Bisphosphonate lipids, lipid nanoparticle compositions comprising the same, mineral tissue-adsorbed compositions thereof, and methods of use thereof

A compound of Formula (V), or a salt, stereoisomer, or isotopologue thereof:

• wherein:
• R1a, R1b, R2a, R2b, and R3 are each independently selected from the group consisting of H, C(═O)RA, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl;
• R4a, R4b, R4c, R4d, R4e, R4f, R4g, and R4h are each independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl;
• R5a and R5b are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, —C(═O)(optionally substituted C1-C24 alkyl), —C(═O)O(optionally substituted C1-C24 alkyl), and R6,
• wherein at least one of R5a and R5b is R6;
• each occurrence of R6 is independently
• two occurrences of R6 can combine with the atoms to which they are
• bound to form
• each occurrence of L1, L2, L3, L5, and L6, if present, is independently selected from the group consisting of -(optionally substituted C1-C3 alkylenyl)-, —C(═O)—, —O—, and —N(RA)—;
• each occurrence of L4 is independently selected from the group consisting of —X—, -(optionally substituted C1-C12 alkylenyl)-, -(optionally substituted C2-C12 alkenylenyl)-, -(optionally substituted C1-C12 alkynylenyl)-, -(optionally substituted C1-C12 heteroalkylenyl)-, -(optionally substituted C3-C8 cycloalkylenyl)-, -(optionally substituted C2-C8 heterocyloalkylenyl)-, -(optionally substituted C6-C10 arylenyl)-, and -(optionally substituted C2-C8 heteroarylenyl)-;
• each occurrence of X, if present, is independently selected from the group consisting of —N(R7d)—, —N(R8)—, —C(═O)—, and —O—;
• each occurrence of R7a, R7b, R7c, R7d, R7c, and R7f, if present, are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl and optionally substituted C1-C24 heteroalkyl;
• each occurrence of R8 is independently
• each occurrence of m and n, o, p, q, and r, if present, are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• and
• each occurrence of RA is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl.

A lipid nanoparticle (LNP) composition comprising:

• (a) at least one ionizable lipid comprising at least one compound of Formula (V), or a salt, stereoisomer, or isotopologue thereof:
• wherein:
• R1a, R1l, R2a, R2b, and R3 are each independently selected from the group consisting of H, C(═O)RA, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl;
• R4a, R4b, R4c, R4d, R4e, R4f, R4g, and R4h are each independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl;
• R5a and R5b are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, —C(═O)(optionally substituted C1-C24 alkyl), —C(═O)O(optionally substituted C1-C24 alkyl), and R6,
• wherein at least one of R5a and R5b is R6;
• each occurrence of R6 is independently
• or
• two occurrences of R6 can combine with the atoms to which they are bound to form
• each occurrence of L1, L2, L3, L5, and L6, if present, is independently selected from the group consisting of -(optionally substituted C1-C3 alkylenyl)-, —C(═O)—, —O—, and —N(RA)—;
• each occurrence of L4 is independently selected from the group consisting of —X—, -(optionally substituted C1-C12 alkylenyl)-, -(optionally substituted C2-C12 alkenylenyl)-, -(optionally substituted C1-C12 alkynylenyl)-, -(optionally substituted C1-C12 heteroalkylenyl)-, -(optionally substituted C3-C8 cycloalkylenyl)-, -(optionally substituted C2-C8 heterocyloalkylenyl)-, -(optionally substituted C6-C10 arylenyl)-, and -(optionally substituted C2-C8 heteroarylenyl)-;
• each occurrence of X, if present, is independently selected from the group consisting of —N(R7d)—, —N(R8)—, —C(═O)—, and —O—;
• each occurrence of R7a, R7b, R7c, R7d, R7c, and R7f, if present, are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl and optionally substituted C1-C24 heteroalkyl;
• each occurrence of R8 is independently
• each occurrence of m and n, o, p, q, and r, if present, are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• and
• each occurrence of RA is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl;
• (b) at least one neutral lipid;
• (c) at least one cholesterol lipid and/or a modified derivative thereof, and
• (d) at least one polymer-conjugated lipid and/or a modified derivative thereof.