- Discovery of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold
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A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.
- Deng, Yongqi,Doty, Amy,Ferguson, Heidi,Fradera, Xavier,Han, Yongxin,Jonathan Bennett, David,Knemeyer, Ian,Lesburg, Charles A.,Li, Derun,Liu, Kun,Martinot, Theo,Otte, Karin,Richard Miller, J.,Sciammetta, Nunzio,Sloman, David,Vincent, Stella,Yu, Wensheng
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- NOVEL TETRAHYDROPYRIDOPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The present invention provides novel compounds having the general formula (I) wherein R1, R2 and Z are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 20; 21
(2018/05/24)
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- 2-(2-pyridine)-6-(2-chloro-3-trifluoromethylbenzoyl)-5,7,8-trihydropyrido [4,3-d] pyrimidine and preparation method thereof
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The invention discloses 2-(2-pyridine)-6-(2-chloro-3-trifluoromethylbenzoyl)-5,7,8-trihydropyrido [4,3-d] pyrimidine and a preparation method thereof. The structure of the 2-(2-pyridine)-6-(2-chloro-3-trifluoromethylbenzoyl)-5,7,8-trihydropyrido [4,3-d] pyrimidine is as shown in the formula (I), and the 2-(2-pyridine)-6-(2-chloro-3-trifluoromethylbenzoyl)-5,7,8-trihydropyrido [4,3-d] pyrimidine belongs to a novel pyridopyrimidine compound and a novel anticancer drug is provided for human beings. The research field of pyridopyrimidine compounds is widened, the reaction total yield of the compound is high, the process is simple, and the method is suitable for industrial production.
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Paragraph 0025; 0030
(2018/03/01)
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- FUSED HETEROCYCLIC COMPOUNDS AS S1P MODULATORS
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The invention relates to heterocyclic compounds as S1P modulators, pharmaceutical compositions comprising such compounds, and uses thereof in the treatment, alleviation or prevention of diseases or disorders mediated by an S1P receptor.
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Page/Page column 70; 71
(2017/03/28)
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- Substituted ring compound and its method and use thereof
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The invention provides a substituted cyclic compound as well as a use method and application thereof. The compound is a compound as shown in a formula (I) or stereoisomers, stereomers, tautomers, nitric oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as shown in the formula (I). The invention further provides a medicament composition containing the compound. The compound and the medicament composition are capable of regulating the activity of protein kinase in a biological sample body and are used for protecting, treating or relieving proliferative diseases of patients. The formula (I) is as shown in the specification.
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Paragraph 0905; 0906; 0907
(2017/08/25)
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- Pyridopyrimidine compounds and preparation method thereof
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The invention discloses pyridopyrimidine compounds and a preparation method thereof. The pyridopyrimidine compounds are 2-(2-pyridyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines; and the derivatives are 2-(2-pyridyl)-6-(2,3-dichlorobenzoyl)-5,7,8-trihydrop
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Paragraph 0027; 0031; 0032
(2016/10/09)
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- Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2
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This invention is directed to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. The compounds of Formula I are useful as protein kinase (PK) inhibitors and can be used to treat such diseases as cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases inflammatory disorders and neurodegenerative disorders.
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Page/Page column 22-23
(2016/04/26)
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- BICYCLIC PYRAZOLE PESTICIDES
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Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N-oxides, and salts thereof, (1) wherein Q is (Q-1) or (Q-2); and A, R1, m, X1, X1a, X1b, X2, R2, R5, q and t are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound or a composition of the invention.
