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Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use

A compound, C1-C12 technology, applied in the field of compounds that inhibit the activity of PI3 kinase, which can solve the problems of impaired signal transduction, B cell proliferation and loss of signal transduction

Inactive Publication Date: 2012-05-16
GENENTECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deletion of the PI3Kδ gene or selective introduction of catalytically inactive mutants of PI3Kδ results in an almost complete absence of B cell proliferation and signaling and also results in impaired signaling through T cells

Method used

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  • Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use
  • Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use
  • Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use

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Experimental program
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Effect test

preparation example Construction

[0420] Preparation of compounds of formula I

[0421] Compounds of formula I can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, in particular according to those methods described for heterocycles contained in this application and in the literature below, which In: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958) ; Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which is expressly incorporated herein by reference. Starting materials are typically obtained from commercial sources (e.g., Aldrich Chemicals (Milwaukee, WI)) or readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuchder organische...

Embodiment 1

[0497] Example 1 3-(Tetrahydropyran-4-yl)azetidine-1-carboxylate tert-butyl ester

[0498]

[0499] Step 1: 3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate

[0500]

[0501] To a solution of diisopropylamine (35.2 mL, 0.25 mol) in dry THF (200 mL) was added 2.5 M n-butyllithium in hexanes (100 mL) over 10 min at -20 °C under argon atmosphere , 0.25mol). The reaction mixture was stirred at -20°C for 15 minutes. A solution of tetrahydropyran-4-one (21.0 mL, 0.23 mol) in dry THF (160 mL) was added dropwise over 20 minutes (internal temperature 2 SO 4 Drying, filtration and concentration gave 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a brown oil (43.7 g, 83%). 1 H NMR (400MHz, CHCl 3 -d): δ5.83-5.80 (m, 1H); 4.26 (dd, J=2.9, 0.4Hz, 2H); 3.89 (t, J=5.5Hz, 2H); 2.46 (ttd, J=5.5, 2.9 , 1.4Hz, 2H).

[0502] Step 2: tert-Butyl 3-(3,6-Dihydro-2H-pyran-4-yl)azetidine-1-carboxylate

[0503]

[0504] Zinc activation: to zinc powder (20.3 g, 0.31 mol) an...

Embodiment 2

[0509] Example 2 (4-Methylpiperidin-4-yl)pyrrolidin-1-ylmethanone

[0510]

[0511] Step 1: tert-butyl 4-methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate

[0512]

[0513] To a solution of 4-methylpiperidine-1,4-dicarboxylate mono-tert-butyl ester (229 mg, 0.94 mmol) in DMF (10 mL) was added DIPEA (0.493 mL, 2.83 mmol), pyrrolidine (0.118 mL) , 1.41 mmol) and HATU (537 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours, then partitioned between water and EtOAc. The organic layer was separated, washed with 0.1N aqueous HCl and brine, washed with Na 2 SO 4 Drying, filtration and concentration gave tert-butyl 4-methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate as a white solid (279 mg, 100%). LCMS (Method H): R T is 4.00 minutes; [M+Na] + 319.

[0514] Step 2: tert-butyl 4-methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (296 mg, 1.0 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) ) was stirred at room ...

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Abstract

Formula (I) ((Ia) and (Ib)) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula (I) for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This non-provisional application is filed under 37 CFR §1.53(b) that requires U.S. Provisional Application 61 / 181452, filed May 27, 2009, and 61 / 12 / 17, 2009, under 35 USC §119(e) 287607, 61 / 181452 and 61 / 287607 are incorporated herein by reference in their entirety. technical field [0003] The present invention generally relates to compounds useful in the treatment of disorders mediated by lipid kinases, such as inflammation, immune diseases and cancer, and more particularly to compounds that inhibit PI3 kinase activity. The invention also relates to methods of diagnosing or treating mammalian cells or related pathological conditions in vitro, in situ and in vivo using the compounds. Background technique [0004] Phosphatidylinositol (PI) is one of the phospholipids found in cell membranes and plays an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositide has been ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D491/04C07D513/04A61K31/519A61P35/00A61P9/00A61P29/00A61P25/00
CPCC07D495/04C07D491/04C07D513/04C07D487/04A61P1/00A61P1/04A61P11/00A61P11/06A61P17/00A61P17/06A61P19/02A61P19/04A61P25/00A61P29/00A61P3/00A61P31/12A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61P5/00A61P7/00A61P7/02A61P9/00A61K31/519C07D491/044
Inventor G.卡斯塔尼多B.钱D.M.戈德斯坦R.K.康德鲁M.C.卢卡斯W.S.帕尔默S.普莱斯B.萨菲娜P.P.A.萨维E.M.苏厄德D.P.萨瑟琳Z.K.斯维尼
Owner GENENTECH INC
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