WO2018042343A2 - Composés inhibant les protéases 3c et 3cl et leurs méthodes d'utilisation - Google Patents

Composés inhibant les protéases 3c et 3cl et leurs méthodes d'utilisation Download PDF

Info

Publication number
WO2018042343A2
WO2018042343A2 PCT/IB2017/055206 IB2017055206W WO2018042343A2 WO 2018042343 A2 WO2018042343 A2 WO 2018042343A2 IB 2017055206 W IB2017055206 W IB 2017055206W WO 2018042343 A2 WO2018042343 A2 WO 2018042343A2
Authority
WO
WIPO (PCT)
Prior art keywords
carbamoyl
alkyl
cycloalkyl
heterocycloalkyl
propan
Prior art date
Application number
PCT/IB2017/055206
Other languages
English (en)
Other versions
WO2018042343A3 (fr
Inventor
Janos Botyanszki
John G. Catalano
Pek Yoke Chong
Hamilton Dickson
Qi Jin
Anna LEIVERS
Andrew Maynard
Xiangmin Liao
John Miller
John Brad Shotwell
Vincent Wing-Fai TAI
Reema Thalji
Original Assignee
Glaxosmithkline Intellectual Property (No.2) Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Intellectual Property (No.2) Limited filed Critical Glaxosmithkline Intellectual Property (No.2) Limited
Publication of WO2018042343A2 publication Critical patent/WO2018042343A2/fr
Publication of WO2018042343A3 publication Critical patent/WO2018042343A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds, specifically protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds.
  • Ribavirin (1 -B-D-ribofuranosyl-1 -1 ,2,4-triazole-3-carboxamide) is a synthetic, non- interferon-inducing, broad spectrum antiviral nucleoside analog sold under the trade name, Virazole®.
  • TEE MERCK INDEX 1304 (Budavari, S., ed., 1 1 th ed., 1989).
  • U.S. Pat. Nos. 3,798,209 and RE 29,835 to Wtkowski disclose and claim Ribavirin.
  • Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae. (Gary L. Davis, 1 18 GASTROENTEROLOGY S 104 (2000)). Ribavirin is indicated for the treatment of severe respiratory syncytial virus (RSV) infection, hepatitis C virus (HCV) infection, and others (including lassa fever, hantavirus, influenza, and rabies). However a major side effect of ribavirin, hemolytic anemia, is so severe that it is reserved for the treatment of only lethal viruses. In addition, ribavirin is a potential teratogen in humans.
  • Viruses are classified by evaluating several characteristics, including the type of viral genome.
  • Viral genomes can be comprised of DNA or RNA, can be double- stranded or single-stranded (which can further be positive-sense or negative-sense), and can vary greatly by size and genomic organization.
  • Positive-sense, single-stranded RNA viruses (“positive-stand RNA viruses”) make up a large superfamily of viruses from many distinct subfamilies. These viruses span both the plant and animal kingdoms causing pathologies ranging from mild phenotypes to severe debilitating disease.
  • composition of the positive strand RNA virus polymerase supergroup includes, at least, the following families: levi-, narna-, picorna-, dicistro-, marna-, sequi-, como-, poty-, calici-, astro-, noda-, tetra-, luteo-, tombus-, corona-, arteri-, roni-, flavi-, toga-, bromo-, tymo-, clostero-, flexi-, seco-, barna, ifla-, sadwa-, chera-, hepe-, sobemo-, umbra-, tobamo-, tobra-, hordei-, furo-, porno-, peclu-, beny-, ourmia-, and idaeovirus.
  • HRVs Human Rhinoviruses
  • the naked RNA genome ( ⁇ 8 kb) is surrounded by a capsid composed of sixty copies each of four structural proteins, denoted VP1 - VP4, in an icosahedral configuration.
  • HRVs enter the cell by triggering receptor-mediated endocytosis, with uncoating occurring through endosomes.
  • HRV replication requires viral RNA-dependant RNA polymerase, as well as multiple viruses and host-cell derived accessory proteins.
  • the HRV genome is translated as a single polyprotein, which is first cleaved following translation by virus- encoded proteases into three proteins, which are themselves cleaved to produce at least eleven proteins.
  • Viral genome replication can begin in as little as one hour following infection, and the release of nearly one million fully assembled virus particles at cell death can occur in as little as four hours following cell entry.
  • Infection with HRVs is a major health problem associated with thirty to fifty percent of all upper respiratory tract infections (common colds), predisposition to acute otitis media and sinusitis, and the development of lower respiratory tract syndromes in individuals with underlying respiratory disorders (like cystic fibrosis), the elderly, and the immunosuppressed. (Gern, 23 PEDIATR. INFECT. DIS. J. S78 (2004); Anzueto et al., 123 CHEST 1664 (2003); Rotbart, 53 ANTMR. RES. 83 (2002)). In addition, infection with HRVs is responsible for about 50% of asthma exacerbations in adults and is one of the factors that can direct the infant immune system towards an asthmatic phenotype. (D.
  • Coronaviruses are family of single-stranded, positive-strand RNA viruses with viral envelopes, classified within the Nidovirales order.
  • the coronavirus family comprises pathogens of many animal species, including humans, horses, cattle, pigs, birds, cats and monkeys, and have been known for more than 60 years.
  • Coronaviruses are common viruses that generally cause mild to moderate upper- respiratory tract illnesses in humans, and are named for the crown-like spikes on their envelope surface. There are four major sub-groups known as alpha, beta, gamma and delta coronaviruses, with the first coronaviruses identified in the mid-1960s.
  • the coronaviruses known to infect humans include 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).
  • MERS-CoV Middle East respiratory syndrome
  • Typical MERS symptoms include fever, cough and shortness of breath. Pneumonia is common, but not always present. Gastrointestinal symptoms, including diarrhea, have also been reported. MERS can infect anyone, with cases reported in patients ranging in age from ⁇ 1 to 99 years old. The CDC is monitoring MERS globally, and recognizes that there is potential for MERS-CoV to spread and cause additional cases globally, including in the U.S.A. and Europe. To date, approximately 36% of patients reported to have MERS have died. Therefore, there is an urgent need to develop therapeutic agents against MERS-CoV.
  • Poliomyelitis is caused by infection with poliovirus (“PV”).
  • PV is a member of the Enterovirus genus, which is one genus of the Picornaviridae family.
  • the PV genome is a single ⁇ 7.5 kb, positive-strand, RNA molecule, and consists of a single, large open reading frame that encodes a polyprotein of ⁇ 2500 amino acids flanked by untranslated regions at both the 5' and 3' ends (5'- and 3'-UTR).
  • the single polyprotein is a precursor to about eleven viral proteins critical for replication and assembly of progeny virus particles.
  • RNA viruses including HRV and other picornaviruses, human coronaviruses such as SARS- CoV and MERS-CoV, and noroviruses require viral RNA to be translated as a polyprotein that must be cleaved into individual enzymes for replication to ensue.
  • Maturation of the polyprotein requires a virally encoded enzyme to catalyze the majority of the cleavage events. This is performed by an enzyme known as 3C protease or picornain for HRV and other picornaviruses, and an analogous enzyme known alternately as 3CL (3C-like), M (main) protease, or nsp5 for coronaviruses and noroviruses. This step is essential for the viral life cycle; without it the viruses would be unable to replicate/survive.
  • the 3C protease enzyme of picornaviruses is a cysteine protease of 20 kD size. It is produced as part of the viral polyprotein and catalyzes the great majority of cleavage events that result in the production of active forms of all virally encoded proteins. These proteins are essential to viral replication so that the virus "life cycle" cannot continue in the absence of cleavage.
  • the 3C enzymes of some viruses are also known to cleave regulatory proteins in the host cell, presumably to enable higher levels of viral replication.
  • the 3C protein of coxsackievirus is reported to cleave the human MAVS and TRIF proteins to reduce the cellular response to viral infection (A Mukherjee et al, vol 7 PLOS Pathogens, 3 e100131 1 )
  • the 3CL protease enzyme of coronavirus and norovirus is a cysteine protease of ⁇ 50 kD size. While it serves an analogous function to the 3C protein of picornavirus, the protein contains an extra domain that allows production of a homodimeric form required for catalytic activity. 3CL protease is produced with one of several viral polyproteins and catalyzes the great majority of cleavage events from the polyprotein that result in the production of active virally encoded enzymes. These proteins are essential to viral replication so that the virus "life cycle" cannot continue in the absence of cleavage. The 3CL enzymes of some viruses are also known to cleave regulatory proteins in the host cell, presumably to enable higher levels of viral replication. For example, the 3CL protein of SARS coronavirus is reported to cleave the human STING protein to reduce the cellular response to viral infection (L Sun et al, vol 7 PLOS One, 2 e30802).
  • HRV human rhinovirus
  • human coronavirus human coronavirus
  • picornavirus picornavirus
  • norovirus infections and disease and symptoms associated with such viruses.
  • the 3C and 3CL protease inhibitors are compounds of Formula I:
  • A is aryl or heteroaryl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8 cycloalkyi or C3-C8 heterocycloalkyl; C3-C8 cycloalkyi or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, thioalkyi; or;
  • R 2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6- alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, NR 6 R 7 ; C3-C8-cycloalkyl optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, halo-substituted alkoxy or the C3-C8 cycloalkyi is fused with aryl to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl;
  • the C3-C8 heterocycloalkyl is fused with aryl to form a bicyclic or tricyclic fused ring; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR 6 R 7 , OR 8 , SR 9 ;
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R 3 and R 4 together form a 5 to 10-membered ring structure optionally substituted
