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Heterocyclic compounds and uses thereof

Active Publication Date: 2019-10-10
RUAN FUQIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds that can inhibit the activity of class I PI3Ks, BRDs, and both simultaneously. These compounds can be used for the treatment of diseases such as cancer and relapsed cancer, which are driven by dysfunctions of these proteins. The compounds have low IC50 values and can be easily synthesized and administered to patients. The invention also includes isotopically labeled compounds for drug distribution and half-life enhancement purposes. Prodrugs, which are converted to the active form in vivo, can be designed to enhance the pharmacological properties of the compound.

Problems solved by technology

Tumors can employ multiple genetic and epigenetic mechanisms to upregulate MYC, and such amplification or overexpression is often correlated with a poor clinical outcome, aggressive biological behavior, increased likelihood of relapse, and advanced stage of disease (Gamberi G., et al, Oncology.
To date, despite unmet medical needs, small molecule inhibitors of MYC have remained elusive, and MYC has thus far proven undruggable (Prochownik, E. V., et al., Genes Cancer.
Although BET bromodomain inhibitors show great promise as cancer therapeutics, emerging studies have shown that cancer cells can acquire resistance to inhibition of BET bromodomain, indicating that single-agent therapies targeting BRD4 may not provide durable therapeutic response.

Method used

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  • Heterocyclic compounds and uses thereof
  • Heterocyclic compounds and uses thereof
  • Heterocyclic compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

of 4-amino-6-(2-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-(piperidin-1-yl)quinolin-3-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (1)

[0075]Compound 1 was prepared according to the procedures set forth in steps 1-10 of Scheme 1 below:

Step 1: N-(4-bromo-3-methoxyphenyl)acetamide

[0076]To a solution of 4-bromo-3-methoxyaniline (2.0 g, 9.9 mmol) in CH2Cl2 (25 mL) at 0° C. was added Et3N (4.1 mL, 29.7 mmol), followed by dropwise addition of Ac2O (1.4 mL, 14.9 mmol). The reaction mixture was stirred under argon at 0° C. for 0.5 hour and at room temperature overnight, diluted with CH2Cl2 (25 mL) and water (25 mL). The organic layer was further washed with 1 N acetic acid aqueous solution (25 mL), saturated NaHCO3 aqueous solution (25 mL), brine (25 mL), dried (MgSO4). Evaporation to dryness yielded the title product (2.2 g) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.04 (s, 3H), 3.80 (s, 3H), 7.10 (dd, J=2.0 Hz and 8.6 Hz, 1H), 7.44 (m, 2H), 10.1 (s, 1H).

Step 2: 6-bromo-2-chloro-7-methox...

example 2

of 4-amino-6-(2-(8-methoxy-1-methyl-7-phenyl-[1,2,4]triazolo[4,3-a]quinolin-4-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (2)

[0087]Compound 2 was prepared according to the procedures set forth in steps 1-4 of Scheme 2 below:

Step 1: tert-butyl 2-(6-bromo-2-hydrazinyl-7-methoxyquinolin-3-yl)pyrrolidine-1-carboxylate

[0088]tert-butyl 2-(6-bromo-2-chloro-7-methoxyquinolin-3-yl)pyrrolidine-1-carboxylate (120 mg, 0.27 mmol) was treated with hydrazine monohydrate (1.0 mL) in EtOH (1 mL) at 110° C. over 24 hours in a sealed tube. The reaction mixture was cooled to room temperature and evaporated to dryness afforded the title compound as a yellow solid. MS (ESI): m / z 437.5, 439.0 (M+H)+; analytical HPLC: 18.8 min.

Step 2: 7-bromo-8-methoxy-1-methyl-4-(pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline

[0089]tert-butyl 2-(6-bromo-2-hydrazinyl-7-methoxyquinolin-3-yl)pyrrolidine-1-carboxylate (75 mg, 0.19 mmol) in acetic acid (3 mL) was stirred at 100° C. for 3 hours. Evaporation to dryness and pur...

example 3

of 4-amino-6-(2-(2-(3,5-dimethylisoxazol-4-yl)-8-methylquinolin-3-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (3)

[0092]Compound 3 was prepared according to the procedures set forth in steps 1-3 of Scheme 3 below:

Step 1: tert-butyl 2-(2-(3,5-dimethylisoxazol-4-yl)-8-methylquinolin-3-yl)pyrrolidine-1-carboxylate

[0093]A mixture of tert-butyl 2-(2-chloro-8-methylquinolin-3-yl)pyrrolidine-1-carboxylate (30 mg, 0.087 mmol; that was prepared according to the procedures disclosed in U.S. Pat. No. 9,637,488), 3,5-dimethylisoxazol-4-ylboronic acid (13.7 mg, 0.097 mmol), and Pd(dppf)2Cl2.CH2Cl2 (3.5 mg), Cs2CO3 (100 mg) in water (0.27 mL) and 1,2-domethoxyethane (0.81 mL) was purged with argon for 5 min and then stirred at 90° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature, and evaporated to dryness. Purification by silica gel chromatography using EtOAc / hexane (12.5% to 25%) afforded the title compound (6.8 mg) as a white solid. MS (ESI): m / z 480.4 (M+H)+.

S...

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Abstract

In recognition of the unmet need to develop novel therapeutic agents, the present invention discloses a novel class of heterocycles as dual inhibitors of BRD4 and class I PI3Ks. The compounds claimed herein could be used alone or in combination therapies for the effective treatment of a wide range of age-related diseases, including cancer. The present invention also provides methods for preparing compounds of the invention thereto.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. provisional patent application Ser. No. 62 / 654,313, filed Apr. 7, 2018, which is hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates generally to MYC, phosphatidylinositol 3-kinases (PI3Ks) and BET bromodomain-containing proteins (BRDs), and more specifically to novel dual inhibitors of class I PI3Ks and BRD4, and methods of making and using such inhibitors.BACKGROUND OF THE INVENTION[0003]MYC (v-myc myelocytomatosis viral oncogene homolog) is a pleiotropic transcription factor that regulates a variety of functions by promoting activation or repression of genes on a global scale, and plays a central role in the pathophysiology of cancer, inflammation, and heart disease.[0004]The overexpression of MYC is common in many types of human cancer. Tumors can employ multiple genetic and epigenetic mechanisms to upregulate MYC, and such amplification or o...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D471/04C07D401/14
CPCA61P35/00C07D413/14C07D471/04C07D401/14C07D487/04A61P9/00A61P19/08A61P35/02A61P11/00A61P13/12A61P1/16A61P1/18A61P29/00A61P11/06A61P19/02A61P17/06A61P37/06A61P25/00A61P3/00A61P31/04A61P7/02A61P31/18A61P1/00A61P37/08Y02A50/30
Inventor RUAN, FUQIANG
Owner RUAN FUQIANG
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