WO2018042343A2 - Compounds that inhibit 3c and 3cl proteases and methods of use thereof - Google Patents

Compounds that inhibit 3c and 3cl proteases and methods of use thereof Download PDF

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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
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carbamoyl
alkyl
cycloalkyl
heterocycloalkyl
propan
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French (fr)
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WO2018042343A3 (en
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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
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Glaxosmithkline Intellectual Property (No.2) Limited
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    • 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.

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Abstract

Compounds, specifically protease inhibitors, more specifically 3C and 3CL protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds.

Description

Compounds That Inhibit 3C and 3CL Proteases and Methods of Use Thereof
FIELD OF THE INVENTION
[0001] The present invention relates to compounds, specifically protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds.
BACKGROUND OF THE INVENTION
[0002] Each year viruses are implicated in the deaths of millions of people around the world. (See, e.g., Fact Sheets on HIV/AIDS, Hepatitis C Virus, and Influenza, WORLD HEALTH ORGANIZATION). The diseases caused by viral infection are numerous and diverse, as are the structures, sizes, genomes, and infection cycles of the viruses that cause them -facts which tend to complicate and fracture research efforts in this area. Despite these difficulties, researchers continue to make advances towards the prevention, control, and treatment of viral diseases. Typically, successful research efforts have focused on viruses of a single species or genus.
[0003] One of the most successful broad-spectrum antiviral agents is ribavirin. 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®. (THE 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. Accordingly, there exists a serious need for the development of novel therapeutic, antiviral agents, especially broad-spectrum antiviral agents. [0004] 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. The 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.
[0005] Human Rhinoviruses ("HRVs") are Enteroviruses of the Picornaviridae family, and have single-stranded, positive-strand RNA genomes. 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.
[0006] 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. J. Jackson et al., 178 AM. J. RESPIR. CRIT. CARE MED. 667 (2008)). HRVs have also been linked to exacerbations of chronic obstructive pulmonary disease (COPD). J-M Perotin et al., vol. 85 J. MED. VIROL. 866 (2013). [0007] The common cold is one of the most frequently occurring human illnesses and is responsible for substantial morbidity. Although HRV-induced upper respiratory illness is often mild and resolved without medical intervention, the socioeconomic impact is enormous and treatment often includes the inappropriate use of antibiotics. It has been estimated that the common cold accounts for at least twenty-five million absences from work, and nearly as many school absences, annually in the United States.
(Rotbart, 53 ANTIVIR. RES. 83 (2002)). Direct and indirect costs from the common cold and related complications in asthmatics alone have been estimated as high as forty billion dollars annually in the United States. (A. M. Fendrick et al., 163 ARCH. INTERN. MED. 487 (2003).
[0008] There are over one hundred distinct serotypes of HRV that have been identified by specific antisera which can be placed into two broad groups based on the cellular receptor through which cell entry is mediated. Approximately ninety percent of HRV serotypes enter host cells through the human intracellular adhesion molecule (ICAM-1), while the remaining approximately ten percent utilize the low-density lipoprotein receptor for cell entry. The differences between the serotypes not only prevent the body from developing cross-immunity, they have greatly impeded the development of vaccines and other virus-specific methods of prevention and treatment.
[0009] Common colds lead to symptoms such as fever, cough, and nasal congestion. These symptoms are believed to be the result of an over or unspecific reaction of the immune system. The mainstay therapy for HRV infections currently includes treatment with a combination of analgesics such as aspirin or acetaminophen (including localized versions targeting the throat), nasal decongestants, cough suppressants (antitussives), and antihistamines. However, it is widely recognized that these "treatments" merely ameliorate cold symptoms; they do not cure the underlying illness. There is some limited evidence that other forms of treatment act to shorten the time-period of HRV infection, including administration of zinc (not practical because of metallic taste), echinacea, and vitamin C (necessary high dosages not suitable for children). These forms of treatment do not target the cold virus itself, but may be acting to influence the body's general immune response to HRV. Currently, there are no medications approved for use in humans that cure the underlying HRV infection.
[0010] Recently, a few attempts to attack HRVs directly have showed some promise. The compound 4-[2-[1 -(6-methyl-3-pyridazinyl)-4-piperidinyl]-ethoxy]benzoate, otherwise known as "pirodavir," is able to function as a capsid-binding inhibitor and progressed through clinical trials in humans, but problems with solubility, endogenous cleavage, and cost have undermined its utility against HRV. Pleconaril (PICOVIR®) was shown to be effective at inhibiting HRV replication, but is currently rejected by the U.S. FDA, because of significant safety concerns. Certain imidazopyrazines have been suggested as being effective antiviral agents against HRV and other viruses. Although their mode of action is uncertain, it is believed to not be due to their effect on cyclin- dependant kinases. (U.S. Pub. App. No. 201 1/0166147 by Macleod et al.). In light of the above, there remains a need for new therapeutics against HRVs, as well as a special need for the development of broad-spectrum antivirals.
[0011] 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. The isolation of the prototype murine coronavirus strain JHM, for example, was reported in 1949.
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). People are commonly infected with human coronaviruses 229E, NL63, OC43 and HKU1 , and symptoms usually include mild to moderate upper-respiratory tract illnesses of short duration, such as runny nose, cough, sore throat and fever. Occasionally human coronaviruses result in lower-respiratory tract illnesses, such as pneumonia, although this is more common in people with
cardiopulmonary disease or compromised immune systems, or in the elderly.
Transmission of the common human coronaviruses is not fully understood. However, it is likely that human coronaviruses spread from an infected person to others through the air by coughing and sneezing, and through close personal contact, such as touching or shaking hands. These viruses may also spread by touching contaminated objects or surfaces then touching your mouth, nose, or eyes.
[0012] SARS-CoV was first recognized in China in November of 2002, and it resulted in a worldwide outbreak with more than 8,000 cases including 774 deaths between 2002 and 2003. Since 2004, there have not been any known cases of SARS- CoV infection reported anywhere in the world. [0013] Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a novel coronavirus (MERS-CoV) that was first identified in Saudi Arabia in 2012, although retroanalysis determined that the first known cases of MERS occurred in Jordan in April of 2012. As of 2015, the virus appears to be primarily circulating throughout the Arabian Peninsula, with 85% of the cases having been reported in Saudi Arabia from 2012-2015. In 2015 an outbreak was documented in the Republic of Korea and was associated with a traveler who was returning from the Arabian Peninsula.
[0014] The majority of human cases of MERS have been attributed to human-to- human infections, but camels are believed to be a major reservoir host for MERS-CoV and an animal source of MERS infection in humans. The route of transmission from animals to humans is not fully understood. Thus, the exact role of camels in transmission of the virus, and the exact route or routes of transmission between animals and humans or humans and humans are not known. However, the virus does not seem to pass easily from person to person unless there is close contact, such as occurs when providing unprotected care to patients. And while clusters of cases have been reported in healthcare facilities, especially when infection prevention and control practices are inadequate, no sustained community transmission has been documented to date.
[0015] 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.
[0016] Poliomyelitis ("polio") 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. While infection with PV initially begins in the gastrointestinal tract, PV infections can spread and have serious health effects in other parts of the body, including the peripheral and central nervous systems. [0017] Prior to the 1950s, polio epidemics left thousands of children and adults paralyzed. While indigenous transmission of live polioviruses has largely been controlled around the world following the introduction of widespread vaccination, reintroduction of poliovirus from countries where it remains uncontained remains a serious health concern. (Thompson et al., 127 PUB. HEALTH REP. 23 (2012)). Another source of polio's continued threat are outbreaks of vaccine-derived poliovirus, as have recently occurred in the Dominican Republic and Haiti in 2000 and in the Phillipines in 2001 . Accordingly, there is a need for new therapeutics against PV.
[0018] Notwithstanding other differences, several families of positive-strand 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.
[0019] 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. For example, 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 )
[0020] 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).
SUMMARY OF THE INVENTION
Embodiments of the present invention features compounds of Formula I
Figure imgf000008_0001
Formula I
[0022] that are 3C and 3CL protease inhibitors and therefore are useful for treating human rhinovirus (HRV), human coronavirus, picornavirus, and norovirus infections, and disease and symptoms associated with such viruses.
[0023] In certain embodiments of the invention the 3C and 3CL protease inhibitors are compounds of Formula I:
Figure imgf000008_0002
[0024] A is aryl or heteroaryl;
[0025] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyl; NR6R7; OR8; SR9; 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;
[0026] R2 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, NR6R7; 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; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl 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 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 NR6R7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR6R7, OR8, SR9;
[0027] R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[0028] R5 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, NR6R7, OR8, SR9;
[0029] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyi or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[0030] R8 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, [0031] or a salt thereof.
[0032] In certain embodiments of the invention the 3C and 3CL protease inhibitors are compounds of Formula IA:
Figure imgf000010_0001
Formula IA
wherein
[0033] A is aryl or heteroaryl;
[0034] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; 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;
[0035] R2 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, NR6R7; 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; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl 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 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 NR6R7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR6R7, OR8, SR9;
[0036] R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[0037] R5 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, NR6R7, OR8, SR9;
[0038] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyl or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[0039] R8 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, [0040] or a salt thereof.
[0041] In certain embodiments there is provided a compound of Formula IA,
Figure imgf000012_0001
Formula IA
wherein:
[0042] A is phenyl or oxazolyl;
[0043] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; or;
[0044] R2 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; NR6R7; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8- cycloalkyl,C3-C8 heterocycloalkyl or NR6R7 is further optionally substituted with halo, alkoxy, halo-substituted alkoxy, O, N, S, NR6R7, OR8, SR9;
[0045] R3 and R4 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, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R3 and R4 together form a 5 to 10- membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3- C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[0046] R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl;
[0047] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[0048] R8 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.
IA,
Figure imgf000013_0001
Formula IA wherein:
[0050] A is phenyl;
[0051] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; or;
[0052] R2 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; NR6R7;; wherein piperidinyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridinyl, pyrimidinyl, quinolinyl, naphthalenyl; NR6R7 is further optionally substituted with halo, O, N, S, NR6R7, OR8, SR9; [0053] R3 and R4 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi;
[0054] R5 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;
[0055] R6 and R7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 and R7 together form a 3 to 10- membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi; and
[0056] R8 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.
[0057] One particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein R3 is H and R4 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 R3 and R4 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.
[0058] Another particular embodiment provides a compound or salt of Formula I or Formula IA as described, wherein R5 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.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] In 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 oxazolyl and substituted oxazolyl.
