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Oxo-heterocycle fused pyrimidine compounds, compositions and methods of use

A technology of compounds and heterocycles, applied in botany equipment and methods, drug combinations, applications, etc., can solve problems such as loss-of-function mutations

Inactive Publication Date: 2012-05-30
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, there is evidence that multiple tumor types, including glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, endometrial cancer, and prostate cancer, contain loss-of-function mutations of negative regulators of the PI3K-AKT pathway [eg Phospholipase and tensin homolog (PTEN) and tuberous sclerosis complex (TSC1 / TSC2) removed on chromosome 10], which also leads to hyperactive signaling of mTOR kinase

Method used

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  • Oxo-heterocycle fused pyrimidine compounds, compositions and methods of use
  • Oxo-heterocycle fused pyrimidine compounds, compositions and methods of use
  • Oxo-heterocycle fused pyrimidine compounds, compositions and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Preparation of 1-ethyl-3-(4-(4-morpholino-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)phenyl)urea (f) :

[0365]

[0366] Step 1 - Synthesis a: Dihydro-2H-pyran-3(4H)-one (9.2mL, 99.8mmol) and methyl thiocyanate (32mL, 401.0mmol) in nitromethane (75mL) at -40°C ) was added trifluoromethanesulfonic anhydride (25 mL, 148.3 mmol). The mixture was stirred at -40 °C for 6 h, then at room temperature overnight. The reaction was quenched by the slow addition of saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was extracted with 2 x 20 mL of dichloromethane. Combined organic phases with MgSO 4 Dry, filter and concentrate. The crude material was purified by flash column chromatography (100% Hex-80% EtOAc / Hex) to give 2,4-bis(methylthio)-7,8-dihydro-6H-pyrano[3,2- d] Pyrimidine (a) (1.7 g, 7%). LC-MS: m / z=229 (M+H). 1 HNMR (400MHz, CDCl 3 ) δ 4.30-4.19 (m, 2H), 2.79 (t, J=6.6, 2H), 2.56 (s, 3H), 2.54 (s, 3H), 2.16-1.98 (m, 2H).

[...

Embodiment 2

[0373] Preparation of (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2 -yl)phenyl)urea (g):

[0374]

[0375] (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2- base)phenyl)urea (g) was prepared in a similar manner as described for Example 1, except that in step 1 tetrahydro-2H-pyran-2-one was used instead of dihydro-2H-pyran-2-one pyran-3(4H)-one and the use of (S)-3-ethylmorpholine in step 5 instead of morpholine. LC-MS: m / z=412 (M+H). 1 H NMR (500MHz, DMSO) δ8.71(s, 1H), 8.10(d, J=8.7, 2H), 7.45(d, J=8.8, 2H), 6.24(s, 1H), 4.34(s, 1H ), 4.24(s, 1H), 3.85(s, 2H), 3.77(d, J=11.3, 1H), 3.67(d, J=8.7, 1H), 3.57(t, J=11.3, 2H), 3.41 (s, 1H), 3.18-3.05(m, 2H), 2.64(s, 2H), 1.93(s, 1H), 1.77(d, J=48.0, 3H), 1.05(t, J=7.2, 3H) , 0.84 (t, J=7.5, 3H).

Embodiment 3

[0377] Preparation of 1-(4-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-6,7-dihydro-5H-pyrano[2,3- d] pyrimidin-2-yl)phenyl)-3-ethylurea (h):

[0378]

[0379]1-(4-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-6,7-dihydro-5H-pyrano[2,3-d ]pyrimidin-2-yl)phenyl)-3-ethylurea (h) was prepared in a manner similar to that described for Example 1, except that in step 1 tetrahydro-2H-pyran- 2-Kone instead of dihydro-2H-pyran-3(4H)-one and 2-oxa-5-azabicyclo[2.2.1]heptane in step 5 instead of morpholine. LC-MS: m / z=396 (M+H). 1 H NMR (400MHz, DMSO) δ8.63(s, 1H), 8.08(d, J=8.8, 2H), 7.44(d, J=8.8, 2H), 6.18(t, J=5.5, 1H), 5.01 (s, 1H), 4.61 (s, 1H), 4.34 (d, J = 11.0, 1H), 4.15 (t, J = 9.4, 1H), 3.88 (dd, J = 23.1, 7.3, 2H), 3.74 ( d, J=9.6, 1H), 3.45(d, J=9.7, 1H), 3.21-3.03(m, 3H), 2.83-2.59(m, 1H), 2.03-1.64(m, 4H), 1.06(t , J=7.2, 3H).

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Abstract

Disclosed are compounds of Formula (I), including steroisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR). Formula (I).

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application 61 / 252,284, filed October 16, 2009, and U.S. Provisional Application 61 / 220,011, filed June 24, 2009, each of which is incorporated by reference for all purposes. into this application. Background technique [0003] The mammalian target of rapamycin (mTOR) is a 289 kDa serine / threonine kinase that is considered a member of the phosphoinositide-3-kinase-like kinase (PIKK) family because it contains A carboxy-terminal kinase domain that shares significant sequence homology with the catalytic domain of a phosphoinositide-3-kinase (PI3K) lipid kinase. In addition to the catalytic domain located at the C-terminus, the mTOR kinase contains a FKBP12-rapamycin-binding (FRB) domain, a putative repressor domain adjacent to the C-terminus, and a HEAT motif repeated up to 20 times consecutively at the N-terminus and FRAP - ATM-TRRAP (FAT) and the FAT C-terminal domai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/54
CPCC07D519/00C07D491/18C07D491/052C07D491/048A61P35/00A61P35/02A61P35/04A61P43/00
Inventor P.伯格龙F.科恩A.埃斯特拉达M.F.T.科勒W.李C.李J.P.利西卡托斯斐中华赵宪瑞
Owner GENENTECH INC
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