- Polycyclic amide derivative as CDK9 inhibitor, and preparation method and application thereof
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The invention belongs to the technical field of polycyclic amide derivatives, and particularly relates to a polycyclic amide derivative as a CDK9 inhibitor, and a preparation method and application thereof. The polycyclic amide derivative shows excellent CDK9 enzyme inhibitory activity, and can be used for preparing drugs for treating cancers, especially hematologic cancers including acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, follicular lymphoma and the like and solid tumors, such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia and follicular lymphoma, including breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, kidney cancer, stomach cancer, colorectal cancer, lung cancer and the like.
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- Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies
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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
- Barlaam, Bernard,Casella, Robert,Cidado, Justin,Cook, Calum,De Savi, Chris,Dishington, Allan,Donald, Craig S.,Drew, Lisa,Ferguson, Andrew D.,Ferguson, Douglas,Glossop, Steve,Grebe, Tyler,Gu, Chungang,Hande, Sudhir,Hawkins, Janet,Hird, Alexander W.,Holmes, Jane,Horstick, James,Jiang, Yun,Lamb, Michelle L.,McGuire, Thomas M.,Moore, Jane E.,O'Connell, Nichole,Pike, Andy,Pike, Kurt G.,Proia, Theresa,Roberts, Bryan,San Martin, Maryann,Sarkar, Ujjal,Shao, Wenlin,Stead, Darren,Sumner, Neil,Thakur, Kumar,Vasbinder, Melissa M.,Varnes, Jeffrey G.,Wang, Jianyan,Wang, Lei,Wu, Dedong,Wu, Liangwei,Yang, Bin,Yao, Tieguang
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supporting information
p. 15564 - 15590
(2021/01/09)
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- Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human
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The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.
- Chen, Jiehao,Efanov, Alexander M.,Fang, Xiankang,Jiang, Yi,Jun Zhang, Xue,Li, Lei,Lin, Hua V.,Liu, Jia,Liu, Lian Zhu,Long Hu, Zhi,Ma, Tianwei,Thomas, Melissa K,Wang, Fan,Wang, Jingru,Xiao, Fei,Xu, Jianfeng,Zeng, Mi,Zhang, Lei,Zhen Zhang, Hai,Zhou, Jingye,Zou, Haixia,Zou, Zack
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supporting information
(2020/01/28)
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- PYRAZOLYL COMPOUNDS AND METHODS OF USE THEREOF
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Compounds having activity as chemotherapeutic agents are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein R1a, R1b, R1c, R1d, L, and are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods for treating cancer (e.g., hematological cancers) are also provided.
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Paragraph 0374-0379; 0192-0193; 0532-0535
(2020/05/14)
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- PYRROLOPYRIMIDINES FOR USE IN INFLUENZA VIRUS INFECTION
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The invention relates to compounds having the structure of formula (I) which can be used for the treatment of or against influenza infections.
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Paragraph 0101-0102
(2017/09/20)
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- ISOXAZOLE DERIVATIVES FOR USE IN THE TREATMENT OF PULMONARY DISEASES AND DISORDERS
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The present disclosure features disclosed method of treating disorders such as COPD, bronchitis and/or asthma using disclosed compounds, optionally together with one or more additional active agents. Contemplated methods include administrating orally or by inhalation to a patient one or more disclosed compounds.
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Paragraph 0583
(2017/03/21)
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- ANTI-INFECTIVE HETEROCYCLIC COMPOUNDS AND USES THEREOF
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The present invention relates to heterocyclic compounds of Formula I useful as anti-infective agents. The present invention further relates to a method of treating an infection by administering such compounds, and to pharmaceutical compositions comprising such compounds.
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Page/Page column 9; 137; 138
(2018/04/11)
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- Chemical Compounds
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Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
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Paragraph 0572
(2017/01/19)
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- COMPOUNDS, COMPOSITIONS AND METHODS OF INCREASING CFTR ACTIVITY
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The present disclosure features disclosed compounds which can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. The present disclosure also features methods of treating a condition associated with decreased CFTR activity or a condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound.