[0063] In another embodiment of the present invention, there is provided a compound selected from the group consisting of:
[0064] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-
(dimethylamino)ethyl]carbamate;
[0065] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(piperidin-1 - yl)ethyl]carbamate;
[0066] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(morpholin-4- yl)ethyl]carbamate;
[0067] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1 -yl]ethyl]carbamate;
[0068] benzyl N-[(1 S)-2-(4,4-difluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 - oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[0069] benzyl N-[(1 S)-2-(4-fluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[0070] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1 -yl]ethyl]carbamate;
[0071] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(4,4- difluoropiperidin-1 -yl)ethyl]carbamate; [0072] benzyl N-[(1 S)-2-[(cyclopropylmethyl)(methyl)amino]-1 -{[(1 S)-3-methyl-1 -
{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[0073] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(cyclopentylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1-yl]ethyl]carbamate;
[0074] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[methyl(2,2,2- trifluoroethyl)amino]ethyl]carbamate;
[0075] benzyl N-[(2S)-1-[(2S)-4,4-diethyl-2-{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1 -yl]-1 -oxo-3-[4- (trifluoromethyl)piperidin-1-yl]propan-2-yl]carbamate;
[0076] benzyl N-[(1 S)-2-(4-fluorophenyl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-
2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[0077] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopentylethyl]carbamoyl}-2-(quinolin-5- yl)ethyl]carbamate;
[0078] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(pyridin-2- yl)ethyl]carbamate;
[0079] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -{[(1 S)-1 -phenylethyl]carbamoyl}propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(pyridin- 2-yl)ethyl]carbamate;
[0080] benzyl N-[(1 S)-3-methyl-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}butyl]carbamate;
[0081] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-3- phenylpropyljcarbamate;
[0082] benzyl N-[2-(6-methoxypyridin-2-yl)-1-{[(1 S)-3-methyl-1 -{[(2S)-1-oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate; [0083] benzyl N-[(1 S,2S)-2-methoxy-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}propyl]carbamate;
[0084] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)pyrimidin-2-yl]ethyl]carbamate;
[0085] benzyl N-[(1 S)-2-(5-fluoropyridin-2-yl)-1-{[(1 S)-3-methyl-1-{[(2S)-1 -oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[0086] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[0087] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[5-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[0088] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -{[(1 S)-1 -cyclohexylethyl]carbamoyl}-1 - oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-
(pyridin-2-yl)ethyl]carbamate;
[0089] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(3- methylphenyl)ethyl]carbamate;
[0090] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[0091] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-2- yl)ethyl]carbamate;
[0092] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(propan-2- yloxy)pyridin-2-yl]ethyl]carbamate;
[0093] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate; [0094] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-4- yl)ethyl]carbamate;
[0095] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-
(trifluoromethoxy)pyridin-2-yl]ethyl]carbamate;
[0096] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-
(trifluoromethoxy)pyridin-2-yl]ethyl]carbamate;
[0097] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[5-
(trifluoromethyl)pyrimidin-2-yl]ethyl]carbamate;
[0098] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4- (trifluoromethyl)-l ,3-thiazol-2-yl]ethyl]carbamate;
[0099] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(5-methyl-1 ,3- thiazol-2-yl)ethyl]carbamate;
[00100] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxypyridin-
2-yl)ethyl]carbamate;
[00101] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(2-methoxy-1 ,3- thiazol-4-yl)ethyl]carbamate;
[00102] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-{4H, 51-1,61-1- cyclopenta[d][1 ,3]thiazol-2-yl}ethyl]carbamate;
[00103] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxy-4- methylpyridin-2-yl)ethyl]carbamate;
[00104] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-ethoxypyridin-2- yl)ethyl]carbamate; [00105] {4-[3-(morpholin-4-yl)propoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -
(tert-butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2- cyclohexylethyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
[00106] {4-[2-(piperidin-1 -yl)ethoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3- methylbutyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
[00107] (4-{[cyclopropyl(methyl)amino]methyl}phenyl)methyl N-[(1 S)-2-(4- fluorophenyl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2- yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00108] (5-methyl-1 ,2-oxazol-3-yl)methyl N-[(S)-{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3- methylbutyl]carbamoyl}(2,3-dihydro-1 H-inden-2-yl)methyl]carbamate;
[00109] benzyl N-[(2S)-1 -[(1 S,3aR,6aS)-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}-octahydrocyclopenta[c]pyrrol-2-yl]-
3-(4-fluorophenyl)-1 -oxopropan-2-yl]carbamate;
[00110] benzyl N-[(2S)-1 -oxo-1 -[(3S)-3-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 - [(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}-2-azaspiro[4.4]nonan-2-yl]-3-(pyridin-2- yl)propan-2-yl]carbamate; and
[00111] benzyl N-[(2S)-1 -[(2S)-4,4-diethyl-2-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1 -yl]-3-(4-fluorophenyl)-1 - oxopropan-2-yl]carbamate, or a salt thereof.
[00112] In one embodiment there is provided 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.
[00113] 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.
[00114] 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.
[00115] 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.
[00116] 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.
[00117] In one embodiment the mammal is a human.
[00118] In another particular embodiment, the virus is a rhinovirus, a coronavirus, a picornavirus, or a norovirus.
[00119] In particular embodiments, the coronavirus is a 229E, NL63, OC43, HKU1 , SARS-CoV or a MERS coronavirus.
[00120] In particular embodiments, the picornavirus is a polio virus, EV-68 virus, EV-71 virus, hepatitis A virus, enterovirus or a coxsackievirus .
BRIEF DESCRIPTIONS OF THE DRAWINGS
[00121] 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 . The foregoing features of the invention will be more readily understood by reference to the following detailed description, taken with reference to the accompanying Tables, in which:
[00122] 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.
[00123] Table 2 is a listing of compounds described herein.
[00124] Table 3 is summary of IC5o biological assay data for the compounds in
Table 2.
[00125] Table 4 is a summary of EC5o biological data for select compounds from Table 2. DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
[00126] Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.
[00127] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
[00128] As used herein unless otherwise specified, "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 The term "alkyl" includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), f-butyl ((CH3)3C-), n-pentyl
(CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[00129] "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.
[00130] "Amino" refers to the group -NR6R7 where R6 and R7 are independently selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocyclic, and wherein R6 and R7 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R6 is hydrogen and R7 is alkyl, the amino group is sometimes referred to herein as alkylamino. When R6 and R7 are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R6 or R7 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R6 nor R7 are hydrogen.
[00131] "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). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring
heteroatoms, the term "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).
[00132] "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. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.
[00133] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[00134] "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).
[00135] "Hydroxy" or "hydroxyl" refers to the group -OH.
[00136] "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.
benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term "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). In some embodiments, 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. More specifically the term 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,
isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
[00137] "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. 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. 1 ,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In one embodiment, 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. More specifically 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., C3-Ci0) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
[00138] Examples of 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, indoline, phthalimide, quinoline, 1 ,2,3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, cyclopentathiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
[00139] "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:
Figure imgf000023_0001
[00140] "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:
Figure imgf000024_0001
[00141] "Compound", "compounds", "chemical entity", and "chemical entities" as used herein 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.
[00142] The term "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.
[00143] ""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:
Figure imgf000024_0002
[00144] "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:
Figure imgf000025_0001
[00145] "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:
Figure imgf000025_0002
[00146] "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
Figure imgf000025_0003
[00147] "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:
Figure imgf000025_0004
[00148] "Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, 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. In general, 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.
[00149] "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. In certain embodiments, solvents are volatile, non-toxic, and/or acceptable for
administration to humans in trace amounts. Suitable solvates include water.
[00150] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[00151] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[00152] "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.
[00153] "Patient" or "subject" refers to mammals and includes humans and non-human mammals.
[00154] "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.
[00155] Wherever dashed lines occur adjacent to single bonds denoted by solid lines, then the dashed line represents an optional double bond at that position. Likewise, wherever 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. For example, the dashed line in the structure below could either indicate a double bond at that position or a single bond at that position:
Figure imgf000027_0001
[00156] Similarly, 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. Likewise, in ring B below, any of X1-X5 could be selected from: C, CH, or CH2, 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:
Figure imgf000027_0002
[00157] Where specific compounds or generic formulas are drawn that have aromatic rings, such as aryl or heteroaryl rings, then it will understood by one of still in the art that the particular aromatic location of any double bonds are a blend of equivalent positions even if they are drawn in different locations from compound to compound or from formula to formula. For example, in the two pyridine rings (A and B) below, the double bonds are drawn in different locations, however, they are known to be the same structure and compound:
Figure imgf000027_0003
[00158] Unless indicated otherwise, the nomenclature of 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. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-. In a term such as "-CCR' , it should be understood that the two Rx groups can be the same, or they can be different if Rx is defined as having more than one possible identity. In addition, certain substituents are drawn as -RxRy, where the "-" indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[00159] In accordance with one embodiment of the present invention, there is provided a compound having the structure of Formula IA
Figure imgf000028_0001
Formula IA
[00160] A is aryl or heteroaryl;
[00161] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; 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;
[00162] R2 is C1 -C6-alkvl. C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6- alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyi, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, NR6R7; 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; C3-C8-heterocycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl 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 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 NR6R7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR6R7, OR8, SR9;
[00163] R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[00164] R5 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, NR6R7, OR8, SR9;
[00165] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyl or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[00166] R8 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, [00167] or a salt thereof.
[00168] In certain embodiments there is provided a compound of Formula IA,
Figure imgf000030_0001
Formula IA
wherein:
[00169] A is phenyl or oxazolyl;
[00170] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[00171] R2 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; NR6R7; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8- cycloalkyl,C3-C8 heterocycloalkyl or NR6R7 is further optionally substituted with halo, alkoxy, halo-substituted alkoxy, O, N, S, NR6R7, OR8, SR9;
[00172] R3 and R4 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, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; or R3 and R4 together form a 5 to 10- membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl, C3- C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[00173] R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl;
[00174] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[00175] R8 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.
IA,
Figure imgf000031_0001
Formula IA wherein:
[00177] A is phenyl;
[00178] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyi; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[00179] R2 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; NR6R7;; wherein piperidinyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridinyl, pyrimidinyl, quinolinyl, naphthalenyl; NR6R7 is further optionally substituted with halo, O, N, S, NR6R7, OR8, SR9; [00180] R3 and R4 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl;
[00181] R5 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;
[00182] R6 and R7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi; and
[00183] R8 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, 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.
[00184] In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA as described, wherein R3 is H and R4 is selected from the group consisting of C1 -C6 alkyl and C1 -C6 substituted alkyl, or R3 and R4 together form a ring structure.
[00185] In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA as described, wherein R5 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.
[00186] In another embodiment of the present invention, there is provided 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.
[00187] In another embodiment of the present invention, there is provided 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. [00188] In another embodiment of the present invention, there is provided 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.
[00189] In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA, wherein A is selected from the group consisting of oxazolyl and substituted oxazolyl.
