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Formal Fluorinative Ring Opening of 2-Benzoylpyrrolidines Utilizing [1,2]-Phospha-Brook Rearrangement for Synthesis of 2-Aryl-3-fluoropiperidines
A ring expansion of 2-benzoylpyrrolidines, which involves the formal fluorinative ring opening utilizing the [1,2]-phospha-Brook rearrangement under Br?nsted base catalysis and a subsequent intramolecular reductive amination, was developed. The operationally simple three-step protocol provides an efficient access to 2-aryl-3-fluoropiperidines. The methodology was further applied to the syntheses of azepanes and tetrahydroquinolines.
Kondoh, Azusa,Ojima, Rihaku,Terada, Masahiro
supporting information
p. 7894 - 7899
(2021/10/20)

Larger scale Stahl oxidation with instant Cu removal in convenient synthesis of chiral bidentate N–heterocyclic carbene precursor
Commercially available N-Boc protected L-proline can be efficiently converted into a chiral, bidentate, aminoalkyl N-heterocyclic carbene ligand precursor in high yield (50% total after 4 steps) without column chromatography purification at any moment. The developed synthetic path includes: (1) redox step leading to an aldehyde, (2) imine condensation and in situ reduction to 1,2-diamine; (3) heterocyclization; (3) removal of the protecting group. Instant separation of Cu traces after the key Stahl oxidation at gram-scale was facilitated by the use of bis(isocyanide) scavenger, SnatchCat, forming insoluble, easy to remove RNC:→[Cu] complexes that allowed usto obtain crude intermediate suitably pure for next steps without tedious purification.
Grudzień, Krzysztof,Noga?, Wojciech,Szczepaniak, Grzegorz,Grela, Karol
(2021/02/26)

NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG
PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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(2021/05/14)

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
p. 8303 - 8332
(2021/06/30)

POTENT HUMAN NEURONAL NITRIC OXIDE SYNTHASE INHIBITORS
Disclosed are 2-aminopyridine derivative compounds for use as inhibitors of nitric oxide synthase (NOS). In particular, the field of the invention relates to 2-aminopyridine derivative compounds for use as inhibitors of neuronal nitric oxide synthase (nNOS), which are formulated as pharmaceutical compositions for treating diseases and disorders associated with nNOS such as Alzheimer's, Parkinson's, and Huntington's diseases, and amytrophic lateral sclerosis, cerebral palsy, stroke/ischemic brain damage, and migraine headaches.
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Paragraph 00355; 00356

(2021/09/04)

l -Proline as a Valuable Scaffold for the Synthesis of Novel Enantiopure Neonicotinoids Analogs
In this research, six neonicotinoid analogs derived from l-proline were synthesized, characterized, and evaluated as insecticides against Xyleborus affinis. Most of the target compounds showed good to excellent insecticidal activity. To the best of our knowledge, this is the first report dealing with the use of enantiopure l-proline to get neonicotinoids. These results highlighted the compound 9 as an excellent candidate used as the lead chiral insecticide for future development. Additionally, molecular docking with the receptor and compound 9 was carried out to gain insight into its high activity when compared to dinotefuran. Finally, the neurotoxic evaluation of compound 9 showed lower toxicity than the classic neonicotinoid dinotefuran.
Bonilla-Landa, Israel,Cuapio-Mu?oz, Ulises,Luna-Hernández, Axel,Reyes-Luna, Alfonso,Rodríguez-Hernández, Alfredo,Ibarra-Juarez, Arturo,Suarez-Mendez, Gabriel,Barrera-Méndez, Felipe,Caram-Salas, Nadia,Enríquez-Medrano, J. Francisco,Díaz De León, Ramón E.,Olivares-Romero, José Luis
p. 1455 - 1465
(2021/02/16)

CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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(2020/05/19)

AZAARYL DERIVATIVE, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF FOR USE IN PHARMACY
An azaaryl derivative with the structure of formula (I), a preparation method therefor and a pharmaceutical use thereof are disclosed in the present invention. The series of compounds of the present invention can be widely applied in the preparation of dr
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Paragraph 0116-0117

