- SUBSTITUTED AMINOQUINOLONES AS DGKALPHA INHIBITORS FOR IMMUNE ACTIVATION
-
The present invention covers aminoquinolone compounds of general formula (I) : in which R1, R2, R3, R4, R5, R6, R7, R8, X and n are as defined herein, methods of prepa
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-
Page/Page column 129-130
(2021/06/04)
-
- Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
-
Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.
- Klug, Dana M.,Mavrogiannaki, Eftychia M.,Forbes, Katherine C.,Silva, Lisseth,Diaz-Gonzalez, Rosario,Pérez-Moreno, Guiomar,Ceballos-Pérez, Gloria,Garcia-Hernández, Raquel,Bosch-Navarrete, Cristina,Cordón-Obras, Carlos,Gómez-Li?án, Claudia,Saura, Andreu,Momper, Jeremiah D.,Martinez-Martinez, Maria Santos,Manzano, Pilar,Syed, Ali,El-Sakkary, Nelly,Caffrey, Conor R.,Gamarro, Francisco,Ruiz-Perez, Luis Miguel,Gonzalez Pacanowska, Dolores,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
-
supporting information
p. 9404 - 9430
(2021/07/25)
-
- Synthesis and Characterization of N-(4-(Piperidin-4-ylsulfonyl) phenyl)5-vinylpyrimidin-2-amine
-
Target product N-(4-(piperidin-4-ylsulfonyl)phenyl)5-vinylpyrimidin-2- amine (13) was synthesized using 6-oxopyran-3-carbaldehyde (M1) and 4-hydroxypiperidine (M2) as starting materials by a series of nucleophilic substitution and oxidation. Different aci
- Dong, Jingjing,Feng, Baicheng,Jin, Yan,Lu, Jianqiang,Wang, Tielin
-
p. 255 - 258
(2021/08/05)
-
- CXCR2 ANTAGONIST
-
A compound as a CXCR2 antagonist and an application thereof in preparing a drug as a CXCR2 antagonist. In particular, the present invention relates to a compound represented by formula (II) or an isomer or pharmaceutically acceptable salt thereof.
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Paragraph 0097-0099; 0122-0124
(2020/11/23)
-
- PYRROLO(PYRAZOLO)PYRIMIDINE DERIVATIVE AS LRRK2 INHIBITOR
-
The present invention relates to a pyrrolo(pyrazolo)pyrimidine derivative having efficacy as an LRRK2 inhibitor, a preparation method therefor, and a pharmaceutical composition for preventing or treating degenerative brain diseases, containing the same.
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-
Paragraph 0119-0120
(2020/11/23)
-
- 1, 2, 4-OXADIAZOLE DERIVATIVES AND USES THEREOF
-
The disclosure provides 1, 2, 4-oxadiazole derivatives useful for stemming bleeding and for treating cancer.
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-
Paragraph 0094
(2020/04/25)
-
- 1, 3, 4-OXADIAZOLE DERIVATIVES AND USES THEREOF
-
The disclosure provides 1, 3, 4-oxadiazole derivatives useful for stemming bleeding and for treating cancer.
- -
-
Paragraph 0082
(2020/04/25)
-
- IRAK DEGRADERS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 00962; 002942-002944
(2020/06/19)
-
- Pyrrolo[2, 3-d] pyrimidine derivatives containing piperidine as well as preparation and application thereof
-
The invention relates to a piperidine-containing pyrrolo[2, 3-d] pyrimidine derivative as shown in a general formula I or a general formula II as well as a use method and a preparation method thereof.The invention also relates to a strong JAK kinase inhibition effect of the compound shown in the general formula I or II, the invention also relates to an application of the compound in preparation of medicines for treating and/or preventing diseases caused by abnormal expression of JAK, and particularly relates to application of the compound in preparation of medicines for treating inflammatory/autoimmune diseases, fibrosis and cancers.
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-
Paragraph 0121; 0124; 0125
(2020/09/16)
-
- Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents
-
The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.
- Andersen, Claire,Bernardelli, Patrick,Cossy, Janine,Daumas, Marc,Ferey, Vincent,Guérinot, Amandine
-
supporting information
(2020/08/05)
-
- Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors
-
Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure-activity relationship enabled efficient potency optimization.
- Schade, Markus,Merla, Beatrix,Lesch, Bernhard,Wagener, Markus,Timmermanns, Simone,Pletinckx, Katrien,Hertrampf, Torsten
-
supporting information
p. 11801 - 11808
(2020/11/26)
-
- Design, synthesis, and structure activity relationship (SAR) studies of novel imidazo[1,2-a] pyridine derivatives as Nek2 inhibitors
-
Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.
