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4-Amino-pyrrolopyridine-5-carboxamide: A novel scaffold for JAK1-selective inhibitors
Despite a high level of interest in selective Janus kinase 1 (JAK1) inhibitors and their potential for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), only a few such inhibitors have been reported to date. In this study, a novel 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C2-methyl imidazopyrrolopyridine. Among the series studied, the 4-(2-aminoethyl)amino-pyrrolopyridine derivative, 2j, exhibited a significant 24.7-fold JAK1/JAK2 selectivity along with reasonable inhibitory activity against JAK1 (IC50=2.2 μM). The noticeable JAK1-selectivity of 2j was then tackled through a molecular docking study, which showed that the aminoethyl functionality of 2j is well positioned to discriminate the subtle but significant difference in the size of the ligand binding sites between JAK1 and JAK2.
Shin, Heerim,Kim, Mi Kyoung,Chong, Youhoon
p. 217 - 220
(2014)
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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; 0212

(2021/06/11)

Design and synthesis of 7-azaindole derivatives and their antitumor and analgesic activities
To develop effective anti-tumor and analgesic drugs, a series of novel 7-azaindole derivatives were designed and synthesized through a four-step reaction. 18 target compounds were obtained and characterized through Nuclear Magnetic Resonance and High Resolution Mass Spectrometry. Their anti-proliferative activities and analgesic effect were evaluated. When the 1-position was a methylsulfonyl group and the 5-position was a nitro group, compound 4f demonstrated the best activity. Furthermore, there was a dramatic difference between the IC50 values of compound 4f in tumor and in healthy cell line. The IC50 values of compound 4f in MCF7 breast cancer cell line was 5.781 μmol/L and 8.077 μmol/L in HepG2 hepatoma carcinoma cell line, but more than 100 μmol/L in HL7702 liver cell line. Preliminary results showed that compounds 3a, 3g and 4i had significant analgesic effects in mice, which were stronger than aspirin. These compounds have good prospects for new drug development.
Liu, Xue-Kun,Wang, Yan-Qiu,Zhao, Tong-Jian,Lu, Yuan-Hua,Zhao, Jia-Nan,Geng, Xiao-Yu,Ma, Jie
p. 460 - 467
(2021/01/20)

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 0009; 0041; 0044-0045; 0054; 0057-0058; 0067; 0071

(2019/07/01)

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
(2018/12/04)

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)

Pyrrolo[3,2-c]pyridine derivatives with potential inhibitory effect against FMS kinase: in vitro biological studies
A series of eighteen pyrrolo[3,2-c]pyridine derivatives were tested for inhibitory effect against FMS kinase. Compounds 1e and 1r were the most potent among all the other tested analogues (IC50 = 60 nM and 30 nM, respectively). They were 1.6 and 3.2 times, respectively, more potent than our lead compound, KIST101029 (IC50 = 96 nM). Compound 1r was tested over a panel of 40 kinases including FMS, and exerted selectivity against FMS kinase. It was further tested against bone marrow-derived macrophages (BMDM) and its IC50 was 84 nM (2.32-fold more potent than KIST101029 (IC50 = 195 nM)). Compound 1r was also tested for antiproliferative activity against a panel of six ovarian, two prostate, and five breast cancer cell lines, and its IC50 values ranged from 0.15–1.78 μM. It possesses also the merit of selectivity towards cancer cells than normal fibroblasts.
El-Gamal, Mohammed I.,Oh, Chang-Hyun
p. 1160 - 1166
(2018/08/12)

