US-12617796-B2 - Antagonists of the adenosine A2a receptor

Abstract

The present invention relates to compounds of formula I shown below: wherein R 0 , R 1 , R 2 , R 3 and A are each as defined in the application. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions in which adenosine A2 a receptor activity is implicated, such as, for example, cancer.

Inventors

• Clive McCarthy
• Benjamin Moulton

Assignees

• JANSSEN PHARMACEUTICA NV

Dates

Publication Date

20260505

Application Date

20210506

Priority Date

20200507

Claims (12)

1. 1 . A compound, or pharmaceutically acceptable salt thereof, having the structural formula Ii3 shown below: wherein R 0 is hydrogen R 1z is cyano R 3 is a group of the formula: wherein R 3a is hydrogen or methyl; A is CH or N; and R 201 is methyl or chloro.
2. 2 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 3-(2-Chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.
3. 3 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 3-(2-Chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide.
4. 4 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 3-(2-Chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide.
5. 5 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 2-(3-Cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.
6. 6 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 2-(3-Cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide.
7. 7 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide.
8. 8 . A pharmaceutical composition comprising 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide: or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
9. 9 . A pharmaceutical composition comprising 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
10. 10 . A pharmaceutical composition comprising 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide: or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
11. 11 . A pharmaceutical composition comprising 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide: or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
12. 12 . A pharmaceutical composition comprising 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide: or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is the § 371 National Stage of PCT/GB2021/051106, filed May 6, 2021, which claims the benefit of GB 2019922.0, filed Dec. 16, 2020, and GB 2006823.5, filed May 7, 2020. The contents of PCT/GB2021/051106 are hereby incorporated by reference in their entirety. INTRODUCTION The present invention relates to certain compounds that function as antagonists of the adenosine A2a receptor. Additionally, some of the compounds are also antagonists of the A2b receptor. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions in which adenosine A2a receptor activity is implicated, such as, for example, cancer. BACKGROUND OF THE INVENTION A number of immunosuppressive pathways are active in the tumour microenvironment which enable tumour cells to evade elimination by cytotoxic T cells and can diminish the clinical response of patients to immunotherapy with anti-checkpoint antibodies. The anti-PD-1 antibodies pembrolizumab and nivolumab and anti-PD-L1 antibodies durvalumab, avelumab and atezolizumab are approved for the treatment of number of solid tumours including non-small cell lung cancer, head and neck squamous cancer and urothelial cancer. However, only 20-30% of patients respond to checkpoint blockade and the side effects of such treatments are significant (Sukari et al, 2016). Consequently, other approaches to enhance the cytotoxic potential of the tumour microenvironment are actively being investigated. This includes agents that could be used as monotherapies or, more likely, used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy. One approach that has attracted attention is to interfere with the production and/or action of adenosine in the tumour microenvironment (Vijayan et al, 2017). Adenosine has immunosuppressive properties and is present in the tumour microenvironment at high concentrations. Recent studies estimate the concentration of adenosine to be about 10 μM in human tumours compared to <1 μM in normal tissue (Houthuys et al 2017). Adenosine is formed at both intracellular and extracellular sites by two distinct pathways that involve two different substrates. Intracellular adenosine is derived from AMP and S-adenosyl homocysteine whilst the high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP and AMP) by the concerted action of CD39 and CD73 (Vijayan et al, 2017). CD39 and CD73 are upregulated in the tumour microenvironment in response to hypoxia. CD73 represents a putative patient stratification method for adenosine antagonists as its expression on tumour cells is also associated with poor overall prognosis in many different cancer types suggesting that adenosine production contributes to the undesirable immunosuppressive phenotype of the tumour microenvironment (Gao et al 2014; Loi et al, 2013;). CD73 expression by tumour-infiltrating immune cells is also important in promoting tumour immune suppression as CD73 negative Treg cells fail to suppress effector T cell functions (Deaglio et al, 2007; Reinhardt et al, (2017). Furthermore, patients resistant to anti-PD1 treatment have elevated levels of CD73 (Reinhardt et al, 2017). Adenosine regulates cell function via occupancy of specific GPCRs on the cell surface of the P1 purinoceptor subtypes. The P1 receptor family is further subdivided into A1, A2a, A2b and A3. A2 receptors are subdivided into A2a and A2b, based on high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes and activation of A2a leads to suppression of cytokine production and other effector functions. Tumour growth is inhibited by genetic ablation of A2a in syngeneic mouse models and this effect has been demonstrated to be due to enhanced lymphocyte activation and cytotoxic function (Ohta et al, 2006; Waickman et al 2012; Beavis et al, 2013; Mittal et al, 2014; Cekic et al, 2014). A2a−/− mice show an increased response to inhibition of checkpoint pathways such as PD-1, with an improvement in both tumourfree survival and overall survival. Adenosine-mediated A2a activation also limits the efficacy of ant-CTLA4 treatment (lannone et al, 2014). The effects of genetic deficiency of A2a in mouse models is mimicked by pharmacological blockade of A2a. A2a antagonists have been shown to enhance the cytotoxic CD8+ T cells and to enhance the ability of NK cells prevent metastasis of CD73-expressing tumours (Beavis et al, 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al, 2015). These findings have prompted the development of selective A2a antagonists for use in cancer immunotherapy and clinical trials are ongoing with CPI-444, the first selective A2a antagonist to be evaluated in cancer,