- Chen, Yunzhong,Du, Yijie,Duan, Yanhong,Gu, Xiaofan,Li, Hongyu,Ma, Mingliang,Ren, Ziwei,Wang, Haili,Wang, Shuting,Xi, Jianbei,Zhang, Xiongwen,Zhu, Tong
-
-
- Hydrochloride of [1, 2, 4] triazine and [6,1-a] isoindole compound and application thereof
-
The invention belongs to the field of chemical medicines, and relates to a [1,2,4]triazine[6,1-a]isoindole compound with ALK/C-MET kinase duplex restraining activity, a pharmaceutical composition containing the compound and application of the compound or the composition in medicine preparation, in particular to hydrochloride and application of the [1,2,4]triazine[6,1-a]isoindole compound. The compound has good dissolubility and stability, and a better option is provided for dosage form research.
- -
-
-
- NITROGENOUS HETEROCYCLIC COMPOUND, PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND USE
-
Disclosed are a nitrogenous heterocyclic compound, intermediates, a preparation method, a composition and use thereof. The nitrogenous heterocyclic compound in the present invention is as shown in formula I. The compound has a high inhibitory activity towards ErbB2 tyrosine kinase and a relatively good inhibitory activity towards human breast cancer BT-474 and human gastric cancer cell NCI-N87 which express ErbB2 at a high level, and at the same time has a relatively weak inhibitory activity towards EGFR kinase. Namely, the compound is a highly selective small-molecule inhibitor targeted at ErbB2, and hence it has a high degree of safety, and can effectively enlarge the safety window in the process of taking the drug.
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-
Paragraph 0280
(2019/01/17)
-
- Discovery of Pyridazinone and Pyrazolo[1,5- a]pyridine Inhibitors of C-Terminal Src Kinase
-
C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1, and a series of modifications led to optimized compound 13. Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose.
- O'Malley, Daniel P.,Ahuja, Vijay,Fink, Brian,Cao, Carolyn,Wang, Cindy,Swanson, Jesse,Wee, Susan,Gavai, Ashvinikumar V.,Tokarski, John,Critton, David,Paiva, Anthony A.,Johnson, Benjamin M.,Szapiel, Nicolas,Xie, Dianlin
-
supporting information
p. 1486 - 1491
(2019/10/14)
-
- Substituted Pyrrolidine Amides I
-
The invention relates to compounds according to general formula (I), which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.
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-
Paragraph 0368-0369
(2019/07/03)
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- Design, synthesis and anti-inflammatory evaluation of novel pyrrolo[2,3-d]pyrimidin derivatives as potent JAK inhibitors
-
Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a–8p and 11a–11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 μM against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1β. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.
- Jiang, Feng,Zang, Linghe,Miao, Xiuqi,Jia, Fang,Wang, Jie,Zhu, Minglin,Gong, Ping,Jiang, Nan,Zhai, Xin
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p. 4089 - 4100
(2019/08/06)
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- HETEROCYCLYLAMINO-SUBSTITUTED TRIAZOLES AS MODULATORS OF RHO-ASSOCIATED PROTEIN KINASE
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This invention relates to novel compounds and pharmaceutical compositions comprising. Compounds of the invention useful as modulators of Rho-associated protein kinase (ROCK), for example ROCK1 and/or ROCK2 inhibitors. Methods of treatment employing the compounds are also contemplated by the present invention. The compounds of the invention are useful in treating ROCK mediated diseases.
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-
Page/Page column 203
(2019/08/12)
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- IRAK DEGRADERS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 2419; 2420
(2019/07/10)
-
- PRMT5 INHIBITORS AND USES THEREOF
-
Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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-
Paragraph 0404-0405
(2019/04/05)
-
- Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging
-
Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.
- Effendi, Nurmaya,Mishiro, Kenji,Takarada, Takeshi,Yamada, Daisuke,Nishii, Ryuichi,Shiba, Kazuhiro,Kinuya, Seigo,Odani, Akira,Ogawa, Kazuma
-
p. 383 - 393
(2019/01/04)
-
- 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 0382-0385
(2018/03/01)
-
- Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis
-
Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a–c, 7 and 8; H37Rv-MIC99 ≤1.25 μM, R5401-MIC99 ≤2.5 μM, X_61-MIC99 ≤5 μM) demonstrated the potential of the reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a–c and 3b (MIC90 ≤13.42 μM) and inhibition of EB efflux demonstrated by these compounds are encouraging.
