM (6 mL) was added EDCI (233.39 mg, 1.22 mmol. 2 eq) and DMAP (14.87 mg, 121.74 pmol, 0.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(l-methyl-2.4-dioxo-pyrido[2.3-d]pyrimidine-7-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate (340 mg, 328.54 pmol, 90.97% yield, 99% purity) as yellow oil.

[0415] ! H NMR (400 MHz, CDCh), 8.60 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.79-7.91 (m. 1H), 4.81-4.84 (m. 1H), 4.03 (t, J=6.8 Hz. 2H), 3.70 (s, 3H), 3.50-3.55 (m, 2H), 2.38-2.48 (m. 6H), 1.47-1.51 (m. 20H), 1.25-1.31 (m, 50H). 1.14 (s, 12H), 0.85-0.89 (m. 9H). (M+H+): 1024.8.

[0416] LCMS-CAD: (M+H+): 1024.8 @ 11.959 min.

[0417] LCMS-ELSD: (M+H+): 1024.8 @ 11.973 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 20: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(4-oxo-lH-pyrimidine-5-carbonyl)amino]butyl] amino]-2,2-dimethyl-octanoate1.(COCI)2, DCM, 0 °C, 1 h 2. TEA, DMAP, DCM, 0 °C, 5 h

[0418] To a solution of 4-oxo-lH-pyrimidine-5-carboxylic acid (155 mg, 1.11 mmol, 1 eq) in DCM (3 mL) was added (COC1)2(168.51 mg, 1.33 mmol, 11.22 pL, 1.2 eq) and DMF (4.04 mg, 55.32 pmol, 4.26 pL, 0.05 eq). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 4-oxo-lH-pyrimidine-5-carbonyl chloride (175 mg, crude) as a white solid. To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l -octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyloctanoate (300 mg, 365.23 pmol, 1 eq) and 4-oxo-lH-pyrimidine-5-carbonyl chloride (86.86 mg, 547.85 pmol, 1.5 eq) in DCM (6 mL) was added TEA (369.58 mg, 3.65 mmol, 508.36 pL, 10 eq) and DMAP (22.31 mg, 182.62 pmol, 0.5 eq). The mixture was stirred at 0 °C for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-MPLC (column: Welch Ultimate XB NH2lOu 100*30 mm; mobile phase: [Heptane-EtOH]; gradient: 0%-30% B over 10.0 min) and column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 1 / 1, 0.5% NEL UO) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octylJ-[4-[(4-oxo-lH-pyrimidine-5-carbonyl)aminoJbutylJ aminoJ-2,2-dimethyl-octanoate (28 mg, 29.38 pmol, 18.48% yield, 99% purity) as yellow oil.

[0419] 'H NMR (400 MHz, CDCh), 9.60-9.70 (m, 1H), 8.87 (s, 1H), 8.28 (s, 1H), 4.81-4.84 (m, 1H), 4.04 (t, J=6.8 Hz, 2H), 3.45-3.50 (m, 2H), 2.65-2.70 (m, 6H), 1.61-1.63 (m, 6H), 1.58-1.60 (m, 12H). 1.50-1.51 (m, 52 H), 1.15 (s. 12H), 0.86-0.89 (m, 9H). (M+H ): 943.8.

[0420] LCMS-CAD: (M+H+): 943.9 @ 10.926 min.

[0421] LCMS-ELSD: (M+H+): 943.9 @ 10.913 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 21:_undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(8-methoxy-3-oxo-4H-l, 4-benzoxazine-6-carbonyl) amino] butyl] amino] -2, 2-dimethyl-octanoateHATU, DIEA, DMF, 25 °C, 3 h

[0422] To a solution of 8-methoxy-3-oxo-4H-l,4-benzoxazine-6-carboxylic acid (271.71 mg, 1.22 mmol, 2 eq), HATU (231.46 mg, 608.72 pmol, 1 eq), DIEA (157.35 mg, 1.22 mmol, 212.06 pL. 2 eq) in DMF (5 mL) was added undecyl 8-[4-aminobutyl-[7.7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2, 2-dimethyl-octanoate (0.5 g, 608.72 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hours. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=l / O to 1 / 1, 3% NH3 THF) and p-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2: 1 ]; gradient: 5%-30% B over 10.0 min) to give a compound undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(8-methoxy-3-oxo-4H-l, 4-benzoxazine-6-carbonyl) amino] butyl] amino] -2. 2-dimethyl-octanoate (299 mg, 291.27 pmol, 66.44% yield, 1 0% purity) as yellow oil.

[0423] 'H NMR (400 MHz, CDCh), 8.10-8.41 (m, 1H), 7.11 (s, 1H), 6.29 (s, 1H), 6.60-6.75 (m, 1H), 4.82-4.85 (m, 1H), 4.70 (s, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.42-3.47 (m, 2H), 2.39-2.46 (m, 6H), 1.50-1.65 (m, 14H), 1.25-1.41 (m, 56H), 1.15-1.16 (m, 12H), 0.86-0.89 (m, 9H). (M+H+): 1027.0.

[0424] LCMS-CAD: (M+H+): 1027.0 @ 11.189 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0425] LCMS-ELSD: (M+H+): 1026.9 @ 11.134 min.Example 22: undecyl 8-[4-[[3-(cyclopropylsulfamoyl)-4-methoxy-benzoyl] amino] butyl- [7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino]-2, 2-dimethyl-octanoate

[0426] To a solution of 3-(cyclopropylsulfamoyl)-4-methoxy-benzoic acid (148.63 mg, 547.85 pmol, 1.5 eq), EDCI (280.06 mg, 1.46 mmol, 4 eq). DMAP (44.62 mg. 365.23 pmol, 1 eq) and TEA (36.96 mg, 365.23 pmol, 50.84 pL, 1 eq) in DCM (3 mL) was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2, 2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hours. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 1 / 1, 3% NH3 THF), p-MPLC (column: Welch Ultimate XB NEL lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-30% B over 10.0 min) and p-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.1% TFA)-ACN: THF=1:1]: gradient: 50%-85% B over 14.0 min). The mixture was diluted with brine 60 mL and extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 30 mL (10 mL*3, 10: 1). The hexane phase w as concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 10 mL and washed with ACN 20 mL (10 mL*2). The hexane phase was concentrated under N2Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 atmosphere to give a compound undecyl 8-[4-[[3-(cyclopropylsulfamoyl)-4-methoxy -benzoyl] amino] butyl-[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino]-2, 2-dimethyl-octanoate (28 mg, 25.79 pmol, 23.10% yield, 99% purity ) as yellow oil.

[0427] 'H NMR (400 MHz, CDCh), 8.19-8.26 (m, 2H), 7.13 (d, J=8.0 Hz. 1H), 6.97 (brs, 1H), 5.30 (s, 1H), 4.81-4.84 (m. 1H), 4.02-4.05 (m. 5H), 3.46-3.48 (m. 2H), 2.10-2.47(m, 7H), 1.58-1.67 (m, 6H), 1.25-1.51 (m, 64H), 0.90 (s, 12H), 0.86-0.89 (m, 9H), 0.61-0.71 (m, 2H), 0.45-0.59 (m, 2H). (M+H“): 1075.0.

[0428] LCMS-CAD: (M+H+): 1075.0 @ 11.508 min.

[0429] LCMS-ELSD: (M+H+): 1075.0 ®! 11.482 min.Example 23:_undecyl 8- [[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] - [4-[[3-(isopropylsulfamoyl)-4-methoxy-benzoyl] amino] butyl] amino]-2, 2-dimethyl-octanoate

[0430] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2,2-dimethyl-octanoate (300 mg, 365.23 pmol, 1 eq) in DCM (3 mL) was added EDCI (210.05 mg, 1.10 mmol, 3 eq), DMAP (44.62 mg, 365.23 pmol, 1 eq and TEA (18.48 mg, 182.62 pmol. 25.42 pL, 0.5 eq) and 3-(isopropylsulfamoyl)-4-methoxy-benzoic acid (109.80 mg, 401.76 pmol, 1.1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition H2O 10 mL at 0 °C, and then extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2: 1]; gradient: 5%-30% B over 10.0 min) to give a compound undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] - [4-[[3-(isopropylsulfamoyl)-4-methoxy-benzoyl] amino] butyl] amino]-2, 2-dimethyl-octanoate (85 mg, 78.95 pmol, 21.62% yield, 100% purity) as yellow oil.

[0431] 'H NMR (400 MHz, CDCh), 8.13-8.15 (m, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.79-6.98 (m, 1H), 4.70-4.81 (m, 1H), 4.64 (d, J=7.2 Hz, 1H), 3.94-3.97 (m, 5H), 3.32-3.41 (m, 3H), 2.25-2.45 (m, 6H), 1.51-1.60 (m, 6H), 1.32-1.43 (m, 12H), 1.18-1.30 (m, 52H), 1.07 (s, 12H), 0.99 (d, J=6.4 Hz. 6H), 0.80-0.82 (m. 9H). (M+H+): 1076.9.

[0432] LCMS-CAD: (M+H+): 1076.9 @ 11.525 min.

[0433] LCMS-ELSD: (M+H+): 1076.9 @ 11.540 min.Example 24: undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[3-[(l-methylpyrazol-4-yl) sulfamoyl] thiophene-2-carbonyl] amino] butyl] amino] -2, 2-dimethyl-octanoateEDCI, DMAP, DCM, 25 °C, 8 h

[0434] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq) and 3-[(l-methylpyrazol-4-yl)sulfamoyl] thiophene-2-carboxylic acid (125.93 mg, 438.28 Limol. 1.2 eq) in DCM (3 rnL) was added EDCI (140.03 mg, 730.47 pmol, 2 eq) and DMAP (8.92 mg, 73.05 pmol. 0.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was filtered and concentratedAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 0 / 1) and prep-HPLC (column: Welchrom CSH Cl 8 100*30*7; mobile phase: [H2O (0.1%TFA)-ACN: THF=l:l]; gradient:55%-85% B over 14.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was purified by pre-TLC (SiCh, Ethyl acetate: Methanol=5 / 1) and diluted with hexane 5 mL and washed with ACN 15 mL (5 mL*3). The hexane phase w as concentrated under N2 atmosphere to give a compound undecyl 8-[[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[3-[(l-methylpyrazol-4-yl) sulfamoyl] thiophene-2-carbonyl] amino] butyl] amino]-2.2-dimethyl-octanoate (15 mg, 13.75 pmol, 46.87% yield, 100% purity) as yellow- oil.

[0435] 'H NMR (400 MHz, CDCh), 7.25-7.27 (m, 2H), 7.21 (s, 1H), 7.11 (s, 1H), 4.79-4.85 (m, 1H), 4.04 (t, J-6.4 Hz, 2H), 3.77 (s, 3H), 3.46-3.49 (m, 2H), 2.56-2.64 (m, 6H), 1.71-1.78 (m, 4H), 1.23-1.63 (m, 66H), 1.15 (s, 12H), 0.86-0.90 (m. 9H). (M+H+): 1090.9.

[0436] LCMS-CAD: (M+H ): 1090.9 @ 11.470 min.

[0437] LCMS-ELSD: (M+H+): 1090.9 @ 11.458 min.Example 25: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3,6-dimethyl-lH-pyrazolo[3,4-b] pyridine-4-carbonyl) amino] butyl] amino] -2, 2-dimethyl-octanoateEDCI, DMAP, DCM, 25 °C, 5 hAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0438] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.9 g, 1.10 mmol, 1 eq), 3,6-dimethyl-lH-pyrazolo[3,4-b] pyridine-4-carboxylic acid (272.33 mg, 1.42 mmol, 1.3 eq)) in DCM (10 mL) was added EDCI (315.07 mg, 1.64 mmol, 1.5 eq), DMAP (66.93 mg, 547.85 pmol. 0.5 eq) at 25 °C. The mixture was stirred at 25 °C for 5 hours. The combined organic phase was diluted with EtOAc 20 mL and washed with water 60 mL (20 mL*3) and brine 40 mL (20 mL*2), dried with anhydrous Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=50 / l to 1 / 1) and p-MPLC(column: Ultimate XB-DIOL 250*200mm*10um; mobile phase: [Heptane-EtOH]; gradient: 0%-30% B over 10.0 min). The mixture was concentrated under N2 to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(3,6-dimethyl-lH-pyrazolo[3,4-b] pyridine-4-carbonyl) amino] butyl] amino]-2,2-dimethyl-octanoate (238 mg, 239.30 pmol, 79.33% yield, 100% purity) as colorless oil.

[0439] H NMR (400 MHz, CDCh), 10.75 (s, 1H), 7.77 (s, 1H), 6.90 (s, 1H), 4.73-4.76 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.41-3.46 (m, 2H), 2.58 (s, 3H), 2.50 (s, 3H), 2.18-2.34 (m, 6H), 1.63-1.66 (m, 2H), 1.51-1.53 (m, 4H), 1.35-1.41 (m, 8H), 1.18-1.27 (m, 44H), 1.07 (s, 24H), 0.78-0.82 (m, 9H). (M+H+): 994.9.

[0440] LCMS-CAD: (M+H ): 994.9 @ 11.004 min.

