- Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors
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Tropomyosin receptor kinases (TRKA, TRKB, TRKC) are transmembrane receptor tyrosine kinases, which are respectively encoded by NTRK1, NTRK2, and NTRK3 genes. Herein, we reported the design, synthesis and Structure-Activity Relationship (SAR) investigation of a series of macrocyclic derivatives as new TRK inhibitors. Among these compounds, compound 9e exhibited strong kinase inhibitory activity (TRKG595R IC50 = 13.1 nM) and significant antiproliferative activity in the Ba/F3-LMNA-NTRK1 cell line (IC50 = 0.080 μM) and compound 9e has shown a better inhibitory effect (IC50 = 0.646 μM) than control drug LOXO-101 in Ba/F3-LMNA-NTRK1-G595R cell line. These results indicate that compound 9e is a potential TRK inhibitor for further investigation.
- Cai, Shi,Guan, Dezhong,Li, Jinruo,Li, Pei,Xu, Lin,Zhang, Huibin,Zhao, Tong,Zhou, Jinpei
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supporting information
(2021/11/11)
-
- Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor
-
Casein kinase 2 (CK2) is a constitutively expressed serine/threonine kinase that has a large diversity of cellular substrates. Thus, CK2 has been associated with a plethora of regulatory functions and dysregulation of CK2 has been linked to disease development in particular to cancer. The broad implications in disease pathology makes CK2 an attractive target. To date, the most advanced CK2 inhibitor is silmitasertib, which has been investigated in clinical trials for treatment of various cancers, albeit several off-targets for silmitasertib have been described. To ascertain the role of CK2 inhibition in cancer, other disease and normal physiology the development of a selective CK2 inhibitor would be highly desirable. In this study we explored the pyrazolo [1,5-a]pyrimidine hinge-binding moiety for the development of selective CK2 inhibitors. Optimization of this scaffold, which included macrocyclization, led to IC20 (31) a compound that displayed high in vitro potency for CK2 (KD = 12 nM) and exclusive selectivity for CK2. X-ray analysis revealed a canonical type-I binding mode for IC20 (31). However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency but limits the cellular activity of IC20 (31) and the cellular IC50 dropped to the low micromolar range. In summary, IC20 (31) represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.
- Berger, Benedict-Tilman,Celik, Ibrahim Ethem,Greco, Francesco Aleksy,Hanke, Thomas,Knapp, Stefan,Kr?mer, Andreas,Kurz, Christian Georg,Tjaden, Amelie
-
-
- Preparation and application of protein receptor kinase inhibitor
-
The invention provides a preparation method of a protein receptor kinase inhibitor. Specifically, the invention discloses a compound as shown in a formula I or a stereoisomer or racemate or pharmaceutically acceptable salt thereof, and the definition of each group is as shown in the specification. The invention also discloses application of the compound as a TRK kinase inhibitor.
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Paragraph 0121-0122; 0132-0134
(2020/05/02)
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- Method for efficiently synthesizing 5-chloropyrazolo[1,5-a]pyrimidine
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The invention discloses a method for efficiently synthesizing 5-chloropyrazolo[1,5-a]pyrimidine. The synthesis route comprises: carrying out a reaction on a compound A and a compound B to obtain a compound C, and carrying out a reaction on the compound C and phosphorus oxychloride to obtain a compound D, ie., 5-chloropyrazolo[1,5-a]pyrimidine, wherein the reaction formulas A, B, C and D are defined in the specification. According to the present invention, the method has characteristics of mild synthesis condition, low influence of post-treatment on environment, simple process, inexpensive andeasily-available raw material, simple operation and wide industrial application prospect and market value, and is suitable for industrial large-scale production.
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Paragraph 0026; 0028
(2019/02/04)
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- COMPOUNDS AND THEIR METHODS OF USE
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The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
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Page/Page column 84
(2018/06/12)
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- Heterocyclic Compound
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The present invention provide a compound having an orexin receptor antagonistic activity, which is expected to be useful as medicaments such as agents for the prophylaxis or treatment of sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
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Paragraph 1820; 1821
(2018/06/15)
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- Pyrazolo [1, 5 - a] pyrimidine compounds and their preparation method and medical use
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The invention relates to a pyrazolo[1,5-a]miazine compound and its preparation method and medical use. The invention relates to the preparation method of the pyrazolo[1,5-a]miazine compound shown in the general formula (I) and its salt, a pharmaceutical c
- -
-
Paragraph 0095; 0097; 0098
(2017/08/02)
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- Concise and Efficient Access to 5,7-Disubstituted Pyrazolo[1,5-a]pyrimidines by Pd-Catalyzed Sequential Arylation, Alkynylation and SNAr Reaction
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A simple and efficient method for synthesis of 5,7-disubstituted pyrazolo[1,5-a]pyrimidines is reported. The synthetic route involved first a one-pot two-step synthesis of 7-substituted pyrazolo[1,5-a]pyrimidin-5-ones from the reaction of 3-aminopyrazole 1 with activated alkynes. These compounds were used as key intermediates to access, with excellent yields, a library of new 5,7-disubstituted pyrazolo[1,5-a]pyrimidines, which are known for their wide range of biological activities, through C–O bond activation with PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate) as an activator reagent.
