83255-86-1Relevant articles and documents
Revisiting Pyrazolo[3,4- d]pyrimidine Nucleosides as Anti- Trypanosoma cruzi and Antileishmanial Agents
Bouton, Jakob,Ferreira De Almeida Fiuza, Ludmila,Cardoso Santos, Camila,Mazzarella, Maria Angela,De Nazaré Correia Soeiro, Maria,Maes, Louis,Karalic, Izet,Caljon, Guy,Van Calenbergh, Serge
, p. 4206 - 4238 (2021/05/04)
Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo[3,4-d]pyrimidine nucleosides with 3′- and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.
CYCLOALKYLIDENE CARBOXYLIC ACIDS AND DERIVATIVES AS BTK INHIBITORS
-
Page/Page column 133, (2021/03/05)
The present invention relates to novel cycloalkylidene carboxylic acids and derivatives thereof useful as Bruton tyrosine kinase (BTK) inhibitors. The present disclosure also relates to processes for their preparation, pharmaceutical compositions containing one or more such compounds, and to the use of such compounds and pharmaceutical compositions for the treatment of disorders involving mediation of BTK in humans (Formula I).
Hydroxamic acid derivative containing pyrazolopyrimidine and preparation method and application thereof
-
Paragraph 0093; 0112; 0113, (2020/09/23)
The invention provides a hydroxamic acid derivative containing pyrazolopyrimidine and a preparation method and application thereof. The hydroxamic acid derivative containing pyrazolopyrimidine has a structure as shown in a formula I, in the formula I, X is selected from oxygen, acylamino and methylene; Y is selected from methine, substituted methine and nitrogen; Z is selected from methylene, benzyl, piperidyl, pyridyl, pyrrolidinyl, pyrimidinyl, imidazolyl and oxadiazolyl; the piperidyl is shown in the specification, or the carbon end of the piperidyl is connected with the nitrogen end of pyrazole; R is selected from hydrogen, halogen, nitro, amino, substituted amino, cyano, methyl, methoxy and trifluoromethyl; n is any integer from 0 to 7; and when X is oxygen, Y is methine, and Z is R and H, n is not 1. The compound shown in the formula I has BTK and/or HDAC inhibitory activity and has a good growth inhibition effect on lymphoma, especially mantle cell lymphoma.
Design and synthesis of novel 1-substituted 3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs as selective BTK inhibitors for the treatment of mantle cell lymphoma
Ran, Fansheng,Liu, Yang,Yu, Shengping,Guo, Kaiwen,Tang, Wendi,Chen, Xin,Zhao, Guisen
, (2019/11/11)
Ibrutinib (IBN), a first-in-class BTK-inhibitor, was approved by the FDA for the treatment of mantle cell lymphoma (MCL). Although IBN shows excellent performance as an anti-lymphoma agent, it has some undesirable side effects due to its off-target activities. Our studies yielded a novel series of 3-(6-phenoxypyridin-3-yl)-4-amine-1H-pyrazolo[3,4-d]pyrimidine derivatives capable of potent inhibition of Bruton's tyrosine kinase (BTK). Notably, compound 13e explained potent BTK inhibitory activity and could completely inhibit the phosphorylation of BTK and PLCγ2 in Z138 cells at low micromolar concentration. Compared with IBN, compound 13e improved anti-proliferative activities 3–40 folds in MCL cell lines with IC50 values lower than 1 μM. Low micromolar doses of 13e could induce strong cell apoptosis in Jeko-1 and Z138 cells. In addition, compound 13e showed greater BTK selectivity and higher stability in human liver microsomes than IBN and potential safety improvement for the treatment of MCL.
1-substituted benzyl pyrazolopyrimidine derivative, preparation method and applications thereof
-
Paragraph 0059; 0083-0084, (2020/05/01)
The invention discloses a 1-substituted benzyl pyrazolopyrimidine derivative, a preparation method and applications thereof, wherein the structure of the 1-substituted benzyl pyrazolopyrimidine derivative is shown as a general formula I, a general formula II or a general formula III, R1 is selected from hydrogen, C1-6 linear chain or branched chain alkyl and trihalomethyl, R2 is selected from hydrogen, halogen, nitro, C1-6 linear chain or branched chain alkyl, trifluoromethyl and cyano, R3 is selected from amino, and R4 is selected from substituted amide group. The compound has a certain BTK inhibition activity.
4 - Phenoxyphenyl pyrazolo pyrimidine amide derivatives and preparation method and application thereof (by machine translation)
-
Paragraph 0068; 0115; 0116, (2020/06/17)
The invention provides a preparation method and application of 4 -phenoxyphenyl pyrazolo pyrimidine amide derivatives. The compound has the structure shown in the formula (I). Wherein X and Y are two linking groups, X is selected from benzyl, substituted benzyl, piperidinyl and C. 1 -6 Straight-chain or branched alkyl; Y is-(CH)2 )n - N is any integer selected from 0-4; R is selected from hydroxyl, hydroxyl and phthalo; the structure of formula (I) contains its racemates and stereoisomers. The compound has BTK K K K/HDAC double-target inhibition effect and growth inhibitory activity on T-cell leukemia cells and cell lymphoma cells, and is used for preparing antitumor drugs. (by machine translation)
Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors
Ouvry, Gilles,Clary, Laurence,Tomas, Lo?c,Aurelly, Michèle,Bonnary, Laetitia,Borde, Emilie,Bouix-Peter, Claire,Chantalat, Laurent,Defoin-Platel, Claire,Deret, Sophie,Forissier, Mathieu,Harris, Craig S.,Isabet, Tatiana,Lamy, Laurent,Luzy, Anne-Pascale,Pascau, Jonathan,Soulet, Catherine,Taddei, Alessandro,Taquet, Nathalie,Thoreau, Etienne,Varvier, Emeric,Vial, Emmanuel,Hennequin, Laurent F.
supporting information, p. 1561 - 1567 (2019/10/14)
Minor structural modifications - sometimes single atom changes - can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.
Heteroaryl compound having pharmaceutical activity
-
Paragraph 0134; 0135; 0136, (2019/01/10)
The present invention provides a class of new compounds having Btk selective inhibition activity, wherein the new compounds have good metabolic stability and the like.
1, 3-di-substituted-4-amino pyrazolopyrimidine compound, preparation method thereof and application of compound
-
Paragraph 0103; 0108-0109, (2019/03/08)
The invention relates to a 1, 3-di-substituted-4-amino pyrazolopyrimidine compound, a preparation method thereof and an application of the compound. The compound is provided with a structure as shownin a formula I. The invention further relates to a preparation method of the compound with the structure as shown in the formula I and a medicine composition. The invention further provides an application of the compound and pharmaceutically acceptable salt thereof to preparation of MCL (mantle cell lymphoma) resistance medicines.
Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold
Yin, Yuan,Chen, Cheng-Juan,Yu, Ru-Nan,Shu, Lei,Zhang, Tian-Tai,Zhang, Da-Yong
, p. 1562 - 1576 (2019/03/06)
Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.
