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a pyridine ring and inhibitor technology, applied in the field of 65 membered fused pyridine ring compounds, can solve the problems of serious adverse effects, prohibitive development of btk inhibitors, and fyn-deficient mice also show pronounced neurological defects,
Inactive Publication Date: 2014-08-07
MERCK SHARP & DOHME CORP +1
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[0009]Hence, an inhibitor that inhibits multiple or all kinases of th
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With dramatic adverse effects reported for knockouts of Src-family kinases, especially for double and triple knockouts, this is seen as prohibitive for the development of Btk inhibitors that are not selective over the Src-
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[1267](trans)-4-(8-Amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (0.129 mmol, 40 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (0.14 mmol, 45.8 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (0.386 mmol, 193 μL) dioxane (6 mL) and water (3 mL). Nitrogen was bubbled through the mixture, followed by the addition of 1,1′-bis(diphenylphosphino)-ferrocene palladium (II) chloride (0.013 mmol, 10.39 mg). The reaction mixture was stirred at 100° C. overnight. Water was added to the reaction mixture, followed by an extraction with ethyl acetate (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. After evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 27 mg of 4-(8-amino-3-((trans)-4-hydroxycyclohexyl)-imidazo[1,5-a...
[1269]This compound was prepared in an analogous manner as described in Example 1, from Intermediate 1 and Intermediate D, to afford the title compound (4.2 mg, 6.6%). Data: UPLC(C) Rt: 2.05 min; m / z 497.2 (M+H)+.
[1271]This compound was prepared, in an analogous manner as described in Example 1, from Intermediate 1 and Intermediate C, to afford the title compound (10.6 mg, 17.5%). Data: UPLC(C) Rt: 1.44 min; m / z 471.3 (M+H)+.
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Abstract
Provided are 6-5 membered fused pyridine ring compounds according to Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and their use in therapy. In particular, provided is the use of membered fused pyridine ring compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.
Description
FIELD OF THE INVENTION[0001]The present invention relates to 6-5 membered fused pyridine ring compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of 6-5 membered fused pyridine ring compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.BACKGROUND OF THE INVENTION[0002]B lymphocyte activation is key in the generation of adaptive immune responses. Derailed B lymphocyte activation is a hallmark of many autoimmune diseases and modulation of this immune response is therefore of therapeutic interest. Recently the success of B cell therapies in autoimmune diseases has been established. Treatment of rheumatoid arthritis (RA) patients with Rituximab (anti-CD20 therapy) is an accepted clinical therapy by now. More recent clinical trial studies show that treatment with Rituximab also ameliorates disease symptoms in relapsing remitting multiple sclerosis (RRMS) and sys...
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Inventor DE MAN, ADRIANUS PETRUS ANTONIUSSTERRENBURG, JAN-GERARDRAAIJMAKERS, HAN C.A.KAPTEIN, ALLARDOUBRIE, ARTHURA A.REWINKEL, JOHANNES BERNARDUS MARIAJANS, CHRISTIAAN GERARDUS JOHANNES MARIAWIJKAMANS, JACOBUS C.H.M.BARF, TJEERD A.COOPER, ALAN B.KIM, RONALD M.BOGA, SOBHANA BABUZHU, HUGH Y.GAO, XIAOLEIYAO, XINANAND, RAJANWULIU, SHILANYANG, CHUNDAOALHASSAN, ABDUL-BASITWANG, JAMESYU, YOUNONGLIU, JIANVACCARO, HENRY M.
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