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyi optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalky
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, [0031] or a salt thereof.
  • the 3C and 3CL protease inhibitors are compounds of Formula IA:
  • A is aryl or heteroaryl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8 cycloalkyi or C3-C8 heterocycloalkyl; C3-C8 cycloalkyi or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, thioalkyi; or;
  • R 2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6- alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, NR 6 R 7 ; C3-C8-cycloalkyl optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, halo-substituted alkoxy or the C3-C8 cycloalkyi is fused with aryl to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl;
  • the C3-C8 heterocycloalkyl is fused with aryl to form a bicyclic or tricyclic fused ring; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR 6 R 7 , OR 8 , SR 9 ;
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R 3 and R 4 together form a 5 to 10-membered ring structure optionally substituted
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyl or heterocycloalkyl ring that is optionally substituted with halo, haloalky
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, [0040] or a salt thereof.
  • A is phenyl or oxazolyl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or;
  • R 2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6- alkyl, C1 -C6-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; NR 6 R 7 ; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8- cycloalkyl,C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo-substituted alkoxy, O, N, S, NR 6 R 7 , OR 8 , SR 9 ;
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-heterocycloalkyl; C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyi substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalky
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, or a salt thereof.
  • A is phenyl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or;
  • R 2 is C1 -C6-alkyl; C1 -C6-alkyl substituted with piperidinyl; morpholinyl; indenyl; phenyl; thiazolyl; pyridinyl; pyrimidinyl; quinolinyl; naphthalenyl;C1 -C6-alkyl, alkoxy; halo-substituted alkoxy; NR 6 R 7 ;; wherein piperidinyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridinyl, pyrimidinyl, quinolinyl, naphthalenyl; NR 6 R 7 is further optionally substituted with halo, O, N, S, NR 6 R 7 , OR 8 , SR 9 ; [0053] R 3 and R 4 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyi or C3-C8 heterocycloalkyl, phenyl; or C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form a 3 to 10- membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi; and
  • R 8 and R9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 - C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, or a salt thereof.
  • One particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein R 3 is H and R 4 is independently selected from H, C1 - C6-alkyl and C1 -C6 alkyl substituted with C1 -C6-alkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl; or R 3 and R 4 together form a 5 to 10-membered cycloalkyi or heterocycloalkyl ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi.
  • Another particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein R 5 is selected from the group C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, phenyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl.
  • Another particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein A is selected from the group consisting of aryl and aryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy or thioalkyi.
  • Another particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein A is selected from the group consisting of heteroaryl and heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy or thioalkyl.
  • Still another particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein A is selected from the group consisting of phenyl and phenyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy or thioalkyl.
  • a method of treating or preventing a virus infection in a subject susceptible to or suffering from the virus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA or a pharmaceutically acceptable salt, solvate or hydrate thereof as described herein.
  • One particular embodiment provides a method of treating or preventing a virus infection from an RNA-based virus in a subject susceptible to or suffering from the RNA-based virus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA pharmaceutically acceptable salt, solvate or hydrate thereof as described herein.
  • Another particular embodiment provides a method of treating or preventing a coronavirus infection in a subject susceptible to or suffering from the rhinovirus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA or a pharmaceutically acceptable salt, solvate or hydrate thereof as described herein.
  • Still another particular embodiment provides a method of treating or preventing a virus infection in a subject susceptible to or suffering from the virus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor comprises a compound from Table 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • Another particular embodiment provides a method of inhibiting viral 3C protease or viral 3CL protease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or Formula IA as described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the mammal is a human.
  • the virus is a rhinovirus, a coronavirus, a picornavirus, or a norovirus.
  • the coronavirus is a 229E, NL63, OC43, HKU1 , SARS-CoV or a MERS coronavirus.
  • the picornavirus is a polio virus, EV-68 virus, EV-71 virus, hepatitis A virus, enterovirus or a coxsackievirus .
  • Embodiments of the present invention features compounds that are 3C and 3CL protease inhibitors, and therefore are useful for treating are useful for treating human rhinovirus (HRV), human coronavirus, picornavirus and norovirus infections, and disease and symptoms associated with such viruses .
  • HRV human rhinovirus
  • HBV human coronavirus
  • picornavirus picornavirus
  • norovirus infections and disease and symptoms associated with such viruses .
  • Table 1 is a listing of positive-sense single-stranded RNA viruses, negative-sense single-stranded RNA viruses, and double-stranded RNA viruses and DNA viruses.
  • Table 2 is a listing of compounds described herein.
  • Table 3 is summary of IC 5 o biological assay data for the compounds in
  • Table 4 is a summary of EC 5 o biological data for select compounds from Table 2.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms
  • alkyl includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH3CH2CH2-), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ((CH 3 ) 3 C-), n-pentyl
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein.
  • Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, n-pentoxy, morpholinylpropoxy, piperidinylethoxy.
  • Amino refers to the group -NR 6 R 7 where R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocyclic, and wherein R 6 and R 7 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 6 is hydrogen and R 7 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 6 and R 7 are alkyl
  • dialkylamino When referring to a monosubstituted amino, it is meant that either R 6 or R 7 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 6 nor R 7 are hydrogen.
  • Aryl refers to an aromatic group of from 5 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • a single ring e.g., phenyl
  • multiple condensed (fused) rings e.g., naphthyl or anthryl.
  • Aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to substitution of alkyl groups with 1 to 9 (e.g. when the alkyl group has 3 carbon atoms, such as a t-butyl group fully-substituted with halogen) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethyl).
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, phosphorus, silicon and boron, and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g.
  • heteroaryl applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8- tetrahydroquinolin-3-yl).
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthyl, naphthylpryidyl, oxazolyl, quinolyl, benzofuranyl, tetrahydrobenzofuranyl,
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non- aromatic ring (e.g.
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2- pyrrolidon-1 -yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (e.g., C 3 -Ci 0 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, naphthalene, oxazole, oxopyrrolidine, piperidine, piperazine
  • Fused heterocyclic refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following cyclopentathiazole structure:
  • “Fused aryl and fused heteroaryl” refers to a 5 to 6 member aryl structure or heteroaryl structure fused with a 5- to 6- member aryl, heteroaryl or cycloalkyl ring at different carbon atoms in the aryl structure or the heteroaryl structure, which may be substituted at one of the carbons in the fused aryl or fused heteroaryl and connected to the core molecule at another of the carbons, as exemplified by the following cyclopentylthiazole, quinoline or naphthalene structures:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + — O " ⁇ and sulfur such as S(O) and S(O) 2 , and the quaternized form of any basic nitrogen.
  • ""Oxazole” and “oxazolyl” refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and may be substituted at one of the three carbons and may be connected to another molecule at another of the three carbons, as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Oxopyrrolidine and “oxopyrrolidinyl” refers to a 5-membered heterocyclic ring containing nitrogen and 4 carbons that is substituted at one of the carbons in the heterocyclic ring by a carbonyl and may be connected to another substituent at another carbon in the heterocyclic ring, as exemplified by the structure below:
  • Pyridine and pyridinyl refers to a 6-membered heteroaryl ring containing one nitrogen and 5 carbons that may also be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures below:
  • Thiazole and thiazolyl refers to a 5-membered heteroaryl containing one sulfur and one nitrogen in the heteroaryl ring and 3 carbons in the heteroaryl ring that may also be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures
  • Pyrimidine and pyrimidinyl refers to a 6-membered heteroaryl ring containing two nitrogens in the heteroaryl ring and 4 carbons in the heteroaryl ring that may be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures below:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formulas I, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for
  • Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient or “subject” refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • dashed line represents an optional double bond at that position.
  • dashed circles appear within ring structures denoted by solid lines or solid circles, then the dashed circles represent one to three optional double bonds arranged according to their proper valence taking into account whether the ring has any optional substitutions around the ring as will be known by one of skill in the art.
  • the dashed line in the structure below could either indicate a double bond at that position or a single bond at that position:
  • ring A below could be a cyclohexyl ring without any double bonds or it could also be a phenyl ring having three double bonds arranged in any position that still depicts the proper valence for a phenyl ring.
  • any of X 1 -X 5 could be selected from: C, CH, or CH 2 , N, or NH, and the dashed circle means that ring B could be a cyclohexyl or phenyl ring or a N-containing heterocycle with no double bonds or a N-containing heteroaryl ring with one to three double bonds arranged in any position that still depicts the proper valence:
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)-.
  • -CCR' it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as -R x R y , where the "-" indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • A is aryl or heteroaryl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, thioalkyi;
  • R 2 is C1 -C6-alkvl.
  • C3-C8-cvcloalkyl optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, halo-substituted alkoxy or the C3-C8 cycloalkyi is fused with aryl to form a bicyclic or tricyclic fused ring;
  • the C3-C8 heterocycloalkyi is fused with aryl to form a bicyclic or tricyclic fused ring; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR 6 R 7 , OR 8 , SR 9 ;
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R 3 and R 4 together form a 5 to 10-membered ring structure optionally substituted
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyl or heterocycloalkyl ring that is optionally substituted with halo, haloalky
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, [00167] or a salt thereof.
  • A is phenyl or oxazolyl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ;
  • R 2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6- alkyl, C1 -C6-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; NR 6 R 7 ; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8- cycloalkyl,C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo-substituted alkoxy, O, N, S, NR 6 R 7 , OR 8 , SR 9 ;
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-heterocycloalkyl; C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyi, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalky
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, or a salt thereof.
  • A is phenyl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ;
  • R 2 is C1 -C6-alkyl; C1 -C6-alkyl substituted with piperidinyl; morpholinyl; indenyl; phenyl; thiazolyl; pyridinyl; pyrimidinyl; quinolinyl; naphthalenyl;C1 -C6-alkyl, alkoxy; halo-substituted alkoxy; NR 6 R 7 ;; wherein piperidinyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridinyl, pyrimidinyl, quinolinyl, naphthalenyl; NR 6 R 7 is further optionally substituted with halo, O, N, S, NR 6 R 7 , OR 8 , SR 9 ; [00180] R 3 and R 4 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyi or C3-C8 heterocycloalkyl, phenyl; or C3-C8-cycloalkyl or C3-C8- heterocycloalkyl substituted with C1 -C6-alkyl;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi; and
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl, or a salt thereof.
  • a compound having the structure of Formula I or Formula IA as described wherein R 5 is selected from the group consisting C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6- alkyl, phenyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl.
  • a compound having the structure of Formula I or Formula IA wherein A is selected from the group consisting of aryl and aryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy or thioalkyl.
  • a compound having the structure of Formula I or Formula IA wherein A is selected from the group consisting of heteroaryl and heteroaryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy or thioalkyl.
  • a compound having the structure of Formula I or Formula IA wherein A is selected from the group consisting of phenyl and phenyl substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy or thioalkyl.
  • Compounds described herein can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (S)-isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I or Formula IA.
  • the pharmaceutical formulation containing a compound of Formula I or Formula IA or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the pharmaceutical formulation containing a compound of Formula I or Formula IA or a salt thereof is a formulation adapted for oral, rectal, topical or intravenous formulation, wherein the pharmaceutical formulation optionally comprises any one or more of a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compounds of Formula I or Formula IA are formulated for oral administration, and can be administered as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • the compounds of Formula I or Formula IA are formulated for parenteral administration, and can be administered as an aqueous or oily suspension injectable, or a nasal drop.
  • a preparation of a compound of Formula I or Formula IA may be prepared by combining (e.g. mixing) a therapeutically effective amount of a compound of Formula I or Formula IA with a pharmaceutically acceptable carrier or diluent.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound of Formula I or Formula IA can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound of Formula I or Formula IA to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulations of compounds of Formula I or Formula IA can also be prepared to prolong or sustain the release of the compound, as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of Formula I or Formula IA or salts, solvates or hydrates thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of Formula I or Formula IA or salts, solvates or hydrates thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide- phenol.polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the compounds of Formula I or Formula IA may be delivered from a patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water- in-oil base.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of Formula I or Formula IA will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • An effective amount of a salt or hydrate thereof may be determined as a proportion of the effective amount of the compound of Formula I or Formula IA or salts, solvates or hydrates thereof per se.
  • Embodiments of the present invention provide administration of a compound of Formula I or Formula IA to a healthy or virus-infected patient, either as a single agent or in combination with (a) another agent that is effective in treating or preventing rhinovirus, coronavirus, picornavirus and/or norovirus infections, (b) another agent that improves immune response and robustness, or (c) another agent that reduces inflammation and/or pain.
  • the compounds of Formula I or Formula IA or salts, solvates or hydrates thereof, are believed to have activity in preventing, halting or reducing the effects of rhinovirus, coronavirus, picornavirus and/or norovirus by inhibiting the viral 3C or 3C protease, thereby interfering with or preventing the polyprotein processing of the translated viral genome, in the host cell, rendering the virus unable to replicate.
  • a method of treating a virus susceptible to 3C or 3CL protease inhibition in a mammal including administering to said mammal a therapeutically effective amount of a compound of Formula I or Formula IA or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the virus is a rhinovirus.
  • the virus is a coronavirus.
  • the virus is a picornavirus.
  • the virus is a norovirus.
  • the protease is a 3C protease. In another embodiment, the protease is a 3CL protease. In one embodiment, the mammal is a human. [00268] In another aspect of the present invention, there is provided a method of inhibiting viral 3C protease or viral 3CL protease in a mammal, including administering to said mammal a therapeutically effective amount of a compound of Formula I or Formula IA or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the mammal is a human.
  • this invention provides for a method of treating a respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease, which comprises administering to a human in need thereof, a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • a respiratory disorder including COPD, asthma, fibrosis, chronic asthma and acute asthma
  • lung disease secondary to environmental exposures acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease
  • this invention relates to a method of treating COPD, which comprises administering to a human in need thereof, a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • this invention provides for the use of a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for the treatment of a respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • a respiratory disorder including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • this invention relates to the use of a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for the treatment of COPD.
  • this invention relates to use of a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, crt antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • a respiratory disorder including COPD, asthma, fibrosis, chronic asthma and acute asthma
