WO2021231782A1 - Inhibiteurs de perk pour le traitement d'infections virales - Google Patents

Inhibiteurs de perk pour le traitement d'infections virales Download PDF

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Publication number
WO2021231782A1
WO2021231782A1 PCT/US2021/032322 US2021032322W WO2021231782A1 WO 2021231782 A1 WO2021231782 A1 WO 2021231782A1 US 2021032322 W US2021032322 W US 2021032322W WO 2021231782 A1 WO2021231782 A1 WO 2021231782A1
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Prior art keywords
amino
difluorophenyl
methylphenyl
hydroxyacetamido
alkyl
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PCT/US2021/032322
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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 WO2021231782A1 publication Critical patent/WO2021231782A1/fr

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/4965—Non-condensed pyrazines

Definitions

  • Embodiments of the present invention relate to novel pyridinyl and pyrazinyl carboxamide 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 10 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).
  • PTR protein kinase R
  • PERK protein kinase R-like endoplasmic reticulum kinase
  • 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 15 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. These stresses are known to disrupt the protein folding capacity of the endoplasmic reticulum (ER) eliciting a cellular remediation response known as the UPR.
  • the UPR serves as a mechanism for cellular survival whereby cells are able to 20 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
  • ER transmembrane sensors of the UPR There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERNl 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 ERNl and ERN2, respectively
  • PKR-like ER kinase PKR-like ER kinase
  • PEK also known as PEK, encoded by EIF2AK3
  • ATF6 activating transcription factor 6a
  • PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphoiylate 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
  • PKR EIF2AK2AK2
  • GCN2 GCN2
  • PERK is an ER transmembrane protein with a stress-sensing domain inside the ER lumen and a cytosolic kinase domain.
  • PERK Upon sensing misfolded proteins, PERK is activated by autophosphorylation and oligomerization through release of BiP/Grp78 from the stress-sensing domain.
  • Activated PERK phosphoiylates and activates its downstream substrate, eukaryotic initiation factor 2a (eIF2a), which inhibits the ribosome translation initiation complex in order to 15 attenuate protein synthesis. This serves to prevent exacerbation of ER stress by preventing the accumulation of additional misfolded proteins.
  • eIF2a eukaryotic initiation factor 2a
  • activated eIF2a causes the translation of specific mRNAs involved in restoring ER homeostasis including activating transcription factor 4 (ATF4).
  • ATF4 mediates the transcription of certain UPR target genes including those for the endoplasmic-reticulum-associated protein degradation (ERAD)
  • 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.
  • C/EBP homologous protein CHoP
  • Phosphorylation of eIF2 results in reduced initiation of general translation due to a reduction 25 in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP.
  • ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient
  • 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 5 (SARS). Coronaviruses can also cause a number of diseases in animals. Human coronaviruses 229E, OC43, NL63, HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV are contagious in the human population.
  • PERK has been found to be activated during SARS-associated coronavirus (SARS-CoV) infection. Studies have found that PERK may be activated in SARS-CoV through S and 3a proteins.
  • PERK kinase inhibiting dominant-negative PERK mutant 10 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):
  • 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 C(R 3a )(R 3b )Co- 6 alkyl, NR 3a , -0-, C(0), CF 2 , CNOR 3bb ;
  • R 3a is H, alkyl, or cycloalkyl
  • R 3b is H, alkyl, 0R 3c , orNR 3d R 3e ;
  • R 3bb is H or alkyl;
  • R 4 is H, alkyl, or OH
  • R 3c , R 34 and R 3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G 3 substituents;
  • R 5 is H, CH3, NHR 9 , or OR 9 ;
  • R 6 is H, alkyl, C0 2 R 8a , or CO(NR 8a R 8b );
  • R 7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
  • R 8a and R 8b are each independently H, C 1-12 alkyl, C 0-12 alkylC 3-12 cycloalkyl, or C 0-12 alkylC 3- 12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; or
  • R 8a and R 8b taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl
  • R 9 is H, alkyl, cycloalkyl, or heterocycloalkyl
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO2, C 1-12 alkyl, Co- 1 2 alkylC 3-12 cycloalkyl, C 0-12 alkylC 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(0)R 10 , C(0)OR 10 , C(O)NR 10 R n , OC(0)R 10 , OC(0)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(0)R 10 , N(R 12 )C(0)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(0) n R 10 , S(0) n OR 10 , S(O) friendshipNR 10 R 11 , N(R 12 )S(0) n R 10 , N(R 12 )S(0) n ,OR 10 , or N(R 12 )S(O)nNR 10 R 11 , optionally substituted by one
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN0 2 ; n is O, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are inhibitors of PERK. 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 believed to be useful in treating viral infections, for example, infections associated with a coronavirus.
