CN-117043166-B - Antiviral heterocyclic compounds

Abstract

The present invention discloses compounds of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, which inhibit Human Respiratory Syncytial Virus (HRSV) or Human Metapneumovirus (HMPV). The invention further relates to pharmaceutical compositions comprising the above compounds for administration to a subject suffering from HRSV or HMPV infection. The invention also relates to methods of treating HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising a compound of the invention.

Inventors

• Adam simaniac
• YU JIANMING
• KEVIN MCGRATH
• LI XIBEN
• Taylor J. Mann
• ROBERT LEON
• JIN RENZHONG
• Ke Rixin
• RUAN LONG

Assignees

• 英安塔制药有限公司

Dates

Publication Date

20260508

Application Date

20220224

Priority Date

20210226

Claims (16)

1. 1. A compound selected from the compounds shown below or pharmaceutically acceptable salts thereof:
2. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
3. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
4. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
5. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
6. 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
7. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
8. 8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
9. 9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
10. 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
11. 11. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
12. 12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 。
13. 13. A compound or a pharmaceutically acceptable salt thereof, which is 。
14. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
15. 15. Use of a compound of any one of claims 1 to 13 in the manufacture of a medicament for treating or preventing RSV infection in a subject in need thereof.
16. 16. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment or prophylaxis of HMPV infection in a subject in need thereof.

Description

Antiviral heterocyclic compounds RELATED APPLICATIONS The application claims the benefits of U.S. provisional application No. 63/154,318 filed on month 26 of 2021, U.S. provisional application No. 63/168,705 filed on month 3 of 2021, U.S. provisional application No. 63/171,895 filed on month 4 of 2021, and U.S. provisional application No. 63/293,339 filed on month 23 of 2021. The entire teachings of the above application are incorporated herein by reference. Technical Field The present invention relates generally to compounds and pharmaceutical compositions useful as inhibitors of Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (HMPV). Background Human Respiratory Syncytial Virus (HRSV) is a negative-sense virus containing a non-segmented single-stranded linear RNA genome. As a pneumovirus (Pneumoviridae) of two serotypes in the genus Paramyxovirus (Paramyxovirus), HRSV contains 10 genes encoding 11 proteins. Nucleocapsid protein (N), RNA polymerase protein (L), phosphoprotein (P) and transcription anti-termination factor (M2-1) together with the RNA genome constitute a Ribonucleoprotein (RNP) complex. Several small molecule compounds have been shown to target RNP complexes. In addition, fusion proteins (F) which are extremely important for the attachment of viruses to hosts have been widely studied. High resolution structures of the F protein have been obtained that interact with inhibitors, while structural studies on the N protein are in an early stage of development. One direct result of HRSV protein research is that F protein, L protein and N protein have become the primary focus of drug development efforts. HRSV is the main cause of acute lower respiratory tract infection (ALRI) in patients of all ages, so the development of HRSV drugs is continuously increasing. In addition to respiratory tract infections, patient populations at high risk during HRSV infections include elderly, immunocompromised, children under two years of age, and patients with Chronic Obstructive Pulmonary Disease (COPD) or Chronic Heart Failure (CHF). HRSV was found to result in 177500 hospitalizations and 14000 deaths in the elderly population in the united states over a period of four years. It is well known that almost all children will be infected with HRSV in the first 3 years after birth, whereas HRSV infection is more severe in premature infants. In fact, HRSV is the most common cause of bronchiolitis and pneumonia in infants less than one year of age in the united states. It is estimated that about 320 tens of thousands of children under 5 years old die from HRSV hospitalization, 66000. HRSV is associated with death and hospitalization of more infants under one year of age than influenza. HRSV infection can also affect healthy individuals, and can even repeatedly infect HRSV over a two month period. Symptoms in healthy individuals resemble colds, however fever, wheezing, shortness of breath and difficulty and cyanosis occur in more severe cases. Currently, the treatment options for HRSV infection are quite limited and no vaccine is available due to unsuccessful attempts to date. Palivizumab (Palivizumab) is a monoclonal antibody that is approved for prophylactic use, but its use is limited due to its high price. Palivizumab is typically only used in high-risk infants, such as premature infants or those with heart/lung disease, but is only 60% effective in reducing hospitalization. Ribavirin (Ribavirin) is approved as an inhalation therapy option, but its efficacy is limited and presents safety concerns associated therewith. Given the consistent seasonality of treatment options and HRSV epidemics, there is a need to develop new therapeutic agents for the treatment of HRSV. Several RSV fusion inhibitors ：WO2010/103306、WO 2012/068622、WO 2013/096681、WO 2014/060411、WO 2013/186995、WO 2013/186334、WO 2013/186332、WO 2012080451、WO 2012/080450、WO 2012/080449、WO 2012/080447、WO 2012/080446、WO 2015/110446、WO 2017/009316、J.Med.Chem.2015,58,1630-1643、Bioorg.Med.Chem.Lett.,2015,25,976-981 and nat.Commun.,2017,8,167 have been disclosed in the following publications. Examples of other N protein inhibitors for the treatment of HRSV have been disclosed in WO 2004/026843, j.med.chem.2006,49,2311-2319 and j.med.chem.2007,50,1685-1692. Examples of L protein inhibitors of HRSV have been disclosed in WO 2011/005842, WO 2005/042530, anti-viral Res.2005,65,125-131 and Bioorg.Med.chem.Lett.2013,23,6789-6793. Examples of nucleoside/polymerase inhibitors have been disclosed in WO 2011/005842, WO 2013/242525, WO 2014/031784, WO 2015/026792, WO 2016/0055791, WO 2016/138158 and J.Med.chem.2015,58,1862-1878. Similarly, human Metapneumovirus (HMPV), a negative-sense single-stranded RNA enveloped virus, belongs to the genus Metapneumovirus (Metapneumovirus) of the family pneumoviridae (Pneumoviridae), and was found by van Den Hoogen in 2001 to be a common cause of acute lower respiratory tract infection (ALTRI). Although usually mild, the virus m