Lipid prodrugs of mycophenolic acid and uses thereof

A method of treating an autoimmune disease, disorder, or condition, organ transplant rejection, graft-versus-host disease, or implant rejection in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula VI:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or —C(O)R3;
• each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain;
• X is —O—, —NR—, —S—, —O(C1-6 aliphatic)—O—, —O(C1-6 aliphatic)—S—, —O(C1-6 aliphatic)—NR—, —S(C1-6 aliphatic)—O—, —S(C1-6 aliphatic)—S—, —S(C1-6 aliphatic)—NR—, —NR(C1-6 aliphatic)—O—, —NR(C1-6 aliphatic)—S—, or —NR(C1-6 aliphatic)—NR—, wherein 0-2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• Y is absent or is —C(O)—, —C(NR)—, or —C(S)—;
• L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid;
• and wherein 1 methylene unit of L is optionally replaced with -M-;
• or L is
• wherein either the right-hand side or left-hand side of L is attached to A;
• each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R4 and R5 is independently hydrogen, deuterium, halogen, —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms;
• or
• two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• -M- is a self-immolative group;
• n is 0-18;
• each m is independently 0-6;
• A is a therapeutic agent selected from mycophenolic acid or a derivative, analogue, or prodrug thereof;
• the autoimmune disease, disorder, or condition is Behcet's disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, retroperitoneal fibrosis, idiopathic thrombocytopenic purpura (ITP), scleroderma (systemic sclerosis or SSc), pemphigus vulgaris, granulomatosis with polyangiitis, immunoglobulin A nephropathy, small vessel vasculitis, retroperitoneal fibrosis, or psoriasis;
• and
• the organ transplant is selected from a skin, liver, heart, kidney, pancreas, thymus, small intestine, large intestine, uterus, a vascularized composite allograft (VCA), bone marrow, allogenic blood and marrow transplant (BMT), cornea, or lung transplant.