[0441] LCMS-ELSD: (M+H+): 994.9 @ 10.984 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 26: undecyl 8- [4- [[3-(azepan-l-ylsulfonyl)-4-meth oxy-benzoyl] amino] butyl-[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2, 2-dimethyl-octanoateEDCI, DMAP, TEA, DCM, 25 °C, 8 h

[0442] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino] -2, 2-dimethyl-octanoate (500 mg, 608.72 pmol, 1 eq) in DCM (5 mL) was added EDCI (350.08 mg, 1.83 mmol, 3 eq), DMAP (74.37 mg, 608.72 µmol, 1 eq), TEA (30.80 mg, 304.36 pmol, 42.36 pL, 0.5 eq) and 3-(azepan-l-ylsulfonyl)-4-methoxy-benzoic acid (228.91 mg, 730.47 pmol, 1.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition H2O 10 mL at 0 °C and extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=20 / l to 0 / 1), diluted with hexane 10 mL and extracted with ACN 20 mL (10 mL*2). The hexane layers were concentrated under reduced pressure to give a compound undecyl 8-[4-[[3-(azepan-l-ylsulfonyl)-4-methoxy-benzoyl] amino] butyl-[7, 7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino]-2. 2-dimethyl-octanoate (320 mg, 286.55 pmol, 47.07% yield, 100% purity) as yellow oil.

[0443] 'H NMR (400 MHz, CDCh), 8.11-8.44 (m, 2H), 7.00-7.02 (m, 1H), 6.70-6.81 (m, 1H), 4.80-4.85 (m, 1H), 4.03 (t, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.45-3.47 (m, 2H), 3.31-3.34 (m, 4H), 2.75-3.11 (m, 3H), 2.10-2.65 (m, 3H), 1.62-1.72 (m, 4H), 1.56-1.59 (m, 8H), 1.45-1.55 (m, 10H), 1.25-1.26 (m, 56H), 1.14 (s, 12H), 0.86-0.89 (m, 9H). (M+H+): 1117.0.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0444] LCMS-CAD (M+H+): 1117.0 @ 12.136 min.

[0445] LCMS-ELSD: (M+H+): 1117.0 @ 12.115 min.Example 27: undecyl 8-[4-[(3, 5-difhioro-4-methoxy-benzoyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2,2-dimethyl-octanoateEDCI, DMAP, DCM, 25 °C, 8 h

[0446] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (500 mg, 608.72 pmol. 1 eq), 3.5-difluoro-4-methoxy-benzoic acid (125.97 mg, 669.60 pmol, 1.1 eq), EDCI (233.39 mg, 1.22 mmol, 2 eq), DMAP (37.18 mg, 304.36 pmol, 0.5 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The mixture was poured into water (10 mL) then extracted with Ethyl acetate (10 mL* 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / ltol / l) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30 mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-30% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound undecyl 8-[4-[(3, 5-difluoro-4-methoxy-benzoyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (120 mg, 119.82 pmol, 29.70% yield, 99% purity) as yellow oil.

[0447] 'II NMR (400 MHz, CDCh), 8.06 (brs, 1H), 7.70-7.72 (m, 2H), 4.72-4.91 (m, 1H), 3.93-4.12 (m, 5H), 3.43-3.62 (m, 2H), 2.85-3.10 (m, 6H), 1.91-2.04 (m, 2H), 1.66-1.85 (m, 6H), 1.61-1.65 (m, 2H), 1.45-1.55 (m, 8H), 1.25-1.36 (m, 52H), 1.15 (s, 12H), 0.86-0.90 (m, 9H). (M+H+): 991.9.

[0448] LCMS-CAD: (M+H+): 991.9 @ 11.951 min.

[0449] LCMS-ELSD: (M+H+): 991.9 @ 12.223 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 28: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(5-ethoxy-lH-pyrazole-3-carbonyl)amino] butyl] amino] -2,2-dimethyl-octanoateHATU, DIEA, DCM, 25 °C, 8 h

[0450] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2,2-dimethyl-octanoate (50 mg, 60.87 pmol, 1 eq) in DCM (1 rnL) was added HATU (18.52 mg, 48.70 pmol, 0.8 eq) and DIEA (23.60 mg, 182.62 pmol, 31.81 pL, 3 eq) and 5-ethoxy-lH-pyrazole-3-carboxylic acid (19.01 mg, 121.74 pmol, 2 eq). The mixture was stirred at 25 °C for 8 hours. (Batch 4). Four of reactions were combined for work up. The reaction mixture was quenched by addition H2O 10 mL at 0 °C, extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) and p-MPLC (column: Ultimate XB-DIOL 250*200mm*10um;mobile phase: [Heptane-EtOH];gradient:0%-30% B over 10.0 min) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(5-ethoxy-lH-pyrazole-3-carbonyl)amino]butyl]amino]-2,2-dimethyl-octanoate (45 mg, 46.90 pmol, 19.26% yield. 100% purity) as yellow oil.

[0451] H NMR (400 MHz. CDC13). 7.05 (brs. 1H), 5.98 (s. 1H), 4.81-4.87 (m, 1H), 4.17-4.23 (m, 2H), 4.05 (t, J=6.8 Hz, 2H), 3.39-3.45 (m, 2H), 2.39-2.46 (m, 6H), 1.61-1.65 (m, 4H),1.48-1.52 (m, 10H), 1.10(t, J=6.8 Hz, 8H), 1.23-1.27 (m, 48H), 1.15 (s, 12H), 0.86-0.91 (m, 12H)(M+H+): 959.9.

[0452] LCMS-CAD: (M+H+): 959.9 @ 11.346 min.

[0453] LCMS-CAD: (M+H+): 960.0 @ 11.319 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 29: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiophene-2-carbonylamino)butyl]amino]-2,2-dimethyl-octanoate

[0454] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (300.00 mg. 365.23 pmol, 1 eq) and thiophene-2-carboxylic acid (70.21 mg, 547.85 pmol, 1.5 eq) in DCM (5 mL) was added DMAP (8.92 mg, 73.05 pmol, 0.2 eq) and EDCI (140.03 mg, 730.47 pmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiophene-2-carbonylamino)butyl]amino]-2,2-dimethyl-octanoate (330 mg, 350.72 pmol, 96.02% yield, 99% purity) as colorless oil.

[0455] 'H NMR (400 MHz, CDCh), 7.48-7.51 (m, 1H), 7.44-7.46 (m, 1H), 7.05-7.08 (m, 1H), 6.67-6.78 (m, 1H). 4.81-4.85 (m, 1H). 4.04 (t. J=6.8 Hz, 2H). 3.42-3.47 (m, 2H). 2.31-2.53 (m, 6H), 1.59-1.71 (m, 8H), 1.49-1.58 (m, 10H), 1.39-1.46 (m, 4H), 1.21-1.33 (m, 48H), 1.15(s, 12H), 0.86-0.91 (m, 9H)(M+H+): 931.8.

[0456] LCMS-CAD: (M+H+): 931.8 @ 11.725 min.

[0457] LCMS-ELSD (M+H+): 931.9 @ 11.708 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 30: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiazole-5-ca rbonylamino)butyl]amino]-2,2-dimethyl-octanoateEDCI, DMAP, DCM, 25 °C, 2 h

[0458] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (300.00 mg. 365.23 pmol, 1 eq) and thiazole-5-carboxylic acid (70.75 mg, 547.85 pmol, 1.5 eq) in DCM (5 mL) was added DMAP (8.92 mg, 73.05 pmol, 0.2 eq) and EDCI (140.03 mg, 730.47 pmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: X-SelectCSHPhenyl-HexylI00*305u; mobilephase:[H2O(0.1%TFA)-ACN: THF=l:l]; gra dient: 50%-90% B over 14.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase w as concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiazole-5-ca rbonylamino)butyl]amino]-2,2-dimethyl-octanoate (140 mg, 150.13 pmol, 41.11% yield, 100% purity) as colorless oil.

[0459] H NMR (400 MHz, CDCh), 8.87 (s, 1H), 8.23 (s, 1H), 7.37 (brs, 1H), 4.81-4.85 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.42-3.47 (m, 2H), 2.41-2.45 (m, 6H), 1.56-1.72 (m, 9H), 1.48-1.54 (m, 9H), 1.36-1.44 (m, 6H), 1.23-1.33(m, 46H), 1.15( s, 12H), 0.86-0.91 (m, 9H)(M+H+): 932.9.

[0460] LCMS-CAD: (M+H+): 932.9 @ 11.312 min.

[0461] LCMS-ELSD: (M+H+): 932.9 @ 11.297 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 31: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiazole-5-ca rbonylamino)butyl]amino]-2,2-dimethyl-octanoateHATU, DIEA, DMF, 25 °C, 8 hstep 1

[0462] To a solution of 2-(furan-2-carbonylamino)-4,5-dimethoxy-benzoic acid (141.84 mg, 486.98 pmol, 1 eq) in DMF (5 mL) was added HATU (222.20 mg, 584.38 pmol, 1.2 eq), DIEA (188.81 mg, 1.46 mmol, 254.46 pL, 3 eq) and undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2.2-dimethyl-octanoate (0.4 g, 486.98 pmol. 1 eq). The mixture was stirred at 25 °C for 8 hours. The mixture was poured into water (30 mL) and extracted with Ethyl acetate (20 mL* 2). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 100*30mm*3um; mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l]: gradient:55%-95% B over 14.0 min). The mixture was diluted with brine 100 ml and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a residue. The reaction mixture was diluted with hexane 10 mL and extracted with ACN 20 mL (10 mL*2). The hexane layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=10 / l to 1 / 0 ) and prep-MPLC (column: Ultimate XB-DIOL 250*100mm* 10um;mobile phase: [Heptane-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 EtOH];gradient:5%-30% B over 10.0 min) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[[2-(furan-2-carbonylamino)-4,5-dimethoxy-benzoy l]amino]butyl]amino]-2,2-dimethyl-octanoate (16 mg, 14.62 pmol, 26.67% yield, 100% purity) as colorless oil.

[0463] 'H NMR (400 MHz, CDC13) 12.33-12.40 (m. 1H), 8.57 (s. 1H), 7.61 (s, 1H), 7.21 (d, J=3.2 Hz, 1H), 6.95-7.05 (m, 1H), 6.87 (brs, 1H), 6.52-6.54 (m, 1H), 4.80-4.84 (m, 1H), 3.93-4.04 (m, 8H), 3.41-3.56 (m, 2H), 2.17-2.94 (m, 6H), 1.60-1.75 (m, 6H), 1.43-1.52 (m, 10H), 1.20-1.38 (m, 54H), 1.15 (s, 12H), 0.86-0.91 (m, 9H).

[0464] LCMS-CAD (M+H+): 1095.0 @ 11.716 min

[0465] LCMS-ELSD (M+H+): 1095.0 @ 11.705 minExample 32: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(thiazole-2-carbonylamino)butyl] amino] -2,2-dimethyl-octanoate

[0466] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2,2-dimethyl-octanoate (200 mg, 243.49 pmol, 1 eq) and thiazole-2-carboxylic acid (37.73 mg, 292.19 pmol, 1.2 eq) in DCM (5 mL) was added EDCI (93.35 mg. 486.98 pmol, 2 eq) and DMAP (5.95 mg, 48.70 pmol, 0.2 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305 u; mobile phase: [H2O (0.05%TFA-ACN: THF= 1:1]; gradient: 60%-95% B over 14.0 min). The mixture was diluted with brine 100 mL and extracted with EtOAc 90 mL (30 mL*3). The combined organicAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a residue. The reaction mixture was diluted with hexane 10 mL and extracted with ACN 20 mL (10 mL*2). The hexane layers were concentrated under reduced pressure to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octyhionoxy)-8-oxo-octyl]-[4-(thiazole-2-carbonylamino)butyl]amino]-2,2-dimethyl-octanoate (110 mg. 117.96 ymol, 48.45% yield, 100% purity) as colorless oil.

[0467] H NMR (400 MHz, CDCI3) 7.84 (d, J=2.8 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51-7.54 (m, 1H), 4.80-4.87 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.45-3.50 (m, 2H), 2.30-2.51 (m, 6H), 1.59-1.67 (m, 6H), 1.46-1.55 (m, 10H), 1.37-1.44 (m, 4H), 1.22-1.31 (m, 50H), 1.15 (s, 12H), 0.86-0.91 (m, 9H).

[0468] LCMS-CAD (M+H+): 932.8 @ 11.584 min.

[0469] LCMS-ELSD (M+H+): 932.9 @ 11.547 min.Example 33: undecyl 8-[4-[(7-chloro-4-quinoly l)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoateAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0470] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1 g, 1.22 mmol, 1 eq) and 4,7-dichloroquinoline (482.23 mg, 2.43 mmol, 2 eq) was degassed and purged with N2 for 3 times. The mixture was stirred at 130 °C for 6 hours under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) extracted with EtOAc 40 mL (20 mL*2). The combined organic layers were washed with brine 40 mL (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*30 5u; mobile phase: [H2O (0.1%TFA)-ACN: THF=l:l]; gradient:40%-75% B over 14.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 200 mL (50 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated underN2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecyl 8-[4-[(7-chloro-4-quinoly l)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (200 mg, 203.46 pmol, 16.71% yield, 100% purity ) as colorless oil.

