- Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization
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A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.
- Jaime-Figueroa, Saul,Bond, Michael J.,Vergara, J. Ignacio,Swartzel, Jake C.,Crews, Craig M.
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p. 8479 - 8488
(2021/06/28)
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- Light-induced [2 + 2] cycloadditions for the construction of cyclobutane-fused pyridinyl sulfonyl fluorides
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Cyclobutanes are an important class of motifs present in a wide range of natural products and other biologically significant molecules. A photocatalytic [2 + 2] cycloaddition between pyridones or isoquinolones and ethenesulfonyl fluoride was achieved, providing a portal to a class of unique cyclobutane-fused pyridinyl sulfonyl fluorides with quaternary rigid rings (30 examples). Further applications of these novel sulfonyl fluoride molecules in SuFEx click chemistry were also accomplished, providing the corresponding sulfonates and sulphonamides with reasonable yields.
- Liu, Jing,Wang, Shi-Meng,Qin, Hua-Li
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p. 4019 - 4023
(2020/06/09)
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- SUBSTITUTED ARYLMETHYLUREAS AND HETEROARYLMETHYLUREAS, ANALOGUES THEREOF, AND METHODS USING SAME
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The present invention includes substituted arylmethyl ureas and heteroarylmethyl-ureas, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infections in a patient.
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- Aromatic compounds and preparation method and application thereof
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The invention discloses aromatic compounds and a preparation method and application thereof. The preparation method of the aromatic compounds includes the step of performing a cyclization reaction between an amide compound and a benzoic acid compound in the presence of a rhodium catalyst, a metal oxidant and base, wherein the aromatic compounds are isoquinolinone compounds or isocoumarin derivatives, and the amide compound is N-vinylformamide or N-vinylacetamide. Through the synergistic effect of the rhodium catalyst, the metal oxidant and the base, the isoquinolinone compounds or isocoumarinderivatives are obtained through the one-step reaction between the benzoic acid compound and the amide compound. The reaction has simple operation, the raw materials are cheap and easily available, reaction substrates can be selected flexibly according to the required isoquinolinone compounds and the isocoumarin derivatives, and the synthesized isoquinolinone compounds and the isocoumarin derivatives can be used as a backbone structure in multiple biologically active molecules and natural products, and have high practicality.
- -
-
Paragraph 0012; 0037-0039; 0071-0073
(2020/02/19)
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- Divergent Synthesis of Isoquinolone and Isocoumarin Derivatives by the Annulation of Benzoic Acid with N-Vinyl Amide
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A simple and efficient method for the synthesis of isoquinolone and isocoumarin derivatives is reported. The method for the first time provides a one-step divergent synthesis of important isoquinolone and isocoumarin skeletons from benzoic acid by switching the coupling partners. In addition, a reliable mechanism has been proposed on the basis of experimental investigations, including kinetic isotope effect experiments, 13C labeling experiments, time-tracking experiments, and competitive experiments, as well as DFT calculation studies.
- Sun, Rui,Yang, Xiao,Li, Qianggen,Xu, Ke,Tang, Juan,Zheng, Xueli,Yuan, Maolin,Fu, Haiyan,Li, Ruixiang,Chen, Hua
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supporting information
p. 9425 - 9429
(2019/11/28)
-
- Hepatitis C virus inhibitors
-
Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 390
(2017/01/23)
-
- HEPATITIS C VIRUS INHIBITORS
-
Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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- Rhodium(III)-catalyzed C-H activation/annulation with vinyl esters as an acetylene equivalent
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The behavior of electron-rich alkenes in rhodium-catalyzed C-H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.
- Webb, Nicola J.,Marsden, Stephen P.,Raw, Steven A.
