nucleosides, nucleotides and the like substituted

专利摘要:
The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof: (I)where the variables in Formula (I) are described in the present invention. Methods of synthesizing such compounds and methods of using them in the treatment of diseases and / or conditions such as viral infections by Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae are also described.
公开号:BR112020005177A2
申请号:R112020005177-2
申请日:2018-09-18
公开日:2020-09-15
发明作者:Leonid Beigelman；Jerome Deval；Marija Prhavc
申请人:Janssen Biopharma, Inc.；
IPC主号:

专利说明:

[0001] [0001] Any and all requests for which a claim of foreign and domestic priority is identified, for example, in the Order Data Request or Sheet as filed with this request, is incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.
[0002] [0002] The present application refers to the fields of chemistry, biochemistry and medicine. More particularly, the present invention relates to nucleotide analogs, pharmaceutical compositions that include one or more nucleotide analogs and methods of synthesizing them. Also described here are methods of treating viral diseases and / or conditions with a nucleotide analog, either alone or in combination therapy with one or more other agents. description
[0003] [0003] Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo and, therefore, have been the subject of widely distributed research for the treatment of viral infections. Analogous nucleosides are generally therapeutically inactive compounds that are converted by host or viral enzymes into their respective active antimetabolites, which, in turn, can inhibit polymerases involved in viral or cell proliferation. Activation occurs through a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.
[0004] [0004] The challenge of developing new antiviral compounds is complicated due to the large number of different viruses and the diversity of their characteristics. Under the hierarchical system of virus classification, viruses are grouped by their shared properties according to four main characteristics: (1) nucleic acid (DNA or RNA); (2) capsid symmetry (icosahedral, helical or complex); (3) naked or enveloped; and (4) genome architecture (positive or negative sense, and single or double strand). Under the Baltimore classification, viruses are grouped both according to their genome structure and the replication method: Group 1 (double-stranded DNA virus); Group II: (single-stranded DNA virus); Group III (double-stranded RNA virus); Group IV (single-stranded positive sense RNA virus); Group V (single-stranded negative sense RNA virus); Group VI (single-stranded positive sense RNA virus that replicates via a DNA intermediary); and Group VII (double-stranded DNA virus virus that replicates via a single-stranded RNA intermediate). Within the recognized groups, there are more than 100 recognized virus families, some of which are also classified into eight different orders (Bunyavirales, Caudovirales, Herpesvirales, Ligamenvirales, Mononegavirales, Nidovirales, Picornavirales and Tymo-virales). In general, due to the differences between these recognized families, there is no expectation that an antiviral compound that is active against a virus that is classified in any specific family will also be active against viruses that are classified in one or more den - among other families. For example, viruses within the Picoraviridae, Flaviviridae, Filoviridae, Pneumoviridae and Coronaviridae families have several characteristics that make it very challenging to develop an antiviral that is active against viruses in two or more of the families.
[0005] [0005] Viruses within the Picornaviridae family are spherical, single-stranded, positive-stranded RNA viruses, not enveloped with an icosahedral capsid. They are group IV viruses under the Baltimore classification, in the order Picornavirales. Picornavirus genomes are approximately 7 to 8 kilobases in length and have an IRES ("Internal Ribosomal Entry Site"). These viruses are polyadenylated at the 3 'end, and have a VPg protein at the 5' end in place of a cap. Genres within the Picornaviridae family include Aphthovirus, Aquamavirus, Avi- hepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Rhinovirus, Software, Sapelovirus, Senecavirus, Senecavirus, Virus and Virus.
[0006] [0006] Enteroviruses are transmitted via the fecal-oral route and / or through aerosols of respiratory droplets, and are highly contagious. The enterovirus genus includes several species, including: entovirus A, enterovirus B, enterovirus C, enterovirus D, enterovirus E, enterovirus F, enterovirus G, enterovirus J, rhinovirus A, rhinovirus B and rhinovirus C. Inside a type of enterovirus previously mentioned are the following serotypes: poliovirus, rhinovirus, Coxsackie virus, ecovirus and enterovirus.
[0007] [0007] Rhinoviruses are the cause of the common cold. Rhinoviruses are so called because of their transmission through the respiratory tract and their replication in the nose. A person can become infected with numerous rhinoviruses throughout his life because immunity develops for each serotype. In this way, each serotype can cause a new infection.
[0008] [0008] Hepatitis A infection is the result of an infection with a hepatitis A virus. Hepatovirus is transmitted via the fecal-oral route. Transmission can occur from person to person through the management of contaminated food or water, or through direct contact with an infectious person.
[0009] [0009] Parecoviruses include human parecovirus 1 (ecovirus 22),
[0010] [0010] Viruses with the Flaviviridae family are spherical, single-stranded, positive-stranded RNA viruses, enveloped with an icosahedral-shaped capsid. They are group IV viruses under the Baltimore classification, and have not been assigned to an order. These viruses are polyadenylated at the 5 'end but do not have a 3' polyadenylate tail. Genera within the family Flaviviridae include: flaviviruses, pestiviruses and hepaciviruses. Flaviviridae viruses are predominantly carried by arthropods, and are often transmitted through mosquitoes and ticks. Effects / symptoms of a viral infection by Pi-cornaviridae depend on the species of virus, and may include, but are not limited to, fever, blisters, rash, meningitis, conjunctivitis, acute hemorrhagic conjunctivitis (AHC), sore throat, congestion nasal, runny nose, sneezing, cough, loss of appetite, painful muscle sensations, headache, fatigue, nausea, jaundice, encephalitis, herpangine, myocarditis, pericarditis, meningitis, Bernholm disease, myalgia, congestion nasal, muscle weakness, loss of appetite, fever, vomiting, abdominal pain, abdominal discomfort, dark urine and muscle pain.
[0011] [0011] Hepaciviruses include hepatitis C virus (HCV). There are several non-structural HCV proteins, such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in HCV RNA replication. Flaviviruses include several encephalitis viruses (for example, Japanese encephalitis virus (JEV), St. Louis encephalitis virus (SLEV) and tick-borne encephalitis virus (TBEV)), dengue virus 1 to 4 ( DENV), West Nile virus (WNV), yellow fever virus (YFV), and Zika virus (ZIKV). West Nile virus infection can result in West Nile fever or severe West Nile disease (also called West Nile meningitis or encephalitis or West Nile polio). Symptoms of West Nile fever include fever, headache, tiredness, body aches, nausea, vomiting, a rash (on the body's trunk) and swollen lymph nodes. Symptoms of West Nile disease include headache, high fever, stiff neck, stupor, disorientation, coma, tremors, convulsions, muscle weakness and paralysis. Current treatment for West Nile virus infection is supportive, and vaccination is not available for humans.
[0012] [0012] According to the World Health Organization (WHO), the global incidence of dengue has grown dramatically in recent decades. So far, there is no treatment for a dengue virus infection. In addition, recovery from infection by a dengue virus serotype provides only partial and temporary immunity against the other serotypes. Subsequent infections with other serotypes increase the likelihood of developing severe dengue fever (formerly known as hemorrhagic dengue fever). Dengue virus infection is presumed to be a high fever (approximately 104 ° F) accompanied by one or more of the following symptoms: severe headache, pain behind the eyes, muscle and joint pain, nausea, vomiting , swollen lymph nodes and skin rash.
[0013] [0013] Yellow fever is an acute viral hemorrhagic disease. As provided by WHO, up to 50% of people seriously affected without treatment die of yellow fever. Worldwide, an estimated 200,000 yellow fever cases occur each year, causing 30,000 deaths. As with other flaviviruses, there is no specific cure or treatment for yellow fever, and treatments with ribavirin and interferons are insufficient. Symptoms of a yellow fever infection include fever, muscle pain with noticeable back pain, headache, chills, loss of appetite, nausea, vomiting, jaundice and bleeding (for example from the mouth, nose, eyes and / or stomach) ). Viruses within the pestivirus genus include the bovine viral diarrhea virus 1, the bovine viral diarrhea virus 2 and the classical swine fever virus. Viral encephalitis causes inflammation of the brain and / or meninges. Symptoms include high fever, headache, sensitivity to light, stiff neck and dorsal stiffness, vomiting, confusion, seizures, paralysis and coma. There is no specific treatment for an encephalitis infection, such as Japanese encephalitis, St. Louis encephalitis and tick-borne encephalitis. According to the Centers for Disease Control, the Zika virus is predominantly spread by the body of an infected Aedes mosquito (Ae. Aegypti and Ae. Al- pictus) and can be passed from a pregnant woman to the her fetus. Infection during pregnancy can cause certain birth defects. Many people infected with the Zika virus will have no symptoms or only mild symptoms. The most common symptoms of Zika are fever, rash, joint pain and conjunctivitis. Zika infection is usually mild with symptoms that last several days to a week. People in general are not sick enough to go to the hospital, and they very rarely die from Zika. For this reason, many people may not realize that they have been infected. Zika's symptoms are similar to the other viruses spread through mosquito bites, such as dengue and chicungunha.
[0014] [0014] Viruses of the Filoviridae family are linear, single-stranded, negative-stranded RNA viruses, enveloped. They are group V viruses under the Baltimore classification, in the order Mononegavirales. Three genera within the Filoviridae family are ebolaviruses, Marburgviruses and "Cuevaviruses" (experimental). The five recognized species of Ebolavirus are Ebola virus (EBOV), Reston Ebolavirus (REBOV), Sudan Ebola virus (SEBOV), Taї Forest Ebolavirus (TAFV) and Bundibugyo Ebolavirus (BEBOV). The two recognized species of Burgundirus are Marburg virus (MARV) and Ravn virus (RAVV). Ebolaviruses and Marburgviruses are highly infectious and contagious. Both viruses are transmitted by direct contact with the blood, body fluids and / or tissues of infected people. Ebolaviruses and Marburgviruses can also be transmitted by handling infected or dead infected wild animals. Ebola hemorrhagic fever (EHF) is caused by an ebolavirus infection. Marburg virus disease (MVD) is a human disease caused by a Marburg virus, and causes hemorrhagic fever by Marburg virus (MHF). Ebolaviruses and Marburgviruses cause viral hemorrhagic fever in several primates, including humans.
[0015] [0015] Pneumoviridae is a relatively new virus family that was created by the elevation of the paramixoviral subfamily Pneumovirinae. Viruses in the Pneumoviridae family are single-stranded, negative-stranded RNA viruses. They are group V viruses under the Baltimore classification, in the order Mononegavirales. The two genera within the Pneumo-viridae family are Metapneumovirus and Ortopneumovirus. The two recognized species of Metapneumovirus are avian metapneumovirus (AMPV) and human metapneumovirus (HMPV). The three recognized species of Ortopneumovirus are bovine respiratory syncytial virus (BRSV), human respiratory syncytial virus (HRSV, including HRSV-A2, HRSV-B1 and HRSV-S2) and murine pneumonia virus (MPV) . Viruses in the Pneumo-viridae family are typically transmitted through respiratory secretions and are often associated with respiratory infections.
[0016] [0016] Coronaviridae viruses are a family of spherical RNA viruses, single-stranded, positive-stranded, enveloped. They are group IV viruses under the Baltimore classification, in the order Nidovirales. Coronaviruses are named after the crown-like spicules on their surface. The Coronaviridae family includes two subfamilies, Corovavirus and Torovirus. The genus Coronavirus has a helical nucleocapsid, and the genus Torovirus has a tubular nucleocapsid. Within the Coronavirus subfamily are the following genera: Alfacoronavirus, Beacoronavirus, Gamacoronavirus and Deltacoronavirus. The genera within the Torovirus subfamily are Bafinivirus and Torovirus.
[0017] [0017] Human coronaviruses in general cause mild to moderate diseases of the upper respiratory tract, such as the common cold, that last for a short time (although some coronaviruses can be deadly). Symptoms can include runny nose, cough, sore throat and fever. These viruses can sometimes cause diseases of the lower respiratory tract, such as pneumonia. This is more common in people with cardiopulmonary disease or compromised immune systems, or in the elderly.
[0018] [0018] The Middle Eastern respiratory syndrome coronavirus (MERS-CoV) is a member of the genus Betacoronavirus, and causes Middle East Respiratory Syndrome (MERS). MERS is an acute respiratory disease. About half of the individuals confirmed as infected with MERS, died. Currently, there is no treatment or vaccine for MERS.
[0019] [0019] Another member of the Betacoronavirus genus is the SARS coronavirus (SARS-CoV). SARS-Co-V is the virus that causes severe acute respiratory syndrome (SARS). SARS was first reported in Asia in February 2003. SARS is an airborne virus, and can spread by inhaling small droplets of water that infected individuals release into the air (for example, through coughing and / or - pimple), by touching a contaminated surface and / or by being in close proximity to an infected individual (for example, in the care or living with a person known to have SARS or having a high probability of direct contact with secretions piratory and / or bodily fluids of a patient known to have SARS, including kissing or hugging, sharing utensils to eat or drink, close conversation (3 feet away), physical examination, and any other direct physical contact between people).
[0020] [0020] The two genera within the Togaviridae family are Alfavrus and Rubivirus. Viruses within this family are linear, single-stranded, positive-sense, enveloped RNA viruses. So far, Rubivirus has only one species, the rubella virus. Viruses classified in the Alpha-virus genus include Venezuelan equine encephalitis (VEE) viruses. VEE viruses are predominantly transmitted by mosquitoes and cause Venezuelan equine encephalitis and encephalitis. The VEE complex of viruses includes six antigenic subtypes (I to VI) divided by antigenic variants. Additionally, VEE viruses are divided into two groups, epizootic (or epidemic) and enzootic (or endemic). Within subtype I, the Venezuelan equine encephalomyelitis virus (VEEV), is divided into five antigenic variants (variants AB to F). Subtype II is known as the Everglades virus, subtype III as the Mucambo virus, and subtype IV as the Pixuna virus. Equine species, along with humans, can be infected with VEE viruses. Currently, there is no vaccine available for horses or humans.
[0021] [0021] Another member of the Alfavirus genus is the chicungunha virus (CHIKV). The chicungunha virus is a virus carried by arthropods and can be transmitted to humans by mosquitoes (such as Aedes mosquitoes). Currently, there are no specific treatments for chicungunha, and no vaccine is currently available.
[0022] [0022] Other Alfaviruses are Barmah Forest viruses, Mayaro virus (MAYV), O'nyong'nyong virus, Ross River virus (RRV), Semliki Forest virus, Sindbis virus (SINV), Una virus , eastern equine encephalitis virus (EEE) and western equine encephalomyelitis virus (WEE). These alphaviruses are predominantly carried by arthropods, and transmitted through mosquitoes.
[0023] [0023] The lack of expectation that a newly developed nucleoside analog will be panviral, for example, active against two or more viruses that are classified in different viral families, is based, in part, on the observation that activity has been discovered panviral to relatively few nucleoside analogs of the many known nucleoside analogs. Although panviral activity is generally considered desirable, the activity of such compounds against various viruses also increases the likelihood that high off-target effects may also be observed. - served, resulting in potential toxicity concerns that tend to slow clinical development. Thus, there is a long-recognized need for panviral nucleoside analogues, and particularly those with low toxicity. SUMMARY
[0024] [0024] Some embodiments disclosed herein refer to a compound of formula (I), or a pharmaceutically acceptable salt thereof. In various embodiments, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof have panviral activity. Such panviral activity is surprising due to the diversity of viruses against which they are active. For example, in some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, has activity against viruses that are in two or more different viral families. In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, has activity against a virus in two or more of the families Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae.
[0025] [0025] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has low toxicity. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is both low in toxicity and panviral, surprisingly showing activity against viruses that are in two or more different viral families despite their low toxicity.
[0026] [0026] Some embodiments disclosed herein refer to a method for attenuating and / or treating a viral infection by Picornaviridae which may include administering to an individual identified as suffering from the viral infection by Picornaviridae, an effective amount of one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof. Other modalities described here refer to the use of one or more compounds of the formula (I), or a pharmaceutically acceptable salt of the same, in the manufacture of a medication for the attenuation and / or treatment of a viral infection by Picornaviridae. Still other embodiments described herein refer to one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition that includes one or more compounds of formula (I), or a pharmaceutical salt. normally acceptable, which can be used to mitigate and / or treat a viral infection by Picornaviridae.
[0027] [0027] Other modalities disclosed herein refer to a method for attenuating and / or treating a viral infection by Picornaviridae, which may include putting a cell infected with the picornavirus in contact with an effective amount of one or more compounds described here (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the attenuation and / or treatment of a viral infection by Picornaviridae which may include putting a cell infected with the picornavirus in contact with an effective amount of the
[0028] [0028] Other modalities disclosed herein refer to a method for attenuating and / or treating a viral infection by Picornaviridae, which may include putting a cell infected with the picornavirus in contact with an effective amount of one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a Picornaviridae virus that can include putting a cell infected with the Picornaviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or to a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, which can be used to inhibit the replication of a Picornaviridae virus by placing a cell infected with the picornavirus in contact with an effective amount of said compound (s). In some modalities, the Picoraviridae virus can be selected from a rhinovirus, hepatitis A virus,
[0029] [0029] Some modalities disclosed herein refer to a method for attenuating and / or treating a viral infection by Flaviviridae which may include administering to an individual identified as suffering from viral infection by Flaviviridae, an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof. Other modalities disclosed herein refer to a method of attenuation and / or treatment of a viral infection by Flaviviridae, which may include putting a cell infected with the Flaviviridae virus in contact with an effective amount of one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein refer to the use of one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the attenuation and / or treatment of a viral infection by Flaviviridae. However, yet other embodiments described herein refer to one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition that includes one or more compounds of the formula (I ), or a pharmaceutically acceptable salt thereof, which can be used to attenuate and / or treat a viral infection by Flaviviridae. Other modalities disclosed herein refer to a method for attenuating and / or treating a viral infection by Flaviviridae, which may include putting a cell infected with Flaviviridae in contact with an effective amount of one or more compounds described here (for example , a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a Flaviviridae virus. Still other embodiments described herein refer to one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or to a pharmaceutical composition that includes one or more compounds described herein. , or a pharmaceutically acceptable salt thereof, which can be used to inhibit the replication of a Flaviviridae virus. In some modalities, the Flaviviridae virus can be selected from the hepatitis C virus (HCV), the dengue virus and the Zika virus.
[0030] [0030] Some modalities disclosed herein refer to a method of attenuation and / or treatment of a viral infection by Filoviridae which may include administering to an individual identified as suffering from viral infection by Filoviridae an effective amount of one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof. Other modalities disclosed herein refer to a method of attenuating and / or treating a viral infection by Filoviridae which may include putting a cell infected with the Filoviridae virus in contact with an effective amount of one or more compounds described here ( for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other modalities described herein refer to the use of one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medication to attenuate and / or treat a viral infection by Filoviridae. However, yet other embodiments described herein refer to one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition that includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, which can be used to attenuate and / or treat a viral infection by Filoviridae. Some of the modalities disclosed herein refer to a method of inhibiting the replication of a Filoviridae virus which may include putting a cell infected with the Filoviridae virus in contact with an effective amount of one or more compounds described herein (for example, a compound from the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other modes described herein refer to the use of one or more compounds described herein (for example a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a virus Filoviridae. Still other modalities described herein refer to one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or to a pharmaceutical composition that includes one or more more compounds described herein, or a pharmaceutically acceptable salt thereof, which can be used to inhibit the replication of a Filoviridae virus. In some embodiments, the Filoviridae virus can be an ebolavirus or a Marburgvirus.
[0031] [0031] Some modalities disclosed herein refer to a method of attenuation and / or treatment of a Pneumoviridae viral infection that may include administering to an individual identified as suffering from Pneumoviridae viral infection an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition that includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof.
[0032] [0032] Some modalities disclosed herein refer to a method of attenuation and / or treatment of a viral infection by Coronaviridae which may include administering to an individual identified as suffering from viral infection by Coronaviridae an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition which includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof. Other modalities disclosed herein refer to a method of attenuating and / or treating a viral infection by Corovaviridae which may include putting a cell infected with the Coronaviridae virus in contact with an effective amount of one or more compounds here described (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other modalities described herein refer to the use of one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medication for the attenuation and / or treatment of a viral infection by Corovaviridae . However, yet other embodiments described herein refer to one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition that includes one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, which can be used to attenuate and / or treat a viral infection by Coronaviridae. Some modalities disclosed herein refer to a method of inhibiting the replication of a Coronaviridae virus which may include putting a cell infected with the Coronaviridae virus in contact with an effective amount of one or more compounds described here (for example, a compound from the formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of one or more compounds described herein (for example a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a Coronaviridae virus. Still other embodiments described herein refer to one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), or to a pharmaceutical composition that includes one or more compounds described herein. , or a pharmaceutically acceptable salt thereof, which can be used to inhibit the replication of a Coronaviridae virus. In some embodiments, the Coronaviridae virus can be a viral infection by human α-coronavirus or a viral infection by human β-coronavirus.
[0033] [0033] These and other modalities are described in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] [0034] Figure 1 illustrates a reaction scheme to produce compound 1.
