WO2021231788A1 - Perk inhibiting pyrrolopyrimidine compounds to treat viral infections - Google Patents

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 INHIBITING PYRROLOPYRIMIDINE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/024,318, filed May 13, 2020, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Embodiments of the present invention relate to novel pyrrolopyrimidine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds. The present invention is in the field of treatment of cancer or 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 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 adapt to cope with ER stress, but under extreme stress the UPR switches the cellular machinery toward apoptosis, contributing to greater tumorigenic potential of cancer cells, tumor metastasis, tumor drug resistance, and the ability of cancer cells to avoid effective immune responses. Tumors are believed to utilize the UPR for survival under stressed conditions such as nutrient deprivation or treatment with chemotherapy. Other stress stimuli that activate UPR include hypoxia, disruption of protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status. There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERN1 and ERN2, respectively); 2) PKR-like ER kinase (PERK, also known as PEK, encoded by EIF2AK3); and 3) the activating transcription factor 6a (encoded by ATF6). Each of these three sensors is regulated similarly through binding of the ER luminal 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.

PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphorylate the eukaryotic translation initiation factor 2a (eIF2-a) and regulate translation initiation. Other family members include HRI (EIF2AK1), PKR (EIF2AK2), and GCN2 (EIF2AK4). Each eIF2 kinase responds to different cellular stress signals to regulate general translation and gene specific translational control.

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 Bi.P/Grp78 from the stress-sensing domain. Activated PERK phosphorylates and activates its downstream substrate, eukaryotic initiation factor 2a (eIF2α), which inhibits the ribosome translation initiation complex in order to 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 eIF2α 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) 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 in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP.

Phosphorylation of eIF2 also increases translation of some mRNAs in a gene specific manner including the transcription factor ATF4. ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient uptake, amino acid metabolism, redox homeostasis, and autophagy. Selective inhibition of the PERK arm of the UPR is expected to profoundly affect tumor cell growth and survival. As such, compounds which inhibit PERK are believed to be useful in treating cancer. 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 (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). Studies have found that PERK may be activated in SARS-CoV through S and 3a proteins. In a separate study, a PERK kinase inhibiting dominant-negative PERK mutant suppressed transcriptional activation of Grp 78 and Grp94 promoters mediated by S proteins of SARS-CoV. Accordingly, compounds that inhibit PERK are believed to be useful in treating viral infections, such as those associated with coronaviruses. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 illustrates a kinase selectivity interaction map for Example 1. FIG. 2 illustrates a kinase selectivity interaction map for Example 9. FIG. 3 illustrates a kinase selectivity interaction map for GSK2656157. SUMMARY OF THE INVENTION 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): 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(R^3a)(R^3b)CO-₂alkyl, -O-, NR^3a, C(O), CF₂, CNOR^3bb, or a direct bond to Ar¹; R^3a is H, alkyl, or cycloalkyl; R^3b is H, alkyl, OR^3c, or NR^3dR^3e; R^3bb 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, C_0-6alkyl-O-C_{1- 12}alkyl, C_0-6alkyl-OH, C_0-6alkyl-O-C_3-12cycloalkyl, or C_0-6alkyl-O-C_3-12heterocycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, CN, NO₂, alkyl, C_0-6alkylcycloalkyl, C_0-6alkyl- O-C_1-12alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3c, R^3d and R^3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; R⁷ is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION 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 also believed to be useful in treating viral infection, for example, infections associated with a coronavirus. 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 froma compound having the structure (I):

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(R^3a)(R^3b)C_0-2alkyl, -O-, NR^3a, C(O), CF₂, CNOR^3bb, or a direct bond to Ar¹; R^3a is H, alkyl, or cycloalkyl; R^3b is H, alkyl, OR^3c, or NR^3dR^3e; R^3bb 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, C_0-6alkyl-O-C_{1- 12}alkyl, C_0-6alkyl-OH, C_0-6alkyl-O-C_3-12cycloalkyl, or C_0-6alkyl-O-C_3-12heterocycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, CN, NO₂, alkyl, C_0-6alkylcycloalkyl, C_0-6alkyl- O-C_1-12alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3c, R^3d and R^3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; R⁷ is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 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. 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 (Ia): wherein:

Y is CR^3aR^3b; R^3a is H or alkyl; R^3b is OR^3c or NR^3dR^3e; each R¹ is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_0- 6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, C_0-6alkylcycloalkyl, C_0-6alkyl-O-C_{1- 12}alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3c, R^3d and R^3e are each independently H or alkyl, optionally substituted by one or more independent G³ substituents; X is CR⁷ or N; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; R⁷ is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; Each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; 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 (Ib):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_{0- 6}alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_{0- 6}alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3a is H or alkyl; R^3b is OR^3c or NR^3dR^3e; R^3c, R^3d and R^3e are each independently H or alkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. The present invention yet further provides the PERK inhibitor having the following structure (Ic):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent G² substituents; R^3b is OR^3c; R^3c is H or alkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; 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 (Id):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, or CN; R⁶ is H, alkyl, CD₃, or CF₃; 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 (Ie): wherein:

X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R⁵ is H, methyl, ethyl, isopropyl,

, optionally substituted by one or more independent H, deuterium, C_1-6alkyl, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. In some embodiments, X is CH. In some embodiments, R¹, for each occurrence, is independently H, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, OCF₃, CF₃, fluoro, or chloro. In some embodiments, R², for each occurrence, is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF₃ or OCF₃. In some embodiments, R⁵ is H, CH₃, or CD₃. In some embodiments, R⁶ is H, methyl, ethyl, isopropyl, CD₃, or CF₃. In some embodiments, each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-6alkyl, C_3-8cycloalkyl, C_3-8heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂. In some embodiments, each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-3alkyl, C_3-6cycloalkyl, C_3-6heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂. In some embodiments, Ar¹ is pyridyl, optionally substituted by one or more independent R¹ substituents. In some embodiments, Ar¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

, optionally substituted by one or more independent R¹ substituents.

