- Meso-piperidine calix[4]pyrrole: Synthesis, structure and ion binding studies
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We report the synthesis, structure and preliminary solution phase ion binding properties of the calix[4]pyrrole 3a-c. Calix[4]pyrrole 3a and 3b, the first to be prepared via one-pot reaction, were obtained by reacting the ketone 7 with pyrrole in the presence of an acid catalyst. On the basis of 1H NMR spectroscopic analyses and the titrations of UV spectrophotometry, it was concluded that compound 3a possesses significantly enhanced selectivity for fluoride anion in chloroform, and formes 1:1 (ligand: anion) complexes with fluoride and chloride anions.
- He, Ying-Chun,Pan, Ji-Gang
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Read Online
- Gold N-Heterocyclic Carbene Catalysts for the Hydrofluorination of Alkynes Using Hydrofluoric Acid: Reaction Scope, Mechanistic Studies and the Tracking of Elusive Intermediates
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An efficient and chemoselective methodology deploying gold-N-heterocyclic carbene (NHC) complexes as catalysts in the hydrofluorination of terminal alkynes using aqueous HF has been developed. Mechanistic studies shed light on an in situ generated catalyst, formed by the reaction of Br?nsted basic gold pre-catalysts with HF in water, which exhibits the highest reactivity and chemoselectivity. The catalytic system has a wide alkyl substituted-substrate scope, and stoichiometric as well as catalytic reactions with tailor-designed gold pre-catalysts enable the identification of various gold species involved along the catalytic cycle. Computational studies aid in understanding the chemoselectivity observed through examination of key mechanistic steps for phosphine- and NHC-coordinated gold species bearing the triflate counterion and the elusive key complex bearing a bifluoride counterion.
- Bédard, Sandrine,Cavallo, Luigi,Falivene, Laura,Gauthier, Rapha?l,Nolan, Steven P.,Paquin, Jean-Fran?ois,Saab, Marina,Tzouras, Nikolaos V.,Van Hecke, Kristof,Zhang, Ziyun
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- TRPML MODULATORS
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Paragraph 0815
(2021/06/26)
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- ATF6 MODULATORS AND USES THEREOF
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Compounds (1-2) as modulators of Activating Transcription Factor 6 (ATF6) are provided. The compounds may find use as therapeutic agents for the treatment of diseases or disorders mediated by ATF6 and may find particular use in the treatment of viral infections, neurodegenerative diseases, vascular diseases, or cancer. (Formula (1-2))
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Paragraph 280
(2021/04/17)
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- TREATMENT OF INDOLENT OR AGGRESSIVE B-CELL LYMPHOMAS USING A COMBINATION COMPRISING BTK INHIBITORS
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Disclosed herein is a method for the prevention, delay of progression or treatment of indolent or aggressive B-cell lymphomas in an individual in need thereof, comprising administering a Btk inhibitor (in particularly (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof) in combination with an anti-PD-1 antibody. The potent and selective BTK inhibitor in combination with the anti-PD-1 antibody have a manageable toxicity profile in patients with indolent and aggressive lymphomas.
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Paragraph 0109
(2019/06/17)
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- USE OF A COMBINATION COMPRISING A BTK INHIBITOR FOR TREATING CANCERS
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A method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a Btk inhibitor, particularly, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a targeted therapy agent. A pharmaceutical combination comprising a Btk inhibitor, particularly, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a targeted therapy agent.
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Paragraph 0102-0103
(2018/03/09)
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- CRYSTALLINE FORM OF (S)-7-(1-ACRYLOYLPIPERIDIN-4-YL)-2-(4-PHENOXYPHENYL)-4,5,6,7-TETRAHYDROPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBOXAMIDE, PREPARATION, AND USES THEREOF
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The present invention relates to a crystalline form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease.