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Paragraph 0634
(2016/02/24)
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- Enantioselective preparation of 3-Arylcycloalkylamines by rhodium-catalyzed 1,4-addition and subsequent stereodivergent reduction
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N-Sulfonylimines of cycloalk-2-enones are well-suited for the enantioselective rhodium(I)/ binap-catalyzed 1,4-additions of arylzinc halides. The cyclic enamides, obtained after quenching, are sensitive towards chromatography, but can undergo diastereosel
- Gebhardt, Sandra,Müller, Christian H.,Westmeier, Johannes,Harms, Klaus,Von Zezschwitz, Paultheo
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p. 507 - 514
(2015/03/05)
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- Synthesis of cyclic γ-amino acids for foldamers and peptide nanotubes
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Cyclic γ-amino acids are molecular building blocks of great interest in peptide and foldamer chemistry, as they allow the preparation of new structures that are not found in Nature. In this paper, we describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This arrangement, in most cases, induces the resulting peptides to adopt a flat conformation, which makes them appropriate for the design of foldamers that adopt β-sheet-type structures. We describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This makes them suitable for the design of foldamers that adopt β-sheet-type structures.
- Rodriguez-Vazquez, Nuria,Salzinger, Stephan,Silva, Luis F.,Amorin, Manuel,Granja, Juan R.
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p. 3477 - 3493
(2013/07/11)
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- An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino] cyclohexanecarboxylic acid
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An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino] cyclohexanecarboxylic acid from 3-aminobenzoic acid is described utilising milder and more selective conditions. Both a classical salt resolution and an enzymatic approach have been shown to give the desired compound in high selectivity.
- Badland, Matthew,Bains, Carol A.,Howard, Roger,Laity, Daniel,Newman, Sandra D.
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experimental part
p. 864 - 866
(2010/11/02)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention provides inhibitors of protein kinases of formula I-a and I-b, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 364
(2010/01/30)
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- NOVEL SEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I: wherein R1, R2, R4, R5, R6, A, B, Y, Z, n, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 53
(2009/05/28)
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- BENZIMIDAZOLE DERIVATIVES
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The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1,R2, R3, R4, R5, A, X, n, and are as defined herein. Such novel benzamidazole derivatives are useful in trv treatment of abnormal cell growth, such as cancer, in mammals. This invention ate relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing sue compounds.
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Page/Page column 83
(2008/12/06)
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- Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides
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Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.
- Pryde, David C.,Maw, Graham N.,Planken, Simon,Platts, Michelle Y.,Sanderson, Vivienne,Corless, Martin,Stobie, Alan,Barber, Christopher G.,Russell, Rachel,Foster, Laura,Barker, Laura,Wayman, Christopher,Van Der Graaf, Piet,Stacey, Peter,Morren, Debbie,Kohl, Christopher,Beaumont, Kevin,Coggon, Sara,Tute, Michael
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p. 4409 - 4424
(2007/10/03)
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- Self-assembled peptide tubelets with 7 A pores
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Here we report the preparation and structural characteristics of self-assembling peptide tubelets composed of 32-membered rings formed of alternating cx-amino acids and cis-3-aminocyclohexanecarboxylic acids. The tubelets possess a partial hydrophobic cor
- Amorin, Manuel,Castedo, Luis,Granja, Juan R.
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p. 6543 - 6551
(2007/10/03)
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- Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure
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Two parallel synthetic methods using solid-supported reagents were established to examine the rapid optimization of weak hit compound 1. Several compounds showed high potency in the low nanomolar range against N-myristoyltransferase. The structure-activity relationship (SAR) and antifungal activities of a series of novel 2-aminobenzothiazole N-myristoyltransferase inhibitors are presented.