  • Embodiments of the present invention provide methods for treating a viral infection in a 10 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
  • 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 C(R 3a )(R 3b )C 0 -6alkyl, NR 3a , -0-, C(0), CF 2 , CNOR 3bb , or a direct bond to Ar 1 ;
  • R 3a is H, alkyl, or cycloalkyl
  • R 3b is H, alkyl, 0R 3c , orNR 3d R 3e ;
  • R 3bb is H or alkyl
  • R 4 is H, alkyl, or OH
  • R 3c , R 3d and R 3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G 3 substituents;
  • R 5 is H, CH3, NHR 9 , or OR 9 ;
  • R 6 is H, alkyl, C0 2 R 8a , or CO(NR 8a R 8b );
  • R 7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
  • R 8a and R 8b are each independently H, C 1-12 alkyl, Co-i 2 alkylC3-i 2 cycloalkyl, or Co-i 2 alkylC3- 1 2 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; or
  • R 9 is H, alkyl, cycloalkyl, or heterocycloalkyl; each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO2, C 1-12 alkyl, Co- i 2 alkylC 3 -i 2 cycloalkyl, C 0-12 alkylC 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(0)R 10 , C(0)OR 10 , C(O)NR 10 R 11 , OC(0)R 10 , OC(0)OR 10 , OC(O)NR 10 R n , N(R 12 )C(0)R 10 , N(R 12 )C(0)OR 10 ,
  • N(R 12 )C(O)NR 10 R 11 S(0) n R 10 , S(0) n OR 10 , S(O)nNR 10 R 11 , N(R 12 )S(0) n R 10 , N(R 12 )S(0) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substitued by one or more independent H, deuterium, halo, OH, CN, orN0 2 ;
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkylandr heterocycloalkyl, optionally substituted by one or more independent H, deuterium, 25 halo, OH, CN, or NO 2 ; nis 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the compound of the present invention, an anti-cancer agent and a pharmaceutically acceptable carrier.
  • the present invention further provides a method for preventing the infection of a cell exposed to a virus or for reducing, retarding or otherwise inhibiting growth and/or replication of a virus in a cell infected with said virus comprising contacting the cell with the compound of the present invention.
  • the present invention yet further provides the PERK inhibitor having the following structure
  • 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, C 0-6 alkyl-O-C 1-12 alkyl, C 0- 6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, C 0-6 alkylcycloalkyl, C 0-6 alkyl-O-C 1- 20 12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents;
  • R 3c , R 3d and R 3e are each independently H or alkyl, optionally substituted by one or more independent G 3 substituents;
  • X is CR 7 or N;
  • R 6 is H, alkyl, COiR 83 , or CO(NR 8a R 8b );
  • R 7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
  • R 8® and R 8b are each independently H, C 1-12 alkyl, C 0-12 alkylC 3-12 cycloalkyl, or C 0-12 alkylCs- nheterocycloalkyl, optionally substituted by one or more independent G 4 substituents;
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN0 2 ; n is 0, 1, or 2;
  • the present invention yet further provides the PERK inhibitor having the following structure (lb):
  • R 3a is H or alkyl
  • R 3b is OR 3e or NR 3d R 3e ;
  • R 3c , R 34 and R 3e are each independently H or alkyl, optionally substituted by one or more 10 independent G 3 substituents;
  • R 6 is C0 2 R 8a or COCNR 8 ⁇
  • R 8a and R 8b are each independently H, C 1-12 alkyl, C 3-12 cycloalkyl, or Cs-izheterocycloalkyl, optionally substituted by one or more independent G 4 substituents; each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NOi, C 1-12 alkyl, C3- 15 ncycloalkyl, C 3 .i 2 heterocycloalkyl, OR 10 , NR 10 R 11 , C(0)R 10 , C(0)OR 10 , C(O)NR 10 R n , OC(0)R 10 , OC(0)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(0)R 10 , N(R l2 )C(0)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(0) n R 10 , S(0) n OR 10 , SCO ⁇ NR 10 ⁇ 1 , N(R
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, N0 2 , alkyl,
  • cycloalkyl and heterocycloalkyl optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN0 2 ; n is O, 1, or 2; p is O, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4;
  • the present invention yet further provides the PERK inhibitor having the following structure (Ic): wherein:
  • each R 1 is independently H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 1-12 alkyl, 5 optionally substituted by one or more independent G 1 substituents;
  • 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 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 6 is CO(NR 8a R 8b );
  • R 88 and R 85 are each independently H, C 1-12 alkyl, C 0-12 alkylC 3-12 cycloalkyl, or C 0-12 alkylCs- laheterocycloalkyl, optionally substituted by one or more independent G 4 substituents; each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO2, C 1-12 alkyl, C3.
