- Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution
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A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-β-keto carbonitriles is described. The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers. A wide range of α-substituted-β-keto carbonitriles were obtained in high yields (94%-98%) and excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.
- Wang, Fangyuan,Yang, Tilong,Wu, Ting,Zheng, Long-Sheng,Yin, Congcong,Shi, Yongjie,Ye, Xiang-Yu,Chen, Gen-Qiang,Zhang, Xumu
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supporting information
p. 2477 - 2483
(2021/02/16)
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- COMPOSITIONS AND METHODS FOR SUBSTITUTED 7-(PIPERAZIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDINE ANALOGS AS INHIBITORS OF KRAS
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In one aspect, the disclosure relates to compounds useful as inhibitors of mutant KRAS proteins, methods of making the same, pharmaceutical compositions comprising the same, and methods of treating cancers associated with mutated forms of KRAS using the same. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.
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Paragraph 0256
(2021/06/22)
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- Stereoselective C?C Oxidative Coupling Reactions Photocatalyzed by Zwitterionic Ligand Capped CsPbBr3 Perovskite Quantum Dots
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Semiconductor quantum dots (QDs) have attracted tremendous attention in the field of photocatalysis, owing to their superior optoelectronic properties for photocatalytic reactions, including high absorption coefficients and long photogenerated carrier lifetimes. Herein, by choosing 2-(3,4-dimethoxyphenyl)-3-oxobutanenitrile as a model substrate, we demonstrate that the stereoselective (>99 %) C?C oxidative coupling reaction can be realized with a high product yield (99 %) using zwitterionic ligand capped CsPbBr3 perovskite QDs under visible light illumination. The reaction can be generalized to different starting materials with various substituents on the phenyl ring and varied functional moieties, producing stereoselective dl-isomers. A radical mediated reaction pathway has been proposed. Our study provides a new way of stereoselective C?C oxidative coupling via a photocatalytic means using specially designed perovskite QDs.
- Cai, Tong,Candler, Yolanda,Chen, Ou,He, Jie,Hills-Kimball, Katie,Shi, Wenwu,Wang, Ping,Wei, Zichao,Yang, Hanjun,Yuan, Yucheng,Zhu, Hua
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supporting information
p. 22563 - 22569
(2020/10/12)
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- Copper-catalysed: N -arylation of 5-aminopyrazoles: A simple route to pyrazolo[3,4- b] indoles
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A copper-catalysed intramolecular N-arylation of 5-aminopyrazoles is demonstrated for the first time. Highly substituted pyrazolo[3,4-b]indoles are synthesized. In particular, the indole core is decorated with halogens and alkyl and methoxy groups. Furthermore, a selective N-arylation of unsymmetrical diaryl bromide containing pyrazoles is exemplified, resulting in valuable pyrazolo[1,5-a]benzimidazoles. This journal is
- Chatterjee, Arpita,Murmu, Chudamani,Peruncheralathan, S.
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supporting information
p. 6571 - 6581
(2020/11/07)
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- APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
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Paragraph 0183-0184
(2019/02/25)
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- Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K inhibitors
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A series of novel 7-aminoalkyl substituted pyrazolo[1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-α-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo[1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo[1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (Ki ≥ 77 μM).
- Petek, Nejc,?tefane, Bogdan,Novinec, Marko,Svete, Jurij
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p. 226 - 238
(2018/12/04)
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- N -Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK
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NF-κB-inducing kinase (NIK), an oncogenic drug target that is associated with various cancers, is a central signalling component of the non-canonical pathway. A blind screening process, which established that amino pyrazole related scaffolds have an effect on IKKbeta, led to a hit-to-lead optimization process that identified the aminopyrazole 3a as a low μM selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile.
- Pippione, Agnese C.,Sainas, Stefano,Federico, Antonella,Lupino, Elisa,Piccinini, Marco,Kubbutat, Michael,Contreras, Jean-Marie,Morice, Christophe,Barge, Alessandro,Ducime, Alex,Boschi, Donatella,Al-Karadaghi, Salam,Lolli, Marco L.
