- Silver-Enabled General Radical Difluoromethylation Reaction with TMSCF2H
-
A silver-mediated oxidative difluoromethylation of styrenes and vinyl trifluoroborates with TMSCF2H is reported for the first time. This method enables direct and facile access to CF2H-alkenes from abundant alkenes with excellent functional-group compatibility. Moreover, this Ag/TMSCF2H protocol could further enable a series of radical difluoromethylation reactions of a wide array of substrates, offering a generic and complementary platform for the construction of diversified C?CF2H bonds.
- Yang, Jun,Zhu, Shengqing,Wang, Fang,Qing, Feng-Ling,Chu, Lingling
-
supporting information
p. 4300 - 4306
(2020/12/25)
-
- Late-Stage 18F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging
-
Despite a growing interest in CHF2 in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF18F into druglike compounds. Herein described is a photoredox flow reaction for 18F-difluoromethylation of N-heteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for a new 18F-difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C?H activation, circumventing the need for pre-functionalization of the substrate. The method is operationally simple and affords straightforward access to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.
- Trump, Laura,Lemos, Agostinho,Lallemand, Bénédicte,Pasau, Patrick,Mercier, Jo?l,Lemaire, Christian,Luxen, André,Genicot, Christophe
-
supporting information
p. 13149 - 13154
(2019/08/20)
-
- Synthesis of new 2-substituted 3-(tri(di)fluoromethyl)-quinoxalines from 3-(trifluoromethyl)quinoxalin-2(1H)-oneand 3-(tri(di)fluoromethyl)quinoxaline-2-carboxylic acids
-
[Figure not available: see fulltext.] Starting from 3-(trifluoromethyl)quinoxalin-2(1H)-one, a wide range of new 2-substituted 3-(trifluoromethyl)quinoxalines were obtained, including amino, bromo, chloro, hydrazino, phenyl, α-furyl, formyl, methylsulfanyl, and methylsulfonyl derivatives. 3-(Tri(di)-fluoromethyl)quinoxaline-2-carboxylic acids were obtained for the first time and used for the synthesis of 2-amino-3-(tri(di)-fluoromethyl)quinoxalines and 2-(2-aminothiazol-4-yl)-3-(trifluoromethyl)quinoxaline.
- Didenko, Andrey V.,Vorobiev, Mikhail V.,Sevenard, Dmitri V.,Sosnovskikh, Vyacheslav Ya.
-
p. 259 - 268
(2016/01/12)
-
- Process for production of DFMB derivatives
-
A process for the production of a compound of formula (III) which comprises a step of reacting a compound of formula (I) with an excess amount of a compound of formula (II) in absence of aromatic solvent, wherein n is 0, 1, 2, 3 or 4; X is NH, O or S; eac
- -
-
Paragraph 0037
(2015/02/05)
-
- QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
-
The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
- -
-
Page/Page column 59; 60
(2014/10/29)
-
- PHOSPHOINOSITIDE 3-KINASE (PI3K) INHIBITORS
-
The invention relates to compounds, and uses of the compounds, that are inhibitors of the enzyme phosphoinositide 3-kinase (PI3K). More particularly the compounds are selective inhibitors of one or more isoforms of PI3K. In particular embodiments the compounds are selective inhibitors of one isoform of PI3K
- -
-
Page/Page column 38-39
(2014/01/18)
-
- PROCESS FOR PRODUCTION OF DFMB DERIVATIVES
-
Disclosed is a process for the production of a compound of formula (ΙΠ). The process comprises a step of reacting a compound of formula (I) with an excess amount of a compound of formula (II) in absence of aromatic solvent:wherein - n is 0 1, 2, 3 or 4; - X is NH, O or S; - each R] group may be the same or different, and is independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, alkyl, carbonyl, carboxyl, carboxylic acid ester groups, amido, cyano, halogenated aliphatic, nitro, or amino groups; - R2 group is selected from the group consisting of hydroxyl, CI, F, Br, amino or alkoxy.
- -
-
Paragraph 0030
(2013/09/12)
-
- Efficient syntheses of 2-fluoroalkylbenzimidazoles and -benzothiazoles
-
We report an efficient one-step route to 2-fluoroalkylbenzimidazoles and -benzothiazoles via the condensation of fluorinated carboxylic acids and aromatic diamines or aminothiophenols. Additionally, we describe the syntheses of fluoroalkyl-azabenzimidazoles, -purines, and -imidazolopyrazines. This method is high-yielding with broad scope and is operationally simple with potential application to parallel synthesis.
