- Tetrahydroindazole inhibitors of CDK2/cyclin complexes
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Over 50 tetrahydroindazoles were synthesized after 7-bromo-3,6,6-trimethyl-1-(pyridin-2-yl)-5,6,7,7a-tetrahydro-1H-indazol-4(3aH)-one (3) was identified as a hit compound in a high throughput screen for inhibition of CDK2 in complex with cyclin A. The activity of the most promising analogues was evaluated by inhibition of CDK2 enzyme complexes with various cyclins. Analogues 53 and 59 showed 3-fold better binding affinity for CDK2 and 2- to 10-fold improved inhibitory activity against CDK2/cyclin A1, E, and O compared to screening hit 3. The data from the enzyme and binding assays indicate that the binding of the analogues to a CDK2/cyclin complex is favored over binding to free CDK2. Computational analysis was used to predict a potential binding site at the CDK2/cyclin E1 interface.
- Lee, Jae Chul,Hong, Kwon Ho,Becker, Andreas,Tash, Joseph S.,Sch?nbrunn, Ernst,Georg, Gunda I.
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- One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis
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An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.
- Akporji, Nnamdi,Braga, Felipe C.,Gabriel, Christopher M.,Landstrom, Evan B.,Lee, Nicholas R.,Lipshutz, Bruce H.
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supporting information
(2020/09/02)
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- Metal free [4+1] and [5+1] annulation reactions to prepare heterocycles using DMF and its derivatives as one-carbon source
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1,2,4-Triazolo[3,4-a]pyridines and related heterocycles and substituted triazines were commonly discovered scaffolds in a variety of pharmaceutical and agrochemical agents. Herein, we report a highly efficient and practical method using DMF and its derivative for the [4+1] and [5+1] annulation reactions to prepare these heterocycles. This metal free reaction takes advantages of shelf stable DMF as solvent and carbon donor, imidazole chloride as a catalyst, the mild reaction condition tolerates a broad substrate range and substitutes. The prepared 3-unsubstituted 1,2,4-triazolo[3,4-a]pyridine and derivatives allow further introduction of a variety of functional group1 at 3-position.
- Liu, Lingfeng,Qiao, Chunhua,Shen, Bei,Xu, Yiwen
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supporting information
(2020/04/01)
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- PYRAZOLE DERIVATIVES AS MALT1 INHIBITORS
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Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT 1. Such compounds are represented by Formula (I) as follows: wherein R1, R2, R3, R4, R5, and G, are defined herein.
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Paragraph 0630-0632; 0635-0637
(2020/01/04)
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- COMPOUNDS AS RAS INHIBITORS AND USE THEREOF
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A compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof is described, wherein the substituents are as defined herein. Pharmaceutical compositions comprising the same and method of using the same are also described.
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Paragraph 0198
(2019/04/11)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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Paragraph 0827
(2018/04/17)
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- Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
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Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
- Beck, Hartmut,Jeske, Mario,Thede, Kai,Stoll, Friederike,Flamme, Ingo,Akbaba, Metin,Ergüden, Jens-Kerim,Karig, Gunter,Keldenich, J?rg,Oehme, Felix,Militzer, Hans-Christian,Hartung, Ingo V.,Thuss, Uwe
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supporting information
p. 988 - 1003
(2018/04/19)
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- SUBSTITUTED AMIDOPYRAZOLE INHIBITORS OF INTERLEUKIN RECEPTOR-ASSOCIATED KINASES (IRAK-4)
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This invention relates to amidopyrazole compounds that are inhibitors of Interieukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment of cellular proliferative diseases. Speifically (5-methylpyridin-2-yl)-1 H-pyrazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide derivatives are disclosed for use in the method of treating inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease and cancer.
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Page/Page column 15; 16
(2015/02/02)
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- Triazolo and imidazo dihydropyrazolopyrimidine potassium channel antagonists
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Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective Kv1.5 inhibitor with an acceptable PK and liability profile.
- Finlay, Heather J.,Jiang, Ji,Caringal, Yolanda,Kover, Alexander,Conder, Mary Lee,Xing, Dezhi,Levesque, Paul,Harper, Timothy,Hsueh, Mei Mann,Atwal, Karnail,Blanar, Michael,Wexler, Ruth,Lloyd, John
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supporting information
p. 1743 - 1747
(2013/04/10)
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- SUBSTITUTED DIPYRIDYL-DIHYDROPYRAZOLONES AND USE THEREOF
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The present application relates to novel substituted dipyridyldihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases, and for promoting wound healing.
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Page/Page column 21
(2010/04/30)
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- SUBSTITUTED DIHYDROPYRAZOLONES FOR TREATING CARDIOVASCULAR AND HEMATOLOGICAL DISEASES
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The invention relates to dihydropyrazolon-derivatives of formula (I), to methods for their production, to their use for treating and/or for preventing diseases and their use for producing medicaments for treating and/or for preventing diseases, in particular cardiovascular and haematological diseases, kidney diseases and for promoting the healing of wounds.
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Page/Page column 21
(2010/12/29)
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- METAL COMPLEX AZO DYES AND THEIR USE IN INK-JET PRINTING
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A metal complex of Formula (1) or salt thereof: wherein: each R1 independently is a substituent; R2 is H or optionally substituted alkyl; each R3 independently is carboxy, phosphato, sulfo, nitro or cyano; each G independe
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