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p. 4718 - 4721
(2015/04/27)
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- Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide ns3 protease inhibitor for the treatment of hepatitis C virus infection
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The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
- Scola, Paul M.,Wang, Alan Xiangdong,Good, Andrew C.,Sun, Li-Qiang,Combrink, Keith D.,Campbell, Jeffrey A.,Chen, Jie,Tu, Yong,Sin, Ny,Venables, Brian L.,Sit, Sing-Yuen,Chen, Yan,Cocuzza, Anthony,Bilder, Donna M.,D'Andrea, Stanley,Zheng, Barbara,Hewawasam, Piyasena,Ding, Min,Thuring, Jan,Li, Jianqing,Hernandez, Dennis,Yu, Fei,Falk, Paul,Zhai, Guangzhi,Sheaffer, Amy K.,Chen, Chaoqun,Lee, Min S.,Barry, Diana,Knipe, Jay O.,Li, Wenying,Han, Yong-Hae,Jenkins, Susan,Gesenberg, Christoph,Gao, Qi,Sinz, Michael W.,Santone, Kenneth S.,Zvyaga, Tatyana,Rajamani, Ramkumar,Klei, Herbert E.,Colonno, Richard J.,Grasela, Dennis M.,Hughes, Eric,Chien, Caly,Adams, Stephen,Levesque, Paul C.,Li, Danshi,Zhu, Jialong,Meanwell, Nicholas A.,McPhee, Fiona
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p. 1708 - 1729
(2014/04/03)
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- Hepatitis C Virus Inhibitors
-
Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column
(2013/05/21)
-
- Hepatitis C Virus Inhibitors
-
Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column
(2013/06/26)
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- Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
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Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
- Ray, Peter,Wright, Jane,Adam, Julia,Boucharens, Sylviane,Black, Darcey,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Man, Jos De,Morphy, Richard,Sherborne, Brad,Sherry, Lorcan,Straten, Nicole Van,Westwood, Paul,York, Mark
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p. 1084 - 1088
(2011/04/16)
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- Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
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Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
- Ray, Peter,Wright, Jane,Adam, Julia,Bennett, Johnathan,Boucharens, Sylviane,Black, Darcey,Cook, Andrew,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Haunso, Anders,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Mestres, Jordi,De Man, Jos,Morphy, Richard,Rankovic, Zoran,Sherborne, Brad,Sherry, Lorcan,Van Straten, Nicole,Westwood, Paul,Zaman, Guido Z.R.
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supporting information; scheme or table
p. 97 - 101
(2011/02/28)
-
- New substituted isoquinoline and isoquinolinone derivatives
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The invention relates to 6-substituted isoquinoline and isochinolone derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.
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Page/Page column 25
(2010/04/23)
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- INHIBITORS OF CATHEPSIN B
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The present invention is directed to a method of using compounds of Formula (I) to inhibit Cathepsin B. Specifically the compounds of the present invention are useful as therapeutic agents for the treatment of tumor invasion, metastasis, Alzheimer's Disease, arthritis, inflammatory diseases such as chronic and acute pancreatitis, inflammatory airway disease, and bone and joint disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, psoriasis, and other autoimmune disorders, liver fibrosis, including liver fibrosis associated with HCV, all types of steatosis (including non-alcoholic steatohepatitis) and alcohol-associated steatohepatitis, non-alcoholic fatty liver disease, forms of pulmonary fibrosis including idiopathic pulmonary fibrosis, pathological diagnosis of interstitial pneumonia following lung biopsy, renal fibrosis, cardiac fibrosis, retinal angiogenesis and fibrosis/gliosis in the eye, schleroderma, and systemic sclerosis. The compounds of Formula (I) are also useful for treating subjects with both HCV and fibrosis in a mammal, particularly liver fibrosis, and subjects affirmatively diagnosed or at risk for both HCV and liver fibrosis.
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-
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- Hepatitis C Virus Inhibitors
-
Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 12
(2009/12/05)
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- NUCLEAR RECEPTOR BINDING AGENTS
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The present invention relates to a novel class of nuclear receptor binding agents (NRBAs). The NRBAs are applicable for use in the prevention and/or treatment of a variety of diseases and conditions including prevention and treatment of cancers such as pr
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Page/Page column 47-48; 65-66
(2008/12/07)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 37; 134
(2008/12/05)
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- MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
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Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers thereof, wherein X is N, CH and where X bears a double bond it is C; R1 is -OR5, -NH-SO2R6; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, or C3-7cycloalkyl; R4 is isoquinolinyl optionally substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, hydroxy, halo, polyhalo- C1-6alkyl, polyhaloC1-6alkoxy, amino, mono- or diC1-6alkylamino, mono- or DiC1-6alkylaminocarbonyl, C1-6alkylcarbonyl-amino, aryl, and Het; n is 3, 4, 5, or 6; each dashed line (represented by ) represents an optional double bond; R5 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R6 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; each aryl is phenyl optionally substituted with one, two or three substituents; and each Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
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Page/Page column 72
(2008/06/13)
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- MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
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Inhibitors of HCV replication of formula (I), the N-oxides, salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by -------) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 9 to 12 membered bicyclic heterocyclic ring system wherein said ring system contains one nitrogen, and optionally one to three additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents; L is a direct bond, -O-. -O-C1-4alkanediyl-, -O-C(=O)-, -O-C(=O)-NR4a- or -O-C(=O)-NR4aC1-4alkanediyl-; R2 is hydrogen, -OR5, -C(O)OR5, -C(=O)R6, -C(=O)NR4aR4b, -C(=O)NHR4c,-NR4aR4b, -NHR4c, -NR4aSOpNR4aR4b, -NR4aSOpR7, or B(OR5)2; R3 is hydrogen, and where X is C or CH, R3 may also be C1-6alkyl; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents ; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
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Page/Page column 87
(2010/11/25)
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- HCV INHIBITORS
-
The present invention is directed to compounds that are antiviral agents. Specifically the compounds of the present invention inhibit replication of HCV and are therefore useful in treating hepatitis C infections. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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Page/Page column 55
(2008/06/13)
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- 2-(ARYLOXY)ACETAMIDE FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS
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The present invention relates generally to novel 2-(aryloxy)acetamides of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the variables W, Y, Z, R7, R8, and R9 are as defined herein. These compounds are selective inhibitors of the serine protease coagulation factor VIIa which can be used as medicaments.
