Pyrrolopyridine and pyrrolopyridazine compounds and application thereof as PKR inhibitors

Abstract

The present invention relates to compositions and methods of use thereof, e.g., for treating and preventing neurological diseases, neuroinflammatory diseases, cognitive disorders, or cancer in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a PCT international application claiming priority to U.S. Provisional Patent Application No. 63 / 434,853 filed on December 22, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates generally to the field of compositions comprising one or more pyrrolopyridine or pyrrolopyridazine derivatives, and to methods of using the same, for example, in the treatment of protein kinase-R (PKR)-related diseases. Background Art

[0004] Neurodegenerative disorders (NDs) are a class of diseases characterized by the expression of characteristic misfolded proteins that aggregate and induce neuronal toxicity and death. Various NDs are known, including multiple sclerosis, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), and prion diseases, among others. Currently, there are no reliable treatments that can significantly slow or halt disease progression. Against this backdrop, there is a need to develop therapeutic and drug targets that can prevent or slow the pathogenesis of neurodegenerative disorders.

[0005] The above examples of the related art and its related limitations are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those skilled in the art after reading the specification. Summary of the Invention

[0006] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools, and methods, which are intended to be exemplary and illustrative, not limiting in scope.

[0007] In one aspect of the present invention, there is a compound or a salt thereof, wherein the compound is represented by or comprises Formula I or Formula IB:

[0008]

[0009]

[0010] in: represents a single bond or a double bond;

[0011] Each L is absent or independently includes optionally substituted C1-C6 alkyl, N, NH, S and O, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1-、-(C1-C6)-NH-(C1-C6) 0-1 - or a combination thereof;

[0012] Each X1 is independently selected from CH, C or N;

[0013] At least one X1 is N;

[0014] X includes S, O, N or NH;

[0015] Each R1 independently represents hydrogen, or includes the following substituents: halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) R1 represents a substituent;

[0016] each of R2, R3 and R4 independently represents hydrogen, or is selected from halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof;

[0017] wherein each R independently represents hydrogen, or is selected from optionally substituted C1-C 10 Alkyl, optionally substituted C3-C10 Cycloalkyl, optionally substituted C3-C 10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

[0018] In one embodiment, the compound is represented by or comprises Formula IIA or Formula IIB:

[0019]

[0020] In one embodiment, the compound is represented by or comprises Formula III:

[0021]

[0022] In one embodiment, each R1 independently represents hydrogen, or comprises a substituent comprising halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR or a combination thereof; wherein at least one R1 represents said substituent.

[0023] In one embodiment, the compound is represented by or comprises Formula IV:

[0024]

[0025] wherein R1 is selected from halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, -CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, or a combination thereof.

[0026] In one embodiment, R2 represents hydrogen, or comprises the following substituents: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-SR, C1-C6 alkyl-Z, -Z, optionally substituted C3-C8 cycloalkyl, optionally substituted (C5-C6) heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; wherein Z is selected from -CO2R, CONR2, -CNNR2 , -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -C02R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, or a combination thereof.

[0027] In one embodiment, R3 and R4 each independently represent hydrogen, or a substituent comprising halogen, unsaturated C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof.

[0028] In one embodiment, the compound is represented by or comprises Formula V or Formula VI:

[0029]

[0030]

[0031] wherein Y is absent or selected from (C0-C6)alkaryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl , optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, or a combination thereof; and wherein R4 is selected from hydrogen, halogen, C1-C6 haloalkyl, C1-C6 alkyl, heterocyclyl optionally substituted by Y and aryl optionally substituted by Y; wherein the aryl is selected from pyridine, phenyl, pyrimidine, pyridazine, pyrazine, triazine, pyrazole, pyrrole, triazole, imidazole, indole, isoindole, isoindolin-1-one, indazole, benzimidazole, azaindazole, purine, azaindole and dihydroindole or a combination thereof.

[0032] In one embodiment, R2 represents hydrogen, or comprises the following substituents: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, C3-C6 cycloalkyl optionally substituted by Y, and C6 aryl optionally comprising a heteroatom selected from N and O and optionally substituted by Y; wherein the C6 aryl is selected from pyridine, phenyl, pyrimidine, pyridazine, pyrazine, triazine or a combination thereof.

[0033] In one embodiment, R2 represents a substituent comprising any of the following: (i) C1-C6 alkyl, or C1-C6 alkyl-CONR2; and (ii) C5-C6 cycloalkyl optionally substituted with halogen, -NO2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, hydroxy(C1-C6 alkyl), -CN, -OH, -(C=O)NH2, -CON(C1-C6 alkyl)2, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), C1-C6 haloalkyl and -SO2(C1-C6 alkyl), or a combination thereof; wherein the C5-C6 cycloalkyl is selected from cyclopentane, cyclohexane, pyridine and phenyl, or a combination thereof.

[0034] In one embodiment, R2 represents a substituent comprising any of the following:

[0035] wherein Y' is selected from hydrogen, halogen, -NO2, -NH2, -OMe, -(C=O)NH2, -SO2(C1-C6) and C1-C6 haloalkyl, or a combination thereof.

[0036] In one embodiment, R4 comprises or is represented by:

[0037] Where B includes any of the following:

[0038]

[0039] or absent, and wherein X1 is selected from C, CH and N.

[0040] In one embodiment, R4 is represented by any of the following:

[0041]

[0042] wherein A comprises a heteroatom selected from N, O, S and P; wherein X' comprises halogen, hydroxy, -CN, nitro, mercapto, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), amino(C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, -CO2R, -CON(R') 0-2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR', -NHCNR', -NC(=O)OR', -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO2R', -SOR', -SR', -SO2OR', -SON(R')2, -CO2H, or a combination thereof; wherein X1 is selected from C, CH, and N; and wherein Cy comprises optionally substituted (C5-C6)heterocyclyl, optionally substituted C1-C6 alkyl-(C5-C6)heterocyclyl, optionally substituted alkaryl, optionally substituted (C5-C6)heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted cycloalkyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; and wherein n is between 0 and 5.

[0043] In one embodiment, R4 is an aryl group selected from pyridine, phenyl, pyrimidine, pyridazine, pyrazine, triazine, pyrazole, indole, azaindole, dihydroindole and isoindolin-1-one or a combination thereof; wherein the aryl group is optionally replaced by Y, Any one or combination thereof can be substituted.

[0044] In one embodiment, R1 is selected from halogen, -NO2, -CN, -(C=O)NH2, -CONH(C1-C6 alkyl)2, C1-C6 haloalkyl, -CO2(C1-C6 alkyl), -CO2H, -SO2H, -SO2(C1-C6 alkyl) or a combination thereof.

[0045] In one embodiment, the compound is stable in aqueous solution for at least 1 hour.

