Opsin-binding ligands, compositions and methods of use

摘要

Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described.

主权项

1. A compound having the structure of Formula Iwherein A is B is —(CH2)n—, —CH═CH—, —CH2—N(R22)—, —CH2—O—, or C(O)NR22—, wherein n=2; Q is C(O)— or —S(O2)—; V is wherein b is 1 or 2 and a is 1 or 2; Y is NR22, N-Q-U, oxygen, S(O)z, N—C(S)—NR22R23, N—(C═N—CN)—NR22R23, N—(C═N—SO2CH3)—NR22R23, C═NOR22, C═N—NR22R23 or CH-Q-U, z is 0, 1 or 2; U is NR22R23, lower alkyl, haloalkyl, alkoxy, OR22 or hydrogen; X is hydrogen, alkyl, or —C═CR9; R1 and R2 are independently —CH3 or —CH2CH3; R3 is hydrogen, —CH3 or —CH2CH3; Ra and Rb, are each independently hydrogen, deuterium or —CH3; Rc and Rd, are each independently hydrogen, alkoxy, lower alkyl or alkenyl; R9 is hydrogen, or —CH3; R22 and R23 are each independently hydrogen or lower alkyl; R24 and R25 are each independently hydrogen or —CH3; R26 is NR22R23 or alkoxy; or R1 and R2 taken together or Ra and Rb taken together along with the carbon to which they are attached are cyclopropyl; or R24 and R25 taken together along with the two carbons to which they are attached are cyclopropyl; or R24 and R25 taken together is oxo; including pharmaceutically acceptable salts, solvates and hydrates thereof.