  • lung disease secondary to environmental exposures acute lung infection, chronic lung infection, crt antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • this invention relates to use of a compound of Formula I or a compound of Formula IA, or a salt, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.
  • this invention relates to a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • This invention relates to a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy, specifically for use in the treatment of a respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • a respiratory disorder including COPD, asthma, fibrosis, chronic asthma and acute asthma
  • lung disease secondary to environmental exposures acute lung infection, chronic lung infection, a1 antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • this invention relates to a compound of Formula I or a compound of Formula IA, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in the treatment of COPD.
  • the compounds of the present invention may be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other antiviral or anti-inflammatory therapeutic agents.
  • the compounds of Formula I or Formula IA and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide,
  • antigen non-specific immunotherapies e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents
  • suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents, antituberculosis agents, and antiviral agents, including those listed at
  • compounds or pharmaceutical formulations of the invention may be administered together with an anti-inflammatory agent such as, for example, a corticosteroid, or a pharmaceutical formulation thereof.
  • an anti-inflammatory agent such as, for example, a corticosteroid, or a pharmaceutical formulation thereof.
  • a compound of the invention may be formulated together with an antiinflammatory agent, such as a corticosteroid , in a single formulation, such as a dry powder formulation for inhalation.
  • a pharmaceutical formulation comprising a compound of the invention may be administered in conjunction with a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, either simultaneously or sequentially.
  • a pharmaceutical formulation comprising a compound of the invention and a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid may each be held in device suitable for the simultaneous administration of both formulations via inhalation.
  • Suitable corticosteroids for administration together with a compound of the invention include, but are not limited to, fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide and prednisilone.
  • a corticosteroids for administration together with a compound of the invention via inhalation includes fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, and flunisolide.
  • compounds or pharmaceutical formulations of the invention may be administered together with one or more bronchodilators, or pharmaceutical formulations thereof.
  • a compound of the invention may be formulated together with one or more bronchodilators in a single formulation, such as a dry powder formulation for inhalation.
  • a pharmaceutical formulation comprising a compound of the invention may be administered in conjunction with a pharmaceutical formulation comprising one or more bronchodilators, either
  • a formulation comprising a compound of the invention and a bronchodilator may be administered in conjunction with a pharmaceutical formulation comprising a further bronchodilator.
  • a pharmaceutical formulation comprising one or more bronchodilators may each be held in device suitable for the simultaneous administration of both formulations via inhalation.
  • a pharmaceutical formulation comprising a compound of the invention together with a bronchodilator and a pharmaceutical formulation comprising a further bronchodilator may each be held in one or more devices suitable for the simultaneous administration of both formulations via inhalation.
  • Suitable bronchodilators for administration together with a compound of the invention include, but are not limited to, p2-adrenoreceptor agonists and
  • p2-adrenoreceptor agonists include, for example, vilanterol, salmeterol, salbutamol.formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol.flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy-2- naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.
  • Suitable anticholinergic agents include umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide).
  • a compound of the invention may be administered together with a p2-adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as umeclidinium.
  • the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of Formula I or Formula IA or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • embodiments provide a method as described comprising administering an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, or an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, or an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, or an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID
  • the antiviral agent is an anti- hepatitis A agent or an antiretroviral agent.
  • the additional agent is administered as part of a single dosage form of said pharmaceutical formulation, or as a separate dosage form.
  • the present invention is directed to compounds, compositions and pharmaceutical compositions that have utility as novel treatments and/or preventative therapies for virus infections. While not wanting to be bound by any particular theory, it is thought that the present compounds are able to inhibit the activity of rhinovirus and coronavirus self-cleaving enzymes - 3C proteases in rhinovirus and 3CL (3C-like) proteases in coronavirus - which play an important role in processing polyprotein precursor proteins into functional viral proteins and enzymes. Inhibition of 3C and 3CL proteases are therefore expected to reduce the ability of the rhinovirus and coronavirus to replicate inside a host cell. By disrupting the ability of the rhinovirus or coronavirus to process its polyprotein precursors after the viral genome has been translated in a host cell, disease and symptoms resulting from rhinovirus and coronavirus infections can be treated and/or prevented.
  • a method of treating or preventing a virus infection in a subject suffering from the virus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA.
  • a method of treating or preventing a virus infection from an RNA-based virus in a subject suffering from the virus infection comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA.
  • a method of treating a coronavirus infection in a subject suffering from the rhinovirus infection comprising administering to the subject an inhibitor of 3C protease wherein the inhibitor is a compound of Formula I or Formula IA.
  • a method of treating a virus infection in a subject suffering from the virus infection comprising administering to the subject a selective chemical inhibitor of a 3C protease enzyme, wherein the inhibitor comprises a compound from Table 2.
  • the compounds described herein are useful for preventing or treating viral infections in a subject caused by a single-stranded RNA virus.
  • RNA virus is a virus that has RNA (ribonucleic acid) as its genetic material. This nucleic acid is usually single-stranded RNA (ssRNA). RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense. Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive- sense RNA; each virion can be transcribed to several positive-sense RNAs.
  • ssRNA single-stranded RNA
  • the compounds described herein are useful for preventing or treating viral infections in a subject caused by a positive-sense, single-stranded RNA virus.
  • the compounds described herein are useful for preventing or treating viral infections in a subject caused by a negative-sense, single-stranded RNA virus.
  • a method for treating a viral infection in a subject mediated at least in part by a virus in the picornaviridae family, or coronaviridae family of viruses comprising administering to the subject a composition comprising a compound of any of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of inhibiting progression of a viral infection in a subject at risk for infection with a virus in the picornaviridae family or coronaviridae family of viruses, comprising administering to the subject a therapeutically effective amount of the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of preventing a viral infection in a subject at risk for infection from a virus in the picornaviridae family or coronaviridae family of viruses, comprising administering to the subject a therapeutically effective amount of the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of treating a virus infection in a subject suffering from said virus infection, wherein the virus is in the picornaviridae family or coronaviridae family of viruses, comprising administering to the subject a therapeutically effective amount of the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • a method of treating a virus infection in a subject suffering from the virus infection comprising administering to the subject a compound of any of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • a method of preventing a virus infection in a subject comprising administering to the subject a compound of any of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of coronavirus 3CL protease selected from the group consisting of a 229E 3CL protease, a NL63 3CL protease, a OC43 3CL protease, a HKU1 3CL protease, a SARS-CoV 3CL protease and a MERS-CoV 3CL protease.
  • a chemical inhibitor of coronavirus 3CL protease selected from the group consisting of a 229E 3CL protease, a NL63 3CL protease, a OC43 3CL protease, a HKU1 3CL protease, a SARS-CoV 3CL protease and a MERS-CoV 3CL protease.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of a coronavirus 229E 3CL protease.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of a coronavirus OC43 3CL protease.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of a coronavirus HKU1 3CL protease.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of a coronavirus SARS-CoV 3CL protease.