In some embodiments, Ar² is monocyclic-aryl or monocyclic-heteroaryl, optionally substituted by one or more independent R² substituents. In some embodiments, Y is a direct bond to Ar¹, -CH₂-, -C(H)(OH)-, -C(CH₃)(OH)-, - C(H)(-OCH₃)-, -(CH₂)₂-, -O-, -NH-, -N(CH₃)-, -C(H)(NH₂)-, or -CF₂-. The present invention yet further provides a compound having the following structure (If):

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(R^3a)(R^3b)C_0-2alkyl, -O-, NR^3a, CF₂, or a direct bond to Ar¹; R^3a is H, or alkyl; R^3b is H, OR^3c, or NR^3dR^3e; each R¹ is independently halo, alkyl, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more halogen substituents; each R² is independently halo, alkyl, C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more halogen substituents; R^3c, R^3d and R^3e are each independently H or alkyl; R⁵ is alkyl; and R⁶ is H, alkyl, or CF₃; or a pharmaceutically acceptable salt thereof. In some embodiments, Ar¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,

,

, optionally substituted by one or more independent R¹ substituents. In some embodiments, R¹, for each occurrence, is independently chloro, fluoro, ethyl, isopropyl, methyl, methoxy, or CF₃. In some embodiments, Y is a direct bond to Ar¹, -CH₂-, -C(H)(OH)-, -C(CH₃)(OH)-, -C(H)(- OCH₃)-, -(CH₂)₂-, -O-, -NH-, -N(CH₃)-, -C(H)(NH₂)-, or -CF₂-. In some embodiments, R⁴ is H. In some embodiments, Ar² is phenyl or pyridyl, optionally substituted by one or more independent R² substituents. In some embodiments, R², for each occurrence, is independently chloro, fluoro, ethyl, methyl, methoxy, CF₃, or -O-CF₃. In some embodiments, R⁵ is methyl. In some embodiments, R⁶ is H, ethyl, methyl, isopropyl or CF₃. In some embodiments, the compound is selected from: N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy-2- phenylacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy- 2-phenylacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy- 2-phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy-2- phenylpropanamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- methoxy-2-phenylacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-methoxy- 2-phenylacetamide; 2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; (R)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; (S)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethyl)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethyl)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(6- methylpyridin-2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(6- methylpyridin-2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(o- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(m- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(p- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- isopropylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(naphthalen- 2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(naphthalen- 1-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(quinolin-5- yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(isoquinolin- 4-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(isoquinolin- 5-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2,3- dimethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclopropylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclobutylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclopentylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclohexylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)benzamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-3- phenylpropanamide; phenyl (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)carbamate; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-3-phenylurea; 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-1-methyl-1- phenylurea; or a pharmaceutically acceptable salt thereof. Embodiments of the present invention further provide a pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof including one or more pharmaceutically acceptable carriers, diluents, or excipients. Embodiments of the present invention further provide a compound or pharmaceutically acceptable salt thereof for use in therapy. Embodiments of the present invention further provide a method for treating a viral infection in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of any of the compounds described herein. In some embodiments, the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id,Ie, If, or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is associated with an RNA virus. In some 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 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 is SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV-2. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus infection is COVID-19. Embodiments of the invention further provide methods of treating a coronavirus infection in a patient in need of such treatment, the method comprising administering to the patient an effective amount of any of the compounds described herein. In some embodiments, the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, If, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of treating viral infections described herein further 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, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, a Fusion inhibitor, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Inosine, an Integrase inhibitor, Interferon type I, Interferon type II, Interferon type III, an Interferon, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nitazoxanide, Norvir, a nucleoside analogue, 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, 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 cells of other organisms. It may also be cultivated in cell culture. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles, also known as virions, include two or three parts: (i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of 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 particles, particularly infectious particles. Examples of viruses include, but are not limited to, viruses from the following families: Retroviridae (e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses; Picornaviridae (e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus); Caliciviridae (such as strains causing gastroenteritis, including norovirus); Togaviridae (e.g. alphaviruses, including Chikungunya virus, horse encephalitis viruses, Semlica virus, Sindbis virus, Ross fever virus rubella viruses); Flaviridae (e.g. virus hepatitis C virus, dengue virus, yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, Povassan virus and other encephalitis viruses); Coronaviridae (e.g. coronaviruses, severe acute respiratory syndrome virus (SARS), such as SARS- CoV and SARS-CoV-2 (COVID-19), and short-term coronavirus respiratory virus syndrome (MERS)); Rhabdoviridae (e.g., vesicular stomatitis virus, rabies virus); Filoviridae (e.g., Ebola virus, Marburg virus); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g., influenza viruses); Bunyaviridae (for example, hantaviruses, Sin Nombre virus, Rift Valley Fever virus, bunyaviruses, phleboviruses and nairoviruses); Arenaviridae (such as Lassa fever virus and other hemorrhagic fever viruses, Machupo virus, Junin virus); Reoviridae (e.g., reoviruses, orbiviruses, rotaviruses); Birnaviridae; Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses, e.g. small mouse virus, dog parvovirus, human parvovirus B19 and AAV; Papovaviridae (papilloma viruses, poliomaviruses, BK virus); Adenoviridae (adenoviruses); Herpesviridae (herpes simplex virus (HSV) -1 and HSV-2 ; cytomegalovirus; Epstein-Barr virus; chickenpox virus and other herpes viruses, including HSV-6); Poxviridae (variola viruses, smallpox viruses, poxviruses) and Iridoviridae (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”, “coronaviruses”, “CoV”, or “CoVs” may refer to a species in the genera of virus belonging to one of two subfamilies Coronavirinae and Torovirinae in the family Coronaviridae, in the order Nidovirales. Herein these terms may refer to the entire family of Coronavirinae (in the order Nidovirales). Coronaviruses may be defined as enveloped viruses with a positive-sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronaviruses may range from approximately 26 to 32 kilobases. The name “coronavirus” is derived from the Latin corona, meaning crown or halo, and refers to the characteristic appearance of virions under electron microscopy (E.M.) with a fringe of large surface projections creating an image reminiscent of a crown. This morphology is created by the viral spike (S) peplomers, which are proteins that populate the surface of the virus and determine host tropism. There are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta. 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 CoV strains have been identified that have been transmitted from animals to humans. For example, severe acute respiratory syndrome coronavirus (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 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, HKU1, 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 subject can feel or observe. As used herein, “treating”, e.g., of a cancer or 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. WO2018/194885, published October 25, 2018, and International Application Publication No. WO2021/041975, 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 mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. The compounds of the present invention may have spontaneous tautomeric forms. 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 structures 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 wherein the isotopic atom is ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, and/or ¹⁸O. 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 may be, for example, ¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, for example, ¹⁵N, and the like. In other embodiments, a particular isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, 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 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. 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 (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 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. 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, when used without further notation, are intended to represent all isotopes of hydrogen, such as ¹H, 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 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 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 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 with well-known principles of chemical structure connectivity. As used herein, “C_0-4alkyl” for example is used to mean an alkyl having 0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group. 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, C₁-C_n as in “C₁– 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-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 C_0-nalkyl-O-C_0-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-C_0-malkyl” is attached directly to the preceding moiety. When m is zero, the alkoxy group is “C_0-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 non- aromatic carbon-carbon double bonds may be present. Thus, C₂-C_n alkenyl is defined to include 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 C₆ 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 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-C_n alkynyl is defined to include groups having 1, 2...., n-1 or n 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 C₂-C_n alkynyl. An embodiment can be C₂-C₁₂ alkynyl, C3-C₁₂ 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, "heteroalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. 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. "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, 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 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 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 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 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-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 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 (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, 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, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, 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 bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH₂-(C₅H₄N), -CH₂-CH₂-(C₅H₄N) and the like. 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 of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). 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. 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. As used herein, the term “carbonyl” refers to a carbon atom double bonded to oxygen. A carbonyl group is denoted as R^xC(O)R^y where R^x and R^y 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 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, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as 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; 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 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 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, 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. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5^th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley- Interscience) 5^th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only methods by which to synthesize or obtain the desired compounds. 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 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 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 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 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, 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 free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance. As used herein, “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally. The compounds used in the method of the present invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. 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 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 solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles. The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect. A dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. 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 effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol.7. (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 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 drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier. The compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. The compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. 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 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 forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. 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 Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen. The compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to 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 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (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 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. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms. Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine. The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention. 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 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 In Vitro Activity Assay (isolated):

In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR.) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536 - 1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA).

Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E, coli. Perform TR-FRET kinase assays in the absence or presence of inhibitors in a reaction buffer consisting of 50 mM HEPES, pH 7.5, 10 mM MgCb, 1.0 niM EGTA, and 0.01% Brij-35, and 100 - 200 nM GFP-elF2a substrate. PKR assays contain 14 ng/mLenzyme 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 μΜ 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 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, C = absolute 1C 50 (concentration causing 50% inhibition), and D = hill slope.

The compounds of Examples 1 to 171 were tested essentially as described above and exhibited IC₅₀ values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 171 inhibit isolated PERK enzyme activity in vitro.

PERK Cellular Assay

Stable cell lines were created in HEK293 cells using lentiviral particles harboring an expression vector for GFP- eIF2α, Cells were selected using puromycin and enriched using fluorescence activated cell sorting against GFP. HEK293-EGFP-eIF2α cells were plated at 5000 cells/well in 384-well assay plates and incubated overnight at 37°C, 5% CO₂. Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% CO₂ prior to induction of ER stress by addition of tunicamycin to 1mM for 2 hours. Cells were lysed and TR-FRET was measured in an EnVision plate reader (PerkinElmer). FRET ratio data was normalized to signal from lysates treated with DMSO vehicle control and plotted as percent inhibition against 10-point; 3-fold dilution series of inhibitors. IC50 values were calculated using 4-parameter logistical fitting in XLFit. The compounds of Examples 1 to 171 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 171 inhibit EIF2a in vitro. The results of exemplary compounds of formula (I) are shown in Table 1. Key: A is 0.001 to 0.025 µM; B is 0.026 to 0.050 µM; C is 0.051 to 0.100 µM; D is 0.101 to 0.250 µM; E is 0.251 to 0.500 µM; F is 0.501 to 1.00 µM; G is 1.001 µM to 2.00 µM; H is 2.001 µM to 3.00 µM; I is 3.001 to 4.00 µM; J is 4.001 to 5.00 µM; K is >5.00 µM; and N/A is “not available”. Table 1: Biochemical and cellular IC₅₀ data of Compounds of Formula I:

Viral Inhibition Test Compound Preparation: A stock concentration of each test article at 10mM in DMSO was utilized to prepare the working stock dilutions. A working stock was prepared in DMEM2 to 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 Vims 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.

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 A). Three-fold serial dilutions was prepared across the plate in DMEM2.

Table A: Testing Concentrations

Experimental Design:

Efficacy for each compound was tested. Each of the concentrations were evaluated in triplicate for efficacy. Veto E6 cells were cultured in 96 well plates one day prior to the day of the assay. Vero E6 cells were at greater than 90% confluency at the start of the study. Cells were inoculated at a

MOI of 0.01 TCID50/cell with SARS-CoV-2 and incubated for one hour in the absence of test articles and control drug. Following 1 hr adsorption, cells were washed and 0.2 mL DMEM2 (DMEM with 2% FBS) containing vehicle, test articles or control drug were added to the respective wells. The plates were then incubated in a humidified chamber at 37°C ± 2°C in 5 ± 2% CO₂. 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 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. Table B: Reduction In Viral CPE

The compounds of Examples 1 and 110 were tested essentially as described above and exhibited a significant reduction in viral cytopathic effect (CPE), as shown in Table B. These data demonstrate that the compounds of Examples 1 to 171 inhibit viral replication in vitro. HPLC Conditions: Method A Column: Polaris C18-A 2.6 µm C18 (100 × 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 Method A Gradient

Method B Column: Eclipse plus C18 3.5 μm 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: 254 nm Method B Gradient

Method C Column: Eclipse plus C183.5 µm 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 nm Method C Gradient

Analytical SFC Conditions: Method A Column: Chiralcel OX-H Mobile Phase: 30% Methanol in CO₂ Temperature: 40 °C Run Time: 10.0 min Detection: 210 nm Method B Column: Chiralpak IC Mobile Phase: 30% Methanol in CO₂ Temperature: 40 °C Run Time: 8.0 min Detection: 215 nm Method C Column: Chiralcel OD-H Mobile Phase: 25% Methanol in CO₂ Temperature: 40 °C Run Time: 10.0 min Detection: 215 nm Method D Column: Chiralpak IA Mobile Phase: 40% Methanol in CO₂ Temperature: 40 °C Run Time: 8.0 min Detection: 210 nm 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 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 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 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 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 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- phosphorylation [Lee, Methods, 2005], Activated PERK then phosphorylates the α-subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylated eIF2α 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 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., 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 eIF2α phosphorylation events that are readily detectable in virus-infected cells [Krähling et al., 2009],

Their knock-down of PKR via morpholino oligomers did not impact SARS-CoV-induced eIF2α phosphorylation but did significantly inhibit SARS-CoV-induced apoptosis [Krahling et al., 2009], One hypothesis is that eIF2α is phosphorylated 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 activate the PERK pathway [Minakshi et al., 2009], Accordingly, without wishing to be bound by theory, it is contemplated that the PERK/PKR- eIF2α-ATF4-GADD153 pathway plays a central role during productive coronavirus infections and thus approaches to abrogate this pathway may provide a productive mechanism of blocking viral replication and disease propagation. Therefore, the compounds of the present invention are useful in treating viral infection. Abbreviations: NMR: nuclear magnetic resonance; mHz: megahertz; DMSO-d₆: dimethyl sulfoxide-d₆; CDCl₃: deuterated chloroform; δ: chemical shift; MS: mass spectrometry; HPLC: high performance liquid chromatography; SFC: Supercritical fluid chromatography m/z: mass-to-charge ratio; [M+H]: molecular ion peak in mass spectrum; ESI: electrospray ionization; ESI⁺: electrospray ionization positive mode; ESI-: electrospray ionization negative mode; rt or RT: room temperature: min: minute(s); h: hour(s) mg: milligram; g: gram; kg: kilogram; mL: milliliter; L: liter; mmol: millimole; μM: micromole; MTBE: methyl tert-butyl ether; THF: tetrahydrofuran; HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; DIPEA or DIEA: N,N-diisopropylethylamine; HOBt: hydroxybenzotriazole; Pd(dppf)Cl₂: [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II); EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Scheme A:

Compounds of Formula A-2 where Ar² = phenyl and R² = 3-methyl can be synthesized as described below for compound A-2.1:

Synthesis of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1):

To a stirred solution of tricyclohexylphosphine (7.18 g, 25.7 mmol) in 1,4-dioxane (1.2 L) under argon 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-1.1, 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 temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (4 × 250 mL). The filtrate was washed with water (2 × 500 mL) and brine (2 × 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1, 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:

Scheme B:

Compounds of Formula B-2 where Ar¹ = 3,5-difluorophenyl and R^3a = H can be synthesized as described below for compound B-2.1:

Synthesis of (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid (B-2.1):

To a stirred solution of Amano lipase (PS) supported on Diatomite (5.0 g; purchased from Sigma-Aldrich) in methyl tert-butyl ether (MTBE, 50 mL) were added 2-(3,5-difluorophenyl)-2- hydroxyacetic 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 tert-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 (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid (B-2.1, 850 mg, yield: 34%): ¹H NMR (400 MHz, DMSO-d6) δ 7.18–7.10 (m, 3H), 5.10 (s, 1H); ESI (m/z) 187 [C₈H₆F₂O₃-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:

Scheme B1:

Compounds of Formula B-2 where Ar¹ = 3-chlorophenyl and R^3a = H can be synthesized as described below for compound B-2.1:

Synthesis of 2-acetoxy-2-(3-chlorophenyl)acetic acid (B-2.1): To a stirred solution of acetyl chloride (2.0 mL) at 0 °C was added 2-(3-chlorophenyl)-2- hydroxyacetic acid (B-1.2, 2.00 g, 10.6 mmol) portion wise over a period of 10 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to get crude material followed by co-distilled with hexanes to afford 2-acetoxy-2-(3-chlorophenyl)acetic acid (B-2.1, 2.10 g, yield: 86%) as a white solid; ¹H NMR (400 MHz, DMSO-d6): δ 7.54-7.44 (m, 4H), 5.87 (s, 1H), 2.14 (s, 3H); ESI (m/z) 228.6 [C₁₀H₉ClO₄ + H]⁺. The compounds of formula B-2 (Table B1) can be synthesized according to the procedures described for compound B-2.1:

Table B1: Compounds C-1:

Scheme B2:

Compounds of Formula B-2’ where Ar¹ = 3-trifluoromethylphenyl and R^3a = H can be synthesized as described below for compound B-2.9:

Step- 1: Synthesis of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B2-2.1):

To a stirred solution of 3-(trifluoromethyl)benzaldehyde (B2-1.1, 25.00 g, 143 mmol) at 0 °C was added ZnI ( 4.50 g, 14.3 mmol), followed drop wise addition of trimethylsilyl cyanide (17.0 mL, 172.0 mmol) and resulting reaction mixture was stirred at 0 °C for 2 h. After this time, to the above reaction mixture HCl (4N in MeOH) (100 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with saturated NaHCO₃ solution up to pH ~8, then added EtOAc (200 mL). The organic layer was washed with water (4 × 200 mL), followed by brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford methyl 2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetate (B2-2.1, 28 g, yield: 83%) as a yellow liquid; ESI (m/z) 235 [C₁₀H₉F₃O₃+H]-. Step 2: Synthesis of 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3):

To a stirred solution of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B2-2.1, 28 g, 119 mmol) in THF (70 mL), Water (20 mL), MeOH (50 mL), at room temperature LiOH (6.00 g, 143 mmol) was added and resulting reaction mixture was stirred for 12 h at same temperature. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with water (100 mL). An aqueous layer was washed with EtOAc (200 mL) to remove impurities. Then water layer was acidified with 2N HCl (pH ~ 2), an aqueous layer extracted with EtOAc(2 x 150 mL). Combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3, 25.00 g, yield: 95%) as a color less liquid: ESI (m/z) 219.1 [C₉H₇F₃O₃-H]-. Step- 3: Synthesis of 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2’9):

To a stirred solution of acetyl chloride (50 mL) at 0 °C was added 2-hydroxy-2-(3- trifluoro methyl)phenyl)acetic acid (B-1.3, 25.00 g, 113 mmol) portion wise over a period of 30 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to get crude material followed by co-distilled with hexanes to afford 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2’.9, 21.00 g, yield: 70%) as a white solid; ¹H NMR (400 MHz, DMSO-d6): δ 7.80 (t, J = 8.0 Hz, 3H), 7.68 (t, J = 8.0 Hz, 1H), 6.00 (s, 1H), 2.15 (s, 3H); ESI (m/z) 262.2 [C₁₁H₉F₃O₄ + H]⁺. The compounds of formula B-2’ (Table B2) can be synthesized according to the procedures described for compound B-2’.9: Table B2: Compounds B-2’:

Scheme C:

Compounds of Formula C-2 where Ar² = phenyl, R² = 3-F, Y² = Br, R^3a = H, Ar¹ = phenyl- R¹ and R¹ = 3-F can be synthesized as described below for compound C-2.1:

Step-1: Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3):

To a stirred solution of acetyl chloride (1.0 mL) at 0 °C was added 2-(3-fluorophenyl)-2- hydroxyacetic acid (B-1.2, 0.601 g, 3.53 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated to crude under vacuum and co-distilled with hexanes to afford 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 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)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1):

To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 0.558 g, 2.63 mmol) and 4- bromo-3-fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added N,N- diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h. 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 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-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 500 mg, yield: 60%) as a pale brown solid: ESI (m/z) 385[C₁₆H₁₂BrF₂NO₃]⁺. Step-3: Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)- 1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1):

To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bis(pinacolato)diboron (0.13 g, 0.52 mmol) and potassium acetate (51 mg, 0.52 mmol. 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 temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 × 15 mL). The filtrate was washed with water (2 × 10 mL) and brine (2 × 10 mL). 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-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1, 50 mg, yield: 60%) as a pale brown solid: ESI (m/z) 432 [C₂₂H₂₄BF₂NO₅ + H]⁺. The compounds of formula C-2 (Table C) can be synthesized according to the procedures described for compound C-2.1: Table C: Compounds C-2:

Scheme D:

Compounds of Formula D-1 where Ar² = phenyl, R² = 3-methyl, R^3a = H, Ar¹ = phenyl-R¹ and R¹ = 3-F can be synthesized as described below for compound D-1.1:

Synthesis of 2-(3-fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetamide (D-1.1):

To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-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,N-diisopropylethylamine (0.26 mL, 1.5 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (0.586, 1.54 mmol) at 0 ^oC. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 × 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 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-1,3,2-dioxaborolan-2- yl)phenyl)acetamide (D-1.1, 0.25 g, yield: 52%) as a pale brown solid: ESI (m/z) 386 [C₂₁H₂₅BFNO₄+H]⁺. The compounds of formula D-1 (Table D) can be synthesized according to the procedures described for compound D-1.1: Table D: Compounds D-1:

Scheme E:

Compounds of Formula E-4 where X = CH, R⁵ = methyl, R⁶ = methyl and Y¹ = Br can be synthesized as described for compound E-4.1:

Step-1: Synthesis of 4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-2.1):

To a stirred solution of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (E-1.1, 2.50 g, 14.9 mmol) in N-methyl-2-pyrrolidone (15 mL) was added cesium carbonate (9.71 g, 29.8 mmol) at 10 °C. After 15 min, methyl iodide (2.32 g, 1.0 mL, 16.4 mmol) was added dropwise at room temperature, and the mixture was stirred under argon atmosphere at ambient temperature for 4 h. After this time, the reaction mixture was poured into ice cold water (20 mL) and stirred for 30 min. The resulting solid was isolated by filtration and dried under vacuum to afford 4-chloro-2,7- dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-2.1, 2.0 g, yield: 74%) as a pale brown solid: ESI (m/z) 182 [C₈H₈ClN₃ + H]⁺. Step-2: Synthesis of 5-bromo-4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-3.1):

To a stirred solution of 4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-2.1, 2.00 g, 11.0 mmol) in dichloromethane (18 mL) was added N-bromosuccinimide (2.10 g, 12.1 mmol) portion-wise at 0 °C. The resulting mixture was warmed to ambient temperature, and stirring continued for 2 h. After this time, the reaction mixture was filtered, and the isolated solid was washed with water (20 mL) and dried to afford 5-bromo-4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-3.1, 1.80 g, yield: 63%) as a light brown solid: ESI (m/z) 260, 262 [C₈H₇BrClN₃ + H]⁺. Step-3: Synthesis of 5-bromo-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (E-4.1):

A solution of 5-bromo-4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (E-3.1, 1.80 g, 6.90 mmol) in 25% aqueous ammonia (17 mL) was stirred in a 100 mL autoclave. The reaction mixture was heated to 120 °C and stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature. The resulting solid was isolated by filtration, washed with water (25 mL), and dried to afford 5-bromo-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (E-4.1, 1.20 g, yield: 72%) as a light grey solid: ESI (m/z) 241, 243 [C₈H₉BrN₄ + H]⁺. The compounds of Formula E-4 (Table E) can be synthesized according to the procedures described for compound E-4.1: Table E: Compounds E-4:

Scheme F:

Compounds of Formula F-1 where Ar² = phenyl, R² = 3-methyl, X = CH, R⁵ = methyl, R⁶ = methyl and Y¹ = Br can be synthesized as described below for compound F-1.1:

Synthesis of 5-(4-amino-2-methylphenyl)-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.1):

To a stirred solution of 5-bromo-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (E-4.1, 200 mg, 0.830 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1, 270 mg, 1.16 mmol) in 2-methyltetrahydrofuran (3.0 mL) was added saturated aqueous sodium bicarbonate (2.00 mL, 1.65 mmol). The mixture was purged with argon for 10 min. Palladium(II) acetate (6.0 mg, 0.027 mmol) was added, followed by di(1-adamantyl)-n-butylphosphine (cataCXium® A) (18.0 mg, 0.0502 mmol), and the mixture was purged with argon for 10 min. The resulting reaction mixture was heated at 100 °C in a sealed tube for 12 h. After this time, the mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (2 × 5 mL). The filtrate was washed with water (5 mL) and brine (5 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% methanol/methylene chloride) to afford 5-(4-amino-2-methylphenyl)-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.1, 150 mg, yield: 68%) as a brown solid: ESI (m/z) 268 [C₁₅H₁₇N₅ + H]⁺. The compounds of formula F-1 (Table F) can be synthesized according to the procedures described for compound F-1.1: Table F: Compounds F:

Scheme G:

Compounds of Formula I can be synthesized according to the procedures for the synthesis of compound of Formula I.1 wherein X = CH, R⁵ = methyl, R⁶ = methyl, Ar² = phenyl, R² = 3- methyl, R^3a = H, Ar¹ = phenyl-R¹ and R¹ = 3-F.

The compounds of formula I (Table 1) can be synthesized according to the procedures described for compound I.1: Synthesis of N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide (I.1: Example 1 and Example 2):

To a solution of 5-(4-amino-2-methylphenyl)-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (F-1.1, 150 mg, 0.56 mmol) and 2-(3-fluorophenyl)-2-hydroxyacetic acid (B-1.2, 115 mg, 0.676 mmol) in tetrahydrofuran (1.50 mL) were added N,N-diisopropylethylamine (362 mg, 2.80 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (320 mg, 0.84 mmol) at 0 ^oC. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 × 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 4% methanol/methylene chloride) to afford N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide (I.1, 140 mg, yield: 60%) as a mixture of enantiomers as a pale brown solid: ESI (m/z) 420 [C₂₃H₂₂FN₅O₂+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 1) (60 mg) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 7.66 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.41–7.33 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.57 (d, J = 4.8 Hz, 1H), 5.54 (br s, 2H), 5.15 (d, J = 4.8 Hz, 1H), 3.68 (s, 3H), 2.39 (s, 3H), 2.14 (s, 3H); ESI (m/z): 420 [C₂₃H₂₂FN₅O₂+H]⁺; HPLC (Method A) 94.6% (AUC), t_R = 6.52 min; Chiral SFC (Chiralcel OX-H, Method A) >99% (AUC), t_R = 5.26 min. Isomer 2 (Example 2) (48 mg) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 7.66 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43–7.33 (m, 3H), 7.14 (d, J =8.0 Hz, 2H), 7.02 (s, 1H), 6.58 (d, J = 4.8 Hz, 1H), 5.54 (br s, 2H), 5.15 (d, J = 4.4 Hz, 1H), 3.68 (s, 3H), 2.39 (s, 3H), 2.14 (s, 3H); ESI (m/z): 420 [C₂₃H₂₂FN₅O₂+H]⁺; HPLC (Method A) 98.1% (AUC), t_R = 6.51 min; Chiral SFC (Chiralcel OX-H, Method A) 95.6% (AUC), t_R = 7.30 min. Scheme H:

Compounds of Formula I can be synthesized according to the procedures for the synthesis of compound of Formula I.2 wherein Y¹ = Br, X = CH, R⁵ = methyl, R⁶ = H, Ar² = phenyl, R² = 3- F, R^3a = H, Ar¹ = phenyl-R¹ and R¹ = 3-F. N