A new synthetic process of the pyrrole compounds and the use of the anti-tumor effect (by machine translation)
The present invention discloses a new synthetic process of the pyrrole compounds and the use of the anti-tumor effect, and in particular relates to compounds 1 - benzenesulfonyl - 4 - chloro - 5 - nitro - 1 H - pyrrolo [2, 3 - b] pyridine, hydrate and its salt of new synthetic process and the use of the anti-tumor effect, this synthesis process takes 1 H - pyrrolo [2, 3 - b] pyridine as the starting material, after chloro-, prepared by acylation reaction such as 1 - benzenesulfonyl - 4 - chloro - 5 - nitro - 1 H - pyrrolo [2, 3 - b] pyridine, hydrate and its salt, provides a simple operation, high yield of the new process, the preparation method is simple, mild reaction conditions, at the same time the compound anti-tumor activity is prominent, little toxicity to normal cell, is favorable to its anti-tumor field widely popularized. (by machine translation)
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Paragraph 0017

(2018/12/05)

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)

Production technology for 4-chlorine-7-azaindole
The invention relates to a production technology for 4-chlorine-7-azaindole. The technology comprises the following steps: adding N-oxo-7-azaindole and tetrahydrofuran into a reaction flask, opening and stirring; adding methylsulfonyl chloride while stirring and naturally releasing heat; heating, preserving heat and stirring till completely consuming the raw materials; after completely consuming the raw materials, reducing temperature to 15 DEG C, controlling the temperature within 15 DEG C-20 DEG C, dropwise adding sodium hydroxide aqueous solution, separating liquid for separating aqueous phase and washing with water; spin-steaming and removing dissolvent from organic phase, thereby acquiring a dark brown solid; using dichloromethane for pulping, thereby acquiring a faint yellow solid, namely, 4-chlorine-7-azaindole. The methylsulfonyl chloride is simultaneously used as a chloride agent and a water removing agent, so that the cost is saved and the operation difficulty is reduced; the special solubility property of the product is utilized, the dichloromethane with excellent solubility is used for pulping and purifying and the effect is excellent; the production technology is easily controlled and is convenient for industrialization and the product is high in purity.
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Paragraph 0009; 0012; 0015; 0016; 0017

(2017/11/16)

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)

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)

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 0040

(2016/11/21)

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 0147; 0148

(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 0311-0315

(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)

4-Amino-7-azaindole-5-carboxamide derivatives selectively inhibiting the activity of Janus kinase 1
In the present invention, provided are a 4-amino-7-azaindole-5-carboxamide derivative and the property of the 4-amino-7-azaindole-5-carboxamide for selectively inhibiting the activity of Janus kinase 1 and uses of the 4-amino-7-azaindole-5-carboxamide used as a drug for treating rheumatoid arthritis. For this, provided is a compound of chemical formula 1 or a pharmaceutical acceptable salt thereof.
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Paragraph 0048; 0049

(2016/11/17)

Cell-based biological evaluation of a new bisamide FMS kinase inhibitor possessing pyrrolo[3,2-c]pyridine scaffold
A bisamide compound 1 possessing the pyrrolo[3,2-c]pyridine nucleus was synthesized and biologically evaluated. It was tested for kinase inhibitory activity over a panel of 47 kinases, and its selectivity toward the FMS kinase was accidentally discovered. Compound 1 was tested over a panel of seven ovarian, two prostate, and six breast cancer cell lines at a single dose concentration of 10μM and showed high activity. It was further tested in a 5-dose mode to determine its IC50 and total growth inhibition (TGI) values over the 15 cell lines. Compound 1 showed high potency on the submicromolar scale and good efficacy. The cytotoxic effect of compound 1 over peritoneal macrophages was also investigated. Compound 1 demonstrated higher selectivity against different cancer cell lines compared with HS-27 fibroblasts.
El-Gamal, Mohammed I.,Abdel-Maksoud, Mohammed S.,El-Din, Mahmoud M. Gamal,Yoo, Kyung Ho,Baek, Daejin,Oh, Chang-Hyun
p. 635 - 641
(2014/11/12)

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)

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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Paragraph 0329

(2014/11/27)

Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
Hu, Yun-Jin,St.-Onge, Miguel,Laliberté, Sébastien,Vallée, Frédéric,Jin, Shujuan,Bedard, Leanne,Labrecque, Jean,Albert, Jeffrey S.
supporting information
p. 3199 - 3203
(2015/02/19)

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)

AZABICYCLO COMPOUND AND SALT THEREOF
It is intended to provide a novel azabicyclo compound which exhibits both HSP90 inhibitory activity and cell proliferation inhibitory effect. Specifically disclosed is a compound represented by the following general formula (I) or a salt thereof: wherein X1 represents CH or N; any one of X2, X3 and X4 represents N, and the others represent CH; any one or two of Y1, Y2, Y3 and Y4 represent C—R4, and the others are the same or different and represent CH or N; R1 represents an optionally substituted monocyclic or bicyclic unsaturated heterocyclic group having 1 to 4 heteroatoms selected from N, S and O; R2 represents an alkyl group having 1 to 6 carbon atoms, or the like; and R3 and R4 represent —CO—R5 or the like.
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Page/Page column 33

(2012/05/07)

Design and synthesis of an anticancer diarylurea derivative with multiple-kinase inhibitory effect
A diarylurea compound 1 possessing pyrrolo[3,2-c]pyridine nucleus was designed and synthesized with structure similarity to Sorafenib. Compound 1 was tested over 60-cancer cell line panel at a single dose concentration of 10 μM and showed high activity. It was further tested in a five-dose mode to determine its IC50, TGI, and LC50 values over the 60 cell lines. Compound 1 showed high potency and good efficacy, and was accordingly tested at a single dose concentration of 10 μM over a panel of 40 kinases. At this concentration, it completely inhibited the enzymatic activities of a number of oncogenic kinases, including ABL, ALK, c-RAF, FLT3, KDR, and TrkB. The target compound was subsequently tested over these 6 kinases in 10-dose testing mode in order to determine its IC50 values. Copyright
El-Gamal, Mohammed I.,Oh, Chang-Hyun
scheme or table
p. 1571 - 1576
(2012/07/31)

NOVEL ARTIFICIAL FLUORESCENT BASES
The present invention relates to novel unnatural fluorescent nucleic acid bases, that is, a purine base, a 2-deazapurine base, and a 2,7-deazapurine base each having a functional group which consists of two or more heterocyclic moieties linked together, at the 6-position thereof (the 6-position of purine ring). The present invention also relates to a compound containing the unnatural base, a derivative thereof, and a nucleic acid containing a nucleotide having the unnatural base. The present invention also relates to a method of preparing the nucleic acid. The unnatural base of the present invention has excellent fluorescence characteristics and also has excellent properties as a universal base.
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Page/Page column 20

(2012/08/28)

Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines
Synthesis of a new series of diarylureas and diarylamides having 1H-pyrrolo[3,2-c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2-c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives (8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a-e showed the highest potency against A375P with IC50 in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC 50 in micromolar range. Compounds 8b, 8g, 9b-d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI.
El-Gamal, Mohammed I.,Jung, Myung-Ho,Lee, Woong San,Sim, Taebo,Yoo, Kyung Ho,Oh, Chang-Hyun
scheme or table
p. 3218 - 3226
(2011/07/31)

5,6-BICYCLIC HETEROARYL-CONTAINING UREA COMPOUNDS AS KINASE INHIBITORS
The present invention provides 5,6-bicyclic heteroaryl-containing urea compounds of Formula I or II and use of the same for treating conditions mediated by protein kinase such as VEGFR2, c-Met, PDGFRβ c-Kit, CSFlR, or EphA2.
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(2011/04/14)

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)

Desulfonylation of indoles and 7-azaindoles using sodium tert-butoxide
A mild method for the desulfonylation of N-indoles and N-azaindoles is described. Deprotection is carried out under basic conditions, using sodium tert-butoxide in dioxane. Several functionalized indoles and 7-azaindoles were efficiently deprotected by this method, which is mild enough to be used to deprotect compounds including functions that are known to be sensitive to acidic or basic conditions.
Chaulet, Charlotte,Croix, Cécile,Basset, Joan,Pujol, Maria-Dolores,Viaud-Massuard, Marie-Claude
experimental part
p. 1481 - 1484
(2010/08/22)

