WO2022175425A1

WO2022175425A1 - Inhaled mtor kinase inhibitors for use in the treatment or the prevention of a respiratory rna virus infection

Info

Publication number: WO2022175425A1
Application number: PCT/EP2022/054032
Authority: WO
Inventors: Joseph E. Pero
Original assignee: Glaxosmithkline Intellectual Property Development Limited
Priority date: 2021-02-22
Filing date: 2022-02-18
Publication date: 2022-08-25

Abstract

The present disclosure relates to an inhaled mTOR kinase inhibitor for use in the treatment or prevention of a respiratory RNA virus. In particular embodiments, the respiratory RNA virus is associated with pneumonia or acute respiratory distress disorder. In other aspects, the patient is undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non-invasive ventilation, receiving oxygen therapy or receiving antiviral or antibiotic treatment.

Description

INHALED MTOR KINASE INHIBITORS FOR USE IN THE TREATMENT OR THE PREVENTION OF A RESPIRATORY RNA VIRUS INFECTION

FIELD OF THE INVENTION

The present disclosure relates to an inhaled mTOR kinase inhibitor for use in the treatment or prevention of a respiratory RNA virus infection. In particular embodiments, the respiratory RNA virus infection is associated with pneumonia or acute respiratory distress disorder. In other aspects, the patient is undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non- invasive ventilation, receiving oxygen therapy or receiving antiviral or antibiotic treatment.

BACKGROUND TO THE INVENTION

A number of RNA viruses modulate the mTOR pathway by activation of PI3K, AKT or mTOR itself. There exists strong scientific evidence that mTOR inhibition suppresses viral protein synthesis in addition to interfering with virus-mediated transcription events ( Viruses . 2016, 8, 152). For example, kinome analysis of MERS-CoV, an RNA virus closely-related to SARS-CoV2, identified mTOR pathway modulation during infection. In vitro studies revealed that PI3K/AKT/mTOR signaling is involved in the pathogenesis of MERS-CoV and suppression of the mTOR pathway resulted in a 60% decrease in infections ( Antimicrob . Agents Chemother. 2015, 59, 1088-1099). Furthermore, it has been shown that mTOR inhibitor rapamycin blocks in vitro replication of MERS-CoV (DOI: 10.1128/ AAC.03659-14). H1N1 influenza patient outcomes have been significantly improved following adjuvant treatment with mTOR inhibitors, supporting their clinical usage for similar diseases (DOI:10.1097/CCM.0b013e3182a2727d). Inhibition of mTOR limited replication of the 1918 influenza A virus ( EBioMedicine . 2018, 32, 142-163) and buformin - a known mTOR inhibitor - was found to enhance survival rates in mouse models indicative of therapeutic potential (Pol. Tyg. Lek. 1970, 25, 332-334). In addition, mTOR inhibitors phenformin and buformin were associated with reduced incidence of H3N2 influenza (5.4%) compared to control group (24%, p < 0.001; Pol. Tyg. Lek. 1973, 28, 1815-1817).

SUMMARY OF THE INVENTION

In one aspect of the invention, there is provided an inhaled mTOR kinase inhibitor for use in the treatment or prevention of a respiratory RNA virus infection.

In further aspect, the invention provides a method of treatment of a subject having a respiratory RNA virus infection, the method comprising administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor. In a further aspect, the invention provides use of an inhaled mTOR kinase inhibitor in the manufacture of a medicament for the treatment or prevention of a respiratory RNA virus infection infection.