- Kumar, Malkeet,Singh, Kawaljit,Ngwane, Andile H.,Hamzabegovic, Fahreta,Abate, Getahun,Baker, Bienyameen,Wiid, Ian,Hoft, Daniel F.,Ruminski, Peter,Chibale, Kelly
-
supporting information
p. 833 - 844
(2018/01/22)
-
- Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
-
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
- Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
-
p. 2753 - 2775
(2018/04/23)
-
- SMALL MOLECULE ACTIVATORS OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) AND USES THEREOF
-
Provided herein are small molecule activators of Nicotinamide Phosphoribosyltransferase (NAMPT), compositions comprising the compounds, and methods of using the compounds and compositions.
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-
Paragraph 01010
(2018/08/03)
-
- Preparation method of nitrogen-containing heterocyclic derivative
-
The invention discloses a preparation method of a nitrogen-containing heterocyclic derivative (4-(4-bromobenyl) piperazine-1-yl) piperidine-1-tert butyl formate. The preparation method comprises the following steps: taking 4-hydroxypyrazole as a starting raw material; and carrying out Boc feeding, condensation, nucleophilic substitution and amidation to obtain an objective product. The compound isan important medical intermediate.
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-
-
- Preparation method of piperazine derivative
-
The invention discloses a preparation method of a piperazine derivative, namely (4-(4-trifluoromethyl benzoyl)piperazine-1-yl)piperidine-1-tert-butyl formate. 4-hydroxy piperazine is taken as a starting material and is subjected to Boc treatment, condensation, nucleophilic substitution and amidation to obtain a target product. The compound is an important medical intermediate.
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-
-
- Preparation method of crizotinib intermediate
-
The invention discloses a synthetic method of anti-tumor molecular targeted drug crizotinib, belongs to the field of pharmaceuticals, and relates to a synthetic method of a crizotinib intermediate. The method comprises two reduction processes: a bromination reaction process comprises the following reaction steps: a reduction process I: carrying out reduction reaction on a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound and sodium dithionate under a mechanical chemical condition to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; a reduction process II: dissolving the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound into an organic solvent, carrying out catalytic hydrogenation and reduction treatment to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; the bromination reaction process comprises a step of carrying out reaction between the compound and potassium hydrogen persulfate as well as bromate to obtain the crizotinib intermediate. The process is low in cost, the raw materials are easy to purchase, the operation is simple, convenient and safe, and the yield is high; moreover, the process is suitable for large-scale production.
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-
-
- Tankyrase inhibitor
-
The invention belongs to the technical field of medicines and particularly relates to a tankyrase inhibitor represented by a general formula (I) shown in the description and pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, wherein R1, R2, R3, m, n, Z, L, Q, A, X1, X2 and Y are as defined in the description. The invention further relates to a preparation method for the compounds, pharmaceutical preparations and pharmaceutical compositions containing the compounds and application of the compound and the pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparation of drugs for treating and/or preventing tankyrase mediated cancers and related diseases.
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-
Paragraph 0375-0377
(2017/10/13)
-
- COMPOUNDS WITH HIV MATURATION INHIBITORY ACTIVITY
-
The present invention relates to compounds characterized by having a structure according to the following Formula (I), or a pharmaceutically acceptable salt thereof. Compounds of the present invention are useful for the treatment or prevention of HIV.
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-
Paragraph 00216
(2017/04/11)
-
- Compounds used as JAK inhibitor, and use of compounds
-
The invention provides compounds used as a JAK inhibitor, and a use of the compounds, and concretely provides compounds (represented by formula (I)) with JAK inhibition activity or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a medicinal composition including the compounds. The invention also discloses a use of the compounds or the medicinal composition thereof in the preparation of medicines used for treating autoimmune diseases or proliferative diseases.
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-
Paragraph 0505; 0506; 0507; 0508
(2017/08/27)
-
- NOVEL COMPOUNDS AS INHIBITORS OF DNA METHYLTRANSFERASES
-
It relates to the compounds of formula (I), or their pharmaceutically or veterinary acceptable salts, or their stereoisomers or mixtures thereof, wherein A, R1, R2, and R3 are as defined herein, which are inhibitors of one or more DNMTs selected from the group consisting of DNMT1, DNMT3A and DNMT3B. It also relates to pharmaceutical or veterinary compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of cancer, fibrosis and/or immunomodulation.
