- PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
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The invention discloses a PARP-1/PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1/PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and/or PI3K.
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Paragraph 0157; 0168-0170; 0191; 0201-0203
(2021/07/01)
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- Piperazinone substitute or derivative thereof, preparation method and application thereof, and pharmaceutical composition
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The invention relates to a piperazinone substitute or a derivative thereof, a preparation method and application thereof, and a pharmaceutical composition, and belongs to the technical field of anti-tumor drugs. The invention designs a piperazinone substituted heterocyclic small molecule compound. The compound shows good affinity to PI3K delta, and the compound can down-regulate the activity of a PI3K pathway in tumor cells, so that the compound shows good inhibitory activity to PI3K delta dependent tumors, and is expected to be used as one of components of a pharmaceutical preparation for treatment of different tumors. The preparation method of the piperazinone substitute is simple and convenient, and the yield is relatively high.
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- 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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- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
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The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a PD-1 signaling inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and the PD-1 signaling inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a PD-1 signaling inhibitor and a pharmaceutically acceptable carrier or excipient.
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- Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents
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To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.
- Ye, Tianyu,Han, Yufei,Wang, Ruxin,Yan, Pingzhen,Chen, Shaowei,Hou, Yunlei,Zhao, Yanfang
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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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- Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors
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Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
- Hu, Rong,Liu, Zhi-Hao,Wang, Ning-Yu,Wang, Wan-Li,Xu, Ying,Yu, Luo-Ting,Zhu, Yong-Xia,Zuo, Wei-Qiong
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- COMPOUNDS AND THERAPEUTIC USES THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, diseases associated with over production
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- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
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The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a BCL-2 inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and a BCL-2 inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a BCL-2 inhibitor and a pharmaceutically acceptable carrier or excipient.
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- Thiophene pyrimidines and preparation and its preparation method and application
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The invention discloses a pyrantel compound and preparation, as well as a preparation method and application of the pyrantel compound and preparation, belonging to the technical field of chemical medicines and preparations thereof. According to the pyrantel compound or pharmaceutically acceptable salt thereof, HDAC (histone deacetylase)/PI3K (phosphatidylinositide 3-kinase) double-target inhibitor is used for selectively inhibiting tumor cell messenger core protein kinase target PI3K and epigenetic target HDAC which are synergized, and is capable of destroying the network of tumor cell messengers, thus exerting a great killing effect on various tumor cells. In multiple blood and entity heterogenic transplanted tumor animal models, the inhibitor can be used for intensively effectively inhibiting tumor growth and especially has a remarkable effect on various blood B-cell malignant tumors, and safety evaluation tests indicate that the inhibitor has high safety and security. The pyrantel compound and preparation can be used for effectively treating patients with later reoccurrence of lymphoma, myeloma and lymphatic leukemia or drug resistance.
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- Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors
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Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.
- Zhan, Miao,Deng, Yufang,Zhao, Lifeng,Yan, Guoyi,Wang, Fangying,Tian, Ye,Zhang, Lanxi,Jiang, Hongxia,Chen, Yuanwei
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p. 4023 - 4035
(2017/05/19)
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- Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
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The invention provides a compound of Formula I, Pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
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- Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
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Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed
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- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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- Phosphoinositides 3-serinekinase inhibitor compd. antialopecic agent and combinations, and method of use
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Combinations of PI3K inhibitor compounds having Formulas I and II and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hyperproliferative disorders such as cancer. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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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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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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- Synthesis and cytotoxic activity of novel 2,6-disubstituted-4-mor- pholinothieno[3,2-d]pyrimidines as potent anti-tumor agents
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A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460, HT-29, MDA-MB-231, U87MG and H1975 cancer cell lines were evaluated in vitro. Most of the target compounds exhibited moderate to excellent activity to the tested cell lines. The most promising compound 23 (0.84 μmol/L, 0.23 μmol/L, 2.52 μmol/L, 1.80 μmol/L) was 1.0, 2.9, 29.3 and 4.3 times more active than GDC-0941 (0.87 μmol/L, 0.66 μmol/L, 73.8 μmol/L, 7.77 μmol/L) against H460, HT-29, MDA-MB-231 and U87MG cell lines, respectively.
- Zhu, Wu Fu,Zhai, Xin,Li, Sai,Cao, Yun Yun,Gong, Ping,Liu, Ya Jing
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p. 703 - 706
(2012/07/16)
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- Design, synthesis and anticancer activity of 4-morpholinothieno[3,2-d]- pyrimidine derivatives bearing arylmethylene hydrazine moiety
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Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003 μM, 0.42 μM and 0.74 μM, which was 1.6- to 290-fold more potent than GDC-0941.
- Zhu, Wufu,Zhai, Xin,Fu, Qiangqiang,Guo, Fei,Bai, Mei,Wang, Jianqiang,Wang, Haiyan,Gong, Ping
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p. 1037 - 1045
(2012/10/08)
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- Potent and highly selective benzimidazole inhibitors of PI3-kinase delta
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Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.