DETAILED DESCRIPTION OF THE INVENTION

SARS-CoV-2 enters the host cell by binding its transmembrane spike glycoprotein to the cellular membrane angiotensin converting enzyme 2 receptor (ACE2) which is expressed in various organs including the lung ( Hypertension research 2020 43(7):648-654). Other coronaviruses show anaologous modes of infection. Cells in the respiratory tract are considered to be the primary route infection of coronaviruses (Cell 2020 182(2):429-446) and SARS-CoV-2 has been shown to be expressed in the nose, ciliated cells in the proximal airway and in type 2 alveolar cells in the distal airway. This infection results in viral replication in the epithelial cells causing cell injury and a vigorous immune response leading to acute lung injury and diffuse alveolar damage leading to high levels of morbidity and mortality. Inhibition of viral entry and replication in the airways is therefore a of paramount importance in preventing infection and subsequent disease therefore an inhaled agent specifically targeted at the lung as a high likelihood of preventing infection. mTOR kinase inhibitors delivered directly to the lungs and/or nose has several key advantages: (1) administration to the target organ maximises the potential to achieve high levels of mTOR inhibition and hence prevention of viral entry and/or replication and/or subsequent transmission (2) Oral administration of mTOR kinase inhibitors is reported to result is substantial acute side-effects and hence prevention of mTOR inhibition at a level required to deliver efficacy (European Urology, 2016, 69(3) 450-456) (3) Systemic inhibition of the mTOR pathway is known to result in immunosuppressive effects potentially preventing the hosts ability to suppress systemic infection (Nat. Rev. Immunol, 2009, 9(5): 324-337)."

Accordingly, the inventors herein disclose the following aspects of the invention:

In one embodiment, the RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the RNA virus Human rhinovirus. In one embodiment, the RNA virus is Respiratory syncytial virus (RSV).

In one embodiment, the RNA virus is Influenza.

In one embodiment, the inhaled mTOR kinase inhibitor is selected from the group consisting of;

1-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin-

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.

In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In one aspect of the invention, there is provided a method of treating a subject having a respiratory RNA virus infection, the method comprising administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor.

In one embodiment, the RNA virus Human rhinovirus.

In one embodiment, the RNA virus is Respiratory syncytial virus (RSV).

In one embodiment, the RNA virus is Influenza.

In one embodiment, the inhaled mTOR kinase inhibitor is selected from the group consisting of: l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin- 2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.

In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof .

In one aspect of the invention, there is provided use of an inhaled mTOR kinase inhibitor in the manufacture of a medicament for the treatment of a respiratoryRNA virus infection.

In one embodiment, the RNA virus Human rhinovirus.

In one embodiment, the RNA virus is Respiratory syncytial virus (RSV).

In one embodiment, the RNA virus is Influenza. In one embodiment, the inhaled mTOR inhibotor is selected from the group consisting of;

In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof. In specific embodiments, the invention provides treating particular populations of patients with RNA virus infections, for example patients in high risk categories and patients with secondary conditions. In particular embodiments, the patient has pneumonia or acute respiratory distress disorder. In additional embodiments, the patient is additionally undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non-invasive ventilation, receiving oxygen therapy or receiving antiviral or antibiotic treatment.

In another embodiment, the subject is not infected with a respiratory RNA virus such that the use is for prevention of a respiratory RNA virus infection. Subjects suitable for such prophylactic use include subjects in high risk categories, health care professionals and close contacts of subjects infected with a respiratory RNA virus.

DEFINITIONS

Treatment of a respiratory RNA virus infection refers to a reduction in the viral load of the RNA virus and/or to a reduction in the viral titre of the respiratory RNA virus, and/or to a reduction in the severity or duration of the symptoms of the disease. Viral load may be measured by a suitable quantitative RT-PCR assay from a specimen from the patient. In one embodiment, the specimen may be a specimen from the upper or lower respiratory tract (such as a nasopharyneal or oropharyngeal swab, sputum, lower respiratory tract aspirates, bronchoalveolar lavage, bronchial biopsy, transbronchial biopsy and nasopharyngeal wash/spirate or nasal aspirate) saliva or plasma.

In a more particular embodiment, the specimen is saliva. Viral titre may be measured by assays well known in the art. In one embodiment, the viral titre is measured by the assay disclosed in US2014/0249143.

In one embodiment, treatment of a respiratory RNA virus infection refers to at least a 5 fold, 10 fold, 50 fold, 100 fold, 500 fold or 1000 fold reduction in the viral load (RNA copies/ml) measured by the same assay from a specimen from the same origin taken prior to treatment (baseline) and the end of the treatment period in a single patient. In another embodiment, treatment of a respiratory RNA virus infection refers to the situation where the mean viral load (RNA copies/ml) from specimens of the same origin from 30 patients measured in the same assay being reduced by at least 5 fold, 10 fold, 50 fold, 100 fold, 500 fold or 1000 fold at the end of the treatment period compared to baseline.

In one embodiment, treatment of a respiratory RNA virus infection refers to the viral load being decreased to below the limit of detection of the [relevant] assay at the end of the treatment period. Prevention of a respiratory RNA virus infection is interpreted in accordance with the usual meaning of the word "prevent".