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-
Page/Page column 55; 56
(2017/08/01)
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- HYDRAZINE COMPOUND AS BLOOD COAGULATION FACTOR Xa INHIBITOR
-
Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is selected from a 3-9 membered carbon ring or its phenyl ring, and a 4-10 membered heterocyclic ring or its benzo ring; Y and Z are independently selected from 4-9 membered saturated heterocyclic rings respectively; RI-3 are independently selected from H, F, Cl, Br, I, CN, OH, SH,NH2, CHO, COOH respectively, or selected from C1-10 alkyls or heteroalkyls optionally substituted by R01, C3-10 alkyls ring hydrocarbon groups or heterocyclic hydrocarbon groups, C1-10 alkyls or heteroalkyls substituted by C3-10 ring hydrocarbon groups or heterocyclic hydrocarbon group. The compound can be used as an anticoagulant for treating and preventing thrombotic disorders, and can meet the real needs of selectivity and a potent inhibitor for coagulation Xa.
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-
Paragraph 0110
(2017/04/11)
-
- NOVEL PYRROLIDINE DERIVED BETA 3 ADRENERGIC RECEPTOR AGONISTS
-
The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of b3-adrenoceptor. Formula (I).
- -
-
Paragraph 0089; 0090
(2017/04/21)
-
- Crizotinib intermediate, preparation method and crizotinib preparation method
-
The invention relates to a crizotinib intermediate, a preparation method and a crizotinib preparation method, in particular to an intermediate of crizotinib which has the structure of a formula (CZT-5) as shown in the description and the structure of a formula (CZT-9) as shown in the description, a preparation method of the intermediate and a preparation method of a crizotinib with the structure of a formula (CZT-11). The method provided by the invention has the characteristics of short route, high yield, easiness in acquisition of raw materials, high reaction selectivity and the like, chiral resolution is not required in a synthetic process, the utilization rate of the raw materials is increased, the path costs are low, and therefore, the method can meet requirements of large-scale industrial production.
- -
-
Paragraph 0058; 0059
(2017/08/28)
-
- GLYCOSIDASE INHIBITORS
-
Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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-
Page/Page column 104; 105
(2017/09/15)
-
- COMPOUNDS FOR BINDING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
-
The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).
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-
-
- Preparation method for piperazine derivative
-
The invention discloses a preparation method for a piperazine derivative (4-(4-methyl benzoyl) piperazine-1-yl) piperidine-1-tert-butyl formate. 4-hydroxy piperazine is taken as an initial raw material and then is subjected to Boc, condensation, nucleophilic substitution and amidation so as to acquire a target product. The compound is an important medical intermediate.
- -
-
-
- Nitrogen-containing, fluoroalkyl sulfonyl chloride method for the preparation of (by machine translation)
-
The invention discloses a nitrogen-containing, fluoroalkyl sulfonyl chloride method for preparing, by containing nitrogen/perfluoroalkyl alcohol as the raw material, under the alkaline condition and a sulfonyl chloride the reaction produces the corresponding nitrogen-containing/perfluoroalkyl sulfonate ester, then nitrogen-containing/perfluoroalkyl sulfonate ester with a thio acetic acid potassium generating affinity substitution reaction to produce the nitrogen-containing/Fluoalkyl thiophosphoro acetate, then the chlorine treatment to obtain nitrogen-containing/fluoroalkyl sulfonyl chloride. The synthesis of this invention containing nitrogen (fluoro) alkyl sulfonyl chloride, the compound is a drug, pesticide research and development and production of important pharmaceutical intermediate, the compound of preparation of the alkyl sulfonyl chloride synthesis of pharmaceutical intermediates database, to the market to provide alkyl sulfonyl chloride can be synthetic fragment. Raw materials used in the present invention chemical reagent is commercially available, low cost, short synthetic route, high yield, high product purity chemical, provides high-purity products, so as to obtain higher economic benefits. (by machine translation)
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-
Paragraph 0023; 0033; 0034; 0057; 0058
(2016/10/10)
-
- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
-
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 0476; 0477
(2016/07/05)
-
- Preparation and applications of 2,4-disubstituted heterocyclic triazole compound having ALK and c-met inhibition activity
-
The present invention relates to preparation and applications of a 2,4-disubstituted heterocyclic triazole compound represented by a formula (I), wherein R1 and R2 are defined in the specification. According to the present invention, the compound represented by the formula (I) is the ALK and c-Met kinase inhibitor, the downstream signal cascade pathway is terminated by blocking the signal pathway so as to provide the cancer cell proliferation inhibition effect; and the compound represented by the formula (I) can be used as the potential anti-cancer therapy drug. The formula (I) is defined in the specification.
