cas 761446-44-0, 1-Methyl-4-pyrazole boronic acid pinacol ester

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Efficient salt-induced kinase inhibitor and preparation method thereof
The invention discloses an efficient salt-induced kinase inhibitor and a preparation method thereof, and the efficient salt-induced kinase inhibitor is characterized by comprising substances of a chemical formula in the invention. The salt-induced kinase inhibitor with excellent performance has high inhibitory activity for in-vitro experiments and also has high cell inhibitory activity.
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(2021/09/04)

AMINOPYRAZINE COMPOUNDS AS HPK1 INHIBITOR AND THE USE THEREOF
Disclosed herein is an aminopyrazine compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.
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Page/Page column 94

(2021/02/26)

IMPROVED METHOD FOR THE MANUFACTURE OF 3-[(1S)-1-IMIDAZO[1,2-A]PYRIDIN-6-YLETHYL]-5-(1-METHYLPYRAZOL-4-YL)TRIAZOLO[4,5-B]PYRAZINE AND POLYMORPHIC FORMS THEREOF
This specification generally relates to an improved method for the manufacture of 3-[(lS)-l -imidazo[ 1,2-a]pyridin-6-ylethyl]-5-(l-methylpyrazol-4-yl)triazolo[4,5- bjpyrazine (I), or pharmaceutically acceptable salts thereof; polymorphic forms thereof; and intermediates useful in the manufacture of such compounds and salts thereof. Formula (I).
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Page/Page column 28-29

(2020/05/07)

Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms
Herein, we describe the design, synthesis, and structure-activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that 18e was a preferred compound, with IC50 values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, 18e was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, 18e exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, 18e showed an excellent bioavailability (F = 58%), a suitable half-life time (T1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.
Yang, Tao,Hu, Mengshi,Qi, Wenyan,Yang, Zhuang,Tang, Minghai,He, Jun,Chen, Yong,Bai, Peng,Yuan, Xue,Zhang, Chufeng,Liu, Kongjun,Lu, Yulin,Xiang, Mingli,Chen, Lijuan
p. 10305 - 10320
(2019/11/19)

C-H Borylation Catalysts that Distinguish between Similarly Sized Substituents like Fluorine and Hydrogen
By modifying ligand steric and electronic profiles it is possible to C-H borylate ortho or meta to substituents in aromatic and heteroaromatic compounds, where steric differences between accessible C-H sites are small. Dramatic effects on selectivities between reactions using B2pin2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for the first time. Judicious ligand and borane combinations give highly regioselective C-H borylations on substrates where typical borylation protocols afford poor selectivities.
Miller, Susanne L.,Chotana, Ghayoor A.,Fritz, Jonathan A.,Chattopadhyay, Buddhadeb,Maleczka, Robert E.,Smith, Milton R.
supporting information
p. 6388 - 6392
(2019/08/26)

Method for preparing aryl boronate at room temperature
The invention discloses a method for preparing aryl boronate represented by a formula I at a room temperature. The method comprises: carrying out a reaction on a diboron compound represented by a formula II and an aryl halide in an organic solvent for 0.5-8 h at a room temperature under the actions of an alkali, a chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) catalyst and a 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl ligand, and carrying out post-treatment to obtain the corresponding aryl boronate. According to the present invention, the method has characteristics of mild reaction conditions, simple operation, wide application range, good compatibility with various functional groups on aryl, high efficiency and economy, can achieve high yield of aryl borate under normal pressure and normal pressure conditions, and is suitable for large-scale preparation of aryl borate. The formulas I and II are defined in the specification, wherein R' represents any one selected from phenyl with substituent, pyridyl, thienyl, indyl, pyrazolyl and naphthyl.
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Paragraph 0020-0022; 0049-0051; 0081-0083

(2019/05/11)

Preparation method of pyrazol compound
The invention belongs to the technical field of organic synthesis, particularly relates to a preparation method of a pyrazol compound, in more particular to a preparation method of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentaborane-2-yl)-1H-pyrazol. The preparation method of the 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentaborane-2-yl)-1H-pyrazol comprises the following steps of by taking tetrahydrofuran and 1-methyl-4-bromo-pyrazol as raw materials, and performing reaction with triisopropyl borate and pinacol to prepare the 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentaborane-2-yl)-1H-pyrazol. The preparation method is liable in operation of the whole reaction process, available in raw material, low in cost and high in purity and yield of products.
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Paragraph 0037-0043; 0046-0051; 0053-0058; 0080-0086

