894416-95-6Relevant articles and documents
Spirocyclic derivatives
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Page/Page column 109, (2016/04/09)
The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease, disorder or condition ameliorated by inhibition of a dopamine transporter); and methods of treating patients with such compounds; wherein R1, R2, R3, R4, R5, R6, R9, R10, Q, X, Y, Z, A, L, B, m, n and p are as defined herein.
Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold
Niculescu-Duvaz, Ion,Roman, Esteban,Whittaker, Steven R.,Friedlos, Frank,Kirk, Ruth,Scanlon, Ian J.,Davies, Lawrence C.,Niculescu-Duvaz, Dan,Marais, Richard,Springer, Caroline J.
experimental part, p. 3261 - 3274 (2009/04/06)
BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)- 6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC 50 = 3.5 μM) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant V600EBRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against V600EBRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant V600EBRAF in vitro several compounds were identified with IC50s of 300-500 nM for V600EBRAF, and all compounds that were assessed showed selectivity for V600EBRAF compared to CRAF by 5->86-fold.
Pyrazines and Pyridines and Derivatives Thereof as Therapeutic Compounds
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Page/Page column 88, (2010/11/29)
The present invention pertains to certain pyrazines and pyridines, and derivatives thereof, which, inter alia, inhibit RAF (e.g., B RAF) activity, inhibit cell proliferation, treat cancer, etc., and more particularly to compounds of the formulae: (I) wherein: Q is independently —N═ or —CH═; one of RP2 and RP3 is independently a group of the formula -J1-L1-Z; wherein: if Q is —N═, then -J1-L1-Z is independently: —NH-Z; —O-Z; or S-Z; if Q is —CH═, then -J1-L1-Z is independently: —NH—(CH2)n-Z, wherein n is independently 0 or 1; —O-Z; or —S-Z; Z is independently: C6-14 carboaryl, C5-14 heteroaryl, C3-12carbocyclic, C3-12 heterocyclic; and is independently unsubstituted or substituted; the other of RP2 and RP3 is independently —H, —NHRN1, or —NHC(═O)RN2; wherein: RN1, if present, is independently —H or aliphatic saturated C1-4alkyl; RN2, if present, is independently —H or aliphatic saturated C1-4alkyl; one of RP5 and RP6 is independently a group of the formula —W—Y; wherein: W is independently: a covalent bond; —NRN4—, —O—, —S—, —C(═O)—, —CH2—; —NRN4—CH2—, —O—CH2—, —S—CH2—, —C(═O)—CH2—, —(CH2)2—; —CH2—NRN4—, —CH2—O—, —CH2—S—, or —CH2—C(═O)—; wherein RN4, if present, is independently —H or aliphatic saturated C1-4alkyl; Y is independently: C6-14carboaryl, C5-14heteroaryl, C3-12carbocyclic, C3-12heterocyclic; and is independently unsubstituted or substituted; the other of RP5 and RP6 is independently —H; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, e.g., both in vitro and in vivo, to inhibit RAF (e.g., B-RAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and conditions that are ameliorated by the inhibition of RAF, RTK, etc., proliferative conditions such as cancer (e.g., colorectal cancer, melanoma), etc.