[00190] In another embodiment of the present invention, there is provided a compound selected from the group consisting of:
[00191] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-
(dimethylamino)ethyl]carbamate;
[00192] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(piperidin-1 - yl)ethyl]carbamate;
[00193] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(morpholin-4- yl)ethyl]carbamate;
[00194] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1-yl]ethyl]carbamate;
[00195] benzyl N-[(1 S)-2-(4,4-difluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 - oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00196] benzyl N-[(1 S)-2-(4-fluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00197] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1-yl]ethyl]carbamate;
[00198] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(4,4- difluoropiperidin-1 -yl)ethyl]carbamate; [00199] benzyl N-[(1 S)-2-[(cyclopropylmethyl)(methyl)amino]-1 -{[(1 S)-3-methyl-1 -
{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00200] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(cyclopentylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-
(trifluoromethyl)piperidin-1-yl]ethyl]carbamate;
[00201] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[methyl(2,2,2- trifluoroethyl)amino]ethyl]carbamate;
[00202] benzyl N-[(2S)-1-[(2S)-4,4-diethyl-2-{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1 -yl]-1 -oxo-3-[4- (trifluoromethyl)piperidin-1-yl]propan-2-yl]carbamate;
[00203] benzyl N-[(1 S)-2-(4-fluorophenyl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-
2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00204] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopentylethyl]carbamoyl}-2-(quinolin-5- yl)ethyl]carbamate;
[00205] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(pyridin-2- yl)ethyl]carbamate;
[00206] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -{[(1 S)-1 -phenylethyl]carbamoyl}propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(pyridin- 2-yl)ethyl]carbamate;
[00207] benzyl N-[(1 S)-3-methyl-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}butyl]carbamate;
[00208] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-3- phenylpropyljcarbamate;
[00209] benzyl N-[2-(6-methoxypyridin-2-yl)-1-{[(1 S)-3-methyl-1 -{[(2S)-1-oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate; [00210] benzyl N-[(1 S,2S)-2-methoxy-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}propyl]carbamate;
[00211] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)pyrimidin-2-yl]ethyl]carbamate;
[00212] benzyl N-[(1 S)-2-(5-fluoropyridin-2-yl)-1-{[(1 S)-3-methyl-1-{[(2S)-1 -oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00213] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[00214] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[5-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[00215] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -{[(1 S)-1 -cyclohexylethyl]carbamoyl}-1 - oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-
(pyridin-2-yl)ethyl]carbamate;
[00216] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(3- methylphenyl)ethyl]carbamate;
[00217] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate;
[00218] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-2- yl)ethyl]carbamate;
[00219] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(propan-2- yloxy)pyridin-2-yl]ethyl]carbamate;
[00220] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-
(trifluoromethyl)pyridin-2-yl]ethyl]carbamate; [00221] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-4- yl)ethyl]carbamate;
[00222] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-
(trifluoromethoxy)pyridin-2-yl]ethyl]carbamate;
[00223] benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1-[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-
(trifluoromethoxy)pyridin-2-yl]ethyl]carbamate;
[00224] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[5-
(trifluoromethyl)pyrimidin-2-yl]ethyl]carbamate;
[00225] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4- (trifluoromethyl)-l ,3-thiazol-2-yl]ethyl]carbamate;
[00226] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(5-methyl-1 ,3- thiazol-2-yl)ethyl]carbamate;
[00227] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxypyridin-
2-yl)ethyl]carbamate;
[00228] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(2-methoxy-1 ,3- thiazol-4-yl)ethyl]carbamate;
[00229] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-{4H, 51-1,61-1- cyclopenta[d][1 ,3]thiazol-2-yl}ethyl]carbamate;
[00230] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxy-4- methylpyridin-2-yl)ethyl]carbamate;
[00231] benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-ethoxypyridin-2- yl)ethyl]carbamate; [00232] {4-[3-(morpholin-4-yl)propoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -
(tert-butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2- cyclohexylethyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
[00233] {4-[2-(piperidin-1 -yl)ethoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3- methylbutyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
[00234] (4-{[cyclopropyl(methyl)amino]methyl}phenyl)methyl N-[(1 S)-2-(4- fluorophenyl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2- yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
[00235] (5-methyl-1 ,2-oxazol-3-yl)methyl N-[(S)-{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3- methylbutyl]carbamoyl}(2,3-dihydro-1 H-inden-2-yl)methyl]carbamate;
[00236] benzyl N-[(2S)-1 -[(1 S,3aR,6aS)-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}-octahydrocyclopenta[c]pyrrol-2-yl]-
3-(4-fluorophenyl)-1 -oxopropan-2-yl]carbamate;
[00237] benzyl N-[(2S)-1 -oxo-1 -[(3S)-3-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 - [(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}-2-azaspiro[4.4]nonan-2-yl]-3-(pyridin-2- yl)propan-2-yl]carbamate; and
[00238] benzyl N-[(2S)-1 -[(2S)-4,4-diethyl-2-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1 -yl]-3-(4-fluorophenyl)-1 - oxopropan-2-yl]carbamate, or a salt thereof.
[00239] 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.
[00240] 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. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, 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. In addition, 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).
[00241] In another embodiment of the invention, there is provided a compound of Formula I or Formula IA, for use in therapy.
[00242] In another embodiment of the intention, there is provided a compound of Formula I or Formula IA, for use in the treatment of a viral infection.
[00243] In another embodiment of the invention, there is provided a use of a compound of Formula I or Formula IA in the manufacture of a medicament for use in the treatment of a viral infection in a human.
[00244] In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I or Formula IA.
[00245] In one embodiment, the pharmaceutical formulation containing a compound of Formula I or Formula IA or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation.
[00246] In one embodiment, 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.
[00247] In one embodiment, 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. In one embodiment, 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. Upon preparation of a parenteral formulation with a compound of Formula I or Formula IA, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used. As an anti-viral-drug, particularly, an oral agent is preferable. 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.
[00248] Pharmaceutical formulations 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.
[00249] For instance, for oral administration in the form of a tablet or capsule, 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. 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.
[00250] 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.
[00251] Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. 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. 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. As an alternative to granulating, 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 sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
[00252] 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.
[00253] Where appropriate, 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.
[00254] 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.
[00255] 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. Furthermore, 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.
[00256] Pharmaceutical formulations 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. For example, 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).
[00257] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water- in-oil base.
[00258] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
[00259] Pharmaceutical formulations 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.
[00260] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
[00261] Pharmaceutical formulations 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.
[00262] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
[00263] 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.
[00264] 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.
[00265] 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.
[00266] Accordingly, there is provided 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. In one embodiment, the virus is a rhinovirus. In one embodiment, the virus is a coronavirus. In one embodiment the virus is a picornavirus. In one embodiment, the virus is a norovirus.
[00267] In another embodiment, 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.
[00269] In a further aspect, 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.
[00270] In one aspect, 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.
[00271] In yet another aspect, 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.
[00272] In one aspect, 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.
[00273] In a further aspect, 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.
[00274] In one aspect, 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. [00275] In a further aspect, 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.
[00276] In one aspect, 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.
[00277]
[00278] In other embodiments, 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
pathophysiology. Thus, 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,
mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert-butylthio)-1 -(4-(6- ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2-yl)methoxy)-1 H-indol-2-yl)-2,2- dimethylpropanoate), bronchodilators (e.g..muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-lgE, anti- TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; 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
https://wvw.drugs.coiT)/ctfug-ciass/anii-infectives.htmi.
[00279] Suitably, for the treatment of asthma, 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. For example, 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. Alternatively, 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. In one embodiment, 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.
[00280] 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. In one embodiment of the invention 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.
[00281] Suitably, for the treatment of COPD, COPD-bronchiectasis overlap syndrome and bronchiectasis, compounds or pharmaceutical formulations of the invention may be administered together with one or more bronchodilators, or pharmaceutical formulations thereof. For example, 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. Alternatively, a pharmaceutical formulation comprising a compound of the invention may be administered in conjunction with a pharmaceutical formulation comprising one or more bronchodilators, either
simultaneously or sequentially. In a further alternative, a formulation comprising a compound of the invention and a bronchodilator may be administered in conjunction with a pharmaceutical formulation comprising a further bronchodilator. In one embodiment, a pharmaceutical formulation comprising a compound of the invention and a
pharmaceutical formulation comprising one or more bronchodilators may each be held in device suitable for the simultaneous administration of both formulations via inhalation. In a further embodiment, 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.
[00282] Suitable bronchodilators for administration together with a compound of the invention include, but are not limited to, p2-adrenoreceptor agonists and
anticholinergic agents. Examples of 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). In one embodiment of the invention, a compound of the invention may be administered together with a p2-adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as umeclidinium.
[00283] 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.
[00284] Alternatively, 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.
[00285] More particularly, 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
immunosuppressant agent. In certain embodiments, the antiviral agent is an anti- hepatitis A agent or an antiretroviral agent. Still more particularly, the additional agent is administered as part of a single dosage form of said pharmaceutical formulation, or as a separate dosage form.
[00286] 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.
[00287] Therefore, in another embodiment of the present invention, there is provided 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.
[00288] In another embodiment of the present invention, there is provided 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.
[00289] In another embodiment of the present invention, there is provided 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. [00290] In another embodiment of the present invention, there is provided 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.
[00291] In one embodiment of the present invention, the compounds described herein are useful for preventing or treating viral infections in a subject caused by a single-stranded RNA virus.
[00292] An 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.
[00293] In one embodiment of the present invention, the compounds described herein are useful for preventing or treating viral infections in a subject caused by a positive-sense, single-stranded RNA virus.
[00294] In one embodiment of the present invention, the compounds described herein are useful for preventing or treating viral infections in a subject caused by a negative-sense, single-stranded RNA virus.
[00295] In some embodiments, provided is 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.
[00296] In yet another aspect, 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.
[00297] In yet another aspect, 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.
[00298] In yet another aspect, 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.
[00299] 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.
[00300] 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.
[00301] 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.
[00302] 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.
[00303] 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.
[00304] 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.
[00305] 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.
[00306] 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. [00307] 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 protease, HRV-68 3C protease, HRV-78 3C protease, HRV-82 3C protease, HRV-88 3C protease, HRV-94 3C protease and HRV-98 3C protease.
[00308] 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.
[00309] 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.
[00310] 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.
[00311] In other embodiments, 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.
[00312] 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. In particular, the treatment and prophylaxis of viral infections such as those caused by RNA or DNA viruses are disclosed.
[00313] In yet other embodiments, 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 .
[00314] 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, 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.
[00315] 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.
[00316] In other embodiments, 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.
[00317] In other embodiments, the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the human coronaviruses.
[00318] In other embodiments, 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.
[00319] In other embodiments, the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the alpha human coronaviruses.
[00320] In other embodiments, 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.
[00321] In other embodiments, the compounds described herein are useful for treating infections in a subject wherein the infection is caused by any of the beta human coronaviruses.
[00322] In other embodiments, 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. [00323] In other embodiments, 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.
[00324] In other embodiments, the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the human coronavirus MERS-CoV.
[00325] In other embodiments, the compounds described herein are useful for treating infections in a subject wherein the infection is caused by the human coronavirus SARS-CoV.
[00326] In other embodiments, 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.
[00327] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by enterovirus A71 .
[00328] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by enterovirus D68.
[00329] In other embodiments, 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.
[00330] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus A.
[00331] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus B.
[00332] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by human rhinovirus C.
[00333] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the poliovirus.
[00334] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the coxackievirus.
[00335] In other embodiments, 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.
[00336] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the echovirus. [00337] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the hepatitis A virus.
[00338] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the calicivirus.
[00339] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by any of the norovirus.
[00340] In other embodiments, the compounds described herein are useful for treating viral infections in a subject where the infection is caused by the Norwalk virus. In further embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 2.