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium,
  • PERK inhibitor having the following structure (Id): wherein:
  • each R 1 is independently H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C l -nalkyl, 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 8® and R 8b are each independently H, C 1-12 alkyl, Cg-ncycloalkyl, or C3-i2heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, C 1-12 alkyl, C 3-12 cycloalkyl, S(O)nNR 10 R 11 , N(R 12 )S(0) n R 10 , N(R 12 )S(0) n OR 10 , orN(R 12 )S(O) n NR 10 R 11 ;
  • R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN0 2 ; n is 0, 1, or 2; p is O, 1, 2, 3, 4, or 5;
  • 20 q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • R 6 is H, X ⁇ or H
  • X is CH.
  • each R 1 is independently H, methyl, ethyl, isopropyl, methoxy, 5 ethoxy, propoxy, isopropoxy, deuterium, CF3, fluoro, or chloro.
  • each R 2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF3 or OCF3.
  • R 83 and R 8b are each independently H, Ci ⁇ alkyl, C 0-6 alkylCi- gcycloalkyl, or C 0-6 alkylC 3-8 heterocycloalkyl. In some embodiments, R 83 and R 8b are each independently H, Cioalkyl, Co-3alkylC 3 . ecycloalkyl, or Co-3alkylC3-6heterocycloalkyl.
  • R 88 and R to are each independently H, Ci-salkyl, C 3-6 cycloalkyl, or C3-6heterocycloalkyl.
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, N0 2 , C h alky], C 3 - 8 cycloalkyl, Cs-eheterocycloalkyl, OR 10 , NR 10 R n , C(0)R 10 , C(0)OR 10 , C(O)NR 10 R n , OC(0)R 10 , OC(0)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(0)R 10 , N(R 12 )C(0)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(0) n R 10 , S(0) n 0R 10 , S(O)nNR 10 R 11 , N(R 12 )S(0) n R 10 , N(R 12 )S(0) n 0R 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substitute
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, N0 2 , Ci-salkyl, C 3 -6cycloalkyl, C 3-6 heterocycloalkyl, OR 10 , NR 10 R 11 , C(0)R 10 , C(0)OR 10 , C(O)NR 10 R n , OC(0)R 10 , OC(0)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(0)R 10 , N(R 12 )C(0)OR 10 , N(R 12 X:(O)NR 10 R 11 , S(0) n R 10 , S(0) n OR 10 , S(O)nNR 10 R 11 , N(R 12 )S(0) n R 10 , N(R 12 )S(0) n OR 10 , or 15 N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, de
  • the present invention yet further provides the PERK inhibitor having the following structure
  • 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;
  • 25 Y is C(R 3a )(R 3b )C 0 - 6 alkyl, NR 3a , -0-, C(0), CF 2 , or a direct bond to Ar 1 ;
  • R 3a is H or alkyl
  • R 3b is OR 3C or NR 3d R 3e ;
  • R 4 is H or OH
  • R 3c , R 3d and R 3e are each independently H or alkyl
  • R 7 is H or alkyl
  • R 8a and R 8b are each independently H, Ci.i2alkyl, C 0-12 alkyl-C 3 -i2cycloalkyl, or C 0-12 alkyl-C 3 . nheterocycloalkyl, optionally substituted by one or more independent G 4 substituents; or
  • each G 1 , G 2 , G 3 , or G 4 is independently halo, OR 10 , NR 10 R n , C(0)R 10 ; and R 10 or R 11 are each independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.