(2019/01/14)

Preparation and application of novel purine analogue JAK (janus kinase) inhibitor
The invention provides medicine for preventing, treating and/or relieving autoimmunity diseases such as Psoriasis, rheumatoid arthritis, inflammatory enteritis diseases, sjogren's syndrome, behcet's diseases, multiple sclerosis and systemic lupus erythematosus. The medicine has excellent JAK inhibitory activity. The invention also provides a medically acceptable composition containing the compoundand a method for preparing the compound.
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Paragraph 0155; 0156; 0157; 0159

(2018/09/21)

Room-temperature borylation and one-pot two-step borylation/Suzuki-Miyaura cross-coupling reaction of aryl chlorides
A highly efficient room-temperature borylation strategy of aryl chlorides is described. Utilizing Buchwald's second-generation preformed catalyst, boronate esters were obtained for a wide range of substrates in high yield. The method was also applied to Suzuki-Miyaura cross-coupling reaction in a one-pot two-step sequential manner, providing a facile and convenient access to the direct synthesis of biaryl compounds from aryl chlorides.
Ji, Hong,Wu, Li-Yang,Cai, Jiang-Hong,Li, Guo-Rong,Gan, Na-Na,Wang, Zhao-Hua
p. 13643 - 13648
(2018/04/24)

Alkenyl compound and its method and use thereof
The invention provides a new substituted alkenyl compound, pharmaceutically acceptable salts of the new substituted alkenyl compound, a medicinal preparation of the new substituted alkenyl compound, and application of the new substituted alkenyl compound, the pharmaceutically acceptable salts and the medicinal preparation of the new substituted alkenyl compound in aspects of regulating the activity of protein kinase and regulating the intercellular or intracellular signal response. The invention also relates to a medicament composition containing the compound at the same time, and relates to a method for treating high-proliferative diseases of mammals especially the human by using the medicament composition.
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Paragraph 0716; 0790; 0791; 0796; 0797

(2018/03/01)

SUBSTITUTED BICYCLE HETEROCYCLIC DERIVATIVES USEFUL AS ROMK CHANNEL INHIBITORS
Disclosed are compounds of Formula (I) or a salt thereof, wherein R1 is (II) or (III); each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3, L1, L2, R1a, R1b, R1c, and n are define herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
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Page/Page column 189

(2018/06/06)

Technology for synthesizing N-substituted pyrazol-4-borate
The invention discloses a technology for synthesizing N-substituted pyrazol-4-borate. The technology comprises the following steps: taking 2-bromomalonaldehyde as a raw material; firstly, causing the 2-bromomalonaldehyde and triethyl orthoformate to react to obtain acetal; transforming bromine into bi(diisopropylamine)boron; then, carrying out a condensation reaction on the bi(diisopropylamine)boron and substituted hydrazine; and finally, causing an obtained product to react with different glycols to obtain the N-substituted pyrazol-4-borate. The method has the advantage of easy obtaining of raw materials, simple synthesis steps and high reaction yield and is suitable for industrialization amplification production.
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Paragraph 0016

(2016/12/01)

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.
Gazzard, Lewis,Williams, Karen,Chen, Huifen,Axford, Lorraine,Blackwood, Elizabeth,Burton, Brenda,Chapman, Kerry,Crackett, Peter,Drobnick, Joy,Ellwood, Charles,Epler, Jennifer,Flagella, Michael,Gancia, Emanuela,Gill, Matthew,Goodacre, Simon,Halladay, Jason,Hewitt, Joanne,Hunt, Hazel,Kintz, Samuel,Lyssikatos, Joseph,Macleod, Calum,Major, Sarah,Médard, Guillaume,Narukulla, Raman,Ramiscal, Judi,Schmidt, Stephen,Seward, Eileen,Wiesmann, Christian,Wu, Ping,Yee, Sharon,Yen, Ivana,Malek, Shiva
p. 5053 - 5074
(2015/07/02)

