Imidazolonylquinoline compounds and therapeutic uses thereof

A compound and composition technology, applied in the field of imidazolone quinoline compounds and their therapeutic uses, can solve the problems of high lipophilicity, KU-55933 is not suitable for in vivo use, etc.

Pending Publication Date: 2021-11-05
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, KU-55933 was found to be unsuitable for in vivo use, presumably due to its high lipophilicity

Method used

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  • Imidazolonylquinoline compounds and therapeutic uses thereof
  • Imidazolonylquinoline compounds and therapeutic uses thereof
  • Imidazolonylquinoline compounds and therapeutic uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0209] According to another aspect, the present invention provides deuterated derivatives of compound Y. According to one embodiment, the present invention provides:

[0210] ● 8-(1,3-Dimethylpyrazol-4-yl)-1-[3-fluoro-5-(trideuteromethoxy)-4-pyridyl]-7-methoxy-3 -(trideutero-methyl)imidazo[4,5-c]quinolin-2-one (compound 3) and

[0211] ● 1-[3-fluoro-5-(trideuteromethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-[3-methyl-(trideutero-methoxy) yl)pyrazol-4-yl]imidazo[4,5-c]quinolin-2-one (compound 4).

[0212] ● 8-(1,3-Dimethylpyrazol-4-yl)-1-[3-fluoro-5-(trideuteromethoxy)-4-pyridyl]-7-methoxy-3 -Methyl-imidazo[4,5-c]quinolin-2-one (compound 5),

[0213] and its salt.

[0214] Compounds 3, 4 and 5 are represented by the formula:

[0215]

[0216] In other embodiments, the invention provides atropisomers 3-a, 3-b, 4-a, 4-b, 5-a, and 5-b:

[0217]

[0218]

[0219]

[0220] or its salt.

[0221] Consistent with what has been set forth above for compounds 1 and 2, the p...

Embodiment 1

[0433] Example 1: Preparation of Compounds 1 and 2

[0434] Compound Y was prepared according to the procedure disclosed in WO 2016 / 155844, followed by isolation of compounds 1 and 2 from compound Y:

[0435] .

[0436] a. 6-Bromo-N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitro-quinolin-4-amine Synthesis

[0437] Under dry nitrogen atmosphere, provide 3-fluoro-5-methoxypyridin-4-amine (447 mg, 3.02 mmol) dissolved in N, N - solution in dimethylformamide (5 mL). Then, sodium hydride (504 mg, 12.6 mmol, 60%) was added to the solution and stirring was continued at room temperature for 5 minutes. followed by 6-Bromo-4-chloro-7-methoxy-3-nitro-quinoline (800 mg, 2.52 mmol) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes, then the reaction was quenched by adding ice water (100 mL). The precipitate was filtered off, washed with ice water and dried to give 1.00 g (94%) of 6-Bromo-N-(3-fluoro-5-methoxy-4-pyridine Pyridyl)...

Embodiment 2

[0450] Example 2: Separation of atropisomers and purification of compound 1

[0451] As in Scenario 1 and Image 6 Compounds 1 and 2 can be isolated from compound Y as shown in and discussed in detail below. Those of ordinary skill in the art will understand that the following methods are equally applicable to the isolation of compounds 3-a and 3-b from 3, 4-a and 4-b from 4, and 5-a and 5-b from 5.

[0452] Scheme 1: Preparation of Chiral Salts

[0453]

[0454] step 1:

[0455] 1. In a 200 L reactor, add acetone (108 L, 20 vol), purified water (8.13 L, 1.5 vol) and compound Y (5.42 Kg, 1.0 eq) at 20~25 °C.

[0456] 2. Charge dibenzoyl-L-tartaric acid (4.33 Kg, 1.0 equiv).

[0457] 3. Heat to 52-55°C to get a clear solution, stir at 52-55°C for 0.5 h.

[0458] 4. Cool to 20~25℃.

[0459] 5. Filter and wash the filter cake once with acetone (5.4 L, 1 vol).

[0460] 6. The filter cake was collected and dried to give L-salt B (L-salt of compound 2) (pale yellow s...

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Abstract

The present invention relates to atropisomers, solid forms, salt forms and deuterated derivatives of the ATM inhibitor 8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one as well as compositions thereof. The stable atropisomers do not interconvert and are represented by the following formulae: Compound1, Compound2.

Description

[0001] field of invention [0002] The present invention provides ATM inhibitor 8-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methanol Atropisomers and deuterated derivatives of oxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one and pharmaceutically acceptable salts and solids thereof form. These compounds are useful for inhibiting, regulating and / or modulating signal transduction of ATM kinase. The present invention also provides compositions comprising said atropisomers, solid forms, pharmaceutically acceptable salts and deuterated derivatives of the present invention, as well as in the treatment of various disorders associated with ATM kinase, especially cancer ) methods of using these compositions. [0003] Background of the invention [0004] The serine / threonine protein kinase ATM (ataxia telangiectasia mutated kinase) belongs to the family of PIKK kinases with a catalytic domain and is homologous to phosphoinositide phospholipid-3 kinase (PI3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00A61K31/4375
CPCC07D471/04A61P35/00A61K31/4745C07B2200/13C07B2200/05
Inventor T·福赫斯A·贝克尔H·库巴斯U·格雷德勒
Owner MERCK PATENT GMBH
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