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supporting information
p. 963 - 968
(2018/06/27)
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- BF3·OEt2-mediated [1,2]-aryl shift: Synthesis of functionalized α-arylnitriles via the bromination/cyanation/deformylation of substituted deoxybenzoin
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A new sequential, tandem synthesis of functionalized α-arylnitriles via the bromination/cyanation/deformylation of substituted deoxybenzoin has developed. CuBr2-promoted bromination of substituted deoxybenzoins gives 2-bromo-2-arylacetophenne 3. The cyanation of 3 with sodium cyanide (NaCN) generates epoxynitrile. Then, a treatment of epoxynitrile with BF3·OEt2 results in the formation of functionalized α-arylnitriles 4 via a 1,2-aryl shift.
- Chan, Chieh-Kai,Chang, Meng-Yang
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p. 5207 - 5213
(2017/07/28)
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- Synthesis and cytotoxic evaluation of some new 1-(6- chloropyridazin-3-Yl)-3-H/Alkyl-4-phenyl-1H-pyrazol- 5-amines and their derivatives
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Synthesis of new 1-(6-chloropyridazin-3-yl)-3-H/alkyl-4-phenyl-1H-pyrazol-5-amines (3) was accomplished by the reaction of 3-chloro-6-hydrazinopyridazine (1) with differently substituted β-ketonitriles (2) under reflux in ethanol. Subsequently, a series of 6-amino derivatives (4, 5 and 6) was synthesized by amino-de-halogenation of 3 with secondry cyclic amines e.g. pyrrolidine, piperidine and morpholine respectively. Structures of all the compounds were established by IR, NMR (1H, 13C and 19F) and mass spectral data, and elemental analysis. All the compounds were screened for their cytotoxic effects against three cancer cell lines (SB-ALL, NALM-6, MCF-7) using colorimetric MTT assay.
- Mamta,Aggarwal, Ranjana,Smith, Jessie,Sadana, Rachna
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- Synthesis of β-ketonitriles, α,β-alkynones and biscabinols from esters using tert-butoxide-assisted C(=O)-C (i.e., acyl-C) coupling under ambient conditions
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We demonstrated the synthesis of β-ketonitriles, α,β- alkynones, and biscarbinols using tert-butoxide-assisted C(CO)-C (i.e., acyl-C) coupling of esters under ambient conditions. tert-Butoxide-assisted C(CO)-C (i.e., acyl-C) coupling of esters with cyanomethylenes and acetylenes under transition metal-free ambient conditions gives β-ketonitriles, α,β-alkynones and/or aryl bis(phenylethynyl)carbinols in moderate-to-good yields. It is noteworthy that this is a rapid, facile, and efficient process under ambient conditions, and use of cheap and stable starting materials.
- Kim, Bo Ram,Lee, Hyung-Geun,Kang, Seung-Beom,Jung, Kwang-Ju,Sung, Gi Hyeon,Kim, Jeum-Jong,Lee, Sang-Gyeong,Yoon, Yong-Jin
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p. 10331 - 10336
(2013/11/19)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 54
(2012/11/08)
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- Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H) -ones as novel Kv7/KCNQ potassium channel activators
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Voltage-gated Kv7/KCNQ/M-potassium channels play a pivotal role in controlling neuronal excitability. Genetic reduction of KCNQ channel activity as a result of mutations causes various human diseases such as epilepsy and arrhythmia. Therefore, discovery of small molecules that activate KCNQ channels is an important strategy for clinical intervention of membrane excitability related disorders. In this study, a series of pyrazolo[1,5-a]pyrimidin-7(4H)- ones (PPOs) have been found to be novel activators (openers) of KCNQ2/3 potassium channels through high-throughput screening by using atomic absorption rubidium efflux assay. Based on structure-activity relationship (SAR), the substituted PPOs have been optimized. The 5-(2,6-dichloro-5-fluoropyridin-3-yl)- 3-phenyl-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (17) was identified as a novel, potent, and selective KCNQ2/3 potassium channel opener by patch-clamp recording assay.