[0035] [0035] Figure 2 illustrates a reaction scheme to produce compound 2.
[0036] [0036] Figure 3 illustrates a reaction scheme to produce compound 3.
[0037] [0037] Figure 4 illustrates a reaction scheme to produce compound 4.
[0038] [0038] Figure 5 illustrates a reaction scheme to produce compound 5.
[0039] [0039] Figure 6 illustrates a reaction scheme to produce compound 6.
[0040] [0040] Figure 7 illustrates a reaction scheme to produce compound 7.
[0041] [0041] Figure 8 illustrates a reaction scheme to produce compound 8.
[0042] [0042] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning, as is commonly understood by the person skilled in the art. All Patents, Orders, Published Orders and other publications mentioned herein are incorporated by reference in their entirety, unless otherwise stated. In the event that there is a plurality of definitions for a term in this document, those in the session prevail, unless stated otherwise.
[0043] [0043] As used here, any "R" groups such as, but not limited to, RA, R1A, R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, R10A, R11A, R12A, R13A , R14A, R15A, R16A, R17A, R18A, R19A, R20A, R21A, R22A, R23A, R24A, R25A, R26A, R27A, R28A, R29A, R30A, R31A, Ra1 and Ra2 represent substituents that can be attached to the indicated atom. A group R can be substituted or unsubstituted. If two "R" groups are described as being "considered together", the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Ra and Rb from an NRa Rb group are indicated to be "considered together," this means that they are covalently linked to one another to form a ring: Ra
[0044] [0044] Whenever a group is described as being "optionally substituted", this group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted", if substituted, the substituent (s) can be selected from one or more of the indicated substituents. If no substituent is indicated, it is understood that the indicated "optionally substituted" or "substituted" group may be replaced by one or more group (s) selected individually and independently from alkyl, alkyl nila, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), heterocyclyl (alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O -tiocarba- mila, N-thiocarbamyl, C-starch, N-starch, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl , haloalkoxy, sulfonyl trihalomethane, sulfonamido trihalomethane, an amino, a monosubstituted amino group and a disubstituted amino group.
[0045] [0045] As used here, "Ca to Cb" where "a" and "b" are whole numbers, refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group.
[0046] [0046] As used here, an asterisk ("*"), used with respect to a chemical group, indicates a point of attachment. For example, the asterisk in the chemical group "* - (CR15AR16A) p – O – alkyl-C1-24" indicates the point of attachment for that chemical group to another group or another molecule.
[0047] [0047] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain comprising a fully saturated hydrocarbon group (without double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (whenever it appears here, a numerical range like "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numeric range is assigned). The alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds can be referred to as "C1-C4 alkyl" or similar designations. As an example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group can be substituted or not substituted.
[0048] [0048] As used herein, "alkenyl" refers to an alkyl group that contains in the linear or branched hydrocarbon chain one or more double bonds. An alkenyl group can be unsubstituted or substituted.
[0049] [0049] As used herein, "alkynyl" refers to an alkyl group that contains in the linear or branched hydrocarbon chain one or more triple bonds. An alkynyl group can be unsubstituted or substituted.
[0050] [0050] As used here, "cycloalkyl" refers to a completely saturated hydrocarbon ring system (without double or triple bonds) monocyclic or multicyclic. When composed of two or more rings, the rings can be joined together in a fused way. Cycloalkyl groups can contain 3 to 10 ring atoms (rings) or 3 to 8 ring (s) atoms (rings). A cycloalkyl group can be unsubstituted or replaced. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0051] [0051] As used here, "cycloalkenyl" refers to a mono- or multicyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a pi-electron system completely displaced by all rings (otherwise, the group would be "aryl," as defined here). When composed of two or more rings, the rings can be connected together in a fused way.
[0052] [0052] As used here, "aryl" refers to a monocyclic or multicyclic carbocyclic (all-carbon) aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) pi-electron system completely relocated by all rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group can be substituted or unsubstituted.
[0053] [0053] As used here, "heteroaryl" refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with a completely delocalized pi-electron system) that contains one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element in addition to carbon, including, but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring (s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 ring atoms (rings), 5 to 10 ring (s) atoms or 5 to 6 ring (s) atoms. In addition, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophen, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2 , 3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, ben-
[0054] [0054] As used here, "heterocyclyl" or "heteroalicyclic" refers to a monocyclic, bicyclic and tricyclic ring system of three, four, five, six, seven, eight, nine, ten, up to 18 members , and the carbon atoms together with 1 to 5 hetero atoms constitute the said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a completely delocalized pi-electron system does not occur across all rings. The heteroatom (s) is / are a different element than carbon, including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle can also contain one or more carbonyl or thiocarbonyl functionalities so that the definition includes oxo systems and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings can be joined together in a fused way. In addition, any nitrogens in a heteroalicyclic can be quaternized. Heterocyclyl or heteroalicyclic groups can be unsubstituted or substituted. Examples of these "heterocyclyl" or "heteroalicyclyl" groups include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1 , 4-dioxolane, 1,3-oxatian, 1,4-oxatin, 1,3-oxathiolan, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiazine , 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline , isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxiran, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidine, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, 2-oxopyrrolidine, 2-oxopyrrolidine
[0055] [0055] As used here, "arylalkyl" and "aryl (alkyl)" refer to a connected aryl group, as a substituent, through a lower alkylene group. The alkylene and lower aryl group of an aryl (alkyl) can be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenyl (alkyl), 3-phenyl (alkyl) and naphthyl (alkyl).
[0056] [0056] As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group connected, as a substituent, through a lower alkylene group. The lower alkylene group and the heteroaryl group of a heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl (alkyl), 3-tienyl (alkyl), furyl (alkyl), thienyl (alkyl), pyrrolyl (alkyl), pyridyl (alkyl), isoxazolyl (alkyl) , imidazolyl (alkyl), and its benzofused analogs.
[0057] [0057] An "(heteroalicyclyl) alkyl" and a "(heterocyclyl) alkyl" refer to a heterocycle or heteroalicyclic group connected, as a substituent, through a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl (alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H- thiopiran-4-yl (methyl) and 1,3-thiazinan-4-yl (methyl).
[0058] [0058] The "lower alkylene groups" are anchoring groups, - CH2-, of linear chain, which form bonds to connect the molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by substituting one or more hydrogen or deuteriums of the lower alkylene group with substituents listed under the definition of "substituted".
[0059] [0059] As used here, "alkoxy" refers to the formula -OR in which R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) al - kyl or (heterocyclyl) alkyl and is defined in the present invention. A non-limiting list of alkoxys includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, ter-butoxy, phenoxy and benzoxy. An alkoxy can be substituted or unsubstituted.
[0060] [0060] As used here, "acyl" refers to a connected hydrogen, alkyl, alkenyl, alkynyl or aryl, as substituents, through a carbonyl group. Examples include formyl, acetyl, propanil, benzoyl and acryl. An acyl can be substituted or unsubstituted.
[0061] [0061] As used here, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen or deuterium atoms are replaced by a hydroxy group. Exemplifying hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl can be substituted or not substituted.
[0062] [0062] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen or deuterium atoms are replaced by a halogen (for example, monohaloalkyl, dihaloalkyl and trihaloalkyl ). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl can be substituted or unsubstituted.
[0063] [0063] As used herein, "haloalkoxy" refers to a group - O-alkyl in which one or more of the hydrogen or deuterium atoms are replaced by a halogen (for example, monohaloalkoxy, dihaloalkoxy and trihaloalkoxy). These groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy can be replaced or not replaced.
[0064] [0064] A "sulfenyl" group refers to a "-SR" group in which R can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl) or (heterocyclyl) alkyl. A sulfenyl can be substituted or unsubstituted.
[0065] [0065] A "sulfinyl" group refers to a "-S (= O) -R" group in which R can be the same as that defined with respect to sulfenyl. A sulfinyl can be substituted or unsubstituted.
[0066] [0066] A "sulfonyl" group refers to a "SO2R" group in which R can be the same as that defined with respect to sulfenyl. A sulfonyl can be substituted or unsubstituted.
[0067] [0067] An "O-carboxy" group refers to an "RC (= O) O-" group in which R can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl , aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl, as defined herein. An O-carboxy can be replaced or not replaced.
[0068] [0068] The terms "ester" and "C-carboxy" refer to a group "- C (= O) OR" in which R can be equal to that defined with respect to O-carboxy. An ester and a C-carboxy can be substituted or unsubstituted.
[0069] [0069] A "thiocarbonyl" group refers to a "-C (= S) R" group in which R can be the same as that defined with respect to O-carboxy. A thiocarbonyl can be replaced or not replaced.
[0070] [0070] A "trihalomethanesulfonyl" group refers to a "X3CSO2-" group, each X being a halogen.
[0071] [0071] A "trihalomethanesulfonamido" group refers to a "X3CS (O) 2N (RA) -" group in which each X is a halogen, and RA is hydrogen, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl.
[0072] [0072] The term "amino", as used here, refers to a group - NH2.
[0073] [0073] As used here, the term "hydroxy" refers to a group - OH.
[0074] [0074] A "cyan" group refers to a "-CN" group.
[0075] [0075] The term "azido", as used here, refers to a group - N3.
[0076] [0076] An "isocyanate" group refers to an "-NCO" group.
[0077] [0077] A "thiocyanate" group refers to a "-CNS" group.
[0078] [0078] An "isothiocyanate" group refers to an "-NCS" group.
[0079] [0079] A "mercapto" group refers to a "-SH" group.
[0080] [0080] A "carbonyl" group refers to a C = O group.
[0081] [0081] An "S-sulfonamido" group refers to a "- SO2N (RARB)" group in which RA and RB can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or (heterocyclyl) alkyl. An S-sulfonamido can be substituted or unsubstituted.
[0082] [0082] An "N-sulfonamido" group refers to an "RSO2N (RA) -" group in which R and RA can independently be hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl. An N-sulfonamido can be substituted or unsubstituted.
[0083] [0083] An "O-carbamyl" group refers to a "- OC (= O) N (RARB)" group in which RA and RB can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl. An O-carbamyl can be replaced or not replaced.
[0084] [0084] A "N-carbamyl" group refers to a "ROC (= O) N (RA) -" group in which R and RA can be independently hydrogen, deuterium,
[0085] [0085] An "O-thiocarbamyl" group refers to an "-OC (= S) - N (RARB)" group in which RA and RB can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl) or (heterocyclyl) alkyl. An O-thiocarbamyl can be substituted or unsubstituted.
[0086] [0086] An "N-thiocarbamyl" group refers to an "ROC (= S) N (RA) -" group in which R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl. An N-thiocarbamyl can be substituted or unsubstituted.
[0087] [0087] A "C-starch" group refers to a "-C (= O) N (RARB)" group in which RA and RB can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl. A C-starch can be substituted or unsubstituted.
[0088] [0088] An "N-starch" group refers to an "RC (= O) N (RA) -" group in which R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, aryl (alkyl), (heteroaryl) alkyl or (heterocyclyl) alkyl. An N-starch can be substituted or unsubstituted.
[0089] [0089] The term "halogen atom" or "halogen" as used here, means either two radioestable atoms in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.
[0090] [0090] If the number of substituents is not specified (for example, haloalkyl), there may be one or more substituents present. For example, "haloalkyl" can include one or more equal or different halogens.
[0091] [0091] As used here, the abbreviations for any protecting groups, amino acids and other compounds, are, except where otherwise indicated, according to their common use, recognized abbreviations, or according to the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 11: 942-944 (1972)).
[0092] [0092] The term "nucleoside" is used here in its common sense, as understood by those skilled in the art, and refers to a compound formed by an optionally substituted pentose portion or a modified pentose portion attached to a heterocyclic base or tautomer thereof via an N-glycosidic bond, as fixed through position 9 of a purine base or position 1 of a pyrimidine base. Examples include, but are not limited to, a ribonucleoside comprising a ribose portion and a deoxyribonucleoside comprising a deoxyribose portion. A modified pentose portion is a pentose portion in which an oxygen atom has been replaced with a carbon and / or a carbon has been replaced with a sulfur or oxygen atom. A "nucleoside" is a monomer that can have a base and / or a substituted sugar portion. In addition, a nucleoside can be incorporated into larger DNA and / or RNA polymers and oligomers. In some cases, the nucleoside may be a nucleoside analog drug.
[0093] [0093] The term "nucleotide" is used here in its common sense as understood by those skilled in the art and refers to a nucleoside having a phosphate ester attached to the pentose portion, for example, at the 5 'position.
[0094] [0094] As used herein, the term "heterocyclic base" refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose portion or to a modified pentose portion. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine base, an optionally substituted pyrimidine base and an optionally substituted triazole base (for example, a 1,2,4-triazole) . The term "purine base" is used here in its common sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term "pyrimidine base" is used here in its common sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthin, 7-alkylguanine (e.g., 7-methylguanine), theobromine, caffeine, uric acid and isoguanine. Examples of pyridimine bases include, but are not limited to, cytosine, thymine, uracil 5, 6-dihydrouracil and 5-alkylcytosine (for example, 5-methylcytosine). An example of an optionally substituted triazole base is 1,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N6-alkydenin (e.g., 8-oxo-N6-methyladenine), 7-deazaxanthin, 7-deazaguanine, 7-deaza-adenine, N4, N4-ethanocytosine, N6, N6-ethane-2,6-diaminopurine, 5-halouracil (for example, 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, and other heterocyclic bases described in US Patent Nos.
[0095] [0095] The term "N-linked amino acid" refers to an amino acid that is linked to the indicated moiety through a main amino chain or a monosubstituted amino group. When the amino acid is linked to an amino acid –N – linked, one of the hydrogens or deuteriums that is part of the amino group in the main chain or the monosubstituted amino group is not present and the amino acid is linked through nitrogen. N-linked amino acids can be substituted or unsubstituted.
[0096] [0096] The term "derivative of amino acid ester –N – linked" refers to an amino acid in which a carboxylic acid group in the main chain has been converted into an ester group. In some embodiments, the ester group has a formula selected from alkyl-OC (= O) -, cycloalkyl-OC (= O) -, aryl-OC (= O) - and aryl (alkyl) -OC (= O ) -. A non-limiting list of ester groups includes substituted and unsubstituted versions of the following: methyl-OC (= O) -, ethyl-OC (= O) -, n-propyl-OC (= O) -, isopropyl-OC (= O) -, n-butyl-OC (= O) -, isobutyl-OC (= O) -, tert-butyl-O-C (= O) -, neopentyl-OC (= O) -, cyclopropyl- OC (= O) -, cyclobutyl-OC (= O) -, cyclopentyl-OC (= O) -, cyclohexyl-OC (= O) -, phenyl-OC (= O) -, benzyl-O- C (= O) - and naphthyl-OC (= O) -. N-linked amino acid ester derivatives can be substituted or unsubstituted.
[0097] [0097] The term "O-linked amino acid" refers to an amino acid that is linked to the moiety indicated by the hydroxy of its carboxylic acid group in the main chain. When the amino acid is attached to an –O – attached amino acid, the hydrogen or deuterium that is part of the hydroxy of its main chain carboxylic acid group is not present and the amino acid is linked via oxygen. O-linked amino acids can be substituted or unsubstituted.
[0098] [0098] As used herein, the term "amino acid" refers to any amino acid (conventional and unconventional amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ -amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, iso-leucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine .
[0099] [0099] The terms "phosphorothioate" and "phosphotioate" refer to a compound with the general formula, its protonated forms (for example, e) and its tautomers (like).
[0100] [0100] As used here, the term "phosphate" is used in its common sense, as understood by those skilled in the art, and includes its protonated forms (for example, e). As used herein, the terms "monophosphate," "diphosphate," and "triphosphate" are used in their common senses, as understood by those skilled in the art, and include protonated forms.
[0101] [0101] The terms "protecting group" and "protecting groups", as used here, refer to any atom or group of atoms added to a molecule to prevent the groups in the molecule from being subjected to unwanted chemical reactions. Examples of portions of protecting groups are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley &
[0102] [0102] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not negate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrochloric acid (for example, hydrochloric acid or hydrobromic acid), sulfuric acid,
[0103] [0103] The terms and phrases used in this application, and variations thereof, especially in the appended claims, except as expressly stated to the contrary, should be interpreted as not limited, rather than limiting. As examples of any of the above, the term 'including (or including)' should be read in such a way as to mean 'including, without limitation (or including, without limitation)', 'including, but not limited to a "(or including, but not limited to)" or similar; the term "comprising", as used herein, is synonymous with "including", "containing", or "characterized by "and is inclusive or non-limiting and does not exclude additional or unmentioned elements or method steps; the term" that has "should be interpreted as" that has at least "; the term" includes "should be interpreted as" includes, but without limitations "; the term" example "is used to provide exemplary cases of the item under discussion, not an exhaustive or limiting list of it; and the use of terms such as" preferentially "," preferred "," desired "or" desirable " and words of similar meaning should not be understood to imply the fact that certain resources are critical, ess essential, or even important to the structure or function, but instead, as merely intended to highlight alternative or additional features that may or may not be used in a particular modality. In addition, the term "which comprises" must be interpreted synonymously to the phrases "which has at least" or "which includes at least". When used in the context of a process, the term "comprising" means that the process includes at least the steps mentioned, however, it can include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the aforementioned features or components, but can also include additional resources or components. Similarly, a group of items linked to the conjunction "and" should not be read in a way that requires any and all of those items to be present in the grouping, but should instead be read as "and / or" , unless expressly stated otherwise. Similarly, a group of items linked by the conjunction "or" should not be read in such a way as to require mutual exclusivity between that group, but should instead be read as "and / or", except when expressly stated otherwise. mode.
[0104] [0104] Regarding the use of substantially any plural and / or singular terms in the present invention, those skilled in the art may change from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. The various single / plural permutations may be expressly shown in the present invention for reasons of clarity. The indefinite article "one / one" does not exclude a plurality. A single processor or other unit can fulfill the functions of several items mentioned in the claims. The mere fact that certain measures are mentioned in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be interpreted in a way that limits the scope.
[0105] [0105] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center can be independently of R configuration or S configuration or a mixture thereof. Therefore, the compounds provided in this document can be enatiomerically pure, enatiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Furthermore, it is understood that, in any compound described herein that has one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond can be independently E or Z or a mixture thereof .
[0106] [0106] Similarly, it is understood that, in any component described, all tautomeric forms are also intended to be included. For example, all tautomers of a phosphate and a phosphorothioate group are designed to be included. Examples of tautomers of a phosphorothioate include the following:,, e. In addition, all heterocyclic base tautomers known in the art are intended to be included, including natural and unnatural purine base tautomers and pyrimidine bases.
[0107] [0107] It should be understood that when the compounds shown here have unfilled valences, then the valences will be filled, as necessary, with hydrogen (also called protium, hydrogen-1 or 1H) or isotopes of it. A suitable isotope of hydrogen is deuterium (also called hydrogen-2 or H).
[0108] [0108] It should be understood that the compounds described in this document can be identified isotopically. Substitution by isotopes such as deuterium can yield certain therapeutic advantages that result from greater metabolic stability, such as, for example, increased half-life in vivo or reduced dosage requirements. Each chemical element as represented in a compound structure can include any isotope of said element. Accordingly, the reference in the present invention to a compound covers all potential isotopic forms, except when the context clearly dictates otherwise or an isotope is already explicitly specified.
[0109] [0109] It is understood that the compounds, methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystalline packaging arrangements of the same elemental composition of a compound), amorphous phases, salts , solvates and hydrates. In some embodiments, the compounds described herein (including those described in the methods and combinations) exist in solvated forms with pharmaceutically acceptable solvents, such as water, ethanol or the like. In other embodiments, the compounds described herein (including those described in methods and combinations) exist in unsolvated form. Solvates contain both stoichiometric and non-stoichiometric amounts of a solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein may exist in unsolvated forms, as well as in solvated forms.
[0110] [0110] When a range of values is provided, it is understood that the upper and lower limits, and each intermediate value between the upper and lower limits of the range is included in the modalities. Compounds
[0111] [0111] Some embodiments of the present invention relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: (I)
[0112] [0112] In various embodiments of the compounds of formula (I), R1A can be selected from the group consisting of fluorine, cyano, azide, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, a C1-4 alkoxy unsubstituted, unsubstituted C1-4 alkyl and substituted C1-4 alkyl. In some embodiments, the unsubstituted C1-4 alkoxy is methoxy. In some embodiments, unsubstituted C1-4 alkyl is methyl. In several modalities, when R1A is substituted C1-4 alkyl, it is substituted with one or more substituents selected from fluorine and chlorine. For example, in some embodiments R1A may be substituted C1-4 alkyl which is selected from the group consisting of - (CH2) 1-4Cl, - (CH2) 1-4F, and -CHF2. Non-limiting examples of substituted C1-4 alkyl, therefore, include chloromethyl, fluoromethyl and difluoro-methyl.
[0113] [0113] In some embodiments of compounds of formula (I), R1A can be cyan. The following formula (Ia1) is an example of compound modalities of the formula (I) in which the variable R1A is cyan and the variables R2A, R3A, R4A, R5A, Ra1 and Ra2 are as described elsewhere here.
