Estrogen-related receptor alpha based protac compounds and associated methods of use
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07K-005/062
C07K-005/097
A61K-045/06
A61K-031/427
A61K-031/426
A61K-038/00
A61K-047/48
출원번호
US-0822309
(2015-08-10)
등록번호
US-10071164
(2018-09-11)
발명자
/ 주소
Crew, Andrew
Crews, Craig
Dong, Hanqing
Ko, Eunhwa
Wang, Jing
출원인 / 주소
Yale University
대리인 / 주소
Saul Ewing Arnstein & Lehr LLP
인용정보
피인용 횟수 :
0인용 특허 :
11
초록▼
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In p
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
대표청구항▼
1. A compound of chemical structure: ULM-L-PTM, wherein: the ULM is a small molecule ubiquitin ligase binding moiety that comprises a group substituted with a hydroxyl group or a functional group that can be metabolized in a subject to a hydroxyl group and that is represented by the chemical structu
1. A compound of chemical structure: ULM-L-PTM, wherein: the ULM is a small molecule ubiquitin ligase binding moiety that comprises a group substituted with a hydroxyl group or a functional group that can be metabolized in a subject to a hydroxyl group and that is represented by the chemical structure: wherein: W3 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and R9 and R10 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; or R9, R10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl;R11 is selected from the group consisting of optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, R12 is selected from the group consisting of H and optionally substituted alkyl;R13 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, and optionally substituted aralkyl;R14a and R14b are each independently selected from the group consisting of H, haloalkyl, and optionally substituted alkyl;W5 is selected from the group consisting of phenyl and a 5-10 membered heteroaryl;R15 is selected from the group consisting of: H; halogen; CN; OH; NO2; NR14aR14b; OR14a; C(═O)NR14aR14b; NR14aC(═O)R14b; S(═O)2NR14aR14b; NR14a S(═O)2R14b; optionally substituted alkyl; optionally substituted haloalkyl; optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; and optionally substituted cycloheteroalkyl;each R16 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy;o is 0, 1, 2, 3, or 4;each R18 is independently selected from the group consisting of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy and a chemical linker; andp is 0, 1, 2, 3, or 4;the L is a bond or a chemical linker that is chemically linked to the ULM and the PTM; andthe PTM is capable of binding to Estrogen Related Receptor alpha (ERRα) and is selected from the group consisting of wherein, upon binding of the EERα to the compound, the ERRα is ubiquitinated by a ubiquitin ligase; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof. 2. The compound of claim 1, wherein: L is -A1 . . . Aq-;A1 to Aq are each independently selected from the group consisting of a bond, CRL1RL2, O, S, S═O, S(═O)2, NRL3, S(═O)2NRL3, S(═O)NRL3, C(═O)NRL3, NRL3C(═O)NRL4, NRL3S(═O)2NRL4, C(═O), CRL1═CRL2, C≡C, SiRL1RL2, P(═O)RL1, P(═O)ORL1, NRL3C(═N—CN)NRL4, NRL3C(═N—CN), NRL3C(═C—NO2)NRL4, C3-11 cycloalkyl optionally substituted with 0-6 substituents selected from the group consisting of RL1 and RL2, C3-11 heterocyclyl optionally substituted with 0-6 substituents selected from the group consisting of RL1 and RL2, aryl optionally substituted with 0-6 substituents selected from the group consisting of RL1 and RL2, and heteroaryl optionally substituted with 0-6 substituents selected from the group consisting of RL1 and RL2, wherein:RL1 and RL2 each independently can be linked to other A groups to form a cycloalkyl or heterocyclyl moeity that can be further optionally substituted with 0-4 RL5 groups;RL1, RL2, RL3, RL4, and RL5 are each independently selected from the group consisting of H, C1-8 alkyl, O(C1-8 alkyl), S(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C3-11 heterocyclyl, O(C1-8 cycloalkyl), S(C1-8 cycloalkyl), NH(C1-8 cycloalkyl), N(C1-8 cycloalkyl)2, N(C1-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2(C1-8 alkyl), P(═O)(OC1-8 alkyl)(C1-8 alkyl), P(═O)(OC1-8 alkyl)2, C≡C—(C1-8 alkyl), C≡CH, CH═CH(C1-8 alkyl), C(C1-8 alkyl)═CH(C1-8 alkyl), C(C1-8 alkyl)═C(C1-8 alkyl)2, Si(OH)3, Si(C1-8 alkyl)3, Si(OH)(C1-8 alkyl)2, C(═O)(C1-8 alkyl), CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH(C1-8 alkyl), SO2N(C1-8 alkyl)2, S(═O)NH(C1-8 alkyl), S(═O)N(C1-8alkyl)2, C(═O)NH(C1-8 alkyl), C(═O)N(C1-8 alkyl)2, N(C1-8 alkyl)C(═O)NH(C1-8 alkyl), N(C1-8 alkyl)C(═O)N(C1-8 alkyl)2, NHC(═O)NH(C1-8 alkyl), NHC(═O)N(C1-8 alkyl)2, NHC(═O)NH2, N(C1-8 alkyl)SO2NH(C1-8 alkyl), N(C1-8 alkyl)SO2N(C1-8 alkyl)2, NHSO2NH(C1-8 alkyl), NHSO2N(C1-8 alkyl)2, and NHSO2NH2; andq is an integer greater than or equal to 1. 3. The compound of claim 1, wherein the ULM is represented by the chemical structure: wherein R1′ is —OH;R2′ is —NH—CH2-Aryl-HET;R3′ is selected from the group consisting of optionally substituted alkyl, —(CH)RCR3′—NH—C(═O)—R3P1, and —(CH)RCR3′—R3P2;RCR3′ is optionally substituted C1-C4 alkyl;R3P1 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted oxetane, —(CH2)nOCH3 wherein n is 1 or 2, optionally substituted phenyl, and morpholino linked to the carbonyl at the 2- or 3-position;R3P2 is selected from the group consisting of and optionally substituted aryl; HET is selected from the group consisting of optionally substituted thiazole, oxazole, isoxazole, and isothiazole;RHET is selected from the group consisting of H, halogen, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted aryl; andthe ULM group is covalently bonded to a linker group to which is attached a PTM group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 4. The compound of claim 3, wherein the ULM is selected from the group consisting of: wherein the ULM group is covalently bonded to the L group to which is attached the PTM group, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph or prodrug thereof. 5. The compound of claim 2, wherein the L is a polyethyleneglycol optionally substituted with aryl or phenyl, having from 1 to 100 ethylene glycol units. 6. The compound of claim 5, wherein the L is a polyethyleneglycol group that is optionally substituted with aryl or phenyl, having from 1 to 10 ethylene glycol units. 7. The compound of claim 3, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, polymorph or prodrug thereof. 8. A pharmaceutical composition comprising the compound of claim 1, further comprising a pharmaceutically acceptable carrier, additive or excipient, and optionally further comprising an additional bioactive agent. 9. The composition of claim 8, wherein the additional bioactive agent is an anticancer agent.
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