EXAMPLES
[00341] Synthetic Schemes
Figure imgf000053_0001
Formula (I) or corresponding pharmaceutically acceptable salts thereof, of the present invention are prepared using conventional organic syntheses, wherein
[00343] A is phenyl or oxazolyl;
[00344] R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo; haloalkyl; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyl, NR6R7, OR8, SR9; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6R7, OR8, SR9; [00345] R2 is C1 -C6-alkyl, C1 -C6-alkyl optionally 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 optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy; NR6R7; aryl optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, halo-substituted alkoxy, hydroxy, thioalkyi; heteroaryl, optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, halo-substituted alkoxy; wherein C1 -C6-alkyl or C1 -C6- cycloalkyi is further optionally substituted with halo, O, N, S, NR6R7, OR8, SR9;
[00346] R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
[00347] R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl or aryl; C3-C8- cycloalkyl or C3-C8-heterocycloalkyl;
[00348] R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
[00349] R8 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.
[00350] 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). In some instances, 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.
[00351] Scheme 1
Figure imgf000055_0001
[00352] As shown in Scheme 1 , 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 S03-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. Preferably, 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.
[00353] Scheme 2
[00354] As shown in Scheme 2, 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. The subsequent oxidation is completed with Dess-Martin periodinane to yield final products.
[00355] Compound Examples
[00356] Abbreviations
[00357] In describing the examples, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical arts. The following abbreviations are used herein:
AcOH acetic acid
Ac20 acetic anhydride
aq aqueous
B4 (S)-2-(((benzyloxy)carbonyl)amino)-3-(4- (trifluoromethyl)piperidin-1 -yl)propanoic acid
BOC (Boc) N-tert-butoxycarbonyl or tert-butyloxycarbonyl
CBz carboxybenzyl
CellTiter-Glo® CellTiter-Glo® Luminescent Cell Viability Assay from Promega
CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-1 - propanesulfonate
Combiflash® automated flash chromatography from Teledyne Isco
CPE cytopathic effect or cytopathogenic effect dba dibenzylideneacetone or dibenzalacetone
DCE dichloroethane
DCM dichloromethane
DCM/EA dichloromethane/ethanol
DIPEA (or DIEA) Ν,Ν-Diisopropylethylamine, or Hiinig's base
DME dimethoxyethane
DMEM Dulbecco's Modified Eagle Medium
DMF dimethylformamide
DMP Dess-Martin periodinane
DMSO-d6 deuterated dimethylsulfoxide
DMSO dimethylsulfoxide
EC5o 50% effective concentration
EDTA ethylenediaminetetraacetic acid
Envision an EnVision Multilabel Reader from PerkinElmer
Et20 diethyl ether
EtOH ethanol
EtOAc, EA, AcOEt ethyl acetate
FBS fetal bovine serum
FRET Forster Resonance Energy Transfer
GlutaMAX™ cell culture supplement from Life Technologies h hour(s)
HEPES 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid
HPLC high performance liquid chromatography
IC50 50% inhibition concentration
iPrOH isopropyl alcohol or isopropanol
LCMS Liquid chromatography mass spectroscopy
MeOH methanol
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NIS N-iodosuccinimide
NXS N-halosuccinimide
NaBH(OAc)3 sodium triacetoxyborohydride
NMR Nuclear Magnetic Resonance spectroscopy
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
PE petroleum ether
PPh3 triphenylphosphine
RB round bottom
rt or r.t. room temperature
RT retention time
SFC supercritical fluid chromatography
SQ3pyr Sulfur trioxide pyridine complex - formula CsHsNSC 2-dicyclohexyl phosphine-2',6'-dimethoxybiphenyl or
dicyclohexyl(2',6'-dimethoxy-[1 ,1 '-biphenyl]-2-yl) methyl t-butyl ether
1 -Propanephosphonic anhydride solution, 2,4,6-Tripropyl- 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide trifluoroacetic acid
a Multidrop™ Combi Reagent Dispenser from Thermo
Fisher Scientific
tetrahydrofuran
ultraviolet
[00358] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). Unless otherwise indicated, all reactions are conducted under an inert atmosphere at ambient temperature.
[00359] All temperatures are given in degrees Celsius, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon (Ar) or nitrogen (N2) atmosphere where necessary.
[00360] The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention.
[00361] While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
[00362] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
[00363] All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted, and all solvents are highest available purity unless otherwise indicated.
[00364] 1H NMR (hereinafter also "NMR") spectra were recorded on a Varian
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, δ 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).
[00365] Mass spectra were run on an open access LC-MS system using electrospray ionization. LC conditions: 10% to 80% CH3CN (0.018% TFA) in 3.0 min with a 1 .25 min hold and 0.5 min re-equilibration; detection by MS, UV at 214 nm, and a light scattering detector (ELS). Column: 2.1 X 50 mm Zorbax SB-C8.
[00366] 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.
[00367] INTERMEDIATES
[00368] Example 1
[00369] Intermediate A
Figure imgf000059_0001
intermediate A
[00370] (3S)-3-((tert-butoxycarbonyl)amino)-1 -(isopropylamino)-1 -oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl benzoate 3
[00371] A solution of tert-butyl ((S)-1 -hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (1 .0g, 3.87mmol) in the mixture of DMSO (1 .4ml_, 19.35mmol) and DCM (10ml_) was cooled to -5 °C, Hunig's base (2.366 mL, 13.55 mmol) was added while stirring. In another round bottle flask, a suspension of sulfur trioxide pyridine complex (1 .232 g, 7.74 mmol) in pyridine (0.626 mL, 7.74 mmol) and DMSO (1 .4mL, 19.35mmol) was stirred for 10 min at room temperature. This suspension was then added into the above pre-formed solution at -5 °C. Additional volumes of DCM (6mL) were used to complete the transfer. The resulting mixture was stirred for additional 2 hours at -5 °C. 2-isocyanopropane (0.438 mL, 4.65 mmol) was then added into the reaction mixture, followed by benzoic acid (3.07 g, 25.2 mmol), and the reaction mixture was stirred overnight at rt (dry ice bath was removed 5 min after addition). The reaction mixture was diluted with EtOAc. After separating EtOAc layer, the organic phase was washed with sat. aq NaHC03, 1 M aq Na2C03, brine, and dried over Na2S04, filtered and
concentrated. The crude material was further purified by column chromatography on silica gel, eluted with 0-100% EtOAc in hexanes (25 min), and then EtOAc was replaced by a 3:1 mixture of EtOAc:EtOH (50%) for 10 min. The desired fraction was collected and concentrated to give (3S)-3-((tert-butoxycarbonyl)amino)-1 -(isopropylamino)-1 -oxo- 4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl benzoate (1 .36 g, 79% yield) as a white color solid. LCMS: M+1 = 448.4. (Mixture of two closely eluting diastereomers.)
[00372] tert-butyl ((2S)-3-hvdroxy-4-(isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-
3- yl)butan-2-yl)carbamate
[00373] (3S)-3-((tert-butoxycarbonyl)amino)-1 -(isopropylamino)-l -oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl benzoate (16.27 g, 36.4 mmol) was taken in tetrahydrofuran (THF) (30 ml_) and water (30 ml_). Lithium hydroxide (3.05 g, 127 mmol) was added to the reaction mixture. The reaction mixture was stirred for 2 hours and the completion was confirmed by LCMS monitoring. The THF was evaporated under reduced pressure and the water layer was extracted with ethyl acetate and the extract was washed with NaHC03 solution, brine, filtered, dried over sodium sulfate and concentrated in vacuo. The crude material was triturated with diethyl ether to yield tert-butyl ((2S)-3-hydroxy-4- (isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (10.61 g, 85%) as white solid. LCMS: [M+1 ]=344.3, (two peaks, one for each alcohol diastereomer).
[00374] (3S)-3-amino-2-hvdroxy-N-isopropyl-4-((S)-2-oxopyrrolidin-3- vDbutanamide hydrochloride
[00375] To a stirring mixture of tert-butyl ((2S)-3-hydroxy-4-(isopropylamino)-4-oxo- 1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (10 g, 29.1 mmol) in Dichloromethane (DCM) (15 mL) and ethyl acetate (100 mL) was added hydrochloric acid (29.1 mL, 1 16 mmol) at 0°C. Five minutes after addition, ice-bath was removed and the reaction mixture was allowed to stir at rt overnight. LCMS indicated completion of reaction.
Precipitated solid was filtered and collected to give (3S)-3-amino-2-hydroxy-N-isopropyl-
4- ((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (8.0g, 28.6mmol, 98 % yield) as a white solid. The hydrochloride salt was taken forward to the next step without any further purification. LCMS: [M+1 ]=244.2, (two peaks, one for each alcohol diastereomer).