[0046] In another aspect, a compound represented by or comprising Formula IA or Formula IB is provided:

[0047] Formula IB, in: represents a single bond or a double bond; each L is absent or independently includes optionally substituted C1-C6 alkyl, N, NH, S and O, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1- or any combination thereof; each X1 is independently selected from CH, C or N, and at least one X1 is N; X includes S, O, N or NH; each R1 independently represents hydrogen, or includes the following substituents: halogen, -NO2, -CN, -OH, -(C=O)NH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, -OR, -(C=O)NH2, -C02R, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, - NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), C1-C6 mercaptoalkyl, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl), -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; wherein at least one R1 represents such a substituent;Any one of R2, R3 and R4 is independently H or represents a substituent including the following: halogen, -NO2, -CN, -OH, -OR, -SR, -(C=O)NH2, -CONR2, -C02R, -S02R, oxo, carbonyl, amino, C1-C6 mercaptoalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, imino, thio, carbonyl, aminoalkyl, fluoroalkyl, optionally substituted alkaryl / heteroaryl, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, -NR2, - MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -C(=O)-R, -S-C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl or a combination thereof; or any one of R2, R3 and R4 is absent; wherein at least one of R2 and R3 is not H or is absent; wherein M is selected from -O-, -S-, -NH-, -C(=O)-, -CONR-, -CNNR-, -CSNR-, -CONH-O-, -CONH-NH-, -NHCO-, -NHCSR-, -NHCN-, -NC(=O)O-, -NC( =O)N-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SO2O-, -SONR-, -NHNR-, -CO2-, -OCO-, -OC(=O)O-, -OC(=O)N-, -OC(=S)O- and -OC(=S)N-; wherein W represents an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 heterocyclyl, an optionally substituted aryl, an optionally substituted alkaryl / heteroaryl or an optionally substituted heteroaryl; wherein each R independently represents hydrogen or is selected from: optionally substituted C1-C8; 10 Alkyl, optionally substituted C1-C 10 Alkenyl / alkynyl, hydroxy, amino, -NH2, -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, -OR, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, optionally substituted C3-C10 Cycloalkyl, optionally substituted C1-C 10 Alkaryl (eg benzyl), optionally substituted C1-C 10 Alkyl-C3-C 10 Cycloalkyl, optionally substituted C3-C 10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; or a salt thereof, wherein the compound includes any tautomer, any isotope, or any salt thereof.

[0048] In one embodiment, the compound is represented by or comprises Formula III or Formula IIIA:

[0049]

[0050] wherein R1 is selected from halogen, cyano and carboxamido (i.e., -(C=O)NH2 or -NH(C=O)H); and wherein R2 represents H or a substituent comprising C1-C6 haloalkyl, C1-C6 fluoroalkyl, -NR2, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, optionally substituted C5 or C6 heteroaryl; and if R2 is H, then R3 is not H.

[0051] In one embodiment, the compound is represented by or comprises Formula IV:

[0052] wherein R1 is selected from halo (e.g. fluoro), cyano and carboxamido; wherein R2 represents H or a substituent comprising C1-C6 fluoroalkyl, NR2 or optionally substituted C5 or C6 heteroaryl; and if R2 is H, then R3 is not H.

[0053] In one embodiment, R3 is H, and R2 represents any of the following:

[0054] wherein Y is hydrogen or represents one or more substituents, each substituent being independently selected from halo, C1-C6 fluoroalkyl, -NO2, -NH2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, -(C1-C6)-OH, or a combination thereof. Compounds of the present invention, wherein R3 is selected from halogen, -NO2, -CN, -OH, -OR, -(C=O)NH2, -CONR2, -SR, -C02R, -S02R, optionally substituted C1-C6 alkyl, amino, oxo, imino, thioxo, carbonyl, aminoalkyl, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 mercaptoalkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof.

[0055] In one embodiment, the compound is represented by or comprises Formula V or Formula VA:

[0056]

[0057] wherein R1 is selected from halo, cyano and carboxamido; R3 is H or selected from (i) halogen, -NO2, -CN, -OH, -OR, -(C=O)NH2, -CONR2, -SR, -C02R, -S02R, optionally substituted C1-C6 alkyl, amino, oxo, imino, thioxo, carbonyl, aminoalkyl, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 mercaptoalkyl, C1-C6 haloalkyl and (ii) optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heteroalkyl, R2 is selected from C1-C6 fluoroalkyl and heteroaryl optionally substituted with one or more substituents, optionally wherein the substituents are linked to each other to form a 5- or 6-membered aliphatic, unsaturated or aromatic ring; if R3 or R4 is H, R2 is not H; if R3 is (ii), R2 is C1-C6 fluoroalkyl.

[0058] In one embodiment, R3 is H, and R2 is selected from C1-C6 fluoroalkyl and heteroaromatic rings optionally substituted with one or more substituents, optionally wherein the substituents are linked to each other to form a 5- or 6-membered aliphatic, unsaturated or aromatic ring.

[0059] In one embodiment, R4 is H or selected from halogen, -OR, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, -CN, optionally substituted C2-C6 alkynyl, -C(=O)-R, -SR, -S -C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NO2, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, -NH2, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl and optionally substituted bicyclic cycloalkyl.

[0060] In one embodiment, R2 is C1-C3 fluoroalkyl or a 5-6 membered heteroaryl ring substituted with one or more substituents selected from -F and C1-C3 fluoroalkyl.

[0061] In one embodiment, the compound is represented by Formula VB:

[0062] wherein X is N or CH; wherein each Y' is independently hydrogen or one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, -OR, -NR2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or wherein two Y' are linked to each other to form a ring; and wherein R2 is selected from the group consisting of H and C1-C6 fluoroalkyl; and wherein R4 is H or selected from the group consisting of halogen, -OR, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, -CN, optionally substituted C2-C6 alkynyl, -C(=O)-R, -SR, -S-C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NO2, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, -NH2, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, and optionally substituted bicyclic cycloalkyl.

[0063] In one embodiment, the compound is represented by Formula VI:

[0064] wherein R1 is selected from cyano and formamide; R2 is selected from C1-C6 haloalkyl, optionally substituted alkaryl / heteroaryl and a 5-6 membered heteroaromatic ring optionally substituted by at least one of -F and C1-C3 fluoroalkyl; R4 is H or selected from halogen, -OR, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, - CN, optionally substituted C2-C6 alkynyl, -C(=O)-R, -SR, -S-C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NO2, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, -NH2, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, and optionally substituted bicyclic cycloalkyl.

[0065] In one embodiment, R2 is selected from -CH2F and a 5-6 membered heteroaryl ring substituted with at least one of -F and C1-C3 fluoroalkyl.