[0471] 'H NMR (400 MHz. CDCh), 8.52 (d, J=5.2 Hz. 1H), 7.95 (d. J=2.0 Hz, 1H). 7.72 (d, J=8.4 Hz, 1H), 7.33-7.36 (m, 1H), 6.40 (d, J=5.6 Hz, 1H), 5.69-5.78 (m, 1H), 4.81-4.84 (m, 1H), 4.03 (t, J=6.8 Hz, 2H), 3.29-3.34 (m, 2H), 2.35-2.56 (m, 6H), 1.80-1.85 (m, 2H), 1.58-1.62 (m, 4H), 1.43-1.51 (m, 12H), 1.21-1.31 (m, 52H), 1.14 (s, 12H), 0.86-0.91 (m, 9H)(M+H+): 982.9

[0472] LCMS-CAD (M+H+): 982.9 @ 8.361 min

[0473] LCMS-ELSD (M+H+): 982.9 @ 8.367 minAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 34: undecyl8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(4-quinoly lamino) butyl] amino] -2,2-dimethyl-octanoate

[0474] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2,2-dimethyl-octanoate (900 mg, 1.10 mmol, 1 eq) and 4-chloroquinoline (358.52 mg, 2.19 mmol, 286.82 y. L, 2 eq) was stirred at 130 °C for 3 hours. The combined organic phase was diluted with EtOAc 20 mL and washed with H2O 60 mL (20 mL*3) and brine 40 mL (20 mL*2), dried with anhydrous NazSC, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Commercial hexanes: Ethyl acetate=5 / l to 0 / 1) to give a compound undecyl8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(4-quinoly lamino) butyl] amino] -2,2-dimethyl-octanoate (36 mg, 37.95 pmol, 3.46% yield, 100% purity) as yellow oil.

[0475] 'H NMR (400 MHz, CDCI3) 8.55 (d, 5.2 Hz, 1H), 7.99 (d, 8.4 Hz, 1H), 7.71-7.86 (m, 1H), 7.58-7.67 (m, 1H), 7.36-7.48 (m, 1H), 6.42 (d, >5.2 Hz, 1H), 5.54 (brs, 1H), 4.81-4.85 (m. 1H), 4.04 (t, >3.2 Hz. 2H), 3.31-3.36 (m. 2H), 2.30-2.62 (m. 6H), 1.78-1.87 (m. 2H), 1.58-1.66 (m, 4H), 1.42-1.53 (m, 12H), 1.20-1.34 (m, 52H), 1.14 (s, 12H), 0.86-0.91 (m, 9H) (M+H+): 949.0

[0476] LCMS-CAD (M+H+): 949.0 @ 8.167 min

[0477] LCMS-ELSD (M+H+): 949.0 (a> 8.136 minAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 35: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(l,3,4-thiadiazole- 2-carbonylamino)butyl]amino]-2,2-dimethyl-octanoateEDCI, HOBt, DMAP, DMF25-40 °C, 4.5 hstep 1

[0478] To a solution of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (300 mg, 365.23 pmol, 1 eq) and l,3,4-thiadiazole-2-carboxylic acid (57.03 mg. 438.28 pmol, 1.2 eq) in DMF (3 mL) was added EDCI (84.02 mg, 438.28 pmol, 1.2 eq), HOBt (59.22 mg, 438.28 pmol, 1.2 eq) and DMAP (13.39 mg, 109.57 pmol, 0.3 eq) at 25 °C. The mixture was stirred at 40 °C for 4.5 hours. The reaction mixture was diluted with H2O 10 mL extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with brine 20 mL (10 mL*2), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.1%TFA)-ACN: THF=1:1]; gradient: 45 %-75% B over 16.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 200 mL (50 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-(l,3,4-thiadiazole-2-carbonylamino)butyl]amino]-2,2-dimethyl-octanoate (72 mg, 77.13 pmol, 21.12% yield, 100% purity) as colorless oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0479] H NMR (400 MHz, CDCI3) 9.24 (s, 1H), 8.00 (brs, 1H), 4.80-4.86 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.48-3.53 (m, 2H), 2.38-2.44 (m, 6H), 1.48-1.72 (m, 18H), 1.38-1.45 (m, 4H), 1.22-1.31 (tn, 48H), 1.15 (s, 12H), 0.86-0.91 (tn, 9H) (M+H+): 933.9

[0480] LCMS-CAD (M+H+): 933.9 @ 11.395 min

[0481] LCMS-ELSD (M+H+): 933.9 @ 11.381 minAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 36: l-octylnony!8-[[8-(2,2-dimethylundecoxy)-8-oxo-octyl]-[4-[[4-methoxy-3- (inethylsulfamoyl)benzoyl] amino] butyl] amino] -2,2-dimethyl-octanoateMeNH225 °C, 3 h step 4

[0482] Step 1: A mixture of tert-butyl N-(4-aminobutyl)carbamate (6.15 g, 32.68 mmol, 4 eq), 1-octylnonyl 8-bromo-2,2-dimethyl-octanoate (4 g. 8.17 mmol, 1 eq), K2CO3 (3.39 g, 24.51 mmol, 3 eq), KI (678.10 mg, 4.08 mmol, 0.5 eq) in DMF (30 mL) was degassed and purged with N2 for 3 times, the mixture was stirred at 80 °C for 8 hours under N2 atmosphere.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 The mixture was poured into water (100 mL) then extracted with Ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL) and dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=50 / l to 0 / 1) to give a compound 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butylami no]-2.2-dimethyl-octanoate (3 g, 4.87 mmol, 59.67% yield, 97% purity) as colorless oil. LCMS (M+H+): 597.6 / <z> 1.578 min.

[0483] Step 2: A mixture of 2,2-dimethylundecyl 8-bromooctanoate (1.97 g, 4.86 mmol, 1 eq), 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butylamino]-2,2-dimethyl-octanoate (2.9 g, 4.86 mmol, 1 eq), K2CO3 (2.01 g, 14.57 mmol, 3 eq), KI (403.21 mg. 2.43 mmol,0.5 eq) in DMF (30 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 80 °C for 8 hours under N2 atmosphere. The mixture was poured into water (80 mL) and extracted with Ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=20 / l to 5 / 1) to give a compound 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(2,2-dimethylundecoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.6 g, 1.63 mmol, 33.60% yield, 94% purity) as colorless oil. LCMS (M+H+): 922.0 @ 2.911 min.

[0484] Step 3: To a solution of 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(2,2-dimethylundecoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.5 g, 1.63 mmol,1 eq) in DCM (15 mL) was added TFA (7.68 g, 67.31 mmol, 5 mL, 41.35 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a compound 1-octylnonyl 8-[4-aminobutyl-[8-(2,2-dimethylundecoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.5 g, 1.60 mmol, 98.51% yield, TFA) as colorless oil.

[0485] Step 4: To a solution of 3-chlorosulfonyl-4-methoxy-benzoic acid (1 g, 3.99 mmol, 1 eq) in MeNFL (8.96 g, 115.40 mmol, 10 mL, 40% purity, 28.93 eq). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was adjusted pH=7 with IM HC1 aqueous and extracted with EtOAc 30 mL (15 mL*2). The combined organic layers were dried over Na₂SO₄. filtered and concentrated under reduced pressure to give a compound 4-methoxy-3-(methylsulfamoyl)benzoic acid (0.8 g, 3.16 mmol, 79.31% yield, 97% purity) as a white solid.LCMS (M+H ): 246.1 @ 0.326 min

[0486] Step 5: To a solution of 4-methoxy-3-(methylsulfamoyl) benzoic acid (432.61 mg. 1.76 mmol, 1.1 eq) in DCM (15 mL) was added DMAP (97.95 mg, 801.79 pmol, 0.5 eq), TEA (486.79 mg, 4.81 mmol, 669.59 pL, 3 eq), 1-octylnonyl 8-[4-aminobutyl-[8-(2,2-dimethylundecoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.5 g, 1.60 mmol, 1 eq, TFA) and EDCI (461.11 mg, 2.41 mmol, 1.5 eq). The mixture was stirred at 25 °C for 8 hours.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O ( 0.05%TFA-ACN: THF=l:lJ; gradient:45%-90% B over 16.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 200 mL (50 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound l-octylnonyl8-[[8-(2,2-dimethylundecoxy)-8-oxo-octyl]-[4-[[4-methoxy-3-(methylsulfamoyl)benzoyl|amino|butyl|amino|-2.2-dimethyl-octanoate (30 mg, 28.61 pmol.4.00% yield, 100% purity) as colorless oil.

[0487] H NMR (400 MHz, CDCI3) 8.17-8.21 (m, 2H), 7.08-7.15 (m, 1H), 6.94-7.06 (m, 1H), 4.79-4.84 (m, 2H), 4.04 (s, 3H), 3.78 (s, 2H), 3.46-3.49 (m, 2H), 2.29-2.70 (m, 11H), 1.61-1.72 (m, 4H), 1.45-1.52 (m, 6H), 1.36-1.41 (m. 3H), 1.21-1.32 (m. 55H), 1.15 (s, 6H). 0.86-0.91 (m, 15H).

[0488] LCMS-CAD (M+H+): 1048.9 @ 11.278 min.

[0489] LCMS-ELSD (M+H+): 1048.9 @ 11.277 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 37: undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(4-methoxy-3-methylsulfonyl-benzoyl)amino]butyl]amino]-2,2-dimethyl-octanoate2 EDCI, DMAP, TEA, DCM, 25 °C, 3 h step 1

[0490] To a solution of 4-methoxy-3-methylsulfonyl-benzoic acid (210.23 mg, 913.09 pmol, 1.5 eq), EDCI (466.77 mg, 2.43 mmol, 4 eq), DMAP (74.37 mg, 608.72 pmol, 1 eq) and TEA (61.60 mg, 608.72 pmol, 84.73 pL, 1 eq) in DCM (5 mL) was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.5 g, 608.72 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hours. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=20 / l to 1 / 1, 3% NH? THF) and prep-MPLC (column: Welch Ultimate XB NEL lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient:5%-50% B over 10.0 min) to give a compound undecyl 8-[[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(4-methoxy-3-methylsulfonyl-benzoyl)amino]butyl]amino]-2,2-dimethyl-octanoate (366 mg, 350.56 pmol. 72.47% yield, 99% purity) as yellow oil.

[0491] 'H NMR (400 MHz, CDCI3) 8.20-8.26 (m. 2H), 7.13 (d, J=8.8 Hz. 1H). 6.81-7.02 (m.1H), 4.81-4.85 (m, 1H), 4.02-4.07 (m, 5H), 3.44-3.47 (m, 2H), 3.23 (s, 3H), 2.14-2.64 (m, 6H), 1.60-1.70 (m, 4H), 1.47-1.53 (m, 8H), 1.20-1.34 (m, 58H), 1.15 (s, 12H), 0.86-0.91 (m, 9H).

[0492] LCMS-CAD (M+H+): 1033.9 @ 11.320 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0493] LCMS-ELSD (M+H+): 1033.8 @ 3.127 min.Example 38: undecyl 8-[4-[(3-acetamido-4-methoxy-benzoyl)amino]butyl-[7,7-dimethyl-8- (l-octylnonoxy)-8-oxo-octyl] amino] -2, 2-dimethyl-octanoateHATU, DIEA, DMF, 25 °C, 3 hstep 1

[0494] To a solution of 3-acetamido-4-methoxy-benzoic acid (114.61 mg, 547.85 pmol, 1.5 eq). HATU (138.87 mg, 365.23 pmol, 1 eq), DIEA (94.41 mg, 730.47 pmol, 127.23 pL,2 eq) in DMF (3 mL) was added undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (0.3 g, 365.23 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hours. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 1 / 1, 3% NEL THF) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2:1]: gradient:5%-50% B over 10.0 min) to give a compound undecyl 8-[4-[(3-acetamido-4-methoxy-benzoyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl] amino] -2, 2-dimethyl-octanoate (173 mg, 170.85 pmol, 57.67% yield, 100% purity) as yellow oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0495] H NMR (400 MHz, CDCI3) 8.71 (s, 1H), 7.61-7.88 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.50 (brs, 1H), 4.81-4.85 (m, 1H), 4.04 (t, J=6.8 Hz, 2H), 3.94 (s, 3H), 3.40-3.51 (m, 2H), 2.04-2.54 (m, 9H), 1.42-1.56 (m, 12H), 1.22-1.38 (m, 58H), 1.15 (s, 12H), 0.86-0.91 (tn, 9H).