[00376] tert-butyl ((2S)-1 -(((2S)-3-hvdroxy-4-(isopropylamino)-4-oxo-1 -((S)-2- oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)carbamate [00377] In a RB flask was added (S)-2-((tert-butoxycarbonyl)amino)-4- methylpentanoic acid (0.909 g, 3.93 mmol), DIPEA (1 .87 mL, 10.72 mmol) and (3S)-3- amino-2-hydroxy-N-isopropyl-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (1 .00 g, 3.57 mmol) in DCM (20 mL). The mixture was stirred at 0 °C when T3P (50 wt % in EtOAc, 2.34 mL, 3.93 mmol) was added dropwise. The mixture was stirred for 2 hours while in ice bath. The mixture was diluted with EtOAc, washed w/ 1 N HCI (aq), NaHC03 (aq), brine, and then dried over Na2S04, filtered and concentrated to give tert-butyl ((2S)- 1 -(((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2- yl)amino)-4-methyl-1 -oxopentan-2-yl)carbamate (1 .36 g, 83% crude yield). This material was used in the next step without further purification. LCMS: M+1 = 457.3. (two peaks, for mixture of diastereomers)
[00378] (2S)-2-amino-N-((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1 -((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-4-methylpentanamide hydrochloride
[00379] To a stirred solution of tert-butyl ((2S)-1 -(((2S)-3-hydroxy-4- (isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 - oxopentan-2-yl)carbamate (7 g, 15.33 mmol) in dichloromethane (DCM) (80 mL) was added hydrochloric acid (15.33 mL, 61 .3 mmol) at 0 °C. Five minutes after addition, ice- bath was removed and the reaction mixture was allowed to stir at rt overnight. LCMS indicated completion of reaction. Precipitated solid was filtered and collected to yield (2S)-2-amino-N-((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3- yl)butan-2-yl)-4-methylpentanamide hydrochloride (6 g, 15.27 mmol, 100 % yield) as a white solid. LCMS: M+1 = 357.2,
[00380] Example 2
[00381] (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1 - vDpropanoic acid
[00382] Under N2, in a RB flask was added 4-(trifluoromethyl)piperidine (2.97 g, 19.39 mmol) and (Z)-trimethylsilyl N-(trimethylsilyl)acetimidate (2.371 mL, 9.70 mmol) in acetonitrile (80 mL). The mixture was stirred at rt for 5 hours, followed by addition of (S)- benzyl (2-oxooxetan-3-yl)carbamate (3.3 g, 14.92 mmol) and continued to stir overnight. The mixture was concentrated and the residue was dissolved in ether, extracted w/ aq. 1 N HCI. The aqueous layer was adjusted to PH6.6 w/ 6N NaOH in an ice-bath and extracted w/ EtOAc. The organic layer was dried over Na2S04, concentrated to give (S)- 2-(((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1 -yl)propanoic acid (4.62 g, 12.34 mmol, 83 % yield). LCMS: M+1 = 375.2, 0.68min
[00383] benzyl ((2S)-1 -(((2S)-1 -(((2S)-3-hvdroxy-4-(isopropylamino)-4-oxo-1 -((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(4- (trifluoromethyl)piperidin-1 -yl)propan-2-yl) carbamate
[00384] In a RB flask was added (2S)-2-amino-N-((2S)-3-hydroxy-4- (isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-4-methylpentanamide, Hydrochloride (900 mg, 2.291 mmol), (S)-2-(((benzyloxy)carbonyl)amino)-3-(4- (trifluoromethyl)piperidin-1 -yl)propanoic acid (917 mg, 2.451 mmol) in dichloromethane (DCM) (30ml_). The mixture was stirred at -5°C for 5 min, N-ethyl-N-isopropylpropan-2- amine (1 .600 ml_, 9.16 mmol) was added. The mixture was stirred at -5°C for 15 min, and then 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1 .501 ml_, 2.52 mmol) in 10ml_ of EtOAc was added via an additional funnel dropwise and continued to stir for 2 hours. The mixture was diluted with EtOAc, washed w/ aqueous NaHC03, brine, dried over Na2S04, concentrated to give crude which was further purified by normal phase chromatography, eluted w/ DCM and iPrOH, with iPrOH up to 50% in 30min, (80g column), obtained benzyl ((2S)-1 -(((2S)-1 -(((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1 - ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3- (4-(trifluoromethyl)piperidin-1 -yl)propan-2-yl)carbamate (1 .36 g, 1 .908 mmol, 83 % yield) as white solid. LCMS M+1 = 713.6
[00385] Benzyl((S)-1 -(((S)-1 -(((S)-4-(isopropylamino)-3.4-dioxo-1 -((S)-2- oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(4- (trifluoromethyl)piperidin-1 -yl)propan-2-yl) carbamate
[00386] In a RB flask, the solution of ((2S)-1 -(((2S)-1 -(((2S)-3-hydroxy-4- (isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 - oxopentan-2-yl)amino)-1 -oxo-3-(4-(trifluoromethyl)piperidin-1 -yl)propan-2-yl)carbamate (2.64g, 3.70 mmol) in Dichloromethane (DCM) (50 mL) was stirred at 0°C when Dess- Martin periodinane (2.356 g, 5.56 mmol) was added in one portion. Ice-bath was removed after 5 min, the mixture was stirred for 2 hours. Additional DMP (0.5g, 1 .17mmol) was added and kept stirring for 1 h. The mixture was concentrated and the residue was directly purified by automated normal phase chromatography, eluted w/ DCM and acetone, with acetone up to 90% in 50min, (240g column). The fractions were sat overnight and DMP by-product was precipitated and filtered off. The filtrate was concentrated to give benzyl ((S)-1 -(((S)-1 -(((S)-4-(isopropylamino)-3,4-dioxo-1 -((S)-2- oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(4- (trifluoromethyl)piperidin-1 -yl)propan-2-yl)carbamate (2.2 g, 3.10 mmol, 84 % yield) as white solid. The material was further purified by triturated with EtOAc/ether, and another normal phase column purification to give 1 .98g material (75%). LCMS 71 1 .5
[00387] Ή NMR (400 MHz, DMSO-de) d ppm 0.77 - 0.95 (m, 6 H) 1 .09 (d, J^6.34 Hz, 6 H) 1 .32 - 1 .52 (m, 4 H) 1 .54 - 1 .80 (m, 5 H) 1 .85 - 1 .96 (m, 1 H) 1 .96 - 2.08 (m, 2 H) 2.09 - 2.29 (m, 2 H) 2.30 - 2.39 (m, 1 H) 2.40 - 2.48 (m, 2 H) 2.96 (d, J^9.38 Hz, 2 H) 3.06 - 3.23 (m, 2 H) 3.90 (dd, JM 4.70, 6.59 Hz, 1 H) 4.18 (q, J^7.44 Hz, 1 H) 4.29 - 4.43 (m, 1 H) 4.93 - 5.13 (m, 3 H) 7.24 - 7.42 (m, 6 H) 7.69 (s, 1 H) 8.24 (d, J^8.1 1 Hz, 1 H) 8.46 - 8.50 (m, 1 H) 8.50 - 8.63 (m, 2 H)
[00388] Example 3
[00389] (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2- vDpropanoate
[00390] To a 50-mL flask under N2 was added zinc (0.894 g, 13.67 mmol) (dust), followed by Ν,Ν-Dimethylformamide (DMF) (10 mL) and l2 (0.174 g) . Some heat was given out and the mixture changed from dark red to a colorless suspension. After 10 min, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1 .5 g, 4.56 mmol) and I2 (0.174 g) were added, and the mixture was stirred at rt for 90 min. 2-bromo-6- (trifluoromethyl)pyridine (1 .339 g, 5.92 mmol), Pd2(dba)3 (0.104 g, 0.1 14 mmol) and dicyclohexyl(2',6'-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (or Sphos) (0.094 g, 0.228 mmol) were added, and the mixture was stirred at 50°C overnight. The reaction was diluted with EtOAc (50 mL) and filtered. The organic solution was washed with water (5 x 15 mL), dried (Na2S04), filtered and concentrated. The residue was purified by
Combiflash automated silica gel chromatography, eluting with [EtOAc/EtOH
76:24]/Hexanes 5-40% to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-2-yl)propanoate (0.783 g, 2.248 mmol, 49.3 % yield) as a light green oil. LCMS: [M+Na]+: 371 .2.
[00391] (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2- vDpropanoate
[00392] To a 100 mL RB flask at 0 °C was added (S)-methyl 2-((tert- butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2-yl)propanoate (0.783 g, 2.248 mmol) in DCM (15 mL), followed by HCI (1 1 .24 mL, 45.0 mmol) (4 M in dioxane). The mixture was stirred at rt for 1 h. The organic solution was concentrated to dryness under vacuum. The residue was taken in DCM (20 mL), and DIPEA (1 .178 mL, 6.74 mmol) and Cbz-CI (0.385 mL, 2.70 mmol) were added. The mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to dryness and the residue was purified by Combiflash automated silica gel column chromatography (120 g Gold column, 18 min run), eluting with [EtOAc/EtOH 76:24]/Hexanes 0-30% to afford (S)-methyl 2- (((benzyloxy)carbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2-yl)propanoate (0.879 g, 2.138 mmol, 95 % yield) as a clear oil. LCMS: [M+H]+: 383.2.
[00393] (S)-2-(((benzyloxy)carbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2- vDpropanoic acid
[00394] To a 50 mL RB flask at rt at 0°C was added (S)-methyl 2- (((benzyloxy)carbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2-yl)propanoate (0.879 g, 2.138 mmol) in tetrahydrofuran (THF) (10 mL), followed by lithium hydroxide (3.21 mL, 3.21 mmol) (1 M in water). The mixture was stirred at rt for 0.5 hr. HCI (3.21 mL, 3.21 mmol) (1 M in water) was added, and the mixture was diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic solution was dried (Na2S04), filtered and concentrated to afford (S)-2-(((benzyloxy)carbonyl)amino)-3-(6- (trifluoromethyl)pyridin-2-yl)propanoic acid (0.891 g, 2.141 mmol, 100 % yield) as a light green solid. LCMS: [M+H]+: 369.1 .
[00395] benzyl ((2SV1 -(((2SV1 -(((2SV3-hvdroxy-4-(isopropylaminoV4-oxo-1 -((SV
2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(6-
(trifluoromethyl)pyridin-2-yl)propan-2-yl)carbamate
[00396] To a 50 mL RB flask under N2 was added (2S)-2-amino-N-((2S)-3- hydroxy-4-(isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-4- methylpentanamide, hydrochloride (0.301 g, 0.767 mmol) and (S)-2- (((benzyloxy)carbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2-yl)propanoic acid (0.319 g, 0.767 mmol) in dichloromethane (DCM) (10 mL), followed by DIPEA (0.669 mL, 3.83 mmol) and 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.671 mL, 1 .150 mmol) . The mixture was stirred at rt for 2 h. LCMS indicated formation of desired product. The organic solution was concentrated and the residue was purified by Combiflash automated silica gel column chromatography (40 g Gold, column, 25 min run), eluting with [EtOAc/EtOH 76:24]/Hexanes 5-80% to afford 2 fractions that corresponded to the 2 diastereomers: P1 105 mg and P2 205 mg as white solid. The two fractions were combined as A1 to yield benzyl ((2S)-1 -(((2S)-1 -(((2S)-3-hydroxy-4- (isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 - oxopentan-2-yl)amino)-1 -oxo-3-(6-(trifluoromethyl)pyridin-2-yl)propan-2-yl)carbamate (0.31 g, 0.439 mmol, 57.2 % yield) as a white solid. LCMS: [M+H]+:707.4.
[00397] benzyl ((S)-1 -(((S)-1 -(((S)-4-(isopropylamino)-3.4-dioxo-1 -((S)-2- oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(6-
(trifluoromethyl)pyridin-2-yl)propan-2-yl)carbamate
[00398] To a 50-mL RB flask under N2 was added benzyl ((2S)-1 -(((2S)-1 -(((2S)-3- hydroxy-4-(isopropylamino)-4-oxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4- methyl-1 -oxopentan-2-yl)amino)-1 -oxo-3-(6-(trifluoromethyl)pyridin-2-yl)propan-2- yl)carbamate (0.31 g, 0.439 mmol) in dichloromethane (DCM) (15 mL), followed by Dess-Martin periodinane (0.205 g, 0.482 mmol) . The mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. Sat aq sodium thiosulfate (3 mL) and sat sodium bicarbonate (3 mL) were added, and the mixture was stirred for another 15 min. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic solution was dried (Na2S04), filtered and concentrated. The residue was purified by Combiflash® automated silica gel column chromatography (24 g Gold column, 20 min run), eluting with i-PrOH/DCM 0-40% to afford benzyl ((S)-1 -(((S)-1 -(((S)- 4-(isopropylamino)-3,4-dioxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1 - oxopentan-2-yl)amino)-1 -oxo-3-(6-(trifluoromethyl)pyridin-2-yl)propan-2-yl)carbamate (0.228 g, 0.304 mmol, 69.3 % yield) as a white solid. LCMS: [M+H]+: 705.6
[00399] Ή NMR (400 MHz, DMSO-cfi) δ ppm 0.87 (dd, JM 8.44, 6.57 Hz, 6 H)
1 .09 (d, J^6.57 Hz, 6 H) 1 .38 - 1 .50 (m, 2 H) 1 .52 - 1 .74 (m, 3 H) 1 .84 -1 .98 (m, 1 H)
2.10 - 2.24 (m, 1 H) 2.30 - 2.43 (m, 1 H) 2.95 - 3.07 (m, 1 H) 3.09 - 3.28 (m, 3 H) 3.83 - 3.98 (m, 1 H) 4.27 - 4.40 (m, 1 H) 4.46 - 4.60 (m, 1 H) 4.94 (s, 2 H) 4.96 - 5.06 (m, 1 H) 7.23 (s, 2 H) 7.33 (s, 1 H) 7.61 (d, J^8.34 Hz, 2 H) 7.69 (s, 1 H) 7.71 - 7.79 (m, 1 H) 7.91 - 8.03 (m, 1 H) 8.09 - 8.16 (m, 1 H) 8.47 - 8.61 (m, 2 H).