[0066] In one embodiment, R2 is selected from -CH2F and pyridine substituted with at least one of -F and C1-C3 fluoroalkyl; and wherein R4 is selected from fluoroalkyl, halo, -OR, -C(=O)-R, substituted C3-C6 cycloalkyl, substituted C3-C6 heterocyclyl containing an unsaturated bond, and substituted aryl.

[0067] In one embodiment, the compound is or includes Table 1 or Figure 4 Any compound in.

[0068] In another aspect, there is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0069] In one embodiment, the pharmaceutical composition is used to inhibit protein kinase-R (PKR) cellular activity.

[0070] In one embodiment, the cell is a neural cell, a glial cell, or both.

[0071] In another aspect, there is a method for preventing or treating a disease or disorder associated with PKR activity in a subject or ameliorating its condition, comprising administering a pharmaceutical composition of the present invention to the subject, thereby (i) preventing or treating the disease or disorder; or (ii) ameliorating a condition associated with abnormal expression and / or activation of PKR in the subject.

[0072] In one embodiment, the disease or disorder comprises a neurodegenerative disorder, a neuroinflammatory disorder, a metabolic disease, a cardiovascular disease, a proliferative disease, or any combination thereof.

[0073] In one embodiment, the neurodegenerative disorder is selected from Alzheimer's disease, multiple sclerosis, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), dystonia, and prion disease, or any combination thereof.

[0074] In one embodiment, the prevention or treatment comprises inhibiting PKR function in a cell.

[0075] In one embodiment, the administration is selected from oral administration, topical administration, nasal administration, sublingual administration, buccal administration, systemic administration, or any combination thereof.

[0076] In one embodiment, improving comprises (i) enhancing cognitive function, or (ii) inhibiting cognitive dysfunction in a subject.

[0077] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent upon consideration of the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 is a schematic representation of a non-limiting general synthetic route to some exemplary compounds of the invention.

[0079] Figure 2 is a schematic representation of a non-limiting general synthetic route to some exemplary compounds of the invention.

[0080] Figure 3 is a schematic representation of a non-limiting general synthetic route to some exemplary compounds of the invention.

[0081] Figure 4 The chemical structures of exemplary compounds of the present invention are shown. DETAILED DESCRIPTION

[0082] In one aspect of the invention disclosed herein, there is a compound represented by Formula I or Formula IB:

[0083]

[0084] in represents a single bond or a double bond;

[0085] Each L is absent or independently includes optionally substituted C1-C6 alkyl, N, NH, S and O, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6)0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1- or any combination thereof; each X1 independently comprises CH, C or N; X comprises S, O, N or NH; each R1 independently represents hydrogen, or comprises the following substituents: halogen, -NO2, -CN, -OH, -(C=O)NH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, -OR, -(C=O)NH2, -C02R, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2 , -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), C1-C6 mercaptoalkyl, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl), -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof;Each of R2, R3 and R4 independently represents hydrogen, or is selected from halogen, -NO2, -CN, -OH, -OR, -SR, -(C=O)NH2, -CONR2, -C02R, -S02R, oxo, carbonyl, amino, C1-C6 mercaptoalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, imino, thio, carbonyl, aminoalkyl, fluoroalkyl, optionally substituted alkaryl / heteroaryl, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, -NR2, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, cyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted wherein R2, R3 and R4 are optionally substituted C2-C6 alkynyl, -C(=O)-R, -S-C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl or a combination thereof, or any one of R2, R3 and R4 is absent (i.e., H or empty, such as when referring to R2 or R4 in combination with X, where L is absent and X is O or S);

[0086] wherein at least one of R2 and R3 is not H or does not exist;

[0087] wherein M is selected from the group consisting of -O-, -S-, -NH-, -C(=O)-, -CONR-, -CNNR-, -CSNR-, -CONH-O-, -CONH-NH-, -NHCO-, -NHCSR-, -NHCN-, -NC(=O)O-, -NC(=O)N-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SO2O-, -SO2NR-, -NHNR-, -CO2-, -OCO-, -OC(=O)O-, -OC(=O)N-, -OC(=S)O-, and -OC(=S)N-;

[0088] wherein W represents an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 heterocyclyl, an optionally substituted aryl, an optionally substituted alkaryl / heteroaryl or an optionally substituted heteroaryl; wherein each R independently represents hydrogen or a member selected from an optionally substituted C1-C8 10 Alkyl, optionally substituted C1-C 10Alkenyl / alkynyl, hydroxy, amino, -NH2, -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, -OR, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C1-C 10 Alkaryl (eg benzyl), optionally substituted C1-C 10 Alkyl-C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl or a combination thereof; and wherein the compound comprises at least one R representing the above-mentioned substituents (e.g., R is not hydrogen); and wherein the compound includes any tautomer thereof, any isotope thereof (e.g., a D-substituted compound substituted by hydrogen deuterium) or a salt thereof. In some embodiments, the compounds of the present invention are represented by Formula IA or Formula IB, as described herein, wherein at least one X is N.

[0089] In one embodiment, provided herein is a composition comprising a compound of Formula I and a carrier. In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of the invention, such as, but not limited to, a compound of Formula I.

[0090] In some embodiments, the composition comprises a compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer, or an isotope thereof. In some embodiments, any compound of the invention, such as, but not limited to, a compound of formula I, a pharmaceutically acceptable salt thereof, a tautomer, or an isotope thereof, is stable in aqueous solution for at least one hour.

[0091] In some embodiments, any compound of the present invention, such as but not limited to a compound of formula I, a pharmaceutically acceptable salt thereof, or both, is stable in aqueous solution for at least 2 hours. In some embodiments, any compound of the present invention, such as but not limited to a compound of formula I, a pharmaceutically acceptable salt thereof, or both, is stable in aqueous solution for at least 5 hours. In some embodiments, any compound of the present invention, such as but not limited to a compound of formula I, a pharmaceutically acceptable salt thereof, or both, is stable in aqueous solution for at least 10 hours. In some embodiments, any compound of the present invention, such as but not limited to a compound of formula I, a pharmaceutically acceptable salt thereof, or both, is stable in aqueous solution for at least 24 hours. In some embodiments, any compound of the present invention, such as but not limited to a compound of formula I, a pharmaceutically acceptable salt thereof, or both, is stable in aqueous solution for at least 36 hours.

[0092] In another aspect, the present invention provides a compound represented by Formula IC or Formula ID:

[0093]

[0094] wherein R, R1, R2, R3, R4, X, X1, and L are as described herein. In one embodiment, provided herein is a composition comprising a compound represented by Formula IC and a carrier. In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound represented by Formula ID.

[0095] In some embodiments, the compounds of the present invention are represented by Formula IE:

[0096] wherein R, R1, R2, R3, R4, X, X1 and L are as described herein.