  • Ar 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
  • each R 1 is independently chloro, fluoro, methyl, ethyl, methoxy, or
  • Y is -C(H)(OH>, -C(CH 3 )(OH>, -C(H)(OCH 3 >, -C(HXNH 2 >, CF 2 , C(O), CH 2I -CH 2 CH 2 -, N(CH 3 ), -0-, or a direct bond to Ar 1 .
  • R 4 is H. In some embodiments, R 4 is OH.
  • Ar 2 is phenyl or pyridyl, optionally substituted by one or more 5 independent R 2 substituents.
  • each R 2 is independently methyl, ethyl, methoxy, fluoro, chloro, CF3, or OCF3.
  • X is CR 7 . In some embodiments, R 7 is H.
  • X is N.
  • R 5 is H, methyl, NH2, or NHCH3. In some embodiments, R 6 is H.
  • the compound is selected from: 2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-#-isopropylnicotinamide;
  • Embodiments of the present invention further provide a pharmaceutical composition
  • 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 5 effective amount of a PERK kinase modulating compound.
  • the PERK kinase modulating compound is any of the compounds described herein.
  • the PERK kinase modulating compound is a compound of formula I, la, lb, Ic, Id or Ie, 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 15 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.
  • the coronavirus 20 is SARS-CoV.
  • the coronavirus is SARS-CoV-2.
  • the coronavirus is MERS-CoV-2.
  • the viral infection is a coronavirus infection.
  • the coronavirus infection is COVID-19.
  • Embodiments of the invention further provide methods of treating a coronavirus infection in 25 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, la, lb, Ic, Id or Ie, or a pharmaceutically acceptable salt thereof.
  • the methods of treating viral infections described herein further 30 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, Emtridtabine, Enfuvirtide, Entecavir, Etravirine 5
  • virus may refer to all types of viruses that replicate inside living ceils of other oiganisms. It may also be cultivated in ceil culture. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not inside 20 an infected cell or in the process of infecting a cell , vimses exist in the form of independent particles.
  • 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.
  • the shapes of 25 these virus particles range from simple helical and icosahedral forms for some virus species to more complex structures for others.
  • the term “virus”, as used herein, also encompasses viral panicles, particularly infectious particles.
  • viruses include, but are not limited to, viruses from the following families: Reiroviridae le g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia vimses; Picornaviridae (e g., poliovirus, hepatitis A vims, enteroviruses, human 30 Coxsackie vimses, rhinoviruses, echoviruses, foot-and-mouth disease vims); Caliciviridae (such as strains causing gastroenteritis, including norovims); Togaviridae (e.g., viruses from the following families: Reiroviridae le g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia vimses; Picornaviridae (e g., poliovirus, hepatitis A vims, enteroviruses, human 30 Coxsackie vimses, rhinoviruses, echoviruses, foot-and
  • aiphaviruses 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.
  • coronavimses severe acute respiratory syndrome virus (SARS), such as SARS- 5 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 parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g., influenza viruses); Bunyaviridae (for example, hantavimses, Sin Nombre virus, Rift Valley Fever virus, bunyaviruses, phleboviruses and 10 nairoviruses); Arenaviridae (such as Lassa fever virus and other hemorrhagic fever viruses, Machupo virus, Junin virus); Reoviridae (e.g.
  • HSV herpes simplex virus
  • Poxviridae variola viruses, smallpox viruses, poxviruses
  • Mdoviridae such as African swine fever virus
  • Astroviridae and unclassified for example, the hepatitis delta pathogen is believed to be a defective satellite in tier hepatitis B).
  • coronavirus may refer to a 20 species in the genera of vims 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).
  • Coronavimses may be defined as enveloped vimses with a positive-sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronavimses 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.
  • E.M. electron microscopy
  • S peplomers which are proteins that populate the surface of the vims and determine host tropism.
  • alpha, beta, gamma, and delta are proteins that populate the surface of the vims and determine host tropism.
  • 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 coronavims
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • coronaviruses known to-date as infecting humans are: alpha coronaviruses 229E and NL63, and beta coronaviruses OC43, HKU 1, 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 10 subj ect 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 20 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 Chemistiy 69, 1469-1474, (1997) ILJPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the 25 cis ( 2 ) and tram (£) 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 5 wherein the isotopic atom is 3 ⁇ 4 3 H, 13 C, 14 C, 15 N, and/or 18 0. Accordingly, in the compounds provided herein 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 10 may be, for example, 13 C or 14 C; oxygen may be, for example, l8 0; nitrogen may be, for example, 1 5 N, and the like.