[00400] Biological Examples
Example 4 HRV-16 3C Protease Enzyme Protocol
[00401] 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 μΜ 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.
[00402] 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 μΙ_ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 μΙ_ of 10 nM enzyme (HRV-16 3C protease, 5 nM final concentration) in assay buffer to columns 1 -17, and 19 -24.
[00403] A FRET substrate peptide (FAM-GRAVFQGPVG-TAMRA) was suspended at 4 μΜ concentration and 5 μΙ_ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 μΜ. 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 EC5o calculations.
[00404] Data from each plate is analyzed and plotted as % inhibition versus compound concentration. Data is normalized using the formula 100*(control1 - unknown)/(control1 -control2) where control 1 is the average of the values for that plate corresponding to the 0% inhibition control wells (DMSO, column 6) and control2 is the average of the values corresponding to the 100% control wells (column 18). Curve fitting was performed with the 4-parameter curve fit equation y=A+((B-A)/(1 +(10Ax/10AC)A D)), where A was the minimum response, B was the maximum response, C is the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC5o values (-C in the above equation) and as max response values at a given concentration.
Example 5 HRV-15 3C Protease Enzyme Protocol
[00405] 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 μΜ 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. [00406] 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 μΙ_ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 μΙ_ of 10 nM enzyme (HRV-15 3C protease, 5 nM final concentration) in assay buffer to columns 1 - 17, and 19 -24.
[00407] A FRET substrate peptide (FAM-GRAVFQGPVG-TAMRA) was suspended at 4 μΜ concentration and 5 μΙ_ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 μΜ. 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 EC5o calculations.
[00408] Data from each plate is analyzed and plotted as % inhibition versus compound concentration. Data is normalized using the formula 100*(control1 - unknown)/(control 1 -control 2) where controU is the average of the values for that plate corresponding to the 0% inhibition control wells (DMSO, column 6) and control 2 is the average of the values corresponding to the 100% control wells (column 18). Curve fitting was performed with the 4-parameter curve fit equation y=A+((B-A)/(1 +(10Ax/10AC)A D)), where A was the minimum response, B was the maximum response, C is the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC5o values (-C in the above equation) and as max response values at a given concentration.
Example 6 Coronavirus OC43 3CL Protease Enzyme Protocol
[00409] 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 μΜ 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.
[00410] 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 μΙ_ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 μΙ_ of 2 nM enzyme (OC43 3CL protease, 1 nM final concentration) in assay buffer to columns 1 -17, and 19-24.
[00411] A FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at 4 μΜ concentration and 5 μΙ_ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 μΜ. 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 EC5o calculations.
[00412] Data from each plate is analyzed and plotted as % inhibition versus compound concentration. Data is normalized using the formula 100*(control1 - unknown)/(control1 -control 2) where controU is the average of the values for that plate corresponding to the 0% inhibition control wells (DMSO, column 6) and control2 is the average of the values corresponding to the 100% control wells (column 18). Curve fitting was performed with the 4-parameter curve fit equation y=A+((B-A)/(1 +(10Ax/10AC)A D)), where A was the minimum response, B was the maximum response, C is the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC5o values (-C in the above equation) and as max response values at a given concentration.
Example 7 Coronavirus 229e 3CL Protease Enzyme Protocol
[00413] 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 μΜ 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.
[00414] 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 μΙ_ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 μΙ_ of 200 pM enzyme (229e 3CL protease, 100 pM final concentration) in assay buffer to columns 1 -17, and 19-24.
[00415] A FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at 4 μΜ concentration and 5 was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 2 μΜ. 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 EC5o calculations.
[00416] Data from each plate is analyzed and plotted as % inhibition versus compound concentration. Data is normalized using the formula 100*(control1 - unknown)/(control1 -control2) where controM is the average of the values for that plate corresponding to the 0% inhibition control wells (DMSO, column 6) and control2 is the average of the values corresponding to the 100% control wells (column 18). Curve fitting was performed with the 4-parameter curve fit equation y=A+((B-A)/(1 +(10Ax/10AC)A D)), where A was the minimum response, B was the maximum response, C is the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC50 values (-C in the above equation) and as max response values at a given concentration.
Example 8 SARS Coronavirus 3CL Protease Enzyme Protocol
[00417] 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 μΜ 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.
[00418] 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 μΙ_ assay buffer only (no enzyme) to column 18 (low control— representing 100% inhibition) and 5 μΙ_ of 60 nM enzyme (SARS 3CL protease, 30 nM final concentration) in assay buffer to columns 1 -17, and 19-24.
[00419] A FRET substrate peptide (FAM-KTSAVLQSG FRKM E-TAM RA) was suspended at 6 μΜ concentration and 5 μΙ_ was added to each reaction well with a Thermo Combi liquid handler for a final reaction concentration of 3 μΜ. 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 EC5o calculations.
[00420] Data from each plate is analyzed and plotted as % inhibition versus compound concentration. Data is normalized using the formula 100*(control1 - unknown)/(control1 -control2) where controM is the average of the values for that plate corresponding to the 0% inhibition control wells (DMSO, column 6) and control2 is the average of the values corresponding to the 100% control wells (column 18). Curve fitting was performed with the 4-parameter curve fit equation y=A+((B-A)/(1 +(10Ax/10AC)A D)), where A was the minimum response, B was the maximum response, C is the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC50 values (-C in the above equation) and as max response values at a given concentration.
Example 9 Protocol for Human Rhinovirus (HRV) Cytopathic Effect Assay
[00421] Compounds of the present invention were tested via high-throughput cellular assays utilizing cytopathic effect (CPE) and cytotoxicity as end-points. For the CPE assay, human epithelial HeLa Ohio cells (ECACC # 84121901 ; Sigma-Aldrich Corporation, St. Louis, MO) were infected with human rhinovirus (HRV) type B strain 14 (ATCC # VR-284; American Type Culture Collection, Manassas, VA) or HRV type A strain 16 (ATCC # VR-283; American Type Culture Collection, Manassas, VA) in a biosafety level 2 (BSL-2) environment. Compounds with anti-viral activity protected the HeLa Ohio cells from CPE induced by viral infection, and cell viability was measured using CellTiter-Glo® reagent (CTG) Promega Corporation, Madison, Wl), which is based on luminescent detection of ATP, an indicator of metabolically active cells. Cellular toxicity due to the effect of compound treatment alone was measured in parallel using a CTG assay with uninfected HeLa Ohio cells.
[00422] In preparation for the assays, test compounds were serially diluted 3-fold in DMSO from a typical top concentration of 5 mM and plated at 0.25 μί 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 μί of DMSO in the presence of virally infected cells for the CPE assay or 0.25 μί 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.
[00423] 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 GlutaMAX™ (Life Technologies Corporation, Grand Island, NY) and 1 X penicillin-streptomycin antibiotic solution (Life Technologies Corporation, Grand Island, NY). The cells were diluted to 40,000 cells/mL in the supplemented DMEM medium, the volume of which was then split equally into two flasks. 50 μΙ_ of the cell suspension from one flask were added to all wells, with the exception of the low control wells, on half of the previously prepared 384-well compound plates, resulting in 2,000 cells/well for the cytotoxicity assay. HRV was added to the second flask of cells at a multiplicity of infection (MOI) of 0.01 , and 50 μΙ_ of the homogenous virus and cell mixture were added to all wells on the remaining 384-well compound plates, resulting in 2,000 cells/well for the CPE assay. The plates, with lids, were then placed in a 33 °C, 5% C02 humidified incubator for 5 days.
[00424] Following incubation, the 384-well plates for both assays were removed and placed in a biosafety cabinet to equilibrate to room temperature for 30 minutes. CellTiter-Glo® was prepared according to the manufacturer's instructions, and 20 μΙ_ were added to each plate well. After a twenty minute incubation at room temperature, luminescence was read on an EnVision® Multilabel Reader (PerkinElmer Inc., Waltham, MA).
[00425] 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.
[00426] Curve fitting was performed with the equation y=A+((B-A)/(1 +(10X/10C)D)), where A was the minimum response, B was the maximum response, C was the log(XC5o) and D was the Hill slope. The results for each test compound were recorded as plC50 values for the CPE assay and as pCC50 values for the cytoxicity assay (-C in the above equation).
Example 10 Protocol for MERS Coronavirus Cellular Assay
[00427] Compounds of the present invention were tested via cellular assays utilizing expression of coronavirus spike protein as an end point. Human lung fibroblast MRC-5 cells were infected with MERS coronavirus (strain Jordan). Compounds with anti-viral activity reduced the expression of spike protein as measured immunologically, and cell viability as measured by nuclear integrity.
[00428] In preparation for the assays, 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 %. Low control wells (100% CPE or 100% cytotoxicity) contained DMSO in the presence of virally infected cells.
[00429] 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.
[00430] Example 11 Additional HRV-strains 3C Protease Enzyme Protocol
[00431] 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.
[00432] The embodiments of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.
