WO2021231784A1 - Composés d'imidazolopyrazine inhibiteurs de perk - Google Patents

Composés d'imidazolopyrazine inhibiteurs de perk Download PDF

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Publication number
WO2021231784A1
WO2021231784A1 PCT/US2021/032324 US2021032324W WO2021231784A1 WO 2021231784 A1 WO2021231784 A1 WO 2021231784A1 US 2021032324 W US2021032324 W US 2021032324W WO 2021231784 A1 WO2021231784 A1 WO 2021231784A1
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Prior art keywords
pyrazin
amino
phenyl
imidazo
methyl
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PCT/US2021/032324
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English (en)
Inventor
Alan C. Rigby
Ari NOWACEK
Mark J. Mulvihill
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Hibercell, Inc.
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Publication of WO2021231784A1 publication Critical patent/WO2021231784A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • Embodiments of the present invention relate to novel imidazolopyrazine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.
  • the present invention is in the field of treatment of cancer and viruses (e.g., coronaviruses) and, other diseases and disorders involving protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).
  • PPKR protein kinase R
  • PERK an eIF2 kinase involved in the unfolded protein response (UPR) regulates protein synthesis, aids cells to alleviate the impact of endoplasmic reticulum stress and has been implicated in tumor genesis and cancer cell survival.
  • Tumor cells thrive in a hostile microenvironment caused mainly by nutrient and oxygen limitation, high metabolic demand, and oxidative stress.
  • UPR endoplasmic reticulum
  • the UPR serves as a mechanism for cellular survival whereby cells are able to adapt to cope with ER stress, but under extreme stress the UPR switches the cellular machinery toward apoptosis, contributing to greater tumorigenic potential of cancer cells, tumor metastasis, tumor drug resistance, and the ability of cancer cells to avoid effective immune responses. Tumors are believed to utilize the UPR for survival under stressed conditions such as nutrient deprivation or treatment with chemotherapy.
  • Other stress stimuli that activate UPR include hypoxia, disruption of protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status.
  • ER transmembrane sensors of the UPR There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERN1 and ERN2, respectively); 2) PKR-like ER kinase (PERK, also known as PEK, encoded by EIF2AK3); and 3) the activating transcription factor 6a (encoded by ATF6).
  • IREla/IREip encoded by ERN1 and ERN2, respectively
  • PKR-like ER kinase PKR-like ER kinase
  • PEK also known as PEK, encoded by EIF2AK3
  • 3) the activating transcription factor 6a encoded by ATF6
  • Each of these three sensors is regulated similarly through binding of the ER luminal chaperone protein GRP78 or BiP (encoded by HSPA5).
  • BiP encoded by HSPA5
  • PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphorylate the eukaryotic translation initiation factor 2a (eIF2-a) and regulate translation initiation.
  • Other family members include HRI (EIF2AK1), PKR (EIF2AK2), and GCN2 (EIF2AK4).
  • EIF2AK1 eukaryotic translation initiation factor 2a
  • GCN2 GCN2
  • PERK is an ER transmembrane protein with a stress-sensing domain inside the ER lumen and a cytosolic kinase domain. Upon sensing misfolded proteins, PERK is activated by autophosphorylation and oligomerization through release of BiP/Grp78 from the stress-sensing domain. Activated PERK phosphorylates and activates its downstream substrate, eukaryotic LQLWLDWLRQ ⁇ IDFWRU ⁇ H,) ⁇ ZKLFK ⁇ LQKLELWV ⁇ WKH ⁇ ULERVRPH ⁇ WUDQVODWLRQ ⁇ LQLWLDWLRQ ⁇ FRPSOH[ ⁇ LQ ⁇ RUGHU ⁇ WR ⁇ attenuate protein synthesis.
  • ATF4 activating transcription factor 4 (ATF4).
  • ATF4 mediates the transcription of certain UPR target genes including those for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway proteins which target misfolded proteins for ubiquitination and degradation by the proteasome.
  • ATF4 also causes the expression of the transcription factor C/EBP homologous protein (CHoP), which sensitizes cells to ER stress-mediated apoptosis, providing a pathway for regulated removal of severely stressed cells by the organism.
  • CHoP transcription factor C/EBP homologous protein
  • Phosphorylation of eIF2 results in reduced initiation of general translation due to a reduction in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP.
  • Phosphorylation of eIF2 also increases translation of some mRNAs in a gene specific manner including the transcription factor ATF4.
  • ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient uptake, amino acid metabolism, redox homeostasis, and autophagy. Selective inhibition of the PERK arm of the UPR is expected to profoundly affect tumor cell growth and survival. As such, compounds which inhibit PERK are believed to be useful in treating cancer.
  • Coronaviruses are a family of viruses that are common worldwide and cause a range of illnesses in humans from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause a number of diseases in animals.
  • PERK has been found to be activated during SARS-associated coronavirus (SARS-CoV). Studies have found that PERK may be activated in SARS-CoV through S and 3a proteins. In a separate study, a PERK kinase inhibiting dominant-negative PERK mutant suppressed transcriptional activation of Grp 78 and Grp94 promoters mediated by S proteins of SARS-CoV. Accordingly, compounds that inhibit PERK are believed to be useful in treating viral infections, such as those associated with coronaviruses.
  • Embodiments of the present invention provide methods for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor.
  • the PERK inhibitor is selected from a compound having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF2, or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; each R 1 is independently H, deuterium, halo,
  • the compounds of the present invention are inhibitors of PERK and are believed to be useful in treating cancer. Certain viruses are believed to utilize PERK during protein synthesis and current therapies are ineffective at treating such viruses. Therefore, the compounds of the present invention are also believed to be useful in treating viral infection, for example, infections associated with a coronavirus.
  • the present invention provides a method for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF 2 , or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; each R 1 is independently H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl, C 0-6 alkyl-
  • the present invention yet further provides the PERK inhibitor having the following structure (Ia): wherein: Y is CR 3a R 3b ; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; each R 1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3c , R 3d and R 3e are each independently H
  • the present invention yet further provides the PERK inhibitor having the following structure (Ib): wherein: X is CR 7 or N; each R 1 is independently H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1-12 alkyl, C 0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1-12 alkyl, C 0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; R 3c , R 3d and R 3e are each independently H or alkyl,
  • the present invention yet further provides the PERK inhibitor having the following structure (Ic): wherein: X is CR 7 ; each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G 2 substituents; R 3b is OR 3c ; R 3c is H or alkyl, optionally substituted by one or more independent G 3 substituents; R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; R 6 is H, alkyl, CD 3 , or CF 3 ; R 7 is
  • each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo
  • each R 2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo
  • R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, or CN
  • R 6 is H, alkyl, CD3, or CF3
  • R 7 is H, deuterium, halo, alkyl, heteroaryl,
  • the present invention yet further provides the PERK inhibitor having the following structure (Ie): wherein: X is CH; each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R 2 is independently H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium or halo; R 5 is H, deuterium halo, methyl, ethyl, isopropyl, , optionally substituted by one or more independent H, deuterium, C 1-6 alkyl, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • R 7 is H, chloro, methyl, ethyl, trifluoromethyl, heteroaryl, or CD3.
  • each R 1 is independently H, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, fluoro, or chloro.
  • each R 2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, fluoro, chloro, CF 3 or OCF 3 .
  • R 5 is H, chloro, methyl, or CD3, ethyl, isopropyl, , .
  • R 6 is H, methyl, ethyl, propyl, isopropyl, CD 3 , or CF 3 . In some embodiments, R 6 is other than H.
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, OR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , OC(O)OR 8 , OC(O)NR 8 R 9 , N(R 10 )C(O)R 8 , N(R 10 )C(O)OR 8 , N(R 10 )C(O)NR 8 R 9 , S(O)nR 8 , S(O)nOR 8 , S(O)nNR 8 R 9 , N(R 10 )S(O)nR 8 , N(R 10 )S(O)nOR 8 , or N(R 10 )S(O)nNR 8 R 9 , optional
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO2, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, OR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , OC(O)OR 8 , OC(O)NR 8 R 9 , N(R 10 )C(O)R 8 , N(R 10 )C(O)OR 8 , N(R 10 )C(O)NR 8 R 9 , S(O) n R 8 , S(O)nOR 8 , S(O)nNR 8 R 9 , N(R 10 )S(O)nR 8 , N(R 10 )S(O)nOR 8 , or N(R 10 )S(O)nNR 8 R 9 , optionally
  • Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents;
  • R 1 is each independently halo or alkyl, optionally substituted by one or more halogen substituents;
  • R 2 is each independently halo, alkyl, or C 0-6 alkyl-O-C 1-12 alkyl, optionally substituted by one or more halogen substituents;
  • R 5 is alkyl or cycloalkyl, optionally substituted by one or more deuterium, hydroxyl, or methyl substituents;
  • R 6 is H or alkyl;
  • R 7 is H, halo, or alkyl, optionally substituted by one or more halogen substituents; and
  • p is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • each R 1 is independently chloro, fluoro, methyl, or trifluoromethyl. In some embodiments, p is 2. In some embodiments, each R 1 is independently fluoro, methyl, or trifluoromethyl.