  • a particular isotope (e.g., 3 ⁇ 4 13 C, 14 C, 18 0, 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 15 isotopic abundance of an element that occupies a specific site of the compound.
  • each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry 25 (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise.
  • 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.
  • 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 1 4 C.
  • any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
  • any notation of a hydrogen in structures throughout this application, 10 when used without further notation, are intended to represent all isotopes of hydrogen, such as 3 ⁇ 4 2H, or 3 H.
  • 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 15 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
  • Co-talkyl 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.
  • Ci-C n as in “Ci-
  • C n alkyl is defined to include groups having 1, 2. , 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 C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4- 10 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 Co-nalkyl-O-Co-malkyl in which oxygen is a bridge between 0, 1, 2 , n-1, m-1, n or m carbons in a linear or branched arrangement.
  • oxygen is a bridge between 0, 1, 2 , n-1, m-1, n or m carbons in a linear or branched arrangement.
  • n is zero
  • “-O-Co-malkyl” is attached directly to the preceding moiety.
  • m zero, the alkoxy group
  • 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 nonaromatic carbon-carbon double bonds may be present.
  • Ca-Cn alkenyl is defined to include 20 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 Ce alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a 25 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-C 11 alkynyl is defined to include groups having 1, 2...., n-1 or n 30 carbons.
  • C2-C6 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.
  • 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 Ca-Cn alkynyl.
  • An embodiment can be C2-C12 alkynyl, C3-C12 5 alkynyl, C4-C12 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.
  • heteroalky 1 includes both branched and straight-chain saturated aliphatic 10 hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups (e.g., spirocyclic groups, fused bicyclic groups, bridged 15 bicyclic compounds).
  • Heterocyclyl therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the 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, 20 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. Examples of such
  • 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
  • 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. Examples of such aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or 5 acenaphthyl. In cases where 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 10 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. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4- trifluoromethylphenylmethyl), 1 -phenyl ethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 15 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 20 (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.
  • Heteroaiyl groups within the scope of this definition include but 25 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
  • heteroaryl substituent is bi cyclic and 10 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 15 bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above.
  • alkylheteroaryl 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, -Cfh-CCsHtN), -CHz-CEb-CCsEUN) and the like.
  • heterocycle 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.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aiyl 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. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • halogen refers to F, Cl, Br, and I.
  • carbonyl refers to a carbon atom double bonded to oxygen.
  • a carbonyl group is denoted as R*C(0)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 10 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, 15 n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; atylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups
  • 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 25 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. In choosing the compounds 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.
  • R groups attached to the aromatic rings of the compounds disclosed herein may 5 be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.
  • the compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, 10 these may not be the only methods by which to synthesize or obtain the desired compounds.
  • 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. Fumis, 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- 15 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.
  • Another aspect of the invention comprises a compound used in the method of the present invention as a pharmaceutical composition.
  • a pharmaceutical composition comprises the compound of the present
  • the term “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 25 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. Department Of Health And Human Services, 30 th edition, 2010), which are hereby incorporated by reference.
  • Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods
  • 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.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, 10 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 15 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 el al. (1977) "Pharmaceutical Salts", J. Pharm. 20 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-deoxy glucose, etc. and any other physiologically non-toxic basic substance.
  • administering an agent may be performed using any of the various methods 25 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 30 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. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
  • This 5 combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable 10 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 15 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 20 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.
  • 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 30 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 5 granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • 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 10 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.
  • the active for oral administration in the dosage unit form of a tablet or capsule, the active
  • the 30 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 5 polymers as targetable drug carriers or as a prodrug. Furthermore, 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 10 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.
  • liquid dosage form the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier.
  • suitable liquid dosage 15 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 20 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 25 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.
  • 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 5 emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directiy, 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, symps, 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 30 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.
  • EIF2AK2 15 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).
  • HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli.
  • PKR assays contain 14 ng/mL enzyme and 2.5 ⁇ ATP (Km, -2.5 ⁇ )
  • PERK assays contain 62.5 ng/mL enzyme and 1.5 ⁇ ATP (Km.
