- Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition
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Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.
- Dong, Jiawen,Fu, Siyu,Han, Yufei,Hou, Yunlei,Jiang, Jia,Qin, Mingze,Tian, Ye,Wang, Ruxin,Zhao, Yanfang
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- INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THE TREATMENT OF DISEASE
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Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.
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Paragraph 0494-0495
(2021/09/04)
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- POLYHETEROCYCLIC COMPOUNDS AS METTL3 INHIBITORS
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The present invention relates to compounds of formula (I) that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity: X-Y-Z (I) wherein X, Y and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, and autoimmune diseases, as well as other diseases or conditions in which METTL3 activity is implicated.
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Page/Page column 288
(2021/06/11)
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- RAS INHIBITORS AND METHODS OF USING THE SAME
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Provided herein are compounds identified as inhibitors of KRAS protein activity that can be used to treat various diseases and disorders, such as cancer.
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Paragraph 000150
(2021/08/06)
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- Application of C-H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib
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This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C-H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.
- Bream, Robert N.,Clark, Hugh,Edney, Dean,Harsanyi, Antal,Hayler, John,Ironmonger, Alan,Mc Cleary, Nadine,Phillips, Natalie,Priestley, Catherine,Roberts, Alastair,Rushworth, Philip,Szeto, Peter,Webb, Michael R.,Wheelhouse, Katherine
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supporting information
p. 529 - 540
(2021/03/01)
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- METTL3 INHIBITORY COMPOUNDS
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The present invention relates to compounds of formula (I) that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity: X-Y-Z5 (I) wherein X, Y and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, and autoimmune diseases, as well as other diseases or conditions in which METTL3 activity 10 is implicated.
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Paragraph 00290; 00437-00438
(2020/10/20)
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- Preparation method of thienopyrimidine compounds and application thereof
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The invention relates to thienopyrimidine derivatives as shown in a general formula I, pharmaceutically acceptable salts or prodrugs and a preparation method thereof, which belong to the technical field of medicinal chemistry. In the general formula I, substituent groups L and R2 have meanings given in the specification. The invention also relates to a compound shown in the general formula I, which has a strong effect of inhibiting PI3K. The invention also relates to an application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparation of drugs fortreating and/or preventing diseases caused by abnormal high expression of PI3K, especially the application in preparation of drugs for treating and/or preventing cancers.
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Paragraph 0093-0095
(2020/05/05)
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- ANTIBODY DRUG CONJUGATES (ADCS) WITH NAMPT INHIBITORS
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Conjugate of a binder having formula: (A) wherein AB stands for a binder, Z' stands for a linker and D stands for an active component of Formula (I): and its use as pharmaceuticals.
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Page/Page column 236; 237; 238; 239
(2019/08/26)
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- CHEMICAL COMPOUNDS
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The specification relates to compounds of Formula (I): and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cell proliferative disorders.
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Paragraph 0882; 0883
(2018/05/03)
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- INDAZOLE DERIVATIVES THAT DOWN-REGULATE THE ESTROGEN RECEPTOR AND POSSESS ANTI-CANCER ACTIVITY
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The specification relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Page/Page column 114-115
(2017/12/28)
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- Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
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Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
- Lai, Andiliy,Kahraman, Mehmet,Govek, Steven,Nagasawa, Johnny,Bonnefous, Celine,Julien, Jackie,Douglas, Karensa,Sensintaffar, John,Lu, Nhin,Lee, Kyoung-Jin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Moon, Michael J.,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Grillot, Kate,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
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supporting information
p. 4888 - 4904
(2015/07/02)
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- QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
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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.
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- A practical synthesis of a PI3K inhibitor under noncryogenic conditions via functionalization of a lithium triarylmagnesiate intermediate
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We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.
- Tian, Qingping,Cheng, Zhigang,Yajima, Herbert M.,Savage, Scott J.,Green, Keena L.,Humphries, Theresa,Reynolds, Mark E.,Babu, Srinivasan,Gosselin, Francis,Askin, David,Kurimoto, Isao,Hirata, Norihiko,Iwasaki, Mitsuhiro,Shimasaki, Yasuharu,Miki, Takashi
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- SERINE/THREONINE PAK1 INHIBITORS
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Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
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Page/Page column 151
(2013/03/26)
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- New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase
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Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N1- and N2-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.
- Lohou, Elodie,Sopkova-De Oliveira Santos, Jana,Schumann-Bard, Pascale,Boulouard, Michel,Stiebing, Silvia,Rault, Sylvain,Collot, Valerie
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p. 5296 - 5304
(2012/11/07)
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- Pyridinium p-toluenesulfonate: A mild and efficient catalyst for the regioselective tetrahydropyranylation of indazole derivatives under solvent-free conditions
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An efficient and regioselective tetrahydropyranyl (THP) protection on substituted 1H-indazoles in solution phase as well as under solvent-free conditions catalyzed by microwave irradiation in the presence of pyridinium p-toluenesulfonate (PPTS) as mild catalyst.
- Thatipally, Suresh,Acharyulu, Palle V.R.,Dubey
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experimental part
p. 451 - 454
(2011/11/01)
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- MTOR KINASE INHIBITORS FOR ONCOLOGY INDICATIONS AND DISEASES ASSOCIATED WITH THE MTOR/P13K/AKT PATHWAY
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Provided herein are Heteroaryl Compounds having the following structure: R2 N (I) or (II) wherein R1 -R4 are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases, or cardiovascular conditions, comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
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Page/Page column 126-127
(2010/06/17)
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- Protected indazole boronic acid pinacolyl esters: Facile syntheses and studies of reactivities in Suzuki-Miyaura cross-coupling and hydroxydeboronation reactions
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The paper describes a rapid and efficient synthesis for the isolation of protected indazolylboronic esters. These compounds were synthesized by reaction between prepared protected haloindazoles and bis(pinacolato)diboron. The effects of solvent, temperature, reaction time, and the nature of halogen atom as well as protecting group were investigated. Additionaly, these compounds reacted either with aryl halides in a Suzuki-Miyaura cross-coupling reaction or with hydrogen peroxide in a hydroxydeboronation reaction showing the potential access to new aryl and hydroxyindazole libraries. Georg Thieme Verlag Stuttgart.
- Crestey, Fran?ois,Lohou, Elodie,Stiebing, Silvia,Collot, Valérie,Rault, Sylvain
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body text
p. 615 - 619
(2009/07/09)
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- HETEROARYL COMPOUNDS, COMPOSITIONS THEREOF, AND USE THEREOF AS PROTEIN KINASE INHIBITORS
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Provided herein are Heteroaryl Compounds having the following structure: (I) wherein R1, R2, L, X, Y, Z, Q, A and B are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
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Page/Page column 159
(2008/12/05)
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