[0097] In some embodiments, R1 represents hydrogen, or a substituent comprising optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted C3-C8 cycloalkyl, or a combination thereof, wherein at least one R1 in the compounds of the present invention represents a substituent, as described herein.

[0098] In some embodiments, R1 represents a substituent selected from the group consisting of halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkane -C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OCOR, -OC(═O)OR, -OC(═O)NR, -OC(═S)OR and -OC(═S)NR or a combination thereof.

[0099] In some embodiments, R1 is selected from halo, nitro, cyano, -CONR2, -(C=O)NH2, -NRCOR, -NHCOH, haloalkyl, -S02R, -RSO2, -C02R, -RC02R, and -CF3, or a combination thereof. In some embodiments, R1 is selected from halo, nitro, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -(C=O)NH2, -N(C1-C6 alkyl)CO(C1-C6 alkyl), -NHCO(C1-C6 alkyl), -NHCOH, haloalkyl, -SO2(C1-C6 alkyl), -(C1-C6 alkyl)SO2, -CO2(C1-C6 alkyl), -CO2H, -(C1-C6 alkyl)CO2(C1-C6 alkyl), and -CF3, or a combination thereof.

[0100] In some embodiments, the compounds of the present invention are represented by any of Formulas IA-IE, wherein R, R2, R3, R4, X, X1, and L are as described herein, and R1 does not contain a cyclic group (e.g., an aryl group). In some embodiments, R1 is selected from halo, nitro, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -(C=O)NH2, -N(C1-C6 alkyl)CO(C1-C6 alkyl), -NHCO(C1-C6 alkyl), -NHCOH, haloalkyl, and -CF3, or a combination thereof. In some embodiments, R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof.

[0101] In some embodiments, the compounds of the present invention are represented by any of Formulas IA-IE, wherein R, R2, R3, R4, X1, and R1 are as described herein, X is N or NH, L is a bond (e.g., absent), or L comprises optionally substituted C1-C6 alkyl, N, NH, S, and O, or any combination thereof. In some embodiments, L is absent. In some embodiments, L comprises C1-C5 alkyl, phosphonate (including phosphate, thiophosphate), -S(O)-, -S(O)2-, -OS(O)2-, -S(O)2N-, or any combination thereof. In some embodiments, L comprises any of the following:

[0102]

[0103] , or a combination thereof, wherein the wavy bond represents the point of attachment to the molecule, and wherein the dotted bond represents the point of attachment to any substituent; wherein A comprises a heteroatom selected from N, O, S, and P; or A is selected from H, -OR', -SR', -N(R')2, and NHR'; X' comprises hydrogen, halogen, hydroxy, -CN, nitro, mercapto, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), amino(C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, -CO2R, -CON(R') 0-2 , -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR', -NHCNR', -NC(=O)OR', -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO2R', -SOR', -SR', -SO2OR', -SON(R')2, -CO2H or a combination thereof, wherein R' is or includes C1-C6 alkyl. In some embodiments, L includes -(C1-C6) 0-1 -A-(C1-C6) 0-1 -, wherein A includes a heteroatom selected from N, O, S and P.

[0104] In some embodiments, L is absent or comprises C1-C6 alkyl, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1 - any one or any combination thereof.

[0105] In some embodiments, the compounds of the present invention are represented by any of the formulas IA-ID, wherein at least one X 1 is a heteroatom. In some embodiments, the compounds of the present invention are represented by any of the formulas IA-ID, wherein both X 1 are heteroatoms. In some embodiments, the compounds of the present invention are represented by any of the formulas IA-ID, wherein at least one X 1 comprises nitrogen. In some embodiments, the compounds of the present invention are represented by any of the formulas IA-ID, wherein both X 1 comprise nitrogen. As used herein, the term "heteroatom" is as described below (e.g., selected from N, NH, O, and S).

[0106] In some embodiments, the compounds of the present invention are represented by any of the formulas IA-ID, wherein the two R groups bound to the outer amine group are connected to each other to form a cyclic group (e.g., a 3-7, 4, 5, 6-membered aromatic ring, a heteroaromatic ring, and / or an aliphatic ring optionally containing heteroatoms), a bicyclic ring, and / or a fused ring. In some embodiments, at least one R comprises an optionally substituted C1-C6 alkyl group, wherein the substituted C1-C6 alkyl group is as described herein. In some embodiments, at least one R comprises -COR, wherein R is as described herein.

[0107] In some embodiments, the compounds of the present invention are represented by Formula IIA or Formula IIB:

[0108]

[0109] Formula IIB, wherein R2, R3, R4, X, X1, L are as described herein; and at least one R1 represents a substituent selected from the group consisting of halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCS R, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -S0R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkyl -C6 alkyl), -C1-C6 alkyl), -C1-C6 alkoxy), -C1-C6 alkyl), -C1-C6 alkoxy), -C1-C6 alkyl), -C1-C6 alkoxy), -C1-C6 alkyl, -C1-C6 alkyl), ...

[0110] In some embodiments, the compounds of the present invention are represented by Formula IIC or Formula IID:

[0111]

[0112] wherein R2, R3, R4, L are as described herein; wherein X is N; and at least one R1 represents a substituent selected from the group consisting of CN, -(C=O)NH2, -NHC(=O)H, -NHCOR, halogen, -NO2, -OH, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -N HCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), -CON H(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR and -OC(=S)NR or a combination thereof.

[0113] In some embodiments, (i) R2 and R3 or (ii) R3 and R4 are interconnected to form a cyclic ring (e.g., a 3-7, 4, 5, 6-membered aromatic ring, a heteroaromatic ring, and / or an aliphatic ring optionally containing a heteroatom), a bicyclic ring, and / or a fused ring. In some embodiments, R2 and R1 are interconnected to form an optionally substituted cyclic ring (e.g., a 3-7, 4, 5, 6-membered aromatic ring, a heteroaromatic ring, and / or an aliphatic ring optionally containing a heteroatom), a bicyclic ring, and / or a fused ring.

[0114] In some embodiments, the compounds of the present invention are represented by any one of Formulae IIA-IID, wherein R1, R2, R3, R4, and L are as described herein, and wherein X is N.

[0115] In some embodiments, the compounds of the present invention are represented by Formula III:

[0116] wherein R1, R2, R3, R4 and L are as described herein.

[0117] In some embodiments, the compounds of the present invention are represented by Formula III, wherein R1 is selected from halo, nitro, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -(C=O)NH2, -N(C1-C6 alkyl)CO(C1-C6 alkyl), -NHCO(C1-C6 alkyl), -NHCOH, haloalkyl, and -CF3, or a combination thereof. In some embodiments, R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof.

[0118] In some embodiments, L is absent or includes any one of -CH2-, C1-C6 alkyl, -S(O)2-, -C(O)-, or any combination thereof.

[0119] In some embodiments, the compounds of the present invention are represented by Formula IIIA:

[0120] wherein R, R1, R2, R3, R4 and L are as described herein.

[0121] In some embodiments, the compounds of the present invention are represented by Formula IIIB:

[0122] wherein R, R1, R2, R3, R4 and L are as described herein.

[0123] In some embodiments, the compounds of the present invention are represented by Formula IIIC:

[0124] wherein R, R1, R2, R3, R4 and L are as described herein.

[0125] In some embodiments, the compounds of the present invention are represented by Formula IIID:

[0126] wherein R, R1, R2, R3, R4 and L are as described herein.

[0127] In some embodiments, the compounds of the present invention are represented by any one of Formulas IIIB-D, wherein R, R1, R2, R3, R4 are as described herein, and L includes or is selected from C1-C6 alkyl, C1-C2 alkyl, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1 - or any combination thereof.

[0128] In some embodiments, the compounds of the present invention are represented by Formula III, wherein L is absent or comprises C1-C2 alkyl, -S(O)2-, -C(O)-, -(C1-C2)-O-(C1-C2) 0-1 -、-(C1-C2)-S-(C1-C2) 0-1 -、-(C1-C2)-NH-(C1-C2) 0-1 - or any combination thereof; wherein R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), HCONH- and -(C=O)NH2 or a combination thereof; wherein each of R2 and R3 independently represents hydrogen, or comprises the following substituents: optionally substituted heteroaryl, optionally substituted aryl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-SR, C1-C6 alkyl-Z, -Z, optionally substituted C3-C8 cycloalkyl, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1 -, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; wherein Z is selected from -C02R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -C02R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -C02R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, or a combination thereof, and wherein at least one of R2 and R3 represents a substituent (i.e., other than H); and wherein R4 is as described herein.

[0129] In some embodiments, the compounds of the present invention are as described above, wherein R2 and / or R3 each independently comprise hydrogen, or represent a substituent comprising C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-SR, C1-C6 alkyl-Z, -Z, optionally substituted C3-C8 cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; wherein substituted is substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of hydroxy (C1-C6 alkyl), halo, nitro, -NR2, hydroxy, thiol, C1-C6 haloalkyl, -SOR, -S0R, -S0N(R)2, -S0OR, and -Z, or a combination thereof. In some embodiments, Z is selected from -CO2R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -CO2R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, or a combination thereof.

[0130] In some embodiments, the compounds of the present invention are as described above, wherein R2 and / or R3 each independently include C1-C6 alkyl-Z and / or -Z, wherein Z is selected from -CO2R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -CO2R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -CO2R, CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, or a combination thereof.

[0131] In some embodiments, R2 represents a substituent including C1-C6 haloalkyl, C1-C6 alkyl-NR2, -NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, (C5-C6)heteroaryl optionally substituted with one or more Y, or a combination thereof. In some embodiments, Y is a substituent selected from the group consisting of C1-C6 haloalkyl, halogen, fluorine, C1-C6 fluoroalkyl, (C0-C6)alkaryl, (C0-C6)alkylheteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCS R, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SO2N(R)2, -NHNR2, -NNR, C1-C6 haloalkoxy, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), hydroxy In some embodiments, Y represents 1 to 2, 2 to 3, 3 to 4, 4 to 5 substituents, including any range or value therebetween. In some embodiments, Y is a single substituent.

[0132] In some embodiments, R2 represents a substituent including C1-C6 haloalkyl, C1-C6 fluoroalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, C5 or C6 cycloalkyl optionally substituted with Y, C5 or C6 heteroaryl optionally substituted with Y, or a combination thereof. In some embodiments, R2 represents a substituent including C1-C3 fluoroalkyl, C1-C2 fluoroalkyl, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, or a combination thereof.

[0133] In some embodiments, the compounds of the present invention are as described above, wherein R2 represents an optionally substituted heteroaryl (e.g., containing nitrogen, sulfur, or N and S as heteroatoms), or an optionally substituted bicyclic heteroaryl, wherein the substitution includes one or more Y attached to any ring atom. In some embodiments, the compounds of the present invention are as described above, wherein R2 represents a C5-C6 heteroaryl, optionally containing one or more Y.

[0134] In some embodiments, R2 is represented by any of the following:

[0135]

[0136] wherein Y is as described herein, and wherein R2 is connected to the scaffold (e.g., pyrrolopyridinyl scaffold) through any ring atom, as indicated by a wavy bond. In some embodiments, R2 represents a heteroaromatic ring as described above, wherein the heteroaromatic ring is connected to the scaffold at an ortho position relative to the heteroatom.

[0137] In some embodiments, R2 is represented by any of the following:

[0138] wherein Y is hydrogen or a substituent selected from halo (e.g., fluorine), C1-C6 haloalkyl, C1-C6 fluoroalkyl, -NO2, -NH2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -S02R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, optionally substituted C1-C6 alkyl, -(C1-C6)OH, or a combination thereof.

[0139] In some embodiments, the compounds of the present invention are represented by any one of Formulas I-III, wherein R2 is represented by any one of the following:

[0140] Wherein Y is selected from halogen (such as fluorine) and C1-C6 fluoroalkyl (such as C1-C3 fluoroalkyl or C1-C2 fluoroalkyl, such as -CH2F, -CHF2, -CF3) or a combination thereof, or Y is absent. In some embodiments, Y is F and / or -CHF2. In some embodiments, Y is not alkyl.

[0141] In some embodiments, R2 does not contain wherein Y is as described herein. In some embodiments, R2 does not contain 2-trifluoromethylpyridine. In some embodiments, R2 does not contain an alkyl group. In some embodiments, R2 represents an aromatic and / or heteroaromatic substituent, wherein the heteroaromatic group is as described herein.

[0142] In some embodiments, the compounds of the present invention are represented by Formula III, wherein L is absent or comprises any one of C1-C6 alkyl, -S(O)2-, -C(O)-, or any combination thereof; wherein R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof; wherein R3 represents hydrogen, or comprises the following substituents: unsaturated C1-C6 alkyl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; and wherein R2 is represented by any one of the following:

[0143] wherein Y is selected from halo (e.g., fluorine), -NO2, -NH2, -OMe, -(C=O)NH2, -SO2(C1-C6) and C1-C6 haloalkyl (e.g., -CH2F, -CHF2, -CF3) or a combination thereof, or Y is absent; such that at least one of R2 and R3 represents said substituent; and wherein R4 comprises hydrogen, halo, C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2F), unsaturated C1-C6 alkyl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl or a combination thereof.