High risk categories include the following: subjects of 60 years of age and over; smokers, subjects having a chronic medical condition including heart disease, lung disease, diabetes, cancer or high blood pressure; immunocompromised subjects such as subjects undergoing treatment for cancer or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease, subjects having a transplant and HIV positive individuals. Close contacts of a subject infected with a respiratory RNA virus are defined as (i) persons living in the same household as the infected subject; (ii) persons having had direct or physical contact with the infected subject; (iii) persons having remained within two metres of an infected subject for longer than 15 minutes on or after the date on which the subject was infected with a respiratory RNA virus , whether or not symptoms were reported by the subject, including persons living in a community residence such as a dormatory, assisted living facility, nursing home, rehabilitation center and the like, and persons having attended a gathering of 10, 25, 50, 100, 500, 1000 or more people not separated by ~6-feet (2 meters) and/or not protected by a face mask or shield; and (iv) persons having travelled to, from or through a region with high levels of the respiratory RNA virus. As used herein "mTOR kinase inhibitor" means a compound or pharmaceutically acceptable salt thereof which inhibits mTOR kinase as measured by assays well known in the art. Suitable assays may be found in WO19/115640 and WO20/249652, among others.

As used herein, "inhaled mTOR kinase inhibitor" means a compound or pharmaceutically acceptable salt thereof which is an mTOR kinase inhibitor and which is formulated for inhaled administration.

IDENTIFICATION OF SUBJECTS INFECTED WITH THE RESPIRATORY RNA VIRUS

Subjects infected with a respiratory RNA virus may be identified by detection of viral RNA from the virus from a specimen obtained from the subject. In one embodiment, the viral RNA is from a respiratory RNA virus selected from the group comsisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. Without intending to be limiting, the specimen may be a specimen from the upper or lower respiratory tract (such as a nasopharyneal or oropharyngeal swab, sputum, lower respiratory tract aspirates, bronchoalveolar lavage and nasopharyngeal wash/spirate or nasal aspirate). Any known methods of RNA detection may be used, such as high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay. In one embodiment, the method comprises the following steps: a) Isolating RNA from a specimen; b) Reverse transcription of the RNA; c) Amplification with forward and reverse primers in the presence of a probe; and d) Detection of the probe; wherein the presence of the respiratory RNA virus is confirmed if the cycle threshold growth curves cross the threshold within 40 cycles.

Accordingly, in one embodiment, the invention comprises a method for treating a respiratory RNA virus infection in a subject comprising a method of detecting viral RNA from a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza, from a specimen obtained from the subject and, where viral RNA is detected, a step of treating a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza as described herein.

In one aspect, the invention provides a method for testing for a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza in a subject and treating a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza infection in the subject, which method comprises the following steps: a) Isolating RNA from a specimen derived from a subject; b) Reverse transcription of the RNA; c) Amplification with forward and reverse primers in the presence of a probe; and d) Detection of the probe; wherein the subject is defined as having a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza infection if the cycle threshold growth curves cross the threshold within 40 cycles; and e) treating the subject having a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza infection with a therapeutically effective amount of an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In specific embodiments of this method, the subject is human. The treatment may also be conducted as described herein. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2- b]pyridin-5-yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In an alternative embodiment, subjects infected with a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza may be identified by detection of an a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza antigen or subject antibodies directed to the respiratory RNA virus in a sample of blood taken from the subject. In one embodiment, subjects infected with a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza may be identified by detection of the respiratory RNA virus antigens in a sample of blood taken from the subject. Any suitable assay may be used. In one embodiment, the assay to identify subjects infected with a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza comprises: a) contacting at least one immobilised antigen from the respiratory RNA viruswith blood from the subject; and b) detection of a complex formed between subject antibodies directed to the immobilised antigen and the immobilised antigen; where the the subject is identified to be infected with the respiratory RNA virus if a complex is detected in step b).

In one embodiment, there is a step of washing the immobilised antigen after step a) and before step b).

In one embodiment, the detection step b) comprises contacting the complex formed with a labelled antibody or antibodies recognising the same antigen or antigens followed by detection of the label. In a more particular embodiment, the complex is washed after addition of labelled antibody(ies) prior to detection of the label.