[0496] LCMS-CAD (M+H+): 1013.0 @ 11.283 min

[0497] LCMS-ELSD (M+H+): 1012.9 @ 3.108 minExample 39: undecyl 8-[4-[(3,5-difluoro-4-hydroxy-benzoyl)amino]butyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate2 EDCI, HOBT, DCM, 25 °C, 8 h step 1

[0498] A mixture of undecyl 8-[4-aminobutyl-[7,7-dimethyl-8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1 g, 1.22 mmol, 1.5 eq), 3,5-difluoro-4-hydroxy-benzoic acid (141.31 mg, 811.63 pmol, 1 eq), HOBt (109.67 mg, 811.63 pmol, 1 eq), EDCI (311.18 mg, 1.62 mmol, 2 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.2%FA)-ACN: THF=l:l]; gradient: 40%-75% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue w as diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10:1). The hexane phase w as concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washedAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound undecyl 8-[4-[(3,5-difluoro-4-hydroxy-benzoyl)amino]butyl-[7,7-dimethyl-8-(l-octyhionoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (135 mg, 136.73 pmol, 22.28% yield, 99% purity) as colorless oil.

[0499] 'H NMR (400 MHz. CDCh), 7.12-7.21 (m. 2H), 6.40-6.55 (m. 1H), 4.75-4.89 (m. 1H), 4.03 (t, J=6.8 Hz, 2H), 3.42-3.46 (m, 2H), 2.75-2.83 (m, 6H), 1.70-1.82 (m, 2H), 1.50-1.67 (m, 10H), 1.07-1.40 (m, 70H), 0.86-0.91 (m, 9H)(M+H ): 978.0.

[0500] LCMS-CAD (M+H+): 978.0 @ 11.457 min.

[0501] LCMS-ELSD (M+H+): 978.0 @ 2.756 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 40: 4-pentylnonyl 8-[4-[[4-methoxy-3-(methylsulfamoyl)benzoyl]amino]butyl-(8-oxo-8-un decoxy-octyl)amino]-2,2-dimethyl-octanoateC10H21 '—OH 2 EDCI, DMAP, DCM, 25 °C, 8 h step 1K2CO3, KI, ACN, 80 °C, 8 h step 3 BocHN TFA, DCM _ 25 °C, 2 h " step 4EDCI, DMAP, TEADCM, 25 °C, 8 h step 5

[0502] Step 1 ■ To a solution of 8-bromooctanoic acid (100 g, 448.22 mmol, 1 eq) and undecan-l-ol (84.95 g, 493.04 mmol, 1.1 eq) in DCM (1.5 L) was added EDCI (171.85 g, 896.43 mmol, 2 eq) and DMAP (10.95 g. 89.64 mmol, 0.2 eq). The mixture was stirred at 25 °C for 8 hours.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 10 / 1) to give a compound undecyl 8 -bromooctanoate (120 g, 317.97 mmol, 70.94% yield) as colorless oil.

[0503] Step 2: To a solution of undecyl 8-bromooctanoate (12.53 g, 33.20 mmol, 1 eq) and tertbutyl N-(4-aminobutyl)carbamate (25 g, 132.79 mmol, 4 eq) in ACN (25 mL) was added K2CO3 (13.76 g, 99.59 mmol, 3 eq) and KI (5.51 g, 33.20 mmol, 1 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 8 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Ethyl acetate: MeOH=100 / l to 0 / 1) to give a compound undecyl 8-[4-(tert-butoxycarbonylamino)butylamino]octanoate (7 g, 13.86 mmol, 41.76% yield. 96% purity) as yellow oil. LCMS (M+H+): 485.5 @ 3.403 min.

[0504] Step 3: To a solution of 4-pentylnonyl 8-bromo-2,2-dimethyl-octanoate (7 g, 15.64 mmol, 1.1 eq) and undecyl 8- [4-(tert-butoxycarbonylamino)butylamino] octanoate (6.89 g, 14.22 mmol, 1 eq) in ACN (70 mL) was added K2CO3 (4.91 g, 35.55 mmol, 2.5 eq) and KI (1.18 g, 7.11 mmol, 0.5 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture w as filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Commercial hexanes: Ethyl acetate=l / O to 0 / 1) to give a compound 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (7.5 g. 7.84 mmol, 55.14% yield) as yellow oil.

[0505] Step 4: To a solution of 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-(8-oxo-8-undecoxy-octyl) amino] -2.2-dimethyl-octanoate (3.5 g, 4.11 mmol, 1 eq) in DCM (70 mL) was added TFA (11.51 g. 100.97 mmol, 7.50 mL, 24.56 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was quenched by addition saturated aqueous NaHCO? 200 mL at 25 °C, extracted with EtOAc 200 mL (100 mL*2). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a compound 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (3 g, 3.99 mmol, 97.14% yield) as yellow oil.

[0506] Step 5: To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.3 g. 399.33 pmol, 1 eq) and 4-methoxy-3-(methylsulfamoyl)benzoic acid (117.52 mg, 479.20 pmol, 1.2 eq) in DCM (3 mL) was added EDCI (191.38 mg, 998.33 pmol, 2.5 eq), DMAP (24.39 mg, 199.67 pmol,0.5 eq) and TEA (40.41 mg, 399.33 pmol, 55.58 pL, 1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture w as filtered and concentrated under reduced pressure toAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 give a residue. The residue was purified by column chromatography (S1O2. Commercial hexanes: Ethyl acetate=l / O to 0 / 1) and p-MPLC (column: Ultimate XB-DIOL 250*50mm*10 um;mobile phase: [Heptane-THF: ACN=2:l];gradient:5%-50% B over 10.0 min) to give a compound 4-pentylnonyl 8-[4-[[4-methoxy-3-(methylsulfamoyl)benzoyl]amino]butyl-(8-oxo-8-un decoxy-octyl)amino]-2.2-dimethyl-octanoate (72 mg, 73.64 pmol. 17.56% yield, 98% purity) as yellow oil.

[0507] 'H NMR (400 MHz, CDCb) 8.16-8.22 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.85-7.08 (m, 1H), 4.72-4.90 (m, 1H), 4.01-4.07 (m, 7H), 3.44-3.49 (m, 2H), 2.35-2.69 (m, 9H), 2.28 (t, J=7.6 Hz. 2H), 1.41-1.80 (m. 20H), 1.24-1.31 (m, 43H). 1.15 (s, 6H), 0.89 (t, J=6.8 Hz, 9H).

[0508] LCMS-CAD (M+H+): 978.9 @ 9.863 min.

[0509] LCMS-ELSD (M+H+): 978.9 @ 2.310 min.Example 41: 4-pentylnonyl 8-[4-[[3-(isopropylsulfamoyl)-4-methoxy-benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl) amino]-2,2-dimethyl-octanoate8 from Example 40DCM’25°C’8 hstep 1

[0510] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.2 g, 266.22 pmol. 1 eq) and 3-(isopropylsulfamoyl)-4-methoxy-benzoic acid (87.31 mg, 319.46 pmol, 1.2 eq) in DCM (3 mL) was added EDCI (127.59 mg, 665.55 pmol, 2.5 eq), DMAP (16.26 mg, 133.11 pmol, 0.5 eq) and TEA (26.94 mg, 266.22 pmol, 37.05 pL, 1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was filtered andAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 concentrated under reduced pressure to give a residue. The residue purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=l / O to 0 / 1) and p-MPLC (column: Ultimate XB-DIOL 250*200mm*10um; mobile phase: [Heptane-THF: ACN=2:1]; gradient:5%-50% B over 10.0 min) to give a compound 4-pentylnonyl 8-[4-[[3-(isopropylsulfamoyl)-4-methoxy-benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl) amino]-2,2-dimethyl-octanoate (48 mg, 47.21 pmol. 17.73% yield, 99% purity) as yellow oil.

[0511] 'H NMR (400 MHz, CDCl₃) 8.16-8.24 (m, 2H), 7.10 (d, J=4.4 Hz, 1H), 6.90-7.08 (m, 1H), 4.72 (d, J=6.8 Hz, 1H), 4.01-4.07 (m, 7H), 3.39-3.49 (m, 3H), 2.15-2.89 (m, 8H), 1.47-1.68 (m. 18H), 1.24-1.33 (m, 45H). 1.15 (s. 6H), 1.07 (d. J=6.4 Hz, 6H). 0.89 (t. J=6.8 Hz, 9H) (M+H+): 1007.0

[0512] LCMS-CAD (M+H+): 1007.0 @ 10.161 min

[0513] LCMS-ELSD (M+H+): 1007.0 @ 2.401 minExample 42: 4-pentylnonyl 2,2-dimethyl-8-[4-[(l-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a] [1,4] diazepine-8-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate

[0514] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (300 mg, 399.33 pmol, 1 eq) and l-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carboxylic acid (232.63 mg, 1.20 mmol, 3 eq) in DMF (3 rnL) was added HATU (151.84 mg, 399.33 pmol, 1 eq) and DIEA (103.22 mg, 798.66 pmol, 139.11 pL, 2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was diluted with H2OAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 10 mL extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with brine 20 mL (10 mL*2), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Commercial hexanes: Ethyl acetate=10 / l to 1 / 1, 3% NH3. THF) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*30 5u; mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l]; gradient:40%-75% B over 14.0 min) to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[(l-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate (16 mg, 16.73 pmol, 4.19% yield, 97% purity) as colorless oil.

[0515] 'H NMR (400 MHz, CDCI3) 7.30-7.52 (m, 1H), 6.98-7.19 (m, 1H), 5.91-6.10 (m, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.01-4.07 (m, 4H), 3.42-3.44 (m, 2H), 3.32-3.37 (m, 2H), 2.32-3.07 (m, 6H), 2.29 (t, J=7.6 Hz, 2H), 1.13-2.20 (m, 2H), 1.60-1.62 (m, 10H), 1.47-1.52 (m, 3H), 1.21-1.32 (m, 50H), 1.16 (s, 6H), 0.89 (t, J=6.8 Hz, 9H) (M+H+): 928.0

[0516] LCMS-CAD (M+H+): 928.0 @ 9.326 min

[0517] LCMS-ELSD (M+H+): 927.9 @ 2.127 minExample 43: 4-pentylnonyl 8-[4-[(3-cyclopropyl-lH-pyrazole-4-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl) amino] -2,2-dimethyl-octanoateEDCI, HOBt, TEA DCM, 25 °C, 8 h

[0518] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (300 mg, 399.33 pmol, 1 eq) and 3-cyclopropyl-1H-pyrazole-4-carboxylic acid (72.91 mg, 479.20 pmol, 1.2 eq) in DCM (3 mL) was added EDCI (99.52 mg, 519.13 pmol, 1.3 eq), TEA (80.82 mg, 798.66 pmol, 111.16 pL, 2 eq) and HOBt (75.54 mg, 559.06 pmol, 1.4 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was diluted with H2OAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 10 mL and extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with brine 20 mL (10 mL*2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO₂, Commercial hexanes: Ethyl acetate=10 / 1 to 1 / 1, 3% NH₃·THF) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*30 5u; mobile phase: [H₂O (0.1%TFA)-ACN: THF=1:1]; gradient:45%-75% B over 14.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 2000 mL (500 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and w ashed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[(3-cyclopropyl-lH-pyrazole-4-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl) amino]-2,2-dimethyl-octanoate (66 mg. 74.54 pmol, 18.67% yield, 100% purity) as colorless oil.

[0519] 'H NMR (400 MHz, CDCI3) 7.71-8.15 (m, 1H), 6.32-6.75 (m, 1H), 4.02-4.08 (m, 4H), 3.39-3.52 (m, 2H), 2.32-2.74 (m, 6H), 2.29 (t, 7.6 Hz, 3H), 1.58-1.64 (m, 10H), 1.47-1.52 (m, 4H), 1.20-1.34 (m, 49H), 1.15 (s, 6H), 1.04-1.08 (m, 2H), 0.87-0.94 (m, 11H)

[0520] LCMS-CAD (M+H+): 885.9 @ 9.682 min.

[0521] LCMS-ELSD (M+H+): 885.9 @ 2.206 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 44: 4-pentylnonyl 2,2-dimethyl-8-[[8-(l-octylnonoxy)-8-oxo-octyl]-[4-[(l-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carbonyl)amino]butyl]amino] octanoate C7H15C7H15DMF, 25 °C, 8 h Step 5

[0522] Step 1 ■ To a solution of heptadecan-9-ol (10 g, 38.99 mmol, 1 eq) in DCM (100 mL) was added EDCI (8.97 g, 46.79 mmol, 1.2 eq), DMAP (2.38 g, 19.50 mmol, 0.5 eq) and 8-bromooctanoic acid (9.57 g, 42.89 mmol, 1.1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition H2O 200 mL at 0 °C and extracted with EtOAcAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 600 mL (200 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) to give a compound 1-octylnonyl 8-bromooctanoate (60 g, 129.99 mmol, 66.68% yield) as yellow oil.

[0523] Step 2: To a solution of 1 -octylnonyl 8-bromooctanoate (40 g, 86.66 mmol,1 eq) in DMF (400 mL) was added K2CO3 (35.93 g, 259.99 mmol, 3 eq) and KI (14.39 g, 86.66 mmol, 1 eq) and tert-butyl N-(4-aminobutyl)carbamate (32.63 g, 173.33 mmol. 2 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was quenched by addition H2O 200 mL at 0 °C, and extracted with EtOAc 600 mL (200 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=100 / l to 0 / 1) to give a compound 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butylamino]octanoate (29 g, 43.84 mmol, 50.58% yield) as yellow oil.

