Novel quinazolinone derivatives inhibiting pi3k and pharmaceutical composition containing same
A composition and drug technology, applied in the field of novel quinazolinone derivatives, can solve the problems of development termination and poor selectivity, and achieve the effects of solving side effects and reducing immunotoxicity
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Embodiment 1
[0185] Example 1: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-fluoro-3-phenylquinazolin-4(3H)-one Preparation of (Formula 7)
[0186] [Reaction 1]
[0187]
[0188] Step 1: Preparation of (S)-tert-butylcyclopropyl(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate
[0189] To a solution in which 2-amino-6-fluorobenzoic acid (1.0 equiv) and (S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (1.0 equiv) were mixed in pyridine solvent Triphenyl phosphite (1.4 equiv) was added while stirring the solution at room temperature. The resulting mixture was stirred at 55°C to 60°C for 12 hours. Aniline (1.4 equivalents) was added thereto, followed by reaction at about 110°C for 7 hours. Thereafter, the mixed reaction solution was cooled to room temperature and extracted with ethyl acetate and water. The obtained organic layer was washed with anhydrous magnesium sulfate (MgSO 4 ) was dehydrated and concentrated under reduced pressure. n-heptane was...
Embodiment 2
[0199] Example 2: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-methyl-3-phenylquinazoline-4(3H)- Preparation of ketone (Formula 8)
[0200] [Reaction 2]
[0201]
[0202] Step 1: Preparation of (S)-tert-butylcyclopropyl(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate
[0203] (S)-tert-butylcyclopropyl (5-methyl-4- Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate.
[0204] 1 H NMR (400MHz, CDCl 3 ):δ8.33(br.s.,3H),7.50(d,4H,J=7.9Hz),7.28(t,11H,J=7.7Hz),7.07(t,2H,J=7.3Hz), 5.35(br.s.,1H),3.61(br.s.,3H),1.32-1.51(m,12H),1.17-1.30(m,1H),0.51-0.73(m,4H),0.47(td , 3H, J=4.7, 9.6Hz).
[0205] Step 2: Preparation of (S)-2-(amino(cyclopropyl)methyl)-5-methyl-3-phenylquinazolin-4(3H)-one
[0206] (S)-2-(Amino(cyclopropyl)methyl)-5-methyl-3-phenylquinazolin-4(3H)-one was prepared in the same manner as in Example 1.
[0207] 1 H NMR (400MHz, DMSO-d 6):δ8.41(br.s.,2H),7.79(t,1H,J=7.7Hz),7.54-7.73(m,2H),7.31-7.46(m,1H),2.74(s,3H) , 1.23 (br.s....
Embodiment 3
[0212] Example 3: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-amino-3-phenylquinazolin-4(3H)-one Preparation of (Formula 9)
[0213] [reaction formula 3]
[0214]
[0215] Step 1: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-((4-methoxybenzyl)amino)-3-phenyl Preparation of quinazolin-4(3H)-one
[0216] Accommodate (S)-2-(((7H-purin-6-yl) amino) (cyclopropyl )methyl)-5-fluoro-3-phenylquinazoline-4(3H) (1.0 equiv) and triethylamine (5.0 equiv), and 4-methoxybenzylamine was added.
[0217] Subsequently, the tube was replaced with nitrogen and sealed, and then the reaction mixture was heated to 180° C. and reacted for one day. After cooling to room temperature, the ethanol solvent was removed under reduced pressure. Thereafter, the crude mixture was subjected to silica gel column chromatography (dichloromethane / methanol 20:1) to afford (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl )methyl)-5-((4-methoxybenzyl)amino)-3-phenylquinazolin-4(3H)-one (yield: 38%).
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