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BRD4 protein inhibitor

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

Inactive Publication Date: 2018-05-29
郭守东 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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Examples

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preparation example Construction

[0086] 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,

[0087]

[0088] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , A, B, C, D, Q, m and n are as defined above.

[0089] 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.

[0090] When n is 1, the reaction scheme is:

[0091]

[0092] Reaction steps:

[0093] The preparation of step 1 compound c

[0094] Dissolve raw material a in acetonitrile, add calcium hydroxide, control the temperature below 30°C,...

Embodiment 1

[0127] Example 1 6-(((S)-6-(4-chlorophenyl)-1-methyl-4,11-dihydro-[1,2,4]-triazol[3',4':3,4 ] Preparation of [1,4]-diaza[5,6-b]-4-indolyl)methyl)piperidin-2-one (compound 1)

[0128] Step 1: Preparation of (4-chlorophenyl)-(2-hydroxy-1H-3-indolyl)methylketone (Intermediate C)

[0129]

[0130] Dissolve raw material A (133 g, 1.0 mol) in 1 L of acetonitrile, add calcium hydroxide (148 g, 2.0 mol), control the temperature below 30 degrees, add raw material B (210 g, 1.2 mol) dropwise, and then overnight at room temperature. TLC monitored the completion of the reaction. Filtrate, spin the filtrate to dryness, then add 2L of water, extract with EA (500ml*3), wash the organic phase with saturated sodium bicarbonate, dry and spin dry to obtain 210g of a yellow solid with a yield of 77.8%, which is directly used in the next step.

[0131] Step 2: Preparation of (4-chlorophenyl)-(2-chloro-1H-3-indolyl)methylketone (Intermediate D)

[0132]

[0133] Intermediate C (210 g,...

Embodiment 2

[0148] Example 2 6-(((S)-6-(4-chlorophenyl)-1-methyl-4,11-dihydro-[1,2,4]-triazol[3',4': 3,4] Preparation of [1,4]-diaza[5,6-b]-4-indolyl)methyl)hexahydropyrimidin-2-one (compound 2)

[0149] For the synthesis method, refer to Reference Example 1.

[0150] Molecular formula: C 24 h 22 N 7 Molecular weight of ClO: 459.16 LC-MS(M+H) + :460

[0151] 1H NMR(DMSO)δ1.56(2H,t),δ1.70(2H,m),δ2.39-2.57(5H,m),δ3.90(1H,m),δ4.60(1H, t),δ7.32-7.67(2H,m)7.49(2H,s),δ7.79(2H,s),δ7.99-8.12(2H,m),δ9.01(1H,br),δ10 .32(2H,br).

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Abstract

The invention belongs to the technical field of medicine, particularly relates to a BRD4 protein inhibitor shown in the general formula (I), acceptable salt, hydrolysable ester, isomer and intermediate in pharmacy, and a preparation method of the compounds and intermediate. The BRD4 protein inhibitor can be used for preparing a drug for treating and / or preventing tumors. R1, R2, R3, R4, R5, A, B, C, D, Q, m and n are defined in the description. The general formula (I) is shown in the description.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and specifically relates to a BRD4 protein inhibitor, its pharmaceutically acceptable salt, its easily hydrolyzed ester, its isomer and intermediate, and the preparation method of these compounds and their intermediates, comprising Pharmaceutical formulations of these compounds. The BRD4 protein inhibitor 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. 2. Background technology [0002] Epigenetics is a research hotspot in recent years. Epigenetics can be understood as the expression of different genes in different environments and situations, and ultimately achieve different physiological phenotypes, but the underlying genetic makeup has not changed. The mech...

Claims

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Application Information

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IPC IPC(8): C07D487/14C07D471/22A61K31/551A61P35/00
CPCC07D471/22C07D487/14
Inventor 郭守东袁清泉
Owner 郭守东
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