The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structures:

##STR00001##

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structures:

##STR00001##

The present invention relates to novel spirobicyclic analogues of Formula (I) ##STR00001##
wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention

##STR00001##

provides lipids having the following structure XXXIII, wherein:
R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention

##STR00001##

provides lipids having the following structure XXXIII, wherein:
R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

Processes for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3 -hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one(13, RX-3117) and its intermediates are described. ##STR00001##

Processes for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3 -hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one(13, RX-3117) and its intermediates are described. ##STR00001##

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure:

##STR00001##

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure:

##STR00001##

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

##STR00001##

wherein R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30alkyl, optionally substituted C.sub.10-C.sub.30alkenyl, optionally substituted C.sub.10-C.sub.30alkynyl, optionally substituted C.sub.10-C.sub.30acyl, or -linker-ligand; R3 is H, optionally substituted C.sub.1-C.sub.10alkyl, optionally substituted C.sub.2-C.sub.10alkenyl, optionally substituted C.sub.2-C.sub.10alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O).sub.2N(Q), S(O).sub.2, N(Q)S(O).sub.2, SS, ON, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, -aminoalkyl, -(substituted)aminoalky, -phosphoalkyl or -thiophosphoalkyl.