Preparation and application of pyrimidinedione indole and pyridone indole compounds

文档序号：1067390 发布日期：2020-10-16 浏览：20次中文

阅读说明：本技术 嘧啶二酮并吲哚和吡啶酮并吲哚类化合物的制备及用途 (Preparation and application of pyrimidinedione indole and pyridone indole compounds ) 是由孙海鹰马宗辉傅源涛方坤森郭天玥袁易南于 2019-04-03 设计创作，主要内容包括：本发明涉及含有嘧啶-2,4-二酮并[5,4-b]吲哚骨架或吡啶-2-酮并[3,2-d]吲哚骨架的化合物的制备方法,本发明进一步涉及其作为BET Bromo结构域抑制剂的医疗用途。<Image he="251" wi="700" file="DSA0000181449190000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to compositions containing pyrimidine-2, 4-diketo [5, 4-b ]]Indole skeleton or pyridine-2-one [3, 2-d ]]The invention further relates to the medical use thereof as BET Bromo domain inhibitors.)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

A¹is-N or-C (R)⁵)-；

A²is-N or-C (R)⁶)-；

A³is-N-or-CH-;

A⁴is-N-or-CH-;

X¹is O or S;

X²is O or S;

R¹is an optionally substituted five membered heteroaryl;

R²hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;

R³is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl) alkyl;

R⁴is hydrogen, amino, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, heteroalkyl, (heterocyclyl) alkyl, (amino) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and carboxamide;

R⁵hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;

R⁶is hydrogen, hydroxy, alkyl, haloalkyl,Alkoxy, alkylthio, amino and fluoro.

2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-1);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-2);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-3);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1-benzyl-1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-4);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-5);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-6);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-7);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-8);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-9);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-10);

7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-11).

3. A process for the preparation of a compound of formula I according to claim 1, of the formula:

the method specifically comprises the following steps:

(1) step a, reacting a compound 1 with acetic anhydride to obtain a compound 2;

(2) step b, preparing a compound 3 from the compound 2 and 2-ethyl bromoacetate;

(3) in the step c, the compound 3 is deacetylated to prepare a compound 4;

(4) in the step d, the compound 4 reacts with ethyl isocyanate and then reacts with sodium methoxide to prepare a compound 5;

(5) step e, reacting the compound 5 with di-tert-butyl dicarbonate to prepare a compound 6;

(6) step f, preparing a compound 7 by using the compound 6 and different halogenated hydrocarbons;

(7) and step g, reacting the compound 7 with 3, 5-dimethylisoxazole-4-boric acid to prepare a compound I-1 to 11.

4. A compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

B¹is-N or-C (R)¹⁰)-；

B²is-N or-C (R)¹¹)-；

B³is-N-or-CH-;

y is O or S;

R⁷is an optionally substituted five membered heteroaryl;

R⁸is hydrogen, hydroxy, alkyl, haloAlkyl, alkoxy, alkylthio, amino and halogen;

R⁹is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl) alkyl

R¹⁰Hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;

R¹¹hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and fluorine.

5. The compound of formula II according to claim 4, wherein the compound is selected from:

7- (3, 5-dimethylisoxazol-4-yl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-1);

7- (3, 5-dimethylisoxazol-4-yl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-2);

7- (3, 5-dimethylisoxazol-4-yl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-3).

6. The process for the preparation of the compound of formula II according to claim 4, of the formula:

the method specifically comprises the following steps:

(1) step h, reacting the compound 7 with tin tetrachloride and silver chloride to obtain a compound 8;

(2) step i, reacting the compound 8 with 4-methoxy benzyl chloride to obtain a compound 9;

(3) step j is that the compound 9 reacts with hydroxylamine hydrochloride and sodium ethoxide to prepare a compound 10;

(4) step k, reacting the compound 10 with aluminum trichloride to obtain a compound 11;

(5) step l, reacting the compound 11 with different halogenated hydrocarbons to obtain a compound 12;

(6) m is that the compound 12 reacts with phosphorus oxychloride and N, N-dimethylformamide to close the ring and prepare a compound 13;

(7) step n is that the compound 13 reacts with 3, 5-dimethylisoxazole-4-boric acid to prepare a compound 14;

(8) step o is the reaction of compound 14 with trifluoroacetic acid to give compound II-1 to 3.

7. Use of a compound of formula I according to any one of claims 1 or a pharmaceutically acceptable salt thereof and a compound of formula II according to any one of claims 2 or a pharmaceutically acceptable salt thereof as BET bromodomain inhibitors for the treatment of cancer.

Technical Field

The present invention relates to a method for preparing a compound having a pyrimidine-2, 4-diketo [5, 4-b ] indole skeleton or a pyridine-2-keto [3, 2-d ] indole skeleton, and further relates to the medical use thereof as a BET Bromo domain inhibitor.

Background

Histone acetylation is an important histone post-transcriptional modification and also an important research content of epigenetics. BRD (Bromodomain) is a conserved protein domain capable of specifically recognizing acetylated lysine, and proteins containing BRD can promote related proteins such as chromatin remodeling factors and transcription factors to be enriched in specific gene transcription sites by combining with the acetylated lysine so as to regulate the transcription expression of genes. Currently, 61 BRDs are found in humans, and are present in 46 proteins, which are classified into 8 major families according to their functions. The BET (Bromodomain and extra-terminal) protein family is class 2 of the BRD protein family, comprising 4 members, BRDT, BRD2, BRD3 and BRD4, respectively. BET family proteins are capable of binding to acetylated lysines in histones H3 and H4 and regulating transcription of genes associated with cell cycle and cell growth by recruiting different transcription complexes. Dysfunction of BET proteins has been linked to the development of a variety of human diseases, and therefore small molecule BET inhibitors have the potential to be developed as drugs for the treatment of human diseases such as cancer, inflammation, viral infection, etc. (j.med.chem.2017, 60, 4533-4558; Future med.chem.2016, 8, 1655-1680.).

The present invention relates to compounds that bind to the Bromo domain of BET family proteins and inhibit the binding of the Bromo domain to acetylated lysine.

Disclosure of Invention

In one embodiment, the present invention discloses a compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:

wherein:

A¹is-N or-C (R)⁵)-；

A²is-N or-C (R)⁶)-；

A³is-N-or-CH-;

A⁴is-N-or-CH-;

X¹is O or S;

X²is O or S;

R¹is an optionally substituted five-membered aromatic heterocycle, and the substituent is hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy;

R²hydrogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio, alkylamino and halogen;

R³is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic aryl, aralkyl, heterocyclic aralkyl;

R⁴is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, (heterocyclyl) alkyl, (amino) alkyl, optionally substituted heterocyclyl, and carboxamide;

R⁵hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;

R⁶hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and fluorine.

Preferred compounds of formula I of the present invention are as follows: