cas 55052-24-9, 7-OXIDE-7-AZAINDOLE | Articles data

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Synthesis and structure?activity?relationship of 3,4?Diaryl?1H?pyrrolo[2,3?b]pyridines as irreversible Inhibitors of mutant EGFR?L858R/T790M
The epidermal growth factor receptor (EGFR) is a well?validated drug target for the treatment of non?small cell lung cancer. Here we present an optimization approach and preliminary structure?activity relationship for 1H?pyrrolo[2,3?b]pyridines as covalent irreversible mutant EGFR inhibitors. We synthesized a focused library to investigate the effect of different aromatic substituents in the 4?position of this scaffold, interacting with the gatekeeper. We determined the activity of the synthesized compounds mutant EGFR enzyme assays and determined the selectivity over the wild type.
Günther, Marcel,Laux, Julian,Laufer, Stefan
p. 91 - 96
(2019)
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Synthesis and biological evaluation of 7-azaindole derivatives, synthetic cytokinin analogues
Cytokinins, N6-substituted adenine derivatives, are plant hormones playing important roles in various processes in plant development. Furthermore, cytokinins and their derivatives are able to control mammalian cell apoptosis and differentiation. The aim of our study was the synthesis of 7-azaindole derivatives as cytokinin analogues with the Hartwig-Buchwald coupling reaction in order to evaluate their biological properties on human myeloblastic leukaemia cells (HL-60 cell line). All these compounds presented a cytotoxic activity on HL-60 cells especially the 4-phenylaminopyrrolo[2,3-b]pyridine and the 4-phenethylaminopyrrolo[2,3-b]pyridine.
Guillard, Jerome,Decrop, Maylis,Gallay, Nathalie,Espanel, Claire,Boissier, Elodie,Herault, Olivier,Viaud-Massuard, Marie-Claude
p. 1934 - 1937
(2007)
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Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia
Serine/threonine-protein kinases 3 and 4 (STK3 and STK4, respectively) are key components of the Hippo signaling pathway, which regulates cell proliferation and death and provides a potential therapeutic target for acute myeloid leukemia (AML). Herein, we
Bakas, Nicole A.,Bata, Nicole,Berger, Lena M.,Celeridad, Maria,Chaikuad, Apirat,Cosford, Nicholas D. P.,Dong, Jing,Knapp, Stefan,Lambert, Lester J.,Layng, Fabiana,Limpert, Allison S.,Liu, Guoxiong,Peng, Yi,Sheffler, Douglas J.,Wang, Li,Yuan, Cunxiang
p. 1352 - 1369
(2021/12/06)

AZAINDOLE CARBOXAMIDE COMPOUNDS FOR THE TREATMENT OF MYCOBACTERIAL INFECTIONS
Provided herein are compounds of Formula (I) and Formula (II): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of tuberculosis.
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Page/Page column 271-272

(2021/04/02)

DERIVATIVES OF AN FGFR INHIBITOR
The present disclosure relates to derivatives (e.g., hydroxyl, keto, glucuronide, sulfonic acid, and deuterated) of a Fibroblast Growth Factor Receptors (FGFR) inhibitor, including methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of FGFR mediated disease such as cancer.
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Paragraph 0210-0211

(2021/06/11)

MACROCYCLIC INHIBITORS OF PEPTIDYLARGININE DEIMINASES
The present disclosure relates to novel compounds for use in therapeutic treatement of a disease associated with peptidylarginine deiminases (PADs), such as peptidylarginine deiminase type 4 (PAD4). The present disclosure also relates to processes and intermediates for the preparation of such compounds, methods of using such compounds and pharmaceutical compositions comprising the compounds described herein.
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Page/Page column 188; 224-225

(2021/11/06)

Ligand compound for copper catalyzed aryl halide coupling reaction, catalytic system and coupling reaction
The invention provides a ligand compound capable of being used for copper catalyzed aryl halide coupling reaction, the ligand compound is a three-class compound containing a 2-(substituted or non-substituted) aminopyridine nitrogen-oxygen group, and the invention also provides a catalytic system for the aryl halide coupling reaction. Thecatalytic system comprises a copper catalyst, a compound containing a 2-(substituted or non-substituted) aminopyridine nitrogen-oxygen group adopted as a ligand, alkali and a solvent, and meanwhile, the invention also provides a system for the aryl halide coupling reaction adopting the catalyst system. The compound containing the 2-(substituted or non-substituted) aminopyridine nitrogen oxygen group can be used as the ligand for the copper catalyzed aryl chloride coupling reaction, and the ligand is stable under a strong alkaline condition and can well maintain catalytic activity when being used for the copper-catalyzed aryl chloride coupling reaction. In addition, the copper catalyst adopting the compound as the ligand can particularly effectively promote coupling of copper catalyzed aryl chloride and various nucleophilic reagents which are difficult to generate under conventional conditions, C-N, C-O and C-S bonds are generated, and numerous useful small molecule compounds are synthesized. Therefore, the aryl halide coupling reaction has a very good large-scale application prospect by adopting the copper catalysis system of the ligand.
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Paragraph 0047; 0053-0056; 0058

(2021/05/29)

Cu(II)-catalyzed sulfonylation of 7-azaindoles using DABSO as SO2-Source and its mechanistic study
DABSO mediated sulfonylation of iodinated 7-azaindoles was achieved for the first time through sulfonylative Suzuki-Miyaura cross coupling (SMC) reaction under mild conditions giving good yields of sulfonylated 7-azaindole derivatives. Interestingly, control experiments suggest that present method involves in-situ generation of ArSO2 free radical followed by the key steps of SMC reaction. Scope of the reaction was explored with both electronically different and bulky group carrying boronic acids as coupling partner. The sulfonylation is scalable and occurred selectively at iodo group, irrespective of its position on azaindole. Moreover, the proposed mechanism has been supported by electron paramagnetic resonance (EPR) and density functional theory (DFT) calculations.
Urvashi,Dar, Mohammad Ovais,Bharatam, Prasad V.,Das, Parthasarathi,Kukreti, Shrikant,Tandon, Vibha
(2020/06/23)

Method for synthesizing Meriolin
The invention belongs to the field of medicinal chemistry, and concretely relates to a method for synthesizing Meriolin. The method comprises the following steps: 7-azaindole used as a raw material undergoes an oxidation reaction to generate an intermediate 2; the intermediate 2 undergoes a halogenations reaction to generate an intermediate 3; the intermediate 3 is subjected to a Friedel-Crafts acylation to generate an intermediate 4; and the amino group of the intermediate 4 is protected to obtain an intermediate 5, the intermediate 5 undergoes an alkylation reaction to generate an intermediate 6, and the intermediate 6 is cyclized to obtain the target products Merilin 10 and Meriolin 7. The method adopting the inexpensive 7-azaindole as the raw material has the advantages of simple operation steps, mild reaction conditions, avoiding the use of CO, high temperature, high pressure and expensive Pd catalytic reagent and hazardous chemicals, obtaining of the Meriolin 10 and Meriolin 7 ata high yield, and provision of a new idea for the synthesis of Meriolins series new derivatives.
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Paragraph 0019; 0041-0043; 0054-0056; 0067-0069

(2019/07/01)

COMPOUNDS FOR USING IN IMAGING AND PARTICULARLY FOR THE DIAGNOSIS OF NEURODEGENERATIVE DISEASES
The invention relates to compounds of formula (II) for using in imaging and particularly for the diagnosis of neurodegenerative diseases
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Paragraph 0594; 0595

(2019/07/23)

Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors
Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound 6f significantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.
Liu, Bin,Yuan, Xia,Xu, Bo,Zhang, Han,Li, Ridong,Wang, Xin,Ge, Zemei,Li, Runtao
p. 1 - 15
(2019/03/17)

SOLID FORMS OF AN FGFR INHIBITOR AND PROCESSES FOR PREPARING THE SAME
The present disclosure relates to 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, solid forms and polymorphs thereof, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the FGFR-associated or mediated diseases such as cancer.
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Page/Page column 86-87

(2019/11/19)

Preparation method of drug composition for treating febrile convulsion in children
The invention relates to a preparation method of a drug composition for treating febrile convulsion in children. The method comprises a route as shown in the specification. A treatment mechanism of the drug of the invention is to prolong the convulsion latency of a febrile convulsion patient, shorten the convulsion duration, relieve the convulsion seriousness, inhibit apoptosis of hippocampal neurons, regulate the levels of GABA and Glu, relieve the cerebral injury of febrile convulsion patient and finally achieve the purpose of treating the febrile convulsion.
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Paragraph 0017; 0018; 0019; 0020; 0021