[0114] [0114] In various modalities of compounds of formula (I), R4A is selected from the group consisting of fluorine, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy substituted, unsubstituted C1-4 alkyl and substituted C1-4 alkyl, said substituted C1-4 alkyl being substituted with one or more substituents selected from fluorine and chlorine. In some modes, R4A is selected from the group consisting of fluorine, cyan, azide and an unsubstituted C1-4 alkyl. In some modalities, R4A is selected from the group consisting of fluorine, cyan, azido and C1-4 alkyl substituted with one or more substituents selected from fluorine and chlorine. In one embodiment, R 4A is fluorine. In another embodiment, R 4A is cyan. In another embodiment, R 4A is azido. In another mode, R4A is unsubstituted C1-4 alkyl. For example, in one mode, R4A is methyl. In several modalities, when R4A is a substituted C1-4 alkyl, it is substituted with one or more substituents selected from fluorine and chlorine. For example, in some modalities, R4A may be substituted C1-4 alkyl which is selected from the group consisting of - (CH2) 1-4Cl, - (CH2) 1-4F and -CHF2. Non-limiting examples of substituted C1-4 alkyl therefore include chloromethyl, fluoromethyl and difluoromethyl. Thus, in one embodiment, the substituted C1-4 alkyl is chloromethyl. In another embodiment, the substituted C 1-4 alkyl is fluoromethyl.
[0115] [0115] In various modalities, the variables R2A and R3A of formula (I) are each independently hydrogen or deuterium. In one embodiment, both R2A and R3A are hydrogen. In one embodiment, both R2A and R3A are deuterium. In one embodiment, one of R2A and R3A is hydrogen and the other is deuterium.
[0116] [0116] In various modalities, the variables Ra1 and Ra2 of formula (I) are each independently hydrogen or deuterium. In one embodiment, both R a1 and R a2 are hydrogen. In one embodiment, both R a1 and R a2 are deuterium. In one embodiment, one of Ra1 and Ra2 is hydrogen and the other is deuterium.
[0117] [0117] In some embodiments of compounds of the formula (I), R1A is selected from the group consisting of fluorine, cyano, azido, an unsubstituted C2-4 alkynyl, an unsubstituted C2-4 alkynyl, a C1- alkoxy 4 unsubstituted, unsubstituted C1-4 alkyl, and substituted C1-4 alkyl, and R4A is selected from the group consisting of fluorine, cyano, azido, unsubstituted C2-4 alkenyl, unsubstituted C2-4 alkynyl - substituted, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl, said substituted C1-4 alkyl being substituted with one or more substituents selected from fluorine and chlorine. For example, in some embodiments, R1A is cyan, and R4A is selected from the group consisting of fluorine, cyan, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, chloromethyl, fluoromethyl and difluoromethyl. In some embodiments, R1A is cyan and R4A is fluorine. In some embodiments, R1A is cyan and R4A fluoromethyl. In some embodiments, R1A is cyan and R4A is chloromethyl. In some modes, R1A is cyan and R4A is azido. In some modalities, both
[0118] [0118] In several modalities, the variable R5A of formula (I) is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, Z1A Z2A Z3A R6AO P R8AO P R10A P OR7A, R9A and R11A. R6A, R7A and R8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, a C3-6 cycloalkyl optionally substituted, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl (C1-6 alkyl), a * - (CR15AR16A) p– O – C1- alkyl 24 optionally substituted, an * - (CR17AR18A) q – O – alkenyl-C1-24 optionally substituted,,,, and.
[0119] [0119] In other modalities, R6A can be
[0120] [0120] In some embodiments, R9A can be independently selected from an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkenyl, an optionally substituted C3-6 alkenyl, a optionally substituted C3-6 cycloalkenyl, NR30AR31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester. The amino acid portion (of the optionally substituted N-linked amino acid and the optionally substituted N-linked amino acid ester) can have various stereochemical configurations. For example, the amino acid moiety can be racemic, a L stereoisomer, a D stereoisomer or a mixture of L and D stereoisomers that is enriched in one or the other of the stereoisomers. In one embodiment, the L stereoisomer content of the amino acid portion is at least about 90%,
[0121] [0121] In some embodiments, R10A and R11A may, independently, be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester; R12A, R13A and R14A may, independently, be absent or be hydrogen; each R15A, each R16A, each R17A and each R18A can be independently hydrogen, an optionally substituted C1-24 alkyl or alkoxy; R19A, R20A, R22A and R23A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R21A and R24A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted –O – C1-24 alkyl, an optionally substituted –O – aryl, an –O– optionally substituted heteroaryl, an optionally substituted monocyclic –O – heterocyclyl and; R25A and R29A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R26A and R27A can be, independently, -C≡N or an optionally substituted substituent selected from C2-8-carbonyl organyl, C2-8-carbonyl alkoxy and C2-8-aminocarbonyl organyl; R28A can be selected from hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally C3-6 cycloalkenyl replaced; R30A and R31A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkylene; R "A can be optionally substituted C1-24 alkyl; met can be independently 0 or 1; p and q can be independently selected from 1, 2 and 3; r can be 1 or 2; s can be 0 , 1, 2 or 3; u can be 1 or 2; and Z1A, Z2A, Z3A and Z4A can each be independently O or S.
[0122] [0122] In some embodiments, R5A can be Z1A R6AO P OR7A.
[0123] [0123] In some embodiments, when R5A is Z1A R6AO P OR7A, one of R6A and R7A can be hydrogen, and the other of R6A and R7A can be selected from an optionally substituted C1-24 alkyl, a C3-24 alkenyl optionally substituted, optionally substituted C3-24 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heteroaryl (C1-6 alkyl) replaced. In some modalities, one of R6A and R7A may be hydrogen and the other of R6A and R7A may be optionally substituted C1-24 alkyl. In other modes, both R6A and R7A can be independently selected from an optionally substituted C1-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, an optionally substituted C3-6 cycloalkyl , an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl (C1-6 alkyl). In some embodiments, both R6A and R7A may be optionally substituted C1-24 alkyl. In other modalities, both R6A and R7A may be an optionally substituted C3-24 alkenyl. In some modalities, R6A and R7A can be, independently, an optionally substituted version of the following: myristoleyl, myristyl, palmitoleyl, palmitile, sapienyl, oleyl, elaidyl, vacenilla, linoleyl, α-linolenyl, arachidonyl, eicosapentaenila, erucila, docosa -hexaenila, caprilila, caprila, laurila, stearila, araquidila, beenila, lignocerila and cerotila.
[0124] [0124] In some modalities, at least one of R6A and R7A can be * - (CR15AR16A) p – O – C1-24-alkyl. In other embodiments, both R6A and R7A can be * - (CR15AR16A) p – O – C1-24-alkyl. In some embodiments, each R15A and each R16A can be hydrogen. In other embodiments, at least one of R15A and R16A may be optionally substituted C1-24 alkyl. In other embodiments, at least one of R15A and R16A may be an alkoxy (for example, benzoxy). In some modalities, p can be 1. In other modalities, p can be
[0125] [0125] In some modalities, at least one of R6A and R7A can be * - (CR17AR18A) Q – O – alkenyl-C2-24. In other embodiments, both R6A and R7A can be * - (CR17AR18A) Q – O – alkenyl-C2-24. In some embodiments, each R17A and each R18A can be hydrogen. In other embodiments, at least each of R17A and R18A may be optionally substituted C1-24 alkyl. In some modalities, q can be 1. In other modalities, q can be 2. In still other modalities, q can be 3. When at least one of R6A and R7A is * - (CR15AR16A) p – O – alkyl-C1- 24 or * - (CR17AR18A) q – O – C2-24 alkenyl, C1-24 alkyl may be selected from caprilila, caprila, laurila, myristila, palmitila, stearila, araquidila, beenila, lignocerila, e cerotila, e the alkylene C2-24 can be selected from myristoleyl, palmitoleyl, sapienil, oleyl, elaidyl, vacenyl, linoleil, α-linolenyl, arachidonyl, eicosapentanyl, erucyl and docosaexamine.
[0126] [0126] In some modalities, when R5A is Z1A R6AO P OR7A, at least one of R6A and R7A can be selected from, and; and the other from R6A and R7A can be selected from absent, hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl (C1-6 alkyl).
[0127] [0127] In some modalities, at least one of R6A and R7A can be or. In some modalities, both R6A and R7A can be
[0128] [0128] In some modalities, both R6A and R7A can be. When one of or both R6A and R7A are, R9A and R23A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; RA2 can be independently selected from hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted –O – C1-24 alkyl, an optionally substituted –O – aryl, an optional –O – heteroaryl- optionally substituted, an optionally substituted monocyclic –O – heterocycly; and Z4A can be independently O (oxygen) or S (sulfur). In some modalities, R22A and R23A can be hydrogen. In other modes, at least one of R22A and R23A can be an optionally substituted C1-24 alkyl or an optionally substituted aryl. In some embodiments, R24A may be an optionally substituted C1-24 alkyl. In other embodiments, R24A can be an optionally substituted aryl. In still other embodiments, R24A can be an optionally substituted - O – C1-24-alkyl or an optionally substituted -O – aryl. In some embodiments, Z4A can be O (oxygen).
[0129] [0129] In some embodiments, both R6A and R7A can be, where R26A and R27A can be independently -C≡N or an optionally substituted substitute selected from C2-8-carbonyl organyl, C2-8-carbonyl alkoxy and C2-8-aminocarbonyl organyl; R28A can be selected from hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally C3-6 cycloalkenyl replaced; and r can be 1 or 2.
[0130] [0130] In some embodiments, both R6A and R7A can be an optionally substituted aryl. In some modalities, at least one of R6A and R7A can be an optionally substituted aryl. For example, both R6A and R7A can be an optionally substituted phenyl or an optionally substituted naphthyl. When substituted, the substituted aryl may be substituted with 1, 2, 3 or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In some embodiments, when at least one of R6A and R7A is a substituted phenyl, the substituted phenyl may be a para-, ortho- or meta-substituted phenyl.
[0131] [0131] In some embodiments, both R6A and R7A may be an optionally substituted aryl (C1-6 alkyl). In some modalities, at least one of R6A and R7A can be an optionally substituted aryl (C1-6 alkyl). For example, both R6A and R7A can be an optionally substituted benzyl. When substituted, the substituted benzyl group may be substituted with 1, 2, 3 or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In some embodiments, the aryl group of the aryl (C1-6 alkyl) may be a para-, ortho- or meta-substituted phenyl.
[0132] [0132] In some modalities, both R6A and R7A can be. In some modalities, at least one of R6A and R7A can be. In some embodiments, R25A may be hydrogen. In other modalities, R25A can be an optionally substituted C1-24 alkyl. In still other modalities, R25A can be an optionally substituted aryl. In some embodiments, R25A may be C1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ter-butyl, pentyl (branched and linear) and hexyl (branched) and linear). In some modalities, t can be 0. In other modalities, t can be 1. In some modalities, one of or both R6A and R7A can be S-acetylthioethyl (SATE).
[0133] [0133] In some modalities, both R6A and R7A can be. In some modalities, at least one of R6A and R7A can be. In some embodiments, R29A may be hydrogen. In other modalities, R29A can be an optionally substituted C1-24 alkyl. In some embodiments, R29A may be C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and ter-butyl. In still other embodiments, R29A can be an optionally substituted aryl, such as an optionally substituted phenyl or an optionally substituted naphthyl. In some embodiments, both R6A and R7A can be a dioxolenone group and form a dioxolenone prodrug.
[0134] [0134] In some embodiments, R5A can be Z1A R6AO P OR7A; R6A can be
[0135] [0135] In some modalities, both R6A and R7A can be considered together to form an optionally substituted one. For example, R5A can be an optionally substituted. When replaced, the ring may be replaced 1, 2, 3 or 3 or more times. When substituted with multiple substituents, the substituents can be the same or different. In some modalities, when R5A is,
[0136] [0136] In some embodiments, R6A and R7A can be considered together to form an optionally substituted one, with the oxygen connected to R 6A and R7A, the phosphorus and the portion form a six-membered to ten-membered ring system. Example of an optionally substituted includes,, and
[0137] [0137] In some modalities, R6A and R7A can be the same. In some embodiments, R6A and R7A may be different.
[0138] [0138] In some modalities, Z1A can be oxygen. In other embodiments, Z1A may be sulfur.
[0139] [0139] In some embodiments, R5A can be Z2A R8AO P R9A. In some embodiments, R8A can be selected from absent, hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and a C3 cycloalkenyl -6 optionally substituted; and R9A can be independently selected from an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and a C3-6 cycloalkenyl optionally replaced. In a modality, R5A is hydrogen, or.
[0140] [0140] In some embodiments, R8A may be hydrogen, and R9A may be optionally substituted C1-6 alkyl. Examples of
[0141] [0141] In some modalities, R8A may be absent or be hydrogen; and R9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In other embodiments, R8A can be an optionally substituted aryl; and R9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In still other embodiments, R8A may be an optionally substituted heteroaryl; and R9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid derivative. In some modalities, R9A may be an amino acid selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylanine , threonine, tryptophan, valine and ester derivatives thereof. The amino acid can have several stereochemical configurations. For example, the amino acid can be racemic, a L stereoisomer, a D stereoisomer or a mixture of L and D stereoisomers that is enriched in one or the other of the stereoisomers. In one embodiment, the L stereoisomer content of the amino acid is at least about 90%, at least about 95%, or at least about 99% by weight, based on the mixture of L and D stereoisomers. Examples of derivatives of optionally substituted N-linked amino acid ester include the optionally substituted versions of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, R9A may have the structure with R33A being selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an aryl (C1-6 alkyl) optionally substituted and an optionally substituted haloalkyl; R34A can be selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted C10 aryl and an aryl (C1 alkyl) -6) optionally substituted; and R35A can be hydrogen or an optionally substituted C1-4alkyl; or R34A and R35A can be considered together to form an optionally substituted C3-6 cycloalkyl. The amino acid portion of the optionally substituted N-linked amino acid ester derivatives can have the various stereochemical configurations that are described above for the amino acids. In one embodiment, R9A is,, or. In one embodiment, R33A is C1-6 alkyl.
[0142] [0142] When R34A is substituted, R34A may be substituted with one or more substituents selected from N-starch, mercapto,
[0143] [0143] In some modalities, when R5A is Z2A R8AO P R9A, Z2A can be O (oxygen). In other embodiments, when R5A is Z2A R8AO P R9A, Z2A can be S (sulfur). In some embodiments, when R5A is Z2A R8AO P R9A, a compound of formula (I) can be a phosphoramidate prodrug, such as an aryl phosphoramidate prodrug.
[0144] [0144] In some embodiments, R5A can be Z3A R10A P R11A. In some embodiments, R10A and R11A may independently be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In some modalities, one of either R10A or R11A may be an amino acid selected from alanine, asparagine, aspartate, cistein, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine , methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof. The amino acid can have several stereochemical configurations. For example, the amino acid can be racemic, a L stereoisomer, a D stereoisomer or a mixture of L and D stereoisomers that is enriched in one or the other of the stereoisomers. In one embodiment, the L-stereoisomer content of the amino acid is at least about 90%, at least about 95%, or at least about 99% by weight, based on the mixture of L and D stereoisomers. some embodiments, R10A and R11A may be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some modalities, R10A and R11A may independently have the structure, with R36A being selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an aryl ( C1-6alkyl) optionally substituted and an optionally substituted haloalkyl; R37A can be selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted C10 aryl and an aryl (C1 alkyl) -6) optionally substituted; and R38A can be hydrogen or an optionally substituted C1-4alkyl; or R37A and R38A can be considered together to form an optionally substituted C3-6 cycloalkyl.
[0145] [0145] When R37A is substituted, R37A may be substituted with one or more substituents selected from N-starch, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino.
[0146] [0146] Examples of suitable groups include the following: 34A 37A 34A 37A R33AO R R35A R36AO R R38A R33AO R R35A R36AO R R38A
[0147] [0147] In some modalities, R10A and R11A can be the same. In some embodiments, R10A and R11A may be different.
[0148] [0148] In some modalities, Z3A can be O (oxygen). In other embodiments, Z3A can be S (sulfur). In some embodiments, when R5A is Z3A R10A P R11A, a compound of formula (I) can be a phosphonic diamide prodrug.
[0149] [0149] Those skilled in the art understand that when R8A, R9A and / or R10A are absent, the associated oxygen will have a negative charge. For example, when R8A is absent, the oxygen associated with R 8A will have a negative charge. The variable m in R7A can be 0, 1 or
[0150] [0150] By neutralizing the charge in the phosphate portion of the compounds of formula (I), cell membrane penetration can be facilitated as a result of the compound's increased lipophilicity. Once absorbed and captured within the cell, groups attached to phosphorus can be easily removed by esterases, proteases and / or other enzymes. In some embodiments, groups attached to phosphorus can be removed by simple hydrolysis. Within the cell, the phosphate released in this way can then be metabolized by cellular enzymes to diphosphate or active triphosphate. In addition, in some modalities, the variation of substituents in a compound described here, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, can help maintain the effectiveness of the compound by reducing undesirable effects.
[0151] [0151] In some embodiments, R5A can be hydrogen. In some embodiments, R5A can be an optionally substituted acyl. In other embodiments, R5A can be –C (= O) R39A, where R39A can be selected from an optionally substituted C1-12 alkyl, an optionally substituted C2-12 alkenyl, an optionally substituted C2-12 alkynyl, a cycloalkyl Optionally substituted C3-8, optionally substituted C5-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl (C1-6 alkyl), heteroaryl ( optionally substituted C1-6 alkyl) and an optionally substituted heterocyclyl (C1-6 alkyl). In some embodiments, R39A may be substituted C1-12 alkyl. In other embodiments, R39A may be unsubstituted C1-12 alkyl.
[0152] [0152] In still other embodiments, R5A can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamine, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydro-
[0153] [0153] When R40A is substituted, R40A can be substituted with one or more substituents selected from N-starch, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some modalities, R40A may be unsubstituted C1-6 alkyl, such as those described here. In some embodiments, R40A may be hydrogen. In other embodiments, R40A may be methyl. In some embodiments, R41A may be hydrogen. In other embodiments, R41A may be an optionally substituted C1-4alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and ter-butyl. In one embodiment, R41A can be methyl. Depending on the groups that are selected for R40A and R41A, the carbon to which R40A and R41A are attached may be a chiral center. In some embodiments, the carbon to which R40A and R41A are attached may be a chiral- (R) center. In other embodiments, the carbon to which R40A and R41A are attached may be a chiral- (S) center.
[0154] [0154] Examples of suitable ones include the following: 40A 40A O R R41A O R R41A O O H3C H O NH2, O NH2, O NH2, NH2, O H CH3 O O H O H O NH2, O NH2, O NH2 and NH2.
[0155] [0155] In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, is a parent compound. As used herein in this context, the term "panviral" refers to a compound (for example, a nucleoside analog or a nucleotide analog) that has pharmaceutically significant activity against viruses in two or more virus families. The degree to which a compound exhibits pharmaceutically significant activity can be determined using a validated assay that is suitable for the virus being tested. Such test methods are known to those skilled in the art and include the test methods described in the Examples below. In general, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is considered to be panviral if it has an EC50 and / or IC50 value of 100 µM or less in at least one test for a virus in a first virus family and also if it has an EC50 and / or IC50 value of 100 µM or less in at least one test for a virus in a second virus family that is different from the first family. It will be evident to those skilled in the art that compounds having greater activity are also considered panviral. For example, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, is also considered to be panviral if it has an EC50 and / or IC50 value of 10 µM or less in at least one assay for a virus in a first virus family and also if it has an EC50 and / or IC50 value of 100 µM or less in at least one test for a virus in a second virus family that is different from the first family.
[0156] [0156] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of low toxicity. As used herein in this context, the term "low toxicity" refers to a compound (for example, a nucleoside analog or a nucleotide analog) that has pharmaceutically insignificant toxicity when tested using a toxicity assay that is suitable for the virus being tested. Such test methods are known to those skilled in the art and include the test methods described in the Examples below. In general, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is considered to have pharmaceutically insignificant toxicity if it has a 50% cytotoxic (CC50) concentration value of 10 µM or more. It will be apparent to those skilled in the art that less toxic compounds are also considered to be of low toxicity. For example, a compound is also considered to have pharmaceutically insignificant toxicity if it has a CC50 value of 100 µM or more.
[0157] [0157] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is a low toxicity panviral nucleoside analog. As used herein in this context, the term "low panviral toxicity" refers to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, which is both low toxicity and panviral, as described above.
[0158] [0158] The compounds of the formula (I), or a pharmaceutically acceptable salt thereof, can be prepared using various methods known to those skilled in the art. The synthesis routes described here are illustrative only and are not designed, nor should they be interpreted, to limit the scope of the claims in any way whatsoever. Those skilled in the art will be able to recognize the modifications of the revealed syntheses and develop alternative routes based on the revelations contained herein; all of these modifications and alternative routes are within the scope of the claims. Examples of methods are described in the Examples below. Pharmaceutical compositions
[0159] [0159] Some embodiments described herein refer to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable vehicle, diluent, excipient or combination thereof. In some embodiments, the pharmaceutical composition may include a single diastereomer of a compound of formula (I), or a pharmaceutically acceptable salt thereof (for example, a single diastereomer is present in the pharmaceutical composition at a concentration greater than 99% compared to the total concentration of the other diastereomers). In other embodiments, the pharmaceutical composition may include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may include a diastereomer concentration of> 50%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90%, ≥ 95% or ≥ 98%, compared to the total concentration of others diastereomers. In some embodiments, the pharmaceutical composition includes a 1: 1 mixture of two diastereomers of a compound of Formula (I),
[0160] [0160] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein with other chemical components, such as diluents or vehicles. The pharmaceutical composition facilitates the administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The pharmaceutical compositions will generally be adapted to the specific intended route of administration. A pharmaceutical composition is suitable for human and / or veterinary applications.
[0161] [0161] The term "physiologically acceptable" defines a vehicle, diluent or excipient that does not impede the biological activity and properties of the compound.
[0162] [0162] As used here, a "vehicle" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used vehicle that facilitates the absorption of many organic compounds in an individual's cells or tissues.
[0163] [0163] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that has no pharmacological activity, but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of a potent drug whose mass is too small for manufacture and / or administration. It can also be a liquid for dissolving a drug to be administered by injection, ingestion or inhalation. A form of diluent common in the art is a buffered aqueous solution, for example, but not limited to phosphate buffered saline that mimics the composition of human blood.
[0164] [0164] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc. ., to the composition. A "thinner" is a type of excipient.