  • Ar 2 is phenyl. In some embodiments, Ar 2 is phenyl, optionally substituted by one substituent selected from R 2 . In some embodiments, each R 2 is independently methyl, ethyl, fluoro, or trifluoromethoxy. In some embodiments, Ar 2 is phenyl, optionally substituted by two substituents each independently selected from R 2 . In some embodiments, each R 2 is independently fluoro or methyl.
  • Ar 2 is pyridyl, optionally substituted by one substituent selected from R 2 .
  • R 2 is methyl.
  • R 5 is methyl, CD3, .
  • R 6 is H or methyl.
  • R 7 is H, chloro, methyl, or trifluoromethyl.
  • the compound is selected from: N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)
  • Embodiments of the present invention further provide a pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof including one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds, or a pharmaceutically acceptable salt thereof.
  • Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds in combination with an anti-cancer agent, or pharmaceutically acceptable salts thereof.
  • Embodiments of the present invention further provide a compound or pharmaceutically acceptable salt thereof for use in therapy.
  • Embodiments of the present invention further provide a method for treating a viral infection in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of any of the compounds described herein.
  • the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof.
  • the viral infection is associated with an RNA virus.
  • the RNA virus is a single-stranded RNA virus.
  • the single- stranded RNA virus is a coronavirus.
  • the viral infection is associated with a coronavirus.
  • the coronavirus is a coronavirus capable of infecting a human.
  • the coronavirus is an alpha coronavirus.
  • the alpha coronavirus is 229E alpha coronavirus or NL63 alpha coronavirus.
  • the coronavirus is a beta coronavirus.
  • the beta coronavirus is selected from the group consisting of OC43 beta coronavirus, HKU1 beta coronavirus, Severe Acute Respiratory Coronavirus (SARS-CoV), SARS- CoV-2, and Middle East Respiratory Syndrome coronavirus (MERS-CoV).
  • the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the coronavirus is SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV-2. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus infection is COVID-19. Embodiments of the invention further provide methods of treating a coronavirus infection in a patient in need of such treatment, the method comprising administering to the patient an effective amount of any of the compounds described herein.
  • the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof.
  • the methods of treating viral infections described herein further comprise administering an antiviral agent.
  • the antiviral agent is selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol, Atazanavir, Atripla, Balavir, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir (Victrelis), Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Ecoliever, Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir,
  • virus may refer to all types of viruses that replicate inside living cells of other organisms. It may also be cultivated in cell culture. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles, also known as virions, include two or three parts: (i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of lipids that surrounds the protein coat when they are outside a cell.
  • viruses include, but are not limited to, viruses from the following families: Retroviridae (e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses; Picornaviridae (e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus); Caliciviridae (such as strains causing gastroenteritis, including norovirus); Togaviridae (e.g.
  • Retroviridae e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses
  • Picornaviridae e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus
  • Caliciviridae such as strains causing gastroenteritis,
  • alphaviruses including Chikungunya virus, horse encephalitis viruses, Semlica virus, Sindbis virus, Ross fever virus rubella viruses); Flaviridae (e.g. virus hepatitis C virus, dengue virus, yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, Povassan virus and other encephalitis viruses); Coronaviridae (e.g.
  • coronaviruses coronaviruses, severe acute respiratory syndrome virus (SARS), such as SARS- CoV and SARS-CoV-2 (COVID-19), and short-term coronavirus respiratory virus syndrome (MERS)); Rhabdoviridae (e.g., vesicular stomatitis virus, rabies virus); Filoviridae (e.g., Ebola virus, Marburg virus); Paramyxoviridae (e.g.
  • Orthomyxoviridae e.g., influenza viruses
  • Bunyaviridae for example, hantaviruses, Sin Nombre virus, Rift Valley Fever virus, bunyaviruses, phleboviruses and nairoviruses
  • Arenaviridae such as Lassa fever virus and other hemorrhagic fever viruses, Machupo virus, Junin virus
  • Reoviridae e.g., reoviruses, orbiviruses, rotaviruses
  • Birnaviridae Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses, e.g.