(2019/01/08)

(AZA)INDOLE-, BENZOTHIOPHENE-, AND BENZOFURAN-3-SULFONAMIDES
Disclosed are sulfonamide compounds with GPR17 modulating properties, which are useful for treating or preventing a variety of CNS and other diseases, in particular for preventing and treating myelinating diseases or disorders.
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Page/Page column 241; 242

(2018/07/29)

Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors – Part I
Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.
Barberis, Claude,Moorcroft, Neil,Arendt, Chris,Levit, Mikhail,Moreno-Mazza, Sandra,Batchelor, Joseph,Mechin, Ingrid,Majid, Tahir
p. 4730 - 4734
(2017/09/27)

OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
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Paragraph 0590; 0591

(2017/03/14)

Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping
The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38α MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established. As a result, we report two reversible inhibitors 11d and 11e of the clinically challenging triple mutant L858R/T790M/C797S with IC50 values in the low nanomolar range. Furthermore, we developed a kinome selective irreversible inhibitor 45a with an IC50 value of 1 nM against the EGFR L858R/T790M double mutant. Target binding kinetics and metabolic stability data are included. These potent mutant EGFR inhibitors may serve as a basis for the development of structurally novel EGFR probes, tools, or candidates.
Juchum, Michael,Günther, Marcel,D?ring, Eva,Sievers-Engler, Adrian,L?mmerhofer, Michael,Laufer, Stefan
supporting information
p. 4636 - 4656
(2017/06/13)

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer's disease
The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.
Sreenivasachary, Nampally,Kroth, Heiko,Benderitter, Pascal,Hamel, Anne,Varisco, Yvan,Hickman, David T.,Froestl, Wolfgang,Pfeifer, Andrea,Muhs, Andreas
p. 1405 - 1411
(2017/03/08)

4-chloro-7-azaindole and preparation method thereof
The invention discloses 4-chloro-7-azaindole and a preparation method thereof. The preparation method comprises the following steps: reacting by virtue of 7-azaindole and an oxidant, and stirring at 5-10 DEG C for 2-4 hours, so as to obtain 7-azaindole oxide; reacting by virtue of 7-azaindole oxide and sodium hydrogen sulfite to generate N-oxide-dihydro-7-azaindole-2-sodium sulfonate; and reacting by virtue of N-oxide-dihydro-7-azaindole-2-sodium sulfonate and phosphorus oxychloride for 2-3 hours under the protection of nitrogen and the catalysis of a catalyst, then adding sodium hydroxide, carrying out oxidative dehydrogenation, and removing organic solvents by virtue of a rotary evaporator, so as to obtain a medical intermediate of 4-chloro-7-azaindole. The medical intermediate of 4-chloro-7-azaindole, prepared by virtue of the preparation method, is high in purity and synthesis ratio and low in production cost.
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Paragraph 0022; 0023

(2016/11/21)

5 - thiazole amides and biological applications
The invention relates to a 5-thiazole amide compound and biology application thereof. The 5-thiazole amide compound has a general formula (I) described in the specification and is used for targeting an AKT/PKB kinase (ATP binding site). Experiments prove that a thiazole amide AKT inhibitor can remarkably inhibit the activity of the AKT kinase in vitro and has strong proliferation inhibition function on various tumor cells with high AKT activity, which indicate that the 5-thiazole amide compound can be used for preparing drugs for resisting tumors.
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Paragraph 0257; 0260-0264

(2018/09/26)

Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
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Page/Page column 362

(2016/04/26)

ARYLOXYACETYLINDOLES AND ANALOGS AS ANTIBIOTIC TOLERANCE INHIBITORS
The disclosure provides compounds and pharmaceutical compositions of aryloxyacetylindoles compounds and analogs useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds of general Formula (I) (I) or a pharmaceutically acceptable salt or prodrug thereof. Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa. Methods of treating bacterial infections in a subject, including Pseudomonas aeruginosa infections, are also provided by the disclosure.
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Paragraph 0445

(2016/08/10)

