- From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons
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Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC50 100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.
- Beaulieu, Pierre L.,Gillard, James,Jolicoeur, Eric,Duan, Jianmin,Garneau, Michel,Kukolj, George,Poupart, Marc-Andre
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Read Online
- Copper-Promoted Thiolation of C(sp2)–H Bonds Using a 2-Amino Alkylbenzimidazole Directing Group
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A copper-promoted thiolation of C(sp2)–H bonds with disulfides was achieved by using 2-amino alkylbenzimidazole (MBIP amine) as a new and removable N,N-bidentate directing group. This strategy gives a variety of functionalized thioethers in moderate to excellent yields in a simple and efficient way. Importantly, the substrate scope is not limited to aromatic amides; diverse alkenyl amides are also compatible. Furthermore, this synthetic approach provides a potentially feasible way to achieve structural modification of related benzimidazole-containing compounds through direct C–H activation.
- Liu, Shuang-Liang,Li, Xue-Hong,Shi, Tan-Hao,Yang, Guang-Chao,Wang, Hai-Li,Gong, Jun-Fang,Song, Mao-Ping
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supporting information
p. 2280 - 2289
(2017/05/01)
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- Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Lymphoproliferative Malignancies
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Methods are provided for treating a lymphoproliferative malignancy to a patient in need of such treatment, comprising administering to the patient an effective amount of compound A as described herein.
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Paragraph 0086; 0154; 0158
(2017/11/07)
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- CRYSTALLINE COMPOUNDS
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Provided herein are polymorph E, a mixed DMAC/toluene solvate and a DMSO solvate of N-(3-{[(2Z)-3-[(2-chloro-5- methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2- methylalaninamide.
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Paragraph 00171
(2014/04/03)
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- TABLET FORMULATION OF A PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR
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Methods are provided for treating cancer to a patient in need of such treatment, comprising administering a PI3K inhibitor.
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Page/Page column 24; 25
(2014/04/03)
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- COMPOUNDS FOR USE IN THE TREATMENT OF BASAL CELL CARCINOMA
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The invention provides a method for treating BCC in a patient in need of such treatment, comprising administering a therapeutically effective amount a compound of formula Ila.
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Paragraph 00250; 00254
(2013/04/25)
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- PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS FOR THE TREATMENT OF CANCER
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The invention provides a method for treating endometrial carcinoma comprising administering a Compound of Formula (I) or (II). Also provided is a method for treating breast cancer, comprising administering letrozole in combination with either a Compound o
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Paragraph 00294
(2013/03/28)
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- PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS FOR THE TREATMENT OF CHILDHOOD CANCERS
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The invention provides a method for treating childhood cancers, including acute lymphocytic leukemia, neuroblastoma, and rhabdomyosarcoma, comprising administering a compound of Formula (I) to a patient in need of such treatment.
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Paragraph 00188
(2013/05/22)
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- N- (3- { [ (3- { [2-CHLORO-5- (METHOXY) PHENYL] AMINO} QUINOXALIN- 2 -YL) AMINO] SULFONYL} PHE NYL) - 2 -METHYLALANINAMIDE AS PHOSPHATIDYLINOSITOL 3 - KINASE INHIBITOR FOR THE TREATMENT OF LYMPHOPROLIFERATIVE MALIGNANCIES
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Methods are provided for treating a lymphoproliferative malignancy to a patient in need of such treatment, comprising administering to the patient an effective amount of compoud A as described herein.
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Paragraph 00120
(2013/05/22)
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- Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV)
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Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.
- Beaulieu, Pierre L.,Boes, Michael,Cordingley, Michael G.,Chabot, Catherine,Fazal, Gulrez,Garneau, Michel,Gillard, James R.,Jolicoeur, Eric,Laplante, Steven,McKercher, Ginette,Poirier, Martin,Poupart, Marc-Andre,Tsantrizos, Youla S.,Duan, Jianmin,Kukolj, George
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p. 7650 - 7666,17
(2020/08/24)
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- ORGANIC COMPOUNDS
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The invention relates to compounds of formula (I): where A is an optionally substituted heteroaryl, useful for treating disorders mediated by acyl coA-diacylglycerol acyl transferase 1 (DGAT1), e.g. metabolic disorders. The invention also provides methods
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Page/Page column 29
(2010/02/17)
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- VIRAL POLYMERASE INHIBITORS
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An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.
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- Viral polymerase inhibitors
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An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein R1 is selected from: H, haloalkyl, (C1-6)alkyl, (C2-6)alkenyl, (C3-7)cycloalkyl, (C2-6)alkynyl, (C5-7)cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C6-10)bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR5, wherein R5 is H, halogen, haloalkyl, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; X is N or CR5; D is N or CR5; each of Y1 and Y2 is independently O or S; Z is O, N, or NRz wherein Rz is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; R3 and R4 are each independently H, (C1-6)alkyl, first (C3-7)cycloalkyl or 6- or 10-membered aryl, Het (C1-6)alkyl-6- or 10-membered aryl, (C1-6)alkyl-Het; or each R3 and R4 are independently covalently bonded together to form second (C3-7)cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R3 or R4 are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R7 is H, (C1-6 alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; or R7 is covalently bonded to either of R3 or R4 to form a heterocycle; A is (C1-6) alkyl-CONHR8 wherein R8 is-6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.
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- 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
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The invention is drawn to 7-substituted-9-(substituted amino)-6-demethyl-6-deoxytetracycline compounds of the formula STR1 wherein R, X, R5 and R6 are defined in the specification. The compounds of the invention are useful as broad s
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- Method of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines
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The invention provides a novel method for producing compounds of the formula I: STR1 wherein X and R are defined in the specifications. The invention also provides a method for making intermediates useful to produce the compounds of formula I. Utilizing a common intermediate, the novel method efficiently produces compounds of the formula I.
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- N-chloro-amino acid derivatives activity
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There is provided, a novel class of compounds exhibiting antibacterial activity, said compounds having the formula: EQU1 wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the pri
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