(2020/04/21)

A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines
A one-pot iodo-cyclization/transition metal-catalyzed cross-coupling sequence is reported to access various C5-functionalized oxazolidin-2-ones from unsaturated N-Boc-allylamines. Depending on the Grignard reagents used for the cross-coupling, e.g., aryl- or cyclopropylmagnesium bromide, a cobalt or copper catalyst has to be used to obtain the functionalized oxazolidin-2-ones in good yields.
Chaumont-Olive, Pauline,Cossy, Janine
supporting information

(2020/05/14)

NOVEL POTASSIUM CHANNEL INHIBITORS
The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of potassium channels.
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Page/Page column 56; 73

(2020/10/20)

Arylation of Aldehydes to Directly Form Ketones via Tandem Nickel Catalysis
A nickel-catalyzed arylation of both aliphatic and aromatic aldehydes proceeds with air-stable (hetero)arylboronic acids, with an exceptionally wide substrate scope. The neutral condition tolerates acidic hydrogen and sensitive polar groups and also preserves α-stereocenters of some chiral aldehydes. Interestingly, this nickel(0) catalysis does not follow common 1,2-insertion of arylmetal species to aldehydes and β-hydrogen elimination.
Lei, Chuanhu,Zhu, Daoyong,Tangcueco, Vicente Iii Tiu,Zhou, Jianrong Steve
p. 5817 - 5822
(2019/08/26)

CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE
What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.
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(2020/01/08)

Compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and application of compounds or pharmaceutical composition
The invention discloses compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and an application of the compounds or the pharmaceutical composition. The compounds are compoundsshown in formula (I) or a stereoisomer, geometric isomer, a tautomer, an enantiomer, sulfur oxide, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compounds shown in formula (I); the compounds are effective antiviral drugs, especially can be used for inhibiting the function of NS5A protein encoded by the HCV, thereby effectively inhibiting the HCV.The method for preventing and/or treating drugs or diseases associated with the HCV by the compounds or the composition containing the new compounds has good market development prospects.
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Paragraph 0104; 0105; 0106; 0107

(2019/02/04)

Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold
Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the pKa of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency (Ki 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.
Do, Ha T.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
supporting information
p. 2690 - 2707
(2019/03/11)

Compound, preparation method thereof, pharmaceutical composition and application of compound
The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
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Paragraph 0136; 0140-0142

(2020/01/03)

CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS
The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.
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(2018/05/27)

Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation
Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report the structure-activity relationship studies of 3 and its analogs against Trypanosoma brucei, which causes human African trypanosomiasis (HAT). The series was also tested against Trypanosoma cruzi, Leishmania major, and Plasmodium falciparum. In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, 3 extended life of treated mice by 50%, compared to untreated controls. At the cellular level, 3 inhibited mitosis and cytokinesis in T. brucei. Thus, the alkynylthieno[3,2-d]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.
Woodring, Jennifer L.,Behera, Ranjan,Sharma, Amrita,Wiedeman, Justin,Patel, Gautam,Singh, Baljinder,Guyett, Paul,Amata, Emanuele,Erath, Jessey,Roncal, Norma,Penn, Erica,Leed, Susan E.,Rodriguez, Ana,Sciotti, Richard J.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
p. 996 - 1001
(2018/09/21)

COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
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(2019/01/10)

NOVEL BETULINIC SUBSTITUTED AMIDE DERIVATIVES AS HIV INHIBITORS
The present invention relates to novel betulinic substituted amide compounds of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and are Formula (II) as defined herein. The invention novel betulinic substituted amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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(2017/02/24)

Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications
We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in?vitro.
Wang, Xin,Dong, Suzhen,Feng, Dengke,Chen, Yazhou,Ma, Mingliang,Hu, Wenhao
p. 2255 - 2266
(2017/03/24)