In one embodiment, the label is capable of producing a coloured product, enabling visual detection of the label.

In one embodiment, the assay is a lateral flow assay. In more particular embodiment, the lateral flow assay has the immobilised antigen(s) on a dipstick.

In one embodiment, the invention provides a method for testing for a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza in a subject and treating the respiratory RNA virus infection in the subject, which method comprises the following steps: a) contacting at least one immobilised antigen from the respiratory RNA virus with blood from the subject; and b) detecting a complex formed between subject antibodies directed to the immobilised antigen and the immobilised antigen; where the the subject is identified to be infected with the respiratory RNA virus if a complex is detected in step b); and c) treating the subject having the respiratory RNA virus infection with a therapeutically effective amount of an mTOR kinase inhibitor selected from: 1-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin-

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof. In specific embodiments of this method, the subject is human, and the assay is conducted as as described above. The treatment may also be conducted as described herein. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2- b]pyridin-5-yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In one embodiment, the assay to identify subjects infected with a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza comprises: a) contacting an immobilised antibody recognising an antigen from the respiratory RNA virus with blood from the subject; and b) detection of a complex formed between an antigen from SARS-CoV-2 and the immobilised antibody recognising said antigen; where the the subject is identified to be infected with the respiratory RNA virus if a complex is detected in step b).

In one embodiment, there is a step of washing the immobilised antibody after step a) and before step b).

In one embodiment, the detection step b) comprises contacting the complex formed in step a) with labelled antibodies recognising the same antigen or antigens followed by detection of the label. In a more particular embodiment, step b) comprises a step of washing prior to detection of the label.

In one embodiment, the label is capable of producing a coloured product, enabling visual detection of the label. In one embodiment, the assay is a lateral flow assay. In more particular embodiment, the lateral flow assay has the immobilised antibod(ies) on a dipstick.

In one embodiment, the invention provides a method for testing for and treating a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza infection, which method comprises the following steps: a) contacting an immobilised antibody recognising an antigen from the respiratory RNA virus with blood from the subject; and b) detecting of a complex formed between an antigen from the respiratory RNA virus and the immobilised antibody recognising said antigen; where the the subject is identified to be infected with the respiratory RNA virus if a complex is detected in step b), and treating the subject having the respiratory RNA virus infection with a therapeutically effective amount of an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof . In specific embodiments of this method, the subject is human, and the assay is conducted as as described above. The treatment may also be conducted as described herein. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2- b]pyridin-5-yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

PROPHYLACTIC USE

In one aspect of the invention, the invention provides an inhaled mTOR kinase inhibitor selected from: l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin- 2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof , for use in the prevention of a respiratory RNA virus infection. In one embodiment, the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof. In one embodiment, a specimen from the subject has been tested for the respiratory RNA virus infection and no respiratory virus RNA was detected. In another embodiment, a specimen from the subject has not been tested for respiratory virus RNA.

In more particular embodiments, the subject is in a high risk category (as defined herein), a health care professional or is a close contact of a patient infected with a respiratory RNA virus, in one embodiment from a respiratory RNA virus selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza (as defined herein).

In one aspect of the invention there is provided a method of preventing a respiratory RNA virus, in a subject at risk of an infection from a respiratory RNA virus, the method comprising: administering to the subject at risk of infection from a respiratory RNA virus a therapeutically effective amount of an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza infection.

In more particular embodiments, the subject is in a high risk category (as defined herein), a health care professional or is a close contact of a subject infected with a respiratory RNA virus (as defined herein).

THERAPEUTIC USE

In one aspect of the invention, the invention provides a an inhaled mTOR kinase inhibitor for use in the treatment of a respiratory RNA virus infection.

In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one aspect of the invention, the invention provides an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof for use in the treatment of a respiratory RNA virus.

In one embodiment, treatment is initated within 24 hours of the onset of symptoms, or within 24 hours of being tested positive for a respiratory RNA virus infection, using for example, the method defined herein. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the subject infected with a respiratory RNA virus is in a high risk category, as defined above.

In particular embodiments, the subject infected with the respiratory RNA virus is undergoing extra corporeal membrane oxygenation or mechanical ventilation, or receiving oxygen supplementation via a nasal cannula or simple mask. Where mechanical ventilation is used, this includes use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmHzO). Where oxygen supplementation is via a nasal cannula, this may be delivered as 2 to 6 l/minute. Where oxygen supplementation is aby a simple mask, this may be delivered at 5 to 10 I/minute.