[0144] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group as described herein that is substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 halogen atoms, wherein the halogen is selected from F, Br, Cl, and I, or a combination thereof. Non-limiting examples of C1-C6 haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2-CF3, -CH2-CF3, -CH2-CH2F, -CCl3, -CHBr2, -CHCl2, -CBr3, -CFBrCHFBr, -CH2I, -CH2Br, -CH2Cl, -CH2-CH2I, -CH2-CH2Cl, -CH2-CH2Br, or any combination thereof.

[0145] In some embodiments, the compounds of the present invention are represented by any one of Formulas I-III, wherein R3 represents hydrogen, or comprises a substituent comprising an unsaturated C1-C6 alkyl, an optionally substituted alkaryl, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, or a combination thereof.

[0146] In some embodiments, R3 represents hydrogen, or includes the following substituents: substituents of aryl optionally substituted with one or more Y; or C5 or C6 heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, pyrazole, isothiazole, imidazole, pyridine, pyrimidine, etc.), or fused heterocycle (e.g., indole, isoindole, benzofuran, benzothiophene, benzotriazole, quinoline, chromene, chroman, quinazoline), which are optionally substituted with one or more Y.

[0147] In some embodiments, R3 includes 7-10 bicyclic rings optionally substituted with one or more Y, wherein the bicyclic ring optionally contains 1 or 2 heteroatoms (eg, O, S, or N, or a combination thereof).

[0148] In some embodiments, R3 includes a fused 7-10 aliphatic ring optionally substituted with one or more Y. In some embodiments, the fused 7-10 aliphatic ring includes norbornane, bicyclooctane, bicyclodecane or a combination thereof. In some embodiments, at least one ring of the bicyclic ring includes a heterocyclic aliphatic ring. In some embodiments, the heterocyclic aliphatic ring includes pyrrolidine, ethylene oxide, tetrahydrofuran, aziridine, pyrans, dioxane, tetrahydrothiophene (thiolane), oxathiolane (oxathiolane), piperidine and / or morpholine.

[0149] In some embodiments, R3 comprises a fused 7-10 heterocyclic ring optionally substituted with one or more Y, wherein the fused 7-10 heterocyclic ring is as described herein.

[0150] In some embodiments, R3 includes a benzene ring or a pyridine ring optionally substituted with one or more Y. In some embodiments, R3 includes any of the following

[0151] Wherein Y is hydrogen or one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, -NH2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or a combination thereof. In some embodiments, R3 comprises pyridine, phenyl, p-methoxyphenyl, or is absent.

[0152] In some embodiments, the compounds of the present invention are represented by Formula III, wherein L is absent or comprises any one of C1-C6 alkyl, -S(O)2-, -C(O)-, or any combination thereof; wherein R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof; wherein R3 represents hydrogen, or a substituent comprising a phenyl ring or a pyridine ring, which is optionally substituted with one or more substituents selected from the following: C1-C6 alkyl, -NH2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or a combination thereof; and wherein R2 is represented by any one of the following: wherein Y is selected from halo (e.g., fluorine), -NO2, -NH2, -OMe, -(C=O)NH2, -SO2(C1-C6) and C1-C6 haloalkyl (e.g., -CH2F, -CHF2, -CF3), or a combination thereof, or Y is absent; and wherein R4 comprises hydrogen, halo, unsaturated C1-C6 alkyl, C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2F, -CH2-CF3, -CH2-CF3, -CH2-CH2F), optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof.

[0153] In some embodiments, the compounds of the present invention are represented by Formula III, wherein L is absent or comprises any one of C1-C6 alkyl, -S(O)2-, -C(O)-, or any combination thereof; wherein R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof; wherein R3 represents hydrogen, or comprises the following substituents: pyridine, phenyl, p-methoxyphenyl, or a combination thereof; and wherein R2 represents hydrogen or a substituent selected from any one of the following: wherein Y is selected from halo (e.g., fluorine), -NO2, -NH2, -OMe, -(C=O)NH2, -SO2(C1-C6) and C1-C6 haloalkyl (e.g., -CH2F, -CHF2, -CF3) or a combination thereof, or Y is absent; such that at least one of R2 and R3 represents a substituent; and wherein R4 comprises hydrogen, halo, unsaturated C1-C6 alkyl, C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2F), optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, optionally substituted heterocyclyl or a combination thereof.

[0154] In some embodiments, the compounds of the present invention are represented by Formula IV:

[0155] wherein R1, R2, R3, R4 and L are as described herein.

[0156] In some embodiments, the compounds of the present invention are represented by Formula IV, wherein L is absent or comprises any one of -CH2-, C1-C6 alkyl, -S(O)2-, -C(O)-, or any combination thereof; wherein R1 is selected from halo, cyano, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), and -(C=O)NH2, or a combination thereof; wherein R3 represents hydrogen, or comprises the following substituents: pyridine, phenyl, p-methoxyphenyl, or a combination thereof; and wherein R2 is represented by any one of the following:

[0157]

[0158] , wherein Y' is selected from halo (e.g., fluorine), -NO2, -NH2, -OMe, -(C=O)NH2, -SO2(C1-C6) and C1-C6 haloalkyl (e.g., -CH2F, -CHF2, -CF3) or a combination thereof, or Y' is absent; and wherein R4 comprises hydrogen, halo, unsaturated C1-C6 alkyl, C1-C6 haloalkyl (e.g., -CF3, -CHF2, -CH2F), optionally substituted alkaryl, optionally substituted heterocyclyl, optionally substituted (C5-C6)heteroaryl, optionally substituted (C5-C6)heterocyclyl, optionally substituted C6 aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl or a combination thereof.

[0159] In some embodiments, R4 includes hydrogen, halogen, or its combination.In some embodiments, R4 comprises C1-C6 haloalkyl (for example-CF3,-CHF2,-CH2F), C1-haloalkyl, C2-haloalkyl, C3-haloalkyl, C4-haloalkyl, including any scope therebetween.In some embodiments, R4 comprises the C1-C6 alkyl that optionally replaces.

[0160] In some embodiments, R4 comprises or is represented by the formula:

[0161] wherein X1 is selected from C, CH and N; and wherein B comprises any one of the following: or wherein B is phenyl or C5-C6 cycloalkyl optionally substituted with one or more Y, or wherein B is absent; wherein each Y independently comprises a hydrogen accepting electron withdrawing group (e.g., sulfone, methylsulfone, amide, carboxyl, ester); or alkyl optionally substituted with hydroxyl, amino, halo, thiol, or a combination thereof, or wherein Y is absent. In some embodiments, B is attached to the C6 (hetero)aryl group through one or two ring atoms.

[0162] In some embodiments, Y is absent or selected from (C0-C6)alkaryl, (C0-C6)alkylheteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8heterocyclyl, halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 halogen wherein the alkyl group is a C1-C6 alkyl, ...

