WO2021231782A1 - Perk inhibitors for treating viral infections - Google Patents

Perk inhibitors for treating viral infections 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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WIPO (PCT)
Prior art keywords
amino
difluorophenyl
methylphenyl
hydroxyacetamido
alkyl
Prior art date
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PCT/US2021/032322
Other languages
French (fr)
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/en

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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

Provided herein are methods for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor selected from a compound having the structure (I):

Description

PERK INHIBITORS FOR TREATING VIRAL INFECTIONS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Provisional Application No. 63/024,311, filed May 13, 2020, which is incorporated herein by reference in its entirety.
5
BACKGROUND OF THE INVENTION
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).
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
25 protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status.
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). Each of these three sensors is regulated similarly through binding of the ER luminal
30 chaperone protein GRP78 or BiP (encoded by HSPA5). When protein folding demands of the ER exceed capacity, reduced BiP binding results in activation of these ER sensor proteins resulting in the induction of coordinated signaling pathways to increase the folding capacity of the ER and alleviate the underlying stress. Effective responses lead to cell adaptation and survival while irreparable ER stress triggers cell death and apoptosis.
5 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). Each eIF2 kinase responds to different cellular stress signals to regulate general translation and gene specific translational control.
10 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 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. Although it inhibits general protein synthesis, 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)
20 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.
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.
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
30 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.
Furthermore, Coronaviruses (CoV) 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. In a separate study, a 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.
SUMMARY OF THE INVENTION
15 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. In various embodiments, the PERK inhibitor is selected from a compound having the structure (I):
Figure imgf000004_0001
20 wherein:
Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents;
Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents;
Y is C(R3a)(R3b)Co-6alkyl, NR3a, -0-, C(0), CF2, CNOR3bb;
25 R3a is H, alkyl, or cycloalkyl;
R3b is H, alkyl, 0R3c, orNR3dR3e; R3bb is H or alkyl;
R4 is H, alkyl, or OH;
X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0-6alkyl-O-Ci- 5 i2alkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-O-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NO2, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- O-C1-12alkyl, C0-6alkyl-OH, or Co-6alkyl-0-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents;
10 R3c, R34 and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents;
R5 is H, CH3, NHR9, or OR9;
R6is H, alkyl, C02R8a, or CO(NR8aR8b);
R7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
15 R8a and R8b are each independently H, C1-12alkyl, C0-12alkylC3-12cycloalkyl, or C0-12alkylC3- 12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; or
R8a and R8b taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl;
R9 is H, alkyl, cycloalkyl, or heterocycloalkyl;
20 each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, Co- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10Rn, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NR10R11, S(0)nR10, S(0)nOR10, S(O)„NR10R11, N(R12)S(0)nR10, N(R12)S(0)n,OR10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, 25 CN, or NO2;
R10, R11, or R12 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, orN02; n is O, 1, or 2; or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
5 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.
In various embodiments, the PERK inhibitor is selected from a compound having the structure
(I):
Figure imgf000006_0001
15 wherein:
Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents;
Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; Y is C(R3a)(R3b)C0-6alkyl, NR3a, -0-, C(0), CF2, CNOR3bb, or a direct bond to Ar1;
20 R3a is H, alkyl, or cycloalkyl;
R3b is H, alkyl, 0R3c, orNR3dR3e;
R3bb is H or alkyl;
R4 is H, alkyl, or OH;
X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-0-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NO2, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- 5 0-Ci-i2alkyl, C0-6alkyl-OH, or C0-6alkyl -O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents;
R3c, R3d and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents;
R5 is H, CH3, NHR9, or OR9;
10 R6is H, alkyl, C02R8a, or CO(NR8aR8b);
R7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
R8a and R8b are each independently H, C1-12alkyl, Co-i2alkylC3-i2cycloalkyl, or Co-i2alkylC3- 12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; or
R8a and R8b taken together with the nitrogen to which they are attached form 5-10 membered
15 heterocyclyl;
R9 is H, alkyl, cycloalkyl, or heterocycloalkyl; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, Co- i2alkylC3-i2cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10R11, OC(0)R10, OC(0)OR10, OC(O)NR10Rn, N(R12)C(0)R10, N(R12)C(0)OR10,
20 N(R12)C(O)NR10R11, S(0)nR10, S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11, optionally substitued by one or more independent H, deuterium, halo, OH, CN, orN02;
R10, R11, or R12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkylandr heterocycloalkyl, optionally substituted by one or more independent H, deuterium, 25 halo, OH, CN, or NO2; nis 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
In some embodiments, a pharmaceutical composition comprising the compound of the present invention, an anti-cancer agent and a pharmaceutically acceptable carrier.
5 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
10 (la):
Figure imgf000008_0001
wherein:
Yis CR3aR3b;
R3a is H or alkyl;
15 R3b is OR3C or NR3dR3e; each R1 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 R2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-C1- 20 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents;
R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents;
X is CR7 or N; R6is H, alkyl, COiR83, or CO(NR8aR8b);
R7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;
R8® and R8b are each independently H, C1-12alkyl, C0-12alkylC3-12cycloalkyl, or C0-12alkylCs- nheterocycloalkyl, optionally substituted by one or more independent G4 substituents;
5 each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, Co- i2alkylC3.i2cycloalkyl, Co.i2alkylC3.i2heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NRl0R11, OC(0)R10, OC(0)OR10, OC(O)NR10Rn, N(R12)C(0)R10, N(R12)C(0)OR10, NCR^Xr^NR1^11, S(=0)nR10, S(0)nOR10, S(O)„NR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, 10 CN, or NO2;
R10, R11, or R12 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, orN02; n is 0, 1, or 2;
15 p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
The present invention yet further provides the PERK inhibitor having the following structure (lb):
.2, H R3a R3b
N
1
20
Figure imgf000009_0001
wherein:
X is CH orN; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, Co- ealkyl-OH, or Co-6alkyl-0-C3-i2cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R2 is independently H, deuterium, halo, alkyl, cycloalkyl, Co-6alkyl-0-Ci-i2alkyl, Co- 5 ealkyl-OH, or Co-6alkyl-0-C3.i2cycloalkyl, optionally substituted by one or more independent G2 substituents;
R3a is H or alkyl;
R3b is OR3e or NR3dR3e;
R3c, R34 and R3e are each independently H or alkyl, optionally substituted by one or more 10 independent G3 substituents;
R6 is C02R8a or COCNR8^);
R8a and R8b are each independently H, C1-12alkyl, C3-12cycloalkyl, or Cs-izheterocycloalkyl, optionally substituted by one or more independent G4 substituents; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NOi, C1-12alkyl, C3- 15 ncycloalkyl, C3.i2heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10Rn, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(Rl2)C(0)OR10, N(R12)C(O)NR10R11, S(0)nR10, S(0)nOR10, SCO^NR10^1, N(R12)S(0)nR10, N(R12)S(0)n0R10, or NCR^SCO^NR1^11, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or N02;
R10, R11, or R12 are each independently selected from H, deuterium, halo, CN, N02, alkyl,
20 cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN02; n is O, 1, or 2; p is O, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4;
25 or a pharmaceutically acceptable salt thereof.
The present invention yet further provides the PERK inhibitor having the following structure (Ic):
Figure imgf000011_0001
wherein:
Xis CH orN; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, 5 optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G2 substituents;
R3b is OR3c;
R3C is H or alkyl, optionally substituted by one or more independent G3 substituents;
10 R6is CO(NR8aR8b);
R88 and R85 are each independently H, C1-12alkyl, C0-12alkylC3-12cycloalkyl, or C0-12alkylCs- laheterocycloalkyl, optionally substituted by one or more independent G4 substituents; each G1, G2, G3, or G4is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C3. iicycloalkyl, C3-12heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10R11, OC(0)R10, 15 S(0)nR10,
Figure imgf000011_0002
1, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2;
R10, R11, or R12 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium,
20 halo, OH, CN, or NO2; nis 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; qis 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof The present invention yet further provides the PERK inhibitor having the following structure (Id):
Figure imgf000012_0001
wherein:
5 Xis CH orN; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C l-nalkyl, optionally substituted by one or more independent H, deuterium, or halo; each R2 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;
10 R8® and R8b are each independently H, C1-12alkyl, Cg-ncycloalkyl, or C3-i2heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, C1-12alkyl, C3-12cycloalkyl,
Figure imgf000012_0002
S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, orN(R12)S(O)nNR10R11;
15 R10, R11, or R12 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, orN02; 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.
In some embodiments, R6 is H, X ·
Figure imgf000013_0001
or H
In some embodiments, X is CH.
In some embodiments, each R1 is independently H, methyl, ethyl, isopropyl, methoxy, 5 ethoxy, propoxy, isopropoxy, deuterium, CF3, fluoro, or chloro.
In some embodiments, each R2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF3 or OCF3.
In some embodiments, R83 and R8b are each independently H, Ci^alkyl, C0-6alkylCi- gcycloalkyl, or C0-6alkylC3-8heterocycloalkyl. In some embodiments, R83 and R8b are each independently H, Cioalkyl, Co-3alkylC3. ecycloalkyl, or Co-3alkylC3-6heterocycloalkyl.
In some embodiments, R88 and Rto are each independently H, Ci-salkyl, C3-6cycloalkyl, or C3-6heterocycloalkyl.
5 In some embodiments, each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, N02, Chalky], C3-8cycloalkyl, Cs-eheterocycloalkyl, OR10, NR10Rn, C(0)R10, C(0)OR10, C(O)NR10Rn, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NR10R11, S(0)nR10, S(0)n0R10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)n0R10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, 10 CN, orN02.
In some embodiments, each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, N02, Ci-salkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10Rn, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12X:(O)NR10R11, S(0)nR10, S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or 15 N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH,
CN, or N02.
The present invention yet further provides the PERK inhibitor having the following structure
(Ie):
Figure imgf000014_0001
wherein:
Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents;
Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents;
25 Y is C(R3a)(R3b)C0-6alkyl, NR3a, -0-, C(0), CF2, or a direct bond to Ar1;
R3a is H or alkyl; R3b is OR3C or NR3dR3e;
R4 is H or OH;
X is CR7 or N; each R1 is independently halo, alkyl, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one 5 or more independent G1 substituents; each R2 is independently halo, alkyl, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G2 substituents;
R3c, R3d and R3e are each independently H or alkyl;
Figure imgf000015_0001
R7 is H or alkyl;
R8a and R8b are each independently H, Ci.i2alkyl, C0-12alkyl-C3-i2cycloalkyl, or C0-12alkyl-C3. nheterocycloalkyl, optionally substituted by one or more independent G4 substituents; or
R8a and R8b taken together with the nitrogen to which they are attached form 5-10 membered
15 heterocyclyl; each G1, G2, G3, or G4 is independently halo, OR10, NR10Rn, C(0)R10; and R10 or R11 are each independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.
In some embodiments, Ar1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
20 pyridyl,
Figure imgf000015_0002
N,
N, v
, or , optionally substituted by one or more independent R1 substituents.
In some embodiments, each R1 is independently chloro, fluoro, methyl, ethyl, methoxy, or
CF3. In some embodiments, Y is -C(H)(OH>, -C(CH3)(OH>, -C(H)(OCH3>, -C(HXNH2>, CF2, C(O), CH2I -CH2CH2-, N(CH3), -0-, or a direct bond to Ar1.
In some embodiments, R4 is H. In some embodiments, R4 is OH.
In some embodiments, Ar2 is phenyl or pyridyl, optionally substituted by one or more 5 independent R2 substituents.
In some embodiments, each R2is independently methyl, ethyl, methoxy, fluoro, chloro, CF3, or OCF3.
In some embodiments, X is CR7. In some embodiments, R7 is H.
In some embodiments, X is N.