  • a method of treating a coronavirus infection in a subject suffering from the coronavirus infection comprising administering to the subject a chemical inhibitor of a coronavirus MERS-CoV 3CL protease.
  • a method of treating a rhinovirus infection in a subject suffering from the rhinovirus infection comprising administering to the subject a chemical inhibitor of rhinovirus 3C protease selected from the group consisting of HRV-1 1 3C protease, HRV- 18 3C protease, HRV-2 3C protease, HRV-21 3C protease, HRV-22 3C protease, HRV- 24 3C protease, HRV-28 3C protease, HRV-43 3C protease, HRV-48 3C protease, HRV-52 3C protease, HRV-56 3C protease, HRV-6 3C protease, HRV-60 3C protease, HRV-65 3C protea
  • a method of treating a rhinovirus infection in a subject suffering from the rhinovirus infection comprising administering to the subject a chemical inhibitor of rhinovirus 3C protease selected from the group consisting of HRV-15 3C protease and HRV-16 3C protease.
  • a method of treating a rhinovirus infection in a subject suffering from the rhinovirus infection comprising administering to the subject a chemical inhibitor of rhinovirus HRV-15 3C.
  • a method of treating a rhinovirus infection in a subject suffering from the rhinovirus infection comprising administering to the subject a chemical inhibitor of rhinovirus HRV-16 3C.
  • the compounds described herein are useful for preventing or treating viral infections in a subject where the infection is caused by a virus belonging to the following families: levi-, narna-, picorna-, dicistro-, marna-, sequi-, como-, poty-, calici-, astro-, noda-, tetra-, luteo-, tombus-, corona-, arteri-, roni-, flavi-, toga-, bromo-, tymo-, clostero-, flexi-, seco-, barna, ifla-, sadwa-, chera-, hepe-, sobemo- , umbra-, tobamo-, tobra-, hordei-, furo-, porno-, peclu-, beny-, ourmia-, and idaeovirus.
  • Compounds, methods and pharmaceutical compositions for treating viral infections, by administering compounds of Formula I or Formula IA in therapeutically effective amounts are disclosed.
  • Methods for preparing compounds of Formula I or Formula IA and methods of using the compounds and pharmaceutical compositions thereof are also disclosed.
  • the treatment and prophylaxis of viral infections such as those caused by RNA or DNA viruses are disclosed.
  • the compounds described herein are useful for preventing or treating viral infections from any phylogenetic order, genus, family or particular species listed in Table 1 .
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by a virus belonging to the picornaviridae family, or coronaviridae family. In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by a virus belonging to the picornaviridae family. In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by a virus belonging to the coronaviridae family.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by a virus belonging to the picornaviridae family.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any one or more viruses selected from the group consisting of rhinovirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), common coronaviridae (including but not limited to OC43, HKU1 , 229e and NL63), enterovirus, poliovirus, coxsackievirus, , hepatitis A virus, foot-and-mouth disease virus (FMDV), and calicivirus.
  • MERS-CoV Middle East Respiratory Syndrome coronavirus
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • common coronaviridae including but not limited to OC43, HKU1 , 229e and NL63
  • enterovirus poliovirus
  • coxsackievirus coxsackievirus
  • FMDV foot-and-mouth disease virus
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the human coronaviruses.
  • the compound described herein are useful for treating infections in a subject wherein the infection is caused by any of the human coronaviruses 229E, NL63, OC43, HKU1 , SARS-CoV and MERS-CoV.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the alpha human coronaviruses.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the alpha human coronaviruses 229E and NL63.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the beta human coronaviruses.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the beta human coronaviruses OC43, HKU1 , SARS-CoV and MERS-CoV.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the human
  • coronaviruses MERS-CoV or SARS-CoV are coronaviruses MERS-CoV or SARS-CoV.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the human coronavirus MERS-CoV.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the human coronavirus SARS-CoV.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the human enteroviruses A-D.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by enterovirus A71 .
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by enterovirus D68.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the human rhinoviruses A-C.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus A.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus B.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus C.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the poliovirus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the coxackievirus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by EV-68 virus or EV- 71 virus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the echovirus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the hepatitis A virus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the calicivirus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the norovirus.
  • the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the Norwalk virus.
  • the compound of the present invention, or a pharmaceutically acceptable salt thereof is chosen from the compounds set forth in Table 2.
  • A is phenyl or oxazolyl
  • R 1 , R' 1 , and R" 1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; [00345] R 2 is C1 -C6-alkyl, C1 -C6-alkyl optionally substituted with C1 -C6-alkyl, C3- C
  • R 3 and R 4 are independently H, C1 -C6-alkyl, C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R 3 and R 4 together form a 5 to 10-membered ring structure optionally substitute
  • R 5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl or aryl; C3-C8- cycloalkyl or C3-C8-heterocycloalkyl;
  • R 6 and R 7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR 6 R 7 , OR 8 , SR 9 ; or R 6 and R 7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl,
  • heteroaryl or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi NR 6 R 7 , OR 8 , SR 9 ; and
  • R 8 and R 9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3- C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, or a salt thereof.
  • Suitable synthetic routes are depicted below in the following general reaction schemes.
  • the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • the lactam alcohol 1 can be prepared according to literature (Journal of Medicinal Chemistry 48(22), 6767-6771 , 2005).
  • the oxidation of 1 by reacting it with a S0 3 -pyridine complex to produce an aldehyde 2, and the following reaction of 2 with an isocyanide, such as isopropyl isocyanide, in the presence of an appropriate acid, such as benzoic acid yields ester 3.
  • the amino-alchol 5 can be obtained by removal of benzoyl group of 3 under basic condition, followed by deprotection of Boc group of 4 using an appropriate acid, such as HCI, in a suitable solvent such as 1 ,4-dioxane.
  • Any suitable amide forming condition can be used to prepare compound 6.
  • 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide is used in this invention.
  • the removal of Boc group of compound 6 with HCI produces amine 7 as a key intermediate.
  • the amine 7 (free or salt thereof) is subjected to an amide formation reaction with a suitable Cbz-amino acid such as (S)-2- (((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1 -yl)propanoic acid (B4 - purchased or prepared as described in examples), by using 2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide as the preferred coupling reagent, to give amide 8.
  • a suitable Cbz-amino acid such as (S)-2- (((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1 -yl)propanoic acid (B4 - purchased or prepared as described in examples), by using 2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide as the preferred
  • DIPEA or DIEA
  • ⁇ , ⁇ -Diisopropylethylamine or Hiinig's base
  • VXR-300 a Varian Unity-300, a Varian Unity-400 instrument, a Brucker AVANCE-400, a General Electric QE-300 or a Bruker AM 400 spectrometer.
  • Chemical shifts are expressed in parts per million (ppm, ⁇ units).
  • Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
  • Flash chromatography was run over Merck Silica gel 60 (230 - 400 mesh), or using a Teledyne Isco Combiflash Companion with normal phase, disposable Redi-Sep flash columns.
  • Test compounds were 3-fold serially diluted in an 1 1 point curve with a solvent of 100% DMSO, starting from a high concentration of 10 mM. Each dilution was transferred in 100 nL volume into black 384-well Greiner (784076) plates yielding a 10 ⁇ top final concentration in the assay.
  • Low control wells in column 18 (0% response, 100% inhibition) contained 100 nl_ of DMSO plus buffer, without enzyme.
  • High control wells in column 6 (100% response, 0% inhibition) contained 100 nl_ DMSO plus buffer and enzyme. Maximum DMSO concentration is approximately 1 % throughout the plate.
  • the assay buffer consists of 25 mM Hepes (pH 7.5), 100 mM NaCI, 1 mM CHAPS, 1 mM EDTA, and 0.05% bovine serum albumin.
  • Assay plate preparation included spinning the plates prior to reaction additions and the addition of 5 ⁇ _ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 ⁇ _ of 10 nM enzyme (HRV-16 3C protease, 5 nM final concentration) in assay buffer to columns 1 -17, and 19 -24.
  • FRET substrate peptide FAM-GRAVFQGPVG-TAMRA
  • 5 ⁇ _ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 ⁇ . Reactions were incubated in the dark at room temperature for 60 minutes. At that time the FRET signal was measured with an Envision or equivalent plate reader and used to quantify the endpoint of the assay for apparent EC 5 o calculations.