- Jismy, Badr,Guillaumet, Gérald,Allouchi, Hassan,Akssira, Mohamed,Abarbri, Mohamed
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p. 6168 - 6178
(2017/11/15)
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- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
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Paragraph 0350; 0352; 0353
(2016/07/05)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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Paragraph 00641
(2014/10/04)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Paragraph 00679-00680
(2013/03/26)
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- AMIDO-BENZYL SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment of an NAMPT-mediated disease or condition in a subject, selected from solid or liquid tumor, rheumat
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Paragraph 0209
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 142
(2013/09/12)
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- PYRIDINYL AND PYRIMIDINYL SULFOXIDE AND SULFONE DERIVATIVES
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Disclosed are certain pyridinyl and pyrimidinyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds and methods of treatment using such compounds.
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Page/Page column 93
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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Page/Page column 68
(2013/09/12)
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- ALKYL-AND DI-SUBSTITUTED AMIDO-BENZYL SULFONAMIDE DERIVATIVES
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The present invention relates to certain alkyl- and di-substituted amido-benzyl sulfonamide compounds, pharmaceutical compositions comprising such compounds, and to methods of treatment of NAMPT-mediated disorders, such as diabetes, rheumatoid arthritis,
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Paragraph 0217
(2013/09/12)
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- PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
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The invention provides JAK kinase inhibitors of Formula Ia, enantiomers, diasteriomers or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and Z are defined herein, a pharmaceutical composition that includes a compound of Formula Ia and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a JAK kinase activity in a patient.
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Page/Page column 33
(2012/02/03)
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- Discovery of potent and selective pyrazolopyrimidine Janus kinase 2 inhibitors
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The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the p
- Hanan, Emily J.,Van Abbema, Anne,Barrett, Kathy,Blair, Wade S.,Blaney, Jeff,Chang, Christine,Eigenbrot, Charles,Flynn, Sean,Gibbons, Paul,Hurley, Christopher A.,Kenny, Jane R.,Kulagowski, Janusz,Lee, Leslie,Magnuson, Steven R.,Morris, Claire,Murray, Jeremy,Pastor, Richard M.,Rawson, Tom,Siu, Michael,Ultsch, Mark,Zhou, Aihe,Sampath, Deepak,Lyssikatos, Joseph P.
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p. 10090 - 10107
(2013/01/16)
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- Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration
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The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
- Bowers, Simeon,Truong, Anh P.,Jeffrey Neitz,Hom, Roy K.,Sealy, Jennifer M.,Probst, Gary D.,Quincy, David,Peterson, Brian,Chan, Wayman,Galemmo Jr., Robert A.,Konradi, Andrei W.,Sham, Hing L.,Tóth, Gergely,Pan, Hu,Lin, May,Yao, Nanhua,Artis, Dean R.,Zhang, Heather,Chen, Linda,Dryer, Mark,Samant, Bhushan,Zmolek, Wes,Wong, Karina,Lorentzen, Colin,Goldbach, Erich,Tonn, George,Quinn, Kevin P.,Sauer, John-Michael,Wright, Sarah,Powell, Kyle,Ruslim, Lany,Ren, Zhao,Bard, Frédérique,Yednock, Ted A.,Griswold-Prenner, Irene
-
scheme or table
p. 5521 - 5527
(2011/10/09)
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- SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS mTOR INHIBITORS
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Compounds of Formula I: and salts thereof in which R1, R2, R2a, R3, n, X and ring B have the meanings given in the specification, are inhibitors of mTOR and are useful in the treatment of diseases which are sensitive to inhibition of mTOR, such as cancers.
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Page/Page column 42
(2011/04/14)
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- PYRAZOLOPYRIMIDINES, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICINE
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The invention relates to pyrazolopyrimidine derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are mGluR5 modulators and are ther
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Page/Page column 68
(2010/06/20)
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- INHIBITORS OF JUN N-TERMINAL KINASE
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The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula (I): or a salt or solvate thereof, wherein ring A, Ca, Cb, Z, R5, W and Cy are defined herein. The disclosure further provides pharmaceutical compositions including the compounds of the present disclosure and methods of making and using the compounds and compositions of the present disclosure, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.
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Page/Page column 141
(2010/08/18)
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- PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
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The invention provides JAK kinase inhibitors of Formula Ia, enantiomers, diasteriomers or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and Z are defined herein, a pharmaceutical composition that includes a compound of Formula Ia and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a JAK kinase activity in a patient. Ia
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Page/Page column 42; 75
(2010/05/14)
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- Synthesis of pyrazolo[1,5-α]pyrimidinone regioisomers
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(Chemical Equation Presented) This work describes two distinct routes to prepare pyrazolo-[1,5-α]pyrimidin-7-ones and two distinct routes to prepare pyrazolo[1,5-α]pyrimidin-5-ones. Use of 1,3-dimethyluracil as the electrophile in the preparation of the p
- Gavrin, Lori K.,Lee, Arthur,Provencher, Brian A.,Massefski, Walter W.,Huhn, Stephen D.,Ciszewski, Gregory M.,Cole, Derek C.,McKew, John C.
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p. 1043 - 1046
(2008/02/04)
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- PHENYLALANINE DERIVATIVES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to phenylalanine derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
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