10 In some embodiments, R5 is H, methyl, NH2, or NHCH3. In some embodiments, R6 is H.
Figure imgf000017_0001
In some embodiments, the compound is selected from: 2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-#-isopropylnicotinamide;
5 (R)-2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-yV-isopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-hydroxy-2-phenylpropanamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R) 2 amino 5 (4 (2 hydroxy 2 phenylpropanamido) 2 methylphenyl) Nisopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-phenylpropanamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide;
(R)-2-aminoALisopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide;
(S)-2-amino-N-isopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide;
5 2-amino-5-(4-(2-amino-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-amino2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-amino-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
10 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 15 methylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-//- methylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylnicotinamide;
20 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-//-ethylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- ethylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- ethylnicotinamide,
25 2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 30 methylphenyl)nicotinamide; 2-amino-N-(/e/7-butyl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(R)-2-amino-N-(/m-butyl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
5 (S)-2-amino-N-(te/7-butyl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- 10 trifluoroethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isobutylnicotinamide;
15 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-2-methylphenyl)-N- i sobutylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isobutylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N^- 20 dimethylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N^V- dimethylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N,N- dimethylnicotinamide;
25 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- yl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- 30 yl)nicotinamide; 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- hydroxycyclobutyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- hydroxycyclobutyl)nicotinamide;
5 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- hydroxycyclobutyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- methoxycyclobutyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- 10 methoxycyclobutyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- methoxycyclobutyl)nicotinamide,
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-methylpyrazine-2- carboxamide;
15 (R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-2-methylphenyl)-N- methylpyrazine-2-caiboxamide;
(S)-3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylpyrazxne-2-carboxamide;
3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 20 methylphenyl)pyrazine-2-carboxamide;
(R)-3-amino-.N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2-carboxamide;
(5r)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
25 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinic acid;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinic acid;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinic acid; isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinate;
(R)-isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-
30 methylphenyl)nicotinate;
(5)-isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinate;
2-amino-N-(azetidin-3-yl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(R)-2-aminoN-(azetidin-3-yl)-5-(4-(2-(3, 5-difluorophenyl)-2 -hydroxy acetamido)-2- 5 methy lpheny l)ni cotinami de;
(S)-2-amino-N-(azetidin-3-yl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l-methylazetidin-
3-yl)nicotinamide;
10 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l- methylazetidin-3 -yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l- methylazetidin-3-yl)nicotinamide;
2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 15 methylphenyl)nicotinamide;
(R)-2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(S)-2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
20 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-2H- pyran-4-yl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-
2H-pyran-4-yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro- 25 2H-pyran-4-yl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2-
(dimethylamino)ethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3, 5-difluorophenyl)-2 -hydroxy acetamido)-2-methylphenyl)-N-(2- (dimethylamino)ethyl)nicotinamide;
30 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- (dimethylamino)ethyl)nicotinamide; 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)nicotinamide;
5 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- 10 hydroxy ethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)nicotinamide;
N-(4-(6-amino-5-(2,6-diazaspiro[3.3 ]heptane-2-carbonyl)pyri din-3 -yl)-3 -methylphenyl)-2-(3 ,5- difluorophenyl)-2-hydroxy acetamide;
15 (/t)-N-(4-(6-amino-5-(2,6-diazaspiro[3.3 ]heptane-2-carbony l)py ridin-3 -yl)-3 -m ethy lpheny l)-2-(3 , 5 - difluorophenyl)-2-hydroxy acetamide;
(S)-N-(4-(6-amino-5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-3-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxy acetamide;
2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
20 (R)-2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
25 2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(S)-2-ami no-5 -(4-(2-(3 -chi orophenyl)-2-hy droxy acetami do)-2-methy lpheny 1 )-N- 30 i sopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- 5 isopropylnicotinamide;
2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropy lnicotinamide;
(S)-2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 10 isopropylnicotinamide;
2-amino-5-(4-(2-(2,3-dihydrobenzofuran-7-yl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropy lnicotinamide;
(R)-2-amino-5-(4-(2-(2,3-dihydrobenzofuran-7-yl)-2 -hydroxy acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
15 (S)-2-amino-5-(4-(2-(2,3 -dihydrobenzofuran-7-yl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- 20 isopropylnicotinamide;
(S)-2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
25 (R)-2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- 30 (methylamino)nicotinamide;
(R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- (methylamino)nicotinamide;
(S)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetaniido)-2-methylphenyl)-N-isopropyl-2-
(methylamino)nicotinamide;
5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- 5 methylnicotinamide;
(R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- methylnicotinamide;
(S)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- methylnicotinamide;
10 2-amino-5-(4-(2-(3,5-difluorophenyl)-N, 2-dihydroxy acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2-methylphenyl)-N- 15 i sopropylnicotinamide;
5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide; (5)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-(methylamino)pyridin-3-yl)phenyl)acetamide; 20 (R}~ 2-(3 , 5-difluoropheny l)-2-hy droxy-N-(3 -methyl -4-(6-(methyl amino)pyri din-3 - yl)phenyl)acetamide;
(S)-2-(3 , 5 -difl uorophenyl )-2-hy droxy -N-(3 -methyl -4-(6-(methyl ami no)pyri din-3 - yl)phenyl)acetamide;
N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide;
25 (R)-N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxy acetamide;
(S)-N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide; 2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-methylpyridin-3-yl)phenyl)acetamide; (R)-2-(3 ,5-difluorophenyl)-2-hydroxy-N-(3 -methyl -4-(6-methylpyri din-3 -yl )pheny 1 )acetamide;
(S)-2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-methylpyridin-3-yl)phenyl)acetamide;
30 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
2-amino-5-(2-chloro4-(2-(3,5-difIuorophenyl)-2-hydroxyacetamido)phenyl)-N-ethylmcotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- ethylnicotinamide;
5 (S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- ethylnicotinamide;
2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylnicotinamide;
(^)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- 10 cyclopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylnicotinamide;
2-amino-5-(2-cMoro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
15 (R)-2-amino-5-(2-cMoro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
2-amino-5-(2-chloro4-(2-(3-chlorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide; 20 (R)-2-amino-5-(2-chloro-4-(2-(3-chlorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3-chlorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylnicotinamide;
2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
25 (R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; (,S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; 2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
30 2-amino-5-(2-chloro-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-cMoro-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3-ethylphenyl)-2 -hydroxy acetamido)phenyl)-N- i sopropylnicotinamide;
2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- 5 isopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
10 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-2-ethylphenyl)-N- ethylnicotinamide;
(,S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- ethylnicotinamide;
15 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- 20 trifluoroethyl)nicotinamide;
2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)nicotinamide;
(R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)nicotinamide;
25 (S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)nicotinamide;
2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
30 2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetaniido)phenyl)-N- i sopropylnicotinamide;
2-amino-5-(4-(2-(3-cMorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide; 5 (R)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- i sopropy lnicotinamide;
2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- 10 isopropylnicotinamide;
(R)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- i sopropy lnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
15 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methoxyphenyl)-N- i sopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methoxyphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetamido)-2-methoxy phenyl)-N- 20 isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- i sopropylnicotinamide;
25 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- i sopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- 30 isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- ethylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- 5 ethylnicotinamide;
(S)-2-amino-5-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetamido)-3 -fluoro-2-methylphenyl)-N- ethylnicotinamide;
2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2- methy lpheny l)ni cotinami de;
10 (R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2- methylphenyl)nicotinamide;
(S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2- methylphenyl)ni cotinami de;
2-amino-5-(4-(2-(3 ,5 -difluorophenyl)-2-hydroxy acetami do)-3 -fluoro-2-methylphenyl)-N-(oxetan-3 - 15 yl)ni cotinami de;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- (oxetan-3 -yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- (oxetan-3 -yl)nicotinamide;
20 2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- isopropylnicotinamide;
(^)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- 25 isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-5-fluoro-2-methylphenyl)-N- isopropylnicotinamide;
(7i)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-5-fluoro-2-methylphenyl)-N- i sopropylnicotinamide;
30 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-5-fluoro-2-methylphenyl)-N- isopropylnicotinamide; 2-amino-5-(4-(2,2-difluoro-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-oxoacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(2-methyl-4-(2-(6-methylpyridin-2-yl)acetamido)phenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
5 2-amino-N-isopropyl-5-(2-methyl-4-(2-phenylacetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(3-phenylpropanamido)phenyl)mcotinamide; 2-amino-5-(4-(2-(2-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(4-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
10 2-amino-N-isopropyl-5-(4-(2-(2-methoxyphenyl)acetamido)-2-methylphenyl)nicotinamide; 2-amino-N-isopropyl-5-(4-(2-(3-methoxyphenyl)acetamido)-2-methylphenyl)mcotinamide; 2-amino-N-isopropyl-5-(4-(2-(4-methoxyphenyl)acetamido)-2-methylphenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(o-tolyl)acetamido)phenyl)mcotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(m-tolyl)acetamido)phenyl)nicotinamide;
15 2-amino-N-isopropyl-5-(2-methyl-4-(2-(p-tolyl)acetamido)phenyl)nicotinamide;
2-amino-5-(4-(2-(2-cMorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3-chlorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(4-chlorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(2-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 20 2-amino-N-isopropyl-5-(2-methyl-4-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(4-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 2-amino-5-(4-(2-(2-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(4-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
25 2-amino-N-isopropyl-5-(2-methyl-4-(2-(naphthalen-l-yl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(naphthalen-2-yl)acetamido)phenyl)mcotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(qmnolin-6-yl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(4-(2-(isoquinolin-4-yl)acetamido)-2-methylphenyl)nicotinamide; 2-amino-N-isopropyl-5-(4-(2-(isoquinolin-5-yl)acetamido)-2-methylphenyl)nicotinamide;
30 2-amino-N-isopropyl-5-(2-methyl-4-(2-(quinolin-5-yl)acetamido)phenyl)nicotinamide; 2-amino-5-(4-(2-cyclopropylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-cyclobutylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-cyclopentylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-cyclohexylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-benzamido-2-methylphenyl)-N-isopropylnicotinamide;
5 2-amino-N-isopropyl-5-(2-methyl-4-(3-methyl-3-phenylureido)phenyl)nicotinamide; phenyl (4-(6-amino-5-(isopropylcarbamoyl)pyridin-3-yl)-3-methylphenyl)carbamate;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-methylpyrazine-2- carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 10 methylpyrazine-2-carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylpyrazine-2-carboxamide;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
15 (R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-2-methylphenyl)-N-(2, 2,2- trifluoroethyl)pyrazine-2-carboxamide;
(5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
3 -amino-N-cyclopropyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hydroxy acetamido)-2-
20 methylphenyl)pyrazine-2-carboxamide;
(R)-3 -amino-N-cy clopropyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hy droxy acetamido)-2- methylphenyl)pyrazine-2-carboxamide;
(5)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
25 3-amino-N-cyclobutyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2-carboxamide;
(R)-3-amino-N-cyclobutyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
(S)-3-amino-N-cyclobutyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-
30 methylphenyl)pyrazine-2-carboxamide;
3-amino-6-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- yl)pyrazine-2-carboxamide;
(R)- 3 -amino-6-(4-(2-(3 ,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
(S)-3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3 - 5 yl)pyrazine-2-carboxamide;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-2H- pyran-4-yl)pyrazine-2-carboxamide;
(R)-3-amino6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro- 2H-pyran-4-yl)pyrazine-2-carboxami de;
10 (5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro- 2H-pyran-4-yl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetamido)-2-methylphenyl)-N-(2- (dimethylamino)ethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- 15 (dimethylamino)ethyl)pyrazine-2-carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2-
(dimethylamino)ethyl)pyrazine-2-caiboxamide;
3-amino-6-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)pyrazine-2 -carboxamide;
20 (R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)pyrazine-2 -carboxamide;
(5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3 ,5 -difluorophenyl)-2-hy droxy acetamido)-2-m ethylphenyl)-N-(2- 25 hydroxy ethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)pyrazine-2-carboxamide;
(5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)pyrazine-2-carboxamide;
30 3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetamido)-2-ethylphenyl)-N-isopropylpyrazine-2- carboxamide; (R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- isopropylpyrazine-2 -carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- isopropylpyrazine-2-carboxamide;
5 3-amino-6-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylpyrazine-2- carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylpyrazine-2- carboxamide;
(5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylpyrazine-2- 10 carboxamide;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
15 (5)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)pyrazine-
2-carboxamide;
(R)- 3 -amino-N-cy clopropyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hydroxy acetamido)-2- 20 ethylphenyl)pyrazine-2-carboxamide;
(iS)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetami do)-2-ethy lpheny l)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
25 (i?)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(oxetan-3- yl)pyrazine-2-carboxamide;
(S)-3 -amino-6-(4-(2-(3 ,5 -difluorophenyl)-2-hy droxyacetamido)-2-ethylphenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
3-amino-6-(2-ethyl-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- 30 carboxamide;
(R)-3-amino-6-(2-ethyl-4 -(2-hydroxy -2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- carboxamide;
(S)-3-amino-6-(2-ethyl-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- carboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylpyrazine- 5 2-carboxamide;
(R)-3-amino-6-(2-chloro-4-(2-(3,5-difIuorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylpyrazine-2-carboxamide;
(5)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylpyrazine-2-carboxamide;
10 3 -amino-6-(2-chloro-4-(2-(3 ,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-caiboxamide;
(R)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(5)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- 15 trifluoroethyl)pyrazine-2-caiboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylpyrazine-2-carboxamide;
(^)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylpyrazine-2-carboxamide;
20 (S)-3 -amino-6-(2-chloro-4-(2-(3 ,5 -difluorophenyl)-2-hy droxy acetami do)phenyl)-N- cyclopropylpyrazine-2-carboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(oxetan-3- yl)pyrazine-2-carboxamide;
(R)- 3 -amino-6-(2-chloro-4-(2-(3 , 5-difluoropheny l)-2-hy droxy acetamido)pheny 1)-N -(oxetan-3 - 25 yl)pyrazine-2-carboxamide;
(,S)-3 -amino-6-(2-chl oro-4-(2-(3 ,5 -difluorophenyl)-2-hy droxy acetamido)phenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention further provide a pharmaceutical composition,
30 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 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. In some embodiments, the PERK kinase modulating compound is any of the compounds described herein. In some embodiments, the PERK kinase modulating compound is a compound of formula I, la, lb, Ic, Id or Ie, or a pharmaceutically acceptable salt thereof.
In some embodiments, the viral infection is associated with an RNA virus. In some 10 embodiments, the RNA virus is a single-stranded RNA virus. In some embodiments, the single- stranded RNA virus is a coronavirus.
In some embodiments, the viral infection is associated with a coronavirus. In some embodiments, the coronavirus is a coronavirus capable of infecting a human. In some embodiments, the coronavirus is an alpha coronavirus. In some embodiments, the alpha coronavirus is 229E alpha 15 coronavirus or NL63 alpha coronavirus. In some embodiments, the coronavirus is a beta coronavirus.
In some embodiments, 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). In some embodiments, the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the coronavirus 20 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 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. In some embodiments, the PERK kinase modulating compound is a compound of formula I, la, lb, Ic, Id or Ie, or a pharmaceutically acceptable salt thereof.
In some embodiments, the methods of treating viral infections described herein further 30 comprise administering an antiviral agent. In some embodiments, 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 (Intelence), Famciclovir, Fomivirsen, Fosamprenavir, Foscamet, Fosfonet, a Fusion inhibitor, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Inosine, an bitegrase inhibitor, Interferon type I, Interferon type Π, Interferon type III, an Interferon, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nitazoxanide, Norvir, a nucleoside analogue, 10 Oseltamivir, Peginterferon alfa-2a, Peginterferon alfa-2b, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, a protease inhibitor, Pyramidine, Raltegravir, Remdesivir, a reverse transcriptase inhibitor, Ribavirin, Rilpivirine (Edurant), Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, a synergistic enhancer, Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir, Trifluridine, Trizivir, 15 Tromantadine, Truvada, Valaciclovir (Valtrex), Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir (Relenza), Zidovudine, and combinations thereof.
As used herein, the term “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. 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. The shapes of 25 these virus particles range from simple helical and icosahedral forms for some virus species to more complex structures for others. Thus, the term “virus”, as used herein, also encompasses viral panicles, particularly infectious particles. Examples of 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. 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., reoviruses, orbiviruses, rotaviruses); Birnaviridae, Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses, e g. small mouse virus, dog parvovirus, human parvovirus B19 and AAV; Papovaviridae (papilloma viruses, poliomavi ruses, BK virus); Adenoviridae (adenoviruses); Herpesviridae (herpes simplex virus (HSV) -1 and HSV-2 15 , cytomegalovirus; Epstein-Barr virus, chickenpox virus and other herpes viruses, including HSV-6);
Poxviridae (variola viruses, smallpox viruses, poxviruses) and 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).
As used herein, the terms “coronavirus”, “coronavimses”, “CoV”, or “CoVs” 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. The name 25 “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 vims and determine host tropism. There are four main sub-groupings of coronavimses, known as alpha, beta, gamma, and delta.
30 There are numerous 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. However, several Co V strains have been identified that have been transmitted from animals to humans. For example, severe acute respiratory syndrome coronavims (SARS-CoV) can infect people and animals, including monkeys, Himalayan palm civets, raccoon dogs, cats, dogs, and rodents. Middle East respiratory syndrome coronavirus (MERS-CoV) has also been found to infect people 5 and animals, including camels and bats. Examples of 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.
As used herein, 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.
As used herein, “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.
The contents of International Application Publication No. WO/2018/194885, published
15 October 25, 2018, and WO2021/041973, published March 4, 2021, are hereby incorporated by reference.
If 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. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. In the compound stmctures depicted herein, 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 ¾ 3H, 13C, 14C, 15N, and/or 180. 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.
In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium); carbon 10 may be, for example, 13C or 14C; oxygen may be, for example, l80; nitrogen may be, for example, 15N, and the like. In other embodiments, a particular isotope (e.g., ¾ 13C, 14C, 180, or 15N) 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.
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.
It is understood that where a numerical range is recited herein, the present invention contemplates each integer between, and including, the upper and lower limits, unless otherwise stated.
20 Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, 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. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral 30 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. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
5 It will be noted that 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 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C 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, 10 when used without further notation, are intended to represent all isotopes of hydrogen, such as ¾ 2H, or 3H. Furthermore, any compounds containing 2H or 3H 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.
In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more
20 hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl.
It is understood that 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
25 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. R1, R2, etc. are to be chosen in conformity
30 with well-known principles of chemical structure connectivity. As used herein, “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.
5 As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, Ci-Cn as in “Ci-
Cn 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. Thus, 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. When n is zero, “-O-Co-malkyl” is attached directly to the preceding moiety. When m is zero, the alkoxy group
15 is “Co-nalkyl-OH.” Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and so on.
The term "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. Thus, Ca-Cn alkenyl is defined to include 20 groups having 1, 2...., n-1 or n carbons. For example, "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. 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 25 substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.
The term "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. Thus, C2-C11 alkynyl is defined to include groups having 1, 2...., n-1 or n 30 carbons. For example, "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. 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 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.
As used herein, "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.
As used herein, "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.
As herein, "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).
As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 12 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such
25 aromatic monocycle elements include but are not limited to: phenyl.
As used herein, "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. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not
30 limited to: naphthalene. As used herein, "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.
As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
The term “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.
The term "heteroaryl", as used herein, 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, pyrimidyl, pyrrolyl, quinazolinyl, 30 quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, 5 dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedi oxy benzoyl, tetrahy drofurany 1 , tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where the 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.
The te i “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.
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. Examples of alkylheteroaryl moieties include, but are not limited to, -Cfh-CCsHtN), -CHz-CEb-CCsEUN) and the like.
20 The term "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. Preferably 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
25 of substitution being allowed. 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). Examples of 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.
30 The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, 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.
As used herein, the term “halogen” or “halo” refers to F, Cl, Br, and I.
5 As used herein, the term “carbonyl” refers to a carbon atom double bonded to oxygen. A carbonyl group is denoted as R*C(0)Ry where Rx and Ry are bonded to the carbonyl carbon atom.
The terms “substitution”, “substituted” and “substituent” refer 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. Examples of 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, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; 20 and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
It is understood that 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. R1, R2, etc. are to be chosen in conformity with well- known principles of chemical structure connectivity.
The various 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) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley- 15 Interscience) 5th 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.
In some embodiments, a pharmaceutical composition comprises the compound of the present
20 invention and a pharmaceutically acceptable carrier.
As used herein, 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, 30th 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
30 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. As used 5 herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. Examples of 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. The term "pharmaceutically acceptable salt" in this respect, 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.
