Prmt5 inhibitors

A C2H5, halogen technology for the genetic persistence of sickle cell and fetal hemoglobin mutations, PRMT5 inhibitors, the treatment of cancer, the preparation of compounds of formula I, which can solve elusive problems

Pending Publication Date: 2021-05-14
MERCK SHARP & DOHME BV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite exhaustive studies of HPFH mutations and strides in many other aspects of globin gene regulation, these mechanisms remain elusive

Method used

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Examples

Experimental program
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specific example

[0350] Some specific examples of tyrosine kinase inhibitors: include N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrole-5 -yl)methylene)indol-2-one, 17-(allylamino)-17-desmethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)- 7-Methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy base)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy -1H-Diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazon-1-one, SH268 , genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine methanesulfonate, 4-(3- Bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-Chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine and EMD121974.

[0351] Combinations with compounds other than anticancer compounds are also included in this method. For example, combinations of c...

Embodiment 1

[0816] (1R, 2S, 3R, 5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol

[0817]

[0818] step 1: ((3aR, 4R, 6R, 6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro-3aH -Cyclopenta[d][1,3]dioxol-4-yl)methanol (1.2g, 3.6mmol), 2-amino-3-bromoquinolin-7-ol (0.934 g, 3.91 mmol) and triphenylphosphine (1.86 g, 7.10 mmol) were coevaporated with dry toluene (three times, 10 mL each) and then redissolved in anhydrous THF (20 mL). The reaction mixture was cooled to 0°C, and (E)-diisopropyldiazene-1,2-dicarboxylate (1.44 g, 7.10 mmol) was added dropwise at 0°C. The mixture was naturally warmed to room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH in DCM). Fractions containing the desired product were combined and...

Embodiment 2

[0821] (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrole And[2,3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol

[0822]

[0823] To a sealed tube (10 mL) was added (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-( 4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol (350mg, 0.675mmol), 1,4-dioxane (3mL) and NH 3 ·H 2 O (5 mL; 25%-28% w / w). The reaction mixture was sealed tightly and then stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0-45% acetonitrile / water) to give (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy) Methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol. MS 499,501 (M+1,M+3). 1 H NMR (400MHz, DMSO-d 6 )δ8.28(s,1H),8.02(s,1H),7.58(d,J=8.7Hz,1H),7.30(d,J=3.6Hz,1H),6.96–6.89(m,4H), 6.57–6.53(m,3H),4.97–4.91(m,2H),4.41(s,1H),4.19–4.10(m,3H),2.45–2.37(m,2H),1.72–...

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Abstract

The present invention provides a compound of Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.

Description

Background technique [0001] PRMT5 (aka JBP1, SKB1, lBP72, SKB1his and HRMTIL5) is a type II arginine methyltransferase first discovered in a double hybrid of proteins interacting with Janus tyrosine kinase (Jak2) (Pollack et al., 1999). PRMT5 plays an important role in the control and regulation of gene transcription. In particular, PRMT5 is known to symmetrically methylate histone H3 on Arg-8 (a different site than that methylated by PRMT4) and on Arg-3 (the same site methylated by PRMT1) Symmetrically methylates histone H4. PRMT5 has been reported to play multiple roles, including but not limited to affecting cell viability, stem cell properties, DNA damage repair, and RNA splicing (Clarke et al., Mol Cell (2017), Chiang et al., Cell Rep (2017), Gerhart et al. al., Sci Rep (2018)). In particular, inhibition of PRMT5 induces alternative splicing of the p53 negative regulator MDM4, resulting in increased expression of the MDM4 short isoform (MDM4-S), decreased expression o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519C07D471/04
CPCA61P35/00A61P7/00C07D487/04C07D519/00A61K31/519C07H19/14
Inventor M·马查猜克D·维特C·吉博黄春辉S·卡瓦穆拉D·L·斯洛曼P·希利法伊万R·奎伊洛兹M·万S·施耐德C·S·杨M·H·鲁特沙恩T·J·亨德森J-L·帕帕里恩H·拉哈利J·M·E·哈格斯S·桑亚尔叶迎春D·A·坎蒂托P·S·费尔S·M·希尔弗曼
Owner MERCK SHARP & DOHME BV
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