- Qi, Jinlong,Zhang, Fan,Mi, Yi,Fu, Yan,Xu, Wen,Zhang, Diqun,Wu, Yibing,Du, Xiaona,Jia, Qingzhong,Wang, Kewei,Zhang, Hailin
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scheme or table
p. 934 - 943
(2011/04/17)
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- Use of Pyrazolo(1,5A)Pyrimidin-7-YL Amine Derivatives in the Treatment of Neurological Disorders
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The invention relates to methods of using the compounds of the invention, including pyrazolo[1,5a]pyrimidin-7-yl amine compounds and salts thereof, as well as pharmaceutical compositions comprising the same, in the treatment of Eph receptor-related (e.g., neurological) injuries and disorders. The invention also relates to modulating the activity of an Eph receptor in a cell, stimulating neural regeneration, and reversing neuronal degeneration, by administering a compound of the invention to a cell or subject in an effective amount.
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Page/Page column 44
(2009/04/24)
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- Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis
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Tuberculosis is an increasing threat, owing to the spread of AIDS and to the development of resistance of the causative organism, Mycobacterium tuberculosis, to the currently available drugs. Dihydrofolate reductase (DHFR) is an important enzyme of the folate cycle; inhibition of DHFR inhibits growth and causes cell death. The crystal structure of M. tuberculosis DHFR revealed a glycerol tightly bound close to the binding site for the substrate dihydrofolate; this glycerol-binding motif is absent from the human enzyme. A series of pyrimidine-2,4-diamines was designed with a two-carbon tether between a glycerol-mimicking triol and the 6-position of the heterocycle; these compounds also carried aryl substituents at the 5-position. These, their diastereoisomers, analogues lacking two hydroxy groups and analogues lacking the two-carbon spacing linker were synthesised by acylation of the anions derived from phenylacetonitriles with ethyl (4S,5R)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, ethyl (4S,5S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, tetrahydrooxepin-2-one and 2,3-O-isopropylidene-d-erythronolactone, respectively, to give the corresponding α-acylphenylacetonitriles. Formation of the methyl enol ethers, condensation with guanidine and deprotection gave the pyrimidine-2,4-diamines. Preliminary assay of the abilities of these compounds to inhibit the growth of TB5 Saccharomyces cerevisiae carrying the DHFR genes from M. tuberculosis, human and yeast indicated that 5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine selectively inhibited M. tuberculosis DHFR and had little effect on the human or yeast enzymes.
- El-Hamamsy, Mervat H.R.I.,Smith, Anthony W.,Thompson, Andrew S.,Threadgill, Michael D.
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p. 4552 - 4576
(2008/03/12)
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- Facile one-pot synthesis of 2-aryl-substituted nitriles and 2-aryl-3-keto nitriles via benzyne reaction
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2-Aryl-substituted nitriles were prepared in good to excellent yields in a one-pot reaction by the reaction of benzyne, generated using neutral conditions from (phenyl)[o-(trimethylsilyl)-phenyl]iodonium triflate, and 2-lithionitriles. 3-Keto nitriles substituted at the 2-position were obtained in good yields when these reactions were trapped with acid chlorides. The mechanism of the benzyne reaction in terms of a N-lithiobenzocyclobutanimine intermediate is discussed. Copyright Taylor & Francis Group, LLC.
- Kamila, Sukanta,Koh, Benjamin,Biehl, Edward R.
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p. 3493 - 3507
(2007/10/03)
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- FUNGICIDAL HETEROCYCLIC COMPOUNDS
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A compound which can specifically or selectively expresses an antifungal activity with a broad spectrum, based on the functional mechanism of 1,6-β-glucan synthesis inhibition, is provided, and an antifungal agent which comprises such a compound, a salt thereof or a solvate thereof is provided. A compound represented by the following formula (I), a salt thereof or a solvate thereof.
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Page/Page column 97
(2010/11/24)
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- Synthesis of N-substituted indole derivatives via PIFA-mediated intramolecular cyclization
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(Chemical Equation Presented) A variety of N-arylated and N-alkylated indole derivatives were synthesized by way of a phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization. This novel method allows for the construction of an indole skeleton by joining the N-atom on the side chain to the benzene ring at the last synthetic step. Other novel pyrrole-fused aromatic compounds can also be achieved by this method.