As used herein, “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.
As used herein, 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.
25 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 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. Examples of 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 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.
15 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
20 Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7.
(David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal
25 Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.
For instance, for oral administration in the dosage unit form of a tablet or capsule, the active
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.
For oral administration in liquid dosage form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier. Examples of 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. In addition, 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. To be administered in the 30 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 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.
Specific examples of pharmaceutically acceptable carriers and excipients that may be used to 10 formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modem 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 15 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. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Dmgs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Dmgs 20 and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Dmg Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Dmgs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.
25 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.
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.
5 Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.
This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are 10 only illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Details
The following materials and methods are used to test the compounds of the present invention.
PERK/w Vitro Activity Assay (isolated):
In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) 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).
Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli. Perform TR-FRET kinase assays in the absence or presence of inhibitors in a reaction buffer 20 consisting of 50 mM HEPES, pH 7.5, 10 mM MgCb, 1.0 mM EGTA, and 0.01% Brij-35, and 100 - 200 nM GFP-eIF2a substrate. PKR assays contain 14 ng/mL enzyme and 2.5 μΜ ATP (Km, -2.5 μΜ), PERK assays contain 62.5 ng/mL enzyme and 1.5 μΜ ATP (Km. app -1.5 uM), and 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). Determine TR-FRET ratios and the resulting IC50 values using a 4-parameter nonlinear logistic equation as shown: Y = (A+((B- A)/(1+((C/X)AD)))) where, Y = % specific inhibition, A = Bottom of the curve, B = Top of the curve, 30 C = absolute IC50 (concentration causing 50% inhibition), and D = hill slope. The compounds of Examples 1 to 219 were tested essentially as described above and exhibited ICso values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 219 inhibit isolated PERK enzyme activity in vitro.
PERK Cellular Assay
5 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.
15 The compounds of Examples 1 to 219 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 219 inhibit EIF2a in vitro.
The results of exemplaiy compounds of formula (I) are shown in Table 1. Key: A is 0.001 to 0.025 μΜ; B is 0.026 to 0.050 μΜ; C is 0.051 to 0.100 μΜ; D is 0.101 to 0.250 μΜ; E is 0.251 20 to 0.500 μΜ; F is 0.501 to 1.00 μΜ; Gis 1.001 pMto 2.00 μΜ; His 2.001 μΜ to 3.00 μΜ; I is 3.001 to 4.00 μΜ; J is 4.001 to 5.00 μΜ; K is greater than 5.00 μΜ; and N/A is “not available”. Table 1: Biochemical and cellular ICso data of Compounds of Formula I inhibiting PERK kinase:
Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
1 A E
2 A D
3 D H
Figure imgf000052_0001
Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
7 G K
8 A B
9 B D
10 A C
11 F G
12 A B
13 A F
14 A B
15 B E
16 B D
17 E F
18 A B
19 D D
20 A B
21 D E
22 F H
23 K K
24 A C
25 B F
26 A D
27 C G
28 A B
29 B E
30 A F
Figure imgf000053_0001
Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
35 C D
36 A C
37 D E
38 A A
39 D D
40 A B
41 D K
42 A B
43 C E
Figure imgf000054_0001
Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
63 N/A N/A
64 N/A D
65 N/A H
66 D G
67 A C
68 D F
69 A B
70 N/A A
71 N/A F
72 A A
73 D E
74 E G
75 D G
Figure imgf000055_0001
Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
91 N/A E
92 N/A A
93 N/A D
94 A A
95 B D
96 N/A N/A
97 N/A N/A
98 A A
99 B D
100 A A
101 A c
102 A A
103 B D
104 N/A C
105 N/A F
106 A A
107 C E
108 A A
109 C D
110 A A
111 D D
112 C E
113 C F
114 E K
115 A A
116 E G
117 A A
118 A B Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
119 A A
120 A C
121 A A
122 E F
123 A A
124 B C
125 D F
126 A D
127 E K
128 C K
129 N/A N/A
130 N/A N/A
131 N/A N/A
132 N/A N/A
133 C D
134 A B
135 A B
136 N/A N/A
137 N/A N/A
138 A B
139 A E
140 N/A B
141 N/A D
142 N/A G
143 N/A B
144 N/A F
145 N/A C
146 B D Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
147 N/A B
148 N/A F
149 N/A N/A
150 N/A N/A
151 A B
152 D D
153 A B
154 A A
155 D D
156 A A
157 D D
158 A A
159 B D
160 A A
161 C E
162 N/A D
163 N/A C
164 G E
165 C B
166 N/A B
167 N/A D
168 C D
169 A A
170 C H
171 E K
172 C G
173 D K
174 D J Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
175 G K
176 C F
177 B E
178 B D
179 D F
180 G K
181 K K
182 E H
183 D H
184 E D
185 A E
186 C D
187 C F
188 E H
189 D F
190 C F
191 C G
192 D H
193 C F
194 F H
195 S E
196 S E
197 D G
198 B F
199 B D
200 F F
201 C F
202 C D Biochemical Cellular ICso (μΜ)
Example
ICso (μΜ) (EIF2a)
203 H G
204 D N/A
205 A D
206 E H
207 A E
208 B D
209 D G
210 C G
211 E H
212 G K
213 G K
214 E K
215 K K
216 G K
217 K F
218 G K
219 G G
Viral Inhibition
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 μΜ 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.
Basis for Selection of 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.
10 Basis for Selection of Test Article Dose Levels: The dose-dependent anti-viral effect of each compound was tested individually. For individual testing, the compounds were tested at eight concentrations with a starting concentration of 10 μΜ for all compounds (Table 2). Three-fold serial dilutions was prepared across the plate in DMEM2.
Table 2: Testing Concentrations
Column Test Article [μΜ]
2 10.00
3 3.33
4 1.11
5 0.3704
6 0.1235
7 0.0412
8 0.0137
9 0.0046
Experimental Design:
5 Efficacy for each compound was tested. Each of the concentrations were evaluated in triplicate for efficacy. 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 10 (DMEM with 2% FBS) containing vehicle, 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.
Cell Culture: African green monkey kidney (Vero E6) cells were maintained in Dulbecco’s 15 Minimum Essential Medium with 10% fetal calf serum. All growth media contains heat-inactivated fetal calf serum and antibiotics.
Challenge Viruses: 2019 Novel Coronavirus, Isolate USA-WA1/2020 (SARS-CoV-2) were used. The virus was stored at approximately < -65°C prior to use. The multiplicity of infection (MOI) was 0.01 TCID50/cell.
20 Table 3: Reduction In Viral CPE
Example % reduction in viral CPE, concentration of compound
12 10-40% @ 3,33 and ΙΟμΜ
123 20% @ luM The compounds of Examples 12 and 123 were tested essentially as described above and exhibited a significant reduction in viral cytopathic effect (CPE), as shown in Table 3. These data demonstrate that the compounds of Examples 1 to 219 inhibit viral replication in vitro.
HPLC Conditions:
5 Method A
Column: Polaris C18-A2.6 pm C18 (100 x 3.0 mm)
Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid
Mobile Phase B: Acetonitrile containing 0.05% v/v Trifluoroacetic Acid Detection: 230 nm
10 Method A Gradient
Time Flow %A %B
(min) (mL/min)
0.0 0.8 95.0 5.0
3.0 0.8 95.0 5.0
6.0 0.8 10.0 90.0
12.0 0.8 10.0 90.0
Method B
Column: Eclipse plus C183.5 pm C18 (100 * 4.6 mm)
Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid
15 Mobile Phase B : Acetonitrile containing 0.05% v/v Trifluoroacetic Acid
Detection: 254 nm
Method B Gradient
Time Flow %A %B
(min) (mL/min)
0.0 0.8 95.0 5.0
3.0 0.8 95.0 5.0
6.0 0.8 10.0 90.0
12.0 0.8 10.0 90.0
Method C
Column: Eclipse plus C183.5 pm C18 (100 * 4.6 mm) Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid
Mobile Phase B: Acetonitrile containing 0.05% v/v Trifluoroacetic Acid
Detection: 270 ran
Method C Gradient
Time Flow %A %B
(min) (mL/min)
0.0 0.8 95.0 5.0
3.0 0.8 95.0 5.0
6.0 0.8 10.0 90.0
12.0 0.8 10.0 90.0
5 Analytical SFC Conditions:
Method A
Column: Chiralcel OX-H
Mobile Phase: 30% Methanol in CO2
Temperature: 40 °C 10 Run Time: 10.0 min Detection: 210 ran
Method B
Column: Chiralpak IC
Mobile Phase: 30% Methanol in CO2
15 Temperature: 40 °C Run Time: 8.0 min Detection: 215 ran
Method C
Column: Chiralcel OD-H
20 Mobile Phase: 25% Methanol in CO2
Temperature: 40 °C Run Time: 10.0 min Detection: 215 ran
PERK Viral Inhibition 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. The dependence on host protein synthesis machinery makes viral mRNAs sensitive to various stress-induced translation repression mechanisms. In support of this, mechanistic 10 studies of CoV infection have demonstrated that several cytokines and chemokines are transiently induced in vitro and in vivo. Importantly, SARS-CoV and MHV viral spike protein expression robustly induce ER stress and Cxcl2 mRNA transcription during infection as observed in vitro [Versteeeg et al., J. Virology. 2007], Continued efforts to abrogate spike protein-host interactions, including the use of neutralizing antibodies and mutated viral spike proteins that prevent spike protein 15 development, have demonstrated ER stress and more generally UPR (unfolded protein response) induction a key mechanism in viral infection and host-virus infections and pathogenesis.
To better define the mechanisms driving viral infection, laboratories have studied and demonstrated that 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). 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). 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],
Accumulation of misfolded protein and the ensuing induction of ER stress, also referred to as 30 proteotoxicity, contributes to the etiology of diseases including diabetes, cancer, neurodegenerative disorders and viral infection [Schroder & Kaufman, Annu Rev Biochem., 2005; Marciniak & Ron, Physiol Rev., 2006; Wek & Cavener, Antioxid Redox Signal, 2007; Oakes, American J. Pathol., 2020; Jordan et al., 2002; Baltzis et al., 2004; Cheng et al., 2005], Viruses have adopted counter measures that inhibit PERK-mediated translation attenuation via direct binding and inhibition of the kinase activity of PERK, which restores viral protein translation [Pavio et al., 2003; Mulvey et al., 5 2007], Translation attenuation has been widely observed as a defense mechanism employed by host cells to prevent viral infection. By reducing protein translation of the viral proteins, virus replication is hampered and the spread of infection is paused, providing time for the immune system to mount an effective antiviral response [Fung & Liu, Frontiers in Microbiology, 2014],
Separately, it has been demonstrated that SARS-CoV infections result in PKR, PERK, and 10 eIF2a phosphorylation events that are readily detectable in virus-infected cells [Krahling et al., 2009], Their knock-down of PKR via morpholino oligomers did not impact SARS-CoV-induced eIF2a phosphorylation but did significantly inhibit SARS-CoV-induced apoptosis [Krahling et al., 2009], One hypothesis is that eIF2a is phosphoiylated by PERK in SARS-CoV-infected cells, a hypothesis that is supported by the overexpression of SARS-CoV accessory protein 3a that has been shown to 15 activate the PERK pathway [Minakshi et al., 2009],
Accordingly, without wishing to be bound by theory, it is contemplated that 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.
Abbreviations:
NMR: nuclear magnetic resonance; mHz: megahertz; DMSO-d6: dimethyl sulfoxide-de;
25 CDCb: deuterated chloroform;
5: chemical shift;
MS: mass spectrometry;
HPLC: high performance liquid chromatography;
SFC: Supercritical fluid chromatography
30 mlz\ mass-to-charge ratio;
[M+H]: molecular ion peak in mass spectrum; ESI: electrospray ionization;
Ε8Γ: electrospray ionization positive mode;
ESI': electrospray ionization negative mode; rt orRT: room temperature:
5 min: minute(s); h: hour(s) mg: milligram; g: gram; kg: kilogram;
10 mL: milliliter;
L: liter; mmol: millimole; μΜ: micromole;
MTBE: methyl tert-butyl ether;
15 THF: tetrahydrofuran;
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;
20 Pd(dppf)Cl2: [1,1 ’-bis(diphenylphosphino)ferrocene]dichloropalladium(II);
EDC : 1 -ethyl-3 -(3-dimethyIaminopropyI) carbodiimide.
Rh/C: Rhodium on Carbon catalyst.
Scheme A:
Figure imgf000066_0001
25
Compounds of Formula A-2 where Ar2 = phenyl and R2 = 3 -methyl can be synthesized as described below for compound A-2.1: O xx.
Figure imgf000067_0001
ή
KOAc, dioxane 95 °C, 4 h XX NH2
A-1.1 A-2.1
Synthesis of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1):
O έ
XX NH2
To a stirred solution of tricyclohexylphosphine (7.18 g, 25.7 mmol) in 1,4-dioxane (1.2 L)
5 under aigon atmosphere were added bis(pinacolato)diboron (89.62 g, 352.9 mmol) and potassium acetate (62.98 g, 641.7 mmol), followed by 4-bromo-3-methylaniline (A-l.l, 60.00 g, 320.8 mmol). 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 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,
15 44.80 g, yield: 60%) as a pale brown solid: ESI (m/z) 234 [C13H20BNO2 + H]+.
The compounds of formula A-2 (Table A) can be synthesized according to the procedures described for compound A-2.1:
Table A: Compounds A-2:
Compound Structure MS 3-methyl-4-(4, 4, 5,5- tetramethyl -1,3,2- ESI (m/z) 234
A-2.1 dioxaborolan-2-yl)aniline [C13H20BNO2 +
H]+
4-(4, 4, 5,5-tetramethyl- 1 ,3,2- E
Figure imgf000068_0001
220 dioxaborolan-2-yl)aniline [C12H18BNO2 +
A-2.2
H]+
3-fluoro-4-(4, 4, 5,5- ESI (m/z) 238 tetramethyl -1,3,2- [C12H17BFNO2
A-2.3 dioxaborolan-2-yl)aniline + H]+
3-chloro-4-(4, 4, 5,5- ESI (m/z) 253, tetramethyl -1,3, 2- 255
A-2.4 dioxaborolan-2-yl)aniline [C12H17BCINO2 + H]+
4-(4, 4, 5,5-tetramethyl- 1 ,3,2- ESI (m/z) 304 dioxaborolan-2-yl)-3 - [C13H17BF3NO3
A-2.5 (trifluoromethoxy)aniline + H]+
4-(4,4,5,5-tetramethyl-l,3,2- ESI (m/z) 288 dioxaborolan-2-yl)-3 - [C13H17BF3NO2
A-2.6 (trifluoromethyl)aniline + H]+
3 -ethy l-4-(4,4, 5, 5-tetram ethyl- ESI (m/z) 248 1, 3, 2-dioxaborolan-2- [C14H22BNO2 +
A-2.7 yl)aniline H]+
Figure imgf000068_0002
3-methoxy-4-(4, 4,5,5- ESI (m/z) 250 tetramethyl-1,3,2- [C13H20BNO3 +
A-2.8 dioxaborolan-2-yl)aniline H]+
Figure imgf000069_0001
Scheme B:
Figure imgf000069_0002
B-1 B-2
Compounds of Formula B-2 where Ar1 = 3 , 5 -difluoropheny 1 and R3a = H can be synthesized as described below for compound B-2.1:
F F
Amano Lipase (PS)
O Immobilized on Diatomite O
F H Vinyl acetate, MTBE, 96 h F iH iH OH
B-1.1 B-2.1
5
Synthesis of (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid (B-2.1):
F
O
F iH
OH
To a stirred solution of Amano lipase (PS) supported on Diatomite (5.0 g; purchased from Sigma-Aldrich) in methyl fert-butyl ether (MTBE, 50 mL) were added 2-(3,5-difluorophenyl)-2- 10 hydroxy acetic acid (B-1.1, 2.50 g, 13.3 mmol) and vinyl acetate (5.37 g, 62.5 mmol). The reaction mixture was allowed to stir for 96 h. After this time, the supported enzyme was filtered off and washed with methyl fert-butyl ether (12 mL). The filtrate was concentrated under reduced pressure. The residue was stirred in methylene chloride (2.5 mL) for 10 min. The resulting white solid was isolated by filtration, washed with methylene chloride (2 mL), and dried under vacuum to obtain pure 15 (R)-2-(3 , 5 -difluoropheny l)-2-hydroxy acetic acid (B-2.1, 850 mg, yield: 34%): lH NMR (400 MHz, DMSO-d6) δ 7.18-7.10 (m, 3H), 5.10 (s, IH); ESI (m/z) 187 [CgHeFiCb-H]'; SFC (chiral) purity >99%. The compounds of formula B-2 (Table B) can be synthesized according to the procedures described for compound B-2.1:
Table B: Compounds B-2:
Compound Name Structure MS
(R)- 2-(3,5- F ESI (m/z): 187 difluorophenyl)-2- O
B-2.1 [CgHfiFlOs-H]· hydroxyacetic acid F iH
OH
Figure imgf000070_0001
Compounds of Formula C-3 where Ar2 = phenyl, R2 = 3-F, Y2 = Br, R3a = H, Ar1 = phenyl-R1 and R1 = 3-F can be synthesized as described below for compound C-3.1:
Figure imgf000070_0002
Step-1: Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-1.1):
O
Λο
F. .OH
10 To a stirred solution of acetyl chloride (1.0 mL) at 0 °C was added 2-(3 -fluoropheny l)-2- hydroxy acetic acid (B-1.2, 0.601 g, 3.53 mmol) portion wise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated to crude under vacuum and co-di stilled with hexanes to afford 2-acetoxy-2-(3 -fluorophenyl)acetic 5 acid (C-l.l, 0.70 g, yield: 94%) as a white solid: ESI (m/z) 211 [C10H9FO4-H]'.