Synthesis of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-

To a stirred solution of 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (E-4.2, 0.500 g, 2.20 mmol) and 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(3- fluorophenyl)-2-oxoethyl acetate (C-3.1, 1.14 g, 2.64 mmol) in a mixture of 1,4-dioxane and water (3:1, 20 mL) was purged with argon for 5 min. Potassium carbonate (0.6 g, 4.40 mmol) was added, followed by 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (90 mg, 0.11 mmol), and the mixture was purged with argon for 10 min. The resulting reaction mixture was heated at 120 °C in a microwave for 1 h. After this time, the mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 × 20 mL). The filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reversed phase column chromatography (C18, 40% acetonitrile/water) to afford N- (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide (I.2, 200 mg, yield: 18%) as a brown solid: ESI (m/z) 410 [C₂₁H₁₇F₂N₅O+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 3) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.13 (s, 1H), 7.83–7.79 (d, J = 12.4 Hz, 1H), 7.63–7.61 (d, J = 8 Hz, 1H), 7.44–7.27 (m, 5H), 7.16–7.12 (m, 1H), 6.70–6.69 (d, J = 4.4 Hz, 1H), 6.00 (br s, 2H), 5.20–5.19 (d, J = 4.4 Hz, 1H), 3.73 (s, 3H); ESI (m/z) 410 [C₂₁H₁₇F₂N₅O+H]⁺; HPLC (Method B) 96.7% (AUC), t_R = 7.16 min; Chiral SFC (Chiralpak IA, Method D) 98.9% (AUC), t_R = 1.83 min. Isomer 2 (Example 4) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.13 (s, 1H), 7.83–7.79 (d, J = 12.4 Hz, 1H), 7.63–7.61 (d, J = 8 Hz, 1H), 7.44–7.27 (m, 5H), 7.16–7.12 (m, 1H), 6.70–6.69 (d, J = 4.4 Hz, 1H), 6.00 (br s, 2H), 5.20–5.19 (d, J = 4.4 Hz, 1H), 3.73 (s, 3H); ESI (m/z) 410 [C₂₁H₁₇F₂N₅O+H]⁺; HPLC (Method B) 96.5% (AUC), t_R = 7.16 min; Chiral SFC (Chiralpak IA, Method D) 97.1% (AUC), t_R = 2.57 min. Scheme I:

Compounds of Formula I can be synthesized according to the procedures for the synthesis of compound of Formula I-2 or I-3, wherein R⁶ = H, X = CH, R⁵ = methyl, Ar² = phenyl, R² = 3- CH₃, R^3a = H, R^3b’ = NH₂, Ar¹ = phenyl:

Step-1: Synthesis of (R)-tert-butyl (2-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3-methyl phenyl)amino)-2-oxo-1-phenylethyl)carbamate (I-2.1):

To a solution of (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I-1.1, 0.51 g, 2.06 mmol), 5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.2, 0.25 g, 1.37 mmol) in DMF (7.0 mL) were added DIPEA (1.20 mL, 6.88 mmol) followed by HATU (0.78 g, 2.06 mmol) at room temperature and stirred for 15 min. After this time, reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL u 2) followed by brine (15 mL u 2). The Organic layer was separated, dried over anhydrous Na2SO₄ and volatiles were removed under reduced pressure. The crude was purified by coloumn chromatography (silica gel, 50% EtOAc in hexanes) to afford (R)-tert-butyl (2-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)amino)-2-oxo-1-phenylethyl)carbamate (I-2.1, 0.21 g, yield: 30%) as pale yellow solid; ESI (m/z) 487 [C₂₇H₃₀N₆O₃ + H]⁺. Step-2: Synthesis of (R)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methyl phenyl)-2-phenylacetamide (I-3.1 = Example 26):

To a solution of (R)-tert-butyl (2-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3-methylphenyl)amino)-2-oxo-1-phenylethyl)carbamate (I-2.1, 0.20 g, 0.41 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (0.62 mL, 8.23 mmol) at 0 ^oC and resulting reaction mixture was stirred for 15 h at room temperature. Volatiles were removed under reduced pressure to afford crude, which was diluted with dichloromethane (50 mL), adjusted pH to ~ 9 (by saturated NaHCO₃ solution). The Organic layer was separated, washed with water (20 mL x 2), brine (15 mL x 2), dried over anhydrous Na2SO₄ and organic layer was removed under reduced pressure to afford (R)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide (I-3.1, 0.13 g, yield: 81%) as a white solid; ¹H-NMR (400 MHz, DMSO- d6) δ 10.22 (brs, 1H), 8.11 (s, 1H), 7.58 (d, J = 8.00 Hz, 2H), 7.55 (d, J = 4.00 Hz, 2H), 7.54-7.48 (m, 2H), 7.36- 7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.27 (d, J = 4.00 Hz, 1H), 7.12 (s, 1H), 5.70 (brs, 2H), 4.55 (s, 1H), 3.72 (s, 3H), 2.20 (s, 3H); ESI (m/z) 387 [C₂₂H₂₂N₆O + H]⁺. Scheme J:

Compounds of Formula J-2 can be synthesized according to the procedures for the synthesis of compound of Formula J-2.1 wherein X = CH, R⁵ = methyl, R⁶ = H, Ar² = phenyl, R² = 3-methyl, Ar¹ = 6-methylpyridin-2-yl:

Synthesis of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl phenyl)-2-(6- methylpyridin-2-yl)acetamide (J-2.1 = Example 136): To a solution of 5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.2, 0.20 g, 0.79 mmol), 2-(6-methylpyridin-2-yl)acetic acid (J-1.1, 0.14 g, 0.94 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (0.42 mL, 2.37 mmol) followed by HATU (0.36 g, 0.94 mmol) at 0 ^oC. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Then reaction mixture was cooled to 0 ^oC, quenched with ice cold water (10 mL), extracted with ethyl acetate (2 x 20 mL). The organic layer was washed brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% methanol/dichloromethane) to to afford N-(4-(4-amino-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(6-methylpyridin-2-yl)acetamide (J-2.1, 0.20 g, yield: 78%) as an off-white solid; ¹H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.13 (s, 1H), 7.66-7.61 (m, 2H), 7.53 (s, 1H), 7.21-7.14 (m, 4H), 5.74 (s, 2H), 3.81 (s, 2H), 3.74 (s, 3H), 2.46 (s, 3H), 2.16 (s, 3H); ESI (m/z) 387 [C₂₂H₂₂N₆O + H]⁺. Scheme K: Synthesis of phenyl (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methyl phenyl)carbamate (Example 169):

To a solution of 5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.2, 0.20 g, 0.79 mmol) and in CH₂Cl₂ (15 mL) were added pyridine (1.27 mL, 0.95 mmol), phenyl carbonochloridate (1.18 mL, 0.95 mmol) at 0 ^oC 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-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)carbamate (Example 169, 0.09 g, yield: 40%) as off white solid; ¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (s, 1H), 8.13 (s, 1H), 7.42-7.50 (m, 4H), 7.15-7.29 (m, 5H), 5.76 (brs, 2H), 3.74 (s, 3H), 2.17 (s, 3H); ESI (m/z) 374 [C₂₁H₁₉N₅O₂ + H]⁺. Scheme L: Synthesis of 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl phenyl)-3-phenylurea (Example 170):