  • GCN2 assays contain 3 nM enzyme and 90 pM ATP (Km, -200 uM).
  • Add test compound initiate the reaction by addition of enzyme, and incubate at room temperature for 45 minutes. Stop the reaction by addition 25 of EDTA to a final concentration of 10 mM, add Terbium-labelled phospho-eIF2a antibody at a final concentration of 2 nM, and incubate for 90 minutes. Monitor the resulting fluorescence in an EnVison® Multilabel reader (PerkinElmer, Waltham, MA).
  • Stable cell lines were created in HEK293 cells using lentiviral particles harboring an expression vector for GFP- eIF2a. Cells were selected using puromycin and enriched using fluorescence activated cell sorting against GFP. HEK293-EGFP-eIF2a cells were plated at 5000 cells/well in 384-well assay plates and incubated overnight at 37°C, 5% C02. Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% C02 10 prior to induction of ER stress by addition of tunicamycin to ImM for 2 hours. Cells were lysed and
  • TR-FRET was measured in an EnVision plate reader (PeridnElmer). 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.
  • Test Compound Preparation A stock concentration of each test article at lOmM in DMSO was utilized to prepare the working stock dilutions. A working stock was prepared in DMEM2 to 5 generate a 10 ⁇ solution then serially diluted in DMEM2. Working concentrations of the test articles to be tested was prepared immediately prior to the start of the experiment.
  • Virus Inoculation Doses Cells were infected with USA-WA1/2020 (SARS-CoV-2), virus at a MOI of 0.01 which produces cytopathic effect (CPE) 72 hours post inoculation.
  • SARS-CoV-2 USA-WA1/2020
  • CPE cytopathic effect
  • 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
  • TCID50/cell with SARS-CoV-2 MOI of 0.01 TCID50/cell with SARS-CoV-2 and incubated for one hour in the absence of test articles and control drug.
  • DMEM2 10 DMEM with 2% FBS
  • test articles or control drug were added to the respective wells.
  • the plates were then incubated in a humidified chamber at 37°C ⁇ 2°C in 5 ⁇ 2% C02. At 72 hours ⁇ 4 hrs post inoculation, wells were evaluated for cytotoxicity/cytoprotection by neutral red assay.
  • 2019 Novel Coronavirus, Isolate USA-WA1/2020 SARS-CoV-2
  • the virus was stored at approximately ⁇ -65°C prior to use.
  • the multiplicity of infection (MOI) was 0.01 TCID50/cell.
  • ER Endoplasmic Reticulum
  • ER homeostasis The Endoplasmic Reticulum (ER) is the protein quality control system that plays a fundamental role in cell growth, homeostasis and protection. 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 5 conditions [Rozpedek et al., Current Molecular Medicine, 2017], The expression of coronavirus (CoV) spike proteins induces ER stress. In addition to CoV, Murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS) are two of the better studied representatives of the family Coronaviridae.
  • 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 20 several eIF2a kinases including, Protein kinase RNA (PKR)-like ER kinase (PERK).
  • PLR Protein kinase RNA
  • PERK Protein kinase RNA
  • the PERK branch of the UPR is believed to be activated first in response to ER stress [Szegezdi et al., 2006], While several laboratories have worked to define the mechanism of PERK activation it is triggered by the dissociation from ER chaperon GRP78/BiP, followed by oligomerization and auto- phosphoiylation [Lee, Methods, 2005], Activated PERK then phosphorylates the a-subunit of 25 eukaryotic initiation factor 2 (eIF2a).
  • eIF2a eukaryotic initiation factor 2
  • Phosphorylated eIF2a forms a stable complex with and inhibits protein turnover of eIF2B, a guanine nucleotide exchange factor that recycles inactive eIF2-GDP to active eIF2-GTP [Teske et al., Mol. Biol. Cell, 2011], This results in a general shutdown of cellular protein synthesis and reduces the protein flux into the ER [Ron and Walter, 2007],
  • the PERK/PKR- eIF2a-ATF4-GADD 153 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 20 treating viral infection.
  • NMR nuclear magnetic resonance
  • mHz megahertz
  • DMSO-d 6 dimethyl sulfoxide-de
  • HATU (l-[bis(dimethylamino)methylene]-l//-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;
  • DIPEA or DIEA NJV-diisopropylethylamine
  • HOBt hydroxybenzotri azole
  • EDC 1 -ethyl-3 -(3-dimethyIaminopropyI) carbodiimide.