  • hepatitis delta pathogen is believed to be a defective satellite in tier hepatitis B).
  • coronavirus may refer to a species in the genera of virus belonging to one of two subfamilies Coronavirinae and Torovirinae in the family Coronaviridae, in the order Nidovirales. Herein these terms may refer to the entire family of Coronavirinae (in the order Nidovirales). Coronaviruses may be defined as enveloped viruses with a positive-sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronaviruses may range from approximately 26 to 32 kilobases.
  • coronavirus is derived from the Latin corona, meaning crown or halo, and refers to the characteristic appearance of virions under electron microscopy (E.M.) with a fringe of large surface projections creating an image reminiscent of a crown. This morphology is created by the viral spike (S) peplomers, which are proteins that populate the surface of the virus and determine host tropism.
  • S viral spike
  • CoVs that naturally infect animals, the majority of which typically infect only one animal species or, at most, a small number of closely related species, but not humans.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • alpha coronaviruses 229E and NL63 examples of coronaviruses known to-date as infecting humans are: alpha coronaviruses 229E and NL63, and beta coronaviruses OC43, HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV.
  • a “symptom” associated with a cancer or a viral infection includes any clinical or laboratory manifestation associated with the cancer or viral infection and is not limited to what the subject can feel or observe.
  • “treating”, e.g., of a cancer or a viral infection encompasses inducing prevention, inhibition, regression, or stasis of the disease or a symptom or condition associated with the cancer or viral infection.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including racemates, enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • the enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • the compounds of the present invention may have spontaneous tautomeric forms.
  • each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
  • This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2 H, 3 H, 13 C, 14 C, 15 N, and/or 18 O.
  • hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
  • compounds described herein may also comprise one or more isotopic substitutions.
  • hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like.
  • a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. It is understood that the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C-14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C. Furthermore, any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein. It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H. Furthermore, any compounds containing 2 H or 3 H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e.
  • R 1 , R 2 , etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
  • C0-4alkyl for example is used to mean an alkyl having 0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration.
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-Cn as in “C1– Cn alkyl” is defined to include groups having 1, 2ising, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C 1 -C 12 alkyl, C 2 -C 12 alkyl, C 3 -C 12 alkyl, C 4 - C12 alkyl and so on.
  • Alkoxy or “Alkoxyl” represents an alkyl group as described above attached through an oxygen bridge.
  • an alkoxy group is represented by C 0-n alkyl-O-C 0-m alkyl in which oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • n is zero
  • -O-C 0-m alkyl is attached directly to the preceding moiety.
  • m zero
  • alkoxy group is “C 0-n alkyl-OH.”
  • alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and so on.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present.
  • C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkenyl As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C2-Cn alkynyl.
  • An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C 4 -C 12 alkynyl and so on.
  • Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • monocycle includes any stable polyatomic carbon ring of up to 12 atoms and may be unsubstituted or substituted.
  • non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aromatic monocycle elements include but are not limited to: phenyl.
  • "bicycle” includes any stable polyatomic carbon ring of up to 12 atoms that is fused to a polyatomic carbon ring of up to 12 atoms with each ring being independently unsubstituted or substituted.
  • non-aromatic bicycle elements include but are not limited to: decahydronaphthalene.
  • aromatic bicycle elements include but are not limited to: naphthalene.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • polycyclic refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4- trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 12 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • alkylheteroaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group.
  • alkylheteroaryl moieties include, but are not limited to, -CH 2 -(C 5 H 4 N), -CH 2 -CH 2 -(C 5 H 4 N) and the like.
  • heterocycle or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like.
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • halogen or “halo” refers to F, Cl, Br, and I.
  • carbonyl refers to a carbon atom double bonded to oxygen.
  • a carbonyl group is denoted as R x C(O)R y where R x and R y are bonded to the carbonyl carbon atom.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfony
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5 th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley- Interscience) 5 th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only methods by which to synthesize or obtain the desired compounds.
  • a pharmaceutical composition comprises the compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically active agent means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.
  • the compounds used in the method of the present invention may be in a salt form.
  • a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
  • “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.
  • the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol.7.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers/diluents.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • parenteral solutions can contain preservatives.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen.