In particular embodiments, the subject infected with the respiratory RNA virus is receiving additional anti-viral and or antibiotic treatment. In a more particular embodiment, the subject infected with SARS-CoV-2 is receiving an additional anti-viral agent. In even more particular embodiments, the anti-viral agent is selected from olsetemivir, remdesivir, ganciclovir, lopinavir, ritonavir and zanamivir. In one embodiment, the patient is receiving oseltamivir (75 mg every 12 h orally). In another embodiment, the subject infected with the respiratory RNA virus is receiving ganciclovir (0.25 g every 12 h intravenously). In another embodiment, the subject infected with the respiratory RNA virus is receiving lopinavir/ritonavir (400/100 mg twice daily orally). In a further embodiment, the subject infected with the respiratory RNA virus is receiving 100 mg remdesivir daily intravenously.

In particular embodiments, the subject infected with the respiratory RNA virus is receiving treatment with steroids. In a more particular embodiment, the steroid is selected from dexamethasone, prednisone, methylprednisone and hydrocortisone. In one embodiment, the subject infected with the respiratory RNA virus is receiving dexamethasone (6 mg once daily, orally or intravenously). In one embodiment, the subject infected with the respiratory RNA virus is receiving prednisone (40 mg daily, in two divided doses). In one embodiment, the subject infected with the respiratory RNA virus is receiving methylprednisone (32 mg daily, in two divided doses). In one embodiment, the subject infected with the respiratory RNA virus is receiving hydrocortisone (160 mg daily, in two to four divided doses). In one embodiment, the subject receiving treatment with any of the above steroids is a subject receiving mechanical ventilation or supplemental oxygen.

In one aspect there is provided a method for treating or preventing a respiratory RNA virus in a subject infected with a respiratory RNA virus or at risk of infection with a respiratory RNA virus, the method comprising administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor.

In one embodiment, the inhaled mTOR kinase inhibitor is selected from:

In one embodiment, the method comprises administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor wherein the subject is at risk of infection with a respiratory RNA virus and the method comprises prevention of COVID-19 in the subject at risk of infection with a respiratory RNA virus. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. In one embodiment, the inhaled mTOR kinase inhibitor is selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; wherein the subject is at risk of infection with SARS-CoV-2 and the method comprises prevention of COVID-19 in the subject at risk of infection with SARS-CoV-2. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In one particular embodiment, the subject is: a close contact of a patient infected with a respiratory RNA virus, in a high risk category; or a healthcare professional. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the method comprises administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor wherein the subject is infected with a respiratory RNA virus and the method comprises treating the respiratory RNA virus infection in the subject infected with the respiratory RNA virus. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the inhaled mTOR kinase inhibitor is selected from: l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin- 2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.

In one embodiment, the method comprises administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor wherein the subject is infected with a respiratory RNA virus and the method comprises treating the respiratory RNA virus infection in the subject infected with the respiratory RNA virus. . In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. In one embodiment, the inhaled mTOR kinase inhibitoris selected from: l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2-b]pyridin- 2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; wherein the subject is infected with a respiratory RNA virus and the method comprises treating a respiratory RNA virus infection in the subject infected with a respiratory RNA virus. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin- 5-yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof. In a particular embodiment, the subject was identified as being infected with the respiratory RNA virus, by detection of viral RNA from the respiratory RNA virus from a specimen obtained from the subject.

In one embodiment, the method comprises administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor, wherein the respiratory RNA virus infection in the subject infected with the RNA virus is associated with pneumonia. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza. In one embodiment, the inhaled mTOR kinase inhibitor isselected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and

(S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.. In one embodiment, the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2- [(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

In a particular embodiment, COVID-19 in the subject infected with a respiratory RNA virus is associated with acute respiratory distress disorder. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the subject infected with a respiratory RNA virus is undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non-invasive ventilation, or receiving oxygen therapy. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In one embodiment, the subject infected with a respiratory RNA virus is receiving an additional anti viral and or antibiotic treatment. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In a particular embodiment, the subject infected with a respiratory RNA virus is receiving an additional anti-viral agent. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In another particular embodiment, the additional anti-viral agent is selected from remdesivir, ganciclovir, lopinavir, olsetemivir ritonavir and zanamivir. In one embodiment, the subject receiving 100 mg remdesivir daily intravenously.