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Page/Page column 24
(2016/10/31)
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- Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
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Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
- Jiang, Fen,Wang, Hui-Jie,Jin, Yu-Hui,Zhang, Qiong,Wang, Zhi-Hui,Jia, Jian-Min,Liu, Fang,Wang, Lei,Bao, Qi-Chao,Li, Dong-Dong,You, Qi-Dong,Xu, Xiao-Li
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p. 10498 - 10519
(2016/12/16)
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- TETRAHYDROPYRIDOPYRIMIDINES AND TETRAHYDROPYRIDOPYRIDINES AS INHIBITORS OF HBSAG (HBV SURFACE ANTIGEN) AND HBV DNA PRODUCTION FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTIONS
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The present invention provides tetrahydropyridopyrimidines and tetrahydropyridopyridines having the general formula (I) wherein R1, R2, U, W, X, Y and Z are as described herein, as inhibitors of HBsAg (HBV surface antigen) and HBV DNA production for the treatment and prophylaxis of hepatitis B virus infections.
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Page/Page column 175; 200
(2016/11/21)
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- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted alkynyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0308
(2014/06/24)
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- Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening
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Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
- Sun, Hao-Peng,Jia, Jian-Min,Jiang, Fen,Xu, Xiao-Li,Liu, Fang,Guo, Xiao-Ke,Cherfaoui, Bahidja,Huang, Hao-Ze,Pan, Yang,You, Qi-Dong
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p. 399 - 412
(2014/05/06)
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- HEDGEHOG PATHWAY SIGNALING INHIBITORS AND THERAPEUTIC APPLICATIONS THEREOF
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The hedgehog (Hh) signaling pathway is a pathway which regulates patterning, growth and cell migration during embryonic development, but in adulthood is limited to tissue maintenance and repair. Mutational inactivation of the inhibitory pathway components leads to constitutive ligand-independent activation of the Hh signaling pathway, results in cancers such as basal cell carcinoma and medulloblastoma. Ligand-dependent activation of Hh signaling is involved in prostate cancer, pancreatic cancer, breast cancer and blood cancers. Therefore, inhibition of the aberrant Hh signaling represents a promising approach toward novel anticancer therapy. The invention provides novel molecules of formula I that inhibit hedgehog pathway signaling and provides therapeutic applications for the treatment of malignancies (basal cell carcinoma, medulloblastoma, glioblastoma, non-small cell lung cancer, prostate cancer, pancreatic cancer, blood cancers, mesenchymal cancers, etc.), prevention of tumor regrowth, sensitization of radio-chemo therapies, and other diseases (inflammation, fibrosis and immune disorders).
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Paragraph 0157; 0158
(2014/08/06)
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- KINASE INHIBITORS
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The present invention relates to compounds of formulae I and II wherein the variables are as defined herein. These compounds are capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
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Paragraph 0252
(2013/09/26)
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- METHOD OF TREATING CONDITIIONS WITH KINASE INHIBITORS
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The present invention relates to a method of treating ophthalmic diseases and conditions, e.g. diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, etc., in a subject comprising administering to said subject a therapeutically effective amount of at least one compound of formula I or a prodrug, pharmaceutically acceptable salt, racemic mixtures or enantiomers of said compound. The compounds of formula I are capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
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Paragraph 0236-0237
(2013/09/26)
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- Substituted Benzamide Compounds
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Substituted benzamide compounds corresponding to formula (I) in which R5, R6, R7, R8, a, b, c, d, t, D and X have defined meanings, a process for their preparation, pharmaceutical compositions comprising such compounds, and a method of using such compounds to treat pain and other conditions mediated at least in part via the bradykinin 1 receptor.
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Page/Page column 136
(2012/04/04)
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- METABOTROPIC GLUTAMATE RECEPTOR MODULATORS
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The invention relates to heterocyclic derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are m GluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.