[0524] Step 3: To a solution of 1-octylnonyl 8-[4-(tert-butoxycarbonylamino)butylamino]octanoate (8 g, 14.06 mmol, 1 eq) in ACN (80 mL) was added K2CO3 (5.83 g, 42.19 mmol, 3 eq) and KI (2.33 g, 14.06 mmol, 1 eq) and 4-pentylnonyl 8-bromo-2,2-dimethyl-octanoate (7.55 g, 16.87 mmol, 1.2 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was quenched by addition H2O 200 mL at 0 °C, and extracted with EtOAc 600 mL (200 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and prep-HPLC (column: WePure Biotech Phenyl-Hexyl 250*70 7u; mobile phase:[H₂O(0.1%TFA)-ACN: THF=1:1]; gradient:60%-80% B over 23.0 min). The mixture was concentrated under reduced pressure, then adjust pH to 8 with sat. NaHCOs, extracted with EtOAc 150 mL (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a compound 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (5 g, 5.24 mmol, 37.25% yield) as yellow oil. 'H NMR (400 MHz, CDCI3) 4.91-5.16 (m, 1H), 4.83-4.89 (m, 1H). 4.03 (t. J=6.4 Hz, 2H). 3.12-3.14 (m, 2H). 2.78-3.04 (m, 2H). 2.31-2.56 (m, 4H), 2.28 (t, J=7.6 Hz, 2H), 1.71-1.78 (m, 6H), 1.58-1.63 (m, 10H), 1.45 (s, 9H), 1.22-1.29 (m, 56H), 1.16 (s, 6H), 0.87-0.91 (m, 12H).

[0525] Step 4: To a solution of 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(l-octylnonoxy)-8-oxooctyl]amino]-2,2-dimethyl-octanoate (2 g, 2.14 mmol, 1 eq) in dioxane (10 mL) was added HCl / dioxane (10 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure, then adjust pH to 8 with sat. NaHCOs. and extractedAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 with EtOAc 90 mL (30 mL*3). The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) to give a compound 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.5 g, 1.80 mmol. 83.99% yield) as yellow oil.

[0526] Step 5: To a solution of l-oxo-2,3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carboxylic acid (348.67 mg, 1.80 mmol, 3 eq) in DMF (5 mL) was added DIEA (154.70 mg. 1.20 mmol, 208.50 pL, 2 eq) and HATU (227.57 mg, 598.50 pmol. 1 eq) and 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (500 mg, 598.50 pmol, 1 eq). The mixture w as stirred at 25 °C for 8 hours. The reaction mixture w as quenched by addition of H2O (20 mL) at 0 °C, and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.05% TFA)-ACN: THF=1:1]; gradient:40%-90% B over 14.0 min). The mixture was diluted with brine 100ml and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue w as diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[[8-(l -octylnonoxy)-8-oxo-octyl]-[4-[(l-oxo-2, 3,4,5-tetrahydropyrrolo[l,2-a][l,4]diazepine-8-carbonyl)amino]butyl]amino] octanoate (180 mg, 177.94 pmol, 45.00% yield, 100% purity ) as y ellow oil.

[0527] 'H NMR (400 MHz, CDCI3) 7.34-7.41 (m, 1H), 6.92-7.11 (m, 1H), 6.14-6.32 (m, 1H), 5.86 (brs, 1H). 4.83-4.90 (m, 1H). 4.22 (t. J=6.8 Hz. 2H). 4.03 (t. J=6.8 Hz. 2H). 3.32-3.42 (m.4H), 2.34-2.47 (m, 4H), 2.28 (t, J=7.6 Hz, 2H), 2.14-2.21 (m, 2H), 1.56-1.63 (m, 8H), 1.47-1.54 (m, 8H), 1.36-1.46 (m, 4H), 1.22-1.34 (m, 55H), 1.16 (s, 6H), 0.87-0.91 (m, 12H).

[0528] LCMS-CAD (M+H+): 1012.0 @ 11.136 min.

[0529] LCMS-ELSD (M+H+): 1012.0 @ 2.637 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 45: 4-pentylnonyl 8-[4-[(3-cyclopropyl-lH-pyrazole-4-carbonyl)amino]butyl-[8- (l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate

[0530] To a solution of 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (500 mg, 598.50 pmol, 1 eq) in DCM (5 mL) was added EDCI (149.15 mg, 778.06 pmol, 1.3 eq), HOBt (113.22 mg, 837.91 pmol, 1.4 eq) and TEA (121.12 mg, 1.20 mmol, 166.61 pL, 2 eq) and 3-cyclopropyl-1H-pyrazole-4-carboxylic acid (118.38 mg, 778.06 pmol, 1.3 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition of H2O (50 mL) at 0 °C and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u;mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l]; gradient: 40%-90% B over 14.0 min) to give a residue. The mixture was diluted with brine 100 mL and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[(3-cyclopropyl-1H-pyrazole-4-carbonyl)amino]butyl-[8-(1-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (70 mg, 72.20 pmol, 23.33% yield, 98% purity) as yellow oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0531] H NMR (400 MHz, CDCI3) 10.12-10.26 (m, 1H), 7.87 (s, 1H), 6.51 (brs, 1H), 4.85-4.89 (m, 1H), 4.03 (t, J=6.8 Hz, 2H), 3.42-3.47 (m, 2H), 2.33-2.50 (m, 6H), 2.20-2.30 (m, 3H), 1.56-1.68 (m, 8H), 1.48-1.54 (m, 6H), 1.37-1.45 (m, 4H), 1.22-1.33 (m, 57H), 1.16 (s, 6H), 1.02-1.08 (m, 2H), 0.86-0.91 (m, 12H).

[0532] LCMS-CAD (M+H+): 970.0 @ 11.421 min.

[0533] LCMS-ELSD (M+H+): 970.0 @ 2.726 min.Example 46: 4-pentylnonyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoateK2CO3, KI, ACN, 80 °C, 8 h 5 from Example 44 3 step 1Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0534] Step 1: To a solution of 1 -octylnonyl 8-[4-(tert-butoxycarbonylamino)butylamino]octanoate (8 g, 14.06 mmol, 1 eq) in ACN (80 mL) was added K2CO3 (5.83 g, 42.19 mmol, 3 eq) and KI (2.33 g, 14.06 mmol, 1 eq) and 4-pentylnonyl 8-bromo-2.2-dimethyl-octanoate (7.55 g, 16.87 mmol, 1.2 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was quenched by addition H2O 200 mL at 0 °C, and extracted with EtOAc 600 mL (200 mL*3). The combined organic layers were dried over Na₂SO₄, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and prep-HPLC (column: WePure Biotech Phenyl-Hexyl 250*70 7u;mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l];gradient:60%-80% B over 23.0 min). The mixture was concentrated under reduced pressure, then adjust pH to 8 with sat. NaHCO3, extracted with EtOAc 150 mL (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a compound 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (5 g, 5.24 mmol, 37.25% yield) as yellow oil. 1H NMR (400 MHz, CDC13), 4.91-5.16 (m, 1H), 4.83-4.89 (m, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.12-3.14 (m, 2H), 2.78-3.04 (m, 2H), 2.31-2.56 (m, 4H), 2.28 (t, J=7.6 Hz, 2H), 1.71-1.78 (m, 6H), 1.58-1.63 (m, 10H), 1.45 (s, 9H), 1.22-1.29 (m, 56H), 1.16 (s, 6H), 0.87-0.91 (m, 12H).

[0535] Step 2: To a solution of 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[8-(1-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (2 g, 2.14 mmol, 1 eq) in dioxane (10 mL) was added HCl / dioxane (10 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure, then adjust pH to 8 with sat. NaHCO3, and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) to give a compound 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (1.5 g, 1.80 mmol. 83.99% yield) as yellow oil.

[0536] Step 3: To a solution of 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (400 mg, 478.80 pmol, 1 eq) in DMF (5 mL) was added EDCI (110.14 mg, 574.56 pmol, 1.2 eq) and DMAP (58.49 mg, 478.80 pmol, 1 eq) and 3-carbamoylisoxazole-5 -carboxylic acid (89.69 mg. 574.56 pmol, 1.2 eq). The mixture was stirred at 80 °C for 8 hrs. The reaction mixture was quenched by addition H2O 20 mL at 0 °C, and then extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and by P-MPLCAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 (column: Welch Ultimate XB-NH2250*50*10 um; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-50% B over 10.0 min) to give compound 4-pentylnonyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (20 mg, 20.13 pmol, 6.53% yield, 98% purity) as yellow oil.

[0537] 'H NMR (400 MHz, CDCh), 8.51-8.54 (m, 1H), 7.29-7.30 (m, 1H), 6.79 (s, 1H), 5.64 (s, 1H), 4.84-4.88 (m, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.47-3.51 (m, 2H), 2.44-3.25 (m, 6H), 2.28 (t, J=7.6 Hz, 2H), 1.71-1.72 (m, 2H), 1.59-1.60 (m, 4H), 1.50-1.51 (m, 8H), 1.24-1.26 (m, 59H), 1.15 (s, 6H), 0.86-0.90 (m, 12H), (M+H+): 974.0Example 47: 4-pentylnonyl 8-[4-[[4-methoxy-3-(inethylsulfamoyl)benzoyl]amino]butyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate

[0538] To a solution of 4-methoxy-3-(methylsulfamoyl)benzoic acid (220.18 mg, 897.76 pmol, 1.5 eq) in DCM (5 mL) was added EDCI (344.20 mg. 1.80 mmol, 3 eq), TEA (30.28 mg, 299.25 pmol, 41.65 pL, 0.5 eq) and DMAP (73.12 mg, 598.50 pmol, 1 eq) and 4-pentylnonyl 8-[4-aminobutyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]-2,2-dimethyl-octanoate (500 mg, 598.50 pmol, 1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was quenched by addition of H2O (50 mL) at 0 °C and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i O2. Petroleum ether / Ethyl acetate=100 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.1%TFA)-ACN: THF=l:l]; gradient: 40%-90% B over 14.0 min) to give mixture.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 The mixture was diluted with brine 100 mL and extracted with EtOAc 90 mL (30 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[[4-methoxy-3-(methylsulfamoyl)benzoyl]amino]butyl-[8-(1-octylnonoxy)-8-oxo-octyl]amino]-2.2-dimethyl-octanoate (85 mg, 79.99 pmol, 28.33% yield, 100% purity) as yellow oil.

[0539] H NMR (400 MHz, CDCI3) 8.10-8.27 (m, 2H), 7.12 (d, J=8.8 Hz, 1H), 6.90-7.04 (m, 1H), 4.90-4.96 (m, 1H), 4.70-4.78 (m, 1H), 4.02-4.06 (m, 5H), 3.43-3.52 (m, 2H), 2.62 (d, J=5.2 Hz, 3H), 2.33-2.54 (m, 6H), 2.27 (t, J=7.6 Hz, 2H), 1.57-1.63 (m, 8H), 1.48-1.52 (m, 6H), 1.37-1.46 (m, 4H), 1.23-1.31 (m, 55H), 1.16 (s. 6H), 0.86-0.91 (m. 12H).

[0540] LCMS-CAD (M+H+): 1063.0 @ 11.540 min.

[0541] LCMS-ELSD (M+H+): 1063.0 @ 2.750 min.Example 48: 4-pentylnonyl 8-[4-[[3-(cyclopropylsulfamoyl)-4-methoxy-benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino] -2,2-dimethyl-octanoateAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0542] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.3 g, 399.33 pmol, 1 eq) and 3-(cyclopropylsulfamoyl)-4-methoxy-benzoicacid (130.00 mg, 479.20 pmol, 1.2 eq) in DCM (3 mL) was added EDCI (191.38 mg, 998.33 pmol, 2.5 eq), DMAP (24.39 mg, 199.67 pmol, 0.5 eq) and TEA (40.41 mg, 399.33 pmol, 55.58 pL, 1 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh. Commercial hexanes: Ethyl acetate=l / O to 0 / 1) and p-MPLC(column: Welch Ultimate XB-Diol 250*50* lOum; mobile phase: [Heptane-THF: ACN=2: 1]: gradient:5%-50% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[[3-(cyclopropylsulfamoyl)-4-methoxy-benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (130 mg, 128.12 pmol, 86.96% yield, 99% purity) as colorless oil.

[0543] 'H NMR (400 MHz, CDCI3) 8.12-8.34 (m, 2H), 7.13 (d, J=8.8 Hz. 1H), 7.04 (brs, 1H), 5.29 (s, 1H), 4.01-4.07 (m, 7H), 3.42-3.51 (m, 2H), 2.22-2.57 (m, 8H), 2.05-2.14 (m, 1H), 1.47-1.85 (m, 16H), 1.26-1.41 (m, 47H), 1.15 (s, 6H), 0.89 (t, J=6.8 Hz, 9H), 0.69-0.74 (m, 2H), 0.55-0.62 (m, 2H).

[0544] LCMS-CAD (M+H+): 1004.9 @ 10.085 min.