- René, Olivier,Souverneva, Alexandra,Magnuson, Steven R.,Fauber, Benjamin P.
-
supporting information
p. 201 - 204
(2013/02/22)
-
- L-aminoacyl-triazine derivatives are isoform-selective PI3Kβ inhibitors that target nonconserved Asp862 of PI3Kβ
-
A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3Kβ. The compounds showed selectivity based upon stereochemistry with l-amino acyl derivatives preferring PI3Kβ, while their d-congeners favored PI3Kδ. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3Kβ-selective inhibitors, distinguishing this class from other reported PI3Kβ-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
- Pinson, Jo-Anne,Zheng, Zhaohua,Miller, Michelle S.,Chalmers, David K.,Jennings, Ian G.,Thompson, Philip E.
-
supporting information
p. 206 - 210
(2013/03/29)
-
- Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)
-
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 -/- mice, and at a dose of 50 mg/kg given by ip injection at a qd ?- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
- Rewcastle, Gordon W.,Gamage, Swarna A.,Flanagan, Jack U.,Frederick, Raphael,Denny, William A.,Baguley, Bruce C.,Kestell, Philip,Singh, Ripudaman,Kendall, Jackie D.,Marshall, Elaine S.,Lill, Claire L.,Lee, Woo-Jeong,Kolekar, Sharada,Buchanan, Christina M.,Jamieson, Stephen M. F.,Shepherd, Peter R.
-
experimental part
p. 7105 - 7126
(2011/12/04)
-
- Synthesis of fluorine-containing benzimidazole derivatives
-
Various fluorine-containing benzimidazoles were obtained by the reaction of o-phenylenediamine, 3,4-diaminotoluene, and 1,2-diamino-4-chlorobenzene with hexafluoropropene or perfluoro(methyl vinyl ether) in DMF. A new efficient method of synthesis of 2-(1,2,2,2-tetrafluoroethyl)benzimidazole by the reaction of o-phenylenediamine with hexafluoropropene in the presence of diethylamine or dimethylamine in ethyl acetate is developed.
- Vasilyeva,Karimova,Slavich
-
experimental part
p. 186 - 191
(2011/01/10)
-
- PYRIMIDINE DERIVATIVES
-
The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their prep
- -
-
Page/Page column 99
(2008/06/13)
-
- PYRIMIDINE DERIVATIVES
-
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
- -
-
Page/Page column 90-91
(2010/11/30)
-
- PYRIMIDINE DERIVATIVES
-
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their pre
- -
-
Page/Page column 90
(2010/11/30)
-
- 2-BENZIMIDAZ0LYL-6-M0RPH0LIN0-4-PIPERIDIN-4-YLPYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
- -
-
Page/Page column 94
(2008/06/13)
-
- 4-BENZIMIDAZ0LYL-6-M0RPH0LIN0-2-PIPERAZINYLPYRIMIDINE DERIVATIVES AS P13K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for
- -
-
Page/Page column 91
(2008/06/13)
-
- 4-BENZIMIDAZ0LYL-6-M0RPH0LIN0-2-PIPERIDIN-4-YLPYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
- -
-
Page/Page column 90
(2008/06/13)
-
- 4-BENZIMIDAZOLYL-2-MORPHOLINO-6-PIPERAZINYLPYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I): wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their pre
- -
-
Page/Page column 90
(2008/06/13)
-
- 4-BENZIMIDAZ0LYL-2-M0RPH0LIN0-6-PIPERIDIN-4-YLPYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their prep
- -
-
Page/Page column 91
(2008/06/13)
-
- PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST PI3K ENZYMES
-
The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, s, t, X1 and Q1 have any of the meanings defined in the description; processes for thei
- -
-
Page/Page column 96-97
(2008/06/13)
-
- 2 -BENZIMIDAZOLYL- 6 -MORPHOLINO-4- (AZETIDINE, PYRROLIDINE, PIPERIDINE OR AZEPINE) PYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, s, t, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
- -
-
Page/Page column 101
(2008/06/13)
-
- 2-BENZIMIDAZOLYL-6-MORPHOLINO-4-PHENYLPYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
- -
-
Page/Page column 98
(2008/06/13)
-
- 6-BENZIMIDAZ0LYL-2-M0RPH0LIN0-4- (AZETIDINE, PYRROLIDINE, PIPERIDINE OR AZEPINE) PYRIMIDINE DERIVATIVES AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
-
The invention concerns pyrimidine derivatives of Formula (I): wherein each of p, R1, R2, q, R3, r, R4, s, t, X1 and Q1 have any of the meanings defined in the description; processes for the
- -
-
Page/Page column 103
(2008/06/13)
-
- Treatment of prostate cancer, melanoma or hepatic cancer