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Page/Page column 51
(2012/07/13)
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- ARYL CARBOXAMIDE DERIVATIVES AS SODIUM CHANNEL INHIBITORS FOR TREATMENT OF PAIN
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The present invention provides compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav 1.7, and are therefore useful for the treatment of diseases treatable by inhibition of these channels, in particular, chronic pain disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 82-83
(2011/09/19)
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- HETEROBICYCLIC COMPOUNDS USEFUL AS KINASE INHIBITORS
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A compound of Formula (I) and enantiomers, diastereomers and pharmaceutically-acceptable salts thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula I, and methods of treating conditions associated with the activity of p3
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Page/Page column 31
(2008/12/08)
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- AROMATIC-RING-FUSED PYRIMIDINE DERIVATIVE
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There are provided novel pyrimidine derivatives which has been fused with an aromatic heterocycle selected from thiophene, thiazole and pyridine or pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising said compound as an
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Page/Page column 17
(2008/06/13)
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- TETRAHYDROPYRIDO[3,4-D]PYRIMIDINES AND RELATED ANALOGUES
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Tetrahydropyrido[3,4-d]pyrimidines and related analogues are provided, of the formula (I) in which variables are as described herein, as are methods for their preparation and use. Such compounds may generally be used to modulate ligand binding to histamin
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Page/Page column 44
(2008/06/13)
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- PYRIMIDINE DERIVATIVE CONDENSED WITH NON-AROMATIC RING
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There are provided new pyrimidine derivatives condensed with a non-aromatic ring selected from dihydrothiophene, dihydrofuran, cycloalkane moiety, and the like or pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising said
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Page/Page column 17
(2010/11/27)
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- Synthesis and SAR of p38α MAP kinase inhibitors based on heterobicyclic scaffolds
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The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38α MAP kinase with good cellular potency toward the inhibition of TNF-α production. X-ray co-crystallography of an oxalamide analog (24) bound to unphosphorylated p38α is also disclosed.
- Murali Dhar,Wrobleski, Stephen T.,Lin, Shuqun,Furch, Joseph A.,Nirschl, David S.,Fan, Yi,Todderud, Gordon,Pitt, Sidney,Doweyko, Arthur M.,Sack, John S.,Mathur, Arvind,McKinnon, Murray,Barrish, Joel C.,Dodd, John H.,Schieven, Gary L.,Leftheris, Katerina
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p. 5019 - 5024
(2008/03/11)
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- SUBSTITUTED 5, 6, 7, 8-TETRAHYDRO-PYRIDO[4, 3-D]PYRIMIDINE-2-YL COMPOUNDS AND 5, 6, 7, 8-TETRAHYDRO-QUINAZOLINE-2-YL COMPOUNDS
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The invention relates to substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine-2-yl compounds and 5,6,7,8-tetrahydro-quinazoline-2-yl compounds, methods for the production thereof, medicaments containing said compounds, and the use thereof for producing medicaments.
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Page/Page column 81
(2008/06/13)
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- Pyrid-2-one derivatives and methods of use
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Selected compounds are effective for treatment of diseases, such as cell proliferation or apoptosis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving stroke, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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- Synthesis of the bicyclic secondary amines via dimethylaminomethylene ketones from 3-pyrrolidone and 4-piperidone
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The reaction of N-protected 3-pyrrolidone and 4-piperidone with N,N-dimethylformamide dimethyl acetal gave the dimethylaminomethylene ketones, which reacted with several types of hydrazines, amidines, and guanidine to afford the secondary amines having fused ring system.
- Fukui, Hideto,Inoguchi, Kiyoshi,Nakano, Jun
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p. 257 - 264
(2007/10/03)
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- Quinoline and quinazoline compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia
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Compounds of formula I, STR1whereinR 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms;R 2 represents H or C 1-6 alkoxy optionally substituted by one or more fluorine atoms;R 3 represents a 5- or 6-membered heterocyclic ring, the ring being optionally substituted;R 4 represents a 4-, 5-, 6-, or 7-membered heterocyclic ring, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring, the ring system as a whole being optionally substituted;X represents CH or N; andL is absent,or represents a cyclic group of formula Ia, STR2or represents a chain of formula Ib, STR3and pharmaceutically acceptable salts thereof, are useful in therapy, in particular in the treatment of benign prostatic hyperplasia.
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