[0163] In some embodiments, R4 comprises wherein Y is as described herein, and wherein any heterocycle shown herein is variably attached to the scaffold (eg, a pyrrolopyridinyl scaffold) as indicated by a wavy bond.

[0164] In some embodiments, R4 includes (C5-C6) heterocyclyl, C1-C6 alkyl-(C5-C6) heterocyclyl or both. In some embodiments, R4 includes (C5-C6) heteroaryl (e.g., pyrazole, oxazole, imidazole) optionally substituted with one or more Y.

[0165] In some embodiments, the compounds of the present invention are represented by Formula V or Formula VA:

[0166]

[0167] in:

[0168] R1 is selected from halo (e.g., fluoro), cyano, and carboxamido; and R2 and R4 are as described herein; R3 is H or selected from halo, -NO2, -CN, -OH, -OR, -(C=O)NH2, -CONR2, -SR, -C02R, -S02R, optionally substituted C1-C6 alkyl, amino, oxo, imino, thioxo, carbonyl, aminoalkyl, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, C1 -C6 mercaptoalkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl or a combination thereof; and wherein the compound includes any salt thereof, any tautomer thereof; and any isotope thereof (e.g., hydrogen-deuterium substitution).

[0169] In some embodiments, the compounds of the present invention are represented by Formula V: wherein R1 is selected from cyano and formamide (i.e., HCONH- or -(C=O)NH2); wherein R2 is H or selected from C1-C6 haloalkyl (e.g., C1-C2 fluoroalkyl, such as -CF3, -CHF2, -CH2F), optionally substituted alkaryl / heteroaryl, optionally substituted aromatic ring or heteroaromatic ring (e.g., single 5-6 membered ring or bicyclic);

[0170] wherein R3 is H, or (i) if R2 is an optionally substituted alkaryl / heteroaryl or an optionally substituted aromatic or heteroaromatic ring, then R3 is selected from halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -SR, -C02R, -S02R, optionally substituted C1-C6 alkyl, amino, oxo, carbonyl, aminoalkyl, -NR2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 or (ii) if R2 is C1-C6 haloalkyl, R3 is selected from optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof;

[0171] and wherein R4 is H or selected from halogen (eg F or Br); -OR (eg -OMe, -OEt, -OPr); -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl (eg ); C1-C6 haloalkyl (e.g. optionally deuterated); optionally substituted C1-C6 alkyl (e.g., ethyl, deuterated ethyl, ); -MW, wherein M is selected from -O-, -S-, -NH-, -C(=O)-, -CONR-, -CNNR-, -CSNR-, -CONH-O-, -CONH-NH-, -NHCO-, -NHCSR-, -NHCN-, -NC(=O)O-, -NC(=O)N-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SO2O-, -SONR-, -NHNR-, -CO2-, -OCO-, -OC(=O)O-, -OC(=O)N-, -OC(=S)O-, and -OC(=S)N-; and wherein W represents an optionally substituted C3-C8 cycloalkyl group (e.g. ), optionally substituted C3-C8 heterocyclic group (e.g. ), optionally substituted aryl, optionally substituted alkaryl / heteroaryl or optionally substituted heteroaryl; optionally substituted C3-C8 saturated / unsaturated heterocyclic group (e.g. ); optionally substituted C3-C8 saturated / unsaturated cycloalkyl (eg ); optionally substituted C2-C6 alkenyl (e.g. ), -CN, optionally substituted C2-C6 alkynyl (e.g. acetylene, ), -C(=O)-R(e.g. ), SR, -S-C1-C6 haloalkyl, -NH-C1-C6 haloalkyl, -NO2, -OH, -(C=O)NH2, -CONR2, -CO2R, -SO2R, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), optionally substituted heteroaryl (e.g., optionally substituted by Y, one or more substituted pyridine / pyrazole / imidazole / thiazole / furan / pyrrole / thiophene), optionally substituted aryl (e.g. phenyl, substituted by one or more Y, substituted phenyl); optionally substituted heterocyclic group; optionally substituted bicyclic heteroaryl (eg ), optionally substituted bicyclic aryl (e.g. ), optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; and if R3 is H, then R2 is not H; wherein Y is selected from haloalkyl, C1-C6 haloalkyl, alkoxy, -C(=O)R, heteroalkyl, aminoalkyl, (C0-C6)alkaryl, (C0-C6)alkylheteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, and optionally substituted C1-C6 alkyl; -MW, optionally substituted C3-C8 heterocyclyl, amino, oxo, imino, thioxo, carbonyl, halogen, -NO2, -CN, -OR, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OR, RCONH-, -NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SO R, -SR, -SO2OR, -SO2N(R)2, -NHNR2, -NNR, optionally substituted C1-C6 alkyl, -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, -CONH(C -C1-C6 alkyl, -CON(C1-C6 alkyl)2, -CO2H, -CO2R, RCO2-, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR or a combination thereof; wherein any of the haloalkyl, alkoxy, heteroalkyl, aminoalkyl, (C0-C6)alkylaryl, (C0-C6)alkylheteroaryl and (C0-C6)alkyl-(C3-C8)cycloalkyl is optionally substituted.

[0172] In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 is H, R1 is cyano or formamide; R2 is selected from C1-C6 fluoroalkyl (e.g., C1-C3 fluoroalkyl, such as -CF3, -CHF2, -CH2F), a heteroaromatic ring (e.g., a monocyclic or fused ring) optionally substituted with one or more substituents, optionally wherein the substituents are linked to each other to form a 5- or 6-membered aliphatic, unsaturated or aromatic ring, and R4 is H or selected from halogen (e.g., F or Br); -OR (e.g., -OMe, -OEt, -OPr); -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl (e.g., ); C1-C6 haloalkyl (e.g. optionally deuterated); optionally substituted C1-C6 alkyl (e.g., ethyl, deuterated ethyl, ); -MW, wherein M is selected from -O-, -S-, -NH-, -C(=O)-, -CONR-, -CNNR-, -CSNR-, -CONH-O-, -CONH-NH-, -NHCO-, -NHCSR-, -NHCN-, -NC(=O)O-, -NC(=O)N-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SO2O-, -SONR-, -NHNR-, -CO2-, -OCO-, -OC(=O)O-, -OC(=O)N-, -OC(=S)O- and -OC(=S)N-, and wherein W represents an optionally substituted C3-C8 cycloalkyl group (e.g. ), optionally substituted C3-C8 heterocyclic group (e.g. ), optionally substituted aryl, optionally substituted alkaryl / heteroaryl or optionally substituted heteroaryl; optionally substituted C3-C8 saturated / unsaturated heterocyclic group (e.g. ); optionally substituted C3-C8 saturated / unsaturated cycloalkyl (eg ); optionally substituted C2-C6 alkenyl (e.g. ), -CN, optionally substituted C2-C6 alkynyl (e.g. acetylene, ), -C(=O)-R(e.g.