NEW IMIDAZOLONE DERIVATIVES, PREPARATION THEREOF AS DRUGS, PHARMACEUTICAL COMPOSITIONS, AND USE THEREOF AS PROTEIN KINASE INHIBITORS, IN PARTICULAR CDC7
The present invention relates to imidazolone derivatives of formula (I) to methods of preparing such derivatives, intermediates thereto, pharmaceutical compositions comprising such derivatives, and methods of inhibiting protein kinase, and methods of treatment comprising administration of such derivatives.
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Page/Page column 36

(2009/10/17)

PYRROLOPYRIDINES AS KINASE INHIBITORS
Compounds of Formula (I) are useful for inhibition of CHK1 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.Formula, (I).
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Page/Page column 53

(2009/09/04)

FUSED HETEROCYCLIC COMPOUND
The present invention provides a fused heterocyclic compound having a tyrosine kinase inhibitory action, which is represented by the formula: wherein R1 is a hydrogen atom, a halogen atom, or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom; R2 is a hydrogen atom, or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 are optionally bonded to each other to form an optionally substituted ring structure; R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to the carbon atom on ring A to form an optionally substituted ring structure; ring A is an optionally substituted benzene ring; and ring B is (i) an optionally substituted fused ring, or (ii) a pyridine ring having optionally substituted carbamoyl (the pyridine ring is optionally further substituted).
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Page/Page column 70

(2009/10/01)

A highly effective synthesis of 2-alkynyl-7-azaindoles: Pd/C-mediated alkynylation of heteroaryl halides in water
The reaction of 4-chloro-2-iodo-7-azaindole with terminal alkynes was investigated using 10% Pd/C-PPh3-CuI as a catalyst system in water. This study afforded a new, mild and selective process for the preparation of 2-alkynyl-4-chloro-7-azaindole in good yields via C-C bond forming reaction. The resulting chloro derivative can be functionalized further via another Pd-mediated C-C bond forming reaction?with arylboronic acid.
Layek, Mohosin,Gajare, Vikas,Kalita, Dipak,Islam, Aminul,Mukkanti,Pal, Manojit
experimental part
p. 4814 - 4819
(2009/10/02)

MULTIKINASE INHIBITOR
It is intended to provide a compound represented by the formula (1): [wherein Ar is an arylene group to be attached selected from the following formula (2): (wherein * represents a binding site to a nitrogen atom and ** represents a binding site to T); T represents -(O)n-R; R represents a C1-C6 alkyl group or the like; n represents 0 or 1; X represents O or the like; R2, R3 and R4 are independently selected from a hydrogen atom or C1-C3 alkyl; or R2 and R3 may join together with an urea structure containing the nitrogen atoms to which they bind to form a 5- or 6-membered heterocycle; Y represents CH or N], or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutical composition containing the same.
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Page/Page column 29-30

(2008/12/05)

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)

Novel Bis-Azaindole Derivatives, Preparation And Pharmaceutical Use Thereof As Kinase Inhibitors
Disclosed are compounds of formula (I): wherein R1, R2, R3, R4, and R5 have the meanings given in the description, and to salts thereof, pharmaceutical compositions comprising said compounds and the use thereof as protein kinase inhibitors.
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Page/Page column 28; 23-24

(2010/11/30)

AURORA KINASE MODULATORS AND METHOD OF USE
The present invention relates to chemical compounds having a general formula I {INSERT STRUCTURE HERE} 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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(2008/12/04)

PYRIDINONYL PDK1 INHIBITORS
The present invention provides pyridinonyl PDKl inhibitors and methods of treating cancer using the same.
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(2008/06/13)

