- Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties
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In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
- Wang, Xiaojing,Barbosa, James,Blomgren, Peter,Bremer, Meire C.,Chen, Jacob,Crawford, James J.,Deng, Wei,Dong, Liming,Eigenbrot, Charles,Gallion, Steve,Hau, Jonathon,Hu, Huiyong,Johnson, Adam R.,Katewa, Arna,Kropf, Jeffrey E.,Lee, Seung H.,Liu, Lichuan,Lubach, Joseph W.,Macaluso, Jen,Maciejewski, Pat,Mitchell, Scott A.,Ortwine, Daniel F.,Dipaolo, Julie,Reif, Karin,Scheerens, Heleen,Schmitt, Aaron,Wong, Harvey,Xiong, Jin-Ming,Xu, Jianjun,Zhao, Zhongdong,Zhou, Fusheng,Currie, Kevin S.,Young, Wendy B.
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supporting information
p. 608 - 613
(2017/06/13)
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- HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS AS INHIBITORS OF BTK ACTIVITY
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Heteroaryl pyridone and aza-pyridone compounds of Formula I are provided, where one or two of X, X, and Xare N, and including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I foranddiagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 0737; 0738
(2015/11/16)
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- HETEROARYL PYRIDONE AND AZA-PYRIDONE AMIDE COMPOUNDS
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Heteroaryl pyridone and aza-pyridone amide compounds of Formula (I) are provided, and various substituents including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk, and for treating cancer and immune disorders such as inflammation mediated by Btk. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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- BICYCLIC PIPERAZINE COMPOUNDS
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Bicyclic piperazine compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 0202; 0203
(2013/05/21)
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- ALKYLATED PIPERAZINE COMPOUNDS
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Alkylated piperazine compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 0406; 0407
(2013/05/21)
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- PHARMACEUTICAL COMPOSITION CONTAINING FUSED HETERO-RING DERIVATIVE
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The present invention provides a compound which indicates a histamine H4 receptor modulating activity.A compound represented by a formula (I): wherein A ring is a ring represented by the following formula: wherein R1 is substituted or unsubstituted alkyl, etc., W is -O-, etc., n is an integer of 0 to 6; X is N(R7)- or -O-; R7 is hydrogen, substituted or unsubstituted alkyl, etc.; Y is-C(R8)= or -N=; R8 is hydrogen, substituted or unsubstituted alkyl, etc.; Z is =O, =S, etc.; B ring is a ring represented by the following formula wherein R10 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino; R11, R12a and R12b are each independently hydrogen or substituted or unsubstituted alkyl, etc.; p is an integer of 0 to 4, or its pharmaceutically acceptable salt, or a solvate thereof.The present invention provides a compound which indicates a histamine H4 receptor modulating activity. A compound represented by a formula (I): wherein A ring is a ring represented by the following formula: wherein R 1 is substituted or unsubstituted alkyl, etc., W is -O-, etc., n is an integer of 0 to 6; X is N(R 7 )- or -O-; R 7 is hydrogen, substituted or unsubstituted alkyl, etc.; Y is-C(R 8 )= or -N=; R 8 is hydrogen, substituted or unsubstituted alkyl, etc.; Z is =O, =S, etc.; B ring is a ring represented by the following formula wherein R 10 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino; R 11 , R 12a and R 12b are each independently hydrogen or substituted or unsubstituted alkyl, etc.; p is an integer of 0 to 4, or its pharmaceutically acceptable salt, or a solvate thereof.
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Page/Page column 79-80
(2012/06/18)
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- PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE
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Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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- Manganese(III)-catalyzed formal [3+2] annulation of vinyl azides and ?-keto acids for synthesis of pyrroles
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Manganese(III)-catalyzed formal [3+2] annnulation of vinyl azides and -keto acids has been developed for the synthesis of substituted NH pyrroles with a wide range of substituents. Georg Thieme Verlag Stuttgart.
- Ng, Eileen Pei Jian,Wang, Yi-Feng,Chiba, Shunsuke
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experimental part
p. 783 - 786
(2011/06/11)
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- A new synthesis of pyrroles
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The radical reaction between an N-ethylsulfonylenamide and an α-xanthyl ketone gives an intermediate γ-keto imine which spontaneously ring-closes to the pyrrole.
- Quiclet-Sire, Beatrice,Wendeborn, Frederique,Zard, Samir Z.