To a solution of 5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.2, 0.25 g, 0.99 mmol) and in THF (10 mL) was added isocyanatobenzene (1.18 mL, 1.09 mmol) at -10 ^oC, then resulting reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2x 25 mL), obtained organic solvent was washed with brine solution (50 mL) and dried over anhydrous sodium sulfate, concentrated under vacuum. The crude product was purified by was purified by column chromatography (silica gel, 4% MeOH in dichloromethane) afforded 1-(4-(4-amino-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl phenyl)-3-phenylurea (Example 170, 0.11 g, yield: 30%) as an off white solid; ¹H-NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.00 Hz, 2H), 8.13 (s, 1H), 7.44- 7.47 (m, 3H), 7.36 (dd, J = 8.00 Hz, 1H), 7.28 (t, J = 8.00 Hz, 2H), 7.16 (s, 1H), 7.13 (s, 1H), 6.97 (t, J = 8.00 Hz, 1H), 5.75 (s, 2H), 3.74 (s, 3H), 2.17 (s, 3H); ESI (m/z) 373 [C₂₁H₂₀N₆O + H]⁺. Scheme M: Synthesis of 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl phenyl)-1-methyl-1-phenylurea (Example 171):

To a solution of 5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (F-1.2, 0.15 g, 0.59 mmol), N-methyl aniline (0.95 g, 0.89 mmol) in DMF (10 mL) was added CDI (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 chromatography (silica gel, 5% MeOH in chloroform) afforded 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl phenyl)-1-methyl-1- phenylurea (Example 171, 0.10 g, yield: 43%) as an off white solid; ¹H NMR (400 MHz, DMSO- d₆): δ 8.19 (s, 1H), 8.12 (s, 1H), 7.33-7.44 (m, 6H), 7.24-7.28 (m, 1H), 7.08-7.12 (m, 2H), 5.76 (brs, 2H), 3.73 (s, 3H), 3.28 (s, 3H), 2.12 (s, 3H); ESI (m/z) 387 [C₂₂H₂₂N₆O+H]⁺. The compounds of formula I (Table 1) can be synthesized according to the procedures described in Scheme G, Scheme H, Scheme I, Scheme J, Scheme K, Scheme L, and Scheme M: Table 1: Compounds of Formula I:

Solubility Compound of Formula Ic when R^3b = OH (Example 6) has the benefit of additional PERK inhibitory effects (biochemical and cellular potency) and increased solubility versus compound of Formula Ic where R^3b = H, Compound A (synthesized according to Scheme G where B-1 is replaced with phenylacetic acid) as noted in Table 2, below. Table 2: Biochemical potency, cellular potency and solubility comparison of Compound A versus Example 6

Kinase Selectivity Compound of Formula Id when R⁶ = Me (Example 1) is more selective than compound of Formula (Id) where R⁶ = H (Example 9) and multi-kinase inhibitor GSK2656157 as noted in Table 3, Treespot^TM analysis in FIGS. 1-3 (experiments performed by KINOMEscan®, San Diego, CA), and Table 4 (experiments performed by KINOMEscan®, San Diego, CA). Table 3: Structures of Examples 1 and 9 where R variables refer to Formula (Id)

Structure of GSK2656157:

Table 4: KINOMEscan® in vitro competition binding assay for select kinases for Examples 1, 9 and GSK2656157 where “Inhibition” refers to greater than 50% inhibition and “No Inhibition” refers to less than 50% inhibition.

References Adrian L. Smith et al., Discovery of 1H-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 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. 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 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S Heindryckx, 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 Biol. 2012, 32, 5129-5139

Bi, M.; Naczki, C.; Koritzinsky, M.; Pels, D.; Blais, J.; Hu, N.; Harding, H.; Novoa, I; Varia, M.; R aleigh, J.;Scheuner, D.; Kaufman, R. J.; Bell, J.; Ron, D.; Wouters, B. G.; Koumenis, C. ER stress- regulated translation increases tolerance to extreme hypoxia and promotes tumor growth EMBO J 2005, 24, 3470-3481

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/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth Cancer Biol Ther. 2006, 5, 723- 728

Jeffrey M. Axten, Stuart P. Romeril, Arthur Shu, Jeffrey Ralph, Jesús R Medina, Yanhong Feng, William Hoi Hong Li, Seth W. Grant, Dirk A. Heerding, Elisabeth Minthorn, Thomas Mencken, Nathan Gaul, Aaron Goetz, Thomas Stanley, Annie M. Hassell, Robert T. Gampe, Charity Atkins, and Rakesh Kumar. Discovery of GSK2656157: An Optimized PERK inhibitor Selected for Preciinicai Development. ACS Medicinal Chemistry Letters 20134 (10), 964-968.

Diego Rojas-Rivera.1,2, Tinneke Delvaeye1,2,3, Ria Roelandt.1,2, Wirn Nerinckx4,5, Koen Augustyns6, Peter Vandenabeelel,2 and Mathieu JM Bertrand. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Ceil Death and Differentiation (2017) 24, 1100-1110.

Krahling, V.; Stein, D.A.; Spiegel, M.; Weber, F.; Mühlberger, E. Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity. J. Virol. 2009, 83, 2298-2309.

Minakshi, R.; Padhan, K.; Rani, M.; Khan, N.; Ahmad, F.; Jameel, S. The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregul ation of the Type 1 Interferon Receptor. PLoS ONE 2009, 4, e8342. Chan, C.-P.; Siu, K.-L.; Chin, K.-T.; Yuen, K.-Y.; Zheng, B.; Jin, D.-Y. Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. J. Virol. 2006, 80, 9279–9287. Siu, K.-L.; Chan, C.-P.; Kok, K.-H.; C-Y Woo, P.; Jin, D.-Y. Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus HKU1. Cell Biosci. 2014, 4, 1–9. 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. 2. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of the formula (I):

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(R^3a)(R^3b)C_0-2alkyl, -O-, NR^3a, C(O), CF₂, CNOR^3bb, or a direct bond to Ar¹; R^3a is H, alkyl, or cycloalkyl; R^3b is H, alkyl, OR^3c, or NR^3dR^3e; R^3bb 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, C_0-6alkyl-O-C_{1- 12}alkyl, C_0-6alkyl-OH, C_0-6alkyl-O-C_3-12cycloalkyl, or C_0-6alkyl-O-C_3-12heterocycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, CN, NO₂, alkyl, C_0-6alkylcycloalkyl, C_0-6alkyl- O-C_1-12alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3c, R^3d and R^3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; R⁷ is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ are each independently selected from H, deuterium, halo, CN, NO₂, alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, and NO₂; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 or 2, wherein the PERK inhibitor is selected from a compound of formula (Ia):

