5804-49-9Relevant articles and documents
BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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, (2018/03/25)
Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
THERAPEUTIC COMPOUNDS
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Paragraph 0395; 0396; 039, (2017/01/23)
The invention provides compounds of formula (I): wherein, A, C, D, X, and Y have any of the values defined in the specification, and salts thereof. The compounds are SIRT2 inhibitors and are useful for treating SIRT2 associated conditions.
Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7, 26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27) ,16,21,23-decaene (SB1518), a potent Janus Kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma
William, Anthony D.,Lee, Angeline C.-H.,Blanchard, Stéphanie,Poulsen, Anders,Teo, Ee Ling,Nagaraj, Harish,Tan, Evelyn,Chen, Dizhong,Williams, Meredith,Sun, Eric T.,Goh, Kee Chuan,Ong, Wai Chung,Goh, Siok Kun,Hart, Stefan,Jayaraman, Ramesh,Pasha, Mohammed Khalid,Ethirajulu, Kantharaj,Wood, Jeanette M.,Dymock, Brian W.
experimental part, p. 4638 - 4658 (2011/09/14)
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2 WT and JAK2V617F, respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylamino}acetate (ON 01910.Na): Synthesis, structure-activity relationship, and biological activity
Reddy, M. V. Ramana,Venkatapuram, Padmavathi,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Cosenza, Stephen C.,Robell, Kimberly A.,Akula, Balaiah,Hoffman, Benjamin S.,Reddy, E. Premkumar
experimental part, p. 6254 - 6276 (2011/11/01)
Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′- trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.
Bicyclic compositions and methods for modulating a kinase cascade
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Page/Page column 75, (2008/06/13)
The invention relates to compounds and methods for modulating one or more components of a kinase cascade.
Traceless solid-phase synthesis of 2-aminothiazoles: Receptor tyrosine kinase inhibitors with dual selectivity for tie-2 and VEGFR-2
Stieber, Frank,Mazitschek, Ralph,Soric, Natascha,Giannis, Athanassios,Waldmann, Herbert
, p. 4757 - 4761 (2007/10/03)
A 10-step (!) solid-phase synthesis employing the traceless hydrazide linker provides efficient access to a 2-aminothiazole library (see scheme) that yielded access to a new class of tyrosine kinase inhibitors with dual selectivity for the vascular endothelial growth factor receptor VEGFR-2 and the Tie-2 receptor tyrosine kinases.
An enzyme-labile safety catch linker for synthesis on a soluble polymeric support
Grether, Uwe,Waldmann, Herbert
, p. 959 - 971 (2007/10/03)
The development of new and broadly applicable linker groups which are stable under a variety of reaction conditions and allow release of the desired products from the solid support under very mild conditions is of great interest in organic synthesis and combinatorial chemistry. We describe an enzyme-labile safety-catch linker which releases alcohols and amines through i) enzymatic cleavage of an amino group and ii)subsequent lactam formation. The linker group was investigated on different polymeric supports: TentaGel, PEGA, CPG-beads and the soluble polymer POE-6000. From these linker-polymer conjugates 2-methoxy-5-nitrobenzyl alcohol was released by penicillin G acylase catalysed cleavage of a phenylacetamide and attack of the liberated benzylamine on the neighbouring ester group in ortho position. The model study revealed that only in the case of soluble POE-6000 conjugate high yields for the cleavage could be achieved. In the case of the other solid supports the enzyme does not have access to the interior of the polymer matrix. The application of the POE-6000 linker conjugate was investigated for various esters in Pd0-catalysed Heck-Suzuki- and Sonogashira reactions as well as in a Mitsunobu reaction and cycloadditions. These studies proved that the linker is stable under a broad variety of reaction conditions and that the enzymatic method allows for release of the desired product alcohols under extremely mild conditions at pH 7 and 37°C. In addition, the enzymatic reaction proceeds with complete chemoselectivity, that is other esters or amides are not attacked by the biocatalyst. In addition to alcohols amines can also be cleaved by means of the enzyme-initiated two-step process. In these cases the higher stability of amides as compared to esters requires warming to 60°C to induce cyclization and release of the desired product.
Intramolecular hydrogen bond-promoted C-C bond formation: Reaction rate enhancement and regioselective allylation of carbonyl compounds
Ito, Hajime,Ujita, Yasuaki,Tateiwa, Jun-Ichi,Sonoda, Motohiro,Hosomi, Akira
, p. 2443 - 2444 (2007/10/03)
An intramolecular hydrogen bond promotes rate enhancement in both the allylation and the reduction of carbonyl compounds and also regioselective allylation.