Step-2: Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-l-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1):
Figure imgf000071_0001
To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-l.l, 0.558 g, 2.63 mmol) and 4- 10 bromo-3 -fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added Nfl- diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1 -[bis(dimethylamino)m ethylene]- \H- 1 ,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h. After this time, the 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. The crude product was purified by column chromatography (silica gel, 4% methanol/dichloromethane) to afford 2-((4-bromo-3 -fluoropheny l)amino)- 1 -(3 -fluoropheny l)-2-oxoethyl acetate (C-2.1, 500 mg, yield: 60%) as a pale brown solid: ESI (m/z) 385 [CieHizBrFzNOs]"1".
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):
Figure imgf000071_0002
To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-l-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bi s(pinacol ato)diboron (0 13 g 052 mmol) and potassium acetate (51 mg 052 mmol The 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 5 temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 x 15 mL). The filtrate was washed with water (2 x 10 mL) and brine (2 x 10 mL). The organic layer was 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 2-((3-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-l-(3-fluorophenyl)-2-oxoethyl acetate 10 (C-3.1, 50 mg, yield: 60%) as a pale brown solid: ESI (m/z) 432 [C22H24BF2NO5 + H]+.
The compounds of formula C-3 (Table C-l) can be synthesized according to the procedures described for compound C-3.1:
Table C-l: Compounds C-3:
Compound Name Structure MS
2-((3-fluoro-4-(4, 4,5,5- F ESI (m/z) 432 o tetramethyl-1,3,2- b. o \ [C22H24BF2NO5 + dioxaborolan-2- F H X H]÷
C-3.1 yl)phenyl)amino)- 1 -(3 - fluorophenyl)-2-oxoethyl acetate
1 -(3-fluorophenyl)-2-((3- ESI (m/z) 428 methyl-4-(4, 4,5,5- [C23H27BFNO5+ tetramethyl- 1,3,2- H]÷
C-3.2 dioxaborolan-2- yl)phenyl)amino)-2- oxoethyl acetate
Figure imgf000072_0001
Figure imgf000073_0001
2-((3-chloro-4-(4, 4,5,5- ESI (m/z) 463 tetramethyl-1,3,2- [C22H24BCI2NO5 +
Cl dioxaborolan-2- H]÷
C-3.9 o yl)phenyl)amino)- 1 -(3 - Cl
9 chlorophenyl)-2-oxoethyl lAc acetate
2-((3-chloro-4-(4, 4,5,5- ESI (m/z) 497 tetramethyl-1,3,2- [C23H24BCIF3NO5
F
F. F dioxaborolan-2- 10 yl)phenyl)amino)-2-oxo- 1 - vi + H]+
C-3. s O
Cl
(3- 9 lAc
(trifluoromethyl)phenyl)eth yl acetate
2-((3-chloro-4-(4, 4,5,5- ESI (m/z) 443 tetram ethyl-1, 3,2- [C23H27 -3.11 dioxaborolan-2- vis BCINO5 +
C o H]+
N yl)phenyl)amino)-2-oxo- 1 - ci
H >Ac (o-tolyl)ethyl acetate
2-((3-chloro-4-(4, 4,5,5- ESI (m/z) 443 tetramethyl- 1,3,2- O [C23H27BCINO5 + c-3.12 dioxaborolan-2- l)amino)-2-oxo- 1 - = HT yl)pheny ,XXJ lAc (wi-tolyl)ethyl acetate
2-((3-chloro-4-(4, 4,5,5- ESI (m/z) 457 tetramethyl- 1,3,2- [C24H29BCINO5 +
•O dioxaborolan-2- H]+
C-3.13 yl)phenyl)amino)- 1 -(3 - ethylphenyl)-2-oxoethyl acetate 'χσ lAc
Figure imgf000075_0001
Scheme C-2:
Figure imgf000076_0001
Compounds of Formula C-3 where Ar2 = phenyl, R2 = 3-CH3, Y2 = Br, R3a = H, Ar1 = phenyl -R1 and R1 = 3 -Cl can be synthesized as described below for compound C-3.16:
Figure imgf000076_0002
Step-1: Synthesis of3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolaii-2-yl)aniline (A-2.1):
Figure imgf000076_0003
To a stirred solution of 44-bromo-3 -methylaniline (A-1.1, 50.00 g, 268 mmol) in triethyl amine (500 mL) under argon atmosphere were added bis(pinacolato)diboron (81.03 g, 321 mmol)
10 and potassium acetate (70.80 g, 804 mmol). The reaction mixture was purged with argon for 15 min. Pd(PPli3)2Cl2 (9.40 g, 13.4 mmol) was added, and the mixture was purged with argon for 10 min. The reaction mixture was heated at 90 °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 dichloromethane (3 * 500 mL). The filtrate was washed with water (2 * 500 mL) and 15 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 -methy l-4-(4,4, 5 , 5 -tetramethy 1- 1,3,2- dioxaborolan-2-yl)aniline (A-2.1, 40.03 g, yield: 63%) as a white solid. LH NMR (400 MHz, DMSO-<fc): δ 7.32 (d, J - 8.0 Hz, 1H), 6.30 (t 7.2 Hz, 2H), 2.30 (s, 3H), 1.24 (s, 12H); ESI 20 (m/z) 234 [C13H20BNO2 + H]+. 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):
Figure imgf000077_0001
C-3.16
To a stirred solution of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A- 5 2.1, 10.03 g, 42.9 mmol) and 2-acetoxy-2-(3 -chlorophenyl)acetic acid (Cl-1.1, 10.70 g, 47.2 mmol) in dichloromethane (200 mL) were added N.A'-diisopropylethylamine (22.40 mL, 128 mmol) followed by propylphosphonic anhydride (T3P) (50% in EtOAc) (41.00 mL, 64.3 mmol) at 0 °C. The 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). The organic layer was separated, washed with water (200 mL) followed by brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford l-(3- chlorophenyl)-2-((3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-2- oxoethyl acetate (C-3.16, 15.00 g, yield: 75%) as off white solid. ‘H NMR (400 MHz, DMSO-dfe): δ 7.70 (t, J = 7.2 Hz, 1H), 7.52-7.42 (m, 1H), 7.43-7.36 (m, 2H), 7.28-7.23 (m, 1H), 6.22 (s, 1H), 15 2.17 (s, 3H), 1.38 (s, 12H); ESI ( m/z ) 444 [C23H27BCINO5 + H]+.
The compounds of formula C-3 (Table C-2) can be synthesized according to the procedures described for compound C-3.16:
Table C-2: Compounds C-3:
Compound Name Structure MS
2-((3-methyl-4- ESI (m/z) 424 (4,4,5,5-tetramethyl- [C24H30BNO5 + 1 ,3 ,2-dioxaborolan-2- o H]+
C-3.17 yl)phenyl)amino)-2- N
H oxo- 1 -(o-tolyl)ethy 1 (Ac acetate
Figure imgf000078_0001
yl)phenyl)amino)-2- oxoethyl acetate
2-((3-methyl-4- ESI (m/z) 431 (4,4,5,5-tetramethyl- [C21H27BN2O5S + 1 ,3 ,2-dioxaborol an-2- H]+
C-3.23 yl)phenyl)amino)- 1 - (2-methylthiazol-4- yl)-2-oxoethyl acetate
H3,5- ESI (m/z) 432 difluorophenyl)-2- [C22H24BF2NO5 + oxo-2-((4-(4, 4,5,5- F H]+
C-3.24 tetramethyl- 1,3,2- o
N •F dioxaborolan-2- H yl)phenyl)amino)ethy 1 acetate
2-((3 -chloro-2-fluoro- ESI (m/z) 483 4-(4, 4,5,5- [C22H22BCIF3NO5 tetra ethyl- 1,3,2- F + H]+
C-3.25 dioxaborolan-2- o ci N F yl)phenyl)amino)- 1 - H )Ac (3 , 5 -difluoropheny 1)- 2-oxoethyl acetate
2,2-difluoro-N-(3- ESI (m/z) 388 methyl-4-(4, 4,5,5- [C21H24BF2NO3 + tetramethyl- 1,3,2- H]+
C-3.26 dioxab ■& o orolan-2- N
H yl)phenyl)-2- F phenyl acetamide
Figure imgf000080_0001
Scheme D:
Ar1
Figure imgf000080_0002
Compounds of Formula D-l where Ar2 = phenyl, R2 = 3 -methyl, R3a = H, Ar1 = phenyl-R1 and R1 = 5 3-F can be synthesized as described below for compound D-l.l : B-1.2 F o
Hi
•O F έ o
XI HATU, DIPEA, THF, rt N
NH2 H
>H
A-2.1 D-1.1
Synthesis of 2-(3-fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4^,5-tetramethyl-13,2- dioxaborolan-2-yl)phenyl)acetamide (D-1.1):
F
O
N
H iH
5 To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1, 0.298 g, 1.28 mmol) and 2-(3-fluorophenyl)-2-hydroxyacetic acid (B-1.2, 0.196 g, 1.15 mmol) in tetrahydrofuran (10 mL) were added #,N-diisopropylethylamine (0.26 mL, 1.5 mmol) followed by l-[bis(dimethylamino)methylene]-l/7-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU) (0.586, 1.54 mmol) at 0 °C. The 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. The crude product was purified by column chromatography (silica gel, 4% methanol/dichloromethane) to afford 2-(3-fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- 15 yl)phenyl)acetamide (D-1.1, 0.25 g, yield: 52%) as a pale brown solid: ESI (m/z) 386 [C2IH25BFN04 + H]+.
The compounds of formula D-l (Table D) can be synthesized according to the procedures described for compound D-1.1:
Table D: Compounds D-l:
Compound Name Structure MS 2-(3 -fluorophenyl)-2- hydroxy-Y-(3 -methyl-4- ESI (m/z) 386
D-l.l (4,4,5,5-tetramethyl- [C2lH2sBFN04+H]+ 1 ,3 ,2-di oxaborolan-2- yl)phenyl)acetamide
Scheme IE:
Figure imgf000082_0001
Compounds of Formula IE-5 can be synthesized according to the procedures described in Scheme IE wherein R5 = NHz, X = CH, Y4 = Br, R88 = cyclopropyl, R8b = H, R2 = 3-methyl, Ar2 = phenyl,
5 R4 = H, R3a = H, Ar1 = 3 , 5 -difluorophenyl can be synthesized as described below for compound 1E-
5.1:
1 E-2.1
.6 A-2.1
Figure imgf000083_0001
Step-1: Synthesis of 2-amino-5-bromo-AT-cyclopropylpyridine-3-carboxamide (IE-3.1):
Figure imgf000083_0002
5
To a suspension of 2-amino-5-bromonicotinic acid (IE-1.1, 10.0 g, 46.0 mmol) in tetrahydrofuran (100 mL) at 0 °C was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (8.57 g, 55.3 mmol), hydroxybenzotriazole (7.46 g, 55.3 mmol), and A^-diisopropylethylamine (16.0 mL, 92.2 mmol). After 15 min, cy cl opropanamine (1 E-2.1, 3.80 mL, 55.3 mmol) was added, and the 10 resulting mixture was stirred at room temperature for 16 h. After this time, the 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. The crude material was purified by column chromatography (silica gel, 30% ethyl acetate/hexanes) to afford 2-amino-5-bromo-N-cyclopropylnicotinamide (IE-3.1, 8.0 g, yield: 68%) : 'H NMR (400 15 MHz, DMSO-i&) 5 8.49 (br s, IH), 8.13 (d, J - 2.4 Hz, IH), 8.03 (d, J - 2.4 Hz, IH), 7.26 (br s, 2H), 2.81-2.77 (m, IH), 0.69 (m, 2H), 0.56 (m, 2H); ESI (m/z) 256 [C9HioBrN30 + H]+.
Step-2: Synthesis of 2-amino-5-(4-amino-2-methyl-phenyl)-N-cyclopropylpyridine-3- carboxamide (IE-4.1): H2N N,
IH
NH2
V"
A stirred solution of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1, 6.53 g, 28.0 mmol) and 2-amino-5-bromo-N-cyclopropylnicotinamide (IE-3.1, 6.50 g, 25.5 mmol) 5 in 1,4-dioxane (60 mL) and water (20 mL) was degassed with nitrogen gas for 10 min. Potassium carbonate (10.50 g, 76.4 mmol) was added, and the mixture was purged with nitrogen gas for 5 min. [l,l'-Bis(diphenylphosphino)fenOcene]dichloropalladium(n) (1.50 g, 2.04 mmol) was added, and the mixture was purged with nitrogen gas for 5 min. The mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. After this time, reaction mixture was allowed to cool to room
10 temperature, filtered through a bed of diatomaceous earth and washed with ethyl acetate (2 χ 100 mL). The filtrate was washed with water (2 x 100 mL) and brine (100 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, 70% ethyl acetate/hexanes) to afford 2-amino-5-(4-amino-2-methylphenyl)-j|V-cyclopropylnicotinamide (IE-4.1, 5.30 g, yield:
15 74%) as a light brown solid: Ή NMR (400 MHz, DMSCMO δ 8.38 (d, J - 3.6 Hz, 1H), 7.96 (d, J
- 2.0 Hz, 1H), 7.78 (d, J - 2.4 Hz, 1H), 7.04 (br s, 2H), 6.87 (d, J - 8.0 Hz, 1H), 6.47-6.43 (m, 2H), 5.03 (br s, 2H), 2.83-2.78 (m, 1H), 2.10 (s, 3H), 0.69-0.64 (m, 2H), 0.55-0.53 (m, 2H); ESI (m/z) 283 [CieHielSUO + H]+.