Synthetic method of 6-chloro-7-azaindole
The invention discloses a synthetic method of 6-chloro-7-azaindole, belonging to the field of chemical synthesis. 7-azaindole is taken as a raw material, and the 6-chloro-7-azaindole is synthesized by three actions of N-oxidation, chlorination and hydrolysis. The process route is optimized, and the yield is improved by 70% or more, and is improved by 7% compared with the prior art. The improved synthetic route is simple to operate and feasible, the economic benefits are effectively improved, and large-scale industrial promotion is facilitated.
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Paragraph 0037; 0038; 0039; 0040

(2017/01/02)

Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition
A solution-phase parallel synthesis of triazole-derived ruxolitinib analogues was developed in the current study. The method employs copper-catalyzed azide-alkyne cycloaddition to build up the central triazole template. Product isolation by precipitation
Gehringer, Matthias,Forster, Michael,Laufer, Stefan A.
supporting information
p. 5 - 10
(2015/01/30)

TRICYCLIC PYRROLOPYRIDINE COMPOUND, AND JAK INHIBITOR
To provide a novel tricyclic pyrrolopyridine compound having a JAK inhibitory activity and useful for prevention, treatment and/or improvement of particularly autoimmune diseases, inflammatory diseases and allergic diseases. A novel tricyclic pyrrolopyridine compound represented by the formula (I), a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof: wherein the respective substituents are defined in detail in the specification, and R1 is a C1-6 alkyl group or the like, R2 is a hydrogen atom or the like, R3 is a hydrogen atom or the like, the ring A is C3-11 cycloalkane or the like, L1 is a C1-6 alkylene group or the like, and R4 is NRaRb or the like.
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Paragraph 0145; 0146

(2016/01/01)

BICYCLIC HETEROAROMATIC COMPOUNDS
Compounds of the formula I, in which X1, X2, X3, X4, X5, R1, R2, R3, R4, R5 and R6 have the meanings indicated in Claim 1, are kinase inhibitors and can be employed, inter alia, for the treatment of tumours.
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Paragraph 0309; 0310

(2015/09/22)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
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Page/Page column 76

(2015/02/19)

Design and synthesis of tricyclic jak3 inhibitors with picomolar affinities as novel molecular probes
The Janus kinase (JAK) signaling pathway is of particular importance in the pathology of inflammatory diseases and oncological disorders, and the inhibition of Janus kinase 3 (JAK3) with small molecules has proven to provide therapeutic immunosuppression. A novel class of tricyclic JAK inhibitors derived from the 3-methyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine scaffold was designed based on the tofacitinib-JAK3 crystal structure by applying a rigidization approach. A convenient synthetic strategy to access the scaffold via an intramolecular Heck reaction was developed, and a small library of inhibitors was prepared and characterized using in vitro biochemical as well as cellular assays. IC50 values as low as 220 pm could be achieved with selectivity for JAK3 over other JAK family members. Both activity and selectivity were confirmed in a cellular STAT phosphorylation assay, providing also first-time data for tofacitinib. Our novel inhibitors may serve as tool compounds and useful probes to explore the role of JAK3 inhibition in pharmacodynamics studies.
Gehringer, Matthias,Pfaffenrot, Ellen,Bauer, Silke,Laufer, Stefan A.
supporting information
p. 277 - 281
(2014/04/03)

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors
7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals
Cincinelli, Raffaella,Musso, Loana,Merlini, Lucio,Giannini, Giuseppe,Vesci, Loredana,Milazzo, Ferdinando M.,Carenini, Nives,Perego, Paola,Penco, Sergio,Artali, Roberto,Zunino, Franco,Pisano, Claudio,Dallavalle, Sabrina
p. 1089 - 1103
(2014/02/14)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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Paragraph 00641

(2014/10/04)

Aurora Kinase Modulators and Method of Use
The present invention relates to chemical compounds having a general formula I wherein A1-8, D′, L1, L2, R1, R6-8 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.
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(2014/11/27)

New CRTh2 antagonists
The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.
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Paragraph 0430-0433

(2013/03/26)

Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors
Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.
Heinrich, Timo,Seenisamy, Jeyaprakashnarayanan,Emmanuvel, Lourdusamy,Kulkarni, Santosh S.,Bomke, J?rg,Rohdich, Felix,Greiner, Hartmut,Esdar, Christina,Krier, Mireille,Gr?dler, Ulrich,Musil, Djordje
p. 1160 - 1170
(2013/04/10)