[0545] LCMS-ELSD (M+H ): 1004.9 (Oj 2.361 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 49: 4-pentylnonyl 2,2-dimethyl-8-[4-[[3-(methylsulfamoyl)benzoyl]amino]butyl- (8-oxo-8-undecoxy-octyl)amino]octanoate

[0546] A mixture of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.7 g, 931.77 pmol, 1 eq), 3-(methylsulfamoyl)benzoic acid (220.60 mg, 1.02 mmol, 1.1 eq), DMAP (113.83 mg, 931.77 pmol, 1 eq), EDCI (714.49 mg, 3.73 mmol, 4 eq) and TEA (18.86 mg, 186.35 pmol. 25.94 pL, 0.2 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2. Commercial hexanes: Ethyl acetate=50 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase:[ACN(0.1% TFA)-ACN: THF=1: 1]; gradient:45%-85% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[[3-(methylsulfamoyl)benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate (90 mg, 93.94 pmol, 10.08% yield, 99% purity) as colorless oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0547] H NMR (400 MHz, CDCI3) 8.25 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.49-7.52 (m, 1H), 4.69 (brs, 1H), 4.01-4.07 (m, 4H), 3.41-3.55 (m, 2H), 2.67 (s, 3H), 2.35-2.56 (m, 6H), 2.29 (t, J=7.2 Hz, 2H), 1.57-1.70 (m, 10H), 1.47-1.52 (m, 2H), 1.37-1.45 (m, 4H), 1.21-1.32 (m, 47H), 1.16 (s, 6H). 0.89 (t. J=6.8 Hz, 9H).

[0548] LCMS-CAD (M+H+): 948.8 @ 9.975 min.

[0549] LCMS-ELSD (M+H+): 948.9 @ 2.336 min.Example 50: 4-pentylnonyl 2,2-dimethyl-8-[4-[[4-(methylsulfamoyl) benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino]octanoate

[0550] A mixture of 4-(methylsulfamoyl)benzoic acid (343.79 mg, 1.60 mmol. 1.2 eq), 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (1 g, 1.33 mmol, 1 eq), EDCI (382.76 mg, 2.00 mmol, 1.5 eq), DMAP (81.31 mg, 665.55 pmol, 0.5 eq) and TEA (404.08 mg, 3.99 mmol, 555.82 pL, 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and the mixture was stirred at 25 °C for 8 hours underN2 atmosphere. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate =10 / 0 to 0 / 1), prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm;mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-50% B over 10.0 min) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.03% TFA)-ACN: THF=1:1]; gradient:45%-85% B over 14.0 min). The mixture was diluted with brine 50 mL and extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3,Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[[4-(methylsulfamoyl) benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino]octanoate (57 mg, 60.10 pmol, 4.51% yield, 100% purity) as colorless oil.

[0551] 'H NMR (400 MHz, CDCI3) 7.78-8.06 (m, 4H), 7.36-7.61 (m, 1H), 4.67 (s, 1H), 3.97-4.14 (m, 4H), 3.40-3.56 (m, 2H), 2.68 (s, 3H), 2.20-2.56 (m, 8H), 1.60-1.73 (m, 6H), 1.45-1.54 (m, 3H), 1.22-1.43 (m, 54H), 1.16 (s, 6H). 0.89 (t. J=6.8 Hz, 9H).

[0552] LCMS-CAD (M+H+): 948.9 @ 9.890 min.

[0553] LCMS-ELSD (M+H+): 948.8 @ 2.231 min.Example 51: 4-pentylnonyl 2,2-dimethyl-8-[4-[[5-(methylsulfamoyl)thiophene-3-carbonyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino] octanoateEDCI, DMAP, TEA DCM, 25 °C, 8 h

[0554] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.2 g, 266.22 pmol, 1 eq) and 5-(methylsulfamoyl)thiophene-3-carboxylic acid (80 mg, 361.58 pmol, 1.36 eq) in DCM (2 mL) was added EDCI (153.10 mg, 798.66 pmol, 3 eq), DMAP (6.50 mg, 53.24 pmol, 0.2 eq) and TEA (80.82 mg, 798.66 pmol, 111.16 pL, 3 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=l / 0 to 0 / 1) to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[[5-(methylsulfamoyl)thiophene-3-carbonyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate (60 mg, 61.60 pmol, 23.14% yield, 98% purity) as colorless oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0555] H NMR (400 MHz, CDCI3) 8.17 (s, 1H), 7.91 (s, 1H), 4.73 (brs, 1H), 3.98-4.09 (m, 4H), 3.33-3.54 (m, 2H), 2.78 (s, 3H), 1.88-2.73 (m, 8H), 1.41-1.71 (m, 20H), 1.25-1.35 (m, 43H), 1.15 (s, 6H), 0.89 (t, J=6.8 Hz, 9H).

[0556] LCMS-CAD (M+H+): 954.8 @ 9.984 min.

[0557] LCMS-ELSD (M+H+): 954.8 @ 2.327 min.Example 52: 4-pentylnonyl 2,2-dimethyl-8-[(8-oxo-8-undecoxy-octyl)-[4-(lH-pyrazole-4-carbonylamino)butyl] amino] octanoate2 EDCI, DMAP, DCM, 25 °C, 8 h step 1 8 from Example 40

[0558] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.3 g, 399.33 pmol, 1 eq) and 1H-pyrazole-4-carboxylic acid (53.71 mg, 479.20 pmol, 1.2 eq) in DCM (5 mL) was added EDCI (229.66 mg, 1.20 mmol,3 eq) and DMAP (24.39 mg, 199.67 pmol, 0.5 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=l / O to 0 / 1) and p-MPLC (column: Welch Ultimate XB-Diol 250*50* 10um;mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-50% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[(8-oxo-8-undecoxy-octyl)-[4-(lH-pyrazole-4-carbonylamino)butyl]amino] octanoate (70 mg, 82.81 pmol, 20.74% yield, 100% purity) as colorless oil.

[0559] 'H NMR (400 MHz, CDCh), 7.99 (s, 2H), 6.76 (brs, 1H), 4.01-4.12 (m, 4H), 3.37-3.54 (m, 2H), 2.18-2.81 (m, 8H), 1.38-1.78 (m, 19H), 1.24-1.34 (m, 44H), 1.16 (s. 6H), 0.89 (t, J=6.8 Hz. 9H).Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0560] LCMS-CAD (M+H+): 845.8 @ 9.368 min.

[0561] LCMS-ELSD (M+H+): 845.8 @ 2.144 min.Example 53: 4-pentylnonyl 8-[4-[(4-cyclopropyl-1H-pyrrole-3-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyloctanoate2 EDCI, DMAP, TEA, DCM, 25 °C, 8 hstep 1 8 from Example 40

[0562] A mixture of 4-cyclopropyl-lH-pyrrole-3-carboxylic acid (193.16 mg, 1.28 mmol, 1.2 eq), 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.8 g, 1.06 mmol, 1 eq), EDCI (306.21 mg, 1.60 mmol, 1.5 eq), DMAP (65.05 mg, 532.44 pmol. 0.5 eq) and TEA (323.26 mg, 3.19 mmol, 444.65 pL. 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethylacetate =10 / 0 to 0 / 1), prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient:5%-50% B over 10.0 min) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u;mobile phase: [H2O(0.03% TFA)-ACN: THF=1:1]; gradient:45%-85% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10: 1). The hexane phase w as concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 atmosphere to give a compound 4-pentylnonyl 8-[4-[(4-cyclopropyl-lH-pyrrole-3-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyloctanoate (142 mg, 157.35 pmol, 14.78% yield, 98% purity) as colorless oil.

[0563] 'H NMR (400 MHz, CDC13) 8.20-8.35 (m, 1H), 7.36 (s, 1H), 6.73 (s, 1H). 6.48 (s, 1H), 4.01-4.09 (m, 4H). 3.38-3.54 (m, 2H). 2.22-2.49 (m, 8H). 1.79-1.89 (m, 1H). 1.60-1.68 (m, 6H).1.48-1.54 (m, 3H), 1.36-1.44 (m, 4H), 1.21-1.35 (m, 50H), 1.16 (s, 6H), 0.89 (t, J=6.4 Hz, 11H), 0.60-0.68 (m, 2H).

[0564] LCMS-CAD (M+H+): 884.9 @ 10.096 min.

[0565] LCMS-ELSD (M+H+): 884.8 @ 2.742 min.Example 54: 4-pentylnonyl 2,2-dimethyl-8-[4-[(5-methyl-4-oxo-7,8-dihydro-6H-pyrazolo [ 1,5- a] [1,4] diazepine-2-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino] octanoateMel, NaH THF, 0-25 °C, 8 h THF, H2O O 1 step 1 25 °C, 1 h step 2HATU, DIEA, DMF, 25 °C, 3 h

[0566] Step i: To a solution of methyl 4-oxo-5,6,7,8-tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxylate (1 g, 4.78 mmol, 1 eq) in THF (10 mL) was added dropwise NaH (286.78 mg, 7.17 mmol, 60% purity, 1.5 eq) at 0 °C under N2. After addition, the mixture was stirred at thisAttomey Docket 96676-435728 | Client Ref: SBM24-112WO1 temperature for 0.5 hour, and then Mel (746.32 mg, 5.26 mmol, 327.33 pL, 1.1 eq) was added dropwise at 0 °C under N2. The resulting mixture was stirred at 25 °C for 7.5 hours. The reaction mixture was quenched by addition of H2O 100 mL at 0 °C under N2 atmosphere. The mixture was extracted with EtOAc 30 mL (10 mL*3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=5 / l to 2 / 1). The crude product was triturated with the mixture of Petroleum ether (10 mL) and Ethyl acetate (0.2 mL) at 15 °C for 30 min. Then the reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give a compound methyl 5-methyl-4-oxo-7,8-dihydro-6H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (370 mg, 1.38 mmol, 54.84% yield, 83% purity) as a white solid. LCMS (M+H+): 224.2 @ 0.312 min

[0567] Step 2: To a solution of methyl 5-methyl-4-oxo-7.8-dihydro-6H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (370 mg, 1.66 mmol, 1 eq) in THF (1.5 mL) and H2O (1.5 mL) was added LiOH. ELO (76.50 mg, 1.82 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H2O 20 mL and washed with EtOAc 40 mL (20 mL*2). The aqueous phase was freeze-dried to give a compound 5-methyl-4-oxo-7,8-dihydro-6H-pyrazolo[l,5-a][1.4]diazepine-2-carboxylic acid (380 mg, crude) as a white solid.

[0568] Step 3: To a solution of 5-methyl-4-oxo-7,8-dihydro-6H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (0.3 g, 1.43 mmol. 3 eq), HATU (272.63 mg, 717.01 pmol. 1.5 eq), DIEA (123.56 mg, 956.02 pmol, 166.52 pL, 2 eq) in DMF (6 mL) was added 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (359.11 mg, 478.01 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hours. The combined organic phase was diluted with EtOAc 20 mL and washed with water 60 mL (20 mL*3) and brine 40 mL (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / l to 1 / 1), p-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm;mobile phase: [Heptane-THF: ACN=2:l];gradient:5%-50% B over 10.0 min) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [1420(0.03% TFA)-ACN: THF=1:1]; gradient:40%-85% B over 14.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 2000 mL (500 mL*4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[(5-methyl-4-oxo-7,8-dihydro-6H-pyrazolo[l,5-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 a][l,4]diazepine-2-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate (30 mg, 31.51 pmol, 14.85% yield, 99% purity) as colorless oil.

[0569] 'H NMR (400 MHz, CDC13) 7.22 (s, 1H), 6.88-6.98 (m, 1H), 4.41 (t, J=6.8 Hz, 2H), 3.98-4.12 (m, 4H), 3.35-3.51 (m, 4H), 3.18 (s. 3H), 2.22-2.52 (m. 10H), 1.59-1.67 (m, 6H), 1.20-1.56 (m, 57H), 1.16 (s, 6H), 0.89 (t, J=6.8 Hz, 9H).

[0570] LCMS-CAD (M+H+): 942.9 @ 9.624 min.

[0571] LCMS-ELSD (M+H+): 942.9 @ 2.192 min.Example 55: 4-pentylnonyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl) amino]-2,2-dimethyl-octanoate8 from Example 40

[0572] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (300 mg, 399.33 pmol, 1 eq) and 3-carbamoylisoxazole-5-carboxylic acid (155.84 mg, 998.33 pmol, 2.5 eq) in DMF (5 mL) was added EDCI (153.10 mg, 798.66 pmol, 210.60 pL, 2 eq) and DMAP (9.76 mg, 79.87 pmol, 0.2 eq). The mixture was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Commercial hexanes: Ethyl acetate=10 / l to 0 / 1, 1% NH3. THF), prep-TLC (SiO2, EA: MeOH = 10:1, 1%NH3. THF) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [ACN(0.1% TFA)-ACN: THF=1: 1]: gradient:40%-80% B over 14.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 200 mL (50 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2atmosphere to give a residue. The residue wasAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[(3-carbamoylisoxazole-5-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl) amino]-2,2-dimethyl-octanoate (33 mg, 37.11 pmol, 9.29% yield, 100% purity) as colorless oil.