Prolyl 4-hydroxylase: Substrate isosteres in which an (E)- or (Z)-alkene replaces the prolyl peptide bond
Collagen prolyl 4-hydroxylases (CP4Hs) catalyze a prevalent posttranslational modification, the hydroxylation of (2S)-proline residues in protocollagen strands. The ensuing (2S,4R)-4-hydroxyproline residues are necessary for the conformational stability of the collagen triple helix. Prolyl peptide bonds isomerize between cis and trans isomers, and the preference of the enzyme is unknown. We synthesized alkene isosteres of the cis and trans isomers to probe the conformational preferences of human CP4H1. We discovered that the presence of a prolyl peptide bond is necessary for catalysis. The cis isostere is, however, an inhibitor with a potency greater than that of the trans isostere, suggesting that the cis conformation of a prolyl peptide bond is recognized preferentially. Comparative studies with a Chlamydomonas reinhardtii P4H, which has a similar catalytic domain but lacks an N-terminal substrate-binding domain, showed a similar preference for the cis isostere. These findings support the hypothesis that the catalytic domain of CP4Hs recognizes the cis conformation of the prolyl peptide bond and inform the use of alkenes as isosteres for peptide bonds.
Vasta, James D.,Choudhary, Amit,Jensen, Katrina H.,McGrath, Nicholas A.,Raines, Ronald T.
p. 219 - 227
(2017/12/08)

As hepatitis c inhibitor spiro compound and its use in medicine
The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
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(2017/12/28)

PYRROLOBENZODIAZEPINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE
The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.
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Paragraph 0581; 0582; 0688; 0689; 0690

(2017/04/23)

METHOD FOR PRODUCING ALDEHYDE
PROBLEM TO BE SOLVED: To provide a new method for producing aldehyde capable of evading reduction under low temperature conditions and having higher selectivity. SOLUTION: Provided is a method for producing aldehyde where activated ester is prepared from carboxylic acid such as saturated fatty acid, unsaturated fatty acid, hydroxy acid, aromatic carboxylic acid and amino acid and an activation ester agent such as halogenated carbonic acid aryl, a carbodiimide-based condensation agent, an imidazole-based condensation agent and a triazine-based condensation agent, and the activated ester is reduced, and being a method for producing aldehyde in which an environmental load is reduce, and having high yield and high selectivity. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0016; 0017-0018

(2017/05/27)

NOVEL BETULINIC PROLINE IMIDAZOLE DERIVATIVES AS HIV INHIBITORS
The present invention relates to novel betulinic proline imidazole derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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(2016/01/25)

A base promoted multigram synthesis of aminoisoxazoles: Valuable building blocks for drug discovery and peptidomimetics
A practical multigram metal free synthesis of isoxazole-containing building blocks from commercially available amino acids was elaborated. The key reaction was a regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides with alkynes/enamines. The obtained building blocks were used in the preparation of bioactive compounds and peptidomimetics.
Chalyk, Bohdan A.,Kandaurova, Inna Y.,Hrebeniuk, Kateryna V.,Manoilenko, Olga V.,Kulik, Irene B.,Iminov, Rustam T.,Kubyshkin, Vladimir,Tverdokhlebov, Anton V.,Ablialimov, Osman K.,Mykhailiuk, Pavel K.
p. 25713 - 25723
(2016/03/25)

Organocatalysis Intermediates as Platforms to Study Noncovalent Interactions: Integrating Fluorine Gauche Effects in Iminium Systems to Facilitate Acyclic Conformational Control
Achieving acyclic conformational control over several bonds has been realized by the strategic installation of a vicinal difluoroethane bridge in a generic proline-derived organocatalyst. The torsion angle φFCCF is governed by stabilizing hyperconjugative interactions (σ→σ?), thus ensuring a 60° relationship. This effect has been telescoped by positioning a stereogenic fluorine center proximal to the nucleophilic amine. Upon iminium formation, this center is rendered electron deficient, thus triggering a dynamic fluorine iminium ion gauche effect. Consequently, conformational control over five atoms and four bonds can be achieved by reversible formation of an iminium π-bond.
Molnár, István Gábor,Holland, Mareike C.,Daniliuc, Constantin,Houk,Gilmour, Ryan
p. 1051 - 1055
(2016/05/19)

SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF
The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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(2016/05/24)

Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
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(2016/10/20)

Chiral Phosphorus-Olefin Ligands for the RhI-Catalyzed Asymmetric Addition of Aryl Boronic Acids to Electron-Deficient Olefins
New chiral phosphorus-olefin hybrid ligands derived from the rigid "privileged" l-proline have been conveniently prepared and applied in the rhodium-catalyzed asymmetric arylation of electron-deficient olefins with arylboronic acids at room temperature; t
Chen, Qian,Li, Liang,Zhou, Guangli,Ma, Xiaoli,Zhang, Lu,Guo, Fang,Luo, Yi,Xia, Wujiong
supporting information
p. 1518 - 1522
(2016/06/01)

Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.
Haghshenas, Pouyan,Quail, J. Wilson,Gravel, Michel
p. 12075 - 12083
(2016/12/23)

A Recyclable Organocatalyst for Asymmetric Michael Addition
In this study, a new organocatalyst derived from proline was developed and shown to be an efficient catalyst for asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with high diastereo- and enantioselectivities. (syn;anti up to
Yang, Mei,Zhang, Yuecheng,Zhao, Jiquan,Yang, Qiusheng,Ma, Yi,Cao, Xiaohui
p. 587 - 595
(2016/03/01)

6-AMINO QUINAZOLINE OR 3-CYANO QUINOLINE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
The present disclosure relates to 6-amino quinazoline or 3-cyano quinoline derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel 6-amino quinazoline or 3-cyano quinoline derivatives presented by formula (I), or its tautomer, enantiomer, diastereomer, racemate or pharmaceutically acceptable salts thereof, or metabolite, metabolic precursor or prodrug thereof, and the uses for treatment especially for protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.
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Page/Page column 33; 34

(2016/10/08)

Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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(2015/03/28)

Gold-catalyzed synthesis of enantioenriched furfurylamines from amino acids
Abstract A convenient gold-catalyzed asymmetric synthesis of polysubstituted furfurylamines starting from amino acids has been achieved. The cyclization proceeded under mild conditions and generally provided the furan or iodofuran derivatives in good to e
Guieu, Benjamin,Le Roch, Myriam,David, Michèle,Gouault, Nicolas
p. 868 - 875
(2015/08/18)

A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H
N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.
Ivkovic, Jakov,Lembacher-Fadum, Christian,Breinbauer, Rolf
p. 10456 - 10460
(2015/11/10)

AURISTATIN ANALOGUES AND THEIR CONJUGATES WITH CELL-BINDING MOLECULES
This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and /or proliferation.
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(2015/11/18)

NOVEL LINKERS AND THEIR USES IN SPECIFIC CONJUGATION OF DRUGS TO A BIOLOGICAL MOLECULE
The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic) group for conjugation of two or more compounds/cytotoxic agents per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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(2015/11/17)

SPIRO COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS
Disclosed are spiro compounds of formula (I), or stereomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. The compounds can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease. Furthermore disclosed are pharmaceutical compositions containing the compounds and the method of using the compounds or pharmaceutical compositions in the treatment of HCV infection or hepatitis C disease.
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(2015/11/09)

DOLASTATIN-10 DERIVATIVE, METHOD OF PRODUCING SAME AND ANTICANCER DRUG COMPOSITION CONTAINING SAME
The present invention provides a dolastatin-10 derivative having excellent anticancer activity, a method of producing the same and anticancer drug composition containing the same as an active ingredient.
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Paragraph 0045; 0046; 0047; 0048

(2015/07/15)

Highly selective bisphosphine ligands for asymmetric hydroformylation of heterocyclic olefins
The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee. The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 β-isomer/α-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.
Zheng, Xin,Xu, Kun,Zhang, Xumu
p. 1149 - 1152
(2015/02/19)

BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND PHARMACEUTICAL APPLICATIONS THEREOF
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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(2014/02/16)

Enantioselective biomimetic cyclization of 2′-hydroxychalcones to flavanones
A new family of organocatalysts based on aminoquinoline and pyrrolidine have been developed and shown to catalyze the direct and highly enantioselective cyclization of 2′-hydroxychalcones in imitation of the natural process of chalcone cyclization. The straightforward synthetic process occurs under mild reaction conditions, tolerates moisture and air, and gives an enantiomeric excess up to 99%. This approach provides a facile and efficient access to chiral flavanones.
Zhang, Yan-Lei,Wang, Yong-Qiang
p. 3255 - 3258
(2014/06/09)

FUSED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
Provided are fused tricyclic compounds effective to inhibit the function of the NS5A protein of formula (I), wherein X, X', Y, Y', A, A',Q1, Q2, R1-R4, X4, R5a, f and W are defined as in the description. Also provided herein are pharmaceutical compositions thereof, and uses in the manufacture of a medicament for treating HCV infection or a HCV disorder thereof.
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(2014/06/23)

SPIRO RING COMPOUND AS HEPATITIS C VIRUS (HCV) INHIBITOR AND USES THEREOF FIELD OF THE INVENTION
A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.
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(2014/06/23)

BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.
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(2014/09/16)

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile - Part 1
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl) -1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation. Resisting resistance: An investigation into the anti-hepatitis C virus (HCV) replicon activity of a series of biaryl-linked pyrrolidine NS5A inhibitors explored a diverse range of core structure modifications as key determinants of antiviral activity and susceptibility to common resistance mutations. Further evaluation of several core structure designs identified a compound with excellent pharmacokinetics, suitable for once daily dosing.
Tran, Thien Duc,Wakenhut, Florian,Pickford, Chris,Shaw, Stephen,Westby, Mike,Smith-Burchnell, Caroline,Watson, Lesa,Paradowski, Michael,Milbank, Jared,Brimage, Rebecca A.,Halstead, Rebecca,Glen, Rebecca,Wilson, Craig P.,Adam, Fiona,Hay, Duncan,Chiva, Jean-Yves,Nichols, Carly,Blakemore, David C.,Gardner, Iain,Dayal, Satish,Pike, Andrew,Webster, Rob,Pryde, David C.
p. 1378 - 1386
(2014/07/21)

Synthesis of phosphonic analog of (S)-homoproline
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Kolodyazhnaya,Kolodyazhnaya,Kolodyazhnyi
p. 169 - 170
(2014/03/21)

Stereocontrol in asymmetric SE' reactions of γ-substituted α,β-unsaturated aldehydes
Asymmetric SE' reactions of (E)-and (Z)-γ-substituted-α,β- unsaturated aldehydes have been studied for the stereocontrolled preparation of nonracemic alcohols. Mild exchange reactions of allylic stannanes provide access to chiral 1,3-bis-(tolylsulfonyl)-4
Williams, David R.,Atwater, Bruce A.,Bawel, Seth A.,Ke, Pucheng,Gutierrez, Osvaldo,Tantillo, Dean J.
supporting information
p. 468 - 471
(2014/04/03)

Anaerobic nitroxide-catalyzed oxidation of alcohols using the NO +/NO· redox pair
A new method for alcohol oxidation using TEMPO or AZADO in conjunction with BF3·OEt2 or LiBF4 as precatalysts and tert-butyl nitrite as a stoichiometric oxidant has been developed. The system is based on a NO+/NO· pair for nitroxide reoxidation under anaerobic conditions. This allows the simple, high-yielding conversion of various achiral and chiral alcohols to carbonyl compounds without epimerization and no formation of nonvolatile byproducts.
Holan, Martin,Jahn, Ullrich
supporting information
p. 58 - 61
(2014/01/23)