[0165] [0165] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, such as in combination therapy, or vehicles, diluents, excipients or combinations of the same. The appropriate formulation depends on the chosen route of administration. Techniques for the formulation and administration of the compounds described herein are known to those skilled in the art.
[0166] [0166] The pharmaceutical compositions disclosed herein can be manufactured in a known manner, for example, by means of mixing, dissolving, granulating, drug making, levigation, emulsification, encapsulation, entrapment or tabletting processes. In addition, the active ingredients are contained in an effective amount to achieve the purpose for which it is intended. Many of the compounds used in the pharmaceutical combinations disclosed herein can be supplied as salts with pharmaceutically compatible counterions.
[0167] [0167] Various techniques for administering a compound exist in the art, including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral, including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal injections , direct intraventricular, intraperitoneal, intranasal and intraocular.
[0168] [0168] One can also administer the compound to a site instead of a systemic form, for example, by injecting the compound directly into the infected area, often in a depot or sustained release formulation. In addition, the compound can be administered in a drug delivery system targeted, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted and absorbed selectively by the organ.
[0169] [0169] The compositions can, if desired, be presented in a package or applicator device that can contain one or more unit dose forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister package. The packaging or applicator device may be accompanied by instructions for administration. The packaging or applicator device may also be accompanied by a note associated with the container in the form prescribed by a government agency that regulates the manufacture, use or sale of drugs, the note of which reflects approval by the agency of the form of the drug for administration to humans or animals. This note, for example, may be the FDA-approved label for the U.S. Food and Drug Administration for prescription drugs, or the approved package insert. Compositions that may include a compound described herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and identified for the treatment of an indicated condition.
[0170] [0170] In one embodiment, a panviral treatment as described elsewhere in this invention is formulated for administration to an individual who has a viral infection. For example, those skilled in the art recognize that, depending on the type of viral infection, it may be more advantageous to administer a panviral treatment that has been formulated in a specific way, for example, in the form of a pharmaceutical composition that facilitates administration by a specific route (for example, oral, aerosol, injection, etc.) and / or with appropriate labeling for the treatment of the condition for which it is indicated. One modality provides a panviral treatment formulated for administration to an individual who has a viral infection by Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae. Usage methods
[0171] [0171] Some modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Picornaviridae which may include administering to an individual infected with the Picornaviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Picornaviridae which may include administering to an individual identified as suffering from the viral infection, an effective amount of one or more compounds described herein (as a composed of formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition that includes a compound described herein, (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) .
[0172] [0172] Some modalities described here refer to the methods of using one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a viral infection by Picornaviridae which may include administering to an individual infected with the Picornaviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt of the same). Still other modalities described here refer to one or more compounds described here (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) that can be used to attenuate and / or treat a viral infection by Picornaviridae by administering to an individual infected with the Picornaviridae virus an effective amount of one or more compounds described herein.
[0173] [0173] Other modalities disclosed herein refer to methods for attenuating and / or treating a viral infection by Picornaviridae which may include putting a cell infected with the Picoraviridae virus in contact with an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I) , or a pharmaceutically acceptable salt thereof). Other modalities described herein refer to the use of one or more compounds described herein (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medication to attenuate and / or treat an infection viral by Picoraviridae which may include putting a cell infected with the Pi-cornaviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to one or more compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used to alleviate and / or treat a Picor infection - naviridae by placing a cell infected with the Picornaviridae virus in contact with an effective amount of said compound (s).
[0174] [0174] Some modalities disclosed herein refer to a method of inhibiting the replication of a Picornaviridae virus, which may include putting a cell infected with the Picornaviridae virus in contact with an effective amount of one or more compounds described here
[0175] [0175] In some modalities, the Picornaviridae virus can be selected from an aftovirus, a rhinovirus, a hepatovirus and a parachovirus. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can alleviate and / or treat a rhinovirus infection. For example, by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to an individual infected with rhinovirus and / or by contacting a cell infected with rhinovirus. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) may be effective in inhibiting the replication of a rhinovirus. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be effective against a rhinovirus, and thus alleviate one or more symptoms of a rhinovirus infection.
[0176] [0176] Various indicators for determining the effectiveness of a method for treating a viral infection by Picornaviridae are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time for seroconversion (virus not detectable in the patient's serum), a reduction in morbidity or mortality - in clinical developments and / or other disease response indicators. Additional indicators include one or more indicators of overall health quality of life, such as reduced disease duration, reduced disease severity, reduced time to return to normal health and normal activity, and reduced time to alleviate disease. one or more symptoms. In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, may result in the reduction, attenuation or positive indication of one or more of the aforementioned indicators compared to an untreated individual. The effects / symptoms of a viral infection by Picornaviridae are described here, and include, but are not limited to, fever, blisters, rash, meningitis, conjunctivitis, acute hemorrhagic conjunctivitis (AHC), sore throat, nasal congestion, runny nose, sneeze, cough, loss of appetite, painful muscle sensations, headache, fatigue, nausea, jaundice, encephalitis, herpangina, myocarditis, pericarditis, meningitis, Bernholm disease, myalgia, nasal congestion, muscle weakness, loss of appetite , fever, vomiting, abdominal pain, abdominal discomfort, dark urine and muscle pain.
[0177] [0177] Some modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Flaviviridae which may include administering to an individual infected with the Flaviviridae virus an effective amount of one or more compounds described herein. - types (as a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Flaviviridae which may include administering to an individual an effective amount of one or more compounds described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof). Some modalities described here refer to the methods of using one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a viral infection by Flaviviridae which may include administering an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof). Still other embodiments described herein refer to one or more compounds described herein (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof) that can be used to attenuate and / or treat a viral infection by Flaviviridae by administering to an individual an effective amount of one or more compounds described herein.
[0178] [0178] Other modalities disclosed herein refer to a method for attenuating and / or treating a viral infection by Flaviviridae which may include putting a cell infected with the Flaviviridae virus in contact with an effective amount of one or more compounds described herein. (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) . Other modalities described herein refer to the use of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a viral infection by Flaviviridae which may include putting a cell infected with the Flaviviridae virus in contact with an effective amount of said compound (s). Still other modalities described herein refer to one or more compounds described here (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used for attenuation and / or treatment of a viral infection by Flaviviridae by placing a cell infected with the Flaviviridae virus in contact with an effective amount of said compound (s).
[0179] [0179] Some of the modalities disclosed herein refer to a method of inhibiting the replication of a Flaviviridae virus, which may include bringing a cell infected with the Flaviviridae virus into contact with an effective amount of one or more compounds described here (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof) or of a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting the replication of a Flaviviridae virus that it may include putting a cell infected with the Flaviviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to a compound described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used to inhibit the replication of a Flaviviridae virus by placing of a cell infected with the Flaviviridae virus in contact with an effective amount of said compound (s). In some embodiments, a polymerase from a Flaviviridae virus can be inhibited by placing a cell infected with the Flaviviridae virus in contact with a compound described here (such as a compound of formula (I), or a pharmaceutically acceptable salt. of the same) and thus inhibit RNA replication.
[0180] [0180] Other modalities disclosed herein refer to a method of attenuating and / or treating an HCV viral infection, which may include bringing an HCV-infected cell into contact with an effective amount of one or more compounds described herein (such as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof). Other modalities described herein refer to the use of one or more compounds described here (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medication for attenuation and / or treatment of an HCV infection which may include putting an HCV-infected cell in contact with an effective amount of said compound (s). Still other embodiments described herein refer to one or more compounds described herein (as a compound of formula (I),
[0181] [0181] Some modalities described herein refer to a method of inhibiting the activity of the NS5B polymerase which may include contacting a cell infected with the hepatitis C virus with an effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof. As noted above, NS5B is believed to be an RNA-dependent RNA polymerase involved in HCV RNA replication. Some embodiments described herein refer to a method of inhibiting NS5B polymerase activity which may include administering to an individual infected with the hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutically salt acceptable value. In some modalities, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit an RNA-dependent RNA polymerase and thereby inhibit HCV RNA replication. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit an HCV polymerase (for example, NS5B polymerase).
[0182] [0182] Some modalities described herein refer to a method of treating a selected condition of liver fibrosis, liver cirrhosis and liver cancer in an individual suffering from one or more of the liver conditions mentioned above, which may include administering to the individual an effective amount of a compound or a pharmaceutical composition described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the liver condition is caused by an HCV infection. Some embodiments described herein refer to a method of increasing liver function in an individual with an HCV infection which may include administering to the individual an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of the Formula (I) or a pharmaceutically acceptable salt thereof). Also contemplated is a method of further reducing or eliminating liver damage caused by viruses in an individual who has an HCV infection by administering to the individual an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I ), or a pharmaceutically acceptable salt thereof). In some embodiments, this method may include slowing or stopping the progression of liver disease. In other modalities, the course of the disease can be reversed, and stasis or improvement in liver function is contemplated. In some modalities, liver fibrosis, liver cirrhosis and / or liver cancer can be treated; liver function can be increased; liver damage caused by the virus can be reduced or eliminated; the progression of liver disease can be slowed or stopped; the course of liver disease can be reversed and / or liver function can be enhanced or maintained by contacting a cell infected with the hepatitis C virus with an effective amount of a compound described here (for example , a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
[0183] [0183] There are a variety of HCV genotypes, and a variety of subtypes within each genotype. For example, at the moment, it is known that there are eleven (11) main HCV genotypes (numbered 1 to 11), although others have classified the genotypes as 6 main genotypes. Each of these genotypes is subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a- 7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of formula (I), or a salt pharmaceutically acceptable product, it can be effective to treat at least one HCV genotype. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) may be effective in treating all 11 HCV genotypes. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) may be effective in treating 3 or more, 5 or more, 7 or more, or 9 or more genotypes HCV. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be more effective against a greater number of HCV genotypes than the standard of treatment. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be more effective against a particular HCV genotype than standard treatments (such as genotype 1, 2, 3, 4, 5 and / or 6).
[0184] [0184] Various indicators for determining the effectiveness of a method for treating HCV infection are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in seroconversion time (virus undetectable in the patient's serum), an increase in the sustained viral response rate by therapy, a reduction in morbidity or mortality in clinical outcomes, a reduction in the rate of decreased liver function; stasis in liver function; improvement in liver function; reduction in one or more markers of liver dysfunction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, glutamyl transpeptidase and / or another indicator of response to the disease. Similarly, successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can reduce the incidence of liver cancer in individuals infected with HCV.
[0185] [0185] In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can be used to alleviate or treat a Flavivirus infection. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) may be effective in inhibiting the replication of a flavivirus.
[0186] [0186] In some embodiments, Flavivirus can be a West Nile virus. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can treat and / or mitigate a dengue virus, such as DENV-1, DENV-2, DENV- 3 and DENV-4. Infection with dengue virus can cause hemorrhagic dengue and / or dengue shock syndrome. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can treat and / or alleviate hemorrhagic dengue and / or dengue shock syndrome. In some modalities, Flavivirus can be the yellow fever virus. In still more modalities, the Flavivirus can be an encephalitis virus from within the genus Flavivirus. Examples of encephalitis viruses include, but are not limited to, Japanese encephalitis viruses, St. Louis encephalitis viruses and tick-borne encephalitis viruses. In some modalities, Flavivirus can be a Zika virus.
[0187] [0187] Some of the modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Filoviridae which may include administering to an individual infected with the Filo-viridae virus an effective amount of one or more compounds described herein
[0188] [0188] Some modalities described here refer to the methods of using one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a Filoviridae viral infection which may include administering to an individual infected with the Filoviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) . Still other modalities described herein refer to one or more compounds described herein (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used for attenuation and / or treatment of a viral infection by Filoviridae upon administration to an individual infected with the Filoviridae virus of an effective amount of one or more compounds described herein.
[0189] [0189] Other modalities disclosed herein refer to a method of attenuating and / or treating a viral infection by Filoviridae, which may include putting a cell infected with the Filoviridae virus in contact with an effective amount of one or more compounds here described
[0190] [0190] Some modalities disclosed herein refer to a method of inhibiting the replication of a Filoviridae virus, which may include putting a cell infected with the Filoviridae virus in contact with an effective amount of one or more compounds described here (such as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof). Other modalities described herein refer to the use of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting the replication of a Filoviridae virus that it may include putting a cell infected with the Filoviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to a compound described herein
[0191] [0191] In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can be used for the alleviation and / or treatment of a viral infection by Filoviridae. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) may be effective in inhibiting the replication of a Filovirus.
[0192] [0192] In some modalities, the Filoviridae virus can be selected from an ebolavirus, a Marburgvirus and a Cuevavirus. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can alleviate and / or treat an infection by ebolavirus. For example, by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to an individual infected with ebolavirus and / or by contacting a cell infected with ebolavirus . In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) may be effective in inhibiting the replication of an ebolavirus. In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, can be effective against an ebolavirus, and thus alleviate one or more symptoms of an ebolavirus infection. The five recognized species of ebolavirus are Ebola virus (EBOV), Reston ebolavirus (RE-BOV), Sudan ebolavirus (SEBOV), Taї Forest ebolavirus (TAFV) and Bundibugyo ebolavirus (BEBOV). The two recognized species of Marburgvirus are Marburg virus (MARV) and Ravn virus (RAVV).
[0193] [0193] Some modalities described here refer to a method of treatment and / or mitigation of a Pneumoviridae viral infection that may include administering to an individual infected with the Pneumoviridae virus an effective amount of one or more compounds described herein. (as a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other modalities disclosed herein refer to a method of treating and / or mitigating a Pneumoviridae viral infection which may include administering to an individual identified as suffering from viral infection an effective amount of one or more compounds described herein (such as one with - post of formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition which includes a compound described herein (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof).
[0194] [0194] Some modalities described here refer to the methods of using one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a Pneumoviridae viral infection which may include administering to an individual infected with the Pneumoviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt of the themselves). Still other embodiments described herein refer to one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used to alleviate and / or treat an infection Pneumoviridae virus by administering to an individual infected with the Pneumoviridae virus an effective amount of one or more compounds described herein.
[0195] [0195] Other modalities disclosed herein refer to a method of attenuation and / or treatment of a Pneumoviridae viral infection, which may include putting a cell infected with the Pneumoviridae virus in contact with an effective amount of one or more compounds here described (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt the same). Other modalities described here refer to the use of one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a Pneumoviridae viral infection that may include putting a cell infected with the Pneumoviridae virus in contact with an effective amount of said compound (s). Still other modalities described here refer to one or more compounds described here (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used for attenuation and / or treatment of a Pneumoviridae viral infection by placing a cell infected with the Pneumoviridae virus in contact with an effective amount of said compound (s).
[0196] [0196] Some embodiments disclosed herein refer to methods of inhibiting the replication of a Pneumoviridae virus which may include putting a cell infected with the Pneumoviridae virus in contact with an effective amount of one or more compounds described herein (as a compound of the formula ( I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other modalities described herein refer to the use of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting the replication of a Pneumoviridae virus that it may include putting a cell infected with the Pneumoviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to a compound described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) that can be used to inhibit the replication of a Pneumovirus virus by placing a cell infected with the Pneu- moviridae virus in contact with an effective amount of said compound (s). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can inhibit an RNA-dependent RNA polymerase, and thereby inhibit RNA replication. In some embodiments, a Pneumoviridae virus polymerase can be inhibited by placing a cell infected with the Pneumoviridae virus in contact with a compound described herein (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof).
[0197] [0197] In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can be used for the mitigation and / or treatment of a Pneumoviridae viral infection. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can inhibit the replication of a Pneumoviridae viral infection. In some embodiments, the Pneumovirus virus can be a human respiratory syncytial virus (HRSV), such as HRSV-A2, HRSV-B1 and HRSV-S2. HRSV can cause respiratory tract infections, bronchiolitis, pneumonia and severe lower respiratory tract disease.
[0198] [0198] Some modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Coronaviridae which may include administering to an individual infected with the Coronaviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (as a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other modalities disclosed herein refer to a method of treatment and / or mitigation of a viral infection by Coronaviridae which may include administering to an individual identified as suffering from viral infection an effective amount of one or more compounds described herein (such as one with - post of formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition which includes a compound described herein (such as a compound of formula (I), or a pharmaceutically acceptable salt thereof).
[0199] [0199] Some modalities described here refer to the methods of using one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medication for attenuation and / or treatment of a Coronaviridae viral infection which may include administering to an individual infected with the Coronaviridae virus an effective amount of one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof) . Still other embodiments described herein refer to one or more compounds described herein (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof) that can be used to attenuate and / or treat a viral infection by Coronaviridae by administering to an individual infected with the Coronaviridae virus an effective amount of one or more compounds described herein.
[0200] [0200] Other modalities disclosed here refer to methods of attenuation and / or treatment of a viral infection by Coronaviridae, which may include putting a cell infected with the Coronaviridae virus in contact with an effective amount of one or more compounds described here ( as a compound of formula (I), or a pharmaceutically acceptable salt thereof), or of a pharmaceutical composition that includes one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof ). Other modalities described here refer to the use of one or more compounds described here (as a compound of the formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicine for attenuation and / or treatment of a viral infection by Coronaviridae which may include putting a cell infected with the Coronaviridae virus in contact with an effective amount of said compound (s). Still other embodiments described herein refer to one or more compounds described herein (as a compound of formula (I), or a pharmaceutically acceptable salt thereof), which can be used to alleviate and / or treat an infection Coronaviridae virus by placing a cell infected with the Coronaviridae virus in contact with an effective amount of said compound (s).