RING-FUSED COMPOUND
The present invention relates to a compound that has URAT1 inhibitory action, and a URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition comprising the compound. More specifically, the present invention relates to a compound represented by Formula (I) below. [in the formula, R1 is -Q1-A1 and the like; ---- is a double bond or a single bond; when ---- is a double bond, W1 is a nitrogen atom or a group represented by the general formula: =C(Ra)-, and W2 is a nitrogen atom or a group represented by the general formula: =C(Rb) -; when ---- is a single bond, W1 is a group represented by the general formula: -C(Raa)(Rab)- or a group represented by the general formula: -(C=O) -, and W2 is a group represented by the general formula: C(Rba)(Rbb)-, a group represented by the general formula: - (C=O) - or a group represented by the general formula: -N(Rbc)-; W3, W4 and W5 are each independently a nitrogen atom or a methine group and the like that may have a substituent; X is a single bond, an oxygen atom and the like; Y is a single bond or (CRYiRYi')n; and Z is a hydroxyl group or COOR2 and the like.
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Paragraph 0652-0653

(2014/01/07)

NEW CRTH2 ANTAGONISTS
The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.
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Page/Page column 99

(2013/03/26)

New thiazole carboxamides as potent inhibitors of Akt kinases
A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit N-(1-amino-3-phenylpropan-2-yl)- 2-phenylthiazole-5-carboxamide (1). One of the most potent compounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC50 values of 25, 196 and 24 nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2 and GSK3β proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhibitors might serve as lead compounds for further development of novel effective anticancer agents.
Chang, Shaohua,Zhang, Zhang,Zhuang, Xiaoxi,Luo, Jinfeng,Cao, Xianwen,Li, Honglin,Tu, Zhengchao,Lu, Xiaoyun,Ren, Xiaomei,Ding, Ke
supporting information; experimental part
p. 1208 - 1212
(2012/03/11)

Scaffold-hopping strategy: Synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents
Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shufflin
Tung, Yen-Shih,Coumar, Mohane Selvaraj,Wu, Yu-Shan,Shiao, Hui-Yi,Chang, Jang-Yang,Liou, Jing-Ping,Shukla, Paritosh,Chang, Chun-Wei,Chang, Chi-Yen,Kuo, Ching-Chuan,Yeh, Teng-Kuang,Lin, Chin-Yu,Wu, Jian-Sung,Wu, Su-Ying,Liao, Chun-Chen,Hsieh, Hsing-Pang
scheme or table
p. 3076 - 3080
(2011/06/25)

Design and synthesis of 1-(2-alkanamidoethyl)-6-methoxy-7-azaindole derivatives as potent melatonin agonists
A series of 7-azaindolic ligands bearing a methoxy group and a N-acetyl chain as melatoninergic pharmacophores were synthesized and their binding affinities towards MT1 and MT2 receptors were evaluated. Compounds 7a-c and 12 (cyclohe
Jeanty, Matthieu,Suzenet, Franck,Delagrange, Philippe,Nosjean, Olivier,Boutin, Jean A.,Caignard, Daniel H.,Guillaumet, Gérald
supporting information; experimental part
p. 2316 - 2319
(2011/05/15)

BICYCLIC PYRIDINES AND ANALOGS AS SIRTUIN MODULATORS
Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
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Page/Page column 140

(2011/06/16)

Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
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Page/Page column 39

(2011/11/30)

Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)
Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC 50 = 1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.
Chowdhury, Sarwat,Sessions, E. Hampton,Pocas, Jennifer R.,Grant, Wayne,Schr?ter, Thomas,Lin, Li,Ruiz, Claudia,Cameron, Michael D.,Schürer, Stephan,Lograsso, Philip,Bannister, Thomas D.,Feng, Yangbo
scheme or table
p. 7107 - 7112
(2012/01/05)

CHEMICAL COMPOUNDS
There is provided pyrimidinyl compounds of Formula (I), wherein: R2 is or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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(2012/01/03)

NOVEL COMPOUNDS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH AMYLOID OR AMYLOID-LIKE PROTEINS
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer?s disease, and of diseases or conditions associated with amyloid-like prote
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(2011/11/01)

