cas 40296-46-6, Ethyl 4,6-dichloronicotinate

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Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization
Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-H
Liu, Zhaoqiang,Chen, Wenmin,Zhan, Peng,De Clercq, Erik,Pannecouque, Christophe,Liu, Xinyong
p. 52 - 62
(2014)
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Novel 1,6-naphthyridin-2(1H)-ones as potential anticancer agents targeting Hsp90
Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evaluated against two breast cancer cell lines. Subsequently, cell cycle progression and apoptosis were conducted on best candidates, finally Western Blot analysis was performed to measure their ability to induce degradation of Hsp90 client proteins.
Montoir, David,Barillé-Nion, Sophie,Tonnerre, Alain,Juin, Philippe,Duflos, Muriel,Bazin, Marc-Antoine
p. 17 - 33
(2016)
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Novel approach towards 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones exploiting cross-coupling and SNAr reactions of a dihalogenated compound
A new route towards the synthesis of a series of 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones in moderate to good yields is reported. The strategy involves the preparation of a 3,7-dihalogenated compound that undergoes differential functionalization using palladium-catalyzed cross-coupling and SNAr reactions.
Dembélé, Ousmane,Montoir, David,Yvorra, Thomas,Sérillon, Dylan,Tonnerre, Alain,Duflos, Muriel,Robert, Jean-Michel,Bazin, Marc-Antoine
p. 3519 - 3523
(2018/08/24)

ROR NUCLEAR RECEPTOR MODULATORS
The invention provides compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological conditions.
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Page/Page column 80; 81

(2016/12/26)

Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity
The diamide insecticides act on the ryanodine receptor (RyR). The synthesis of various bicyclic anthranilic derivatives is reported. Their activity against the insect ryanodine receptor (RyR) and their insecticidal activity in the greenhouse is presented,
Jeanguenat, André,Durieux, Patricia,Edmunds, Andrew J.F.,Hall, Roger G.,Hughes, Dave,Loiseleur, Olivier,Pabba, Jagadish,Stoller, André,Trah, Stephan,Wenger, Jean,Dutton, Anna,Crossthwaite, Andrew
p. 403 - 427
(2016/01/25)

Quinolone amides as antitrypanosomal lead compounds with In Vivo activity
Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei. Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
Hiltensperger, Georg,Hecht, Nina,Kaiser, Marcel,Rybak, Jens-Christoph,Hoerst, Alexander,Dannenbauer, Nicole,Müller-Buschbaum, Klaus,Bruhn, Heike,Esch, Harald,Lehmann, Leane,Meinel, Lorenz,Holzgrabe, Ulrike
supporting information
p. 4442 - 4452
(2016/08/02)

COMPOUNDS FOR REGULATING FAK AND/OR SRC PATHWAYS
The present application provides novel optionally substituted fused pyridine and pyrimidine bicyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating FAK and/or Src activity by administering a therapeutically effective amount of one or more of the compounds to a subject. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the FAK and/or Src pathway. Advantageously, these compounds perform as dual FAK and/or Src inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.
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Page/Page column 76

(2015/03/28)

Differential functionalization of 1,6-naphthyridin-2(1H)-ones through sequential one-pot Suzuki-Miyaura cross-couplings
A practical synthesis of 7-chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)- one is described that starts from 2-chloro-4-(methylamino)nicotinaldehyde. The dihalo compound then undergoes sequential, site-selective Suzuki-Miyaura cross-coupling reactions to afford highly functionalized 1,6-naphthyridones in good yields. One-pot, sequential, site-selective Suzuki-Miyaura cross-coupling reactions of 7-chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)-one afforded highly functionalized 1,6-naphthyridones in good yields. Copyright
Montoir, David,Tonnerre, Alain,Duflos, Muriel,Bazin, Marc-Antoine
supporting information
p. 1487 - 1495
(2014/03/21)

Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones through Sequential One-Pot Suzuki-Miyaura Cross-Couplings
A practical synthesis of 7-chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)-one is described that starts from 2-chloro-4-(methylamino)nicotinaldehyde. The dihalo compound then undergoes sequential, site-selective Suzuki-Miyaura cross-coupling reactions to afford highly functionalized 1,6-naphthyridones in good yields.
Montoir, David,Tonnerre, Alain,Duflos, Muriel,Bazin, Marc-Antoine
p. 1487 - 1495
(2015/10/05)

Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity
The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.
Yule, Ian A.,Czaplewski, Lloyd G.,Pommier, Stephanie,Davies, David T.,Narramore, Sarah K.,Fishwick, Colin W.G.
supporting information
p. 31 - 38
(2014/09/17)

MULTIPLE KINASE PATHWAY INHIBITORS
Kinase with inhibitory activity against kinases disposed in multiple signaling pathways and their therapeutic uses.
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Page/Page column 165-166

(2014/04/17)

Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
The invention relates to dihydronaphthyridines and related compounds; compositions comprising an effective amount of a dihydronaphthyridine or a related compound; and methods for treating or preventing proliferative diseases comprising the administration of an effective amount of a dihydronaphthyridine or a related compound.
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Page/Page column 66

(2013/06/27)

DIHYDRONAPHTHYRIDINES AND RELATED COMPOUNDS USEFUL AS KINASE INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
The invention relates to dihydronaphthyridines and related compounds; compositions comprising an effective amount of a dihydronaphthyridine or a related compound; and methods for treating or preventing proliferative diseases comprising the administration of an effective amount of a dihydronaphthyridine or a related compound. The present invention discloses the unexpected utility of compounds that inhibit cKIT kinase across a broad range of c-KIT mutations, including complex occurrences of primary mutations (KIT exon 9 or 11) and secondary KIT mutations (exons 13, 14, 17 and 18) that may arise in individual, refractory GIST patients. Also unexpected is the utility of compounds of the present invention to inhibit the problematic exon 17 D816V c-KIT mutation, for which there is currently no effective therapy.
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Paragraph 0204

(2014/01/08)

HETEROCYCLIC UREA COMPOUNDS
The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture
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Page/Page column 66; 67

(2013/07/05)

Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (Kd) and enzyme inhibition (IC 50) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.
Kohlmann, Anna,Zech, Stephan G.,Li, Feng,Zhou, Tianjun,Squillace, Rachel M.,Commodore, Lois,Greenfield, Matthew T.,Lu, Xiaohui,Miller, David P.,Huang, Wei-Sheng,Qi, Jiwei,Thomas, R. Mathew,Wang, Yihan,Zhang, Sen,Dodd, Rory,Liu, Shuangying,Xu, Rongsong,Xu, Yongjin,Miret, Juan J.,Rivera, Victor,Clackson, Tim,Shakespeare, William C.,Zhu, Xiaotian,Dalgarno, David C.
p. 1023 - 1040
(2013/03/28)

A concise synthesis of HIV integrase inhibitors bearing the dipyridone acid motif
An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a one-pot three-step formation of the core template (containing one point of structural diversity) followed by a regioselective benzylation and in situ depr
Platts, Michelle Y.,Barber, Christopher G.,Chiva, Jean-Yves,Eastwood, Rachel L.,Fenwick, David R.,Paradowski, Kerry A.,Blakemore, David C.
scheme or table
p. 512 - 514
(2011/03/18)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides a novel class of compounds of Formula (I) (wherein A, Y, R2, R3, R4 and R5 are defined in the summary of the invention), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf.
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Page/Page column 30

(2011/09/14)

Investigation of the pyrazinones as PDE5 inhibitors: Evaluation of regioisomeric projections into the solvent region
We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of an alternate projection into the solvent region to identify compounds with excellent potency, selectivity and pharmacokinetic profiles.
Hughes, Robert O.,Maddux, Todd,Rogier, D. Joseph,Lu, Sharon,Walker, John K.,Jacobsen, E. Jon,Rumsey, Jeanne M.,Zheng, Yi,MacInnes, Alan,Bond, Brian R.,Han, Seungil
scheme or table
p. 6348 - 6352
(2011/11/29)

HETEROCYCLIC COMPOUNDS AND COMPOSITIONS AS C-KIT AND PDGFR KINASE INHIBITORS
The invention provides a novel class of compounds of Formula I: (I) pharmaceutical compositions comprising such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of c-kit, PDGFRα and PDGFRβ kinases.
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Page/Page column 35-36

(2009/10/18)

Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors
A series of pyrimidinopyridones has been designed, synthesized and shown to be potent and selective inhibitors of the FMS tyrosine kinase. Introduction of an amide substituent at the 6-position of the pyridone core resulted in a significant potency increase. Compound 24 effectively inhibited in vivo LPS-induced TNF in mice greater than 80%.
Huang, Hui,Hutta, Daniel A.,Hu, Huaping,DesJarlais, Renee L.,Schubert, Carsten,Petrounia, Ioanna P.,Chaikin, Margery A.,Manthey, Carl L.,Player, Mark R.
p. 2355 - 2361
(2008/09/20)

COMPOSITIONS AND METHODS FOR MODULATING C-KIT AND PDGFR RECEPTORS
The invention provides compounds and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit, PDGFR , PDGFR , CSF1R, Abl, BCR-Abl, CSK, JNK1, JNK2, p38, p70S6K, TGF , SRC, EGFR, trkB, FGFR3, FLT3, Fes, Lck, Syk, RAF, MKK4, MKK6, SAPK2 , BRK, KDR, c-raf or b-raf kinase, or mutant forms thereof.
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Page/Page column 31-32

(2008/12/05)