Table 1
Positive-sense single stranded RNA viruses
Order Nidovirales
o Family Arteriviridae
o Family Coronaviridae - includes Coronavirus, SARS
o Family Roniviridae
• Order Picornavirales
o Family Bacillariornaviridae
o Family Caliciviridae - includes Norwalk virus
o Family Dicistroviridae
o Family Iflaviridae
o Family Labyrnaviridae
o Family Marnaviridae
o Family Picornaviridae - includes Poliovirus, the "common cold" virus (Rhinovirus), Hepatitis A virus, Coxsackievirus
o Family Potyviridae
o Family Secoviridae includes subfamily Comovirinae
o Family Sequiviridae
• Order Tymovirales
o Family Alphaflexiviridae
o Family Betaflexiviridae
o Family Gammaflexiviridae
o Family Tymoviridae
• Unassigned
o Family Alvernaviridae
o Family Astroviridae
o Family Barnaviridae
o Family Bromoviridae
o Family Closteroviridae
o Family Flaviviridae - includes Yellow fever virus, West Nile virus,
Hepatitis C virus, Dengue fever virus
o Family Leviviridae
o Family Luteoviridae
o Family Narnaviridae
o Family Nodaviridae
o Family Retroviridae - includes human immunodeficiency virus 1 and 2
o Family Tetraviridae
o Family Togaviridae - includes Rubella virus, Ross River virus,
Sindbis virus, Chikungunya virus
o Family Tombusviridae
o Family Virgaviridae Negative-sense single stranded RNA viruses
• Order Mononegavirales
o Family Bornaviridae - Borna disease virus
o Family Filoviridae - includes Ebola virus, Marburg virus
o Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus
Family Rhabdoviridae - includes Rabies virus
• Unassigned families:
o Family Arenaviridae - includes Lassa virus, Junin virus
o Family Bunyaviridae - includes Hantavirus, Crimean-Congo hemorrhagic fever
o Family Ophioviridae
o Family Orthomyxoviridae - includes Influenza viruses
• Unassigned genera:
o Genus Deltavirus
o Genus Emaravirus
o Genus Nyavirus - includes Nyamanini and Midway viruses
Double stranded RNA viruses
o Family Reoviridae - includes Rotavirus
o Family Pycobirnaviridae - includes human pycobirnavirus
Family Parvoviridae - includes Parvovirus B19 o Family Adenoviridae- includes adenovirus
o Family Poxyiridae - includes monkey pox
o Family Polyomaviridae - includes BK virus
o Family Herpesviridae - includes herpes simplex virus
TABLE 2
Figure imgf000075_0001
Figure imgf000076_0001
Ex. Compound
Structure name o. No. benzyl N-[(1S)-1-{[(1S)- 1-{[(2S)-1- (butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3- yl]propan-2-
7
yl]carbamoyl}-3- methylbutyl]carbamoyl
}-2-[4-
(trifluoromethyl)piperid in-l-yl]ethyl]carbamate
benzyl N-[(1S)-1-{[(1S)- 1-{[(2S)-1- (butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3- yl]propan-2-
8
yl]carbamoyl}-3- methylbutyl]carbamoyl }-2-(4,4- difluoropiperidin-1- yl)ethyl]carbamate
benzyl N-[(lS)-2- [(cyclopropylmethyl)(m ethyl)amino]-l-{[(lS)-3- methyl-l-{[(2S)-l-oxo- 3-[(3S)-2-oxopyrrolidin-
9
3-yl]-l-[(propan-2- yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}ethyl]carbamate Ex. Compound
Structure name o. No. benzyl N-[(1S)-1-{[(1S)-
1-{[(2S)-1-
(cyclopentylcarbamoyl)
-l-oxo-3-[(3S)-2- oxopyrrolidin-3-
10 yl]propan-2- yl]carbamoyl}-3- methylbutyl]carbamoyl
}-2-[4-
(trifluoromethyl)piperid in-l-yl]ethyl]carbamate
benzyl N-[(1S)-1-{[(1S)-
1-{[(2S)-1-
(butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3-
11 yl]propan-2- yl]carbamoyl}-3- methylbutyl]carbamoyl
}-2-[methyl(2,2,2- trifluoroethyl)amino]et hyl]carbamate
benzyl N-[(2S)-1-[(2S)-
4,4-diethyl-2-{[(2S)-l- oxo-3-[(3S)-2-
1 I H oxopyrrolidin-3-yl]-l-
[(propan-2-
12 rvJ yl)carbamoyl]propan-2-
I s0 yl]carbamoyl}pyrrolidin
-l-yl]-l-oxo-3-[4- (trifluoromethyl)piperid in-l-yl]propan-2- yl]carbamate
Figure imgf000079_0001
Ex. Compound
Structure name o. No. benzyl N-[(1S)-1-{[(1S)-
3-methyl-l-{[(2S)-l- oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-l-
{[(IS)-l-
16 phenylethyl]carbamoyl} propan-2- yl]carbamoyl}butyl]carb amoyl}-2-(pyridin-2- yl)ethyl]carbamate
benzyl N-[(lS)-3- methyl-l-{[(lS)-3- methyl-l-{[(2S)-l-oxo-
3-[(3S)-2-oxopyrrolidin-
17 3-yl]-l-[(propan-2- yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}butyl]carbamate
Figure imgf000080_0001
benzyl N-[(1S)-1-{[(1S)-
3-methyl-l-{[(2S)-l- oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-l-
[(propan-2-
18 yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}-3- phenylpropyl]carbamat e Ex. Compound
Structure name o. No. benzyl N-[2-(6- methoxypyridin-2-yl)-l-
{[(lS)-3-methyl-l- {[(2S)-l-oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-l-
19
[(propan-2- yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}ethyl]carbamate
benzyl N-[(lS,2S)-2- methoxy-l-{[(lS)-3- methyl-l-{[(2S)-l-oxo- 3-[(3S)-2-oxopyrrolidin-
3-yl]-l-[(propan-2-
20
yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}propyl]carbamat e
benzyl N-[(1S)-1-{[(1S)- 3-methyl-l-{[(2S)-l- oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-l- [(propan-2- yl)carbamoyl]propan-2-
21
yl]carbamoyl}butyl]carb amoyl}-2-[4- (trifluoromethyl)pyrimi din-2- yl]ethyl]carbamate
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Ex. Compound
Structure name o. No. benzyl N-[(1S)-1-{[(1S)- 1-{[(2S)-1- (butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3- yl]propan-2-
34 yl]carbamoyl}-3- methylbutyl]carbamoyl
}-2-[5- (trifluoromethyl)pyrimi din-2- yl]ethyl]carbamate
benzyl N-[(1S)-1-{[(1S)- 1-{[(2S)-1- (butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3- yl]propan-2-
35
yl]carbamoyl}-3- methylbutyl]carbamoyl }-2-[4-(trifluoromethyl)- l,3-thiazol-2- yl]ethyl]carbamate
benzyl N-[(1S)-1-{[(1S)- 1-{[(2S)-1- (butylcarbamoyl)-l- oxo-3-[(3S)-2- oxopyrrolidin-3- yl]propan-2-
36
yl]carbamoyl}-3- methylbutyl]carbamoyl }-2-(5-methyl-l,3- thiazol-2- yl)ethyl]carbamate
Figure imgf000087_0001
Figure imgf000088_0001
Ex. Compound
Structure name o. No.
{4-[2-(piperidin-l- yl)ethoxy]phenyl}methy
1 N-[(1S)-1-{[(1S)-1-
{[(2S)-l-(tert- butylcarbamoyl)-l-oxo-
3-[(3S)-2-oxopyrrolidin-
43
3-yl]propan-2-
CX V·· yl]carbamoyl}-3- methylbutyl]carbamoyl
}-2-(naphthalen-l- yl)ethyl]carbamate
(4-
{[cyclopropyl(methyl)a mino]methyl}phenyl)m ethyl N-[(lS)-2-(4- fluorophenyl)-l-{[(lS)-
3-methyl-l-{[(2S)-l-
44 oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-l-
[(propan-2- yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carb amoyl}ethyl]carbamate
(5-methyl-l,2-oxazol-3- yl)methyl N-[(S)-{[(1S)-
1- {[(2S)-l-(tert- butylcarbamoyl)-l-oxo- 3-[(3S)-2-oxopyrrolidin-
45 3-yl]propan-2- yl]carbamoyl}-3- methylbutyl]carbamoyl }(2,3-dihydro-lH-inden-
2- yl)methyl]carbamate
Figure imgf000090_0001
Figure imgf000091_0001
TABLE 3
Biological Assay Data
Figure imgf000092_0001
HRV16_ HRV15_ OC43COV_ SARSCOV3_ E229COV3_ HRV14_ HRVA16_ MERS
Compound
enzyme enzyme. enzyme_ enzyme_ enzyme_ cell_ cell_ cell No.
PIC50 plC50 PXC50 plC50 plC50 plC50 PXC50 _plC50
21
8.3 8 7.6 7 6.8 6.8 6.7
22
8.2 7.9 7.8 7 7.2 6.8 6.6
23
8.3 8 7.8 7.2 7.1 7 7 6.04
24
8.2 8.1 7.8 7.2 7.2 6.9 6.5 6.03
25
8.2 8.1 7.8 7.2 6.6 7.1 6.8 6.13
26
8.1 8.1 7.8 7.3 7 7.2 7.1 6.21
27
8.1 8 7.7 7.2 6.9 7 6.9 5.96
28
8.4 8.2 7.9 7.4 7.2 6.9 6.9 6.10
29
8.1 7.9 7.6 7.1 6.5 6.9 6.8 6.20
30
8.3 8 7.9 7.3 7.1 7.1 7.2 6.49
31
8.4 8.2 8 7.4 7.2 6.6 6.7
32
8.1 7.9 7.8 7.3 6.9 7.2 7.1 6.40
33
8 7.9 7.5 7 6.6 7.3 7 6.36
34
7.8 7.6 7.5 7 6.9 6.9 6.9
35
8 7.9 7.9 7.5 7.5 7.4 7.3 6.49
36
8.2 8.1 8 7.5 7.5 6.8 7 6.22
37
8 7.8 7.8 7.3 7 7 6.9 6.43
38
8 7.8 7.9 7.3 7.2 7.1 7 6.26
39
8.3 8.2 7.9 7.5 7.4 7 7 6.48
40
8.3 8.1 7.8 7.3 6.8 7.4 7.4 6.59
41
8.4 8.1 8 7.5 7.2 7.2 7
42
7.9 7.5 8.1 6.6 6.6 6.9 6.6
43
8.3 8.1 8.6 7.1 7.2 6.3 6.8 HRV16_ HRV15_ OC43COV_ SARSCOV3_ E229COV3_ HRV14_ HRVA16_ MERS
Compound
enzyme enzyme. enzyme_ enzyme_ enzyme_ cell_ cell_ cell No.
PIC50 plC50 PXC50 plC50 plC50 plC50 PXC50 _plC50
44
7.9 7.8 7.8 7.1 7.3 6.6 6.6
45
8.2 8 7.7 7.1 7.1 6.3 6.9 5.79
46
7.9 7.6 7.8 7.5 7.5 6.6 6.6 6.33
47
8.3 7.9 7.7 7.1 7.6 6 6
48
8.1 7.8 7.3 7.4 7.5 6.6 6.9 6.21
TABLE 4
Figure imgf000095_0001
A=EC5o <50 nM
B=EC50 50-100 nM
C=EC5o >100 nM

Claims

What is claimed is:
1 . A compound of Formula I:
Figure imgf000096_0001
wherein
A is aryl or heteroaryl;
R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo;
haloalkyi; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi; C3-C8 cycloalkyl or C3-C8 heterocycloalkyi; C3-C8 cycloalkyl or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, hydroxy, alkoxy, thioalkyi; or;
R2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6-alkyl, C3- C8-cycloalkyl, C3-C8 heterocycloalkyi, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi, NR6R7; 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 cycloalkyl is fused with aryl to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl; C3-C8-cycloalkyl or C3-C8- heterocycloalkyl 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 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 heterocycloalkyi or NR6R7 is further optionally substituted with halo, alkoxy, halo- substituted alkoxy, NR6R7, OR8, SR9;
R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9;
R5 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, NR6R7, OR8, SR9;
R6 and R7 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, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyl or heterocycloalkyi ring that is optionally substituted with halo, haloalkyi, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi NR6R7, OR8, SR9; and
R8 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.