-
The present application describes a method of treating prostate cancer, melanoma or hepatic cancer in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of the heterocyclic compound represented by Formula I or its pharmaceutically acceptable salt:
- -
-
Page/Page column 4
(2008/06/13)
-
- One-pot synthesis of 2-trifluoromethyl and 2-difluoromethyl substituted benzo-1,3-diazoles
-
2-Trifluoromethyl and 2-difluoromethyl substituted benzimidazole, benzoxazole and benzothiazole derivatives were efficiently prepared through a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with commercially available o-p
- Ge, Fenglian,Wang, Zengxue,Wan, Wen,Lu, Wencong,Hao, Jian
-
p. 3251 - 3254
(2008/02/02)
-
- Bioactivation of S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteines and S- (trihalovinyl)-L-cysteines by cysteine S-conjugate β-lyase: Indications for formation of both thionoacylating species and thiiranes as reactive intermediates
-
The covalent binding of reactive intermediates, formed by β-elimination of cysteine S-conjugates of halogenated alkenes, to nucleophiles was studied using 19F-NMR and GC-MS analysis. β-Elimination reactions were performed using rat renal cytosol and a β-lyase model system, consisting of pyridoxal and copper(II) ion. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFE-Cys) was mainly converted to products derived from difluorothionoacetyl fluoride, namely, difluorothionoacetic acid, difluoroacetic acid, and N- difluorothionoacetylated TFE-Cys. In the presence of o-phenylenediamine (OPD), as a bifunctional nucleophilic trapping agent, the major product formed was 2-(difluoromethyl)benzimidazole. This product results from initial reaction of difluorothionoacetyl fluoride with one of the amino groups of OPD, followed by a condensation reaction between the thionoacyl group and the adjacent amino group of OPD. In incubations with S-(2-chloro-1,1,2- trifluorofluoroethyl)-L-cysteine (CTFE-Cys) and S-(2,2-dichloro-1,1- difluorofluoroethyl)-L-cysteine (DCDFE-Cys), formation of thionoacylated cysteine S-conjugates was also observed by GC-MS analysis, indicating formation of the corresponding thionoacyl fluorides. However, according to 19F-NMR analysis, chlorofluorothionoacyl fluoride-derived products accounted for only 10% of the CTFE-Cys converted. In the presence of OPD, next to the corresponding 2-(dihalomethyl)benzimidazoles, 2- mercaptoquinoxaline was identified as the main product in incubations with CTFE-Cys. When chlorofluorothionoacylating species were generated from the unsaturated S-(2-chloro-1,2-difluorovinyl)-L-cysteine (CDFV-Cys), 2- (chlorofluoromethyl)benzimidazole and 2-mercaptoquinoxaline were also found as OPD adducts. However, with CDFV-Cys the ratio of 2- (chlorofluoromethyl)benzimidazole to 2-mercaptoquinoxaline was 12-fold higher than in the case of CTFE-Cys. These results suggest an important second mechanism of formation of 2-mercaptoquinoxaline with CTFE-Cys. The formation of 2-mercaptoquinoxaline could also be explained by reaction of OPD with 2,3,3-trifluorothiirane as a second reactive intermediate for CTFE-Cys. Comparable results were obtained when comparing OPD adducts from DCDFE-Cys and TCV-Cys. Both DCDFE-Cys and TCV-Cys form dichlorothionoacylating species. However, DCDFE-Cys forms 21-fold more 2-mercaptoquinoxaline than TCV-Cys, which may be explained by its capacity to form 3-chloro-2,2-difluorothiirane next to dichlorothionoacyl fluoride. In order to explain the apparent differences in the preference of thiols to form different reactive intermediates, free enthalpies of formation (Δ(f)G) of thiolate anions and their possible rearrangement products, thionoacyl fluorides and thiiranes, derived from TFE-Cys, CTFE-Cys, and DCDFE-Cys, were calculated by ab initio calculations. For TFE-thiolate, formation of difluorothionoacetyl fluoride is energetically favored over formation of the thiirane. In contrast, the thiirane pathway is favored over the thionoacyl fluoride pathway for CTFE- and DCDFE-thiolates. The results of these quantum chemical calculations appear to be consistent with the experimental data.
- Commandeur, Jan N. M.,King, Laurence J.,Koymans, Luc,Vermeulen, Nico P. E.
-
p. 1092 - 1102
(2007/10/03)
-