Step-3: Synthesis of (R)-2-amino-iV-cyclopropyl-5-(4-{2-(3,5-difluorophenyl)-2-
20 hydroxyacetamido)-2-methylphenyl)nicotinamide (Example 14: IE-5.1): h2N N
F
O
IH
F
V" H IH
To a solution of 2-amino-5-(4-amino-2-methylphenyl)-7/-cyclopropylnicotinamide (IE-4.1, 5.30 g, 18.7 mmol) and (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid (B-l.l, 3.70 g, 19.7 mmol)
25 in THF (55 mL) were added N^-diisopropylethylamine (6.50 mL, 37.4 mmol) followed by 1- [bis(dimethylamino)methylene]-17f-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU, 8.54 g, 22.4 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 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 x 80 mL) and brine (2 x 75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and 5 concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90% ethyl acetate/hexanes) followed by reversed phase chromatography (Cl 8, 60% acetonitrile/water) to afford (R)-2-ami no-A-cycl opropyl-5-(4-(2-(3 , 5-difluorophenyl)-2- hydroxyacetamido)-2-methylphenyl)nicotinamide (IE-5.1, 1.20 g, yield: 14% with 98.8% chiral purity and 2.80 g impure material with 90% chiral purity) as an off white solid: !H NMR (400 MHz, 10 DMSO-d6) δ 9.96 (br s, IH), 8.41 (d, J - 4.0 Hz, IH), 8.03 (d, J - 2.8 Hz, IH), 7.84 (d, /- 2.4 Hz, IH), 7.61 (d, J = 2.0 Hz, IH), 6.87 (dd, / = 8.0 Hz, 2.0 Hz, IH), 7.24-7.20 (m, 2H), 7.19-7.15 (m, 4H), 6.74 (d, J - 5.2 Hz, IH), 5.17 (d, J - 4.8 Hz, IH), 2.82-2.77 (m, IH), 2.12 (s, 3H), 0.69-0.64 (m, 2H), 0.55-0.53 (m, 2H); ESI (m/∑) 453 [C24H22F2N403+H]+; HPLC (Method C) 97.0% (AUC), t« = 8.72 min; Chiral SFC (Chiralcel OD-H, Method C) 98.8% (AUC), tR = 3.40 min.
15 Scheme 2E:
Figure imgf000085_0001
Compounds of Formula 2E-5 can be synthesized according to the procedures described in Scheme 2E wherein R5 = NH2, X = CH, Y4 = Br, Rte = methyl, R8b = H, R2 = 3-methyl, Ar2 = phenyl, R4 = H, R3a = H, Ar1 = 3,5-difluorophenyl can be synthesized as described below for compound 2E-5.1:
B-1.1
Α-2.1 F
Κϊ O
Figure imgf000086_0002
j
2E-1.1 55 "C, 12 h 2E-2.1
Figure imgf000086_0001
2E-6.1
5 Step-1: Synthesis of methyl 2-Amino-5-(4-amino-2-methylphenyl)nicotmate (2E-2.1):
N,
°JU
NHj
A stirred solution of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1, 15.20 g, 65.50 mmol) and methyl 2-amino-5-bromonicotinate (2E-1.1, 10.09 g, 43.66 mmol) in 1,4- dioxane (75 mL) and water (25 mL) was degassed with nitrogen for 10 min. Potassium carbonate 10 (18.07 g, 131.0 mmol) was added, and the mixture was purged with nitrogen for 5 min. [1,1 -
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Ch, 1.60 g, 2.18 mmol) was added, and the mixture was purged with nitrogen for 5 min. The reaction mixture was stirred at 55 °C under nitrogen for overnight. After this time, the reaction mixture was allowed to cool to room temperature, filtered through a bed of diatomaceous earth, and washed with ethyl acetate (2 χ 75 mL). 15 The filtrates were combined and washed with water (2 * 50 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 45% ethyl acetate/hexanes) to afford methyl 2-amino-5-(4-amino-2-methylphenyl)nicotinate (2E-2.1, 7.7 g, yield: 68%) as yellow solid: ESI (m/z): 258 [C14H15N3O2 + H]+.
5 Step-2: Synthesis of methyl 2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2 methylphenyl)nicotinate (2E-3.1):
Figure imgf000087_0001
To a solution of methyl 2-amino-5-(4-amino-2-methylphenyl)nicotinate (2E-2.1, 11.0 g, 42.8 mmol) and 2-(3,5-difluorophenyl)-2-hydroxy acetic acid (B-l.l, 8.05 g, 42.8 mmol) in tetrahydrofuran (220 10 mL) were added MN-diisopropylethylamine (DIPEA, 15.0 mL, 85.6 mmol) followed by 1- [bis(dimethylamino)methylene]-l/M,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU, 19.5 g, 51.4 mmol) at 0 °C. 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 ¾ 75 mL) and 15 brine (2 * 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 40% ethyl acetate/hexanes) to afford methyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)- 2-methylphenyl)nicotinate (2E-3.1, 8.0 g, yield: 44%) as a yellow solid: ESI (m/z): 428 [C22H19F2N3O4 -HH]+.
20 Step-3: Synthesis of 2-amino-5-(4-(2-(3,5-difIuorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinic acid (2E-4.1):
HjN ,N.
F
O
N F
H
To a solution of methyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinate (2E-3.1, 8.01 g, 18.7 mmol) in a mixture of tetrahy drofuran:methanol : water 25 (5:3:2, 80 mL) was added lithium hydroxide monohydrate (1.18 g, 28.1 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. After this time, the reaction mixture was concentrated under reduced pressure The crude material was acidified with 2N hydrochloric acid solution and stirred for 15 min. The solids were filtered and washed with methyl tert- butyl ether (40 mL) to give 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinic acid (2E-4.1, 5.8 g, yield: 75%) as a pale yellow solid: ESI (m/z): 414 [C2IHI7F2N304+H]+.
5 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):
Figure imgf000088_0001
Example 10 Example 11
To a solution of 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinic acid (2E-4.1, 0.40 g, 0.96 mmol) and methyl amine hydrochloride (0.098 g, 10 1.45 mmol) in tetrahydrofuran (8 mL) were added N,N-diisopropyl ethyl amine (DIPEA, 0.40 mL,
2.4 mmol) followed by l-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU, 0.441 g, 1.16 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for overnight. After this time, the reaction mixture was concentrated under reduced pressure. The crude material was diluted with ethyl acetate (20 mL)
15 and washed with water (2 x 15 mL) and brine (2 x 15 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 50% ethyl acetate/hexanes) followed by reversed phase chromatography (Cl 8, 52% acetonitrile/water) to afford methyl 2-amino-5-(4-(2-(3,5- difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-methylnicotinamide (2E-5.1, 0.16 g,
20 yield: 39%) as an off-white solid: ESI (m/∑): 427 [C22H20F2N4O3 +H]+.
The mixture of enantiomers was purified by chiral supercritical fluid chromatography (SFC) (Chiralcel® OX-H column, 30% methanol in CO2, 40 °C temperature) to afford:
Isomer 1 (Example 10) as an off-white solid: 'HNMR(400 MHz, DMSO-d6) δ 9.95 (s, IH), 842 (d J = 40 Hz IH) 803 (d J= 1 6 Hz IH) 784 (s IH) 760 (s IH) 7 57 (d J= 84 Hz IH) 7.24-7.03 (m, 6H), 6.72 (d, 4.8 Hz, IH), 5.18 (d, J= 4.8 Hz, IH), 2.73 (d, 4.4 Hz, 3H), 2.22
(s, 3H); ESI ( M/Z): 427 [C22H20F2N4O3 +H]+; HPLC (Method B) >99% (AUC), tR = 7.11 min; Chiral SFC (Chiralpak IC, Method B) >99% (AUC), tR = 2.17 min.
Isomer 2 (Example 11) as an off-white solid: 1HNMR(400 MHz, DMSO-d6) δ 9.97 (s, IH), 5 8.53 (d,J= 4.0 Hz, 1H), 8.06 (d, J = 2.0Hz, 1H), 7.98 (s, 1H), 7.62 (s, IH), 7.59 (d,J= 8.8 Hz, IH),
7.46-7.15 (m, 6H), 6.73 (d, J= 4.8 Hz, 1H), 5.18 (d, J = 4.8 Hz, IH), 2.74 (d, J= 4.4 Hz, 3H), 2.23 (s, 3H); ESI (m/z): 427 [C22H20F2N4O3 +H]+; HPLC (Method B) 98.1% (AUC), tR = 7.10 min; Chiral SFC (Chiralpak IC, Method B) >99% (AUC), tR = 3.36 min.
Table E-l: Compounds 2E-4:
Figure imgf000089_0001
Figure imgf000090_0001
Scheme 3E:
Figure imgf000091_0001
Compounds of Formula 3E can be synthesized according to the procedures described in Scheme 3E wherein R5 = NH2, X = CH, Y4 = Br, R8a = Isopropyl, R8b = H, R2 = 3-Cl, Ar2 = phenyl, R3a = H,
Ar1 = 3,5-difluorophenyl can be synthesized as described below for compound 3E.3.1:
5
Figure imgf000091_0002
Synthesis of (R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)- N-isopropylnicotinamide (Example 34) and (S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-
2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide (Example 35):
10
Figure imgf000091_0003
A stirred solution of 2-amino-5-bromo-N-isopropylnicotinamide (3E-3.1, 0.50 g, 1.9 mmol) and 2-((3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-l-(3,5- difluorophenyl)-2-oxoethyl acetate (C-3.6, 1.0 g, 2.3 mmol) in a mixture of 1,4-dioxane and water 5 (3:1, 20 mL) was purged with argon for 5 min. Potassium carbonate (0.53 g, 3.8 mmol) was added, followed by [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.056 g, 0.077 mmol.), and the mixture was purged with argon for 10 min. The resulting reaction mixture was heated to 90 °C 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 ethyl acetate (2 * 15 mL). The filtrate was 10 washed with water (15 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (C18, 35% acetonitrile/water) to afford 2-amino-5-(2-chloro-4-(2-(3,5- difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide (I-E.3, 150 mg, yield: 18%) as a mixture of enantiomers as an off-white solid: ESI (m/z) 475 [C23H21CIF2N4O3 + H]+.
15 The mixture of enantiomers was purified by chiral supercritical fluid chromatography (SFC) (Chiralpak IC column, 30% methanol in CO2, 40 °C temperature).
Isomer 1 (Example 34) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 7.6 Hz, 2H), 8.11 (d, J = 2.4 Hz, 2H), 8.02 (d, J = 2 Hz, 2H), 7.94 (d, J= 2 Hz, 1H), 7.74 (d, J= 2.4 Hz, 2H), 7.72 (d, J= 2 Hz, 2H), 7.42 (s, 1H), 7.40 (s, 1H), 7.24-7.15 (m, 10H), 6.81 (d, J= 2 Hz, 20 2H), 5.20 (d, J = 5.2 Hz, 2H), 4.10-4.03 (m, 1H), 1.14 (d, J = 6.4 Hz 6H); ESI (m/z) 475
[C2.3H21CIF2N4O3 + H]+; HPLC (Method C) 98.1% (AUC), tR = 9.28 min; Chiral SFC (Chiralpak IC, Method B) 96.2% (AUC), (R = 1.85 min.
Isomer 2 (Example 35) as off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J - 7.6 Hz, 2H), 8.11 (d, J = 2.4 Hz, 2H), 8.02 (d, J = 2 Hz, 2H), 7.94 (d, J= 2 Hz, 1H), 7.74 (d, J= 2.4 25 Hz, 2H), 7.72 (d, J= 2 Hz, 2H), 7.42 (s, 1H), 7.40 (s, 1H), 7.24-7.15 (m, 10H), 6.81 (d, J= 2 Hz, 2H), 5.20 (d, J = 5.2 Hz, 2H), 4.10-4.03 (m, 1H), 1.14 (d, J =6.4 Hz, 6H); ESI (m/z) 475 [C23H2IClF2N403+H]+; HPLC (Method C) 95.6% (AUC), tR = 9.30 min; Chiral SFC (Chiralpak IC, Method B) 92.6% (AUC), tR = 2.51 min.
Scheme 4E:
Figure imgf000093_0001
Compounds of Formula 4E-6 can be synthesized according to the procedures described in Scheme 4E wherein R5 = NHCH3, Y4 = Br, R4 = H, R2 = 3-CH3, Ar2 = phenyl, R3a = H, Ar1 = 3,5- 5 difluorophenyl can be synthesized as described below for compound 4E-6.1 :
Figure imgf000093_0002
Step-1: Synthesis of 2-chloro-l-(3,5-difluorophenyl)-2-oxoethyl acetate (4E-4.1):
Figure imgf000094_0002
To a stirred solution of 2-acetoxy-2-(3,5-difluorophenyl)acetic acid (4E-3.1, 0.60 g, 2.60 mmol) in dichloromethane (6.0 mL), oxalyl chloride (0.671 mL, 7.82 mmol) was added drop-wise. 5 After addition completed, the reaction mixture was stirred for 5 h at room temperature. After this time, the solvent was concentrated under reduced pressure to afford 2-chloro-l-(3,5- difluorophenyl)-2-oxoethyl acetate (4E-4.1, 0.65 g crude)as an off white solid, which was taken to next step without any purification.
Step-2: Synthesis of 5-(4-amino-2-methylphenyl)pyridin-2-amme (4E-2.1):
10
Figure imgf000094_0001
To a stirred solution of 5-bromopyridin-2-amine (4E-1.1, 1.00 g, 5.81 mmol), 3 -methyl -4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-2.1, 2.03 g, 8.72 mmol) in 1,4-dioxane (7 mL): H2O (3 mL) was added K2CO3 (2.0 g, 14.53 mmol). After addition completed, resulting reaction mixture was purged with N2 gas for 5 min. then PdCl2 (dppf) (0.21 g, 0.29 mmol) was 15 added and again purged with N2 gas for 1 min. The reaction mixture was sealed and heated at 110 °C for 24 h. After this time the reaction mixture was allowed to cool to room temperature, filtered through celite bed, washed with EtOAc (100 x 2 mL). The filtrate was washed with H2O (100 x 2 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2S O4 and concentrated under reduced pressure. The crude was purified by column chromatography (silica 20 gel, 70% ethyl acetate in hexanes) to afford 5-(4-amino-2-methylphenyl)pyridin-2-amine (4E-2.1, 0.52 g, yield 45%) as an off white solid; ESI (m/z) 200 [C12H13N3 + H] + . Step-3: Synthesis of 2-((4-(6-aminopyridm-3-yl)-3-methylphenyl)amino)-l-(3,5-difluoro phenyl)-2-oxoethyl acetate (4E-5.1):
Figure imgf000095_0002
To a stirred solution of 5-(4-amino-2-methylphenyl)pyridin-2-amine (4E-2.1, 0.50 g, 2.51 5 mmol) in dichloromethane (5 mL), pyridine (1.01 mL, 12.56 mmol) was added at 0 °C followed by drop-wise addition of 2-chloro- 1 -(3,5-difluorophenyl)-2-oxoethyl acetate (4E-4.1, 0.68 g, 2.76 mmol) at same temperature. After addition, completed resulting reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mass was diluted with sat NaHCO3 (50 mL), and an aqueous layer extracted with EtOAc (2 * 50 mL). The combined organic layer was 10 dried over Na2S04 and concentrated under reduced pressure to obtain crude material. The obtained crude material was purified by column chromatography (silica gel, 50% to 70% ethyl acetate in hexanes) to afford 2-((4-(6-aminopyridin-3 -yl)-3 -methy lpheny l)amino)- 1 -(3 ,5-difluoropheny l)-2- oxoethyl acetate (4E-5.1, 0.39 g, yield: 38%); ESI (m/z) 412 [C22H19F2N3O3 + H]+.
Step-4: Synthesis of N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2- 15 hydroxyacetamide (I-E.4):
Figure imgf000095_0001
To a stirred solution of 2-((4-(6-aminopyridin-3-yl)-3-methylphenyl)amino)-l-(3,5- difluorophenyl)-2-oxoethyl acetate (4E-5.1, 0.39 g, 0.94 mmol) in MeOH (5.0 mL), K2CO3 (0.39 g, 2.84 mmol) was added portion wise at room temperature. After addition completed, resulting 20 reaction mixture was stirred for 4 h at room temperature. After this time, the solvent was concentrated under reduced pressure to afford viscous mass, which was diluted with water (20 mL). An aqueous layer extracted using EtOAc (2 * 20 mL). The combined organic layer was dried over Na2SC>4 and concentrated to obtain crude material, which was purified by column chromatography (silica gel, 50% to 70% ethyl acetate in hexanes) to afford N-(4-(6-aminopyridin-3-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxy acetamide (4E-6.1, 0.25 g, yield: 71%) as an off white solid; 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (brs, 1H), 7.84 7.83 (m, 1H), 7.58 7.52 (m, 2H), 7.36 7.33 (m, 1H), 7.25 7.15 (m, 3H), 7.08 (d, 7= 8.00 Hz, 1H), 6.72 (d, 7= 4.80 Hz, 1H),
5 6.48 (dd, 7= 0.80 , 8.40 Hz, 1H), 5.97 (brs, 2H), 5.17 (d, 7= 4.80 Hz, 1H), 2.20 (s, 3H); ESI (m/z)
370 [C20H17F2N3O2 + H]+.