  • the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms. Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine.
  • the compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention.
  • PERK In Vitro Activity Assay In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536 - 1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA). Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli.
  • PSR EIF2AK2
  • PERK EIF2AK3
  • PKR assays contain 14 ng/mL HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ -2.5 ⁇ 3(5. ⁇ DVVD ⁇ V ⁇ FRQWDLQ ⁇ QJ ⁇ P/ ⁇ HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ DSS ⁇ -1.5 uM), and GCN2 DVVD ⁇ V ⁇ FRQWDLQ ⁇ Q0 ⁇ HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ -200 uM).
  • Add test compound initiate the reaction by addition of enzyme, and incubate at room temperature for 45 minutes.
  • HEK293-EGFP-H (HEK293-EGFP-H,) ⁇ FHOOV ⁇ ZHUH ⁇ SODWHG ⁇ DW ⁇ cells/well in 384-well assay plates and incubated overnight at 37°C, 5% CO2.
  • Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% CO2 prior to induction of ER stress by addition of tunicamycin to 1mM for 2 hours.
  • Cells were lysed and TR-FRET was measured in an EnVision plate reader (PerkinElmer). FRET ratio data was normalized to signal from lysates treated with DMSO vehicle control and plotted as percent inhibition against 10-point; 3-fold dilution series of inhibitors.
  • IC50 values were calculated using 4- parameter logistical fitting in XLFit.
  • the compounds of Examples 1 to 187 were tested essentially as described above and exhibited cellular IC50 values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 187 inhibit EIF2a in vitro.
  • the results of exemplary compounds of formula (I) are shown in Table 1.
  • Table 1 Biochemical and cellular IC50 data of Compounds of Formula I:
  • Viral Inhibition Test Compound Preparation A stock concentration of each test article at 10 mM in DMSO was utilized to prepare the working stock dilutions. A working stock was prepared in DMEM2 to JHQHUDWH ⁇ D ⁇ 0 ⁇ VROXWLRQ ⁇ WKHQ ⁇ VHULDOO ⁇ GLOXWHG ⁇ LQ ⁇ '0(0 ⁇ :RUNLQJ ⁇ FRQFHQWUDWLRQV ⁇ RI ⁇ WKH ⁇ WHVW ⁇ articles to be tested was prepared immediately prior to the start of the experiment.
  • Vero E6 cells were cultured in 96 well plates one day prior to the day of the assay. Vero E6 cells were at greater than 90% confluency at the start of the study. Cells were inoculated at a MOI of 0.01 TCID50/cell with SARS-CoV-2 and incubated for one hour in the absence of test articles and control drug. Following 1 hr adsorption, cells were washed and 0.2 mL DMEM2 (DMEM with 2% FBS) containing vehicle, test articles or control drug were added to the respective wells.
  • DMEM2 DMEM with 2% FBS
  • the multiplicity of infection (MOI) was 0.01 TCID50/cell.
  • Table J Reduction In Viral CPE
  • the compound of Example 128 was tested essentially as described above and exhibited a significant reduction in viral cytopathic effect (CPE), as shown in Table J. This data demonstrates that the compounds of Examples 1 to 187 inhibit viral replication in vitro.
  • ER homeostasis External perturbation of ER homeostasis may originate from hypoxia, glucose deficiency and the presence of mutant or viral proteins, which directly or indirectly impair the protein folding capacity within the ER lumen resulting in ER stress conditions [Rozpedek et al., Current Molecular Medicine, 2017].
  • coronavirus (CoV) spike proteins induces ER stress.
  • CoV coronavirus
  • MHV Murine hepatitis virus
  • SARS severe acute respiratory syndrome
  • virus infection triggers a massive production of viral proteins that disrupt ER homeostasis and overload the folding capacities of the ER leading to a stress-induced activation of several eIF2 ⁇ NLQDVHV ⁇ LQFOXGLQJ ⁇ Protein kinase RNA (PKR)-like ER kinase (PERK).
  • PPR Protein kinase RNA
  • PERK branch of the UPR is believed to be activated first in response to ER stress [Szegezdi et al., 2006].
  • the PERK/PKR- eIF2 ⁇ -ATF4-GADD153 pathway plays a central role during productive coronavirus infections and thus approaches to abrogate this pathway may provide a productive mechanism of blocking viral replication and disease propagation. Therefore, the compounds of the present invention are useful in treating viral infection.
