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no 2 -Carbamoyl aromatic ring-2-aminopyrimidine derivatives and their medical use

A carbamoyl aromatic ring and aminopyrimidine technology, applied in the application field of antitumor drugs, can solve the problems of off-target, secondary drug resistance, poor monotherapy effect, etc., to reduce toxic side effects and overcome drug resistance. Effect

Active Publication Date: 2022-06-17
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problems facing FLT3 small molecule inhibitors are drug resistance and toxic side effects
The first-generation FLT3 inhibitors were originally developed for other targets and indications, which are prone to off-targets, which will cause some side effects, and because of dose-limiting toxicity, monotherapy is not effective
These inhibitors generally show good inhibitory activity in the pre-clinical phase, but are not effective when used in AML patients in the clinical phase I / II
The second-generation FLT3 inhibitors are obtained through rational drug design, and their selectivity is better than that of the first-generation FLT3 inhibitors. At present, there are few second-generation FLT3 inhibitors that have entered the clinic. The main problems encountered are drug resistance caused by mutations. Drug resistance and some toxic side effects, such as quizartinib has the disadvantages of myelosuppression, QTc interval prolongation, and drug resistance due to mutations such as D835 and F691 after medication

Method used

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  • no <sup>2</sup> -Carbamoyl aromatic ring-2-aminopyrimidine derivatives and their medical use
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Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0145] Preparation Example 1 Preparation of Compounds 1 to 7

[0146]

[0147] Step 1. 4-Chloro-5-trifluoromethyl-2-aminopyrimidine (1-2)

[0148]

[0149] Dissolve 2,4-dichloro-5-trifluoromethylpyrimidine (6.5 g, 30.0 mmol) in acetonitrile (30 mL), slowly add ammonia water (20 mL) dropwise under ice bath, move to room temperature to react for 40 min, reduce The solvent was recovered by pressure distillation to obtain a residue. Purified by silica gel column chromatography with PE:EA (6:1) as eluent to obtain intermediate 1-2 as a white solid. Yield: 46%; 1 H NMR (500MHz, CDCl 3 ) δ8.47(s, Ar-H, 1H), 5.57(s, NH, 2H); ESI-MS: m / z=217[M+H] + .

[0150] Step 2. 1-Boc-4-(((2-amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)piperidine (1-3)

[0151]

[0152] Intermediate 1-2 (593mg, 3.0mmol) was dissolved in anhydrous methanol (12mL), triethylamine (303mg, 3.0mmol), 1-Boc-4-aminomethylpiperidine (771mg, 3.6mmol) were added successively , heated to reflux for 8h,...

preparation Embodiment 2

[0171] Preparation Example 2 Preparation of Compounds 8-16

[0172]

[0173] Step 1. Synthesis of compounds 1-12~1-19

[0174] Synthesis steps Referring to step 2 of Example 1, compounds 1-12 to 1-19 were prepared by substituting the corresponding amine for 1-Boc-4-aminomethylpiperidine.

[0175] 1.1N 4 -(Tetrahydropyran-4-ylmethyl)-5-trifluoromethylpyrimidine-2,4-diamine (1-12) 1 H NMR (500MHz, CDCl 3 )δ8.05(s,Ar-H,1H),5.35–4.99(m,s,NH×3,3H),4.00–3.97(m,CH 2 ,2H),3.42–3.34(m,CH 2 ×2,4H),1.91–1.82(m,CH,1H),1.65–1.60(m,CH 2 ,2H),1.38–1.30(m,CH 2 ,2H); ESI-MS: m / z=277[M+1] + .

[0176] 1.2 1-Boc-N 4 -(1r,4r)-4-Aminocyclohexyl-5-trifluoromethylpyrimidine-2,4-diamine (1-13) 1 H NMR (500 MHz, DMSO-d 6 )δ7.96(s, Ar-H, 1H), 6.76(d, J=8.5Hz, NH 2 ,NH 2 -a,3H),6.05(d,J=8.5Hz, NH 2 -b, 1H), 4.19–3.94 (m, CH, 1H), 3.22–3.15 (m, CH, 1H), 1.78–1.73 (m, CH 2 ×2,4H),1.55– 1.42(m,CH 2 ,2H),1.37(s,CH 3 ×3,9H),1.24–1.16(m,CH 2 , 2H); ESI-MS: m / z=376[M+1] + .