  • Test compounds were 3-fold serially diluted in an 1 1 point curve with a solvent of 100% DMSO, starting from a high concentration of 10 mM. Each dilution was transferred in 100 nl_ volume into black 384-well Greiner (784076) plates yielding a 10 ⁇ top final concentration in the assay.
  • Low control wells in column 18 (0% response, 100% inhibition) contained 100 nL of DMSO plus buffer, without enzyme.
  • High control wells in column 6 (100% response, 0% inhibition) contained 100 nL DMSO plus buffer and enzyme. Maximum DMSO concentration is approximately 1 % throughout the plate.
  • the assay buffer consists of 25 mM HEPES (pH 7.5), 100 mM NaCI, 1 mM CHAPS, 1 mM EDTA, and 0.05% bovine serum albumin.
  • Assay plate preparation included spinning the plates prior to reaction additions and the addition of 5 ⁇ _ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 ⁇ _ of 10 nM enzyme (HRV-15 3C protease, 5 nM final concentration) in assay buffer to columns 1 - 17, and 19 -24.
  • a FRET substrate peptide (FAM-GRAVFQGPVG-TAMRA) was suspended at 4 ⁇ concentration and 5 ⁇ _ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 ⁇ . Reactions were incubated in the dark at room temperature for 60 minutes. At that time the FRET signal was measured with an Envision or equivalent plate reader and used to quantify the endpoint of the assay for apparent EC 5 o calculations.
  • Test compounds were 3-fold serially diluted in an 1 1 point curve with a solvent of 100% DMSO, starting from a high concentration of 10 mM. Each dilution was transferred in 100 nl_ volume into black 384-well Greiner (784076) plates yielding a 10 ⁇ top final concentration in the assay.
  • Low control wells in column 18 (0% response, 100% inhibition) contained 100 nl_ of DMSO plus buffer, without enzyme.
  • High control wells in column 6 (100% response, 0% inhibition) contained 100 nl_ DMSO plus buffer and enzyme. Maximum DMSO concentration is approximately 1 % throughout the plate.
  • the assay buffer consists of 25 mM HEPES (pH 7.5), 50 mM NaCI, 1 mM CHAPS, and 1 mM EDTA.
  • Assay plate preparation included spinning the plates prior to reaction additions and the addition of 5 ⁇ _ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 ⁇ _ of 2 nM enzyme (OC43 3CL protease, 1 nM final concentration) in assay buffer to columns 1 -17, and 19-24.
  • a FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at 4 ⁇ concentration and 5 ⁇ _ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 ⁇ . Reactions were incubated in the dark at room temperature for 60 minutes. At that time the FRET signal was measured with an Envision or equivalent plate reader and used to quantify the endpoint of the assay for apparent EC 5 o calculations.
  • Test compounds were 3-fold serially diluted in an 1 1 point curve with a solvent of 100% DMSO, starting from a high concentration of 10 mM. Each dilution was transferred in 100 nl_ volume into black 384-well Greiner (784076) plates yielding a 10 ⁇ top final concentration in the assay.
  • Low control wells in column 18 (0% response, 100% inhibition) contained 100 nl_ of DMSO plus buffer, without enzyme.
  • High control wells in column 6 (100% response, 0% inhibition) contained 100 nl_ DMSO plus buffer and enzyme. Maximum DMSO concentration is approximately 1 % throughout the plate.
  • the assay buffer consists of 25 mM Hepes (pH 7.5), 50 mM NaCI, 1 mM CHAPS, and 1 mM EDTA.
  • Assay plate preparation included spinning the plates prior to reaction additions and the addition of 5 ⁇ _ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 ⁇ _ of 200 pM enzyme (229e 3CL protease, 100 pM final concentration) in assay buffer to columns 1 -17, and 19-24.
  • a FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at 4 ⁇ concentration and 5 was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 ⁇ . Reactions were incubated in the dark at room temperature for 60 minutes. At that time the FRET signal was measured with an Envision or equivalent plate reader and used to quantify the endpoint of the assay for apparent EC 5 o calculations.
  • Test compounds were 3-fold serially diluted in an 1 1 point curve with a solvent of 100% DMSO, starting from a high concentration of 10 mM. Each dilution was transferred in 100 nl_ volume into black 384-well Greiner (784076) plates yielding a 10 ⁇ top final concentration in the assay.
  • Low control wells in column 18 (0% response, 100% inhibition) contained 100 nl_ of DMSO plus buffer, without enzyme.
  • High control wells in column 6 (100% response, 0% inhibition) contained 100 nl_ DMSO plus buffer and enzyme. Maximum DMSO concentration is approximately 1 % throughout the plate.
  • the assay buffer consists of 25 mM Hepes (pH 7.5), 50 mM NaCI, 1 mM CHAPS, and 1 mM EDTA.
  • Assay plate preparation included spinning the plates prior to reaction additions and the addition of 5 ⁇ _ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 ⁇ _ of 60 nM enzyme (SARS 3CL protease, 30 nM final concentration) in assay buffer to columns 1 -17, and 19-24.
  • a FRET substrate peptide (FAM-KTSAVLQSG FRKM E-TAM RA) was suspended at 6 ⁇ concentration and 5 ⁇ _ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 3 ⁇ . Reactions were incubated in the dark at room temperature for 60 minutes. At that time the FRET signal was measured with an Envision or equivalent plate reader and used to quantify the endpoint of the assay for apparent EC 5 o calculations.
  • CPE cytopathic effect
  • HRV human rhinovirus
  • test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.25 ⁇ in 384-well, polystyrene, clear bottom, tissue culture treated plates with lids (Corning Incorporated, Tewksbury, MA) to generate 1 1 -point dose response curves.
  • Low control wells (100% CPE or 100% cytotoxicity) contained either 0.25 ⁇ of DMSO in the presence of virally infected cells for the CPE assay or 0.25 ⁇ of DMSO in the absence of cells for the cytoxicity assay, and high control wells (0% CPE or 0% cytotoxicity) contained either 0.25 of a small molecule control test compound in the presence of virally infected cells for the CPE assay or 0.25 of the same nontoxic small molecule control test compound in the presence of uninfected cells for the cytoxicity assay.
  • Frozen stocks of HeLa Ohio cells were washed and recovered in DMEM, high glucose medium (Life Technologies Corporation, Grand Island, NY) supplemented with 10% v/v qualified , heat inactivated fetal bovine serum (FBS) (Life Technologies Corporation, Grand Island, NY), 1X GlutaMAXTM (Life Technologies Corporation, Grand Island, NY) and 1 X penicillin-streptomycin antibiotic solution (Life Technologies Corporation, Grand Island, NY).
  • FBS heat inactivated fetal bovine serum
  • 1X GlutaMAXTM Life Technologies Corporation, Grand Island, NY
  • penicillin-streptomycin antibiotic solution Life Technologies Corporation, Grand Island, NY
  • the data for dose responses in the CPE assay were plotted as % viability versus compound concentration following normalization using the formula 100*((U- C2)/(C1 -C2)), where U was the unknown value, C1 was the average of the high (0% CPE) control wells and C2 was the average of the low (100% CPE) control wells.
  • the data for dose responses in the cytotoxicity assay were plotted as % cytotoxicity versus compound concentration following normalization using the formula 100-(100*((U- C2)/(C1 -C2))), where U was the unknown value, C1 was the average of the high (0% cytotoxicity) control wells and C2 was the average of the low (100% cytotoxicity) control wells.
  • test compounds were serially diluted in 100% DMSO with a 3-fold 8-point curve for a top assay concentration of 50 uM.
  • DMSO was normalized in reaction wells to a final concentration of 1 %.
  • MRC-5 Cells were treated with compounds for 2 hours prior to infection with MERS at an MOI of 1 .
  • Virus was allowed to replicate for 48 hours, after which virus was inactivated with formalin.
  • Infected cells were detected by immunostaining with anti- S protein antibodies and quantified by a PE Opera confocal platform. Signal for S protein staining was converted to % infection, and % inhibition was calculated using the positive and negative controls.
  • EC50s were calculated with a standard equation using GeneData software.
  • Test compounds were diluted and assayed against additional HRV strains 3C proteases following the protocols as essentially described in Examples 4 and Example 5 for testing compounds against HRV-16 and HRV-15 3C proteases, respectively. EC50 values for the compounds tested against these additional HRV3C proteases were obtained, and are shown in Table 4.
  • Coronavirus SARS
  • o Family Picornaviridae - includes Poliovirus, the "common cold” virus (Rhinovirus), Hepatitis A virus, Coxsackievirus
  • o Family Secoviridae includes subfamily Comovirinae
  • o Family Flaviviridae - includes Yellow fever virus, West Nile virus,
  • o Family Retroviridae includes human immunodeficiency virus 1 and 2
  • o Family Togaviridae - includes Rubella virus, Ross River virus,
  • o Family Filoviridae - includes Ebola virus, Marburg virus
  • o Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus
  • o Family Arenaviridae - includes Lassa virus, Junin virus
  • o Family Bunyaviridae - includes Hantavirus, Crimean-Congo hemorrhagic fever
  • o Family Orthomyxoviridae - includes Influenza viruses
  • o Genus Nyavirus - includes Nyamanini and Midway viruses
  • o Family Reoviridae - includes Rotavirus
  • o Family Polyomaviridae - includes BK virus
  • Herpesviridae includes herpes simplex virus
  • enzyme enzyme enzyme enzyme. enzyme_ enzyme_ enzyme_ cell_ cell_ cell No.
  • enzyme enzyme enzyme enzyme. enzyme_ enzyme_ enzyme_ cell_ cell_ cell No.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés, en particulier des inhibiteurs de protéase, plus particulièrement des inhibiteurs de protéase 3C et 3CL, destinés au traitement d'infections virales, et des méthodes de préparation et d'utilisation de tels composés.
PCT/IB2017/055206 2016-08-30 2017-08-30 Composés inhibant les protéases 3c et 3cl et leurs méthodes d'utilisation WO2018042343A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662381560P 2016-08-30 2016-08-30
US62/381,560 2016-08-30
US201662382410P 2016-09-01 2016-09-01
US62/382,410 2016-09-01