- Murray, Jeremy M.,Sweeney, Zachary K.,Chan, Bryan K.,Balazs, Mercedesz,Bradley, Erin,Castanedo, Georgette,Chabot, Christine,Chantry, David,Flagella, Michael,Goldstein, David M.,Kondru, Rama,Lesnick, John,Li, Jun,Lucas, Matthew C.,Nonomiya, Jim,Pang, Jodie,Price, Stephen,Salphati, Laurent,Safina, Brian,Savy, Pascal P. A.,Seward, Eileen M.,Ultsch, Mark,Sutherlin, Daniel P.
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p. 7686 - 7695
(2012/10/29)
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- LIGAND-DIRECTED COVALENT MODIFICATION OF PROTEIN
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The present invention relates to enzyme inhibitors. More specifically, the present invention relates to ligand-directed covalent modification of proteins; method of designing same; pharmaceutical formulation of same; and method of use.
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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- PI3 KINASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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- COMBINATIONS OF PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF HEMATOPOIETIC MALIGNANCIES
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Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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- Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor
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Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.
- Heffron, Timothy P.,Berry, Megan,Castanedo, Georgette,Chang, Christine,Chuckowree, Irina,Dotson, Jennafer,Folkes, Adrian,Gunzner, Janet,Lesnick, John D.,Lewis, Cristina,Mathieu, Simon,Nonomiya, Jim,Olivero, Alan,Pang, Jodie,Peterson, David,Salphati, Laurent,Sampath, Deepak,Sideris, Steve,Sutherlin, Daniel P.,Tsui, Vickie,Wan, Nan Chi,Wang, Shumei,Wong, Susan,Zhu, Bing-yan
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scheme or table
p. 2408 - 2411
(2010/07/16)
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- Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available Pan-PI3-kinase and dual Pan-PI3-kinase/mTOR inhibitors for the treatment of cancer
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The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural in
- Sutherlin, Daniel P.,Sampath, Deepak,Berry, Megan,Castanedo, Georgette,Chang, Zhigang,Chuckowree, Irina,Dotson, Jenna,Folkes, Adrian,Friedman, Lori,Goldsmith, Richard,Heffron, Tim,Lee, Leslie,Lesnick, John,Lewis, Cristina,Mathieu, Simon,Nonomiya, Jim,Olivero, Alan,Pang, Jodie,Prior, Wei Wei,Salphati, Laurent,Sideris, Steve,Tian, Qingping,Tsui, Vickie,Wan, Nan Chi,Wang, Shumei,Wiesmann, Christian,Wong, Susan,Zhu, Bing-Yan
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scheme or table
p. 1086 - 1097
(2010/08/05)
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- THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS
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Thienopyrimidines of formula (I) wherein W and R1 to R4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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Page/Page column 64
(2009/05/28)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Insert Formula Ic and Id]
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Page/Page column 134
(2008/12/06)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. Formula (Ic) and (Id).
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Page/Page column 160
(2008/12/06)
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- The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
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Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110α. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
- Folkes, Adrian J.,Ahmadi, Khatereh,Alderton, Wendy K.,Alix, Sonia,Baker, Stewart J.,Box, Gary,Chuckowree, Irina S.,Clarke, Paul A.,Depledge, Paul,Eccles, Suzanne A.,Friedman, Lori S.,Hayes, Angela,Hancox, Timothy C.,Kugendradas, Arumugam,Lensun, Letitia,Moore, Pauline,Olivero, Alan G.,Pang, Jodie,Patel, Sonal,Pergl-Wilson, Giles H.,Raynaud, Florence I.,Robson, Anthony,Saghir, Nahid,Salphati, Laurent,Sohal, Sukhjit,Ultsch, Mark H.,Valenti, Melanie,Wallweber, Heidi J. A.,Nan, Chi Wan,Wiesmann, Christian,Workman, Paul,Zhyvoloup, Alexander,Zvelebil, Marketa J.,Shuttleworth, Stephen J.
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experimental part
p. 5522 - 5532
(2009/09/06)
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- Pharmaceutical compounds
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A thienopyrimidine of formula (I): and the pharmaceutically acceptable salts thereof have activity as inhibitors of PI3K with selectivity for the P110α subtype, and may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour, particularly those associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 7
(2008/06/13)
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- Pharmaceutical compounds
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Compounds of Formulae Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 73
(2008/06/13)
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- PYRIMIDINE DERIVATIVES AS PI3K INHIBITORS
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Thienopyrimidines of formula (Ia) or (Ib): wherein R1, R2, R3, are as defined in the claims.
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Page/Page column 63
(2008/06/13)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of Formulas (Ia) and (Ib), and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula (Ia) and (Ib) for in vitro, in situ, and in vivodiagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 136
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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Fused pyrimidines of formula (I); wherein A represents a thiophene or furan ring; n is 1 or 2; R1 is a group of formula (II); wherein m is 0 or 1; R30 is H or C1-C6 alkyl; R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and O, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N-containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated N-containing heterocyclic group as defined above; R2 is selected from formula (a); wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and formula (b); wherein Y is a C2-C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from O, N and S, and which is unsubstituted or substituted; and R3 is an indazole group which is unsubstituted or substituted; and the pharmaceutically acceptable salt thereof have activity as inhibitors of P13K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with P13 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 30
(2008/06/13)
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