In a particular embodiments, the subject infected with a respiratory RNA virus is receiving treatment with steroids. In one embodiment the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

In another particular embodiment, the steroid is selected from dexamethasone, prednisone, methylprednisone and hydrocortisone. In one embodiment, the subject is receiving dexamethasone (6 mg once daily, orally or intravenously). In one embodiment, the subject receiving treatment with steroids is a patient receiving mechanical ventilation or supplemental oxygen. COMPOUND

Compounds disclosed herein may be produced using methods know in the art, for example using the methods disclosed in WO19/11640 and WO20/249652.

PHARMACEUTICAL COMPOSITIONS/ROUTES OF ADMINISTRATION/DOSAGES The compounds of the invention can be formulated in a dosage form adapted for administration to a patient by nasal or inhaled administration, for example, as a dry powder, an aerosol, a suspension, or a solution formulation.

Dry powder formulations for delivery to the lung by inhalation typically comprise a compound of of the invention or a pharmaceutically acceptable salt thereof as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders. Pharmaceutically- acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. The finely divided powder may be prepared by, for example, micronisation and milling. Generally, the size-reduced (for example micronised) compound can be defined by a D50 value of about 1 to about 10 microns (for example as measured using laser diffraction).

The dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form. RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position. For example, the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation. The dry powder formulations for use in accordance with the present invention may be administered via inhalation devices. As an example, such devices can encompass capsules and cartridges of for example gelatin, or blisters of, for example, laminated aluminium foil. In various embodiments, each capsule, cartridge or blister may contain doses of formulation according to the teachings presented herein. Examples of inhalation devices may include those intended for unit dose or multi-dose delivery of formulation, including all of the devices set forth herein. As an example, in the case of multi-dose delivery, the formulation can be pre-metered (e.g., as in Diskus, see GB2242134, U.S. Patent Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and 6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, US Pat. Nos. 4,778,054, 4,811,731, 5,035,237) or metered in use (e.g. as in Turbuhaler, see EP 69715, or in the devices described in U.S. Patent No 6,321,747). An example of a unit-dose device is Rotahaler (see GB 2064336). In one embodiment, the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing the compound optionally with other excipients and additive taught herein. The peelable seal is an engineered seal, and in one embodiment the engineered seal is a hermetic seal. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. Also, preferably the engineered seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the base sheet. A dry powder formulation may also be presented in an inhalation device which permits separate containment of two different components of the formulation, Thus, for example, these components are administrable simultaneously but are stored separately, e.g. in separate pharmaceutical formulations, for example as described in WO 03/061743 A1 WO 2007/012871 Al, W02007/068896, as well as U.S. Patent Nos. 8,113,199, 8,161,968, 8,511,304, 8,534,281, 8,746,242 and 9,333,310.

In one embodiment an inhalation device permitting separate containment of components is an inhaler device having two peelable blister strips, each strip containing pre-metered doses in blister pockets arranged along its length, e.g., multiple containers within each blister strip, e.g., ELLIPTA®. Said device has an internal indexing mechanism which, each time the device is actuated, peels open a pocket of each strip and positions the blisters so that each newly exposed dose of each strip is adjacent to the manifold which communicates with the mouthpiece of the device. When the patient inhales at the mouthpiece, each dose is simultaneously drawn out of its associated pocket into the manifold and entrained via the mouthpiece into the patient's respiratory tract. A further device that permits separate containment of different components is DUOHALERTM of Innovata. In addition, various structures of inhalation devices provide for the sequential or separate delivery of the pharmaceutical formulation(s) from the device, in addition to simultaneous delivery.

Alternatively, the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape. Each capsule, cartridge, or blister may, for example, contain between 200pg-10mg of an inhaled mTOR kinase inhibitor or a pharmaceutically acceptable salt thereof.

Aerosols may be formed by suspending or dissolving an inhaled mTOR kinase or a pharmaceutically acceptable salt thereof in a liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquified gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising an inhaled mTOR kinase inhibitor or a pharmaceutically acceptable salt thereof will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations described herein may include other agents conventional in the art.