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- PROCESS FOR THE PREPARATION OF SUBSTITUTED HETEROCYCLES
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The present disclosure generally relates to a process for the preparation of hydroxy-substituted heterocycles such as isoquinolines, naphthyridines, pyridopyridazines, and pyridopyrimidines.
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Page/Page column 4
(2010/11/27)
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- PHENYLGLYCINAMIDE DERIVATIVES USEFUL AS ANTICOAGULANTS
-
The present invention relates generally to phenylglycinamide derivatives that inhibit serine proteases. In particular it is directed to novel phenylglycinamide derivatives, and analogues thereof, which are useful as selective inhibitors of serine protease enzymes of the coagulation cascade; for example thrombin, factor VIIa, factor Xa, factor XIa, factor IXa, and/or plasma kallikrein. In particular, it relates to compounds that are factor VIIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
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Page/Page column 149
(2008/06/13)
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- Hepatitis C virus inhibitors
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which inhibit the function of the NS3 protease (also referred to herein as “serine protease”) encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS3 protease.
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Page/Page column 46
(2008/06/13)
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- HEPATITIS C INHIBITOR DIPEPTIDE ANALOGS
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The present invention relates to compounds of formula (I): wherein R1, R2, R4, n and m are as defined herein and R3 is selected from: (i) -C(O)OR31 wherein R31 is (C1-6)alkyl or aryl, wherein the (C1-6)alkyl is optionally substituted with one to three halogen substituents; (ii) -C(O)NR32R33, wherein R32 and R33 are each independently selected form H, (C1-6)alkyl, and Het; (iii) -SOvR34, wherein v is 1 or 2 and R34 is selected from: (C1-6)alkyl, aryl, Het, and NR32R33 wherein R32 and R33 are as defined above; and (iv) -CO(O)-R35, wherein R35 is selected from (C1-8)alkyl, (C3-7)cycloalkyl-(C1-4)alkyl, aryl, aryl-(C1-6)alkyl, Het and Het-(C1-6)alkyl, each of which are optionally substituted with one or more substituents each independently selected from halo, (C1-6)alkyl, (C3-7)cycloalkyl, aryl, Het, hydroxyl, -O-(C1-6)alkyl, -S-(C1-6)alkyl, -SO-(C1-6)alkyl, -SO2-(C1-6)alkyl, -O-aryl, -S-aryl, -SO-aryl and -SO2-aryl, wherein the aryl portion of the -O-aryl, -S-aryl, -SO-aryl and -SO2-aryl are each optionally substituted with one to five halo substituents. The present invention further relates to pharmaceutical compositions containing the compounds of formula (I) and methods for using these analogs in the treatment of HCV infection.
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Page/Page column 75
(2008/06/13)
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- Hepatitis C inhibitor peptide analogs
-
Compounds of formula (I): wherein R1, R2, R3, R4, R5, Y, n and m are as defined herein. The compounds are useful as inhibitors of HCV NS3 protease.
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Page/Page column 33
(2010/02/15)
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- HEPATITIS C INHIBITOR PEPTIDE ANALOGS
-
The invention relates to compounds of formula (I) wherein R', R2, R3, R4, R5, R6, Y, n and m are as defined herein. The compounds are useful for the treatment and prevention of hepatitis C viral infections in mammals by inhibiting HCV NS3 protease. The invention further relates to azalactone compounds of the formula (III) which can be reacted with an amide anion to produce the compounds of formula (I).
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Page/Page column 89
(2010/02/15)
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- HEPATITIS C VIRUS INHIBITORS
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Compounds are disclosed having general formula (I), wherein R1, R2, R3, R4, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 57; 58
(2010/02/11)
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- Hepatitis C virus inhibitors
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Hepatitis C virus inhibitors are disclosed having the general formula: wherein R1, R2, R3, R′, B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 34
(2010/02/12)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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