OXAZOLE TYROSINE KINASE INHIBITORS
The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1 : provided that the sum of a and b is 0 or 1; T is O or NH Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1; Ar2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; and R1 and R2are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.
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Page/Page column 136-137

(2009/01/20)

PHARMACEUTICAL COMPOUNDS
The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH=CH, N=CH, CH=N, HN-C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
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Page/Page column 86

(2008/06/13)

PHARMACEUTICAL COMPOUNDS
Compounds of the formula (I), and salts, solvates, tautomers and N-oxide thereof; wherein TG is selected from groups (1) and (2): wherein the asterisk (*) represents the point of attachment of the group E to the group X; Rla is an optionally substituted aryl or heteroaryl group; Rlb is hydrogen or a group Rla; X is an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 are heteroatoms selected from O, N and S; and A, E, R2, R3, R4, Q1 and Q2 are as defined in the claims; provided that when E is aryl or heteroaryl, then Q2 is other than a bond; and further provided that the moiety (a) is other than a group (BG1) or (BG2); wherein (BGl) and (BG2) are each optionally substituted; T is N or CRZ; J1-J2 is selected from N=C(RZ), (RZ)C=N, (RZ)N-C(O), (RZ)2C-C(O), N=N and (RZ)C=C(R6); J4 -J3 is a group N=C(RZ) or a group (RZ)N-CO; and RZ is hydrogen or a substituent. The compounds of the formula (I) have PKA and PKB kinase inhibiting activity and are useful in the treatment of cancers.
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Page/Page column 134-135

(2008/06/13)

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
(2007/10/03)

PHARMACEUTICAL COMPOUNDS
The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4 alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R3, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3, R4, R6 and R8 are as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated.
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Page/Page column 117-118

(2008/06/13)

Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED50 = 16.3 mg/kg).
Potashman, Michele H.,Bready, James,Coxon, Angela,Demelfi Jr., Thomas M.,DiPietro, Lucian,Doerr, Nicholas,Elbaum, Daniel,Estrada, Juan,Gallant, Paul,Germain, Julie,Gu, Yan,Harmange, Jean-Christophe,Kaufman, Stephen A.,Kendall, Rick,Kim, Joseph L.,Kumar, Gondi N.,Long, Alexander M.,Neervannan, Seshadri,Patel, Vinod F.,Polverino, Anthony,Rose, Paul,Van Der Plas, Simon,Whittington, Douglas,Zanon, Roger,Zhao, Huilin
p. 4351 - 4373
(2008/02/13)

FUSED HETEROBICYCLIC KINASE INHIBITORS
Compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein X1, X2, X3, X4, X5, X6, X7, R1, and Q1 are defined herein, inhibit kinase enzymes and are useful for the treatment and/or prevention of hyperproliferative diseases such as cancer. The compounds are also useful in the treatment of inflammation, allergy, asthma, disease and conditions of the immune system, disease and conditions of the nervous system, cardiovascular diseases, disease and conditions of the eye, dermatological diseases, osteoporosis, diabetes, multiple sclerosis, and infections.
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Page/Page column 93

(2008/06/13)

Intracellular Kinase Inhibitors
Intracellular kinase inhibitors and their therapeutic uses for patients with T cell malignancies, B cell malignancies, autoimmune disorders, and transplanted organs.
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Page/Page column 26

(2008/06/13)

BICYCLIC HETEROAROMATIC DERIVATIVES USEFUL AS ANTICANCER AGENTS
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Page/Page column 73-74

(2008/06/13)

A practical synthesis of 2-((1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino)-5- fluoronicotinic acid
A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.
Wang, Xin,Zhi, Ben,Baum, Jean,Chen, Ying,Crockett, Richard,Huang, Liang,Eisenberg, Shawn,Ng, John,Larsen, Robert,Martinelli, Mike,Reider, Paul
p. 4021 - 4023
(2007/10/03)