Novel DCLK1 inhibitor as well as preparation method and application thereof
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An inhibitor, a new type of technology, applied in the field of medicine, can solve problems such as research that has not been reported, and achieve the effect of delaying the occurrence and development
Pending Publication Date: 2022-05-13
THE NAVAL MEDICAL UNIV OF PLA
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At present, studies have shown that the compound LRRK2-IN-1 has good anti-tumor activity in vivo and in vitro against pancreatic cancer and colon cancer, but its research on anti-acute inflammation has not been reported yet.
In addition, it has also been reported that XMD8-92, a BMK1 / ERK5 inhibitor similar in structure to LRRK2-IN-1, and NVP-TAE684, a selective ALK inhibitor, also have certain inhibitory activity on DCLK1, but only LRRK2-IN-1 -1 exhibited the best inhibitory activity against DCLK1
[0008] Regarding the novel DCLK1 inhibitor of the present invention, there is no report yet
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Embodiment 1
[0101] Example 1 2-((2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H- Synthesis of Benzo[e]pyrimidinyl[5,4-b][1,4]diazepin-6-one
[0102] Step a. Synthesis of methyl 2-((2-chloro-5-nitropyrimidin-4-yl)(methyl)amino)benzoate:
[0103] Methyl 2-(methylamino)benzoate (1 g, 6.1 mmol) and 2,4-dichloro-5-nitropyrimidine (1.4 g, 7.3 mmol) were dissolved in 1,4-dioxane (50 mL ), slowly drop DIPEA (1.6g, 12.4mmol) under stirring, and stir at 50°C for more than 5h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gelcolumn chromatography (hexane:EtOAc=15:1-10:1) to obtain 1.6 g of a yellow solid, yield: 82%. 1 H NMR (300MHz, DMSO-d 6 )δ:8.72(s,1H),7.93(dd,J=8.3,1.6Hz,1H),7.65-7.76(m,1H),7.46-7.59(m,2H),4.03-4.26(m,2H) , 3.47 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).
[0104] Step b. Synthesis of 2-chloro-11-methyl-5,11-dihydro-6H-...
Embodiment 2
[0110] Example 2 2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e Synthesis of ]pyrimidinyl[5,4-b][1,4]diazepin-6-one
[0111] With reference to the synthetic method of Example 1, the intermediate (4-amino-3-methoxyphenyl) (4-methylpiperazin-1-yl) ketone in Example 1 is replaced by (4-amino- 3-methoxyphenyl) (morpholine) ketone, obtains white solid compound, is 2-((2-methoxy-4-(morpholine-4-carbonyl) phenyl) amino)-5, 11-Dimethyl-5,11-dihydro-6H-benzo[e]pyrimidinyl[5,4-b][1,4]diazepin-6-one (Compound 2).
Embodiment 3
[0112] Example 3 2-((2-methoxy-4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)amino)-5,11-dimethyl-5,11- Synthesis of Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one
[0113] With reference to the synthetic method of Example 1, the intermediate (4-amino-3-methoxyphenyl) (4-methylpiperazin-1-yl) ketone in Example 1 is replaced by (4-amino- 3-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone to obtain a white solid compound, namely 2-((2-methoxy-4-(4- (Pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidinyl[5,4- b] [1,4]diazepin-6-ones (Compound 3).
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Abstract
The invention relates to the technical field of medicines, in particular to a novel DCLK1 inhibitor which is a compound shown in a general formula (i) or pharmaceutically acceptable salts of the compound. The invention also relates to a preparation method and application of the DCLK1 inhibitor. The compound shows good DCLK1 enzyme inhibitory activity, can relieve diseases such as tumors and inflammations by specifically inhibiting intracellular and extracellular DCLK1 protein levels, and has an obvious treatment effect on acute inflammations such as acute lung injury and sepsis.
Description
technical field [0001] The invention relates to the technical field of medicine, specifically, a novel DCLK1 inhibitor and its preparation method and application. Background technique [0002] Acute lung injury (ALI) is an acute inflammatory reaction in which alveolar epithelial cells and vascular endothelial cells are damaged due to various injury factors. Its pathological feature is the accumulation of a large number of neutrophils in the lungs, accompanied by chemokines (such as CXCL-8, ENA-78), pro-inflammatory cytokines (such as IL-6, TNF-α), and acute phase sensory substances. (such as CRP, lipocalin), the release of matrix remodeling enzymes (such as MMP-9) and other inflammatory reactants. Severe neutrophil inflammation often compromises the alveolar-capillary barrier, leading to noncardiogenic pulmonary edema and ventilation / perfusion imbalance. The clinical manifestations of ALI are severe dyspnea, shortness of breath, and drug-resistant hypoxemia. When ALI deve...
Claims
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