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Paragraph 0055; 0091; 0095
(2018/08/19)
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- CRYSTALLINE FORMS OF (S) -7- (1- (BUT-2-YNOYL) PIPERIDIN-4-YL) -2- (4-PHENOXYPHENYL) -4, 5, 6, 7-TETRAHY DROPYRAZOLO [1, 5-A] PYRIMIDINE-3-CARBOXAMIDE, PREPARATION, AND USES THEREOF
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The present invention relates to a crystalline form of (S) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyri midine-3-carboxamide for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease.
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Paragraph 00137; 00138
(2018/09/08)
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- HETEROCYCLIC COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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The invention relates to a novel heterocyclic compound inhibiting a cyclin-dependent kinase (CDK) and a pharmaceutical composition comprising the same as an effective ingredient. The heterocyclic compound according to the present invention or pharmaceutically acceptable salt thereof can be effectively used in treating or preventing cancers, degenerative brain diseases, etc.
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Paragraph 0209; 0212
(2018/01/11)
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- Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of Aliphatic Ketones: Synthesis of Enantioenriched Chiral Tertiary α-Hydroxyboronates
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A new method was developed for the first catalytic enantioselective borylation of aliphatic ketones. A variety of substrates reacted efficiently with bis(pinacolato)diboron in the presence of a copper(I)/chiral N-heterocyclic carbene complex catalyst to furnish optically active tertiary α-hydroxyboronates with moderate to high enantioselectivities (up to 94 % ee). Notably, the product could be converted into the chiral tertiary alcohol derivative using a stereospecific boron functionalization process. The theoretical study of the mechanism for the enantioselectivity is also described.
- Kubota, Koji,Osaki, Shun,Jin, Mingoo,Ito, Hajime
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supporting information
p. 6646 - 6650
(2017/05/29)
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- SMYD INHIBITORS
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The present disclosure provides carboxamides and sulfonamides having Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, Y, B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.
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Paragraph 0614; 0620-0622
(2017/07/18)
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- ISOXAZOLE CARBOXAMIDE COMPOUNDS
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The present disclosure provides substituted isoxazole carboxamide compounds having Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, A, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.
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Paragraph 0269
(2016/06/01)
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- HEPATITIS B ANTIVIRAL AGENTS
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The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Page/Page column 191
(2013/07/05)
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- Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors
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A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC50's were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.
- Shen, Hong C.,Ding, Fa-Xiang,Zhou, Changyou,Xiong, Yusheng,Verras, Andreas,Chabin, Renee M.,Xu, Suoyu,Tong, Xinchun,Xie, Dan,Lassman, Michael E.,Bhatt, Urmi R.,Garcia-Calvo, Margarita M.,Geissler, Wayne,Shen, Zhu,Chen, Dunlu,Sinharoy, Ranabir,Hale, Jeffery J.,Tata, James R.,Pinto, Shirly,Shen, Dong-Ming,Colletti, Steven L.
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experimental part
p. 1299 - 1305
(2011/04/16)
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- NEW GPR119MODULATORS
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The application relates to compounds of Formula (Ia): and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomersor N-oxides thereof. The application also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the prophylaxis and treatment of medical conditions relating to disorders of the G-protein- coupled receptor GPR119, such as diabetes, obesity and osteoporosis.
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Page/Page column 139
(2010/01/07)
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- SUBSTITUTED ARYL SULFONE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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A series of substituted aryl sulfone derivatives represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, calcium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, epilepsy, diabetic neuropathy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, sleep disorder, bipolar disorder and stroke, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds.
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Page/Page column 33
(2009/05/29)
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- 1, 7-NAPHTHYRIDINE DERIVATIVES AS P38 MAP KINASE INHIBITORS
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This invention is directed to new inhibitors of the p38 mitogen-activated protein kinas having the general formula (I) to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy.
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Page/Page column 62
(2008/06/13)
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- CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present application describes modulators of MIP-1α of formula (I), or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein n, A, T, R1, R2 and R8, are as defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using the modulators of formula (I) are disclosed.
