Polysubstituted triaryl macrocyclic compound and application thereof

A macrocyclic compound and triaryl technology, applied in the field of medicinal chemistry, can solve the problems of drug resistance in patients, and achieve the effects of strong plasticity, great transformation potential, and great development potential.

Active Publication Date: 2022-04-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many types of drugs, in clinical use, patients will eventually develop resistance to these drugs. Therefore, it is necessary to develop new ALK inhibitors with a unique core structure

Method used

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  • Polysubstituted triaryl macrocyclic compound and application thereof
  • Polysubstituted triaryl macrocyclic compound and application thereof
  • Polysubstituted triaryl macrocyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1:3 5 -Chloro-1 6 ,5 6 -Dimethoxy-1 4 -(Piperidin-1-yl)-2,4,6,9-tetraaza-3(2,4)-pyrimidine-1,5(1,3)-dibenzocyclononan-8-one Hydrochloride (H-1)

[0084]

[0085] The synthetic route is as follows:

[0086]

[0087] Step 1. Synthesis of N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-methoxyphenyl)acetamide (3)

[0088] N-(3-Amino-4-methoxyphenyl)acetamide (1) (9 g, 50 mmol), 2,4,5-trichloropyrimidine (2) (10.23 g, 55 mmol), potassium phosphate (21.2 g, 100 mmol) and DMF (150 ml) were added to a 500 ml round-bottomed flask, under argon protection, the temperature was raised to 65 °C for reaction for 24 hours. After cooling, it was poured into 1L water for recrystallization to obtain a pale yellow solid, which was filtered and dried to obtain the product N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-methoxyphenyl)ethyl Amide (3) (pale yellow solid, 95% yield). 1H NMR (300 MHz, Chloroform- d ) δ 8.40 (s, 1H), 8.20 (t, J = 1.6 Hz, 1H), 8.14 (s, 1H), 7.59 (d...

Embodiment 2

[0103] Example 2: 3 5 -chloro-1 6 ,5 6 -Dimethoxy-1 4 -(pyrrolidin-1-yl)-2,4,6,9-tetraaza-3(2,4)-pyrimidin-1,5(1,3)-dibenzocyclononan-8-one Hydrochloride (H-2)

[0104]

[0105] The synthetic route is as follows:

[0106]

[0107] Step 1. tert-butyl(3-((5-chloro-2-((2-methoxy-5-nitro-4-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl )amino)-4-methoxyphenyl)carbamate (11) synthesis

[0108] Referring to the synthetic method of compound (8), the yield was 80%, red solid. 1 H NMR (400 MHz, Chloroform- d ) δ 8.81 – 8.68 (m, 1H), 8.34 (s, 1H), 8.11 – 8.01 (m, 1H), 7.91(d, J = 5.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 6.87(d, J = 7.5 Hz, 1H), 6.84 – 6.76 (m, 1H), 6.36 – 6.28 (m, 1H), 3.94 (d, J =8.1 Hz, 3H), 3.91 (t, J = 4.8 Hz, 3H), 3.31 – 3.20 (m, 4H), 2.03 – 1.94 (m,4H), 1.53 – 1.43 (m, 9H).

[0109] Step 2. tert-Butyl (3-((2-((5-amino-2-methoxy-4-(pyrrolidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl) Synthesis of amino)-4-methoxyphe...

Embodiment 3

[0115] Example 3: 3 5 -chloro-1 6 ,5 6 -Dimethoxy-1 4 -(pyrrolidin-1-yl)-2,4,6,9-tetraaza-3(2,4)-pyrimidin-1,5(1,3)-dibenzocyclononan-8-one Hydrochloride (H-3)

[0116]

[0117] The synthetic route is as follows:

[0118]

[0119] Step 1. tert-butyl(3-((5-chloro-2-((2-methoxy-4-morpholine-5-nitrophenyl)amino)pyrimidin-4-yl)amino)-4- Synthesis of methoxyphenyl) carbamate (14)

[0120] Referring to the synthetic method of compound (8), the yield was 80%, red solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ9.07 (s, 1H), 8.57 (s, 1H), 8.21 (d, J = 10.7 Hz, 3H), 7.82 (s, 1H), 7.34 –7.27 (m, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 3.97 (s, 3H), 3.79 (s,3H), 3.74 – 3.70 (m, 4H), 3.02 (d, J = 4.5 Hz, 4H), 1.48 (s, 9H).

[0121] Step 2. tert-Butyl(3-((2-((5-amino-2-methoxy-4-morpholinephenyl)amino)-5-chloropyrimidin-4-yl)amino)-4-methanol Synthesis of oxyphenyl) carbamate (15)

[0122] Referring to the synthetic method of compound (8), the yield is 80%, white solid. ...

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Abstract

The invention discloses a polysubstituted triaryl macrocyclic compound, and belongs to the technical field of medicinal chemistry. The polysubstituted triaryl macrocyclic compound is a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof. The invention also discloses an application of the polysubstituted triaryl macrocyclic compound in preparation of drugs for treating ALK-mediated diseases. The compound disclosed by the invention has remarkable activity on ALK kinase, the IC50 value of most of the synthesized compounds is kept at nM level, and the compound has the characteristics of novel skeleton, strong plasticity and great future transformation potential.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to polysubstituted triaryl macrocyclic compounds, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical combination thereof, and a compound in the treatment of ALK-mediated diseases. use. Background technique [0002] Anaplastic Lymphoma Kinase (ALK) belongs to the insulin receptor protein tyrosine kinase superfamily, and its normal physiological function mainly plays an important role in regulating the peripheral and central nervous systems. Not expressed in lung and other tissues. [0003] In abnormal cases, ALK is often gene fusion with other genes, resulting in new abnormal genes, such as NMP-ALK fusion can lead to graded large cell lymphoma, EML4-ALK fusion can lead to non-small cell lung cancer. This suggests that selective inhibitors designed for ALK can treat a variety of diseases caused by ALK fusions. Afte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/08A61P35/00A61P29/00A61P37/02A61P37/06A61P31/00A61P31/12A61P9/00A61P3/00A61K31/529A61K31/5377
CPCC07D487/08A61P35/00A61P29/00A61P37/02A61P37/06A61P31/00A61P31/12A61P9/00A61P3/00
Inventor 杨鹏张昊霖谢逸石李嘉兴董豪杰朱亚胜王格非
Owner CHINA PHARM UNIV
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