Publications (2)

Publication Number Publication Date
WO2018042343A2 true WO2018042343A2 (fr) 2018-03-08
WO2018042343A3 WO2018042343A3 (fr) 2018-04-19

Family

ID=59966793

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/055206 WO2018042343A2 (fr) 2016-08-30 2017-08-30 Composés inhibant les protéases 3c et 3cl et leurs méthodes d'utilisation

Country Status (3)

Country Link
TW (1) TW201817714A (fr)
UY (1) UY37381A (fr)
WO (1) WO2018042343A2 (fr)

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113015726A (zh) * 2018-08-09 2021-06-22 中国科学院上海药物研究所 酮酰胺类化合物及其制备方法、药物组合物和用途
US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2021191827A1 (fr) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Dérivés tripeptidiques pour le traitement d'infections par le sras-cov-2
WO2021191875A1 (fr) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de cathepsine pour la prévention ou le traitement d'infections virales
WO2021207729A1 (fr) * 2020-04-10 2021-10-14 Mubarak Kamal Khan Compositions et procédés de modulation du récepteur de l'ace2
WO2021206877A1 (fr) * 2020-04-10 2021-10-14 Cocrystal Pharma, Inc. Inhibiteurs de la réplication de norovirus et de coronavirus
WO2021226546A1 (fr) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de protéase pour le traitement ou la prévention d'une maladie à coronavirus
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
CN113773259A (zh) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 病毒主蛋白酶抑制剂及其制备方法和用途
WO2022013684A1 (fr) 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
WO2022020242A1 (fr) 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
KR20220031547A (ko) * 2020-09-03 2022-03-11 화이자 인코포레이티드 니트릴-함유 항바이러스 화합물
US11319325B1 (en) 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents
US11325916B1 (en) 2021-07-29 2022-05-10 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
US11339170B1 (en) 2021-07-23 2022-05-24 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
EP4001279A1 (fr) 2020-11-23 2022-05-25 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
US11352363B1 (en) 2020-11-23 2022-06-07 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2022129953A1 (fr) * 2020-12-18 2022-06-23 Heptares Therapeutics Limited Composés inhibiteurs de mpro du sars-cov-2
US11384090B2 (en) 2020-11-23 2022-07-12 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2022212707A1 (fr) * 2021-04-01 2022-10-06 Primmune Therapeutics, Inc. Inhibiteurs de protéase 3cl du sars
WO2022208262A1 (fr) * 2021-03-30 2022-10-06 Pfizer Inc. Composés antiviraux à liaison éther
WO2022218442A1 (fr) * 2021-04-16 2022-10-20 南京明德新药研发有限公司 Composé de peptide court de proline à cycle modifié et son utilisation
WO2023003610A1 (fr) * 2021-07-23 2023-01-26 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
WO2022265577A3 (fr) * 2021-06-15 2023-02-02 Agency For Science, Technology And Research Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations
WO2023009187A1 (fr) * 2021-07-29 2023-02-02 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
WO2023036093A1 (fr) * 2021-09-09 2023-03-16 广东众生睿创生物科技有限公司 Dérivé de cétoamide et son application
WO2023043816A1 (fr) * 2021-09-17 2023-03-23 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2023044171A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs méthodes d'utilisation
JP2023513048A (ja) * 2020-01-31 2023-03-30 中国科学院上▲海▼▲薬▼物研究所 ケトアミド系化合物の薬学的用途
WO2023086352A1 (fr) * 2021-11-12 2023-05-19 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
WO2023086400A1 (fr) * 2021-11-12 2023-05-19 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
WO2023107417A1 (fr) * 2021-12-08 2023-06-15 Enanta Pharmaceuticals, Inc. Agents antiviraux hétérocycliques
WO2023107419A1 (fr) * 2021-12-08 2023-06-15 Enanta Pharmaceuticals, Inc. Composés spirocycliques saturés utilisés comme agents antiviraux
WO2023149982A1 (fr) * 2022-02-07 2023-08-10 Purdue Research Foundation Composés pour le traitement du sars
WO2023185763A1 (fr) * 2022-04-01 2023-10-05 中国科学院上海药物研究所 Composé peptidomimétique, procédé de préparation, composition pharmaceutique et utilisation associée
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds
US11858945B2 (en) 2021-11-12 2024-01-02 Enanta Pharmaceuticals, Inc. Alkyne-containing antiviral agents
CN117836272A (zh) * 2021-08-02 2024-04-05 北京华益健康药物研究中心 用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途
WO2024078294A1 (fr) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Forme amorphe de dérivé de cétoamide et procédé pour la préparer
WO2024078302A1 (fr) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Forme cristalline d'un dérivé de cétoamide et son procédé de préparation
US11970502B2 (en) 2021-05-04 2024-04-30 Enanta Pharmaceuticals, Inc. Macrocyclic antiviral agents
US11976084B2 (en) 2020-11-23 2024-05-07 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2024112621A1 (fr) * 2022-11-22 2024-05-30 Merck Sharp & Dohme Llc Dérivés de 2-amino-n-(4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)benzamide utilisés en tant qu'inhibiteurs de protéase pour le traitement ou la prévention d'une infection à coronavirus
WO2024131615A1 (fr) * 2022-12-23 2024-06-27 广东众生睿创生物科技有限公司 Composition pharmaceutique pour le traitement ou l'atténuation de la covid-19 et formulation la comprenant

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022357033A1 (en) * 2021-09-30 2024-03-21 Hainan Simcere Pharmaceutical Co., Ltd. Cyano compound, and preparation method therefor and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3798209A (en) 1971-06-01 1974-03-19 Icn Pharmaceuticals 1,2,4-triazole nucleosides
USRE29835E (en) 1971-06-01 1978-11-14 Icn Pharmaceuticals 1,2,4-Triazole nucleosides
US20110166147A1 (en) 2007-08-21 2011-07-07 Angus Macleod Imidazopyrazine compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061714A2 (fr) * 2004-12-09 2006-06-15 Pfizer Inc. Compositions et composes anti-coronaviraux, leur utilisation pharmaceutique et materiaux destines a leur synthese
EP2760827A4 (fr) * 2011-09-27 2015-06-24 Univ Kansas State Antiviraux à large spectre contre des protéases 3c ou 3c-associées du super-groupe des picornavirus-associés : picornavirus, calicivirus et coronavirus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3798209A (en) 1971-06-01 1974-03-19 Icn Pharmaceuticals 1,2,4-triazole nucleosides
USRE29835E (en) 1971-06-01 1978-11-14 Icn Pharmaceuticals 1,2,4-Triazole nucleosides
US20110166147A1 (en) 2007-08-21 2011-07-07 Angus Macleod Imidazopyrazine compounds

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"THE MERCK INDEX", 1989, pages: 1304
A MUKHERJEE ET AL., PLOS PATHOGENS, vol. 7, no. 3, pages e1001311
A. M. FENDRICK ET AL., ARCH. INTERN. MED., vol. 163, 2003, pages 487
ANZUETO ET AL., CHEST, vol. 123, 2003, pages 1664
D. J. JACKSON ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 178, 2008, pages 667
GARY L. DAVIS, GASTROENTEROLOGY, vol. 118, 2000, pages 104
GERN, PEDIATR. INFECT. DIS. J., vol. 23, 2004, pages S78
J-M PEROTIN ET AL., J. MED. VIROL., vol. 85, 2013, pages 866
JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 22, 2005, pages 6767 - 6771
L SUN ET AL., PLOS ONE, vol. 7, no. 2, pages e30802
PHARMACEUTICAL RESEARCH, vol. 3, no. 6, 1986, pages 318
ROTBART, ANTIVIR. RES., vol. 53, 2002, pages 83
T. GREENE; P. WUTS: "Protecting Groups in Chemical Synthesis", 1999, JOHN WILEY & SONS
THOMPSON ET AL., PUB. HEALTH REP., vol. 127, 2012, pages 23