PYRIDINE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
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Page/Page column 163

(2014/09/29)

ALKENYL COMPOUNDS AND METHODS OF USE
The present invention provides novel substituted alkenyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0277

(2014/12/12)

Process development and large-scale synthesis of a c-Met kinase inhibitor
A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material (S)-epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).
Stewart, Gavin W.,Brands, Karel M. J.,Brewer, Sarah E.,Cowden, Cameron J.,Davies, Antony J.,Edwards, John S.,Gibson, Andrew W.,Hamilton, Simon E.,Katz, Jason D.,Keen, Stephen P.,Mullens, Peter R.,Scott, Jeremy P.,Wallace, Debra J.,Wise, Christopher S.
scheme or table
p. 849 - 858
(2011/03/20)

Substituted inmidazoles as bombesin receptor subtype-3 modulators
Certain novel substituted imidazoles are ligands of the human bombesin receptor and, in particular, are selective ligands of the human bombesin receptor subtype-3 (BRS-3). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of BRS-3, such as obesity, and diabetes.
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Page/Page column 44

(2010/02/17)

N-sulfonylanthranilic acid derivatives as allosteric inhibitors of dengue viral RNA-dependent RNA polymerase
A novel class of compounds containing N-sulfonylanthranilic acid was found to specifically inhibit dengue viral polymerase. The structural requirements for inhibition and a preliminary structure-activity relationship are described. A UV cross-linking experiment was used to map the allosteric binding site of the compound on the viral polymerase.
Yin, Zheng,Chen, Yen-Liang,Kondreddi, Ravinder Reddy,Chan, Wai Ling,Wang, Gang,Ng, Ru Hui,Lim, Joanne Y. H.,Lee, Wan Yen,Jeyaraj, Duraiswamy A.,Niyomrattanakit, Pornwaratt,Wen, Daying,Chao, Alex,Glickman, J. Fraser,Voshol, Hans,Mueller, Dieter,Spanka, Carsten,Dressler, Sigmar,Nilar, Shahul,Vasudevan, Subhash G.,Shi, Pei-Yong,Keller, Thomas H.
supporting information; scheme or table
p. 7934 - 7937
(2010/07/07)

PHOSPHATIDYLINOSITOL 3 KINASE INHIBITORS
Provided are compounds according to Formula (I), or stereoisomer, prodrug, polymorph, or pharmaceutically acceptable salt forms thereof, wherein X, Y, R1, R6 , R7, and R8 are as defined, which compounds are effective inhibitors of PI3-kinase and/or other medically and clinically relevant kinases. Also provided are pharmaceutical compositions and methods of using the compounds and compositions as PB -kinase and kinase inhibitors. More particularly, the compounds of the invention provide treatments and therapeutics for human diseases regulated by, or associated with, the activity of, PI3-kinases and/or protein kinases, or mutant or variant forms thereof.
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Page/Page column 137-138

(2010/01/12)

Process for producing oxazole, imidazole, pyrrazole boryl compounds
Process for the preparation of oxazole, imidazole, and pyraxole boryl compounds. The compounds are intermediates to functionalized compounds, both natural and synthetic which are cytotoxic, anticancer and antiviral agents.
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Page/Page column 6

(2010/11/30)

INHIBITORS OF AKT ACTIVITY
Invented are novel pyridine compounds, the use of such compounds as inhibitors of PKB/AKT kinase activity and in the treatment of cancer and arthritis.
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Page/Page column 90-91

(2010/02/14)

Synthesis of pinacol esters of 1-alkyl-1H-pyrazol-5-yl- and 1-alkyl-1H-pyrazol-4-ylboronic acids
Starting from 1H-pyrazol, a wide number of 1-alkyl-1H-pyrazol-4-yl and 1-alkyl-1H-pyrazol-5-ylboronic acids and their pinacol esters were synthesized and characterized. The key step in the described methodology is the regioselective lithiation of the pyrazole ring. The synthesized pinacolates are stable under prolonged storage and can be used as convenient reagents in organic synthesis.
Ivachtchenko, Alexandre V.,Kravchenko, Dmitry V.,Zheludeva, Valentina I.,Pershin, Dmitry G.
p. 931 - 939
(2007/10/03)