The present invention also provides unitary pharmaceutical compositions in which the compound or pharmaceutically acceptable salt thereof of the present invention and one or more other pharmaceutically active agent(s) may be administered together or separately. In one embodiment, the pharmaceutical composition contains an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof, and one or more additional antiviral agents or antibiotics. In one embodiment, the pharmaceutical composition contains l-{6- [(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4- yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof, and one or more additional antiviral agents or antibiotics. In one embodiment, the pharmaceutical composition contains an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereofand one or more additional other antiviral agents. In one embodiment, the pharmaceutical composition contains l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof, and one or more additional other antiviral agents.In one embodiment, the anti-viral agents are selected from the group consisting of: olsetemivir, remdesivir, ganciclovir, lopinavir, ritonavir and zanamivir. In one embodiment, the pharmaceutical composition contains a single anti-viral agent.

In a more particular embodiment, the single anti-viral agent is remdesivir.

In one embodiment, the pharmaceutical composition contains a an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereofand one or more steroids.

In one embodiment, the pharmaceutical composition contains l-{6-[(3S)-3-ethylmorpholin-4-yl]-2- {2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4-yl}-N,N- dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof, and one or more steroids. In one embodiment, one or more steroids are selected from the group consisting of: dexamethasone, prednisone, methylprednisone and hydrocortisone. In one embodiment, the pharmaceutical composition contains a single steroid. In a more particular embodiment, the single steroid is dexamethasone.

Appropriate doses will be readily appreciated by those skilled in the art. When an inhaled mTOR kinase inhibitor selected from:

2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-lH- pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and (S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2-b]pyridin-2- yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereofis used in combination with a second therapeutic agent, the dose of each compound may differ from that when the compound is used alone.

Claims

1. An inhaled mTOR kinase inhibitor for use in the treatment or prevention of a respiratory RNAvirus infection.

2. The inhaled mTOR kinase inhibitor for use according to claim 1, wherein the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza.

3. The inhaled mTOR kinase inhibitor for use according to claim 2, wherein the the respiratory RNA virus is Human rhinovirus.

4. The inhaled mTOR kinase inhibitor for use according to claim 2, wherein the the respiratory RNA virus is Respiratory syncytial virus (RSV).

5. The inhaled mTOR kinase inhibitor for use according to claim 2, wherein the the respiratory RNA virus is Influenza.

6. The inhaled mTOR kinase inhibitor for use according to any one of claims 1 to 5, wherein the inhaled mTOR kinase inhibitor is selected from the group consisting of l-{6-[(3S)-3- ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4- yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl> lH-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and

(S)-l-(5-(6-(3-ethylmorpholino)-4-((methylsulfonyl)methyl)pyridin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.

7. The inhaled mTOR kinase inhibitor for use according to claim 6, wherein the inhaled mTOR inhibitor is l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2- b]pyridin-5-yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

8. The inhaled mTOR kinase inhibitor for use according to any one of claims 1 to 7, wherein the use is prevention of a respiratory RNA virus in a subject at risk of infection with the respiratory RNA virus.

9. The inhaled mTOR kinase inhibitor for use according to claim 8, wherein the subject is: a close contact of a patient infected with the respiratory RNA virus ; in a high risk category; or a healthcare professional.

10. The inhaled mTOR kinase inhibitor for use according to any one of claims 1 to 7, wherein the use is treating a respiratory RNA virus in a subject infected with the respiratory RNA virus.

11. The inhaled mTOR kinase inhibitor for use according to claim 10, wherein the subject was identified as being infected with the respiratory RNA virus by detection of viral RNA from the respiratory RNA virus from a specimen obtained from the subject.

12. The inhaled mTOR kinase inhibitor for use according to any one of claims 10 to 11, wherein the respiratory RNA virus infection in the subject is associated with pneumonia.

13. The inhaled mTOR kinase inhibitor for use according to any one of claims 10 to 11, wherein the respiratory RNA virus infectionin the subject is associated with acute respiratory distress disorder.

14. The inhaled mTOR kinase inhibitor thereof for use according to any one of claims 10 to 13, wherein the subject infected with the respiratory RNA virus is undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non-invasive ventilation, or receiving oxygen therapy.