[0573] 'H NMR (400 MHz, CDCh) 8.44-8.65 (m, 1H), 7.29 (s, 1H), 6.81 (s, 1H), 5.67 (s, 1H), 4.01-4.07 (m, 4H), 3.42-3.49 (m, 2H), 2.45 (s. 6H), 2.29 (t, J=7.6 Hz, 2H), 1.69-1.74 (m. 2H), 1.56-1.64 (m, 10H), 1.40-1.52 (m. 6H), 1.23-1.31 (m. 45H), 1.16 (s, 6H). 0.89 (t. J=6.8 Hz, 9H).

[0574] LCMS-CAD (M+H+): 889.8 @ 9.490 min.

[0575] LCMS-ELSD (M+H+): 889.8 @ 2.557 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 56: 4-pentylnonyl 8-[4-[[4-methoxy-3-(methylsulfamoyl) benzoyl] amino] butyl- [6- (l-octylnonoxycarbonyloxy)hexyl]amino]-2,2-dimethyl-octanoatedioxane, HCI / dioxane 25 °C, 2 h step 4 O°' NH / 9 1. (COCI)2, DMF, DCM, 25 °C, 2 h 2. NaHCO3DCM, 25 °C, 8 h step 5

[0576] Step 1: To a solution of 6-bromohexan-l-ol (15 g, 82.84 mmol, 10.84 mL, 1 eq), (4- nitrophenyl) carbonochloridate (18.37 g, 91.12 mmol. 1.1 eq), DMAP (20.24 g, 165.68 mmol, 2 eq) in DCM (150 mL) at 25 °C. The mixture was stirred at 25 °C for 3 hours. Then was addedAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 heptadecan-9-ol (25.49 g, 99.41 mmol, 1.2 eq) and TEA (16.77 g, 165.68 mmol, 23.06 mL, 2 eq) to above reaction at 25 °C. The mixture was stirred at 25 °C for 5 hours. The mixture was poured into water (200 mL) then extracted with DCM (100 mL*2). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 80 / 1) to give a compound 6-bromohexyl 1-octylnonyl carbonate (7.8 g, 16.83 mmol, 20.31% yield) as colorless oil.

[0577] Step 2: A mixture of tert-butyl N-(4-aminobutyl)carbamate (12.67 g, 67.31 mmol, 4 eq), 6-bromohexyl 1 -octylnonyl carbonate (7.8 g, 16.83 mmol, 1 eq), K2CO3 (6.98 g, 50.48 mmol, 3 eq), KI (1.40 g, 8.41 mmol, 0.5 eq) in DMF (78 mL) was degassed and purged with N2 for 3 times, the mixture w as stirred at 80 °C for 8 hours under N2 atmosphere. The mixture was poured into water (150 mL) then extracted with Ethyl acetate (100 mL*2). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4, filtered and concentrated under reducedpressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 3 / 1) to give a compound 6-[4-(tert-butoxycarbonylamino)butylamino]hexyl 1-octylnonyl carbonate (2.5 g, 3.68 mmol, 21.86% yield) as colorless oil.

[0578] Step 3: A mixture of 4-pentylnonyl 8-bromo-2,2-dimethyl-octanoate (1.96 g, 4.38 mmol, 1 eq), 6-[4-(tert-butoxycarbonylamino) butylamino]hexyl 1-octylnonyl carbonate (2.5 g, 4.38 mmol, 1 eq). KI (363.48 mg. 2.19 mmol, 0.5 eq), K2CO3 (1.82 g, 13.14 mmol, 3 eq) in DMF (25 mL) was degassed and purged with N2 for 3 times, the mixture was stirred at 80 °C for 8 hours under N2 atmosphere. The residue w as diluted with H2O 50 ml and extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine 50 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=50 / l to 5 / 1) to give a compound 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[6-(l-octyhionoxycarbonyloxy)hexyl]amino]-2,2-dimethyl-octanoate (1.2 g, 1.16 mmol, 26.60% yield, 91% purity) as colorless oil. LCMS (M+H+): 938.0 @ 2.932 min.

[0579] Step 4: To a solution of 4-pentylnonyl 8-[4-(tert-butoxycarbonylamino)butyl-[6-(l-octylnonoxycarbonyl oxy)hexyl]amino]-2,2-dimethyl-octanoate (1.2 g, 1.28 mmol, 1 eq) in dioxane (2 mL) was added HCl / dioxane (4 M. 12.00 mL, 37.50 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a compound 4-pentylnonyl 8-[4-aminobutyl-[6-(l -octylnonoxy carbonyloxy )hexyl]amino]-2, 2-dimethyl-octanoate (1 g, 1.19 mmol, 93.30% yield) as colorless oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0580] Step 5: A mixture of 4-methoxy-3-(methylsulfamoyl)benzoic acid (0.4 g, 1.63 mmol, 1 eq) in DCM (4 mL) was added oxalyl dichloride (414.04 mg, 3.26 mmol, 285.54 pL, 2 eq), DMF (23.84 mg, 326.20 pmol, 25.10 pL, 0.2 eq). The mixture was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a 4-methoxy-3-(methylsulfamoyl)benzoyl chloride. To a solution of 4-pentylnonyl 8-[4-aminobutyl-[6-(l-octylnonoxy carbonyloxy) hexyl] amino] -2, 2-dimethyl-octanoate (0.65 g, 776.22 pmol, 1 eq) in DCM (6 mL) was added NaHCOs (652.08 mg, 7.76 mmol, 302.03 pL, 10 eq) and 4-methoxy-3-(methylsulfamoyl)benzoyl chloride (245.63 mg. 931.47 pmol, 1.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =10 / 0 to 0 / 1) and prep-HPLC (column: WePure Biotech Phenyl-Hexyl 250*70 7u;mobile phase: [H2O(0.1% TFA)-ACN: THF=l:l];gradient:55%-75% B over 23.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 200 mL (50 mL*4). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[[4-methoxy-3-(methylsulfamoyl) benzoyl]amino]butyl-[6-(l-octylnonoxycarbonyloxy)hexyl]amino]-2, 2-dimethyl-octanoate (75 mg, 69.74 Limo I. 8.98% yield, 99% purity’) as colorless oil.

[0581] H NMR (400 MHz, CDCI3) 7.97-8.43 (m, 2H), 7.11-7.16 (m, 1H), 4.56-4.97 (m, 2H), 4.18 (t, J=3.2 Hz, 2H), 4.02-4.07 (m, 5H), 3.39-3.54 (m, 2H), 2.38-2.88 (m, 9H), 1.44-1.74 (m, 20H), 1.22-1.34 (m, 50H), 1.17 (s, 6H), 0.88-0.93 (m, 12H).

[0582] LCMS-CAD (M+H+): 1064.9 @ 11.293 min.

[0583] LCMS-ELSD (M+H+): 1064.9 @ 2.708 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 57: 4-pentylnonyl 8-[4-[[3-(dimethylsulfamoyl)-4-methoxy-benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate8 from Example 40

[0584] To a solution of 3-(dimethylsulfamoyl)-4-methoxy-benzoic acid (258.84 mg, 998.33 pmol, 1.5 eq), EDCI (510.35 mg, 2.66 mmol, 4 eq). TEA (67.35 mg, 665.55 umol. 92.64 yL, 1 eq), DMAP (81.31 mg, 665.55 pmol, 1 eq) in DCM (5 mL) was added 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.5 g, 665.55 pmol, 1 eq). The mixture was stirred at 25 °C for 3 hrs. The combined organic phase was diluted with EtOAc 10 mL and washed with water 15 mL (5 mL*3) and brine 10 mL (5 mL*2), dried with anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=20 / l to 1 / 1, 3% NH3 THF) and prep-MPLC (column: Welch Ultimate XB NH2 lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2:1]; gradient: 5%-50% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[[3-(dimethylsulfamoyl)-4-methoxy-benzoyl]amino]butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (100 mg, 100.75 pmol, 33.33% yield, 100% purity) as yellow oil.

[0585] 'II NMR (400 MHz, CDCb) 7.97-8.34 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (brs, 1H), 3.98-4.08 (m, 7H), 3.37-3.57 (m, 2H), 2.87 (s. 6H), 2.18-2.58 (m. 8H), 1.58-1.70 (m. 8H), 1.21-1.51 (m, 55H), 1.16 (s, 6H), 0.91 (t, J=6.8 Hz, 9H).

[0586] LCMS-CAD (M+H+): 992.9 (a 10.157 min

[0587] LCMS-ELSD (M+H+): 992.9 @ 2.360 minAttomey Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 58: 4-pentylnonyl 8-[4-[(4-methoxy-3-sulfamoyl-benzoyl)amino]butyl-(8-oxo-8-undecoxy-octyl)ainino] -2,2-dimethyl-octanoateEDCI, DMAP, TEA, DCM, 25 °C, 8 h8 from Example 40

[0588] A mixture of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2.2-dimethyl-octanoate (0.7 g, 931.77 pmol, 1 eq), 4-methoxy-3-sulfamoyl-benzoic acid (236.99 mg, 1.02 mmol, 1.1 eq), EDCI (714.48 mg, 3.73 mmol, 4 eq), DMAP (113.83 mg, 931.77 pmol, 1 eq) and TEA (18.86 mg, 186.35 pmol, 25.94 pL, 0.2 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, the mixture was stirred at 25 °C for 8 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=50 / l to 0 / 1) and prep-HPLC (column: Welchrom CSH C18 100*30*7; mobile phase: [1420(0.05% TFA)-ACN: THF=1:1]; gradient:40%-70% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was purified by prep-MPLC (column: Welch Ultimate XB NFL lOu 100*30mm; mobile phase: [Heptane-THF: ACN=2: 1 ]; gradient:5%-50% B over 10.0 min) to give a compound 4-pentylnonyl 8-[4-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 [(4-methoxy-3-sulfamoyl-benzoyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino] -2,2-dimethyl-octanoate (110 mg, 114.05 pmol, 20.59% yield, 100% purity) as colorless oil.

[0589] 'H NMR (400 MHz, CDC13) 8.25-8.29 (m, 1H), 8.01-8.11 (m, 1H), 7.23-7.26 (m, 1H), 7.05-7.09 (m,lH), 4.93-5.62 (m, 2H), 3.97-4.13 (m, 7H), 3.41-3.50 (m, 2H), 2.36-2.52 (m, 6H), 2.27 (t. J=7.6 Hz, 2H). 1.55-1.70 (m, 10H), 1.46-1.52 (m. 2H) 1.36-1.44 (m, 4H) 1.21-1.32 (m, 47H) 1.16 (s, 6H), 0.88 (t, J=6.8 Hz, 9H).

[0590] LCMS-CAD (M+H+): 964.8 @ 9.696 min.

[0591] LCMS-ELSD (M+H+): 964.9 @ 2.235 min.Example 59: 4-pentylnonyl 8-[4-[[4-methoxy-3-(oxetan-3-yIsulfamoyl) benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate

[0592] Step 1: To a solution of 3-chlorosulfonyl-4-methoxy -benzoic acid (200 mg, 797.91 pmol, 1 eq) in DCM (2 mL) was added TEA (161.48 mg, 1.60 mmol, 222.12 pL, 2 eq) and dropwise oxetan-3-amine (58.32 mg, 797.91 pmol, 1 eq) in DCM (2 mL) at 0 °C. The mixture was degassed and purged with N2 for 3 times. Then the mixture was stirred at 0 °C for 4 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc at 25 °C for 15 min to give a compound 4-methoxy-3-(oxetan-3-ylsulfamoyl)benzoic acid (170 mg, 520.73 pmol. 65.26% yield) as white solid.

[0593] Step 2: To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (222.2 mg, 295.77 pmol, 1 eq) and 4-methoxy-3-(oxetan-Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 3-ylsulfamoyl)benzoic acid (170 mg, 591.54 pmol, 2 eq) in DMF (4 mL) was added EDCI (113.44 mg, 591.54 pmol, 2 eq) and DMAP (7.23 mg, 59.15 pmol, 0.2 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was diluted with H2O 10 mL, extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with brine 20 mL (10 mL*2). dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=10 / l to 1 / 1, NHs. THF) and prep-HPLC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, lOum); mobile phase: [Heptane-THF: ACN= 2:1]; gradient: 5%-50% B over 10.0 min). The mixture was concentrated under N2 atmosphere to give compound 4-pentylnonyl 8-[4-[[4-methoxy-3-(oxetan-3-ylsulfamoyl) benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (100 mg, 48.01 (imol, 16.23% yield, 98% purity) as colorless oil.

[0594] ! H NMR (400 MHz, CDCI3) 8.28 (brs, 1H), 8.10-8.19 (m, 1H), 7.09 (d, J=8.8 Hz, 1H), 5.57-5.71 (m, 1H), 4.68 (t. J=6.8 Hz, 2H), 4.50-4.61 (m, 1H), 4.44 (t, J=6.4 Hz, 2H), 4.07 (s. 3H), 3.98-4.04 (m, 4H), 3.43-3.55 (m, 2H), 2.37-3.10 (m, 6H), 2.29 (t, J=7.2 Hz, 2H), 1.66-1.74 (m, 3H), 1.55-1.65 (m, 8H), 1.45-1.54 (m, 4H), 1.22-1.33 (m, 48H), 1.16 (s, 6H), 0.89 (t, J=6.8 Hz, 9H).

[0595] LCMS-CAD (M+H+): 1020.9 @ 9.742 min.

