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Heteroaromatic ring derivatives

A drug and compound technology, applied in the field of medicine, can solve problems such as short patent protection period and poor drug metabolism

Active Publication Date: 2021-04-27
郭守东 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the poor drug metabolism of the JQ1 compound and the short patent protection period, it has not entered human clinical research

Method used

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preparation example Construction

[0069] The preparation method of the compound of the general formula (I) of the present invention comprises making the compound shown in the general formula (IV), its pharmaceutically acceptable salt or its easily hydrolyzed ester, and the compound shown in the general formula (V), its pharmaceutically acceptable Accepted salts, their readily hydrolyzable esters, or their isomers react,

[0070]

[0071] Among them, R 1 , R 2 , R 3 , A, B, C, D, E, m, n, p and q are as defined above.

[0072] The above-mentioned compounds of the present invention can be synthesized by the methods described in the following schemes and / or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.

[0073] When n=1, the reaction scheme is:

[0074]

[0075] Reaction steps:

[0076] Step 1: Preparation of compound b

[0077] The raw material a was added into aqueous hydrobromic acid solution, refluxed overnight, and the reaction was alm...

Embodiment 1

[0112] Example 1 ((S)-6-(4-chlorophenyl)-1-methyl-4,11-dihydro-[1,2,4]-triazol[3',4':3,4 ][1, 4] Preparation of tert-butyl acetate (compound 1)-diaza[5,6-b]-4-indolyl)methyl)acetate

[0113] Step 1: Synthesis of 4-Bromo-5-nitro-1H-indole (Intermediate B)

[0114] Add raw material A (81 g, 0.5 mol) into 500 ml of hydrobromic acid aqueous solution, reflux overnight, and HPLC monitors that the reaction is almost complete. Cool down, adjust the pH to 7 with solid sodium carbonate, extract with ethyl acetate (100ml 3 times), and dry the organic phase to obtain 75g of intermediate B as a brown solid with a yield of 62.5%.

[0115] Step 2: Synthesis of (4-chloromethyl)-(5-nitro-1H-indole-4-)-methylketone (Intermediate D)

[0116] Dissolve intermediate B (70g, 0.29mol) in 500mL of tetrahydrofuran, cool down to -78°C under nitrogen protection, add n-butyllithium (2.5M, 140ml, 0.35mol) dropwise, raise the temperature to -40°C for 1 hour, and cool down again To -78°C, a tetrahydrof...

Embodiment 2

[0127] Example 2 ((S)-6-(4-chlorophenyl)-1-methyl-4,11-dihydro-[1,2,4]-triazol[3',4':3,4 ][1, Preparation of tert-butyl 4]-diaza-[5,6-b]-4-[1,8a-dihydro-imidazo[1,2-a]pyridine)acetate (compound 2)

[0128] The preparation method of reference example 1.

[0129] Molecular formula: C 24 h 23 N 6 ClO 2 Molecular weight: 462.16LC-MS(M+H) + :463

[0130] 1H NMR(DMSO)δ1.41(9H,s),δ2.37(3H,s),δ2.92(2H,d),δ4.89(1H,t),δ7.12(2H,d)7.30 (2H,s), δ7.45(2H,d), δ7.90(2H,d)

[0131] Example 2 ((S)-6-(4-chlorophenyl)-1-methyl-4,11-dihydro-[1,2,4]-triazol[3',4':3,4 ][1, Preparation of tert-butyl 4]-diaza-[5,6-b]-4-[1,3a-dihydro-pyrrole[1,5-a]pyridine)acetate (Compound 3)

[0132] The preparation method of reference example 1.

[0133] Molecular formula: C 24 h 23 N 6 ClO 2 Molecular weight: 462.16LC-MS(M+H) + :463

[0134] 1H NMR(DMSO)δ1.41(9H,s),δ2.37(3H,s),δ2.92(2H,d),δ5.01(1H,t),δ7.15(2H,d)7.33 (2H,s), δ7.45(2H,d), δ7.60(1H,t), δ7.90(1H,d)

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Abstract

The present invention belongs to the technical field of medicine, and specifically relates to heteroaryl ring derivatives represented by general formula (I), their pharmaceutically acceptable salts, their easily hydrolyzed esters, their isomers and intermediates, and these compounds and their Intermediate preparation method. The heteroaryl ring derivatives of the present invention can be used to prepare medicines for treating and / or preventing tumors. where R 1 , R 2 , R 3 , A, B, C, D, E, m, n, p and q are as defined in the description.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of medicine, and specifically relates to heteroaryl ring derivatives, pharmaceutically acceptable salts thereof, easily hydrolyzed esters, isomers and intermediates thereof, and preparation methods of heteroaryl ring derivatives and intermediates thereof . The heteroaromatic ring derivatives of the present invention can be used for cancer diseases including lung cancer, breast cancer, leukemia, skin cancer and lymphoma, and autoimmune diseases including rheumatoid arthritis, psoriasis, Crohn's disease and ulcerative colitis treatment and prevention of these diseases. [0003] 2. Background technology [0004] Epigenetics is a research hotspot in recent years. Epigenetics can be understood as the expression of different genes in different environments and situations, and finally achieve different physiological phenotypes, but the underlying genetic makeup has not changed. The mechanism of this sel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/14C07D471/22A61K31/551A61K31/5517A61P35/00A61P35/02A61P37/02A61P19/02A61P17/06A61P1/00A61P1/04
CPCC07D471/22C07D487/14
Inventor 郭守东林佳玮
Owner 郭守东
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