Improved synthesis of the selective rho-kinase inhibitor 6-chloro-n4-{3,5-difluoro-4-[(3-methyl-1h-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl} pyrimidin-2,4-diamine
A highly potent and selective Rho-kinase inhibitor containing a 7-azaindole moiety has been developed at Bayer Schering Pharma. Herein we disclose details of a significantly improved synthesis of the compound in 8.2% overall yield. Key aspects include cost and safety considerations and the uncommon use of a trifluoromethyl group with controllable reactivity as a masked methyl group.
Schirok, Hartmut,Paulsen, Holger,Kroh, Walter,Chen, Gang,Gao, Ping
scheme or table
p. 168 - 173
(2010/04/29)

3-SUBSTITUTED-1H-INDOLE, 3-SUBSTITUTED-1H-PYRROLO[2,3-B]PYRIDINE AND 3-SUBSTITUTED-1H-PYRROLO[3,2-B]PYRIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
The invention relates to 3-substituted-1H-indole, 3-substituted-1H-pyrrolo[2,3-b]pyridine, and 3-substituted-1H-pyrrolo[3,2-b]pyridine compounds of the Formula (I): or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 120

(2010/04/06)

Discovery of a new potent bisamide FMS kinase inhibitor
FMS is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony stimulating factor (M-CSF or CSF-1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. In this study, we report the discovery of a new potent inhibitor of FMS kinase. The synthesized pyrrolo[3,2-c]pyridine derivative (compound 1) was initially tested at a single concentration of 1 μM against 47 different kinases. At this concentration, the% inhibitions of the enzymatic activities of FMS and KDR kinases were 90% and 71%, respectively, while the inhibition in activity was less than 58% for all of the other kinases. For compound 1, the IC50 values against FMS and KDR were 96 and 1058 nM, respectively. So, compound 1 was found to be 11 times more selective for FMS kinase than KDR kinase. Compound 1 can be used as a promising lead for the development of new selective inhibitors of FMS kinase, which can be used as useful therapeutic tools for treatment of several inflammatory and cancer disorders.
El-Gamal, Mohammed I.,Jung, Myung-Ho,Oh, Chang-Hyun
scheme or table
p. 3216 - 3218
(2010/08/22)

Site-selective azaindole arylation at the azine and azole rings via N-oxide activation
Subjection of N-methyl 6-and 7-azaindole N-oxides to a Pd(OAc) 2/DavePhos catalyst system enables regioselective direct arylation of the azine ring. Following deoxygenation, 7-azaindole substrates undergo an additional regioselective azole direct arylation event in good yield.
Huestis, Malcolm P.,Fagnou, Keith
supporting information; experimental part
p. 1357 - 1360
(2009/09/05)

Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitor
Seefeld, Mark A.,Rouse, Meagan B.,McNulty, Kenneth C.,Sun, Lihui,Wang, Jizhou,Yamashita, Dennis S.,Luengo, Juan I.,Zhang, ShuYun,Minthorn, Elisabeth A.,Concha, Nestor O.,Heerding, Dirk A.
scheme or table
p. 2244 - 2248
(2009/12/07)

3-SUBSTITUTED-1H-PYRROLO[2,3-B]PYRIDINE AND 3-SUBSTITUTED-1H-PYRROLO[3,2-B]PYRIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
The invention relates to 3-substituted-1H-pyrrolo[2,3-b]pyridine, and 3-substituted-1H-pyrrolo[3,2-b]pyridine compounds of the Formula 1: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 36-37

(2009/12/23)

PYRROLOPYRIDINES AS KINASE INHIBITORS
Compounds of Formula (I) are useful for inhibition of CHKl and/or CHK2. Methods of using compounds of Formula (I) and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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(2009/12/23)

AMINE DERIVATIVES USEFUL AS ANTICANCER AGENTS
The invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: A is a moiety of formula (Il) and to pharmaceutically acceptable salts and solvates thereof, wherein X, Z, D, E, V, W, Y, R1, R2, R5, R6, L, and u are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula I to a patient in need thereof, and to compositions for treating such disorders which contain the compounds of formula (I). The invention also relates to methods of making the compounds of formula (I).
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Page/Page column 80

(2010/11/30)