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Page/Page column 96
(2008/06/13)
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- CHEMICAL COMPOUNDS
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Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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- Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains
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Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
- Shen, Dong-Ming,Shu, Min,Mills, Sander G.,Chapman, Kevin T.,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Siciliano, Salvatore J.,Kwei, Gloria Y.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Schleif, William A.,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael D.,Emini, Emilio A.
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p. 935 - 939
(2007/10/03)
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- N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
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The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: wherein, generally, Q is R1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C1-4alkyl or halogen, such as methyl, fluorine or bromine; R2 is hydrogen or C1-4alkyl such as methyl; R3 is phenyl; R4 is hydrogen; R5 is hydrogen or C1-6alkylcarbonyl such as methylcarbonyl; X is —SO2— or —C(O)N(R2)SO2— where R2 is preferably hydrogen; Y is a bond, CH2 or Z1 where Z1 is —N(Rf)— in which Rf is C1-6alkylcarbonyl such as ethylcarbonyl; and R6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C1-6alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.
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Page/Page column 23; 38
(2010/11/30)
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- GAMMA-AMINOAMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present invention is directed to compounds of the formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R11, R12, W, X, and n are defined herein, which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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Page/Page column 69
(2010/02/07)
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- HETEROARYLPIPERIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present invention is directed to compounds of the formula (I): (wherein R>12345610 and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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- Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin- 1-yl-acetic acid antagonists of the human CCR5 chemokine receptor
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Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
- Shankaran,Donnelly, Karla L.,Shah, Shrenik K.,Guthikonda, Ravindra N.,MacCoss, Malcolm,Mills, Sander G.,Gould, Sandra L.,Malkowitz, Lorraine,Siciliano, Salvatore J.,Springer, Martin S.,Carella, Anthony,Carver, Gwen,Hazuda, Daria,Holmes, Karen,Kessler, Joseph,Lineberger, Janet,Miller, Michael D.,Emini, Emilio A.,Schleif, William A.
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p. 3419 - 3424
(2007/10/03)
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- Modulators of CCR5 chemokine receptor activity
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Compounds of Formula I: (wherein R1, R2, R3, R4, Q, and X are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
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- Studies on new platelet aggregation inhibitors 1. Synthesis of 7-nitro-3,4-dihydroquinoline-2(1H)-one derivatives
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A series of 6-cyclic aliphatic amino-7-nitro-3,4-dihydroquinoline-2(1H)-ones were prepared and tested for platelet aggregation inhibitory effect, cardiotonic activity and chronotropic activity. These compounds appeared to show selective inhibitory activity against platelet aggregation. Among them, 6-(4-ethoxycarbonylpiperidino)-7-nitro-3,4-dihydroquinoline-2(1H)-one (22f) showed the most potent inhibitory activity and high selectivity. A divergent synthetic route to 6-cyclic aliphatic amino-7-nitro-3,4-dihydroquinoline-2(1H)-one derivatives has also been investigated.
- Iyobe,Uchida,Kamata,Hotel,Kusama,Harada
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p. 822 - 829
(2007/10/03)
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula I: (wherein R1, R2, R3, R4, R5, R6, R14and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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- N-acyl cyclic amine derivatives
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The invention relates to compounds represented by the general formula [I][wherein Ar means an aryl group or a heteroaryl group which may have a substitutive group selected from a group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R1 means a C3-C6 cycloalkyl group which is substitutable with a fluorine atom; R2 and R4 mean hydrogen atoms, groups represented by -(A1)m-NH-B or the like; R3 and R5 mean hydrogen atoms, C1-C6 aliphatic hydrocarbon groups or the like which are substitutable with a lower alkyl group(s); n means 0 or 1; and X means an oxygen atom or a sulfur atom]. Compounds according to the invention, since they not only have potent selective antagonistic activity against muscarinic M3 receptors but also exhibit excellent oral activity, durability of action and pharmacokinetics, are very useful as safe and effective remedies against respiratory, urinary and digestive diseases with little adverse side effects.
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