[0201] [0201] Some modalities disclosed here refer to the methods of inhibiting the replication of a Coronaviridae virus, which may include putting a cell infected with the Coronaviridae virus in contact with an effective amount of one or more compounds described here
[0202] [0202] In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can be used for the mitigation and / or treatment of a Coronaviridae viral infection. In some embodiments, a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) can inhibit the replication of a viral infection by Coronaviridae. In some embodiments, the Coronavirus virus can be a human alpha-coronavirus (HRSV) or a human beta-coronavirus. The six coronaviruses that can infect people are: alpha-coronaviruses 229E and NL63, and beta-coronaviruses OC43, HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome, or SARS), and MERS- CoV (the coronavirus that causes Middle East respiratory syndrome, or MERS).
[0203] [0203] Various indicators for determining the effectiveness of a method for treating a viral infection by Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time for seroconversion (undetectable virus in the patient's serum), a reduction in morbidity or mortality clinical developments and / or other disease response indicators. Additional indicators include one or more indicators of overall health quality of life, such as reduced disease duration, reduced disease severity, reduced time to return to normal health and normal activity, and reduced time to alleviate one or more symptoms. In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, may result in the reduction, attenuation or positive indication of one or more of the aforementioned indicators compared to an individual who is receiving the standard of treatment or an untreated individual.
[0204] [0204] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may result in a reduction in the duration and / or severity of one or more symptoms associated with a viral infection by Picornaviridae, Flaviviridae, Filoviridae, Pneu- moviridae and / or Coronaviridae compared to an individual receiving the standard of care or an untreated individual. Table 1 provides some modalities of the percentage improvements obtained with the use of a compound of formula (I), or of a pharmaceutically acceptable salt of it, in comparison with the standard of treatment or an untreated individual.
[0205] [0205] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is a panviral nucleoside analog. Some modalities provide a pan-viral treatment that comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof. In this context, the term "panviral treatment" refers to a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is panviral as described above. Such panviral treatments are thus effective for treating two or more viral infections, where the viruses that cause the infections are viruses from two or more viral families. For example, in one embodiment, panviral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, which is effective for treating viral infections caused by viruses in two or more families selected from the group consisting of Picornaviridae, Flaviviridae, Filoviridae , Pneumoviridae and Coronaviridae. Those skilled in the art are aware of numerous subfamilies, genera and species of viruses and the families in which they are categorized. For example, in one embodiment, pan-viral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, which is effective for treating viral infections selected from a rhinovirus infection in the Picornaviridae family; an infection by Dengue virus or an infection by Hepacivirus in the family Flaviviridae; an Ebolavirus infection in the Filoviridae family; a human respiratory syncytial virus (HRSV) infection in the Pneumoviridae family; and a viral infection by human α-coronavirus or a viral infection by human β-coronavirus in the family Coronaviridae. In several modalities, panviral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, which has low toxicity as described elsewhere elsewhere. Examples of panviral treatments include those comprising compounds 1 to 15 as described in the Examples below, and pharmaceutically acceptable salts thereof.
[0206] [0206] In some embodiments, the compound may be a compound of formula (I), the compound of formula (I) being a monophosphate, diphosphate or triphosphate, or a pharmaceutically acceptable salt of any of the above mentioned. In some embodiments, the compound may be a compound of the formula (I), the compound of the formula (I) being a monophosphate, diphosphate or triphosphate, or a pharmaceutically acceptable salt of any of the above. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt of any of the above, that can be used to attenuate and / or treat a viral infection by Picornaviridae, Flaviviridae, Filoviridae, Pneu- moviridae and / or Coronaviridae and / or inhibit the replication of a virus Picoraviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae can be any of the modalities described here.
[0207] [0207] As used in this document, an "individual" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold or warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees and howler monkeys and, in particular, human beings. we. In some modalities, the individual is a human being.
[0208] [0208] As used here, the terms "treat", "treatment", "therapeutic" or "therapy" do not necessarily mean total cure or suppression of the disease or condition. Any relief from unwanted signs or symptoms of an illness or condition, to any extent can be considered treatment and / or therapy. In addition, treatment may include actions that can worsen the patient's overall sense of well-being or appearance.
[0209] [0209] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the indicated biological response or medicine. For example, an effective amount of the compound may be the amount needed to prevent, alleviate or alleviate symptoms of disease or prolong the survival of the individual being treated. This response can occur in a tissue, system, animal or human and includes relief from the signs or symptoms of the disease being treated. The determination of an effective amount is well within the ability of those skilled in the art, in view of the disclosure provided in this document. The effective amount of the compounds disclosed in the present document required as a dose will depend on the route of administration, the type of animal, including humans, that is treated, and the physical characteristics of the specific animal under consideration. The dose can be adapted to achieve a desired effect, however, it will depend on such factors as weight, diet, concomitant medications and other factors that those skilled in the medical technique will recognize.
[0210] [0210] As will be readily apparent to the person skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending on age, weight, severity of the disease and the species of mammal treated, the compounds specific employees, and the specific use for which these compounds are used. The determination of the effective dose levels, that is, the dosage levels necessary to obtain the desired result, can be obtained by a person skilled in the art with the use of routine methods, for example, clinical tests on human beings and in vitro studies. vitro.
[0211] [0211] The dosage can vary widely, depending on the desired effects and the therapeutic indication. Alternative dosages can be based and calculated on the patient's surface area, as understood by those skilled in the art. Although the exact dosage is determined based on the individual drug, in most cases, some generalizations related to the dosage can be made. The daily dosage regimen for an adult human patient can be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, for example, 5 to 200 mg. The dosage can be a single dose or a series of two or more given over the course of one or more days, as needed by the individual. In some embodiments, the compounds will be administered for a period of continuous therapy, for example, for a week or more, or for months or years. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered less frequently compared to the frequency of administration of an agent with the standard of treatment. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered once daily. For example, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered once daily to an individual suffering from a picornavirus infection. In some modalities, the total treatment regimen time with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be shorter compared to the total treatment regimen time with the treatment standard. .
[0212] [0212] In cases where human dosages for the compounds have been established for at least some conditions, the same dosages can be used, or dosages between about 0.1% and 500%, more preferably between about 25 % and 250% of the dosage established for humans. Where no dosage is established for human beings, as will be the case for newly discovered pharmaceutical compositions, an appropriate human dosage can be inferred from the ED50 or ID50 values, or other suitable values derived from in vitro studies or in vivo, as qualified by toxicity studies and animal efficacy studies.
[0213] [0213] In cases of administration of a pharmaceutically acceptable salt, the dosages can be calculated as the free base. As will be understood by those skilled in the art, in certain cases, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even exceed, the preferred dose range stated above, in order to treat effectively and aggressively particularly aggressive diseases or infections.
[0214] [0214] The amount and range of dosages can be individually adjusted to provide plasma levels of the active portion that are sufficient to maintain modulation effects, or the minimum effective concentration (MEC). The minimum effective concentration will vary for each compound, but can be estimated from in vitro data. The dosages required to obtain the minimum effective concentration will depend on the individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the effective minimum concentration value. The compositions should be administered using a regimen that maintains plasma levels above the minimum effective concentration for 10 to 90% of the time, preferably between 30 to 90% and, most preferably, between 50 to 90%. In cases of local administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration.
[0215] [0215] It should be noted that the responsible physician must know how and when to terminate, discontinue, or adjust administration due to toxicity or organ dysfunction. Conversely, the doctor in charge would also know how to adjust treatment to higher levels if the clinical response was not adequate (excluding toxicity). The magnitude of a dose administered in the management of the disorder of interest will vary with the severity of the condition to be treated and the route of administration. The severity of the condition can, for example, be assessed, in part, by standard prognostic assessment methods. In addition, the dose and perhaps the frequency of dosing will also vary according to age, body weight, and the response of the individual patient. A program comparable to the one discussed above can be used in veterinary medicine.
[0216] [0216] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a specific compound, or a subset of compounds that share certain chemical moieties, can be established by determining in vitro toxicity for a cell line, such as a mammalian cell line, and preferably , human. The results of these studies are often predictive of toxicity in animals, such as mammals, or, more specifically, humans. Alternatively, the toxicity of specific compounds in an animal model, such as mice, rats, rabbits, or monkeys, can be determined using known methods. The effectiveness of a specific compound can be established with the use of several recognized methods, such as in vitro methods, animal models, or clinical tests on humans. When selecting a model to determine efficacy, the person skilled in the art can be guided by the state of the art to choose a model, dose, route of administration and / or an appropriate regimen. Combination therapies
[0217] [0217] In some embodiments, the compounds described herein, such as a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt of the even, they can be used in combination with one or more additional agents for the treatment, attenuation and / or inhibition of a viral infection by Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae.
[0218] [0218] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agents together in a single pharmaceutical composition. In some embodiments, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agents as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in a pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other agents additives may be in a second pharmaceutical composition.
[0219] [0219] The dosage amount (s) and dosing schedule (s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are (are) within the knowledge of those skilled in the art. For example, when a conventional standard of treatment therapy is performed with the use of dosage amounts and dosage schedules recognized in the art, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective dosage amounts and protocols as described here.
[0220] [0220] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agents may vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered before all additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered before at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered concomitantly with one or more additional agents. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered after administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered after administration of all additional agents.
[0221] [0221] In some embodiments, the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents can result in an additive effect. In some embodiments, the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, used in combination with one or more additional agents, can result in a synergistic effect. In some embodiments, the combination of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, used in combination with one or more additional agents, can result in a strongly synergistic effect. In some modalities, the combination of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents is non-antagonistic.
[0222] [0222] As used here, the term "antagonistic" means that the activity of the combination of the compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (that is, as a single compound). As used herein, the term "synergistic effect" means that the activity of the compound combination is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term "additive effect" means that the activity of the compound combination is approximately equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
[0223] [0223] A potential advantage of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents may be a reduction in the amount (s) required ( s) one or more additional agents that is effective in treating a viral infection, compared to the amount needed to achieve the same therapeutic result when one or more additional agents are administered without a compound of formula (I), or a pharmaceutically acceptable salt thereof. Another potential advantage of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents is that the use of two or more compounds having different mechanisms of action can create a greater barrier to development of resistant viral strains compared to the barrier created when a compound is administered as a monotherapy.
[0224] [0224] The additional advantages of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents may include little or no cross-resistance between a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents thereof; different routes for the elimination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents; little or no toxicity overlap between a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents; little or no significant effect on cytochrome P450; little or no pharmacokinetic interaction between a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents; a higher percentage of individuals who achieve a sustained viral response compared to when a compound is administered as monotherapy and / or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.
[0225] [0225] For the treatment of a viral infection, examples of additional agents that can be used in combination with a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, include, but are not limited to, ribavirin and an interferon (including those described herein). Examples
[0226] [0226] Additional modalities are revealed in more detail in the following examples, which are in no way designed to limit the scope of the claims. Compounds
[0227] [0227] The compounds of formula (I) illustrated in Tables 1 to 3 can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided here. For example, the compounds of the formula (I) illustrated in Tables 1 to 3 can be easily prepared considering the detailed instructions presented here including Examples 1 to 15 below and also the reaction schemes illustrated in Figures 1 to 8. Those skilled in the art will understand that the numerous structures shown in Tables 1 to 3 are stereospecific (or non-stereospecific) and / or are represented as having unfilled valences, and that isotopic and / or stereochemical variants, including racemates , diastereomers, enantiomers and / or deuterated versions, can be prepared according to the guidance provided here. Table 1 No. Structure of Compound No. Structure of Compound 1 2 3 4
[0228] [0228] Examples of compounds useful in methods of the invention will now be described with reference to illustrative synthetic schemes for their general preparation, below, and the specific examples below.
[0229] [0229] Exemplary compounds useful in methods of the invention will now be described with reference to illustrative synthetic schemes for their general preparation, below, and the following specific examples.
[0230] [0230] According to SCHEME 1, fluorination of a compound of formula (V), where PG is benzyl, is achieved with the use of a fluorinating agent such as diethylaminosulfur trifluoride (DAST), and the like, in a suitable solvent such as toluene, DCM and the like, at temperatures ranging from 0 ° C to 60 ° C. A compound of formula (VII) is prepared in two stages from a compound of formula (VI) where PG is benzyl. The acid-catalyzed hydrolysis of 1,2-acetonide with HCl in a mixture of dioxane-methanol followed by reaction with NaH and benzyl bromide produces a compound of formula (VII), where PG is benzyl and R4A is CH2F . SCHEME 2
[0231] [0231] According to SCHEME 2, a compound of the formula (VII), where PG is benzyl and R4A is H, is prepared from D-ribofuranose in two stages. In a first step, D-ribofuranose is methylated using an acid such as H2SO4, in MeOH. In a second step, protection with a suitable protecting group such as benzyl, using conditions known to those skilled in the art, produces a compound of formula (VII). The removal of the methyl group in a compound of formula (VII), where R4A is H is performed with the use of an acid such as TFA, and the like, in water, for a period of 10 to 15 h, to produce a compound of formula (VIII), where PG is benzyl. Where R4A is CH2F, the Scheme 2 process can be modified as indicated in Scheme 2A.
[0232] [0232] According to SCHEME 3, a compound of the formula (VIII) where PG is benzyl and R4A is H or CH2F, is oxidized using chromium-mediated oxidation as PCC, or DMSO / Ac2O, to produce a ribolactone compound of formula (IX). SCHEME 4
[0233] [0233] According to SCHEME 4, a compound of formula (X) is prepared in two stages from a compound of formula (III) commercially available or synthetically accessible, where HAL is Br, and a compound of formula ( IX) commercially available or synthetically accessible, where PG is benzyl, and R4A is H or CH2F. For example, in a first step, a compound of formula (III) such as 7-bromopyrrolo [2,1-f] [1,2,4] triazine-4-amine is reacted with a base such as NaH and similar, in a suitable solvent such as tetrahydrofuran (THF), and the like, and 1,2-bis (chlorodimethylsilyl) ethane to produce a compound of formula (IV) that was not isolated but used directly in the next step. In a second step, a compound of formula (IV) is reacted with a base such as n-BuLi, t-BuLi, and the like, in a suitable solvent such as THF, Et2O, and the like, at a temperature of
[0234] [0234] According to SCHEME 5, a cyano compound of the formula (XI), where R4A is H and PG is benzyl, is prepared from a compound of the formula (X). For example, a compound of the formula (X) is reacted with TMSCN and TMSOTf in a solvent such as DCM, and the like, at a temperature of about -78 ° C, to produce a compound of the formula (XI). The removal of the three benzyl protecting groups is achieved with a reagent such as boron trichloride to produce a compound of the formula (XII), where R1A is CN and R4A is H. SCHEME 6
[0235] [0235] According to SCHEME 6, a compound of the formula (XII) where R4A is H, R1A is CN, is halogenated using triphenylphosphine, imidazole and iodine, to produce a compound of the formula (XIII). An iodine compound of the formula (XIII) is subjected to the elimination promoted by base to produce an olefinic compound of the formula (XIV).
[0236] [0236] According to SCHEME 7, the treatment of an olefinic compound of the formula (XIV), where R1A is CN, is halogenated with N-iodosuccinimide (NIS) and TEA-3HF, in a suitable solvent such as ACN, to produce a fluorine-iodine compound of the formula (XIII), where R1A is CN, R4A is F.
[0237] [0237] An azide compound of the formula (XIII), where R4A is N3, is prepared by adding iodine to the double bond-4 'of a compound of the formula (XIV) in a regioselective and stereospecific manner. For example, iodine azide (generated in situ from iodine monochloride and sodium azide) is added to a compound of the formula (XIV), where R1A is CN, in a suitable solvent like DMF, to produce a compound of azide of the formula (XIII), where R4A is N3 and R1A is CN.
[0238] [0238] The protection, using benzoyl chloride, in a solvent such as pyridine, at temperatures in the range of 0 ° C to room temperature, produces a compound of the formula (XVI), where R1A is CN, R4A is N3 or F, and PG is benzoyl. SCHEME 8
[0239] [0239] According to SCHEME 8, a compound of the formula (XIII), where R1A is CN and R4A is F, is protected to produce a methoxymethylene compound of the formula (XVII). The reaction of a compound in the
[0240] [0240] According to SCHEME 9, the protection of 2'-OH and 3'-OH of a compound of the formula (XIV), where R1A is CN, with ter-butyl-dimethylsilyl groups is achieved using ter-butyl ( chlorine) dimethylsilane, in the presence of imidazole and DMAP, in a suitable solvent such as DMF, and the like, at a temperature of about 40 to 60 ° C. The subsequent protection with benzoyl, using the conditions previously described, produces a compound of the formula (XX), where each PG 1 is TBDMS, and PG is Bz. Stereoselective epoxidation with dioxirane as dimethyldioxirane (DMDO, generated in situ by adding acetone to an aqueous solution containing potassium peroxymonosulfate (Oxone), in a suitable solvent such as DCM, produces an epoxy compound of the formula (XXI) A compound of formula (XXII), where R1A and R4A are CN, and PG2 is trimethylsilyl, is prepared by opening an epoxide ring of a compound of formula (XXI) in the presence of a Lewis acid such as InBr3, TiCl4, and similar, and cyanotrimethylsilane (TMSCN), in a suitable solvent such as DCM, and the like.
[0241] [0241] According to SCHEME 10, a chlorophosphoramidate of the formula (XXV), where Z3A is O, and R9A is an N-linked amino acid or an optionally substituted N-linked amino acid derivative, is prepared by the phosphorodichlorohydrate reaction phenyl with a commercially available or synthetically accessible amino acid or an optionally substituted amino acid ester derivative, a base such as triethylamine (TEA), and the like, in a suitable solvent such as DCM. Using the Uchiyama procedure (Uchiyama, M .; Aso, Y .; Noyori, R .; Hayakawa, Y. "O-selective phosphorylation of nucleosides without N-protection". J. Org. Chem. 1993, 58, 373−379), a chlorophosphoramidate compound of the formula (XXV) is reacted with a compound of the formula (XIX), where R1A is CN and R4A is F, in the presence of N-methylimidazole, in a suitable solvent such as ACN. The subsequent deprotection of the anchored oxomethylene is achieved by employing an acid such as HCl, HCOOH, and the like, in a suitable solvent such as dioxane, water, or a mixture thereof, to produce a compound of the formula (Ia), where R1A is CN , R2A and R3A are H, and R4A is F.
[0242] [0242] The compounds of Formula (I) can be converted to their corresponding salts using methods known to one skilled in the art. For example, an amine of Formula (I) is treated with trifluoroacetic acid, HCl or citric acid in a solvent such as Et2O, CH2Cl2, THF, MeOH, chloroform or isopropanol to produce the corresponding salt form. Alternatively, salts of trifluoro acetic acid or formic acid are obtained as a result of purification conditions by reverse phase HPLC. The crystalline forms of the pharmaceutically acceptable salts of the compounds of formula (I) can be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from solvents non-polar (including mixtures of non-polar solvents).
[0243] [0243] If the compounds described herein have at least one chiral center, they can therefore exist as enantiomers. When compounds have two or more chiral centers, they must additionally exist as diastereomers. It should be understood that all of these isomers and mixtures thereof are within the scope of the present invention.
[0244] [0244] The compounds prepared according to the schemes described above can be obtained as unique forms, as unique enantiomers, by specific synthesis as to form or by resolution. The compounds prepared according to the above schemes can alternatively be obtained as mixtures of various forms, such as racemic (1: 1) or non-racemic (not 1: 1) mixtures. In cases where racemic and non-racemic mixtures of enantiomers are obtained, unique enantiomers can be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, formation of diastereomeric salt, derivatization in diasteromeric adducts, biotransformation or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers can be separated using conventional methods such as chromatography or crystallization.