  • RBF Round bottom flask
  • NMR nuclear magnetic resonance
  • mHz megahertz
  • DMSO-d6, dimethyl sulfoxide-d6 ;
  • the reaction mixture was purged with argon for 10 min.
  • Palladium(II) acetate (5.77 g, 25.7 mmol) was added, and the mixture was purged with argon for 10 min.
  • the reaction mixture was heated at 95 °C with stirring for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (4 ⁇ 250 mL). The filtrate was washed with water (2 ⁇ 500 mL) and brine (2 ⁇ 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2 Synthesis of 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3): B-1.3 To a stirred solution of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B1-2.1, 28 g, 119 mmol) in THF (70 mL), Water (20 mL), MeOH (50 mL), at room temperature LiOH (6.00 g, 143 mmol) was added and resulting reaction mixture was stirred for 12 h at same temperature. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with water (100 mL). An aqueous layer was washed with EtOAc (200 mL) to remove impurities.
  • EtOAc 200 mL
  • Step- 3 Synthesis of 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2.9): B-2.9 To a stirred solution of acetyl chloride (50 mL) at 0 °C was added 2-hydroxy-2-(3- trifluoro methyl)phenyl)acetic acid (B-1.3, 25.00 g, 113 mmol) portion wise over a period of 30 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h.
  • Step-1 Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-2.3): To a stirred solution of acetyl chloride (1.0 mL) at 0 °C was added 2-(3-fluorophenyl)-2- hydroxyacetic acid (B-1.2, 0.601 g, 3.53 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h.
  • Step-2 Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1): To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 0.558 g, 2.63 mmol) and 4- bromo-3-fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added N,N- diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h.
  • HATU 1-[bis(dimethyl
  • Step-3 Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)- 1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1): To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bis(pinacolato)diboron (0.13 g, 0.52 mmol) and potassium acetate (51 mg, 0.52 mmol.
  • reaction mixture was purged with argon for 10 min. 1,1-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (9.5 mg, 0.01 mmol) was added and the mixture was purged with argon for 10 min.
  • the reaction mixture was exposed to microwave irradiation (SEM Company) at 100 °C for 1 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 ⁇ 15 mL). The filtrate was washed with water (2 ⁇ 10 mL) and brine (2 ⁇ 10 mL).
  • reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 ⁇ 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step-2 Synthesis of N-((3-Chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 0.652 g, 4.14 mmol) in methylene chloride (15.0 mL) were added N,N-diisopropylethylamine (362 mg, 2.80 mmol) followed by acetic anhydride (E-3.1, 320 mg, 0.84 mmol) at 0 o C and stirred for 14 h.
  • (3-chloro-5-methylpyrazin-2-yl)methanamine E-2.1, 0.652 g, 4.14 mmol
  • N,N-diisopropylethylamine 362 mg, 2.80 mmol
  • acetic anhydride E-3.1, 320 mg, 0.84 mmol
  • Step-3 Synthesis of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1, 0.65 g, 3.2 mmol) in acetonitrile (10.0 mL) were added N,N-dimethylformamide (0.3 mL) followed by phosphorous(V) oxychloride (1.5 g, 9.7 mmol) at 0 o C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • Step-4 Synthesis of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1): To a stirred solution of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1, 0.561 g, 3.09 mmol) in N,N-dimethylformamide (8.0 mL) was added N-iodosuccinimide (0.835 g, 3.71 mmol) at room temperature. This reaction mixture was heated to 60 °C and stirred for 3 h.
  • Step-5 Synthesis of 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1): A stirred solution of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1, 0.701 g, 2.28 mmol) in 2.0 M ammonia in isopropanol (200.0 mL) was stirred in an autoclave for 48 h at 120 °C.
  • Step-2 Synthesis of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1): To a stirred solution of N-[(3-chloropyrazin-2-yl)methyl]-2,2,2-trideuterio-acetamide (F-3.1, 40.00 g, 212.7 mmol) in EtOAc (500 mL) were added dimethylformamide (20 mL) followed by phosphoryl chloride (81.3 g, 531.9 mmol) at 0 o C and the resulting reaction mixture was stirred for 16 h at room temperature. After this time, the reaction mixture was poured into mixture of sat.
  • F-4.1 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine
  • Step-3 Synthesis of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.1): To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 10.00 g, 58.8 mmol) in THF (350 mL) at -78 °C, n-butyllithium (2.5 M, 35.2 mL, 88.23 mmol) was added drop-wise and resulting reaction mixture was stirred for 10 min. at the same temperature.
