Deuterated compounds useful for treating neurodegenerative diseases

摘要

The present application is related to deuterated compounds which are novel neurotrophin mimetics. The application also discloses the treatment of disorders involving degradation or dysfunction of cells expressing p75 in a mammal by administering an effective amount of such deuterated compounds.

主权项

1. A compound of Formula I, II, IIIA, IIIB, or IV,
wherein Formula I has the structure: or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
each of R1, R1′, R2, R2′, R3, and R4 is independently hydrogen, deuterium, optionally substituted alkyl, or optionally substituted deuterated-alkyl; or R2 and R2′ taken together form ═O, ═S, ═CH2, ═CHD, or ═CD2;R4′ is hydrogen or deuterium;R5 is heterocycloalkyl or deuterated-heterocycloalkyl;X is CH2, CDH, CD2, NH, O or S;n is 0, 1, 2, 3, 4, or 5; andm is 1 or 2;with the proviso that the compound of Formula I comprises at least one carbon-bound deuterium with at least 45% deuterium incorporation; wherein Formula II has the structure: or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
p is 0, 1, 2, 3, 4, 5, or 6;A1 is hydrogen or deuterium;each of Y, V, and W is independently CH2, CDH, CD2, NH, O, or S;each of R10 and R11 is independently hydrogen, deuterium, optionally substituted alkyl, or optionally substituted deuterated-alkyl;each of R12 and R13 is independently hydrogen, —NRaRb, —OH, —C(═O)ORa, —C(═O)NHRa, —NHC(═O)Ra, —NHS(═O)2Ra, optionally substituted alkyl, or optionally substituted deuterated-alkyl;each of Ra and Rb is independently hydrogen, optionally substituted alkyl, or optionally substituted deuterated-alkyl; andZ is an optionally substituted heterocycloalkyl, an optionally substituted deuterated-heterocycloalkyl, an optionally substituted heteroaryl, an optionally substituted deuterated-heteroaryl, or L1 is a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted deuterated-alkylene, optionally substituted cycloalkylene, optionally substituted deuterated-cycloalkylene, optionally substituted alkenylene, optionally substituted deuterated-alkenylene, optionally substituted arylene, optionally substituted deuterated-arylene, optionally substituted cycloalkenylene, and optionally substituted deuterated-cycloalkenylene;E is selected from the group consisting of:  pyrrolidinyl, and deuterated-pyrrolidinyl;each of E1, E2, E4, E5, and E6 independently is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted deuterated-alkyl, optionally substituted cycloalkyl, optionally substituted deuterated-cycloalkyl, optionally substituted aryl, optionally substituted deuterated-aryl, optionally substituted arylalkyl, and optionally substituted deuterated-arylalkyl;each E3 is independently selected from the group consisting of hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted deuterated-alkyl, optionally substituted aryl, optionally substituted deuterated-aryl, acyloxyl, alkoxyl, and deuterated-alkoxyl;with the proviso that the compound of Formula II comprises at least one carbon-bound deuterium with at least 45% deuterium incorporation; wherein Formula IIIA has the structure: or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
X is CH2, CDH, CD2, NH, O or S;each of A1, A2, A3, and A4 is independently hydrogen or deuterium;s is 0, 1, 2, 3 or 4;each of R19, R19′, R20, R20′, R21, R21′, R22, R22′ and R24 is independently hydrogen, deuterium, optionally substituted alkyl, or optionally substituted deuterated-alkyl; orR20 and R20′ taken together form ═O, ═S, ═CH2, ═CDH, or ═CD2; orR20 and R21 taken together with the atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted deuterated-cycloalkyl; or R20 and R21 taken together with the atoms to which they are attached form an optionally substituted aryl or optionally substituted deuterated-aryl; orR19 and R20 taken together with the atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted deuterated-cycloalkyl; or R19 and R20 taken together with the atoms to which they are attached form an optionally substituted aryl or optionally substituted deuterated-aryl; andR23 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl or optionally substituted deuterated-aryl; or R22 and R23 taken together with the atoms to which they are attached form an optionally substituted heterocycloalkyl or optionally substituted deuterated-heterocycloalkyl;with the proviso that the compound of Formula IIIA comprises at least one carbon-bound deuterium with at least 45% deuterium incorporation; wherein Formula IIIB has the structure: or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
X is CH2, CDH, CD2, NH, O or S;each of A1, A2, A3, A4, and R25a is independently hydrogen or deuterium;s is an integer from 1 to 8;each of R19, R19′, R26, and R27 is independently hydrogen, deuterium, optionally substituted alkyl, or optionally substituted deuterated-alkyl;R24 is hydrogen, optionally substituted alkyl, or optionally substituted deuterated-alkyl;R25b is hydrogen, deuterium, halo, hydroxyl, alkoxy, deuterated-alkoxy, optionally substituted alkyl, optionally substituted deuterated-alkyl, optionally substituted cycloalkyl, optionally substituted deuterated-cycloalkyl, optionally substituted aryl, or optionally substituted deuterated-aryl;with the proviso that the compound of Formula IIIB comprises at least one carbon-bound deuterium with at least 45% deuterium incorporation; and wherein Formula IV has the structure: or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
p is 1, 2, 3, 4, 5, or 6;each of Y, V, and W is independently CH2, CDH, CD2, NH, O or S;A1 is hydrogen or deuterium;each of R30, R31, R32, R32′, R33, R34, R34′, R35, R35′, R36, and R36′ is independently hydrogen, deuterium, optionally substituted alkyl, or optionally substituted deuterium-alkyl; orR34 and R36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic ring or optionally substituted deuterated-carbocyclic ring;E is —CHRcRd, —CDRcRd, —NRcRd, —ORc, or —SRC; andeach of Rc and Rd is independently hydrogen, deuterium, optionally substituted deuterated-alkyl, or optionally substituted alkyl; or Rc and Rd taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring or optionally substituted deuterated-heterocyclic ring; or Rc and Rd taken together with the carbon atom to which they are attached form an optionally substituted carbocyclic ring or optionally substituted deuterated-carbocyclic ring;with the proviso that the compound of Formula IV comprises at least one carbon-bound deuterium with at least 45% deuterium incorporation.