[0245] [0245] The specific Examples described below are provided to further illustrate the invention and the various preferred embodiments.
[0246] [0246] Unless otherwise specified, the reaction mixtures were stirred magnetically at room temperature (ta) under an atmosphere of nitrogen. When the solutions were "dried", they were generally subjected to drying with a drying agent such as Na2SO4 or MgSO4. In cases where mixtures, solutions and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure. The reactions under microwave irradiation conditions were performed on a Discover Biotage Initiator or CEM (Microwave Reactor) instrument.
[0247] [0247] Chromatography on normal phase silica gel (FCC) was performed on silica gel (SiO2) using prepackaged cartridges.
[0248] [0248] Prepared reverse phase high-performance liquid chromatography (RP HPLC) was performed on an Agilent HPLC with an Xterra Prep RP18 column (5 µm, 30 mm x 100 mm or 50 mm x 150 mm) or an XBridge column C18 OBD (5 µm, 30 mm x 100 mm or 50 mm x 150 mm), and a mobile phase of 5% ACN in 20 mM NH4OH was maintained for 2 min, then a gradient of 5 to 99% ACN for 15 min, then 99% ACN was maintained for 5 min, with a flow rate of 40 or 80 mL / min.
[0249] [0249] Mass spectra (MS, "mass spectra") were obtained on an Agilent 1100 MSD series equipment, with the use of electrospray ionization (ESI) in positive mode, except where indicated otherwise. The calculated mass (calc.) Corresponds to the exact mass.
[0250] [0250] Nuclear magnetic resonance (NMR) spectra were obtained on Bruker 400 MHz model DRX spectrometers. Definitions for multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible in an NMR spectrum depending on the choice of the solvent used to perform the NMR spectrum and the concentration of the compound in the solution.
[0251] [0251] Chemical product names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA, USA) or ACD / Name Version 10.01 (Advanced Chemistry). Intermediate 1 (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl-3,4-dihydro- 5- (hydroxymethyl) ) tetrahydrofuran-2-carbonitrile.
[0252] [0252] Step A. 7-Bromopyrrolo [2,1-f] [1,2,4] triazine-4-amine. To a solution of pyrrole [2,1-f] [1,2,4] triazine-4-amine (2.1 g, 15.66 mmol, 1.00 equiv) in DMF (20 mL) was added 1, 3-dibromo-2,5-dimethylimidazolidine-2,4-dione (2.24 g, 7.83 mmol, 0.53 equiv) at -20 ° C in batches. The resulting solution was stirred for 1 h at -20 ° C, then the reaction was quenched by the addition of 30 ml of sat. Sodium sulfite. (aq). After filtration, the filtrate was dissolved in 200 ml of ethyl acetate, washed with 100 ml of sat. Sodium carbonate. (aq.), dried with sodium sulfate and concentrated under reduced pressure. This resulted in 2.50 g (75%) of the title compound as a white solid. MS m / z [M + H] + (ESI): 213, 215.
[0253] [0253] Step B. (3R, 4R, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) - 5 - ((benzyloxy) methyl) tetrahydrofuran-2 ol. To a solution of 7-bromopyrrolo [2,1-f] [1,2,4] triazine-4-amine (2 g, 9.39 mmol,
[0254] [0254] Step C. (3R, 4R, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) - 5 - ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile. To a solution of (3R, 4R, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol (2.2 g, 3.98 mmol, 1.00 equiv) in DCM (80 mL) under an inert atmosphere, trimethylsilanecarbonitrile (1.86 mL, 3, 50 equiv) by dripping at 0 ° C. The resulting solution was stirred for 10 min. To this was added trimethylsilyl trifluoromethanesulfonate (3.26 mL, 4.50 equiv) by dripping at 0 ° C. The resulting solution was stirred for 2 h at 0 ° C, then the reaction was quenched by the addition of 200 ml of sat. Sodium bicarbonate. (aq.). The resulting solution was extracted with 200 ml of DCM and the organic layers were combined and subjected to drying with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column with ethyl acetate / petroleum ether (1:10 to 2: 1). This resulted in 1.2 g (54%) of the title compound as a yellow solid. MS m / z [M + H] + (ESI): 562.
[0255] [0255] Step D. (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-di -hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile. To a solution of (3R, 4R, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile (1 g, 1.78 mmol, 1.00 equiv) in DCM (5 mL) under an inert atmosphere, a boron trichloride solution (1 M in DCM, 8 mL, 3.4 eq) by dripping at 0 ° C. The resulting solution was stirred for 1 h at 0 ° C, then the reaction was quenched by the addition of potassium carbonate in methanol. After filtration, the resulting solution was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography (ACN / H2O). This resulted in 207 mg (40%) of the title compound as a white solid. MS m / z [M + H] + (ESI): 292. 1H NMR (DMSO-d6): δ 7.90 (s, 1H), 7.6 to 8.0 (br, 2H), 6, 88 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.1 (br s, 1H), 5.19 (br s, 1H), 4.91 (br s, 1H), 4.62 (d, J = 5.2 Hz, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.62 (m, 1H), 3.49 (m, 1H). Intermediate 2 (3R, 4S, 5R) -3,4-Bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) dihydrofuran-2 (3H) -one.
[0256] [0256] Step A. (3aR, 5R, 6S, 6aR) -6- (Benzyloxy) -5 - ((benzyloxy) methyl) - 5- (fluoromethyl) -2,2-dimethyltetrahydrofuro [2,3-d ] [1,3] dioxol. To a solution of diethylamino sulfur trifluoride (DAST) (16 g, 99.38 mmol, 1.99 equiv) in toluene (200 mL) under an inert atmosphere, a solution of ((3aR, 5R, 6S, 6aR) was added ) -6- (benzyloxy) -5 - ((benzyloxy) methyl) -2,2-di-methyl-tetrahydrofuro [2,3-d] [1,3] dioxol-5-yl) methanol (20 g, 49 , 94 mmol,
[0257] [0257] Step B. (3R, 4S, 5R) -4- (Benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) -2-methoxytetrahydrofuran-3-ol. To a solution of (3aR, 5R, 6S, 6aR) -6- (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) -2,2-dimethyltetrahydrofuro [2,3-d] [ 1.3] dioxol (10 g, 24.8 mmol, 1.00 equiv) in methanol (100 mL) a solution of hydrogen chloride (4 M in 1,4-dioxane, 30 mL) was added at 0 ° C . The resulting solution was stirred for 1 h at 25 ° C, and concentrated under reduced pressure to produce 9 g (crude) of the title compound as a yellow oil, which was used directly in the next step without purification. MS m / z: 377 [M + H] +.
[0258] [0258] Step C. (2R, 3S, 4R) -3,4-Bis (benzyloxy) -2 - ((benzyloxy) methyl) - 2- (fluoromethyl) -5-methoxytetrahydrofuran. To a solution of (3R, 4S, 5R) - 4- (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) -2-methoxytetrahydrofuran-3-ol (20 g, 53, 13 mmol, 1.00 equiv) in tetrahydrofuran (400 mL) under an inert atmosphere, sodium hydride (4.3 g, 179.17 mmol, 2.10 equiv) was added at 0 ° C in batches and stirred for 0.5 h. To the resulting solution, benzyl bromide (18 g, 105.88 mmol, 2.00 equiv) was added and stirred for 4 h at 25 ° C. The reaction was then inactivated by the addition of aq. (200 ml), and extracted with ethyl acetate (2 x 500 ml). The organic layers were combined, washed with aq. (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to produce 15 g (crude) of the title compound as a yellow oil, which was used directly in the next step without purification. MS m / z: 489 [M + H] +.
[0259] [0259] Step D. (3R, 4S, 5R) -3,4-Bis (benzyloxy) -5 - ((benzyloxy) methyl) - 5- (fluoromethyl) tetrahydrofuran-2-ol. A solution of (2R, 3S, 4R) -3,4- bis (benzyloxy) -2 - ((benzyloxy) methyl) -2- (fluoromethyl) -5-methoxytetrahydrofuran (11 g, 38.58 mmol , 1.00 equiv) in 90% TFA in water (200 mL) was stirred for 3 h at 25 ° C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with aq. (500 mL), and dried with anhydrous sodium sulfate. Purification of the evaporated residue (silica gel column with ethyl acetate / petroleum ether (1/3)) produced 8.9 g (46%) of the title compound as a yellow oil. MS m / z: 475 [M + H] +.
[0260] [0260] Step E. (3R, 4S, 5R) -3,4-Bis (benzyloxy) -5 - ((benzyloxy) methyl) - 5- (fluoromethyl) dihydrofuran-2 (3H) -one. To a solution of (3R, 4S, 5R) - 3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-ol (1 g, 2.21 mmol , 1.00 equiv) in DMSO (20 ml), Ac2O (15 ml) was added. The resulting solution was stirred for 16 h at room temperature. The reaction was then inactivated by the addition of Na2CO3 (50 ml), and extracted with ethyl acetate (3 x 50 ml). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column with ethyl acetate / petroleum ether (1: 5)) produced 578 mg (58%) of the title compound as a yellow oil. MS m / z: 473 [M + H] +. Intermediate 3 (3R, 4S, 5R) -5- (chloromethyl) -3,4-dihydroxy-5- (hydroxymethyl) dihydrofuran-2 (3H) -one.
[0261] [0261] The title compound can be prepared in a similar way to Intermediate 2, Steps A to E, with the modification of DAST replacement by PPh3, CCl4, DCE, higher temperature, in Step A. Example 1 Compound 1: (2R, 3R, 4S, 5S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 5-fluoro-3,4-dihydroxy -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile
[0262] [0262] Step A. (2R, 3R, 4S, 5S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-di -hydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile. To a solution of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5 - (hydroxymethyl) tetrahydrofuran-2-carbonitrile (Intermediate 1.6 g, 20.5 mmol) in tetrahydrofuran (120 mL) under an inert atmosphere, triphenylphosphine (10.8 g, 41.2 mmol, 2.00 equiv) and imidazole (6.99 g, 102.7 mol, 5.00 equiv). A solution of iodine (10.4 g, 41.2 mmol, 2.00 equiv) in tetrahydrofuran (10 ml) was added dropwise to the reaction mixture with stirring at room temperature. The resulting solution was stirred for 2 h at 50 ° C. After concentration under reduced pressure, the residue was purified by reverse phase chromatography with ACN / H2O to yield 6 g (72.6%) of the title compound as a yellow solid. MS m / z: 402 [M + H] +.
[0263] [0263] Step B. (2R, 3R, 4S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5 -methylene tetrahydrofuran-2-carbonitrile. To a solution of (2R, 3R, 4S, 5S) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy -5- (iodomethyl) tetrahydrofuran-2-carbonitrile (12 g, 29.9 mmol) in acetonitrile (240 mL) was added 1,8-diazabicyclo [5.4.0] undec-7- ene (15 g, 59 , 8 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred for 4 h at 60 ° C. After concentration under reduced pressure, the residue was purified by reverse phase chromatography with ACN / H2O to yield 7 g (79%) of the title compound as a yellow solid. MS m / z: 274 [M + H] +.
[0264] [0264] Step C. (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-fluoro-3 , 4-dihydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile. To a solution of (2R, 3R, 4S) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5-methylenetetra -hydrofuran-2-carbonitrile (2 g, 7.32 mmol, 1.00 equiv) in tetrahydrofuran (60 mL) under an inert atmosphere, triethylamine trifluorohydrate (2.94 g, 18.3 mmol, 2.50 equiv) and N-iodosuccinimide (2.47 g, 10.98 mmol, 1.50 equiv) at room temperature. The resulting solution was stirred for 2 hours. After concentration under reduced pressure, the residue was purified by reverse phase chromatography with ACN / H2O to yield 1 g (33%) of the title compound as a yellow solid. MS m / z: 420 [M + H] +.
[0265] [0265] Step D. (2R, 3R, 4S, 5R) -2- (4-benzamidopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -2-cyan dibenzoate -5-fluoro-5- (iodomethyl) tetrahydrofuran-3,4-diyl. To a solution of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -5-fluoro-3,4-di -hydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile (1.1 g, 2.62 mmol) in pyridine (22 mL) under an inert atmosphere benzoyl chloride (1.66 g, 11.8 mmol) was added , 4.50 equiv) by dripping with stirring at 0 ° C. The resulting solution was stirred for 2 h at 0 ° C, and then the reaction was quenched by the addition of water (100 ml). The resulting solution was extracted with dichloromethane (100 mL x 2) and the combined organic extracts were subjected to drying with anhydrous sodium sulfate. After filtration, the resulting solution was concentrated under reduced pressure. Purification (silica gel column with ethyl acetate / petroleum ether (1: 10-1: 2)) produced 1.1 g (58%) of the title compound as a yellow solid. MS m / z: 732 [M + H] +.
[0266] [0266] Step E. (2R, 3R, 4S, 5S) -2- (4-benzamidopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- ( (benzoyloxy) methyl) -2-cyano-5-fluorotetrahydrofuran-3,4-diyl. To a dibenzoate solution of (2R, 3R, 4S, 5R) -2-
[0267] [0267] Step F. (2R, 3R, 4S, 5S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-fluoro-3 , 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbo-nitrile. A dibenzoate solution of (2R, 3R, 4S, 5S) -2- (4-benzamidopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5 - ((benzoyloxy) methyl) -2-cyano-5-fluorotetrahydrofuran-3,4-diyl (590 mg, 0.58 mmol, 1.00 equiv) in 2N NH3 / MeOH (20 mL) was stirred for 20 h at room temperature. The resulting mixture was concentrated under reduced pressure. Purification (silica gel column with DCM / MeOH (6: 1)) produced 150 mg (60%) of the title compound as a white solid. MS m / z: 310 [M + H] +. 1H NMR (CD3OD): δ 7.89 (s, 1H), 7.01 (d, J = 4.6 Hz, 1H), 6.90 (d, J = 4.6 Hz, 1H), 4 , 75 (d, J = 6.3 Hz, 1H), 4.49 (dd, J = 20.0, 6.4 Hz, 1H), 3.90 - 3.71 (m, 2H). 19F NMR (CD3OD): δ -125.07. Example 2 Compound 2: (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 5-azido-3,4- dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile.
[0268] [0268] Step A. (2R, 3R, 4S, 5S) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-azido-3 , 4-dihydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile. To a solution of ICl (1.19 g, 7.3 mmol, 2.50 equiv) in DMF (4 mL) was added NaN3 (951 mg, 14.6 mmol, 5.00 equiv). After stirring for 30 min at 30 ° C, a solution of (2R, 3R, 4S) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl ) -3,4-dihydroxy-5-methylenetetrahydrofuran-2-carbonitrile (Compound 1, product from Step B, 800 mg, 2.92 mmol, 1.00 equiv) (8 mL) in DMF was added to the stirred solution at room temperature. The resulting solution was stirred for 1 h at room temperature, and then the reaction was quenched by the addition of 8 ml of Na2S2O3 (aq.). The resulting mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography (ACN / H2O) to produce 0.88 g (60%) of the title compound as a light yellow solid. MS m / z: 443 [M + H] +.
[0269] [0269] Step B. (2S, 3S, 4R, 5R) -2-azido-5- (4-benza-midopyrrolo [2,1-f] [1,2,4] triazin-7-yl dibenzoate) -5-cyano-2- (iodomethyl) tetrahydrofuran-3,4-diyl. To a solution of (2R, 3R, 4S, 5S) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -5-azido-3,4-di -hydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile (500 mg, 1.13 mmol) in anhydrous pyridine (6 mL) under an inert atmosphere, benzoyl chloride (715 mg, 5.1 mmol, 4.5 equiv) at 0 ° C and the mixture was stirred for 1.5 h at 0 ° C. The reaction was inactivated by the addition of MeOH (2 mL), and concentrated under reduced pressure and then dissolved in ethyl acetate (100 mL), washed with NaHCO3 aq. (30 mL), aq. (30 mL) and the organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column with PE / EA = 2/1) produced 597 mg (70%) of the title compound as a yellow solid. MS m / z: 755 [M + H] +.
[0270] [0270] Step C. Dibenzoate of (2R, 3S, 4R, 5R) -2-azido-5- (4-benza-
[0271] [0271] Step D. (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-azido-3 , 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbo-nitrile. The (2R, 3S, 4R, 5R) -2-azido-5- (4-benza-midopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- dibenzoate mixture cyano-2 - ((2,2,2-trifluoroacetoxy) methyl) tetrahydrofuran-3,4-diyl and dibenzoate (2R, 3S, 4R, 5R) -2-azido-5- (4 -benzamidopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-cyano-2- (hydroxymethyl) terhydrofuran-3,4-diyl (400 mg, 1 , 78 mmol) was dissolved in 2N NH3 in methanol (10 mL) and stirred for 20 h at room temperature. The resulting solution was concentrated under reduced pressure. Purification by RP-HPLC (XBridge Prep C18 OBD Column, 19 mm x 150 mm, 5 µm; mobile phase, A: 10 mM NH4HCO3 in water, B: 10 mM NH4HCO3 in ACN (ACN 5.0% up to 27.0 % for 7 min); Detector, UV 254/220 nm) produced 56.3 mg (34%) of the title compound as a light yellow solid. MS m / z: 333 [M + H] +. 1H NMR (CD3OD) δ 7.88 (s, 1H), 7.03 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 5, 02 (d, J = 5.8 Hz, 1H), 4.43 (d, J = 5.8 Hz, 1H), 3.82 (d, J = 12.2 Hz, 1H), 3.69 ( d, J = 12.2 Hz, 1H). Example 3 Compound 3: (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 5- (fluoromethyl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile.
[0272] [0272] Step A. (3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) - 5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-ol. To a solution of 7-bromopyrrolo [2,1-f] [1,2,4] triazine-4-amine (0.781 g, 3.667 mmol, 1.1 equiv) in anhydrous THF (200 mL) under an inert atmosphere, was Sodium hydride (60%, 293 mg, 7.33 mmol, 2.2 equiv) is added, then immediately added 1,1,4,4-tetramethyl-1,4-dichloro-disethylene (0.78 g, 3.667 mmol , 1.1 equiv). The mixture was stirred for 20 min at room temperature. The reaction was then cooled to - 78 ° C and n-butyllithium (2.5 M in hexanes, 4.4 mL, 11 mmol, 3.3 equiv) was added slowly over 10 min. The reaction was left under stirring for 20 min before (3R, 4S, 5R) -3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) dihydrofuran- 2 (3H) -one (Intermediate 2, 1.5 g, in 5 mL of THF, 3.33 mmol, 1.00 equiv) is added by dripping. The resulting solution was stirred for 1 h at -78 ° C, then the reaction was quenched by the addition of aq. (200 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers were combined, subjected to drying with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography (ACN / H2O) to yield 1.15 g (59%) of the title compound (two isomers, ratio: 1/1) as a yellow solid. MS m / z: 585 [M + H] +.
[0273] [0273] Step B. (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydro-furan-2-carbonitrile and (2S, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-carbonitrile. To a solution of (3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) - 5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-ol (1.15 g, 1.97 mmol, 1.00 equiv) in DCM (20 mL) under an inert atmosphere, was trimethylsilanocarbonitrile (682 mg, 6.90 mmol, 3.50 equiv) was added by dripping at 0 ° C. The resulting solution was stirred for 10 min. To this solution, trimethylsilyl trifluoromethanesulfonate (1.96 g, 8.87 mmol, 4.50 equiv) was added by dripping at 0 ° C. The resulting solution was stirred for 2 h at 0 ° C, then the reaction was quenched by the addition of aq. (200 mL). The resulting solution was extracted with DCM (2 x 200 ml) and the organic layers were combined and subjected to drying with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by reverse phase flash chromatography (ACN / H2O) produced 397 mg (35%) of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2 , 4] triazin-7-yl) - 3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-carbonitrile as a yellow solid and 390 mg (35% ) of (2S, 3R, 4S, 5R) - 2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-carbonitrile as a yellow solid. MS m / z: 594 [M + H] +.
[0274] [0274] Step C. (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- (fluoromethyl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile. To a solution of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) - 5 - ((benzyloxy) methyl) -5- (fluoromethyl) tetrahydrofuran-2-carbonitrile (350 mg, 0.59 mmol, 1.00 equiv) in DCM (1 mL) under an inert atmosphere, an boron trichloride solution (1M in DCM, 20 mL) by dripping at -20 ° C. The resulting solution was stirred for 1 h at -20 ° C, and then the reaction was quenched by the addition of K2CO3 / MeOH. The pH value of the solution was adjusted to 7 with TEA. The solids were filtered and the resulting filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by RP-HPLC (Column XBridge Prep C18 OBD, 19 mm x 150 mm 5 µm; Mobile phase, A: 10 mM aq. NH4HCO3, B: NH4HCO310 mM in MeCN; Gradient 5 a 27% B; Detector, UV 254/220 nm) to yield 59.3 mg (31.3%) of the title compound as a white solid. MS m / z: 324 [M + H] +. 1H NMR (CD3OD): δ 7.86 (s, 1H), 6.89 (d, J = 4.8 Hz, 1H), 6.82 (d, J = 4.8 Hz, 1H), 5 .09 (d, J = 5.6 Hz, 1H), 4.60 - 4.80 (m, 2H), 19 4.37 (d, J = 5.6 Hz, 1H), 3.20-3 , 23 (m, 2H). F NMR (CD3OD): δ - 237.30. Example 4 Compound 4: (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 3,4-dihydroxy- 5- (hydroxymethyl) tetrahydrofuran-2,5-dicarbonitrile.
[0275] [0275] Step A. (2R, 3R, 4S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-bis ((tert- butyldimethylsilyl) oxy) -5-methylenetetrahydrofuran-2-carbo-nitrile. To a solution of (2R, 3R, 4S) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5 -methylenetetrahydrofuran-2-carbonitrile (800 mg, 2.92 mmol) in DMF (8 mL) under an inert atmosphere, imidazole (981 mg, 14.7 mmol, 5 equiv), DMAP (356.2 mg, 2.92 mmol, equiv), tert-butyl (chloro) dimethylsilane (TBDMSCl) (2.2 g, 14.7 mmol, 5 equiv) and the mixture was stirred for 5 h at 60 ° C. The reaction was inactivated by the addition of CH3OH (5 ml), diluted with ethyl acetate (100 ml), washed with aq. (30 mL × 2), aq. (30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Column purification of DCM / MeOH silica gel (30: 1) produced 1 g (68%) of the title compound as a light yellow solid. MS m / z [M + H] + (ESI): 502.
[0276] [0276] Step B. N- (7 - ((2R, 3R, 4S) -3,4-Bis ((tert-butyldimethylsilyl) oxy) - 2-cyano-5-methylenetetrahydrofuran-2-yl) pyrrole [ 2,1-f] [1,2,4] triazin-4-yl) benzamide. To a solution of (2R, 3R, 4S) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -3,4-bis ((tert-butyldimethylsilyl) oxy) -5-methylenetetrahydrofuran-2-carbonitrile (1 g, 2.0 mmol, 1.0 equiv) in anhydrous pyridine (10 mL) under an inert atmosphere, benzoyl chloride (330 mg, 2, 4 mmol, 1.2 equiv) at 0 ° C and the mixture was stirred for 2 h at 0 ° C. The reaction was quenched by the addition of MeOH (2 ml), and the reaction mixture was concentrated under reduced pressure. The crude evaporated residue was dissolved in ethyl acetate (100 ml), washed with aq. (30 mL), aq. (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification on a PE / EA silica gel column (5: 1) yielded 700 mg (58%) of the title compound as a yellow solid. MS m / z [M + H] + (ESI): 606.
[0277] [0277] Step C. N- (7 - ((5R, 6R, 7S) -6,7-Bis ((tert-butyldimethylsilyl) oxy) - 5-cyano-1,4-dioxaspas [2.4] heptan-5- il) pyrrolo [2,1-f] [1,2,4] triazin-4-yl) benzamide. To a solution of N- (7 - ((2R, 3R, 4S) -3,4-bis ((tert-butyldimethylsilyl) oxy) -2-cyano-5-methylenetetrahydrofuran-2-yl) pyrrole [ 2,1- f] [1,2,4] triazin-4-yl) benzamide (700 mg, 1.16 mmol, 1.00 equiv) in DCM (10 mL), NaHCO3 (1.46 g, 17.4 mmol, 15 equiv), H2O
[0278] [0278] Step D. N- (7 - ((2R, 3R, 4S) -3,4-Bis ((tert-butyldimethylsilyl) oxy) - 2,5-diciano-5 - ((((trimethylsilyl) oxy) methyl) ) tetrahydrofuran-2-yl) pyrrolo [2,1-f] [1,2,4] triazin-4-yl) benzamide. To a solution of N- (7 - ((5R, 6R, 7S) -6,7- bis ((tert-butyldimethylsilyl) oxy) -5-cyano-1,4-dioxaspas [2.4] heptan-5-yl) pyrrolo [2,1-f] [1,2,4] triazin-4-yl) benzamide (750 mg, 1.20 mmol) in DCM (20 mL), TMSCN (831 mg, 8.4 mmol, 7.0 eq). To this mixture was added InBr3 (1.1 g, 3.0 mmol, 2.5 eq) at 0 ° C. The reaction mixture was stirred for 3 h at 0 ° C. The reaction mixture was diluted with ethyl acetate (100 ml), washed with aq. (30 mL × 2), then with brine (30 mL). The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure to produce 800 mg of the crude title compound (two isomers, 3/1 ratio) as a yellow solid which was used directly in the following steps. MS m / z [M + H] + (ESI): 721.
[0279] [0279] Step E. N- (7 - ((2R, 3R, 4S) -2,5-Dicyano-3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrole [2,1-f] [1,2,4] triazin-4-yl) benzamide. To a solution of N- (7 - ((2R, 3R, 4S) -3,4-bis ((tert-butyldimethylsilyl) oxy) - 2,5-diciano-5 - ((((trimethylsilyl) oxy) methyl) tetra -hydrofuran-2-yl) pyrrolo [2,1- f] [1,2,4] triazin-4-yl) benzamide (800 mg, 1.11 mmol, 1.00 equiv) in DCM (8 mL), TEA.3HF (2.14 g, 13.3 mmol, 12 equiv) and TEA were added
[0280] [0280] Step F. (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -3,4-di -hydroxy-5- (hydroxymethyl) tetrahydrofuran-2,5-dicarbonitrile and (2R, 3R, 4S, 5S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin- 7-yl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2,5-dicarbonitrile. A solution of N- (7 - ((2R, 3R, 4S) -2,5-dicyano-3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrole [2, 1-f] [1,2,4] triazin-4-yl) benzamide (450 mg, 1.07 mmol) in methanolic ammonia (2N, 14 mL) was stirred for 20 h at room temperature. The resulting solution was concentrated under reduced pressure. Purification by RP-HPLC (XBridge Prep C18 OBD column, 19 mm x 150 mm 5 µm; mobile phase, A: 10 mM aq. NH4HCO3, B: 10 mM NH4HCO3 in ACN; gradient 5% to 27% B over 7 min; detector, UV 254/220 nm) produced 60 mg (16% for four steps) of (2R, 3R, 4S, 5R) -2- (4-Aminopyrrole [2,1-f] [1,2,4 ] triazin-7-yl) -3,4-dihydro- 5- (hydroxymethyl) tetrahydrofuran-2,5-dicarbonitrile (Compound 4) as a light yellow solid. MS: m / z 317 [M + H] +. 1H NMR (CD3OD) δ 7.91 (s, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 5, 39 (d, J = 4.6 Hz, 1H), 4.68 (d, J = 4.6 Hz, 1H), 4.05 (s, 2H). Example 5 Compound 5: ((((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-cyano-2 -fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -D isopropyl alaninate.
[0281] [0281] Step A. (3aR, 4R, 6R, 6aS) -4- (4-Aminopyrrolo [2,1-f] [1,2,4] tri-azin-7-yl) -6-fluoro-6 - (iodomethyl) -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbonitrile. To a solution of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-fluoro-3,4 -dihydroxy-5- (iodomethyl) tetrahydrofuran-2-carbonitrile (Compound 1, product of Step C, 500 mg, 1.19 mmol) in dioxane (10 mL) under inert atmosphere, trimethoxymethane was added (10 mL), and PTSA (158.2 mg, 0.92 mmol, 0.77 equiv). The resulting solution was stirred for 3 h at 50 ° C. The reaction was then inactivated by the addition of triethylamine, and concentrated under reduced pressure. Purification on a DCM / MeOH silica gel column (100: 1-20: 1) yielded 340 mg (62%) of the title compound as a yellow oil. MS m / z [M + H] + (ESI): 462.
