| 主权项 |
1. A pharmaceutical composition comprising: a retromer-stabilizing agent and a pharmaceutically acceptable carrier,
wherein the retromer-stabilizing agent specifically binds to a conformational-specific target corresponding to an interface formed by at least two components of the retromer, wherein said at least two components includes VPS35; andwherein the retromer-stabilizing agent is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted bivalent 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted bivalent 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0-5; each Ra is independently —R, —CN, —OR, a suitably protected hydroxyl group, —SR, a suitably protected thiol group, —S(O)R, —SO2R, —OSO2R, —N(R)2, a suitably protected amino group, —N(R)C(O)R, —N(R)C(O)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —C(O)OR, —OC(O)R, —C(O)N(R)2, —OC(O)N(R)2; each R is independently deuterium, hydrogen, halogen, an optionally substituted C1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or wherein: two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form an optionally substituted 3-8 membered, saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or wherein: two R on the same carbon are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated spirocycle having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and L1 and L2 are each independently a valence bond or a bivalent optionally substituted C1-10 alkylene chain wherein one, two, or three methylene units are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —C(═NR)— —OC(O)—, —C(O)O—, —OC(O)O—, —S(O)—, —S(O)2—, —OSO2O—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)NR—, —N(R)C(O)NR—, and wherein L1 and L2 are each independently optionally substituted with 1-6 R groups; and R1 and R2 are each independently selected from —R, —CN, —OR, a suitably protected hydroxyl group, —SR, a suitably protected thiol group, —S(O)R, —SO2R, —OSO2R, —N(R)2, a suitably protected amino group, —N(R)C(O)R, —N(R)C(O)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —C(O)OR, —OC(O)R, —C(O)N(R)2, —OC(O)N(R)2, —SC(═NR)N(R)2, or an optionally substituted C1-20 aliphatic group. |