- Yamazaki, Kazuo,Kaneko, Yasushi,Suwa, Kie,Ebara, Shinji,Nakazawa, Kyoko,Yasuno, Kazuhiro
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p. 2509 - 2522
(2007/10/03)
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- New cyclic peptide assemblies with hydrophobic cavities: The structural and thermodynamic basis of a new class of peptide nanotubes
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A new class of self-assembling peptides based on cyclic peptides made of alternating 3-aminocyclohexanecarboxylic acid (γ-Acc) and α-amino acids is described. The studied cylindrical assemblies are models for a new class of self-assembling peptide nanotub
- Amorin, Manuel,Castedo, Luis,Granja, Juan R.
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p. 2844 - 2845
(2007/10/03)
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- Pyridine derivatives
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Pyridine compounds of general formula: wherein —R1represents in which R11is hydrogen, C1-6alkyl, halogen, hydroxy, C1-12alkoxy, nitro, amino, C1-6alkylsulfonylamino, C1-6alkoxycarbonyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkanoylamino, phenyl C1-6alkylamino, phenylsulfonylamino, or —O—(CH2)n—R111; R2represents hydrogen or halogen; R3represents hydrogen, —CR31R32R33, or —NR34R35; R4is hydrogen, carbamoyl, CN, carboxyl, etc.; R5is amino, C1-6alkylamino, di C1-6alkylamino, etc. or salt thereof. The compound has an excellent anti-inflammatory activity, and other biological activity.
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- N-benzenesulfonyl l-proline compounds as bradykinin antagonists
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This invention provides a compound of the formula (I): or the pharmaceutically acceptable salts thereof wherein X1 and X2 are halo; R1 and R2 are independently hydrogen or C1-4 alkyl; R3 and R4 are each hydrogen or halo; and R5 is (a) —C3-9 diazacycloalkyl optionally substituted with C5-11 azabicycloalkyl; (b) —C3-9 azacycloalkyl-NH—(C5-11 azabicycloalkyl optionally substituted with C1-4 alkyl); (c) —NH—C1-3 alkyl-C(O)—C5-11 diazabicycloalkyl; (d) —NH—C1-3 alkyl-C(O)—NH—C5-11 azabicycloalkyl, the C5-11 azabicycloalkyl being optionally substituted with C1-4 alkyl; (e) —C3-9 azacycloalkyl optionally substituted with C3-9 azacycloalkyl; or (f) —NH—C1-5 alkyl-NH—C(O)—C4-9 cycloalkyl-NH2. These compounds are useful for the treatment of medical conditions mediated by bradykinin such as inflammation, allergic rhinitis, pain, etc. This invention also provides a pharmaceutical composition comprising the above compound.
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- N-benzenesulfonyl L-proline compounds as bradykinin antagonists
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This invention provides a compound of the formula (I): or the pharmaceutically acceptable salts thereof wherein X1 and X2 are halo; R1 andR2 are independently hydrogen or C1-4 alkyl; R3 and R4 are each hydrogen or halo; andR5 is(a) -C3-9 diazacycloalkyl optionally substituted with C5-11 azabicycloalkyl;(b) -C3-9 azacycloalkyl-NH-(C5-11 azabicycloalkyl optionally substituted with C1-4 alkyl);(c) -NH-C1-3 alkyl-C(O)-C5-11 diazabicycloalkyl;(d) -NH-C1-3 alkyl-C(O)-NH-C5-11 azabicycloalkyl, the C5-11 azabicycloalkyl being optionally substituted with C1-4 alkyl;(e) -C3-9 azacycloalkyl optionally substituted with C3-9 azacycloalkyl; or(f) -NH-C1-5 alkyl-NH-C(O)-C4-9 cycloalkyl-NH2. These compounds are useful for the treatment of medical conditions mediated by bradykinin such as inflammation, allergic rhinitis, pain, etc. This invention also provides a pharmaceutical composition comprising the above compound.
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