4-Anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain,
Spicer, Julie A.,Rewcastle, Gordon W.,Kaufman, Michael D.,Black, Shannon L.,Plummer, Mark S.,Denny, William A.,Quin III, John,Shahripour, Aurash B.,Barrett, Stephen D.,Whitehead, Christopher E.,Milbank, Jared B. J.,Ohren, Jeffrey F.,Gowan, Richard C.,Omer, Charles,Camp, Heidi S.,Esmaeil, Nadia,Moore, Kelley,Sebolt-Leopold, Judith S.,Pryzbranowski, Sally,Merriman, Ronald L.,Ortwine, Daniel F.,Warmus, Joseph S.,Flamme, Cathlin M.,Pavlovsky, Alexander G.,Tecle, Haile
p. 5090 - 5102
(2008/03/13)

5-Oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of c-fms kinase
The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase. The invention is directed to the novel compounds of Formula I: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: W, A, Y, Z, R101 and R200 are described in the specification.
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Page/Page column 30; 43

(2010/11/26)

1-(PIPERIDIN-4-YL)-1H-INDOLE DERIVATIVE
The present invention provides a compound represented by the formula (1) or a pharmacologically acceptable salt thereof, or a hydrate thereof (provided that a compound in which all of R4a, R4b, and R4c are hydrogen atoms is excluded.): [wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, R3 represents the formula: wherein R4a, R4b, and R4c are the same as or different from each other and each represents a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, etc.]
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Page/Page column 122

(2010/11/28)

COMPOSITIONS AND METHODS FOR FGF RECEPTOR KINASES INHIBITORS
Described are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent disease or disordered associated with abnormal or deregulated kinase activity, particularly diseases or disorders that
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Page/Page column 33

(2008/06/13)

NOVEL 4-ARYLAMINO PYRIDONE DERIVATIVES AS MEK INHIBITORS FOR THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS
The invention provides novel, substituted 4-arylamino pyridone compounds (formula (I)), pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R 1, R2, R9, R 10, R 11, R 12, R 13, R 14 and L are as defined in the specificati
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Page/Page column 40; 43

(2010/11/08)

Heterocyclic inhibitors of MEK and methods of use thereof
Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R7, R8, R9 and R10, W and Y are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.
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Page/Page column 24

(2008/06/13)

Heterocyclic inhibitors of MEK and methods of use thereof
Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R7, R8, R9 and R10, W and Y are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.
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(2008/06/13)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, BCR-Abl, CSK, JNK1, JNK2, PDGF-R, p38, p70S6K, TGF beta , SRC, EGFR, c-Kit, trkB, FGFR3, Fes, Lck, Syk, RAF, MKK4, MKK6 and SAPK2 beta kinases.
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Page/Page column 39-40

(2008/06/13)

5-SUBSTITUTED-4-`(SUBSTITUTED PHENYL)!AMINO!-2-PYRIDONE DEVIATIVES FOR USE AS MEK INHIBITORS
The present invention relates to 5-substituted-4-(substituted) phenylamino-2-pyridone derivatives of formula (I), pharmaceutical compositions and methods of use thereof as MEK inhibitors. Formula (I) wherein W is formula (II), formula (III), formula (IV),
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Page 35; 91

(2010/02/10)

Cyclic compounds
1. A cyclic compound of the formula (I) or a pharmacologically acceptable salt thereof, wherein X is ═CH— or ═N—, Y is —NH—, —NR4—, —S—, —O—, —CH═N—, —N═CH—, —N═N—, —CH═CH—, etc., R1 is a lower alkoxy group, an amino group, a heterocyclic ring containing N atom(s), or a hydroxy group substituted by a heterocyclic ring containing N atom(s) (each of which is optionally substituted), R2 is a lower alkylamino group which is optionally substituted by an aryl group, a lower alkoxy group which is optionally substituted by an aryl group, a lower alkoxy group substituted by an aromatic heterocyclic ring containing N atom(s), R3 is an aryl group, a heterocyclic ring containing N atom(s), a lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group, a hydroxy group substituted by a heterocyclic ring containing N atom(s), or an amino group (each of which is optionally substituted), and R3 and a substituent in Y may be combined to form a lactone ring. The compound of the present invention has excellent selective PDE V inhibitory activity and therefore, is useful as a therapeutic or prophylactic drug for treating various diseases due to functional disorders on cGMP-signaling.
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(2008/06/13)

3-SUBSTITUTED-6-ARYL PYRIDINES
3-substituted-6-aryl pyridines of Formula (I) are provided: Formula (I) wherein R1, R2, R3, R8, R9, A and Ar are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula (I) bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. The present invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. In addition, the present invention provides labeled 3-substituted-6-aryl pyridines, which are useful as probes for the localization of C5a receptors.
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Page 66

(2008/06/13)

PYRIDOPYRIMIDINE OR NAPHTHYRIDINE DERIVATIVE
A pyridopyrimidine or a naphthyridine derivative of the formula (I): wherein R1 is an optionally substituted nitrogen-containing heterocyclic group, etc.; R2 is H or a lower alkyl group; R3 is H or an optionally substitute
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Page/Page column 39

(2010/02/07)