Figure imgf000097_0001
Formula IA wherein
A is aryl or heteroaryl;
R1 , R'1 , and R"1 are independently selected from H; C1 -C6-alkyl; halo;
haloalkyl; NR6R7; OR8; SR9; C1 -C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi; C3-C8 cycloalkyi or C3-C8 heterocycloalkyi substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, hydroxy, alkoxy, thioalkyl;
R2 is C1 -C6-alkyl, C1 -C6-alkyl substituted with aryl, heteroaryl, C1 -C6-alkyl, C3- C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, alkoxy, halo- substituted alkoxy, hydroxy, thioalkyl, NR6R7; C3-C8-cycloalkyl optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, hydroxy, alkoxy, halo-substituted alkoxy or the cycloalkyi is fused with aryl to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl; optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl or NR6R7; wherein the aryl, heteroaryl, C1 -C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyi or NR6R7 is further optionally substituted with halo, hydroxy, alkoxy, halo-substituted alkoxy, NR6R7, OR8, SR9;
R3 and R4 are independently H, C1 -C6-alkyl, substituted C1 -C6 alkyl, C3-C8- cycloalkyl, optionally substituted C3-C8-cycloalkyl or optionally substituted C3-C8- heterocycloalkyl, or R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl;
R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, NR6R7, OR8, SR9; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C3-C8-cycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl NR6R7, OR8, SR9;
R6 and R7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyi, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; C1 -C6 cycloalkyi substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6R7, OR8, SR9or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyi ring that is optionally substituted with halo, haloalkyl; and R8 and R9 are independently 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.
3. The compound of Formula I or Formula IA according to claim 1 or claim 2, wherein:
A is phenyl or oxazolyl;
R1 is H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; 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, NR6R7, OR8, SR9; R2 is C1 -C6-alkyl, C1 -C6-alkyl optionally 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 optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy; NR6R7; aryl optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, halo-substituted alkoxy, hydroxy, thioalkyi; heteroaryl, optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, halo-substituted alkoxy; wherein C1 -C6-alkyl or C1 -C6- cycloalkyl is further optionally substituted with halo, O, N, S, NR6R7, OR8, SR9;
R3 and R4 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, NR6R7, OR8, SR9; R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8 cycloalkyl,, aryl, heteroaryl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyi; or; C3-C8-cycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; R6 and R7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6R7, OR8, SR9; or R6 and R7 together form a 3 to 10-membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyl, amino, NR6R7, OR8, SR9; aryl; aryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyl, NR6R7, OR8, SR9; heteroaryl; or heteroaryl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl NR6R7, OR8, SR9; and
R8 and R9 are independently H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, 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, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy, thioalkyl, or a salt thereof.
4. The compound of Formula I or Formula IA according to claim 1 or claim 2, wherein:
A is phenyl;
R1 is H, C1 -C6-alkyl;C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, 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, haloalkyl, NR6R7, OR8, SR9;
R2 is C1 -C6-alkyl optionally substituted with C1 -C6-alkyl, alkoxy; NR6R7; aryl optionally substituted with C1 -C6-alkyl, haloalkyl; heteroaryl, optionally substituted with C1 -C6- alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, halo-substituted alkoxy; wherein C1 -C6-alkyl or C1 -C6- cycloalkyi is further optionally substituted with halo, O, N, S, NR6R7, OR8, SR9;
R3 and R4 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R3 and R4 together form a 5 to 10- membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxy, thioalkyl;
R5 is C1 -C6 alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl,C3-C8 cycloalkyi, phenyl; or C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1 -C6-alkyl;
R6 and R7 are independently H, C1 -C6-alkyl; C1 -C6 alkyl substituted with C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 and R7 together form a 3 to 10- membered cycloalkyi or heterocycloalkyl ring that is optionally substituted with halo, haloalkyi; and
R8 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.
5. The compound or salt of Formula I or Formula IA according to claims 1 -4, wherein R3 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 R3 and R4 together form a 5 to 10-membered ring structure optionally substituted with C1 -C6-alkyl, C3-C8- cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyi, amino, aminoalkyi, alkoxy, hydroxy, thioalkyi.
6. The compound or salt of Formula I or Formula IA according to claims 1 -5, wherein R5 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.
7. The compound or salt of Formula I or Formula IA according to claims 1 -6, wherein A is selected from the group consisting of aryl and heteroaryl.
8. The compound or salt of Formula I or Formula IA according to claims 1 -7, wherein A is phenyl or A is oxazolyl.
9. A compound of Formula I or Formula IA according to claim 1 or claim 2 selected from the group consisting of:
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(dimethylamino)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(piperidin-1 - yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(morpholin-4- yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2- yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-(trifluoromethyl)piperidin-1- yl]ethyl]carbamate;
benzyl N-[(1 S)-2-(4,4-difluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S)-2-(4-fluoropiperidin-1 -yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(trifluoromethyl)piperidin-1- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(4,4-difluoropiperidin-1- yl)ethyl]carbamate;
benzyl N-[(1 S)-2-[(cyclopropylmethyl)(methyl)amino]-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-
[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(cyclopentylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-
3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(trifluoromethyl)piperidin-1- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[methyl(2,2,2- trifluoroethyl)amino]ethyl]carbamate;
benzyl N-[(2S)-1-[(2S)-4,4-diethyl-2-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1 -yl]-1-oxo-3-[4-
(trifluoromethyl)piperidin-1-yl]propan-2-yl]carbamate; benzyl N-[(1 S)-2-(4-fluorophenyl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-2-cyclopentylethyl]carbamoyl}-2-(quinolin-5- yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(pyridin-2-yl)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -{[(1 S)-1 - phenylethyl]carbamoyl}propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(pyridin-2- yl)ethyl]carbamate;
benzyl N-[(1 S)-3-methyl-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -
[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}butyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-3-phenylpropyl]carbamate; benzyl N-[2-(6-methoxypyridin-2-yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S,2S)-2-methoxy-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]-1 -[(propan-2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}propyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan- 2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-(trifluoromethyl)pyrimidin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-2-(5-fluoropyridin-2-yl)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]-1 -[(propan-2-yl)carbamoyl]propan-2- yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-(trifluoromethyl)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[5-(trifluoromethyl)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -{[(1 S)-1 -cyclohexylethyl]carbamoyl}-1 -oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(pyridin-2- yl)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-(3- methylphenyl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-
2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[4-(trifluoromethyl)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-2-yl)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(propan-2-yloxy)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-(trifluoromethyl)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(1 ,3-thiazol-4-yl)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[6-(trifluoromethoxy)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-3-methyl-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan- 2-yl)carbamoyl]propan-2-yl]carbamoyl}butyl]carbamoyl}-2-[6-(trifluoromethoxy)pyridin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[5-(trifluoromethyl)pyrimidin-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-[4-(trifluoromethyl)-1 ,3-thiazol-2- yl]ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(5-methyl-1 ,3-thiazol-2- yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxypyridin-2- yl)ethyl]carbamate; benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(2-methoxy-1 ,3-thiazol-4- yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-{4H, 51-1,61-1- cyclopenta[d][1 ,3]thiazol-2-yl}ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-methoxy-4-methylpyridin-2- yl)ethyl]carbamate;
benzyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(butylcarbamoyl)-l -oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}-2-(6-ethoxypyridin-2- yl)ethyl]carbamate;
{4-[3-(morpholin-4-yl)propoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2- cyclohexylethyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
{4-[2-(piperidin-1 -yl)ethoxy]phenyl}methyl N-[(1 S)-1 -{[(1 S)-1 -{[(2S)-1 -(tert- butylcarbamoyl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3- methylbutyl]carbamoyl}-2-(naphthalen-1 -yl)ethyl]carbamate;
(4-{[cyclopropyl(methyl)amino]methyl}phenyl)methyl N-[(1 S)-2-(4-fluorophenyl)-1 -{[(1 S)-
3-methyl-1 -{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[(propan-2-yl)carbamoyl]propan-
2-yl]carbamoyl}butyl]carbamoyl}ethyl]carbamate;
(5-methyl-1 ,2-oxazol-3-yl)methyl N-[(S)-{[(1 S)-1 -{[(2S)-1 -(tert-butylcarbamoyl)-l -oxo-3- [(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}(2,3-dihydro- 1 H-inden-2-yl)methyl]carbamate;
benzyl N-[(2S)-1 -[(1 S,3aR,6aS)-1 -{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2- yl)carbamoyl]propan-2-yl]carbamoyl}-octahydrocyclopenta[c]pyrrol-2-yl]-3-(4- fluorophenyl)-1 -oxopropan-2-yl]carbamate;
benzyl N-[(2S)-1-oxo-1 -[(3S)-3-{[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan-2- yl)carbamoyl]propan-2-yl]carbamoyl}-2-azaspiro[4.4]nonan-2-yl]-3-(pyridin-2-yl)propan-2- yl]carbamate; and
benzyl N-[(2S)-1-[(2S)-4,4-diethyl-2-{[(2S)-1 -oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1 -[(propan- 2-yl)carbamoyl]propan-2-yl]carbamoyl}pyrrolidin-1-yl]-3-(4-fluorophenyl)-1 -oxopropan-2- yl]carbamate,
or a salt thereof.
10. A pharmaceutical composition comprising a compound of any one of claims 1 -3 and a pharmaceutically acceptable carrier or excipient.
1 1 . A method of treating or preventing a virus infection, including a virus infection from an RNA-based virus, a coronavirus, a rhinovirus and a norovirus, in a subject susceptible to or suffering from the virus infection, the method comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound of Formula I or Formula IA according to any one of claims 1 -9.
12. 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.
13. 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 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
14. The method according to claim 13, wherein the mammal is a human.
15. A method according to claim 1 1 , wherein the virus is a coronavirus selected from a 229E, NL63, OC43, HKU1 , SARS-CoV or a MERS coronavirus.
16. A method according to claim 1 1 , wherein the virus is a picornavirus selected from a polio virus, EV-68 virus, EV-71 virus, hepatitis A virus, enterovirus or a coxsackievirus.
17. 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 any one of claims 1 -9 or a pharmaceutical composition according to claim 10.
18. The method according to claim 17 wherein the compound or pharmaceutical composition is administered orally, intravenously or by inhalation.
19. The method according to claim 18 wherein the compound or pharmaceutical composition is administered by inhalation.
20. The method according to claim 17 wherein the disease is COPD.
21 . A compound of Formula I or Formula IA according to any of claims 1 -9, or a pharmaceutical composition according to claim 10, for use in therapy.
22. A compound of Formula I or Formula IA according to any of claims 1 -9, or a pharmaceutical composition according to claim 10, for use in the treatment of a viral infection.
23. Use of a compound of Formula I or Formula IA according to any of claims 1 -9 or a pharmaceutical composition according to claim 10, in the manufacture of a
medicament for use in the treatment of a viral infection in a human.
24. A compound of Formula I or Formula IA according to any of claims 1 -9, or a pharmaceutical composition according to claim 10, 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.
25. Use of a compound of Formula I or Formula IA according to any of claims 1 -9 or a pharmaceutical composition according to claim 10, in the manufacture of a
medicament for use in the treatment of a respiratory disorder in a human, 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.
26. Use of a compound of a compound of Formula I or Formula IA according to any of claims 1 -9, or a pharmaceutical composition according to claim 10, together with a p2-adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as umeclidinium.
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