15. The inhaled mTOR kinase inhibitor for use according to any one of claims 10 to 14„ wherein the subject infected with the respiratory RNA virus is receiving an additional anti-viral and or antibiotic treatment.

16. The inhaled mTOR kinase inhibitor for use according to claim 15, wherein the subject infected with the respiratory RNA virus is receiving an additional anti-viral agent.

17. The inhaled mTOR kinase inhibitor for use according to claim 16, wherein the additional anti- viral agent is selected from remdesivir, ganciclovir, lopinavir, olsetemivir ritonavir and zanamivir.

18. A method of treatment of a subject having a respiratory RNA virus infection, the method comprising administering a therapeutically effective amount of an inhaled mTOR kinase inhibitor.

19. The method of treatment according to claim 18, wherein the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza,

20. The method of treatment according to claim 19, wherein the respiratory RNA virus is Human rhinovirus.

21. The method of treatment according to claim 19, wherein the respiratory RNA virus is Respiratory syncytial virus (RSV).

22. The method of treatment according to claim 19, wherein the respiratory RNA virus is Influenza.

23. The method according to any one of claims 18 to 21, wherein the inhaled mTOR inhibotor is selected from the group consisting of; l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof;

(S)-l-(5-(4-(3-ethylmorpholino)-6-((isopropylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(4-(3-ethylmorpholino)-6-((propylsulfonyl)methyl)pyrimidin-2-yl)-lH-pyrrolo[3,2- b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; (S)-l-(5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl> lH-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof; and

24. The method according to claim 23, wherein the inhaled mTOR kinase inhibitor is l-{6-[(3S)-

3-ethyl morpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-

4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.

25. The method according to according to any one of claims 18 to 24, wherein the use is prevention of COVID-19 in a subject at risk of infection with the respiratory RNA virus.

26. The method according to claim 25, wherein the subject is: a close contact of a patient infected with the respiratory RNA virus; in a high risk category; or a healthcare professional.

27. The method according to any one of claims 18 to 24, wherein the use is treating the respiratoy RNA virus infection in a subject.

28. The method according to claim 27, wherein the subject was identified as being infected with the respiratory RNA virus by detection of viral RNA from a specimen obtained from the subject.

29. The method according to any one of claims 18 to 24, and 27 to 28, wherein the respiratory RNA virus infectionin the subject is associated with pneumonia.

30. The method according to any one of claims 18 to 24, and 27 to 28, wherein the respiratory RNA virusin the subject is associated with acute respiratory distress disorder.

31. The method according to any one of claims 18 to 24, and 27 to 28, wherein the subject infected with the respiratory RNA virus is undergoing extra-corporeal membrane oxygenation, mechanical ventilation, non-invasive ventilation, or receiving oxygen therapy.

32. The method according to any one of claims 18 to 24, and 27 to 31, wherein the subject infected with the respiratory RNA virusis receiving an additional anti-viral and or antibiotic treatment.

33. The method according to claim 32, wherein the subject infected with the respiratory RNA virus is receiving an additional anti-viral agent.

34. The method according to claim 33, wherein the additional anti-viral agent is selected from remdesivir, ganciclovir, lopinavir, olsetemivir ritonavir and zanamivir.

35. A use of an inhaled mTOR kinase inhibitor in the manufacture of a medicament for the treatment or prevention of a respiratory RNA virus infection.

36. The use accoding to claim 35 wherein the respiratory RNA virus is selected from the group consisting of Human rhinovirus, Respiratory syncytial virus (RSV) and Influenza..

37. The use according to claim 36, wherein the respiratory RNA virus is Human rhinovirus.

38. The use according to claim 36, wherein the respiratory RNA virus is Respiratory syncytial virus (RSV).

39. The use according to claim 36, wherein the respiratory RNA virus is Influenza.

40. The use according to claim 35 to 49, wherein the the inhaled mTOR inhibotor is selected from the group consisting of; l-{6-[(3S)-3-ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5- yl}pyrimidin-4-yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof;

41. The use according to claim 40, wherein the inhaled mTOR kinase inhibitor is l-{6-[(3S)-3- ethylmorpholin-4-yl]-2-{2-[(methylamino)methyl]-lH-pyrrolo[3,2-b]pyridin-5-yl}pyrimidin-4- yl}-N,N-dimethylmethanesulfonamide or a pharmaceutically acceptable salt thereof.