- -
-
Paragraph 0065; 0066; 0067
(2016/10/08)
-
- GLYCOSIDASE INHIBITORS
-
Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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-
Page/Page column 104
(2016/03/22)
-
- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
-
The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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-
Paragraph 0262; 0263
(2016/08/17)
-
- Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders
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Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key
- Xu, Heng,Lu, Hongfu,Xu, Zhongmiao,Luan, Linbo,Li, Chengyong,Xu, Yan,Dong, Kelly,Zhang, Jinqiang,Li, Xiong,Li, Yvonne,Liu, Gentao,Gong, Sophie,Zhao, Yong-Gang,Liu, Ailian,Zhang, Yueting,Zhang, Wei,Cai, Xin,Xiang, Jia-Ning,Elliott, John D.,Lin, Xichen
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supporting information
p. 397 - 402
(2016/05/19)
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- Novel anti-tumor compound
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The invention provides a pyrazolopyridine derivative anti-tumor compound with excellent anti-tumor activity. The anti-tumor compound is shown as a formula I, wherein X represents -NH2, -NHOH, -NHX, amino acid residue and the like (shown as the accompanying diagram); Y represents hydrogen atoms, alkyl groups, naphthenic bases, benzyl groups, aryl groups, heteroaryl, alkyl amino groups, -COX2 or -CONHX3, wherein the aryl group, the heteroaryl and the alkyl group are respectively, independently and randomly substituted by one or a plurality of materials from halogen, trifluoromethyl, amino groups, alkyl amino groups, hydroxyl, hydroxyalkyl, alkoxy, cyanogroup, nitryl, aryl groups and heteroaryl; the definitions of R1, R2, X1 and X2 are identical to the definitions in the specifications. The invention also provides a preparation method of an anti-tumor agent and application of the anti-tumor agent to lung cancer, colon cancer and ovarian cancer anti-tumor medicine.
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Paragraph 0106; 0107
(2016/10/09)
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- Novel pyrazolopyridine antineoplastic compound
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The invention provides a novel pyrazolopyridine antineoplastic compound with excellent antineoplastic activity. The antineoplastic compound is shown as the formula I, wherein M groups are freely selected from hydrogen atoms, alkyl groups and naphthenic groups, Y represents N atom site substituted or non-substituted nitrogen atom containing 5-8 membered rings, and the substituent group is a -X1 group or -CO2X2 or -COX3 or -CONHX4. The definitions of X1, X2, X3 and X4 are the same as definitions in the description. The invention further provides a preparation method of the antineoplastic compound and an application of the antineoplastic compound in antineoplastic drugs for lung cancer, colon cancer and ovarian cancer. The compound has good antineoplastic activity. The formula is shown in the description.
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Paragraph 0090; 0091
(2016/10/09)
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- With anti-platelet aggregation activity of the piperidinyl substituted 5- hydroxy color acid derivatives
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The invention relates to the field of pharmaceutical chemistry, particularly piperidyl substituted 5-hydroxytryptophane derivatives (I) with anti-platelet aggregation activity, and a preparation method and pharmaceutical application thereof, wherein R1, R2 and n are defined in the specification. The pharmacodynamical test proves that the piperidyl substituted 5-hydroxytryptophane derivatives have favorable anti-platelet aggregation activity.
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Paragraph 0057; 0058
(2017/02/09)
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- Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization
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Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
- Kuhne, Sebastiaan,Kooistra, Albert J.,Bosma, Reggie,Bortolato, Andrea,Wijtmans, Maikel,Vischer, Henry F.,Mason, Jonathan S.,De Graaf, Chris,De Esch, Iwan J.P.,Leurs, Rob
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p. 9047 - 9061
(2016/10/22)
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- Pyridone protein kinase inhibitor
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The invention discloses a compound capable of regulating protein kinase activity and used for treating or preventing diseases related to protein kinase, particularly relates to a pyridone protein kinase inhibitor, belongs to compounds for regulating anaplastic lymphoma kinase (ALK) activity, and provides a preparation method of the compounds and pharmaceutical application of the compounds to the treatment or prevention of the diseases related to ALK.
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Paragraph 0088; 0092; 0093
(2017/04/19)
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- SUBSTITUTED BENZAMIDES AND METHODS OF USE THEREOF
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The invention provides compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein the variables RA, RAA, subscript n, ring A, X2, L, subscript m, X1, R1, R2, R3, R4, R5, and RN have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
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Page/Page column 618; 634
(2015/06/11)
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