  • methyl iodide (7.5 mL, 117.6 mmol) was added to it and stirred for 15 min. at -78 °C. After this time, the reaction mixture was quenched with sat. ammonium chloride solution (50 mL) at -78 °C. The reaction was warm to room temperature, stirred for 20 min. and extracted with EtOAc (2 x 200 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1): F-6.1 To a stirred solution of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 5.1, 25.00 g, 135 mmol) in dichloromethane (400 mL) was added N-bromosuccinimide (29.10 g, 163 mmol) portion-wise at room temperature and stirred for 1 h at same temperature.
  • Step-5 Synthesis of 1-bromo-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (F-7.1): F-7.1 In a 5 L autoclave, 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1, 30.00 g, 114 mmol) and ammonia (2 M in isopropanol) (2 L) was stirred for 40 h at 120 °C.
  • Step-1 Synthesis of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2): To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 5.00 g, 29.4 mmol) in THF (150 mL) n-butyllithium (2.5 M, 17.6 mL, 44.1 mmol) was added drop-wise at - 78 °C and stirred for 10 min. at the same temperature.
  • Step-2 Synthesis of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 6.2): F-6.2 To a stirred solution of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2, 8.50 g, 41.4 mmol) in DMF (90 mL), N-bromosuccinimide (8.80 g, 49.7 mmol) was added portion- wise at room temperature and stirred for 4 h. After this time, the reaction mixture was quenched with ice cold water (200 mL).
  • Step-3 Synthesis of 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1): To a stirred solution of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.2, 11.20 g, 39.4 mmol) in 1,4-dioxane (150 mL) were added DIPEA (13.1 g, 78.9 mmol) followed by (2,4-dimethoxyphenyl)methanamine (13.90 g, 78.9 mmol) at room temperature.
  • Step-4 Synthesis of 1-bromo-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-2.1): G-2.1 In a 1 L multi neck RBF, 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1, 15.00 g, 36.3 mmol.) and TFA (150 mL) was stirred for 3 h at 80 °C. After this time, the reaction mixture was cooled to room temperature and excess of TFA was distilled off to obtain crude viscous mass.
  • reaction mixture was cooled to room temperature and excess of solvent was distilled off under reduced pressure to obtain crude material.
  • the crude material was basified with aqueous ammonia solution, an aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-2 Synthesis of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3): To a stirred suspension of 2-aminomalonamide (I-2, 17.68 g, 151.16 mmol) and biacetyl (13 g, 151.16 mmol) in water (25 mL) was added aqueous NaOH (50% solution) (15 mL, 188.95 mmol) over a period of 20 min at 10 o C. After completion of addition, resulting reaction mixture was stirred for additional 2 h at the same temperature, pH of reaction mixture was adjusted to 6.0 (by acetic acid).
  • Step-3 Synthesis of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4): To a stirred solution of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3, 12.00 g, 71.85 mmol) in chlorobenzene (60 mL) was added phosphoryl chloride (26.8 mL, 287.4 mmol) at room temperature. The resulting reaction mixture was heated to 60 o C and then added DIEA (37.57 mL, 215.55 mmol) dropwise over 30 min. Then the reaction mixture was stirred at 90 o C for another 3 h.
  • phosphoryl chloride 26.8 mL, 287.4 mmol
  • reaction mixture was cooled to room temperature, poured into mixture of sat. sodium bicarbonate solution (150 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5): I-5 In 450 mL autoclave, to a stirred solution of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4, 8.00 g, 47.9 mmol) in acetic acid (150 mL) was added Raney Nickel (1.6 g) under inert atmosphere and resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (100 psi) at room temperature. After this time, the reaction mixture was passed through the celite bed and washed with acetic acid (2 ⁇ 20 mL).
  • Step-5 Synthesis of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl)acetamide (I-6): To a stirred solution of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5, 5.00 g, 29.13 mmol) in dichloromethane (50 mL) was added DIEA (10.15 mL, 58.27 mmol) followed by acetic anhydride (5.5 mL, 58.27 mmol) at 0 °C. After, that reaction mixture was stirred for 2 h.