[0177] 1.3 ...

preparation Embodiment 3

[0194] Preparation Example 3 Preparation of Compounds 17-19

[0195]

[0196] Step 1. Preparation of Intermediates 1-21 to 1-22

[0197] Synthetic steps refer to step 3 of Example 1, and the corresponding amines are used to prepare compounds 1-21 to 1-22.

[0198] 1.1 5-Bromo-N-picolinamide (Intermediate 1-21) 1 H NMR (500MHz, CDCl 3 )δ8.58(d,J=2.0Hz,Ar-H,1H),8.08(d,J=8.5Hz,Ar-H,1H),7.96(dd,J=8.5,2.0Hz,Ar-H, 1H), 7.93–7.84(m, NH, 1H), 3.02(d, J=5.0Hz, CH 3 ,3H).ESI-MS: m / z=215[M+1] + .

[0199] 1.2 5-Bromo-N,N-lutidine amide (Intermediate 1-22) 1 H NMR (500MHz, CDCl 3 )δ8.63(d, J=2.0Hz,Ar-H,1H),7.92(dd,J=8.5,2.0Hz,Ar-H,1H),7.57(dd,J=8.5,2.0Hz,Ar- H,1H),3.12(s,CH 3 ,3H),3.09(s,CH 3 ,3H).ESI-MS: m / z=229[M+1] + .

[0200] Step 2. Preparation of Compounds 17-19

[0201] For the synthesis steps, refer to step 4 of Preparation Example 1, replace 1-3 with 1-13 / 1-14, replace 1-5-1-11 with 1-21-1-22 / 1-9, and prepare compounds 17-19 .

[0202] 2.1N-(5-((4-(((1r,4r)-4-a...

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Abstract

The present invention provides N 2 ‑Carbamoyl aromatic ring‑2‑aminopyrimidine derivatives and their medicinal uses. N provided by the present invention 2 -Carbamoyl aromatic ring-2-aminopyrimidine derivatives include optical isomers and pharmaceutically acceptable salts thereof. Pharmacodynamic studies have shown that the compound has FLT3 inhibitory activity, has proliferation inhibitory activity on various leukemia cell lines, has moderate inhibitory effect on breast cancer cells, and has a variety of mutations in AML, such as internal tandem repeat mutations in the proximal membrane domain. The D835 point mutation of the activation loop in the kinase domain is effective, has almost no inhibitory effect on c-KIT, can overcome the drug resistance brought by the clinical point mutation, can reduce the side effects of myelosuppression, and can be used in the preparation of antitumor drugs. application. N 2 The structures of the general formula Ia and Ib of the carbamoyl aromatic ring-2-aminopyrimidine derivatives are as follows:

Description

technical field [0001] The present invention relates to the field of medicine, in particular to N 2 -carbamoyl aromatic ring-2-aminopyrimidine derivatives and their medicinal uses, mainly N 2 -Carbamoyl aromatic ring-2-aminopyrimidine derivative optical isomers or salts or solvates and their use in the preparation of antitumor drugs as Fms-like tyrosine kinase 3 (FLT3) inhibitors. Background technique [0002] Fms-like tyrosine kinase 3 (FLT3), also known as Fetal Liver Kinase-2 (FLK2) and Stem Cell Kinase-1 (STK1) in mice ), which belong to the type III receptor tyrosine kinases together with stem cell growth factor receptor (c-Kit), macrophage colony stimulating factor receptor (Fms) and platelet-derived growth factor receptor (PDGFR). FLT3 is mainly distributed in hematopoietic cells and neural tissues, but also in placenta, gonads and brain tissues, and plays a key role in the proliferation of hematopoietic cells and lymphocytes. Abnormal activation of FLT3 is closely...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42C07D239/47C07D239/48C07D401/04C07D401/12C07D401/14C07D403/04C07D405/14A61P35/00A61P35/02
CPCC07D401/14C07D405/14C07D401/12C07D401/04C07D239/48C07D239/42C07D403/04C07D239/47A61P35/02A61P35/00
Inventor 刘滔李佳童乐仙周宇波董晓武王培培徐高亚李佳楠
Owner ZHEJIANG UNIV
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