[0282] [0282] Step B. ((3aS, 4S, 6R, 6aR) -6- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6- benzoate cyano-4-fluoro-2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl. To a solution of (3aR, 4R, 6R, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-fluoro-6- ( iodomethyl) -2-methoxytetrahydro-hole [3,4-d] [1,3] dioxol-4-carbonitrile (1.0 g, 2.2 mmol) in DMF (100 mL) under inert atmosphere BzOK was added (1.74 g, 11 mmol, 5.00 equiv), and 18-Crown-6 (1.15 g, 4.4 mmol, 2.00 equiv). The resulting solution was stirred for 16 h at 100 ° C. The resulting solution was diluted with EtOAc, washed with H2O and dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Purification on EA / PE silica gel column (1: 10-3: 1) yielded 600 mg (61%) of the title compound as a yellow solid. MS m / z [M + H] + (ESI): 456.
[0283] [0283] Step C. (3aR, 4R, 6S, 6aS) -4- (4-Aminopyrrolo [2,1-f] [1,2,4] tri-azin-7-yl) -6-fluoro-6 - (hydroxymethyl) -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbonitrile. A ((3aS, 4S, 6R, 6aR) -6- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-cyano-4-fluoro benzoate solution -2-methoxytetra-hydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl (170 mg, 0.37 mmol) in 2N methanol ammonia (2N, 10 mL) was stirred for 20 h at room temperature. The resulting solution was concentrated under reduced pressure. Purification on a DCM / MeOH silica gel column (100: 1-20: 1) produced 72 mg (55%) of the title compound as a white solid. MS m / z [M + H] + (ESI): 352.
[0284] [0284] Step D. (((((3aS, 4S, 6R, 6aR) -6- (4-Aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -6-cyano- Isopropyl 4-fluoro-2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -D-alaninate. To a solution of (3aR, 4R, 6S, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-fluoro-6- (hydroxymethyl) -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbonitrile (25 mg, 0.07 mmol) in ACN (1 mL) under inert atmosphere 1-methyl-1H-imidazole was added (58.4 mg, 0.71 mmol, 10.00 equiv). Isopropyl (chloro (phenoxy) phosphoryl) -D-alaninate (39.1 mg, 0.13 mmol, 1.80 equiv) (prepared according to McGuigan et al. J. Med. Chem. 2005, 48 (10) , 3504-3515) in ACN (0.4 mL) was added to the drip reaction mixture with stirring at 0 ° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, washed with H2O and dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Purification on a DCM / MeOH silica gel column (10: 1)) yielded 25 mg (57%) of the title compound as a yellow oil. MS m / z [M + H] + (ESI): 621.
[0285] [0285] Step E. ((((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- isopropyl cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -D-alaninate. A solution of
[0286] [0286] Step A. (((((3aS, 4S, 6R, 6aR) -6- (4-Aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -6-cyano- Isopropyl 4-fluoro-2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -L-alaninate. To a solution of (3aR, 4R, 6S, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-fluoro-6- (hydroxymethyl) -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbonitrile (Compound 5, product of Step C) (29 mg, 0.08 mmol) in ACN (1.16 mL) under inert atmosphere 1-methyl-1H-imidazole (67.7 mg, 0.82 mmol, 10.00 equiv) was added. This was followed by the addition of an isopropyl (chlorine (phenoxy) phosphoryl) -L-alaninate solution (45.36 mg, 0.15 mmol, 1.80 equiv) (prepared according to McGuigan et al. J. Med Chem. 2005, 48 (10), 3504-3515) in ACN (0.5 ml) by dripping with stirring at 0 ° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, washed with H2O and dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Purification on a DCM / MeOH silica gel column (10: 1) yielded 29 mg (57%) of the title compound as a yellow oil. MS m / z [M + H] + (ESI): 621.
[0287] [0287] Step B. (((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- isopropyl cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alaninate. A solution of (((((3aS, 4S, 6R, 6aR) -6- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-cyano-4-fluoro -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -Isopropyl L-alaninate (80 mg, 0.13 mmol) in HCOOH aq. 80% (8 ml) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The evaporated crude residue was purified by RP-HPLC (XBridge Shield RP18 OBD column, 5 µm, 19 mm × 150 mm; mobile phase, A; 0.1% aq. HCOOH, B: 0.1% HCOOH in ACN gradient 19% to 44% B over 9 min; detector, UV 254 nm) to produce 31.8 mg (43%) of the title compound as a white solid. MS: m / z 579 [M + H] +. 1H NMR (CD3OD): δ 7.80 (d, J = 4.6 Hz, 1H), 7.29-7.24 (m, 2H), 7.16-7.10 (m, 3H), 6, 93-6.83 (m, 2H), 4.92-4.85 (m, 1H), 4.75 (d, J = 6.5 Hz, 1H), 4.55-4.46 (m, 1H), 4.34-4.29 19 (m, 2H), 3.87-3.70 (m, 1H), 1.27-1.13 (m, 9H). F NMR (CD3OD): δ -123.83, -124.03. 31 P NMR (CD3OD): δ 3.45, 3.29. Example 7 Compound 7: ((((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-cyano-2 -fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-diisopentyl aspartate.
[0288] [0288] Step A. Diisopentyl L-aspartate hydrochloride. To a solution of L-aspartic acid (1 g, 7.51 mmol) in 3-methylbutan-1-ol (40 mL) was added chlorotrimethylsilane (5.72 mL, 6.00 equiv) by dripping with stirring at 0 ° C. The resulting solution was stirred for 48 h at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was purified on a silica gel column with dichloromethane / methanol (50: 1-10: 1) to yield 2.1 g (91%) of the title compound as a yellow oil. MS m / z [M + H] + (ESI): 274.
[0289] [0289] Step B. (Diisopentyl chlorine (phenoxy) phosphoryl) -L-aspartate. To a solution of phenoxyphosphonoyl dichloride (340 mg, 1.61 mmol) in dichloromethane (8 mL) was added diisopropyl L-aspartate hydrochloride (521 mg, 1.69 mmol, 1.05 equiv), TEA (0.47 mL, 3.38 mmol, 2.10 equiv) by dripping with stirring at -78 ° C. The resulting solution was stirred for 3 h at -78 ° C to room temperature. The reaction mixture was diluted with dry cyclohexane, filtered and concentrated under reduced pressure. Purification on a silica gel column with hexane: EA (10: 1) yielded 340 mg (47%) of the title compound as a yellow oil. 31P NMR (CDCl3): δ 8.39, 8.29.
[0290] [0290] Step C. (((((3aS, 4S, 6R, 6aR) -6- (4-Aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -6-cyano- 4-fluoro-2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -L-diisopentyl aspartate. To a solution of (3aR, 4R, 6S, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-fluoro-6- (hydroxymethyl) -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbonitrile (Compound 5, product of Step C, 25 mg, 0.07 mmol) in ACN (1 mL) was added Im (58.4 mg, 0.71 mmol, 10.00 equiv),
[0291] [0291] Step D. ((((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (pheoxy) phosphoryl) -L-diisopentyl aspartate. A solution of (((((3aS, 4S, 6R, 6aR) -6- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-cyano-4-fluoro -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -Disisopentyl L-aspartate (85 mg, 0.11 mmol, 1.00 equiv) in aq. 80% (10 ml) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (85 mg) was purified by RP-HPLC (XBridge Shield RP18 OBD column, 5 µm, 19 mm x 150 mm; Mobile phase, A: HCOOH, 0.1% aq, B: HCOOH 0.1 % in ACN; Gradient 15% to 46% B over 10 min; Detector, UV 254 nm) to produce 37.4 mg (47%) of the title compound as a white solid. MS: m / z 721 [M + H] +. 1H NMR (CD3OD): δ 7.88 (d, J = 7.0 Hz, 1H), 7.43-7.27 (m, 2H), 7.20 (m, 3H), 7.06- 6.83 (m, 2H), 4.79 (d, J = 6.4 Hz, 1H), 4.61 - 4.31 (m, 3H), 4.26 (m, 1H), 4.22 -3.79 (m, 4H), 2.89-2.54 (m, 2H), 1.74-1.56 (m 2H), 1.56-1.28 (m, 4H), 0, 91 19 31 (m, 12H). F-NMR (CD3OD): δ -123.52, -123.78. P NMR (CD3OD): δ 3.29, 3.07. Example 8 Compound 8: ((((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-cyano-2 -fluoro-3,4-dihydroxytetrahydrofuran-2-
[0292] [0292] A mixture of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -3,4-dihydroxy -5- (hydroxymethyl) tetrahydrofuran-2,5-dicarbonitrile (Compound 4, 11 mg, 0.04 mmol), (chloro (phenoxy) phosphoryl) -L-neopentyl alaninate (prepared according to PCT Publication n ° WO 2012/12776 A1) (40 mg, 0.12 mmol) and N-methylimidazole (NMI) (40 µL, 0.48 mmol) in anhydrous acetonitrile (0.4 mL) was stirred overnight under Air at room temperature, then was concentrated and purified by RP-HPLC (5 to 95% B; A: 0.1% aq HCOOH, B: 0.1% HCOOH in MeCN) to produce 3.2 mg (13 %) of the title compound. MS m / z: 607.1 [M + 1] +. 31 P NMR (CD3CN, D2O): δ 2.89 (s), 19 NMR
[0293] [0293] Step A. (((((3aS, 4S, 6R, 6aR) -6- (4-Aminopyrrolo [2,1- f] [1,2,4] triazin-7-yl) -6-cyano- 2-ethylbutyl 4-fluoro-2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -L-alaninate. A mixture of (3aR, 4R, 6S, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-fluoro-6- (hydroxymethyl) - 2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-carbo-nitrile (Compound 5, product from Step C, 14 mg, 0.04 mmol), NMI (40 µL, 0.48 mmol) and 2-ethylbutyl (chloro (phenoxy) phosphoryl) -L-alaninate (43 mg, 0.12 mmol) in acetonitrile (0.5 mL) was stirred at room temperature overnight under Ar. The mixture was then diluted with EtOAc and washed consecutively with 1N citric acid, water, sat. NaHCO3. aq., brine and subjected to drying (Na2SO4). The crude evaporated residue was purified by flash chromatography on silica gel with a gradient of 4 to 10% MeOH in DCM to produce the title compound as a colorless friable foam (20 mg, 76%). MS m / z: 663.1 [M + 1] +.
[0294] [0294] Step B: (((((2S, 3S, 4R, 5R) -5- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5- 2-ethylbutyl cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alaninate. A solution of (((((3aS, 4S, 6R, 6aR) -6- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6-cyano-4-fluoro -2-methoxytetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-2-ethylbutyl L-alaninate (20 mg, 0.03 mmol) in aq. 80% (1 ml) was stirred for 4 h at room temperature, then it was concentrated and coevaporated several times with a mixture of toluene and MeCN, and finally with MeOH containing 1 drop of Et3N. The crude evaporated residue was purified by flash chromatography on silica gel with a gradient of 4 to 10% MeOH in DCM to yield 14 mg (77%) of the title compound. MS m / z: 618.9 [M-1] -. 31 NMR
[0295] [0295] Step A. Propyl L-alaninate hydrochloride. To a solution of L-alanine (500 mg, 5.61 mmol) in propan-1-ol (20 mL) was added thionyl chloride (4 g, 33.62 mmol, 6.00 equiv) by dropping with stirring at 0 ° C. The resulting solution was stirred for 3 h at 90 ° C, and concentrated under reduced pressure. The resulting solution was diluted with n-hexane. The solids were collected by filtration. This resulted in 900 mg (95%) of propyl L-alaninate hydrochloride as a white solid. MS m / z [M + H] + (ESI): 132.
[0296] [0296] Step B. 2,2 '- ((Chlorophosphoryl) bis (azanedi-yl)) (2S, 2'S) -diethyl dipropylate. To a solution of propyl L-alaninate hydrochloride (855 mg, 6.52 mmol, 2.00 equiv) in dichloromethane (20 mL) under an inert atmosphere was added POCl3 (500 mg, 3.26 mmol, 1, 00 equiv) at room temperature. This was followed by the addition of TEA (2.73 ml, 19.56 mmol, 6.00 equiv) by dropping with stirring at -70 ° C. The resulting solution was stirred for 3 h at -70 ° C to room temperature. The resulting solution was diluted with dry cyclohexane. The solids were filtered and the solution was then concentrated under reduced pressure. The residue was purified on a silica gel column with hexane: EA (10: 1-2: 1). This resulted in 400 mg (36%) of 2.2 '- ((chlorophosphoryl) bis (azododiyl)) (2S, 2'S) -dipropyl dipropylate as yellow oil. 31 P NMR (CDCl3, 400 MHz): δ 16.2.
[0297] [0297] Step C. To a solution of (3aR, 4R, 6S, 6aS) -4- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -6 -fluoro-6- (hydroxymethyl) -2-methoxytetrahydro-puncture [3,4-d] [1,3] dioxol-4-carbonitrile (product from Step C of Example 5) (27 mg, 0.08 mmol ) in THF (1.5 mL) under inert atmosphere, t-BuMgCl (1 M in THF, 0.23 mL, 3.00 equiv) was added by dropping with stirring at -78 ° C. The resulting solution was stirred for 30 min at room temperature. To this was added a solution of 2,2 '- ((chlorophosphoryl) bis (azanedi-yl)) (2S, 2'S) -diopropyl dipropionate (131.8 mg, 0.38 mmol, 5.00 equiv) in tetrahydrofuran (0.2 ml) by dripping with stirring at -78 ° C. The resulting solution was stirred for 1 hour at room temperature. The reaction was then inactivated with aq. (50 ml),
[0298] [0298] Compound 10 was prepared as follows: A solution of Compound 10A (110 mg, 0.17 mmol, 1.00 equiv) in 80% HCOOH / H2O (8 mL) was stirred for 15 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by RP-HPLC (Column XBridge Prep OBD C18, 19 mm x 250 mm, 5 µm; mobile phase, A: 0.1% aq. HCOOH, B: 0.1% HCOOH in ACN; gradient 27% to 42% B over 8 min; detector, UV 220 nm). This resulted in 31.7 mg (31%) of Compound 10 as a light yellow solid. MS m / z [M + H] + (ESI): 616. 1H NMR (CD3OD): δ 7.93 (s, 1H), 7.01 (d, J = 4.6 Hz, 1H), 6 , 93 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 6.6 Hz, 1H), 4.61 (dd, J = 20.3, 6.6 Hz, 1H) , 4.34-4.17 (m, 2H), 4.13-3.97 (m, 4H), 3.94-3.80 (m, 2H), 1.75-1.59 (m, 4H), 1.33-1.27 (m, 6H), 0.95-0.89 (m, 6H). 19F NMR (CD3OD): δ -124.38. 31 P NMR (CD3OD): δ 13.675. Example 11 Compound 11: ((((((2R, 3S, 4R, 5R) -5- (4-Aaminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -2-azido-5 -cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -Isopropyl D-alaninate
[0299] [0299] A mixture of nucleoside (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-azido- 3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile (Compound 2, 10 mg, 0.03 mmol), NMI (30 µL, 0.36 mmol) and phosphoryl (chlorine (phenoxy)) Isopropyl L-alaninate (28 mg, 0.1 mmol) in acetonitrile (0.4 mL) was stirred at room temperature under Ar for 1 h. The mixture was concentrated and the residue was partitioned between CH2Cl2 and 1N citric acid. The organic layer was washed with water, sat. NaHCO3. aq., and brine. The combined aqueous washes were re-extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4), evaporated and purified by flash chromatography on silica gel with a gradient of 3 to 12% MeOH in DCM to produce 4 mg (22%) of the title compound . MS m / z: 602.1 [M + 1] + -. -31P NMR (CD3OD): δ 3.21, 3.18 (2s). Example 12 Compound 12: ((2S, 3S, 4R, 5R) -5- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - tetrahydrogen triphosphate 5-cyano-2-fluoro-3,4-dihydroxytetrahydro-furofuran-2-yl) methyl.
[0300] [0300] (2R, 3R, 4S, 5S) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -5-fluoro-3,4-di- hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile dry (Compound 1, 0.05 mmol) was dissolved in dry PO (OMe) 3 (0.7 mL). N-Methylimidazole (0.009 ml, 0.11 mmol) was added followed by POCl3 (0.009 ml, 0.11 mmol), and the mixture was kept at room temperature for 20 to 40 min. The reaction was controlled by LCMS and monitored for the appearance of corresponding nucleoside-5'-monophosphate. After the completion of the reaction, pyrophosphate tetrabutylammonium salt (150 mg) was added, followed by DMF (0.5 mL) to obtain a homogeneous solution. After 1.5 hours at room temperature, the reaction was diluted with water (10 mL) and loaded onto a HiLoad 16/10 column with Q Sephaler High Performance. The separation was performed in a linear gradient of 0 to 1N NaCl in a 50 mM TRIS buffer solution (pH 7.5). The triphosphate was eluted from 75 to 80% of B. The corresponding fractions were concentrated. Desalination was achieved by reverse phase HPLC on the Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer solution to produce the title compound (see Table 5). Example 13 Compound 13: ((2R, 3S, 4R, 5R) -5- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - tetrahydrogen triphosphate 5-cyano-2- (fluoromethyl) -3,4-dihydroxy-tra-hydrofuran-2-yl) methyl.
[0301] [0301] The title compound was prepared in the similar manner described in Example 12 using (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazine -7-yl) -5- (fluoromethyl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile (Compound 3) as a starting material (see Table 5). Example 14 Compound 14: ((2R, 3S, 4R, 5R) -5- (4-amine) tetrahydrogen triphosphate
[0302] [0302] The title compound was prepared in the similar manner described in Example 12 using (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [2,1- f] [1,2,4] triazine -7-yl) -5-azido-3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile (Compound 2) as a starting material (see Table 5). Example 15 Compound 15: (2R, 3R, 4S, 5R) -2- (4-Aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) - 5- (chloromethyl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile.
[0303] [0303] The title compound can be prepared in a manner analogous to Compound 3, using (3R, 4S, 5R) -5- (chloromethyl) -3,4-dihydroxy-5- (hydroxymethyl) di- hydrofuran-2 (3H) -one instead of (3R, 4S, 5R) - 3,4-bis (benzyloxy) -5 - ((benzyloxy) methyl) -5- (fluoromethyl) dihydrofuran-2 (3H) - ona (Intermediate 2) in Step A. Table 5 Compound MS (M-1) P (γ) P (β) P (α) 12 548.3 -10.91 (d) -22.27 (t) - 12.22 (d) 13 561.8 -10.98 (d) -23.43 (t) -11.96 (d) 14 571.2 -11.00 (d) -22.40 (t) - 12.45 (d) Example A Antiviral assay against Dengue virus (DENV)
[0304] [0304] Dengue virus type 2, New Guinea C strain (NG-C) and Dengue virus type 4, strain H241, were purchased from the ATCC (Manila, VA, USA; item numbers VR- 1584 and VR-1490, respectively). Twenty-four hours before dosing, Huh-7.5 cells were plated in 96-well plates at a density of 1.5 x 105 / mL in DMEM medium supplemented with 10% fetal bovine serum, 1% HEPES buffer, 1% Penicillin / Streptomycin and 1% non-essential amino acids (all from Mediatech, Manassas, VA, USA). On the day of infection, the serially diluted compounds were added to the cells and incubated for 4 hours. After the end of the 4-hour pre-incubation period, the cells were infected with either the Dengue virus type 2 NG-C or the Dengue virus type 4 H241. The viral inoculum was selected to cause an 80 to 90% cytopathic effect in five to six days. Infected cells were incubated for five (NG-C) to six (H241) days at 37 ° C, 5% CO2. To develop the assay, 100 µL of medium was replaced with 100 µL of CellTiter Glo® reagent (Pro-mega, Madison, WI, USA), and incubated for 10 minutes at room temperature. Luminescence was measured in a Victor X3 multi-marker plate reader. The cytotoxicity of the potential compound was determined using uninfected parallel cultures. The compounds of Formula (I) showed activity in this DENV assay as indicated by the EC50 values provided in Table 6. The compounds of Formula (I) also showed relatively low values of toxicity in the assay as indicated by the values of CC50 provided in Table 6. Example B Antiviral assay against rhinovirus (HRV1B)
[0305] [0305] HeLa-OHIO cells (Sigma Aldrich, St. Louis, MO, USA) were plated in 96-well plates at a density of 1.5 x 10 5 cells per well in assay medium (MEM without red of phenol or L-
[0306] [0306] HeLa-derived cells containing the stable RSV replicon were cultured in DMEM containing 4,500 mg / L of D-L-glucose, L-glutamine and 110 mg / L of sodium pyruvate. The medium was additionally supplemented with 10% (v / v) FBS (Mediatech), 1% (v / v) penicillin / streptomycin (Mediatech), and 10 µg / mL Blasticidin (BSD) (Invi - vogen). The cells were maintained at 37 ° C in a humidified 5% CO2 atmosphere. On the first day, 5000 cells of the RSV replicon per well were plated on a 96-well plate. The next day, the compounds to be tested were solubilized in 100% DMSO to 100 × the desired final test concentration. The cells were incubated with the compounds for 7 days at 37 ° C in an atmosphere of 5% CO2 before measuring the luciferase reading. Cell viability (CC50) was measured with a CellTiter-Glo cell proliferation assay (Promega). The compounds of Formula (I) showed activity in this RSV assay as indicated by the EC50 values provided in Table 6. The compounds of Formula (I) also showed relatively low values of toxicity in the assay as indicated by the values of CC50 provided in Table 6. Example D Antiviral assay against Ebolavirus (EBOV)
[0307] [0307] HEp-2 cells were plated on 96-well plates at a density of 40,000 cells / well. The following day, modified Ankara-T7 vaccinia virus (MVA-T7) in the multiplicity of infection of 1 was added to provide T7-RNA polymerase. After 2 hours of viral transduction, each well was transfected with Lipofectamine2000 (Thermo Fisher) with 0.01 µg of a mixture of 6 plasmids including Ebolavirus minigenome, plasmids encoding L, NP, VP-35, VP-30 proteins from Ebolavirus. After an additional 48 hours of incubation, cells were lysed with RIPA buffer (Pierce), transferred to a 96-well black plate and fluorescence was read at 0.1 s / well at ex485 nm, emission 535 nm in a plate reader Victor. The sigmoidal dosage response curves used to generate 50% inhibitory or effective concentrations were analyzed by non-linear regression using the four-parameter logistic equation (GraphPad Prism). The compounds of Formula (I) showed activity in this EBOV assay as indicated by the EC50 values provided in Table 6. The compounds of Formula (I) also showed relatively low values of assay toxicity as indicated by the CC50 values provided in the Table 6.
[0308] [0308] Human β-coronavirus, strain OC43, was purchased from the ATCC (Manassas, VA, USA; item numbers VR-1558 and VR-740, respectively). Twenty-four hours prior to dosing, HeLa human cervical epithelial cells (ATCC, CCL-2) or human lung fibroblast MRC-5 (ATCC, CCL-171) were plated in 96-well plates at a density of 1, 5 x 10 5 / mL in DMEM supplemented with 10% fetal bovine serum, 1% HEPES buffer, 1% Penicillin / Streptomycin and 1% non-essential amino acids (all from Mediatech, Manassas, VA, USA). On the day of infection, the serially diluted compounds were added to the cells and incubated for 4 hours. After the end of the 4-hour pre-incubation period, the cells were infected with coronavirus or the OC43 or 229E strain. The viral inoculum was selected to cause an 80 to 90% cytopathic effect. The infected cells were incubated for five days at 37 ° C, 5% CO2. To develop the assay, 100 µL of medium was replaced with 100 µL of CellTiter Glo® reagent (Promega, Madison, WI, USA), and incubated for 10 minutes at room temperature. Luminescence was measured in a Victor X3 multi-marker plate reader. The cytotoxicity of the potential compound was determined using uninfected parallel cultures. The compounds of Formula (I) showed activity in this assay against human β-coronavirus, strain OC43, as indicated by the EC50 values provided in Table 6. The compounds of Formula (I) also showed relatively low values of toxicity in the assay as indicated by the CC50 values provided in Table 6. Table 6 EBOV No. HRV 1B OC43CoV DENV RSV EC50 (uM) CC50 EC50 (uM) CC50 EC50 (uM) CC50 EC50 (uM) CC50 EC50 CC50 (uM) (uM) (uM) (uM) (uM) C1 0.8 51 0.12 6 0.065 69 0.13 22 0.02 3 5 25.3> 100 7.37> 100 2.74> 100 6 2, 5> 100 4.1> 100 1.7> 100 0.25, 0.33 78, 69 0.02 43
[0309] [0309] The enzymatic activity of the NS5 domain of dengue virus polymerase (DENVpol, serotype 2, New Guinea C strain) was measured as an incorporation of NMP ("Nucleoside MonoPhosphate", Nucleoside-Monophosphate) triturated in products of acid-insoluble RNA. The DENVpol assay reactions contained 100 nM of recombinant enzyme, 50 nM of heteropolymeric RNA, about 0.5 µCi of tritiated NTP ("Nucleoside TriPhosphate", nucleoside-triphosphate), 0.33 µM of cold competitor NTP, 40 mM HEPES (pH 7.5), 3 mM dithiothreitol, and 2 mM MgCl2. The standard reactions are incubated for 3 h at 30 ° C, in the presence of an increasing concentration of inhibitor. At the end of the reaction, the RNA is precipitated with TCA ("TriChloroAcetic acid", 10% trichloroacetic acid) and the acid-insoluble RNA products are filtered through a 96-well plate by size exclusion. After washing the plate, a scintillation liquid is added and the radiolabeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The concentration of the compound at which the enzyme catalyzed rate was reduced by 50% (IC 50)
[0310] [0310] The enzymatic activity of the hepatitis C virus RNA polymerase (HCVpol) and human rhinovirus 16 RNA polymerase (HRV16pol) is measured as an incorporation of tritiated NMP in acid-insoluble RNA products. The HCVpol and HRV16pol assay reactions contain 30 to 100 nM of recombinant enzyme, 50 to 500 nM of heteropolymeric RNA, 0.5 µCi of tritiated NTP, 0.1 to 1 µM of other NTPs, in a reaction buffer standard containing MgCl2. The enzymatic reactions are incubated for 2.5 h at 30 ° C, in the presence of an increasing concentration of inhibitor. At the end of the reaction, the total RNA is precipitated with 10% TCA and the acid-insoluble RNA products are filtered through a 96-well plate by size exclusion. After washing the plate, a scintillation liquid is added and the radiolabeled RNA products are detected according to standard procedures with a Trilux Microbeta scintillation counter. The concentration of the compound at which the enzyme-catalyzed rate is reduced by 50% (IC50) is calculated by adjusting the data for a non-linear (sigmoidal) regression. The compounds of Formula (I) showed activity in these tests. Example H RSV polymerase assay (RSVpol)
[0311] [0311] Standard RSV polymerase assays were conducted in the presence of 3 µL of extract from cells infected with RSV in a reaction buffer containing 50 mM tris-acetate pH 8, 120 mM K acetate, 4, 5 mM MgCl2, 5% glycerol, 2 mM EDTA, 50 µg / ml BSA and 3 mM DTT. Varied concentrations of NTPs were used to initiate RNA synthesis for 120 minutes at 30 degrees, and 33P-radioactive GTP (15 µCi) was used as a signal. The reaction was interrupted by the addition of 50 mM EDTA, and the RNA samples were purified by means of spin columns by exclusion of size G-50 and extraction with phenol-chloroform. The radiolabeled RNA products were resolved by electrophoresis in a 6% polyacrylamide gel in TBE buffer (Tris / Borate / EDTA), and visualized and quantified after being exposed on a phosphorImager screen. The polymerase inhibition experiments (IC50s) were conducted in the same manner in the presence of an increasing concentration of NTP analogs. The compounds of Formula (I) showed activity in these tests. Table 7 No. HRV16pol HCVpol DENVpol RSVpol IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) C2 0.27 1 3.6 0.12 12 0.13 0.4 1.1 0.03 13 0 , 21> 10> 10> 10 14 0.04 0.3 1.1 0.03 Compound No. "C2" is a comparison compound having the following structure: (C2)
[0312] [0312] Although the aforementioned has been described in some details by means of illustrations and examples for the purposes of clarity and understanding, it will be understood by those skilled in the art that countless and various modifications can be made without departing from the spirit of the present revelation. Therefore, it should be clearly understood that the forms disclosed in this document are illustrative only and are not intended to limit the scope of this description, but instead to cover, also, all modifications and alternatives covered by the true scope and spirit of the invention.