- Du, Yunfei,Liu, Renhe,Linn, Gregory,Zhao, Kang
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p. 5919 - 5922
(2007/10/03)
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- Photochemistry of 4- and 5- phenyl substituted isoxazoles
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5-Phenylisoxazole (4) and 4-phenylisoxazole (22) underwent phototransposition to 5-phenyloxazole (5) and 4-phenyloxazole (24) respectively. Labeling with deuterium or methyl confirmed that these phototrans-positions occurred via the P4 pathway which involves only interchange of the N2 and C3 ring position. Thus, 4-deuterio-5-phenylisoxazole (4-4d), 4-methyl-5-phenylisoxazole (10), and 5-methyl-4-phenylisoxazole (23) phototransposed to 4-deuterio-5-phenyloxazole (5-4d), 4-methyl-5-phenyloxazole (11), and 5-methyl-4-phenyloxazole (25) respectively. In addition to phototransposition, isoxazoles 4, 10, and 23 also underwent photo-ring cleavage to yield benzoylacetonitrile (9), α-benzoylpropionitrile (15), and aceto-α-phenyl-acetonitrile (26) respectively. Irradiation of 5-phenyl-3-(trifluoromethyl)isoxazole (16) in acetonitrile led to 5-phenyl-2-(trifluoromethyl)oxazole (17), the P4 phototransposition product. Irradiation of 16 in methanol led to a substantial decrease in the yield of 17 and to the formation of a mixture of (E) and (Z)-2-methoxy-2- (trifluoromethyl)-3-benzoylaziridines 18a and 18b.
- Pavlik, James W.,St. Martin, Heather,Lambert, Karen A.,Lowell, Jennifer A.,Tsefrikas, Vikki M.,Eddins, Cheryl K.,Kebede, Naod
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p. 273 - 281
(2007/10/03)
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- Organic compounds
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The invention relates to the use of pyrazolo[1,5a]pyrimidin-7-yl amine compounds and salts thereof in the treatment of kinase dependent diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds, and a process for the preparation of the novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds.
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Page/Page column 37
(2008/06/13)
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- PYRAZOLO[1,5-A]PYRIMIDIN-7-YL-AMINE DERIVATIVES FOR USE IN THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
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The invention relates to the use of pyrazolo[1,5a]pyrimidin-7-yl amine compounds and salts thereof in the treatment of kinase dependent diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds, and a process for the preparation of the novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds.
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Page/Page column 78
(2008/06/13)
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- Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility
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In our efforts to identify potent CRF1 antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF1 receptor. Moreover, this compound had proper lipophilicity (logD=2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.
- Chen, Chen,Wilcoxen, Keith M.,Huang, Charles Q.,McCarthy, James R.,Chen, Takung,Grigoriadis, Dimitri E.
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p. 3669 - 3673
(2007/10/03)
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- Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine resistant Plasmodium falciparum
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The reduced binding of pyrimethamine to Serl08Asn (S108N) mutants of parasite dihydrofolate reductase (DHFR), which forms the basis of resistance of Plasmodium falciparum to pyrimethamine, is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5-p-Cl-phenyl group. This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil. Less effect on binding to some bulky mutants was observed for trimethoprim, with greater flexibility for the 5-substituent. S108N DHFR also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p-Cl, and the binding was generally progressively poorer for the double (C59R+S108N) mutant. Removal of the p-Cl or replacement with m-Cl led to better binding with the mutant DHFRs. Pyrimethamine analogues with unbranched hydrophobic 6-substituents showed generally good binding with the mutant DHFRs. A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR. Some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines.
- Tarnchompoo, Bongkoch,Sirichaiwat, Chawanee,Phupong, Worrapong,Intaraudom, Chakapong,Sirawaraporn, Worachart,Kamchonwongpaisan, Sumalee,Vanichtanankul, Jarunee,Thebtaranonth, Yodhathai,Yuthavong, Yongyuth
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p. 1244 - 1252
(2007/10/03)
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