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EP300/CBP inhibitor

A deuterated, selected technology, applied in the field of pharmaceutical synthesis

Pending Publication Date: 2021-03-30
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the reported EP300 / CBP inhibitors still cannot meet the clinical needs. Therefore, it is of great significance to develop more EP300 / CBP inhibitors with novel structures, higher selectivity and better inhibitory activity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 100

[0142] Example 100 compound (1S, 4S, 5R)-3-(3,4-difluorophenyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-( (1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexa-2 -Synthesis of ketone (compound 100):

[0143] (1R,2S,5S)-3-tert-butyl-2-methyl-6,6-dimethyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,3-di Synthesis of Carboxylate (Compound 100-2):

[0144]

[0145] Starting material 100-1 (269 mg, 1 mmol), sodium periodate (850 mg, 4 mmol) was dissolved in 8 mL of acetonitrile and 8 mL of water. Under cooling in an ice-water bath, 5 mg of ruthenium trichloride was added and reacted for 5 hours. It was poured into water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain 112 mg of the product (intermediate 100-2), with a yield of 40%.

[0146] Ms:284(M+H + )

[0147] Synthesis of (1R,2S,5S)-6,6-dimethyl-4-oxo-3-azabicyclo[3.1.0]hexa-2-carboxylic acid methyl ester (in...

Embodiment 101

[0163] Example 101 Compound 2-(3,4-difluorophenyl)-1-(5-(3,5-dimethylisoxazol-4-yl)-1-((trans)-4-methan Synthesis of oxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-3-one (101):

[0164] Synthesis of 4-(2-hydroxyethyl)-1,3,2-dioxothioalkane-2,2-dioxide (Intermediate 101-1):

[0165]

[0166] Add 1,2,4-tributanol (10.0g, 94.2mmol) into pyridine (15.2mL) and acetonitrile (100mL), add thionyl chloride (34.4mL) dropwise at 0°C, and the reaction solution is The stirring reaction was continued for 15h. After the reaction was complete, ethyl acetate (20 mL) and 0.1 M hydrochloric acid solution (10 mL) were added, and extracted with ethyl acetate (10 mL×2). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The solvent was distilled off from the filtrate under reduced pressure to obtain 14.5 g of an oily substance.

[0167] The above 14.5g oil was dissolved in acetonitrile (20...

Embodiment 102

[0193] Example 102 compound (1S,5S)-2-(3,4-difluorophenyl)-1-(5-(3,5-dimethylisoxazol-4-yl)-1-((trans Formula)-4-(methoxy-d3)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-3-one (102) synthesis:

[0194] Synthesis of (S)-4-(2-hydroxyethyl)-1,3,2-dioxothioalkane-2,2-dioxide (Intermediate 102-1):

[0195]

[0196] Add (S)-1,2,4-tributanol (10.0g, 94.2mmol) into pyridine (15.2mL) and acetonitrile (100mL), add thionyl chloride (34.4mL) dropwise at 0°C, and react The solution was stirred and reacted for 15 h at room temperature. After the reaction was complete, ethyl acetate (20 mL) and 0.1 M hydrochloric acid solution (10 mL) were added, and extracted with ethyl acetate (10 mL×2). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The solvent was distilled off from the filtrate under reduced pressure to obtain 14.2 g of an oily substance.

[0197] The above 14.2g oil was d...

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Abstract

The invention discloses an EP300 / CBP inhibitor, and particularly provides a compound shown as a formula I, or a deuterated compound, or a salt, or a conformational isomer, or a crystal form, or a solvate thereof. The compound has high selectivity on EP300 / CBP, can effectively inhibit the activity of EP300 / CBP, and has an excellent inhibition effect on various tumor cells including prostate cancercells, leukemia cells, breast cancer cells and multiple myeloma cells, so that the compound provided by the invention has a wide application prospect in preparation of an EP300 / CBP inhibitor, prevention and / or treatment of tumors and malignant diseases of myeloid hematopoietic stem / progenitor cells, and regulation and control of regulatory T cells.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to an EP300 / CBP inhibitor with a novel structure and its pharmaceutical use. Background technique [0002] Histone acetyltransferase (histone acetyltransferase, HAT) and histone deacetylase (histone deacetylase, HDAC) can affect the acetylation of histones, the recruitment and normal function of HAT and HDAC are the key to gene expression and cell cycle Regulatory steps, functional defects in these enzymes may lead to various diseases including tumors. [0003] The EP300 / CBP family, consisting of a highly homologous adenosine E1A-related 300kDa protein (EP300) and a cyclic adenosine monophosphate response element binding protein (CREB) binding protein (CBP), is the main histone acetyltransferase (HAT) family. one of the members. Studies have found that EP300 and CBP bind to chromatin through their bromodomain (BRD), participate in cell cycle progression and cell...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D413/04C07D403/04C07D401/14C07D401/04A61K31/553A61K31/513A61K31/5377A61K31/5355A61K31/422A61K31/4439A61K31/454A61P35/00A61P35/02
CPCC07D413/14C07D413/04C07D403/04C07D401/14C07D401/04A61K31/553A61K31/513A61K31/5377A61K31/5355A61K31/422A61K31/4439A61K31/454A61P35/00A61P35/02C07B2200/07A61K2300/00Y02P20/55A61K45/06A61K31/519
Inventor 樊磊王飞吴孝全胥珂馨罗童川张少华霍永旭李兴海陈元伟
Owner HINOVA PHARM INC
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