The compounds of formula 4E (Table 4E) can be synthesized according to the procedures described for compound 4E-6.1 :
Table 4E: Compounds 4E:
Figure imgf000096_0002
10 Scheme 5E:
Figure imgf000096_0001
Compounds of Formula 5E-2 can be synthesized according to the procedures described in Scheme 5E wherein R5 = NHCH3, R4 = H, R2 = 3-CH3, Ar2 = phenyl, R8a = Isopropyl, R8b = H, R3a = H, Ar1 = 3,5-difluorophenyl can be synthesized as described below for compound 5E-2.1:
Figure imgf000097_0001
5 Synthesis of 5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methyIphenyI)-N-isopropyl- 2-(methylamino)nicotinamide (5E-2.1):
To a stirred solution of 5-(4-amino-2-methylphenyl)-N-isopropyl-2-methylnicotin amide (5E-1.1, 0.31 g, 1.04 mmol), 2-(3,5-difluorophenyl)-2-hydroxy acetic acid (B-l.l (racemic), 35.2, 0.26 g, 1.14 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (0.4 mL, 2.08 mmol), 10 HATU (0.470 g, 1.20 mmol) were added and resulting reaction mixture was stirred at room temperature for 16 h. After this time the reaction mass was diluted with sat NaHCO3 solution (50 mL), an aqueous layer extracted with dichloromethane (2 * 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude material, which was purified by column chromatography (silica gel, 20 % to 30% ethyl acetate in hexanes) to 15 afford 5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2-
(methylamino)nicotinamide (5E-2.1, 0.40 g, yield: 82%); 1H NMR (400 MHz, DMSO-d6): S 9.95 (brs, 1H), 8.24-8.17 (m, 2H), 8.13 (d, J= 2.00 Hz, 1H), 7.89 (d, J= 2.40 Hz, 1H), 7.62-7.57 (m, 2H), 7.24-7.15 (m, 4H), 6.73 (d ,J= 5.60 Hz, 1H), 5.19 (d, J= 4.80 Hz, 1H), 4.11-4.02 (m, 1H), 2.93 (d, J= 4.00 Hz, 3H), 2.20 (s, 3H), 1.14 (d, ./= 6.80 Hz, 6H); ESI (m/z) 469 [C25H26F2N4O3 +
20 H]+. The compounds of formula 5E (Table 5E) can be synthesized according to the procedures described for compound 5E-2.1:
Table 5E: Compounds 5E:
H
T
N,
N
H
Figure imgf000098_0001
5 Scheme 6E:
Figure imgf000099_0003
6E-7
Compounds of Formula 6E-5 can be synthesized according to the procedures described in Scheme 6E wherein R5 = NH2, X = CH, Y4 = Br, R8a = Isopropyl, R8b = H, R2 = 3-CH3, Ar2 = phenyl, R3a = 5 F, R3b = F, Ar1 = phenyl can be synthesized as described below for compound 6E-5.1 :
Figure imgf000099_0001
Step-1: Synthesis of 2-Amino-5-(4-amino-2-methyl-phenyl)-N-isopropyl-pyridine-3-carbox amide (6E-1.1):
Figure imgf000099_0002
6E-1.1
10
To a stirred solution of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A- 2.1, 25.20 g, 108.5 mmol), 2-amino-5-bromo-N-isopropyl-pyridine-3-carboxamide (A-2.1, 20.00 g, 77.5 mmol) in a mixture of 1,4-dioxane (225 mL): H20 (75 mL), was degassed with nitrogen gas for 10 min. Then K2CO3 (32.0 g, 232.5 mmol) followed by PdCl2(dppf) (4.50 g, 6.2 mmol) was added and resulting reaction mixture was purged with N2 gas for 5 min. After, this reaction mixture was heated to 90 °C for 4 h. The reaction mixture was allowed to cool to room temperature; the reaction mixture was filtered through celite bed, washed with EtOAc (100 x 2 mL). The filtrate was washed with H2O (100 x 2 mL) and brine (150 mL). The organic layer was dried over anhydrous 5 NazS04 and concentrated under reduced pressure to afford crude material, which was purified by column chromatography (silica gel, 80% EtOAc in hexanes) to afford 2-amino-5-(4-amino-2- methyl-phenyl)-A-isopropyl-pyridine-3-carbox amide (6E-1.1, 17.00 g, yield: 80%) as light brown solid; 1HΝΜR (400 MHz, DMSO-d6) δ 8.19-8.18 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 6.99 (s, 2H), 6.89-6.87 (d, J = 7.6 Hz, 1H), 6.47-6.44 (m, 2H), 5.03 (s, 2H), 4.10-4.01 (m, 1H),
10 2.10 (s, 3H), 1.14-1.12 (d, .J=6.4 Hz, 6H); ESI m!z 285 [C16H20N4O + H]+.
Step-2: Synthesis of 5-(4-(2,2-difluoro-2-plienylacetamido)-2-methylphenyl)-N-isopropyl-2- methylnicotinamide (6E-5.1):
Figure imgf000100_0001
6E-5.1
To a solution of 5-(4-amino-2-methylphenyl)-N-isopropyl-2-methylnicotinamide (6E-5.1,
15 0.30 g, 1.06 mmol), 2,2-difluoro-2-phenylacetic acid (6E-2.1, 0.20 g, 1.16 mmol) in DMF (6.0 mL) were added DIPEA (1.00 mL, 5.30 mmol) followed by HATU (0.805 g, 2.12 mmol) at room temperature and stirred for 16h at same temperature. After this time, reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL x 2) followed by brine (15 mL x 2). The organic layer was washed brine (10 mL), dried over anhydrous sodium sulfate and concentrated under 20 reduced pressure. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to afford 5-(4-(2,2-difluoro-2-phenylacetamido)-2-methyl phenyl)- N- isopropyl-2-methylnicotinamide (6E-5.1, 0.15 g, yield: 32%) as an off white solid: LH NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.20 (d, J= 8.0 Hz, 1H), 8.04 (d, J= 2.4 Hz, 1H), 7.91 (d, J=
4.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 2H), 7.62-7.59 (m, 5H), 7.24 (d ,J= 8.0 Hz, 1H), 7.13 (s, 2H),
25 4.12-4.05 (m, 1H), 2.24 (s, 3H), 1.13 (d, .J=8.0 Hz, 6H); ESI (m/z) 437 [C25H25F2N3O2 + H]+ The compounds of formula 6E-5 (Examples 183, 185-217) can be synthesized according to the procedures described for compound 6E-5.1.
Compounds of Formula 6E-6 can be synthesized according to the procedures described in Scheme 6E wherein R5 = NH2, X = CH, Y4 = Br, R8a = Isopropyl, R8b = H, R2 = 3-CH3, Ar2 = phenyl, R3a = 5 CH3, AT1 = phenyl can be synthesized as described below for compound 6E-6.1:
Figure imgf000101_0001
Synthesis of 2-amino-N-isopropyl-5-(2-methyl-4-(3-methyl-3-phenylureido) phenyl)nicotinamide (6E-6.1):
10 To a solution of 2-amino-5-(4-amino-2-methyl-phenyl)-N-isopropyl-pyridine-3-carbox amide (6E-1.1, 167.8 mg, 0.59 mmol), N-methyl aniline (6E-3.1, 0.95 g, 0.89 mmol) in DMF (10 mL) was added 1,1’ -caibonyldiimidazole (CD, 0.192 g, 1.18 mmol) at room temperature and stirred for 16 h at same temperature. The reaction mixture was quenched with water (10 mL), solid was precipitated out, was filtered and dried afforded crude material, which was purified by column
15 chromatography (silica gel, 5% MeOH in chloroform) afforded 2-amino-N-isopropyl-5-(2-methyl- 4-(3 -methyl-3 -phenylureido)phenyl)nicotinamide (6E-6.1); ^-NMR (400 MHz, DMSO-d6): d 8.21 (d ,J= 6.80 Hz, 1H), 8.16 (s, 1H), 8.02 (d, J= 2.40 Hz, 1H), 7.90 (d, J= 2.00 Hz, 1H), 7.44- 7.32 (m, 6H), 7.27-7.24 (m, 1H), 7.11-7.09 (m, 3H), 4.12-4.03 (m, 1H), 3.28 (s, 3H), 2.15 (s, 3H), 1.14 (d, J = 6.80 Hz, 6H); ESI (m/z) 418 [C24H27N5O2 + H]+.
20 The compounds of formula 6E-6 (Example 218) can be synthesized according to the procedures described for compound 6E-6.1. Compounds of Formula 6E-7 can be synthesized according to the procedures described in Scheme 6E wherein R5 = NH2, X = CH, Y4 = Br, R8a = Isopropyl, R8b = H, R2 = 3-CH3, Ar2 = phenyl, Ar1 = phenyl can be synthesized as described below for compound 6E-7.1 :
Figure imgf000102_0001
5
Synthesis of phenyl (4-(6-amino-5-(isopropylcarbamoyl)pyridin-3-yl)-3- methylphenyl)carbamate (6E-7.1):
To a solution of 2-amino-5-(4-amino-2-methyl-phenyl)-N-isopropyl-pyridine-3-carbox amide (6E-1.1, 224.6 mg, 0.79 mmol) and in CH2CI2 (15 mL) were added pyridine (1.27 mL, 0.95 10 mmol), phenyl carbonochloridate (6E-4.1, 1.18 mL, 0.95 mmol) at 0 °C and resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this, reaction mixture was concentrated under vacuum afforded crude product, which was purified by column chromatography (silica gel, 5% MeOH in chloroform) afforded phenyl (4-(6-amino-5- (isopropylcarbamoyl)pyridin-3-yl)-3-methylphenyl)carbamate (6E-7.1); 1H NMR (400 MHz,
15 DMSO-d6): δ 10.22 (brs, 1H), 8.19 (d, J =7.60 Hz, 1H), 8.04 (d, J =2.00 Hz, 1H), 7.91 (d, J =1.60 Hz, 1H), 7.46-7.41 (m, 4H), 7.29-7.19 (m, 4H), 7.11 (s, 2H), 4.12-4.02 (m, 1H), 2.24 (s, 3H), 1.14 (d, J =6.40 Hz, 6H); ESI (m/z) 404 [C23H24N4O3 + H]+.
The compounds of formula 6E-7 (Example 219) can be synthesized according to the procedures described for compound 6E-7.1.
20 Scheme 7E: Preparation of 2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2- methyl phenyl)-N-isopropylnicotinamide (Example 182):
Figure imgf000103_0002
Step-1: Synthesis of 4,4»5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)-l,3,2-dioxaborolane (182-
5 2):
Figure imgf000103_0001
182-2
To a stirred solution of 1 -bromo-2-methyl -4-nitrobenzene (182-1, 2.00 g, 9.3 mmol) in 1,4- dioxane (30 mL) under argon atmosphere were added bis(pinacolato)diboron (3.53 g, 13.95 mmol) and potassium acetate (1.82 g, 18.6 mmol). The reaction mixture was purged with argon for 10 min.
10 followed by addition of PdCl2(dppf) (682 mg, 0.93 mmol .) and again the reaction mixture was purged with argon for 10 min. After addition completed, the reaction mixture was heated to 100 °C for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, diluted with water (50 mL), extracted with EtOAc (3 * 300 mL). The filtrate was washed with water (2 x 25 mL) and brine (2 × 15 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 50% ethyl acetate/hexanes to afford 4,4,5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)- 1 ,3 ,2-dioxaborolane (182-2, 2.20 g, yield: 90%) as a white solid. ESI (m/z) 264 [C13H18BNO4 +
5 H]+.
Step-2: Synthesis of 2-amino-N-isopropyl-5-(2-methyl-4-nitrophenyl)nicotinamide (182-3):
Figure imgf000104_0001
182-3
To a stirred solution of 2-amino-5-bromo-N-isopropylnicotinamide (IE-3.1, 1.95 g, 7.6 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)-l,3,2-dioxaborolane (182-2, 2.00 g, 7.6 10 mmol) in a mixture of 1,4-dioxane and water (3:1, 60 mL), potassium carbonate (3.67 g, 26.6 mmol) was added at room temperature and resulting reaction mixture was purged with argon for 10 min. After 10 min. PdCl2(dppf) (550 mg, 0.76 mmol.) was added and the mixture was again purged with argon for 10 min. The resulting reaction mixture was heated to 90 °C and stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, diluted with water 15 (100 mL). An aqueous layer washed with CH2CI2 (2 * 100 mL), the combined organic layer was washed with water (20 mL) followed by brine (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 60% ethyl acetate/hexanes to afford 2-amino-N-isopropyl-5-(2-methyl-4- nitrophenyl)nicotinamide (182-3, 2.2 g, yield: 90%) as an off white solid: ESI (m/z) 315 20 [C16H18N4O3 + H]+.
Step-3: Synthesis of 2-amino-N-isopropyl-5-(2-methyl-4-nitrophenyl)nicotinamide (182-4):
Figure imgf000104_0002
182-4 To a stirred solution of 2-amino-N-isopropyl 1 -5 -(2 -methyl -4-nitrophenyl )ni cotinamide (182- 3, 0.30 g, 0.955 mmol) in THF (15.0 mL) was added Rh/C (40 mg) at 0-5 °C followed by drop-wise addition of hydrazine hydrate (0.14 g, 2.86 mmol) and stirred for 2 h at same temperature. After this time reaction mixture was passed through a bed of diatomaceous earth, washed with EtOAc (2 × 50 5 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-amino-5-(4-(hydroxyamino)-2-methylphenyl)-N-isopropylnicotinamide (182-4, 0.25 g) as a yellow solid. ESI (m/z) 301 [C16H20N4O2 + H]+.
Step-4: Synthesis of 2-((4-(6-amino-5-(isopropylcarbamoyl)pyridin-3-yl)-3-methylphenyl) (hydroxy)amino)-l-(3,5-difluorophenyl)-2-oxoethyl acetate (182-5):
Figure imgf000105_0001
182-5
10
To a stirred solution of 2-amino-N-isopropyl-5-(2-methyl-4-nitrophenyl)ni cotinamide (182-4, 0.25 g, 0.83 mmol) in THF (10.0 mL) were added NaHCO3 (0.14 mg, 1.66 mmol) at 0-5 °C followed by addition of 2-chloro- 1 -(3 , 5-difluoropheny l)-2-oxoethyl acetate (4E-4.1, 0.29 g, 2.86 mmol). After this time, the reaction mixture was allowed to cool to room temperature, diluted with 100 ml water,
15 washed with CH2CI2 (2 * 100 mL). The organic layer was washed with water (20 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude material. The crude material was purified by column chromatography (silica gel, 60% ethyl acetate/hexanes) to afford 2-((4-(6-amino-5-(isopropylcarbamoyl)pyridin-3-yl)-3- methy lphenyl)(hy droxy)amino)- 1 -(3 , 5 -difluoropheny l)-2-oxoethy 1 acetate (182-5, 0.20 g, yield:
20 47%) as an off white solid: ESI ( m/z ) 513 [C26H26F2N4O5 + H]+. Step-5: Synthesis of 2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2-methyl phenyl)-N-isopropylnicotinamide (Example 182):
Figure imgf000106_0002
Example 182
To a stirred solution of 2-amino-N-isopropyl-5-(2-methyl-4-nitrophenyl)nicotinamide (182- 5 5, 0.20 g, 0.39 mmol.) in MeOH(10.0 mL) was added NaOMe (0. 42 g, 0.78 mmol) at 0-5 °C and stirred for 4 h at RT. After this time, the reaction mixture diluted with water (50 mL), washed with CH2CI2 (3 × 100 mL). The combined organic layers were washed with water (20 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography eluted with 10% water/Acetonitrile 10 to afford 2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2-methyl phenyl)-N- isopropyl nicotinamide (Example 182, 0.11 g, yield: 56%) as an off white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 10.90 (s, 1H), 8.22 (d, >7.60 Hz, 1H), 8.06 (s, 1H), 7.93 (d, .J=1.60 Hz, 1H), 7.54-7.52 (m, 2H), 7.27 (d, >8.00 Hz, 1H), 7.21-7.16 (m, 5H), 6.01 (d, >7.20 Hz, 1H), 5.77 (d, J =5.60 Hz, 1H), 4.13-4.03 (m, 1H), 2.27 (s, 3H), 1.14 (d, J= 6.00 Hz, 6H); ESI m/z 471 15 [C24H24F2N4O4 + H]*.
