- BIFUNCTIONAL MOLECULES CONTAINING AN E3 UBIQUITINE LIGASE BINDING MOIETY LINKED TO A BCL6 TARGETING MOIETY
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Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00360; 00361
(2021/04/23)
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- COMPOUNDS AND METHODS FOR TARGETED DEGRADATION OF KRAS
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Bifunctional compounds, which find utility as modulators of Kirsten ras sarcoma protein (KRas or KRAS), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase and on the other end a moiety which binds KRas, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00238
(2021/10/15)
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- BIFUNCTIONAL DEGRADERS OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASES AND THERAPEUTIC USE THEREOF
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The present disclosure provides bifunctional compounds as IRAK4 degraders via ubiquitin proteasome pathway, and method for treating diseases modulated by IRAK4.
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Page/Page column 129; 131
(2021/08/27)
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- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1466; 1467
(2020/03/29)
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- ANDROGEN RECEPTOR PROTEIN DEGRADERS
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The present disclosure provides compounds represented by Formula (I): A—L—B (I), and the salts or solvates thereof, wherein A, L, and B are as defined in the specification. Compounds having Formula (I) are androgen receptor degraders useful for the treatment of cancer.
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Paragraph 0175; 0208
(2020/07/21)
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- (4-HYDROXYPYRROLIDIN-2-YL)-HYDROXAMATE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.
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Paragraph 0626
(2019/05/15)
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- (4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to bifunctional compounds of formula (I), which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands of formula (III).
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Paragraph 0659; 0684; 0835
(2019/05/15)
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- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00688-00689; 00889-00890
(2019/10/29)
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- Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer
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We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.
- Han, Xin,Wang, Chao,Qin, Chong,Xiang, Weiguo,Fernandez-Salas, Ester,Yang, Chao-Yie,Wang, Mi,Zhao, Lijie,Xu, Tianfeng,Chinnaswamy, Krishnapriya,Delproposto, James,Stuckey, Jeanne,Wang, Shaomeng
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p. 941 - 964
(2019/01/21)
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- HYDROXYL PURINE COMPOUNDS AND USE THEREOF
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Disclosed are a series of hydroxyl purine compounds and the use thereof as PDE2 or TNFα inhibitors, in particular, the compounds as shown in formula (I), or tautomers thereof or pharmaceutically acceptable salts thereof.
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Paragraph 0159; 0162; 0163
(2018/04/05)
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- TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0661
(2018/05/24)
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- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS
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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.
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Paragraph 00226
(2017/03/21)
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- AGONISTS OF GPR40
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The present invention relates to compounds that have the ability to modulate the activity of GPR40 and are there-fore useful in the treatment of GPR40 related disorders. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders related to GPR40 activity.
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Page/Page column 128-129
(2012/02/05)
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- An improved bouveault-blanc ester reduction with stabilized alkali metals
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Significantly improved Bouveault-Blanc conditions for ester reduction have been developed using sodium in silica gel (Na-SG), a free-flowing powder that can be easily handled in the open atmosphere. Primary alcohols were prepared in excellent yield from a variety of aliphatic esters under mild reaction conditions. The chemistry presented here is far safer than the classic Bouveault-Blanc reduction and is competitive with more modern hydride reduction methods.
- Bodnar, Brian S.,Vogt, Paul F.
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supporting information; experimental part
p. 2598 - 2600
(2009/08/07)
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- Substituted imidazo-[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine derivatives
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The present invention is concerned with substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives of the following formula wherein the definition of substituents is described in the claims. This class of compounds shows high affinity
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Page/Page column 36
(2008/06/13)
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- Antidiabetic agents
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The present invention provides compounds of Formula (I): wherein A, X, Q, Y, B, D, Z, and E have any of the values defined in the specification, and pharmaceutically acceptable salt thereof, that are useful as antidiabetic agents. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula I, processes for preparing compounds of Formula I, and intermediates useful for preparing compounds of Formula I.
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- Catalytic asymmetric cyclopropanation of heteroaryldiazoacetates
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Rh2(S-DOSP)4-catalyzed decomposition of heteroaryldiazoacetates in the presence of styrene results in highly diastereoselective and enantioselective cyclopropanations. Heteroaryldiazoacetates containing both electron-rich and electron-deficient heterocycles, such as thiophene, furan, pyridine, indole, oxazole, isoxazole, and benzoxazole, are effective in this chemistry. These studies broaden the range of diazo compounds containing both electron-withdrawing and electron-donating groups, which undergo highly diastereoselective cyclopropanations.
- Davies,Townsend
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p. 6595 - 6603
(2007/10/03)
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- Synthesis of Isoxazole-Containing β-Triketones of the Cyclohexane Series
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Condensation of 4-methyl-3-penten-2-one with methyl 3-methyl-5-isoxazolylacetate results in formation of 4-(3-methyl-5-isoxazolyl)-5,5-dimethylcyclohexane-1,3-dione, whose acylation with propionyl and butyryl chlorides and methyl ω-chloroformylpentanoate yields corresponding 2-acylcyclohexane-1,3-diones in overall yields of 70-75percent.Reactions of cyclohexane-1,3-diones with 3-methylisoxazole-5-carbonyl chloride yield β-triketones containing isoxazole ring in the side acyl chain.
- Rubinov, D. B.,Rubinova, I. L.,Akhrem, A. A.
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p. 386 - 389
(2007/10/03)
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