权利要求:
Claims (55)
[1]
1. Compound of Formula (I), or a pharmaceutically acceptable salt thereof, characterized by having the structure: (I) in which: R1A is selected from the group consisting of fluorine, cyano, azido, an unsubstituted C2-4 alkenyl , an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl, wherein said C1-4 alkyl is substituted with one or more substituents selected from fluorine and chlorine; R4A is selected from the group consisting of fluorine, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and an substituted C1-4 alkyl, wherein said C1-4 alkyl is substituted with one or more substituents selected from fluorine and chlorine; R2A, R3A, Ra1, and Ra2 are each independently hydrogen or deuterium; R5A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, Z1A Z2A Z3A R6AO P R8AO P R10A P OR7A, R9A and R11A; R6A, R7A and R8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, an optional C3-6 cycloalkyl - optionally substituted, optionally substituted C3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-6 alkyl) aryl, optionally substituted * - (CR15AR16A) p – O – C1-24 alkyl, one * - (CR17AR18A) q – O – C1-24 alkenyl optionally substituted,,,, and; or R6A is
O O R12AO P O P OR13A OR14A m and R7A is absent or is hydrogen; or R6A and R7A are considered together to form a selected portion of the group consisting of an optionally substituted and an optionally substituted one, in which the oxygen connected to R6A and R7A, the phosphorus and the portion form a six-membered ring system ten members; R9A is independently selected from the group consisting of an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, a C3 cycloalkyl -6 optionally substituted, NR30AR31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R10A and R11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R12A, R13A and R14A are independently absent or are hydrogen; each R15A, each R16A, each R17A and each R18A are independently hydrogen, an optionally substituted C1-24 alkyl or alkoxy; R19A, R20A, R22A and R23A are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R21A and R24A are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted –O – C1-24 alkyl, an optionally substituted –O – aryl, one - the optionally substituted O – heteroaryl, an optionally substituted monocyclic –O – heterocyclyl, and
; R25A and R29A are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R26A and R27A are independently -C≡N or an optionally substituted substituent selected from the group consisting of C2-8 organo-carbonyl, C2-8 alkoxycarbonyl and C2-8 organylaminocarbonyl; R28A is selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and a C3-6 cycloalkenyl optionally replaced; R30A and R31A are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl; m and t are independently 0 or 1; p and q are independently selected from the group consisting of 1, 2 and 3; r is 1 or 2; s is 0, 1, 2 or 3; u is 1 or 2; and
[2]
A compound or pharmaceutically acceptable salt thereof, according to claim 1, characterized in that Z1A, Z2A, Z3A and Z4A are independently O or S, and R1A is cyano.
[3]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 and 2, characterized in that R4A is selected from the group consisting of fluorine, cyano, azido, and an unsubstituted C1-4 alkyl.
[4]
A compound or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R4A is fluorine.
[5]
Compound or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R4A is cyano.
[6]
A compound or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R4A is azido.
[7]
A compound or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R4A is unsubstituted C1-4 alkyl.
[8]
A compound or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R4A is substituted C1-4 alkyl.
[9]
Compound or pharmaceutically acceptable salt thereof, according to claim 8, characterized in that the substituted C 1-4 alkyl is selected from the group consisting of - (CH2) 1-4Cl, - (CH2) 1-4F and -CHF2.
[10]
A compound or pharmaceutically acceptable salt thereof, according to claim 9, characterized in that the substituted C 1-4 alkyl is selected from the group consisting of chloromethyl, fluoromethyl and difluoromethyl.
[11]
A compound or pharmaceutically acceptable salt thereof, according to claim 10, characterized in that the substituted C1-4 alkyl is chloromethyl.
[12]
Compound or pharmaceutically acceptable salt thereof, according to claim 10, characterized in that the substituted C1-4 alkyl is fluoromethyl.
[13]
13. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that R5A is hydrogen.
[14]
Compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that R5A is Z1A R6AO P OR7A.
[15]
Compound or pharmaceutically acceptable salt thereof, according to claim 14, characterized in that R 6A and R7A are hydrogen.
[16]
Compound or pharmaceutically acceptable salt thereof, according to claim 14, characterized in that R6A is
O O R12AO P O P OR13A OR14A m.
[17]
A compound or pharmaceutically acceptable salt thereof, according to claim 16, characterized in that R12A, R13A and R14A are hydrogen.
[18]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 14 to 17, characterized in that Z1A is O.
[19]
19. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that R5A is Z2A R8AO P R9A.
[20]
A compound according to claim 19, characterized in that R8A is an optionally substituted aryl; and R9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
[21]
A compound or pharmaceutically acceptable salt thereof, according to claim 19 or 20, characterized in that Z2A is O.
[22]
22. A compound according to claim 1, characterized in that the compound of Formula (I) is selected from the group consisting of:,,,,,,,,,, and, or a pharmaceutically acceptable salt of the compounds shown above.
[23]
23. Pharmaceutical composition, characterized in that it comprises an effective amount of a compound, as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination of the same.
[24]
24. Method for attenuating or treating a viral infection by Picornaviridae, characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, or of the composition pharmaceutical, as defined in claim 23, to an individual suffering from viral infection by Picornaviridae.
[25]
25. Method according to claim 24, characterized in that the viral infection by Picornaviridae is a rhinovirus infection.
[26]
26. Method for attenuating or treating a viral infection with Flaviviridae, characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, or of the composition pharmaceutical as defined in claim 23, to an individual suffering from viral infection by Flaviviridae.
[27]
27. Method according to claim 26, characterized in that the viral infection by Flaviviridae is an infection by Dengue virus.
[28]
28. Method according to claim 26, characterized in that the viral infection by Flaviviridae is an infection by Hepacivirus.
[29]
29. Method for attenuating or treating a viral infection by Filoviridae, characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition pharmaceutical as defined in the claim
23, to an individual suffering from viral infection by Filoviridae.
[30]
30. Method according to claim 29, characterized in that the viral infection by Filoviridae is an infection by Ebolavirus.
[31]
31. Method for attenuating or treating a viral Pneumoviridae infection, characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition pharmaceutical company, as defined in claim 23, to an individual suffering from Pneumoviridae viral infection.
[32]
32. Method according to claim 31, characterized in that the Pneumoviridae viral infection is an infection by human respiratory syncytial virus (HRSV).
[33]
33. Method for attenuating or treating a viral Coronaviridae infection, characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition pharmaceutical company, as defined in claim 23, to an individual suffering from Coronaviridae viral infection.
[34]
34. Method according to claim 33, characterized in that the viral infection by Coronaviridae is a viral infection by human α-corovavirus.
[35]
35. Method according to claim 33, characterized in that the viral infection by Coronaviridae is a viral infection by human β-cororavirus virus.
[36]
36. Panviral treatment, characterized in that said treatment comprises an effective amount of the compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 22.
[37]
37. Panviral treatment according to claim 36, characterized in that the compound, or a pharmaceutically acceptable salt thereof, is effective for treating viral infections caused by viruses in two or more families selected from the group consisting of Picornaviridae, Flaviviridae , Filoviridae, Pneumoviridae and Coronaviridae
[38]
38. Panviral treatment according to claim 36 or 37, characterized in that the compound, or a pharmaceutically acceptable salt thereof, has low toxicity.
[39]
39. Panviral treatment according to any one of claims 36 to 38, characterized in that viral infections are selected from a rhinovirus infection in the family Picornaviridae; an infection by Dengue virus or an infection by Hepacivirus in the family Flaviviridae; an Ebolavirus infection in the Filoviridae family; an infection with human respiratory syncytial virus (HRSV) in the Pneumoviridae family; and a viral infection by human α-coronavirus or a viral infection by human β-coronavirus in the family Coronaviridae.
[40]
40. Panviral treatment according to any one of claims 36 to 39, characterized in that the compound is selected from the group consisting of:,,,,,,
,,,, and, or a pharmaceutically acceptable salt of the compounds shown above.
[41]
41. Panviral treatment according to any of claims 36 to 40, characterized in that the treatment is formulated for administration to an individual having a viral infection by Picoraviridae, Flaviviridae, Filoviridae, Pneumoviridae and / or Coronaviridae.
[42]
42. Panviral treatment according to any one of claims 36 to 41, characterized in that the treatment is formulated in the form of a pharmaceutical composition.
[43]
43. Use of an effective amount of a compound, as defined in any of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the mitigation or treatment of a viral infection by Picornaviridae.
[44]
44. Use according to claim 43, characterized in that the viral infection by Picornaviridae is an infection by Rhinovirus.
[45]
45. Use of an effective amount of a compound, as defined in any of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the mitigation or treatment of a viral infection by Flaviviridae.
[46]
46. Use according to claim 45, characterized in that the viral infection by Flaviviridae is an infection by Dengue virus.
[47]
47. Use according to claim 45, characterized in that the viral infection by Flaviviridae is an infection by Hepacivirus.
[48]
48. Use of an effective amount of a compound, as defined in any of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the mitigation or treatment of a viral infection by Filoviridae.
[49]
49. Use according to claim 48, characterized in that the viral infection by Filoviridae is an infection by Ebolavirus.
[50]
50. Use of an effective amount of a compound, as defined in any of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the mitigation or treatment of a viral infection Pneumoviridae.
[51]
51. Use according to claim 50, characterized in that the Pneumoviridae viral infection is an infection by human respiratory syncytial virus (HRSV).
[52]
52. Use of an effective amount of a compound, as defined in any of claims 1 to 22, or of a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the mitigation or treatment of a viral infection by Coronaviridae.
[53]
53. Use according to claim 52, characterized in that the viral infection by Coronaviridae is a viral infection by human α-corona-virus.
[54]
54. Use according to claim 52, characterized in that the viral infection by Coronaviridae is a viral infection by human β-corona-virus.
[55]
55. Compound of Formula (Ia2), or a pharmaceutically acceptable salt thereof, characterized by having the structure: (Ia2) in which: R4A is selected from the group consisting of: fluorine, cyano, azido and C1-4 alkyl replaced with one or more substituents selected from fluorine and chlorine; R5A is hydrogen, or; R9A is, or, and R33A is C1-6 alkyl.

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PH12020550114A1|2020-12-07|

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EP3684782A1|2020-07-29|

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WO2019053696A1|2019-03-21|

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JP2020534361A|2020-11-26|

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SG11202002295QA|2020-04-29|

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ECSP20022130A|2020-07-31|

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US20200277321A1|2020-09-03|

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US20210395288A1|2021-12-23|

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法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762560110P| true| 2017-09-18|2017-09-18|

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US62/560,110|2017-09-18|

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PCT/IB2018/057188|WO2019053696A1|2017-09-18|2018-09-18|Substituted nucleosides, nucleotides and analogs thereof|

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