Scheme 8E: Preparation of 2-amino-5-(4-(2-(3, 5-difluorophenyl)-2-oxoacetamido)-2-methyl phenyl)-N-isopropyl nicotinamide (Example 184):
Figure imgf000106_0001
Example 8/9 Example 184
20 To a solution of 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methyl phenyl)-N-i sopropyl nicotinamide (Example 8/9, 0.50 g, 1.101 mmol) in dichloromethane (10.0 mL) Mn02 (0.96 g, 11.01 mmol) was added at rt and resulting reaction mixture was stirred at room temperature for 10 h. After this time, the reaction mixture was diluted with dichloromethane (50 mL) and passed through celite bed The filtrate was dried over anhydrous sodium sulfate concentrated under reduced pressure to afford crude material, which was purified by column chromatography (silica gel, 50% Ethyl Acetate in Hexanes) to afford 2-amino-5-(4-(2-(3,5- difluorophenyl)-2-oxoacetamido)-2-methylphenyl)-iV-isopropylnicotinamide (Example 184, 0.25 g, yield: 52%); Ή-ΝΜΚ (400 MHz, DMSO^): δ 10.98 (s, 1H), 8.22 (d ,J= 8.00 Hz, 1H), 8.07 (s,
5 1H), 7.93 (s, 1H), 7.64-7.78 (m, 5H), 7.28 (d ,J= 8.00 Hz, 1H), 7.15 (s, 2H), 4.06-4.11 (m, 1H),
2.28 (s, 3H), 1.13-1.15 (m, 6H). ESI {m/z) 453 [C24H22F2N4O3 + H]+.
The compounds of formula I (Table 1) can be synthesized according to the procedures described in Scheme IE to Scheme 8E:
Table I: Compounds of Formula I:
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
References
Adrian L. Smith et al., Discovery of 1 H-Pyrazol-3 (2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), J. Med Chem., 2015, 58 (3), pp 1426-1441
5 Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response Nat. Rev. Mol. Cell Biol. 2007, 8, 519- 529
Shore, G. C.; Papa, F. R.; Oakes, S. A. Signaling cell death from the endoplasmic reticulum stress response Curr. Opin. Cell Biol. 2011, 23, 143- 149
Carrara, M.; Prischi, F.; Ali, M. M. U. UPR signal activation by luminal sensor domains Int. J. Mol. 10 Sci. 2013, 14, 6454- 6466
Ma, Y.; Hendershot, L. M. The role of the unfolded protein response in tumor development: friend or foe? Nat. Rev. Cancer 2004, 4, 966- 977
Walter, P.; Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation Science 2011, 334, 1081- 1086
15 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S Heindiyckx, F.; van Vlierberghe, H. The paradox of the unfolded protein response in cancer Anticancer Res. 2013, 33, 4683-4694
Gao, Y.; Sartori, D. J.; Li, C.; Yu, Q.-C.; Kushner, J. A.; Simon, M. C.; Diehl, J. A. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis Mol. Cell.
20 Biol. 2012, 32, 5129-5139
Bi, M.; Naczki, C.; Koritzinsky, M.; Pels, D.; Blais, J.; Hu, N.; Harding, H; Novoa, L; 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. 2005, 24, 3470-3481
25 Kim, I; Xu, W.; Reed, J. C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities Nat. Rev. Drug Discovery 2008, 7, 1013- 1030
Pels, D. R.; Koumenis, C. The PERK/eIF2a/ATF4 module of the UPR in hypoxia resistance and tumor growth Cancer Biol. Ther. 2006, 5, 723- 728 WO2018/194885
U S. Publication No. 2017/0165259
U S. Patent No. 8,598,156

Claims

What is claimed is:
1. A method for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor.
5
2. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of formula (I):
Figure imgf000174_0001
wherein:
10 Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents;
Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; Y is C(R3a)(R3b)Co-6alkyl, NR3a, -0-, C(0), CF2, CNOR3bb, or a direct bond to Ar1;
R3a is H, alkyl, or cycloalkyl;
15 R3b is H, alkyl, 0R3c, orNR3dR3e;
R3bb is H or alkyl;
R4 is H, alkyl, or OH;
X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NOz, alkyl, cycloalkyl, C0-6alkyl-O-Ci- 20 izalkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-O-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NOz, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- O-C1-12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents;
25 R3c, R3d and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents;
R5 is H, CH3, NHR9 , or OR9; R6is a alkyl, CO2R8a, or CO(NR8aR8b);
R7 is a CN, or alkyl, optionally substituted by one or more independent deuterium or halo; R8a and R85 are each independently H, C1-12alkyl, C0-12alkyl-C3-12cycloalkyl, or C0-12alkyl-C3- 12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; or
5 R8a and R8b taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl;
R9 is H, alkyl, cycloalkyl, or heterocycloalkyl; each G1, G2, G3, or G4 «independently H, deuterium, halo, CN, NOz, C1-12alkyl, C0-12alkyl- C3-12cycloalkyl, C0-12alkyl-C3-12heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10,
10 C(O)NRl0R11, OC(0)R10, OC(0)OR10, OC(O)NR10Rn, N(R12)C(0)R10, N(R12)C(0)OR10,
N(R12)C(O)NR10R11, S(0)nR10, S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11, optionally substitued by one or more independent H, deuterium, halo, OH, CN, or NO2;
R10, R11, or R12 are each independently selected from H deuterium, halo, CN, NOz, alkyl, 15 cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H deuterium, halo, OH, CN, orN02; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
20 3. The method according to claim 1 or 2, wherein the PERK inhibitor is selected from a compound of formula (la):
Figure imgf000175_0001
25 wherein:
Y is CR3aR3b;
R3a is H or alkyl;
R3b is OR3c or NR3dR3e; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, Co- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-Ci- 5 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents;
R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents;
Xis CR7 orN;
10 R6is H, alkyl, COiR83, or CO(NR8aR8b);
R7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; R8a and R8b are each independently H, Ci.i2alkyl, C0-12alkylC3-12cycloalkyl, or C0-12alkylC3- 12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; each G1, G2, G3, or G4 isindependently H, deuterium, halo, CN, NO2, C1-12alkyl, Co- 15 i2alkylC3-12cycloalkyl, C0-12alkylC3-i2heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10Rn, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12X:(O)NR10R11, S(=0)nR10, S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN02;
20 R10, R11, or R12 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, or N02; n is O, 1, or 2; p is 0, 1, 2, 3, 4, or 5;
25 qis 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
4. The method according to any one of claims 1-3, wherein the PERK inhibitor is selected from a compound of formula (lb):
Figure imgf000177_0001
wherein:
X is CH orN; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 5 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 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 G2 substituents;
10 R3a is H or alkyl;
R3b is OR3C or NR3dR3e;
R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents;
R6 is CO2R83 or CO(NR8aR8b);
15 R8a and R8b are each independently H, C1-12alkyl, C3-12cycloalkyl, or C3-12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C3- 12cycloalkyl, C3-12heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10R11, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NR10R11, S(0)nR10,
20 S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)n0R10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2;
R10, R11, or R12 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, orN02;
25 n is 0, 1, or 2; p is O, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof
5. The method according to any one of claims 1-4, wherein the PERK inhibitor is selected from a compound of formula (Ic):
Figure imgf000178_0001
5 wherein:
Xis CH orN; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl,
10 optionally substituted by one or more independent G2 substituents;
R3b is OR3c;
R3c is H or alkyl, optionally substituted by one or more independent G3 substituents;
R6is COCNR8aR8b);
R8a and R8b are each independently H, C1-12alkyl, C0-12alkylC3-12cycloalkyl, or C0-12alkylC3-
15 12heterocycloalkyl, optionally substituted by one or more independent G4 substituents; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C3- 12cycloalkyl, C3.i2heterocycloalkyl, OR10, NR10R11, C(0)R10, C(OX)R10, C(O)NR10R11, OC(0)R10, OC(OX)R10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NRl0R11, S(0)nR10, S(0)nOR10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)n0R10, or N(R12)S(O)nNR10R11, optionally
20 substituted by one or more independent H, deuterium, halo, OH, CN, or NO2;
R10, R11, or R12 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, orN02; nis 0, 1, or 2;
25 p is 0, 1, 2, 3, 4, or 5; qis 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
6. The method according to any one of claims 1-5, wherein the PERK inhibitor is selected from a compound (Id):
5 wherein:
Figure imgf000179_0001
Xis CH orN; each R1 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 R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, 10 optionally substituted by one or more independent H, deuterium or halo;
R8a and R8b are each independently H, C1-12alkyl, C3-12cycloalkyl, or C3-i2heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, C1-12alkyl, C3-12cycloalkyl, C3.i2heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10R11, OC(0)R10, OC(0)OR10, OC(O)NR10R11, N(R12)C(0)R10, N(R12)C(0)0R10, NCR^OJNR^R11, S(0)nR10, S(0>,0R10,
15 S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11;
R10, R11, or R12 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, or N02; nis 0, 1, or 2;
20 p is 0, 1, 2, 3, 4, or 5; qis 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
7. The method according to any one of claims 2-5, wherein R6 is
Figure imgf000180_0001
8. The method according to any one of claims 2-7, wherein X is CH.
5 9. The method according to any one of claims 2-7, wherein each R1 is independently H, methyl, ethyl, isopropyl, m ethoxy, ethoxy, propoxy, isopropoxy, deuterium, CF3, fluoro, or chloro.
10. The method according to any of one of claims 2-7, wherein each R2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF3 or
10 OCF3.
11. The method according to any one of claims 2-6, wherein R8a and R8b are each independently H, C1-6alkyl, C0-6alkyl C3-8cycl oalkyl, or C0-6alkylC3-8heterocycloalkyl.
15 12. The method according to any one of claims 2-6, wherein R8a and R8b are each independently
H, C1-3alkyl, C0-3alkylC3-6cycloalkyl, or C0-3alkylC3-6heterocycloalkyl .
13. The method according to any one of claims 2-6, wherein R8a and R8b are each independently H, C1-3alkyl, C3-6cycloalkyl, or C3-6heterocycloalkyl .
20
14. The method according to any one of claims 2-5, wherein each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, Ci-ealkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, OR10, NR10R11, C(0)R10, C(OX)R10, C(O)NR10R11, OC(0)R10, OC(OX)R10, OC(O)NR10Rn, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NR10 R11, s(0)nRl°, s(0)n0R10, s(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R12)S(O)nNR10R11, optionally substituted by one or more independent H, deuterium, halo, OH, CN, orN02.
5 15. The method according to any one of claims 1-4, wherein each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C 1-3alkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR10, NR10R11, C(0)R10, C(0)OR10, C(O)NR10R11, OC(0)R10, OC(0)OR10, 0C(0)NR10R11, N(R12)C(0)R10, N(R12)C(0)OR10, N(R12)C(O)NR10R11, s(0)nR10, S(0)n0R10, S(O)nNR10R11, N(R12)S(0)nR10, N(R12)S(0)nOR10, or N(R11)S(O)nNR10R11, optionally substituted by one or more 10 independent H, deuterium, halo, OH, CN, or NO2.
16. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of the formula (Ie):
15
Figure imgf000181_0001
wherein:
Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents;
Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents;
20 Y is C(R3a)(R3b)Co-6alkyl, NR3a, -0-, C(O), CF2, or a direct bond to Ar1;
R3a is H or alkyl;
R3b is OR3C or NR3dR3e;
R4is H or OH;
X is CR7 or N;
25 each R1 is independently halo, alkyl, or C0-6alkyl-O- C1-12alkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently halo, alkyl, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H or alkyl;
R5 is H, CH3, NH2, or NHCH3;
R6is H, C02R8a, or CO(NR8aR8b);
R7 is H or alkyl;
5 R8a and R8b are each independently H, C1-12alkyl, C0-12alkyl-C3.12cycloalkyl, or C0-12alkyl-C3. i2heterocycloalkyl, optionally substituted by one or more independent G4 substituents; or
R88 and R85 taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl; each G1, G2, G3, or G4 is independently halo, OR10, NR10 R11, C(0)R10; and
10 R10 or R11 are each independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.
16. The method according to claim 15, wherein Ar1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,
Figure imgf000182_0001
15
Figure imgf000182_0002
, optionally substituted by one or more independent R1 substituents.
17. The method according to claim 15 or 16, wherein each R1 is independently chloro, fluoro, methyl, ethyl, methoxy, or CF3.
20
18. The method according to any one of claims 15-17, wherein Y is -C(H)(OH)-, -C(CH3)(OH)- , -C(H)(OCH3)-, -C(H)(NH2>, CF2, C(0), CH2, -CH2CH2-, N(CH3), -0-, or a direct bond to Ar1.
19. The method according to any one of claims 15-18, wherein R4 is H.
25
20 Th th d di t f l i 15 18 h i R4 i OH
21. The method according to any one of claims 15-20, wherein Ar2 is phenyl or pyridyl, optionally substituted by one or more independent R2 substituents.
5 22. The method according to any one of claims 15-21, wherein each R2 is independently methyl, ethyl, methoxy, fluoro, chloro, CF3, or OCF3.
23. The method according to any one of claims 15-22, wherein X is CR7.
10 24. The method according to any one of claims 15-23, wherein R7 is H.