_wherein: Y is CR^3aR^3b; R^3a is H or alkyl; R^3b is OR^3c or NR^3dR^3e; each R¹ is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_{0- 6}alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, C_0-6alkylcycloalkyl, C_0-6alkyl-O-C_{1- 12}alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3c, R^3d and R^3e are each independently H or alkyl, optionally substituted by one or more independent G³ substituents; X is CR⁷ or N; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; R⁷ is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 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 (Ib): wherein:

X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_{0- 6}alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, cycloalkyl, C_0-6alkyl-O-C_1-12alkyl, C_{0- 6}alkyl-OH, or C_0-6alkyl-O-C_3-12cycloalkyl, optionally substituted by one or more independent G² substituents; R^3a is H or alkyl; R^3b is OR^3c or NR^3dR^3e; R^3c, R^3d and R^3e are each independently H or alkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; p is 0, 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):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent G¹ substituents; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent G² substituents; R^3b is OR^3c; R^3c is H or alkyl, optionally substituted by one or more independent G³ substituents; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G⁴ substituents; R⁶ is H, alkyl, CD₃, or CF₃; each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-12alkyl, C_{0- 12}alkylC_3-12cycloalkyl, C_0-12alkylC_3-12heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂; R⁸, R⁹, or R¹⁰ 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 NO₂; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 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 of formula (Id):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R⁵ is H, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, C_1-6alkyl, halo, OH, or CN; R⁶ is H, alkyl, CD₃, or CF₃; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1-6, wherein the PERK inhibitor is selected from a compound of formula (Ie):

wherein: X is CH or N; each R¹ is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R² is independently H, deuterium, halo, alkyl, C_0-6alkyl-OH, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R⁵ is H, methyl, ethyl, isopropyl,

, optionally substituted by one or more independent H, deuterium, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

8. The method according to any one of claims 2-7, wherein X is CH.

9. The method according to any one of claims 2-7, wherein R¹, for each occurrence, is independently H, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, CF₃, OCF₃, fluoro, or chloro.

10. The method according to any of one of claims 2-7, wherein R², for each occurrence, is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF₃ or OCF₃.

11. The method according to any one of claims 2-7, wherein R⁵ is H, CH₃, or CD₃.

12. The method according to any one of claims 2-6, wherein R⁶ is H, methyl, ethyl, isopropyl, CD₃, or CF₃.

13. The method according to any one of claims 2-5, wherein each G¹, G², G³, or G⁴ is independently H, deuterium, halo, CN, NO₂, C_1-6alkyl, C_3-8cycloalkyl, C_3-8heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂.

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, C_1-3alkyl, C_3-6cycloalkyl, C_3-6heterocycloalkyl, OR⁸, NR⁸R⁹, C(O)R⁸, C(O)OR⁸, C(O)NR⁸R⁹, OC(O)R⁸, OC(O)OR⁸, OC(O)NR⁸R⁹, N(R¹⁰)C(O)R⁸, N(R¹⁰)C(O)OR⁸, N(R¹⁰)C(O)NR⁸R⁹, S(O)_nR⁸, S(O)_nOR⁸, S(O)_nNR⁸R⁹, N(R¹⁰)S(O)_nR⁸, N(R¹⁰)S(O)_nOR⁸, or N(R¹⁰)S(O)_nNR⁸R⁹, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO₂.

15. The method according to claim 1, wherein Ar¹ is pyridyl, optionally substituted by one or more independent R¹ substituents.

16. The method according to claim 1, wherein Ar¹ is cyclopropyl, cyclobutyl, cyclopentyl,

17. The method according to claim 1, wherein Ar² is monocyclic-aryl or monocyclic-heteroaryl, optionally substituted by one or more independent R² substituents.

18. The method according to claim 1, wherein Y is a direct bond to Ar¹, -CH₂-, -C(H)(OH)-, - C(CH₃)(OH)-, -C(H)(-OCH₃)-, -(CH₂)₂-, -O-, -NH-, -N(CH₃)-, -C(H)(NH₂)-, or -CF₂-.

19. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of formula (If):

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(R^3a)(R^3b)C_0-2alkyl, -O-, NR^3a, CF₂, or a direct bond to Ar¹; R^3a is H, or alkyl; R^3b is H, OR^3c, or NR^3dR^3e; each R¹ is independently halo, alkyl, or C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more halogen substituents; each R² is independently halo, alkyl, C_0-6alkyl-O-C_1-12alkyl, optionally substituted by one or more halogen substituents; R^3c, R^3d and R^3e are each independently H or alkyl; R⁵ is alkyl; and R⁶ is H, alkyl, or CF₃; or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19, wherein Ar¹ is cyclopropyl, cyclobutyl, cyclopentyl,

21. The method according to claim 20, wherein R¹, for each occurrence, is independently chloro, fluoro, ethyl, isopropyl, methyl, methoxy, or CF₃.

22. The method according to any one of claims 19-21, wherein Y is a direct bond to Ar¹, -CH₂-, -C(H)(OH)-, -C(CH₃)(OH)-, -C(H)(-OCH₃)-, -(CH₂)₂-, -O-, -NH-, -N(CH₃)-, -C(H)(NH₂)-, or -CF₂- .

23. The method according to any one of claims 19-22, wherein Ar² is phenyl or pyridyl, optionally substituted by one or more independent R² substituents.

24. The method according to claim 23, wherein R², for each occurrence, is independently chloro, fluoro, ethyl, methyl, methoxy, CF₃, or -O-CF₃.

25. The method according to any one of claims 19-24, wherein R⁵ is methyl.

26. The method according to any one of claims 19-25, wherein R⁶ is H, ethyl, methyl, isopropyl or CF₃.

27. The method according to claim 1, wherein the PERK inhibitor is a compound selected from the group consisting of: N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy-2- phenylacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy- 2-phenylacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy- 2-phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-hydroxy-2- phenylpropanamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- methoxy-2-phenylacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-methoxy- 2-phenylacetamide; 2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; (R)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; (S)-2-amino-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethoxy)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethyl)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethyl)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- (trifluoromethoxy)phenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (R)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(4-amino-2-isopropyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(6- methylpyridin-2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(6- methylpyridin-2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- phenylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- methoxyphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(o- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(m- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(p- tolyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- ethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- isopropylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- chlorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(naphthalen- 2-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(naphthalen- 1-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(quinolin-5- yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(isoquinolin- 4-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(isoquinolin- 5-yl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(4- (trifluoromethyl)phenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(3- fluorophenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2-(2,3- dimethylphenyl)acetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclopropylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclobutylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclopentylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-2- cyclohexylacetamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)benzamide; N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-3- phenylpropanamide; phenyl (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)carbamate; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-3-phenylurea; 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-1-methyl-1- phenylurea; or a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 1-27, wherein the compound or a pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers, diluents, or excipients.

29. The method according to any one of claims 1-27, wherein the viral infection is associated with a coronavirus.

30. The method according to claim 29, wherein the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV.

31. The method according to any one of claims 1-30, wherein the patient is a mammal.

32. The method according to any one of claims 1-30, wherein the patient is a human.