  • Rh/C Rhodium on Carbon catalyst.
  • reaction mixture was allowed to cool to room 10 temperature, passed through a bed of diatomaceous earth, and washed with methyl fe/7-butyl ether (4 x 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.
  • the crude product was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1,
  • Step-1 Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-1.1):
  • Step-2 Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-l-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1):
  • reaction mixture was diluted with dichloromethane (6.0 mL) and washed with water (4 * 4 mL) and brine (4 mL).
  • the organic layer 15 was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-3 Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)phenyl)amino)- 20 l-(3-fluorophenyl)-2-oxoethyl acetate (C-3.1):
  • Step-1 Synthesis of3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolaii-2-yl)aniline (A-2.1):
  • Step-2 Synthesis of l-(3-chlorophenyl)-2-((3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxa boroIan-2-yl)phenyl)amino)-2-oxoethyl acetate (3):
  • reaction mixture was allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was cooled to 0 °C and diluted with dichloromethane (100 mL) and sat. NaHCCfo solution 10 (50 mL).
  • reaction mixture was allowed to warm to room 10 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-1 Synthesis of 2-amino-5-bromo-AT-cyclopropylpyridine-3-carboxamide (IE-3.1):
  • reaction mixture was diluted with EtOAc (120 mL) and washed with water (2 * 100 mL) and brine (2 * 100 mL). The organic layer was separated, dried over anhydrous NaaSCL, and concentrated under reduced pressure.
  • Step-2 Synthesis of 2-amino-5-(4-amino-2-methyl-phenyl)-N-cyclopropylpyridine-3- carboxamide (IE-4.1): H 2 N N ,
  • Step-3 Synthesis of (R)-2-amino-iV-cyclopropyl-5-(4- ⁇ 2-(3,5-difluorophenyl)-2-
  • Step-1 Synthesis of methyl 2-Amino-5-(4-amino-2-methylphenyl)nicotmate (2E-2.1):
  • Step-2 Synthesis of methyl 2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2 methylphenyl)nicotinate (2E-3.1):
  • the reaction mixture was allowed to warm to room temperature and stirred for 4 h. After this time, the reaction mixture was concentrated under reduced pressure.
  • the crude material was diluted with ethyl acetate (100 mL) and washed with water (2 3 ⁇ 4 75 mL) and 15 brine (2 * 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-3 Synthesis of 2-amino-5-(4-(2-(3,5-difIuorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinic acid (2E-4.1):
  • Step-4 Synthesis of 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)-N-methylnicotinamide (Racemate, Example 10 and Example 11: 2E-5.1):

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 présentant la structure (I) :
PCT/US2021/032322 2020-05-13 2021-05-13 Inhibiteurs de perk pour le traitement d'infections virales WO2021231782A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010080992A1 (fr) * 2009-01-09 2010-07-15 The Trustees Of The University Of Pennsylvania Régulateurs de la chaîne du récepteur 1 de l'interféron alpha (ifnar1) du récepteur d'interféron
WO2018194885A1 (fr) * 2017-04-18 2018-10-25 Eli Lilly And Company Composés de phényl-2-hydroxy-acétylamino-2-méthyl-phényle
WO2019191115A1 (fr) * 2018-03-26 2019-10-03 Icahn School Of Medicine At Mount Sinai Procédés de traitement d'un cancer résiduel minimal
WO2020070053A1 (fr) * 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'inhibiteurs de formation de granules de stress pour cibler la régulation de réponses immunitaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010080992A1 (fr) * 2009-01-09 2010-07-15 The Trustees Of The University Of Pennsylvania Régulateurs de la chaîne du récepteur 1 de l'interféron alpha (ifnar1) du récepteur d'interféron
WO2018194885A1 (fr) * 2017-04-18 2018-10-25 Eli Lilly And Company Composés de phényl-2-hydroxy-acétylamino-2-méthyl-phényle
WO2019191115A1 (fr) * 2018-03-26 2019-10-03 Icahn School Of Medicine At Mount Sinai Procédés de traitement d'un cancer résiduel minimal
WO2020070053A1 (fr) * 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'inhibiteurs de formation de granules de stress pour cibler la régulation de réponses immunitaires

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