25. The method according to any one of claims 15-24, wherein X is N.
26. The method according to any one of claims 15-25, wherein R5 is H, methyl, NH2, or 15 NHCH3.
27. The method according to any one of claims 15-26, wherein R6 is H,
Figure imgf000184_0001
28. The method according to claim 1, wherein the PERK inhibitor is a compound selected from 5 the group consisting of:
2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-W-isopropylnicotinamide; (R)-2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-iV-isopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-phenylacetamido)-2-methylphenyl)-vV-isopropylnicotinamide; 2-amino-5-(4-(2-hydroxy-2-phenylpropanamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2 -hydroxy-2 -phenylpropanamido)-2-methylphenyl)-N-isopropylnicotinamide;
5 (S)-2-amino-5-(4-(2-hydroxy-2-phenylpropanamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-N-isopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide;
(R)-2-amino-N-isopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide;
(S)-2-amino-N-isopropyl-5-(4-(2-methoxy-2-phenylacetamido)-2-methylphenyl)nicotinamide; 2-amino-5-(4-(2-amino-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
10 (R)-2-amino-5-(4-(2-amino-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-amino-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 15 i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylnicotinamide;
20 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-ethylmcotinamide; 25 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- ethylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- ethylnicotinamide;
2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 30 methylphenyl)nicotinamide; (R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
5 2-amino-N-(tert-butyl)-5-(4-(2-(3 ,5-difl uoroph enyl)-2-hy droxy acetami do)-2- methylphenyl)nicotinamide;
(R)-2-amino-N-(tert-butyl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(S)-2-amino-N-(tert-butyl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 10 methylphenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(R)-2-amino5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
15 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
2-amino-5-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isobutylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 20 i sobutylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isobutylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N,N- dimethylnicotinamide;
25 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N,N- dimethylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N,N- dimethylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- 30 yl)nicotinamide; (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-.N-(oxetan-3- yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3- yl)nicotinamide;
5 2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- hydroxycyclobutyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- hydroxy cyclobutyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- 10 hydroxy cyclobutyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- methoxycyclobutyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- methoxycyclobutyl)nicotinamide;
15 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(3- methoxycyclobutyl)nicotinamide,
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-methylpyrazine-2- carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 20 methylpyrazine-2-caiboxamide;
(S)-3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylpyrazxne-2-carboxamide;
3-amino-N-cyclopropyl-6-(4-(2 -(3, 5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
25 (R)- 3 -amino-N-cyclopropyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hy droxy acetamido)-2- methylphenyl)pyrazine-2-carboxamide;
(S)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinic acid;
30 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinic acid;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)mcotinic acid; isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinate;
(R)-isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinate;
(S)-isopropyl 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- 5 methylphenyl)nicotinate;
2-amino-N-(azetidin-3-yl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(R)-2-amino-N-(azetidin-3-yl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methy lpheny l)ni cotinami de;
10 (S)-2-amino-N-(azetidin-3-yl)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l-methylazetidin- 3 -yl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l- 15 methylazetidin-3 -yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(l- methylazetidin-3 -yl)nicotinamide;
2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
20 (R)-2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)nicotinamide;
(S)-2-amino-N-cyclobutyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)ni cotinami de;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-2H- 25 pyran-4-yl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-
2H-pyran-4-yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-
2H-pyran-4-yl)nicotinamide;
30 2-amino-5-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxy acetamido)-2-methy lpheny l)-N-(2-
(dimethylamino)ethyl)nicotinamide; (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2-
(dimethylamino)ethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2-
(dimethylamino)ethyl)nicotinamide;
5 2-amino-5-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- 10 methoxyethyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)nicotinamide;
(R)-2-amino5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxy ethyl)nicotinamide;
15 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)nicotinamide;
N-(4-(6-amino-5-(2,6-diazaspiro[3.3 ]heptane-2-carbonyl)pyridin-3 -yl)-3 -methylphenyl)-2-(3 ,5- difluorophenyl)-2-hydroxy acetamide;
(R)-N-(4-(6-amino-5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-3-yl)-3-methylphenyl)-2-(3,5- 20 difluorophenyl)-2-hydroxy acetamide;
(S)-N-(4-(6-amino-5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-3-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxy acetamide;
2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
25 (S)-2-amino-5-(4-(2-hydroxy-2-(o-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; (S)-2-amino-5-(4-(2-hydroxy-2-(m-tolyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- 30 isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- 5 isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
10 2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(,S)-2-amino-5-(4-(2-(3-ethylphenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
15 2-amino-5-(4-(2-(2,3-dihydrobenzofuran-7-yl)-2-hydroxyacetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(R)-2-amino-5-(4-(2-(2,3-dihydrobenzofuran-7-yl)-2-hydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(2,3-dihydrobenzofuran-7-yl)-2-hydroxyacetamido)-2-methylphenyl)-N- 20 isopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
25 (S)-2-amino-5-(4-(2-hydroxy-2-(l-methyl-lH-indazol-7-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- i sopropylnicotinamide;
(R)-2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- 30 isopropylnicotinamide;
(S)-2-amino-5-(4-(2-hydroxy-2-(2-methylthiazol-4-yl)acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2-
(methylamino)nicotinamide;
(R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- 5 (methylamino)nicotinamide;
(S)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2-
(methylamino)nicotinamide;
5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- methylnicotinamide;
10 (R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- methylnicotinamide;
(5)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropyl-2- methylni cotinamide;
2-amino-5-(4-(2-(3>5-dif1uorophenyl)-N,2-dihydroxyacetamido)-2-methylphenyl)-N- 15 i sopropylni cotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-N, 2-dihydroxy acetamido)-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-N,2-dihydroxyacetamido)-2-methylphenyl)-N- isopropylnicotinamide;
20 5 -(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylni cotinamide;
(R)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide; (5)-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-(methylamino)pyridin-3-yl)phenyl)acetamide; (R)-2-(3 , 5-difluoropheny l)-2-hy droxy-N-(3 -methyl -4-(6-(methylamino)pyridin-3 - 25 yl)phenyl)acetamide;
(S)-2-(3 ,5-difl uoropheny 1 )-2-hy droxy -N-(3 -methy l-4-(6-(methy lami no)py ridin-3 - yl)phenyl)acetamide;
N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide;
(R)-N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3>5-difluorophenyl)-2-hydroxy acetamide;
30 (S)-N-(4-(6-aminopyridin-3-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide; 2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-methylpyridin-3-yl)phenyl)acetamide; (R)-2-(3 , 5-difluoropheny l)-2-hy droxy-N-(3 -methyl-4-(6-methylpyridin-3 -yl)phenyl)acetamide; (S)-2-(3,5-difluorophenyl)-2-hydroxy-N-(3-methyl-4-(6-methylpyridin-3-yl)phenyl)acetamide; 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
5 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide; 2-amino-5-(2-chloro4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-ethylmcotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- ethylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- 10 ethylnicotinamide;
2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylnicotinamide;
15 (S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylnicotinamide;
2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- 20 trifluoroethyl)nicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
2-amino-5-(2-chloro-4-(2-(3-chlorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3-chlorophenyl)-2-hydroxyacetamido)phenyl)-N- 25 i sopropy lnicotinamide;
(,S)-2-amino-5-(2-chloro-4-(2-(3-chlorophenyl)-2 -hydroxy acetamido)phenyl)-N- isopropylnicotinamide;
2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotmamide;
30 (S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; 2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; (R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; 2-amino-5-(2-chloro-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino5-(2-chloro-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N- 5 isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3-ethylphenyl)-2 -hydroxy acetamido)phenyl)-N- i sopropylnicotinamide;
2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
10 (R)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylnicotinamide; 15 (R)-2-amino-5-(4-(2-(3, 5-difluorophenyl)-2 -hydroxy acetamido)-2-ethylphenyl)-N- ethylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- ethylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2-
20 trifluoroethyl)nicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)nicotinamide;
25 2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)nicotinamide;
(R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)nicotinamide;
(S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-
30 ethylphenyl)nicotinamide;
2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; (R)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(o-tolyl)acetamido)phenyl)-N-isopropylnicotinamide; 2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetamido)phenyl)-N- 5 isopropylnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-(3-ethylphenyl)-2-hydroxyacetaniido)phenyl)-N- i sopropylnicotinamide;
2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- 10 isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3-chlorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- i sopropylnicotinamide;
2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
15 (R)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(2-ethyl-4-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-N- isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methoxyphenyl)-N- 20 isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methoxyphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methoxyphenyl)-N- i sopropylnicotinamide;
25 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-(trifluoromethoxy)phenyl)-N- 30 isopropylnicotinamide;
2-amino-5-(4-(2-(3 ,5 -difluorophenyl)-2-hydroxy acetami do)-3 -fluoro-2-methylphenyl)-N- isopropylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- i sopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- 5 isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- ethylnicotinamide;
(R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- ethylnicotinamide;
10 (S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- ethylnicotinamide;
2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2- methylphenyl)nicotinamide;
(R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)- 2-hydroxy acetamido>3-fluoro-2- 15 methylphenyl)nicotinamide;
(S)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2- methylphenyl)nicotinamide;
2-amino-5-(4-(2-(3 ,5 -difluorophenyl)-2-hydroxy acetami do)-3 -fluoro-2-methylphenyl)-N-(oxetan-3 - yl)nicotinamide;
20 (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- (oxetan-3 -yl)nicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluoro-2-methylphenyl)-N- (oxetan-3 -yl)nicotinamide;
2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- 25 isopropylnicotinamide;
(R)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-3-fluorophenyl)-N- i sopropylnicotinamide;
30 2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-5-fluoro-2-methylphenyl)-N- isopropylnicotinamide; (R)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-5-fluoro-2-methylphenyl)-N- isopropylnicotinamide;
(S)-2-amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-5-fluoro-2-methylphenyl)-N- isopropylnicotinamide;
5 2-amino-5-(4-(2,2-difluoro-2-phenylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)-2-oxoacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(2-methyl-4-(2-(6-methylpyridin-2-yl)acetamido)phenyl)nicotinamide;
2-amino-5-(4-(2-(3,5-difluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(2-methyl-4-(2-phenylacetamido)phenyl)nicotinamide;
10 2-amino-N-i sopropyl-5 -(2-methyl-4-(3 -phenylpropanamido)phenyl)nicotinamide;
2-amino-5-(4-(2-(2-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-(3-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-5-(4-(2-(4-fluorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(4-(2-(2-methoxyphenyl)acetamido)-2-methylphenyl)nicotinamide;
15 2-amino-N-isopropyl-5-(4-(2-(3-methoxyphenyl)acetamido)-2-methylphenyl)nicotinamide; 2-amino-N-isopropyl-5-(4-(2-(4-methoxyphenyl)acetamido)-2-methylphenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(o-tolyl)acetamido)phenyl)nicotinamide;
2-amino-N-i sopropyl-5-(2-methyl-4-(2-(m-tolyl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(p-tolyl)acetamido)phenyl)nicotinamide;
20 2-amino-5-(4-(2-(2-chlorophenyl)acetamido)-2-methylphenyl)-N-i sopropylnicotinamide; 2-amino-5-(4-(2-(3-chlorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(4-chlorophenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(2-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 25 2-amino-N-isopropyl-5-(2-methyl-4-(2-(4-(trifluoromethyl)phenyl)acetamido)phenyl)nicotinamide; 2-amino-5-(4-(2-(2-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(3-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-(4-ethylphenyl)acetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(naphthalen-l-yl)acetamido)phenyl)nicotinamide;
30 2-amino-N-isopropyl-5-(2-methyl-4-(2-(naphthalen-2-yl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(2-methyl-4-(2-(quinolin-6-yl)acetamido)phenyl)nicotinamide; 2-amino-N-isopropyl-5-(4-(2-(isoquinolin-4-yl)acetamido)-2-methylphenyl)nicotinamide;
2-amino-N-isopropyl-5-(4-(2-(isoquinolin-5-yl)acetamido)-2-methylphenyl)mcotinamide;
2-amino-N-isopropyl-5-(2-methyl-4-(2-(quinolin-5-yl)acetamido)phenyl)nicotinamide;
2-amino-5-(4-(2-cyclopropylacetamido)-2-methylphenyl)-N-isopropylnicotinamide;
5 2-amino-5-(4-(2-cyclobutylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-cyclopentylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-(2-cyclohexylacetamido)-2-methylphenyl)-N-isopropylnicotinamide; 2-amino-5-(4-benzamido-2-methylphenyl)-N-isopropylnicotinamide;
2-amino-N-isopropyl-5-(2-methyl-4-(3-methyl-3-phenylureido)phenyl)nicotinamide;
10 phenyl (4-(6-amino-5-(isopropylcarbamoyl)pyridin-3-yl)-3-methylphenyl)carbamate;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-methylpyrazine-2- carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylpyrazine-2-carboxamide;
15 (S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N- methylpyrazine-2-caiboxamide;
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxy acetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- 20 trifluoroethyl)pyrazine-2-carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
25 (R)- 3 -amino-N-cy clopropyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hy droxy acetamido)-2- methylphenyl)pyrazine-2-carboxamide;
(S)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2 -carboxamide;
3-amino-N-cyclobutyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-
30 methylphenyl)pyrazine-2-carboxamide;
(R)-3 -amino-N-cy clobutyl-6-(4-(2-(3 , 5-difluorophenyl)-2-hydroxy acetami do)-2- methylphenyl)pyrazine-2-carboxamide;
(S)-3-amino-N-cyclobutyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxy acetamido)-2-methylphenyl)-N-(oxetan-3 - 5 yl)pyrazine-2-carboxamide;
(R)- 3 -amino-6-(4-(2-(3 ,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
(S)-3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
10 3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro-2H- pyran-4-yl)pyrazine-2-carboxamide;
(R)-3-amino6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro- 2H-pyran-4-yl)pyrazine-2-carboxami de;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(tetrahydro- 15 2H-pyran-4-yl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-m ethylphenyl)-N-(2- (dimethylamino)ethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2-
(dimethylamino)ethyl)pyrazine-2-carboxamide;
20 (S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- (dimethylamino)ethyl)pyrazine-2-carboxamide;
3-amino-6-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2 -hydroxy acetamido)-2-methylphenyl)-N-(2- 25 methoxyethyl)pyrazine-2-carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- methoxyethyl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-m ethylphenyl)-N-(2- hydroxyethyl)pyrazine-2-carboxamide;
30 (R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)pyrazine-2-carboxamide; (S)-3 -amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)-N-(2- hydroxyethyl)pyrazine-2-caiboxamide;
3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetajmido)-2-ethylphenyl)-N-isopropylpyrazine-2- carboxamide;
5 (R)- 3 -amino-6-(4-(2-(3 , 5-difluorophenyl)-2-hydroxy acetami do)-2-ethy lpheny 1)-N- isopropylpyrazine-2 -carboxamide;
(S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N- i sopropyl pyrazine-2-carb oxami de;
3-amino-6-(4-(2-(3>5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylpyrazine-2- 10 carboxamide;
(R)-3-amino-6-(4-(2-(3, 5-difluorophenyl)-2 -hydroxy acetamido)-2-ethylphenyl)-N-ethylpyrazine-2- carboxamide;
(,S)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-ethylpyrazine-2- carboxamide;
15 3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(S)- 3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(2,2,2- 20 trifluoroethyl)pyrazine-2-carboxamide;
3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)pyrazine-
2-carboxamide;
(R )-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)pyrazine-2-carboxamide;
25 (5)-3-amino-N-cyclopropyl-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- ethylphenyl)pyrazine-2-carboxamide;
3 -amino-6-(4-(2-(3 , 5 -difluorophenyl)-2-hy droxy acetami do)-2-ethy lpheny l)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
(R)-3-amino-6-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-(oxetan-3- 30 yl)pyrazine-2-carboxamide;
(S)-3 -amino-6-(4-(2-(3 ,5 -difluorophenyl)-2-hy droxyacetamido)-2-ethylphenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide;
3-amino-6-(2-ethyl-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- carboxamide;
(R)-3-amino-6-(2-ethyl-4 -(2-hydroxy -2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- 5 carboxamide;
(S)-3-amino-6-(2-ethyl-4-(2-hydroxy-2-(m-tolyl)acetamido)phenyl)-N-isopropylpyrazine-2- carboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-isopropylpyrazine-
2-carboxamide;
10 (i?)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylpyrazine-2 -carboxamide;
(5)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- isopropylpyrazine-2-carboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- 15 trifluoroethyl)pyrazine-2-carboxamide;
(R)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
(5)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(2,2,2- trifluoroethyl)pyrazine-2-carboxamide;
20 3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylpyrazine-2-carboxamide;
(R)-3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N- cyclopropylpyrazine-2-carboxamide;
(S)-3 -amino-6-(2-chloro-4-(2-(3 ,5 -difluorophenyl)-2-hy droxy acetami do)phenyl)-N- 25 cyclopropylpyrazine-2-carboxamide;
3-amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(oxetan-3- yl)pyrazine-2-carboxamide;
(R)- 3 -amino-6-(2-chloro-4-(2-(3 , 5-difluoropheny l)-2-hy droxy acetamido)pheny 1)-N -(oxetan-3 - yl)pyrazine-2-carboxamide;
30 (S)-3 -amino-6-(2-chloro-4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)phenyl)-N-(oxetan-3 - yl)pyrazine-2-carboxamide; and a pharmaceutically acceptable salt thereof.
29. The method according to any one of claims 1-28, wherein the compound or a pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically 5 acceptable carriers, diluents, or excipients.
30. The method according to any one of claims 1-29, wherein the viral infection is associated with a coronavirus.
10 31. The method according to claim 30, wherein the coronavirus is SARS-CoV, SARS-CoV-2, or
MERS-CoV.
32. The method according to any one of claims 1-31, wherein the patient is a mammal.
15 33. The method according to any one of claims 1-32, wherein the patient is a human.
PCT/US2021/032322 2020-05-13 2021-05-13 Perk inhibitors for treating viral infections WO2021231782A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010080992A1 (en) * 2009-01-09 2010-07-15 The Trustees Of The University Of Pennsylvania Regulators of the interferon-alpha receptor 1 (ifnar1) chain of the interferon receptor
WO2018194885A1 (en) * 2017-04-18 2018-10-25 Eli Lilly And Company Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compounds
WO2019191115A1 (en) * 2018-03-26 2019-10-03 Icahn School Of Medicine At Mount Sinai Methods of treating minimal residual cancer
WO2020070053A1 (en) * 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010080992A1 (en) * 2009-01-09 2010-07-15 The Trustees Of The University Of Pennsylvania Regulators of the interferon-alpha receptor 1 (ifnar1) chain of the interferon receptor
WO2018194885A1 (en) * 2017-04-18 2018-10-25 Eli Lilly And Company Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compounds
WO2019191115A1 (en) * 2018-03-26 2019-10-03 Icahn School Of Medicine At Mount Sinai Methods of treating minimal residual cancer
WO2020070053A1 (en) * 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses

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