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4-aminopyrimidine or 2-aminotriazine compound and preparation method thereof

A compound, alkyl technology, applied in the field of medicine, can solve problems such as action limitation

Active Publication Date: 2021-11-26
TUOJIE BIOTECH (SHANGHAI) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CDK4 / 6 inhibitors have shown remarkable clinical efficacy in estrogen receptor ER-positive metastatic breast cancer, like other kinases, their effects may be over time controlled by primary or acquired resistance. development restrictions

Method used

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  • 4-aminopyrimidine or 2-aminotriazine compound and preparation method thereof
  • 4-aminopyrimidine or 2-aminotriazine compound and preparation method thereof
  • 4-aminopyrimidine or 2-aminotriazine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153]

[0154] 6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine -4-amine

[0155]

[0156] first step

[0157] 6-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-4-amine 1c

[0158] Dissolve 2,4-dichloropyrimidine 1a (0.2g, 1.3mmol) and 1-(methylsulfonyl)piperidin-4-amine 1b (0.26g, 1.5mmol) in 5mL DMSO, add N,N-di Isopropylethylamine (0.52g, 4.0mmol) was reacted at 90°C until the reaction was almost complete. The reaction liquid was added to 10mL ice-water mixture, filtered, washed with ice water, and the obtained solid was concentrated and dried under reduced pressure to obtain the title compound 1c ( 0.35 g, yield: 90%).

[0159] MS(ESI)m / z 291.1[M+H] +

[0160] 1 H NMR (400MHz, CDCl 3 )δ=8.37(s,1H),6.37(d,J=0.8Hz,1H),5.05(s,1H),4.04-3.88(m,1H),3.87-3.77(m,2H),2.90(dt , J=2.4, 12.4Hz, 2H), 2.83(s, 3H), 2.21-2.12(m, 2H), 1.65-1.58(m, 2H).

[0161] second step

[0162] 5-Bromo-2-chloro-N-(2,2-dimeth...

Embodiment 2

[0167]

[0168] 4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- For 1,3,5-triazin-2-amine, refer to Example 1, wherein compound 2,4-dichloro-1,3,5-triazine was replaced by compound 2,4-dichloropyrimidine to obtain the aforementioned compound 2.

[0169] MS(ESI)m / z 462.2[M+H] +

Embodiment 3

[0171] (3R,4R)-4-((4-(4-fluoro-2-((R)-1-hydroxyethyl)-1-isopropyl-1H-benzo[d]imidazol-6-yl) -1,3,5-Triazin-2-yl)amino)-1-(methylsulfonyl)piperidin-3-ol

[0172]

[0173] first step

[0174] (3R,4R)-4-((4-Chloro-1,3,5-triazin-2-yl)amino)-1-(methylsulfonyl)piperidin-3-ol 3b

[0175] The compound methyl 2,4-dichloro-1,3,5-triazine (93 mg, 0.62 mmol) and N,N-diisopropylethylamine (107 mg, 0.82 mmol) were dissolved in 3 mL of N,N-di in methylformamide. Compound (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol 3a (synthesized with reference to patent WO2019207463A1, 80mg, 0.41mmol) was added to the reaction solution in batches at room temperature. The reaction was carried out until TLC detected that the reaction was substantially complete. Add 20 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, collect the filtrate, concentrate the filtrate under redu...

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PUM

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Abstract

The invention relates to a 4-aminopyrimidine or 2-aminotriazine compound and a preparation method thereof. In particular, the present disclosure provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotaisomer or tautomer thereof, in which R1 to R4 and X are as defined herein. The compound shown in the formula I can be used as a cyclin-dependent kinase inhibitor and is used for preventing and / or treating related diseases, such as cell proliferative diseases, cancers or immune diseases.

Description

technical field [0001] The disclosure belongs to the field of medicine and relates to a 4-aminopyrimidine or 2-aminotriazine compound. Background technique [0002] Cyclin-dependent kinases (CDKs) are important cellular enzymes that play an important role in regulating eukaryotic cell division and proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cell cycle proteins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6 and possibly other heterodynes are important regulators of cell cycle progression. Other functions of cyclin / CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291). [0003] In recent years, the greatest progress in the field of breast cancer treatment is undoubtedly the CDK4 / 6 monotherapy or combined ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D405/14A61K31/506A61K31/53A61P35/00A61P37/00
CPCC07D401/14C07D405/14A61P35/00A61P37/00Y02P20/55
Inventor 邹昊李正涛祝伟余健
Owner TUOJIE BIOTECH (SHANGHAI) CO LTD
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