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p. 2214 - 2215
(2007/10/03)
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- Porphyrins with Exocyclic Rings. 2. Synthesis of Geochemically Significant Tetrahydrobenzoporphyrins from 4,5,6,7-Tetrahydro-2H-isoindoles
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Benzo- and tetrahydrobenzoporphyrins are widespread constituents of oil shales and petroleum.Although the origins of these materials are not known, a case is made for divinylchlorophyll a, a widespread pigment in marine algae, being the precursor to many of these geoporphyrins.Total syntheses of four tetrahydrobenzoporphyrins related to etioporphyrin III are described.Tetrahydroisoindoles were prepared by condensation of isocyanoacetates with 1-nitrocyclohexene in the presence of DBU or by reaction of aminomalonates with 2-formylcyclohexanone.Condensation of 3-unsubstituted 4,5,6,7-tetrahydro-2H-isoindoles 23c and 23d with (acetoxymethyl)pyrroles in the presence of Montmorillonite clay gave dipyrrylmethanes 28a and 36a in excellent yield.Hydrogenolysis of the benzyl esters and subsequent acid-catalyzed condensation with pyrrole aldehydes 37a and /or 37b gave a series of a,c-biladiene dihydrobromides.Copper(II) mediated cyclization of the a,c-biladienes 32, 33, 35, and 38, followed by demetallation with 15percent sulfuric acid-trifluoroacetic acid, gave four isomeric tetrahydrobenzoporphyrins 10-13 in unusually high yield.This work provides a general route for the synthesis of these important porphyrin molecular fossils.
- May, Donald A.,Lash, Timothy D.
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p. 4820 - 4828
(2007/10/02)
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- Transition Metal- and Acid-Induced Transformations of 6-Siloxy-Substituted 5,6-Dihydro-4H-1,2-oxazines: Preparation of Pyrroles, Nitrones, 1,4-Dicarbonyl Compounds and Derivatives Thereof
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A variety of 6-siloxy-substituted 5,6-dihydro-4H-1,2-oxazines (abbreviation: 1,2-oxazines) 1, 3 could be transformed into di- and trisubstituted pyrroles 2, 4 by means of molybdenum hexacarbonyl.The mechanism of this deoxygenating ring contraction is discussed.With two bicyclic 1,2-oxazines an acid-catalyzed fragmentation affording α-methylenecycloalkanones 7 has been observed, while other 1,2-oxazines rearrange in methanolic acid to give nitrones 9, 10.The desilylation of 6-siloxy-substituted 1,2-oxazines 1.3 employing NEt3*3HF is a very general and smooth process providing 6-hydroxy-1,2-oxazines 11, 12 or their corresponding acyclic tautomers 13, 14 in high yields.For two examples of 11 deoximations by use of formalin could be achieved with moderate efficiency giving 1,4-dicarbonyl compounds 15.
- Hippeli, Claudia,Zimmer, Reinhold,Reissig, Hans-Ulrich
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p. 469 - 474
(2007/10/02)
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- Synthesis of Pyrrole Derivatives from 5,6-Dihydro-4H-1,2-oxazines via Reductive Deoxygenation by Use of Fe3(CO)12
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α-Bromooximes such as α-bromoacetophenone oxime and ethyl 3-bromo-2-(hydroxyimino)propanoate react with enamines to give 5,6-dihydro-4H-1,2-oxazines in good yields.Dihydro-1,2-oxazine derivatives are also obtained by the reaction of α-bromooximes with vinyl ethers and silyl enol ethers in the presence of Na2CO3.Dihydro-1,2-oxazines can be converted into pyrrole derivatives via reductive deoxygenation by treating with Fe3(CO)12 in moderate to excellent yields.Iron carbonyl complexes other than Fe3(CO)12 are also effective for the pyrrole-forming reaction.The efficiency of the complexes for this reaction decreases in the or der: Fe3(CO)12 >> Et3NH > Fe2(CO)9 >> Fe(CO)5.Both of the dihydro-1,2-oxazine- and pyrrole-forming reactions can be carried out in a single flask, giving pyrrole derivatives in good yields.
- Nakanishi, Saburo,Otsuji, Yoshio,Itoh, Keiji,Hayashi, Nobuaki
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p. 3595 - 3600
(2007/10/02)
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- SYNTHESIS OF PYRROLE DERIVATIVES VIA DEOXYGENATION OF 4H-1,2-OXAZINES BY IRON CARBONYLS
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The reaction of 5,6-dihydro-4H-1,2-oxazines, which are derived from α-bromooximes and enamines, with iron carbonyl complexes such as Fe3(CO)12 and (C2H5)3NH gives pyrrole derivatives in high yields, accompaning deoxygenation from the oxazines.
- Nakanishi, Saburo,Shirai, Yoshihiro,Takahashi, Kenji,Otsuji, Yoshio
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p. 869 - 872
(2007/10/02)
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