  • Step-6 Synthesis of 8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-7): To a stirred solution of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl) acetamide (I-6, 5.00 g, 29.94 mmol.) in acetonitrile (100 mL) were added dimethylformamide (0.50 mL) followed by phosphoryl chloride (8.3 mL, 153.3 mmol) at 0 °C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • Step-7 Synthesis of l-bromo-8-chIoro-3,5 ; 6-trimethylimidazo[l,5- ⁇ ]pyrazin e (I-8):
  • Step-8 Synthesis of 1- bromo-8-chIoro-3,5,6-trimethyIimidazo[1,5-a]pyrazine (1-9):
  • Step-2 Synthesis of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3-oxocyclobutanecarboxamide (J-4): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 3.00 g, 26.3 mmol) in dichloromethane (80 mL) were added N,N-diisopropylethylamine (22.9 mL, 131.5 mmol), T3P (50% in EtOAc) (12 mL, 39.47 mmol) followed by 3-oxocyclobutanecarboxylic acid (J-3, 5.10 g, 26.31 mmol) at 0 o C and stirred for 1 h.
  • Step-3 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-5): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3- oxocyclobutanecarboxamide (J-4, 4.70 g, 18.5 mmol) in EtOAc (80 mL) were added dimethylformamide (3 mL) followed by phosphoryl chloride (5.3 mL, 55.7 mmol) at 0 o C. This reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was cooled to room temperature and poured into mixture of sat.
  • Step-4 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-6): To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-5, 3.00 g, 12.7 mmol) in dimethylformamide (15 mL) was added N- Bromosuccinimide (2.21 g, 12.7 mmol.) at room temperature. This reaction mixture was stirred at room temperature for 40 min.
  • reaction mixture was warmed to –20 °C for 30 min. The mixture was cooled back to –78 °C, aqueous layer extracted with EtOAc (100 mL x 2), combined filtrate was washed with brine (50 mL). The combined organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-6 Synthesis of 3-(8-amino-1-bromo-6-methylimidazo[1,5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-8): In a 450 mL autoclave, a mixture of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3- yl)-1-methylcyclobutanol (J-7, 1.50 g, 4.54 mmol) and ammonia (2M in isopropanol) (150 mL) was stirred for 18 h at 120 °C.
  • the unfolded protein response from stress pathway to homeostatic regulation Science2011, 334, 1081– 1086 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S .; Heindryckx, F.; van Vlierberghe, H.
  • PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis Mol. Cell. Biol. 2012, 32, 5129–5139 Bi, M.; Naczki, C.; Koritzinsky, M.; Fels, D.; Blais, J.; Hu, N.; Harding, H.; Novoa, I.; Varia, M.; R aleigh, J.;Scheuner, D.; Kaufman, R. J.; Bell, J.; Ron, D.; Wouters, B. G.; Koumenis, C. ER stress- regulated translation increases tolerance to extreme hypoxia and promotes tumor growth EMBO J.

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Abstract

L'invention concerne des méthodes de traitement d'une infection virale chez un patient, qui consistent à administrer audit patient une quantité thérapeutiquement efficace d'un inhibiteur de PERK choisi parmi un composé ayant la structure (I).
PCT/US2021/032324 2020-05-13 2021-05-13 Composés d'imidazolopyrazine inhibiteurs de perk WO2021231784A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685301A (zh) * 2022-03-31 2022-07-01 山东省药学科学院 一种2-氨基丙二酰胺的生产改良方法

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2019099564A1 (fr) * 2017-11-14 2019-05-23 Children's Medical Center Corporation Nouveaux composés d'imidazopyrimidine et leurs utilisations
US20200031834A1 (en) * 2018-07-06 2020-01-30 Gilead Sciences, Inc. Therapeutic heterocyclic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019099564A1 (fr) * 2017-11-14 2019-05-23 Children's Medical Center Corporation Nouveaux composés d'imidazopyrimidine et leurs utilisations
US20200031834A1 (en) * 2018-07-06 2020-01-30 Gilead Sciences, Inc. Therapeutic heterocyclic compounds

Non-Patent Citations (1)

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Title
DAHAL BIBHA ET AL.: "PERK IS CRITICAL FOR ALPHAVIRUS NONSTRUCTURAL PROTEIN TRANSLATION", VIRUSES, vol. 13, no. 5, 12 May 2021 (2021-05-12), pages 892, XP055837967 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685301A (zh) * 2022-03-31 2022-07-01 山东省药学科学院 一种2-氨基丙二酰胺的生产改良方法

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