[0596] LCMS-ELSD (M+H+): 1020.9 @ 2.243 min.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1 Example 60: 4-pentylnonyl 2,2-dimethyl-8-[4-[[3-(methylsulfamoyl)benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino]octanoate

[0597] A mixture of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.7 g, 931.77 pmol, 1 eq), 5-chloro-3-cyclopropyl-1H-pyrazole-4-carboxylic acid (208.64 mg, 1.12 mmol. 1.2 eq), DMAP (56.92 mg, 465.89 pmol, 0.5 eq), EDCI (267.93 mg, 1.40 mmol, 1.5 eq) and TEA (282.86 mg, 2.80 mmol, 389.08 pL, 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=50 / 1 to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*30 5u; mobile phase: [H2O(0.03% TFA)-ACN: THF=1:1]; gradient:45%-85% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 2,2-dimethyl-8-[4-[[3-(methylsulfamoyl)benzoyl] amino] butyl-(8-oxo-8-undecoxy-octyl)amino]octanoate (90 mg, 93.94 pmol, 10.08% yield, 98% purity) as colorless oil.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1

[0598] H NMR (400 MHz, CDCI3) 9.75-10.20 (m, 1H), 6.61-6.76 (m, 1H), 4.01-4.10 (m, 4H), 3.39-3.52 (m, 2H), 2.63-2.75 (m, 1H), 2.25-2.49 (m, 8H), 1.55-1.65 (m, 10H), 1.48-1.52 (m, 2H), 1.35-1.42 (m, 4H), 1.21-1.34 (m, 47H), 1.17-1.20 (m, 6H), 1.06-1.11 (m, 2H), 0.89 (t, J=6.8 Hz, 9H), 0.80-0.84 (m, 2H).

[0599] LCMS-CAD (M+H+): 919.9 @ 9.937 min.

[0600] LCMS-ELSD (M+H+): 919.8 @ 2.297 min.Example 61: 4-pentylnonyl 8-[4-[(3-cyclopropylisothiazole-4-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate2 EDCI, DMAP, TEA DCM, 25 °C, 8 h8 from Example 40

[0601] A mixture of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (0.7 g, 931.77 pmol. 1 eq), 3-cyclopropylisothiazole-4-carboxylic acid (189.19 mg, 1.12 mmol, 1.2 eq). DMAP (56.92 mg. 465.89 pmol, 0.5 eq), EDCI (267.93 mg, 1.40 mmol, 1.5 eq) and TEA (282.86 mg, 2.80 mmol, 389.07 pL, 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiCh. Commercial hexanes: Ethyl acetate=50 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.03% TFA)-ACN: THF=1:1]; gradient:45%-85% B over 14.0 min). The mixture was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN andAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 TEA 15 mL (5 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give compound 4-pentylnonyl 8-[4-[(3-cyclopropylisothiazole-4-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (100 mg, 380.08 pmol, 40.79% yield, 98% purity) as colorless oil.

[0602] 'H NMR (400 MHz, CDCI3) 8.85 (s, 1H), 7.01 (brs, 1H), 3.98-4.10 (m, 4H), 3.41-3.51 (m, 2H), 2.55-2.65 (m, 1H), 2.33-2.52 (m, 5H), 2.27-2.31 (m, 2H), 1.55-1.68 (m, 10H), 1.47-1.53 (m, 2H), 1.21-1.43 (m, 52H), 1.13-1.19 (m, 8H), 1.00-1.06 (m, 2H), 0.89 (t, J=6.8 Hz, 9H).

[0603] LCMS-CAD (M+H+): 902.9 @ 10.597 min.

[0604] LCMS-ELSD (M+H+): 902.8 @ 2.487 min.Example 62: 4-pentylnonyl 8-[4-[(3-cyclopropylisoxazole-4-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate2EDCI, DMAP, TEADCM, 25 °C, 8 h

[0605] A mixture of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2.2-dimethyl-octanoate (0.7 g, 931.77 pmol, 1 eq), 3-cyclopropylisoxazole-4-carboxylic acid (171.22 mg, 1.12 mmol, 1.2 eq), DMAP (56.92 mg, 465.89 pmol, 0.5 eq), EDCI (267.93 mg, 1.40 mmol, 1.5 eq) and TEA (282.86 mg, 2.80 mmol, 389.07 pL, 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 8 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate=50 / l to 0 / 1) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O(0.03% TFA)-ACN: THF=1:1]; gradient: 40%-80% B over 14.0 min). The mixtureAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 was diluted with brine 500 mL and extracted with EtOAc 300 mL (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 15 mL (5 mL*3, 10:1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give a compound 4-pentylnonyl 8-[4-[(3-cyclopropylisoxazole-4-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (120 mg, 513.33 pmol, 55.09% yield, 100% purity) as colorless oil.

[0606] 'H NMR (400 MHz, CDCI3) 8.73 (s, 1H), 6.87 (s, 1H). 3.99-4.08 (m, 4H). 3.37-3.48 (m, 2H), 2.37-2.50 (m, 5H), 2.21-2.33 (m, 3H), 1.53-1.69 (m, 10H), 1.47-1.53 (m, 2H), 1.37-1.45 (m, 4H), 1.18-1.35 (m, 48H), 1.14-1.17 (m, 6H), 1.05-1.11 (m, 4H), 0.89 (t, J=6.8 Hz, 9H).

[0607] LCMS-CAD (M+H+): 886.9 @ 10.374 min.

[0608] LCMS-ELSD (M+H+): 886.9 @ 2.422 min.Example 63: 4-pentylnonyl 2,2-dimethyl-8-[4-[(4-oxo-5,6,7,8-tetrahydropyrazolo[l,5-a] [1,4] diazepine-2-carbonyl)amino] butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate8 from Example 40

[0609] To a solution of 4-pentylnonyl 8-[4-aminobutyl-(8-oxo-8-undecoxy-octyl)amino]-2,2-dimethyl-octanoate (240 mg, 319.46 pmol, 1 eq) and 4-oxo-5,6,7,8-tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (62.35 mg, 319.46 pmol, 1 eq) in DCM (4 mL) was added EDCI (122.48 mg, 638.93 pmol, 2 eq), DMAP (7.81 mg, 63.89 pmol, 0.2 eq), TEA (64.65 mg, 638.93 pmol, 88.93 pL, 2 eq). The mixture was stirred at 25 °C for 8 hours. TheAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 reaction mixture was concentrated under reduced pressure to give a residue. The residue diluted with H2O 10 mL then extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with brine 20 mL (10 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=10 / l to 1 / 1, 1% NH3. THF) and prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H20(0.03% TFA)-ACN: THF=1:1]; gradient:40%-85% B over 14.0 min). The mixture was diluted with EtOAc 60 mL and washed with brine 2000 mL (500 mL*4). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with the mixture of ACN and TEA 60 mL (20 mL*3, 10: 1). The hexane phase was concentrated under N2 atmosphere to give a residue. The residue was diluted with hexane 20 mL and washed with ACN 40 mL (20 mL*2). The hexane phase was concentrated under N2 atmosphere to give compound 4-pentylnonyl 2,2-dimethyl-8-[4-[(4-oxo-5,6,7,8-tetrahydropyrazolo[l,5-a][1,4]diazepine-2-carbonyl)amino]butyl-(8-oxo-8-undecoxy-octyl)amino] octanoate (47 mg, 50.12 pmol, 15.69% yield, 99% purity) as colorless oil.

[0610] 'H NMR (400 MHz, CDCI3) 7.33 (s, 1H), 6.96 (s, 1H), 6.12-6.20 (m, 1H), 4.51 (t, 6.8 Hz. 2H), 4.01-4.07 (m. 4H), 3.37-3.47 (m. 4H), 2.33-2.49 (m. 6H), 2.27-2.32 (m. 4H), 1.55-1.67 (m. 12H), 1.46-1.54 (m, 4H), 1.37...

Claims

Attorney Docket 96676-435728 | Client Ref: SBM24-112WO1CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula (1)z(CH2)n-L2-R2R1-L -(CH2)p-N(CH2)n-L2-R2(I)or a pharmaceutically acceptable salt thereof, wherein:R1is Ce-io aryl, a 5- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring wherein the Ce-io aryl, 5- to 10-membered heterocyclyl ring or 5- to 10- membered heteroaryl ring is optionally substituted with one to four R3;each R2is independently C10-C20 alkyl, C8-C18 alkenyl, N(C8-C16 alkyl)2, CH(C4-C12 alkoxy)2, or a 4- to 6-membered heterocyclyl substituted with one or two C4-C20 alkyl;each R3is independently halogen, OH. oxo, SH. thioxo. C1-6 alkyl, C1-6 alkoxy. C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C(O)N(Rc)2, N(RC)2, N(RD)C(O)-RE, S(O)2RB, S(O)2N(RA)2, S-C1-6 alkyl, or phenyl wherein the phenyl is optionally substituted with one to two RB;each RAis independently H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with Ci- 6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl optionally substituted with C1-6 alkyl;each RBis independently C1-6 alkyl or C1-6 alkoxy;each Rcis independently H, C1-6 alkyl. C3-6 cycloalkyl, or C1-6 alkoxy;each RDis independently H or C1-6 alkyl;each REis independently C1-6alkyl or a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6alkyl;Li is C(O)N(H), C(O)O, or N(H);each L2 is independently absent, C(CH3)2C(O)O, C(O)O, or OC(O)O;p is 1, 2, 3, 4, 5, or 6; andeach n is independently 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyAttorney Docket 96676-435728 | Client Ref: SBM24-112WO13. The compound of any claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl optionally substituted with one to four R3, optionally wherein:each R3is independently halogen, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, C(O)N(Rc)2, N(RD)C(O)-RE, S(O)2RB, or S(O)2N(RA)2;each RAis independently H, Ci-6 alkyl, C3-6 cycloalkyl, a 4-6 membered heterocyclyl, a 5-membered heteroaryl wherein the 5-membered heteroaryl is optionally substituted with C1-6 alkyl, or two RAtogether with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl,each RBis independently C1-6 alkyl; andeach Rcis independently H or C1-6 alkyl.

4. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heteroaryl or a 6-membered heterocyclyl wherein the 6-membered hctcroaryl or 6-membered heterocyclyl is optionally substituted with one to four R3, optionally wherein:R1is a pyrimidine or pyridine optionally substituted with one to four R3; or R1is a 6-membered heterocyclyl optionally substituted with one to four R3; optionally wherein each R3is independently OH, oxo. SH, thioxo, Ci-6 alkyl, S(O)2N(RA)2, or S-Ci-6 alkyl, optionally wherein each R3is independently OH, Ci-6 alkyl, S(O)2N(RA)2, or S- Ci-6 alkyl.Attorney Docket 96676-435728 | Client Ref: SBM24-112WO15. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one to four R3, optionally wherein:R1is selected from a pyrrole, pyrazole, imidazole, triazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole wherein the pyrrole, pyrazole, imidazole, triazole, furan, isoxazole, isothiazole, thiophene, thiazole, or thiadiazole is optionally substituted with one R3,optionally wherein each R3is independently halogen, oxo, OH, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, C(0)NH2, S(O)2N(RA)2, or phenyl wherein the phenyl is optionally substituted with one to two RB,each RAis independently H, C1-6 alkyl, or a 5-membered heteroaryl wherein the 5- membered heteroaryl is optionally substituted with C1-6 alkyl, andeach RBis independently C1-6 alkoxy.

6. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is a 9-membered heteroaryl optionally substituted with one to four R3;optionally wherein each R3is independently halogen, OH, or C1-6 alkyl.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is a 10-membered heteroaryl optionally substituted with one to four R3;optionally wherein wherein R1is a quinoline optionally substituted with one R3; optionally wherein each R3is independently halogen or OH, optionally wherein each R3is independently halogen.

8. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, whereina) R1is a 9-membered heterocyclyl optionally substituted with one to four R3; or b) R1is a 10-membered heterocyclyl optionally substituted with one to four R3.

9. The compound of any of claims 1 to 20. or a pharmaceutically acceptable salt thereof, wherein:each R2is independentlyp is 4; andAttorney Docket 96676-435728 | Client Ref: SBM24-112WO1 each n is 6.

10. The compound of claim 1, wherein the compound is selected from Table A, or a pharmaceutically acceptable salt thereof.

11. A nanoparticle composition comprising a lipid compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof;optionally wherein the nanoparticle further comprises a lipid carrier;optionally, wherein:a) the lipid carrier comprises a cationic lipid, a non-cationic lipid, a sterol, and a PEG- modified lipid; orb) the lipid carrier comprises a natural lipid.

12. A pharmaceutical composition comprising (a) the compound of any of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or (b) the nanoparticle composition of claim 11, and a pharmaceutically acceptable carrier,optionally wherein the pharmaceutical composition is a vaccine.

13. The pharmaceutical composition of claim 12, further comprising a therapeutic agent or a prophylactic agent; optionally wherein the therapeutic agent is a nucleic acid, a protein, or small molecule drug.

14. The nanoparticle composition of claim 11 or the pharmaceutical composition of claim 12 for use in treating a disease or disorder.

Images