Activators of class I histone deacetlyases (HDACs) and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-405/12
C07D-409/12
C07D-411/12
C07C-219/28
C07D-307/52
C07D-487/04
C07C-217/58
C07D-307/40
출원번호
US-0834587
(2015-08-25)
등록번호
US-10167277
(2019-01-01)
발명자
/ 주소
Tsai, Li-Huei
Pan, Ling
Haggarty, Stephen J.
Patnaik, Debasis
출원인 / 주소
Massachusetts Institute of Technology
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
0인용 특허 :
60
초록▼
The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The pr
The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D).
대표청구항▼
1. A compound of Formula (B): or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein: each of XB1, XB3, and XB4 is independently oxygen, sulfur, NRB4a, or C(RB4b)2, wherein RB4a is hydrogen, a nitrogen protecting group, or optionally substituted C1-6 alkyl, and e
1. A compound of Formula (B): or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein: each of XB1, XB3, and XB4 is independently oxygen, sulfur, NRB4a, or C(RB4b)2, wherein RB4a is hydrogen, a nitrogen protecting group, or optionally substituted C1-6 alkyl, and each occurrence of RB4b is independently hydrogen, halogen, or optionally substituted C1-6 alkyl, or two RB4b groups are joined to form an optionally substituted, carbocyclic or heterocyclic ring;XB2 is nitrogen or CRB2a, wherein RB2a is hydrogen, halogen, or optionally substituted C1-6 alkyl;each instance of RB1 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORB1a, —N(RB1a)2, —SRB1a, —C(═O)RB1a, —C(═O)ORB1a, —C(═O)SRB1a, —C(═O)N(RB1b)2, —OC(═O)RB1a, OC(═O)ORB1a, —OC(═O)SRB1a, —OC(═O)N(RB1b)2, —NRB1bC(═O)RB1b, —NRB1bC(═O)ORB1a, —NRB1bC(═O)SRB1a, —NRB1bC(═O)N(RB1b)2, —SC(═O)RB1a, —SC(═O)ORB1a, —SC(═O)SRB1aSC(═O)N(RB1b)2, —C(═NRB1b)RB1a, —C(═NRB1b)ORB1a, —C(═NRB1b)SRB1a, —C(═NRB1b)N(RB1b)2, —OC(═NRBb)RB1a, —OC(═NRB1b)ORB1a, —OC(═NRB1b)SRB1a, —OC(═NRB1b)N(RB1b)2, —NRB1bC(═NRB1b)RB1b, —NRB1bC(═NRB1b)ORB1a, —NRB1bC(═NRB1b)SRB1a, NRB1bC(═NRB1b)N(RB1b)2, —SC(═NRB1b)RB1a, —SC(═NRB1b)ORB1a, —SC(═NRB1b)SRB1a SC(═NRB1b)N(RB1b)2, —C(═S)RB1a, —C(═S)ORB1a, —C(═S)SRB1a, —C(═S)N(RB1b)2, —OC(═S)RB1a, OC(═S)ORB1a, —OC(═S)SRB1a, —OC(═S)N(RB1b)2, —NRB1bC(═S)RB1b, —NRB1bC(═S)ORB1a, —NRB1bC(═S)SRB1a, —NRB1bC(═S)N(RB1b)2, —SC(═S)RB1a, —SC(═S)ORB1a, —SC(═S)SRB1a, SC(═S)N(RB1b)2, —S(═O)RB1a, —SO2RB1a, —NRB1bSO2RB1a, —SO2N(RB1b)2, —CN, —SCN, or —NO2, wherein each occurrence of RB1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of RB1b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two RB1b groups are joined to form an optionally substituted heterocyclic ring;each of RB2, RB3, RB4, and RB5 is independently hydrogen, halogen, or optionally substituted C1-6 alkyl;RB6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —N(RB6b)2, or —SRB6a, wherein RB6a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of RB6b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two RB6b groups are joined to form an optionally substituted heterocyclic ring; andp is 0, 1, 2, 3, or 4;provided that the compound is not of the formula: 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein XB1 is NH, and XB2 is nitrogen. 3. The compound of claim 2, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 4. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein XB3 is sulfur. 5. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 6. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein XB4 is oxygen. 7. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 8. The compound of claim 7, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 9. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein RB2 and RB3 are hydrogen. 10. The compound of claim 9, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein RB4 and RB5 are optionally substituted C1-6 alkyl. 11. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 12. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 13. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 14. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein RB6 is unsubstituted ethyl. 15. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 16. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. 17. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. 18. A method for therapeutically treating a neurological disorder in a subject, the method comprising administering to a subject in need of therapeutic treatment for a neurological disorder a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein the neurological disorder is Alzheimer's disease or frontal temporal dementia. 19. The method of claim 18, wherein the neurological disorder is Alzheimer's disease. 20. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein p is 0. 21. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein RB6 is optionally substituted C1-6 alkyl. 22. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein RB6 is unsubstituted C1-6 alkyl. 23. The method of claim 18, wherein the neurological disorder is frontal temporal dementia. 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof. 25. The pharmaceutical composition of claim 17 comprising the compound, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 26. The method of claim 18 comprising administering to a subject in need of therapeutic treatment for Alzheimer's disease a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof. 27. The method of claim 18 comprising administering to a subject in need of therapeutic treatment for frontal temporal dementia a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
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