Cited By (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021534133A (ja) * 2018-08-09 2021-12-09 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズShanghai Institute Of Materia Medica, Chinese Academy Of Sciences ケトアミド系化合物およびその調製方法、医薬組成物および用途
CN113015726A (zh) * 2018-08-09 2021-06-22 中国科学院上海药物研究所 酮酰胺类化合物及其制备方法、药物组合物和用途
EP3835296A4 (fr) * 2018-08-09 2022-05-18 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Composé de cétoamide et procédé de préparation, composition pharmaceutique et utilisation associée
CN113015726B (zh) * 2018-08-09 2024-03-08 中国科学院上海药物研究所 酮酰胺类化合物及其制备方法、药物组合物和用途
EP4098258A4 (fr) * 2020-01-31 2024-02-28 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Utilisation pharmaceutique d'un composé à base de cétoamide
JP2023513048A (ja) * 2020-01-31 2023-03-30 中国科学院上▲海▼▲薬▼物研究所 ケトアミド系化合物の薬学的用途
WO2021191827A1 (fr) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Dérivés tripeptidiques pour le traitement d'infections par le sras-cov-2
WO2021191875A1 (fr) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de cathepsine pour la prévention ou le traitement d'infections virales
WO2021207729A1 (fr) * 2020-04-10 2021-10-14 Mubarak Kamal Khan Compositions et procédés de modulation du récepteur de l'ace2
WO2021206877A1 (fr) * 2020-04-10 2021-10-14 Cocrystal Pharma, Inc. Inhibiteurs de la réplication de norovirus et de coronavirus
US11472793B2 (en) 2020-04-17 2022-10-18 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11312704B2 (en) 2020-04-17 2022-04-26 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2021226546A1 (fr) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de protéase pour le traitement ou la prévention d'une maladie à coronavirus
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11524940B1 (en) 2020-06-09 2022-12-13 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2022013684A1 (fr) 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
GB2607514B (en) * 2020-07-20 2023-06-21 Enanta Pharm Inc Functionalized peptides as antiviral agents
DE112021000413T5 (de) 2020-07-20 2022-12-01 Enanta Pharmaceuticals, Inc. Funktionalisierte Peptide als antivirale Wirkstoffe
GB2619610A (en) * 2020-07-20 2023-12-13 Enanta Pharm Inc Functionalized Peptides as Antiviral Agents
GB2607514A (en) * 2020-07-20 2022-12-07 Enanta Pharm Inc Functionalized peptides as antiviral agents
DE112021000413B4 (de) 2020-07-20 2023-02-23 Enanta Pharmaceuticals, Inc. Funktionalisierte Peptide als antivirale Wirkstoffe
DE202021004113U1 (de) 2020-07-20 2022-08-29 Enanta Pharmaceuticals, Inc. Funtkionalisierte Peptide als antivirale Wirkstoffe
US11358953B2 (en) 2020-07-20 2022-06-14 Enanta Pharmaceuticals, Inc. Functionalized peptides as antiviral agents
WO2022020242A1 (fr) 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux
EP4051265A4 (fr) * 2020-07-20 2022-12-28 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux
CN114466838A (zh) * 2020-09-03 2022-05-10 辉瑞大药厂 含腈的抗病毒化合物
JP7126628B2 (ja) 2020-09-03 2022-08-26 ファイザー・インク ニトリル含有抗ウイルス化合物
JP2022534186A (ja) * 2020-09-03 2022-07-28 ファイザー・インク ニトリル含有抗ウイルス化合物
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
KR102481876B1 (ko) 2020-09-03 2022-12-29 화이자 인코포레이티드 니트릴-함유 항바이러스 화합물
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
KR20220031547A (ko) * 2020-09-03 2022-03-11 화이자 인코포레이티드 니트릴-함유 항바이러스 화합물
EP4001279A1 (fr) 2020-11-23 2022-05-25 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
US11352363B1 (en) 2020-11-23 2022-06-07 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
US11976084B2 (en) 2020-11-23 2024-05-07 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
US11384090B2 (en) 2020-11-23 2022-07-12 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2022129953A1 (fr) * 2020-12-18 2022-06-23 Heptares Therapeutics Limited Composés inhibiteurs de mpro du sars-cov-2
WO2022208262A1 (fr) * 2021-03-30 2022-10-06 Pfizer Inc. Composés antiviraux à liaison éther
WO2022212707A1 (fr) * 2021-04-01 2022-10-06 Primmune Therapeutics, Inc. Inhibiteurs de protéase 3cl du sars
CN117003813A (zh) * 2021-04-16 2023-11-07 福建广生中霖生物科技有限公司 环修饰的脯氨酸短肽化合物及其应用
JP2023543729A (ja) * 2021-04-16 2023-10-18 福建▲広▼生中霖生物科技有限公司 環修飾プロリンショートペプチド化合物及びその使用
CN115698012B (zh) * 2021-04-16 2023-06-16 福建广生中霖生物科技有限公司 环修饰的脯氨酸短肽化合物及其应用
CN115698012A (zh) * 2021-04-16 2023-02-03 南京明德新药研发有限公司 环修饰的脯氨酸短肽化合物及其应用
JP7469562B2 (ja) 2021-04-16 2024-04-16 福建▲広▼生中霖生物科技有限公司 環修飾プロリンショートペプチド化合物及びその使用
US12116367B2 (en) 2021-04-16 2024-10-15 Fujian Akeylink Biotechnology Co., Ltd. Ring-modified proline short peptide compound and use thereof
CN117003813B (zh) * 2021-04-16 2024-03-08 福建广生中霖生物科技有限公司 环修饰的脯氨酸短肽化合物及其应用
WO2022218442A1 (fr) * 2021-04-16 2022-10-20 南京明德新药研发有限公司 Composé de peptide court de proline à cycle modifié et son utilisation
US11970502B2 (en) 2021-05-04 2024-04-30 Enanta Pharmaceuticals, Inc. Macrocyclic antiviral agents
US11319325B1 (en) 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents
WO2022265577A3 (fr) * 2021-06-15 2023-02-02 Agency For Science, Technology And Research Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds
CN113773259A (zh) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 病毒主蛋白酶抑制剂及其制备方法和用途
US11339170B1 (en) 2021-07-23 2022-05-24 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2023003610A1 (fr) * 2021-07-23 2023-01-26 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
WO2023009187A1 (fr) * 2021-07-29 2023-02-02 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
US11325916B1 (en) 2021-07-29 2022-05-10 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
CN117836272A (zh) * 2021-08-02 2024-04-05 北京华益健康药物研究中心 用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途
TWI827245B (zh) * 2021-09-09 2023-12-21 大陸商廣東眾生睿創生物科技有限公司 酮醯胺衍生物及其應用
WO2023036093A1 (fr) * 2021-09-09 2023-03-16 广东众生睿创生物科技有限公司 Dérivé de cétoamide et son application
US12065428B2 (en) 2021-09-17 2024-08-20 Aligos Therapeutics, Inc. Anti-viral compounds
WO2023043816A1 (fr) * 2021-09-17 2023-03-23 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2023044171A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs méthodes d'utilisation
WO2023086400A1 (fr) * 2021-11-12 2023-05-19 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
US11912714B2 (en) 2021-11-12 2024-02-27 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
US11919910B2 (en) 2021-11-12 2024-03-05 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2023086352A1 (fr) * 2021-11-12 2023-05-19 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine
US11858945B2 (en) 2021-11-12 2024-01-02 Enanta Pharmaceuticals, Inc. Alkyne-containing antiviral agents
WO2023107417A1 (fr) * 2021-12-08 2023-06-15 Enanta Pharmaceuticals, Inc. Agents antiviraux hétérocycliques
US11993600B2 (en) 2021-12-08 2024-05-28 Enanta Pharmaceuticals, Inc. Saturated spirocyclics as antiviral agents
WO2023107419A1 (fr) * 2021-12-08 2023-06-15 Enanta Pharmaceuticals, Inc. Composés spirocycliques saturés utilisés comme agents antiviraux
WO2023149982A1 (fr) * 2022-02-07 2023-08-10 Purdue Research Foundation Composés pour le traitement du sars
WO2023185763A1 (fr) * 2022-04-01 2023-10-05 中国科学院上海药物研究所 Composé peptidomimétique, procédé de préparation, composition pharmaceutique et utilisation associée
WO2024078302A1 (fr) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Forme cristalline d'un dérivé de cétoamide et son procédé de préparation
WO2024078294A1 (fr) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Forme amorphe de dérivé de cétoamide et procédé pour la préparer
WO2024112621A1 (fr) * 2022-11-22 2024-05-30 Merck Sharp & Dohme Llc Dérivés de 2-amino-n-(4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)benzamide utilisés en tant qu'inhibiteurs de protéase pour le traitement ou la prévention d'une infection à coronavirus
WO2024131615A1 (fr) * 2022-12-23 2024-06-27 广东众生睿创生物科技有限公司 Composition pharmaceutique pour le traitement ou l'atténuation de la covid-19 et formulation la comprenant

Also Published As

Publication number Publication date
UY37381A (es) 2018-03-23
TW201817714A (zh) 2018-05-16
WO2018042343A3 (fr) 2018-04-19

Similar Documents

Publication Publication Date Title
WO2018042343A2 (fr) Composés inhibant les protéases 3c et 3cl et leurs méthodes d'utilisation
TWI625330B (zh) 經取代之多環性吡啶酮衍生物及其前體藥物
CN105722831B (zh) 哒嗪酮化合物及其用途
US9156839B2 (en) Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11247965B2 (en) Hepatitis B capsid assembly modulators
US8088806B2 (en) Thiazole compounds and methods of use
CN105001225B (zh) 脂质合成的杂环调节剂
ES2289161T3 (es) Derivados de 4-(heteroaril de 6 miembros)-acil pirrolidina como inhibidores de hcv.
TWI557127B (zh) 布魯頓氏酪胺酸激酶抑制劑
NL2000380C2 (nl) 3-aminocyclopentaancarboxamiden als modulatoren van chemokine-receptoren.
US20160046616A1 (en) Nrf2 small molecule inhibitors for cancer therapy
CN113004304B (zh) 经取代的多环性吡啶酮衍生物及其前药
US8691982B2 (en) Pyrazolo[1,5-a]-1,3,5-triazine derivatives, preparation thereof, and therapeutic use thereof
ES2399101T3 (es) Derivados de tiazol y uso de los mismos
CN105008353B (zh) 2‑酰基氨基噻唑衍生物或其盐
KR20130128436A (ko) 인플루엔자 바이러스 복제의 억제제
JP2023537402A (ja) 抗ウイルス剤としての機能化ペプチド
CN115504968B (zh) 三嗪衍生物
TW200930715A (en) Thiazole derivatives and methods of use thereof
US20230107941A1 (en) Hepatitis b capsid assembly modulators
US20240293380A1 (en) Protease inhibitors and methods of use
TW202045516A (zh) 雙環磺醯胺
TW202330537A (zh) Wee1抑制劑及其製備和用途
JP2008517969A (ja) Ｃ型肝炎ウイルス阻害薬としての４−（ピラジン−２−イル）−ピロリジン−２−カルボン酸化合物およびその誘導体
JP2008546837A (ja) 非ヌクレオシド逆転写酵素阻害剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17772475

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17772475

Country of ref document: EP

Kind code of ref document: A2