[0173] ); -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -CONR2; -CONR2; -CO2R; -SO2R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl (e.g., by one or more Y, substituted pyridine / pyrazole / imidazole / thiazole / furan / pyrrole / thiophene); optionally substituted aryl (e.g. phenyl, substituted by one or more Y,

[0174]

[0175] substituted phenyl); optionally substituted heterocyclic group; optionally substituted bicyclic heteroaryl (eg ); optionally substituted bicyclic aryl (eg ); optionally substituted bicyclic heterocyclyl; optionally substituted bicyclic cycloalkyl, or a combination thereof.

[0176] In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 is H, R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F, -CF3), or a 5-6 membered heteroaromatic ring substituted with one or more substituents (such as pyridine, pyrimidine, thiazole, furan, pyrazole), wherein at least one of the one or more substituents is selected from -F, amino (such as -NH2), fluoroalkyl (for example, C1-C3 fluoroalkyl, such as -CH2F, optionally deuterated fluoroalkyl) and fluoroalkyl substituted with one or more non-fluorine substituents; and R4 is as described above for formula V. In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 is H, R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F) or a 5-6 membered heteroaromatic ring substituted with -F or C1-C3 fluoroalkyl; and R4 is selected from haloalkyl (e.g., fluoroalkyl), halo, -OR, -C(=O)-R, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heterocyclyl containing an unsaturated bond, and optionally substituted aryl.

[0177] In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 is H, R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F) or a 5-6 membered heteroaromatic ring substituted with -F or C1-C3 fluoroalkyl; R4 is selected from haloalkyl (such as fluoroalkyl), halo, -OR (such as methoxy), -C(=O)-R (such as ), substituted C3-C6 heterocyclic group (e.g. ), substituted C3-C6 cycloalkyl (e.g. ), a substituted C3-C6 heterocyclic group containing an unsaturated bond (e.g. ) and substituted aryl groups (e.g. ) and wherein any one of the substituted C3-C8 heterocyclyl and aryl is substituted by at least one substituent selected from the group consisting of haloalkyl, C1-C6 haloalkyl, alkoxy, C1-C6 hydroxyalkyl, oxo, optionally substituted C1-C6 alkyl and -C(=O)-R.

[0178] In some embodiments, the compounds of the present invention are represented by Formula VB:

[0179] wherein X is N or CH; wherein each Y' is independently hydrogen or one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, -OR, -NR2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or wherein two Y' are linked to each other to form a ring (e.g., a 5-6 membered ring, e.g., ); wherein R1 is selected from halo, cyano and carboxamido-(C=O)NH2; wherein R2 is selected from H and C1-C6 fluoroalkyl (e.g., C1-C2 fluoroalkyl, such as -CF3, -CHF2, -CH2F); and wherein R4 is H or selected from halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkene C2-C6 alkynyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -C02R; -S02R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl.

[0180] In some embodiments, the compounds of the present invention are represented by Formula VB:

[0181] wherein X is N or CH; wherein each Y' is independently hydrogen or one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, -OR, -NR2, -O(C1-C6 alkyl), -OMe, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or wherein two Y' are linked to each other to form a ring (e.g., a 5-6 membered ring, e.g., ); wherein R1 is selected from halo, cyano and carboxamido -(C=O)NH2; wherein R2 is selected from H and C1-C6 fluoroalkyl (e.g., C1-C2 fluoroalkyl, such as -CF3, -CHF2, -CH2F); and wherein R4 is H or selected from halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -CO2R; -SO2R; -NH2; -NR2; -NH(C1-C6 alkyl) and hydroxyl(C1-C6 alkyl).

[0182] In some embodiments, the compounds of the present invention are represented by formula VA, wherein R3 is H, R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F, -CF3), or a 5-6 membered heteroaromatic ring substituted with one or more substituents (such as pyridine, pyrimidine, thiazole, furan, pyrazole), wherein at least one of the one or more substituents is selected from -F, amino (such as -NH2), fluoroalkyl (e.g., C1-C3 fluoroalkyl, such as -CH2F, optionally deuterated fluoroalkyl) and fluoroalkyl substituted with one or more non-fluorine substituents; and wherein R4 is selected from H, halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; - MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -C02R; -S02R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl.

[0183] In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 is H, R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F, -CF3), or a 5-6 membered heteroaromatic ring substituted with one or more substituents (such as pyridine, pyrimidine, thiazole, furan, pyrazole), wherein at least one of the one or more substituents is selected from -F, amino (such as -NH2), fluoroalkyl (e.g., C1-C3 fluoroalkyl, such as -CH2F, optionally deuterated fluoroalkyl) and fluoroalkyl substituted with one or more non-fluorine substituents; and wherein R4 is selected from halogen; -OR; -O -C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -CO2R; -SO2 R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl; and if R2 is a 5-6 membered heteroaryl ring, R4 is selected from H, halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3- C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -C02R; -S02R; -NH2; -NH(C1-C6 alkyl); hydroxyl(C1-C6 alkyl); wherein W represents optionally substituted C3-C8 cycloalkyl or optionally substituted C3-C8 heterocyclyl.

[0184] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R3 is hydrogen; and wherein R2 is selected from pyridine, pyrimidine, and a 5-membered heteroaromatic ring substituted with one or two Y″ (e.g., thiazole, furan, or pyrazole), wherein each Y″ is independently selected from fluorine, -(C=O)NH2, and C1-C6 fluoroalkyl (e.g., -CH2F, -CHF2, -CF3); and wherein R4 is as described above for Formula V.

[0185] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises wherein Y, X and X' are as described above, and wherein n is 0, 1 or 2.

[0186] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises , wherein Y is selected from -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SOR, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, -C02R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, or a combination thereof, or wherein Y is absent and wherein R is as described herein. In some embodiments, Y is attached to a heteroatom.

[0187] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises wherein Y is absent or selected from (C0-C6)alkaryl, (C0-C6)alkylheteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C -C6 alkyl), -C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OCOR, -OC(═O)OR, -OC(═O)NR, -OC(═S)OR, -OC(═S)NR, or a combination thereof.

[0188] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises wherein X1 is CH or N; and wherein Y is selected from hydrogen, -NHCOR, -S02R, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, -C02R, C1-C6 alkyl-NR2 substituted by one or more X', C1-C6 alkyl-OR substituted by one or more X', C1-C6 alkyl-SR substituted by one or more X', (C0-C6)alkaryl, (C0-C6)alkylheteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8heterocyclyl, optionally substituted C1-C6 alkyl, -NO2, -CN, halo, -CF3, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCS R, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-SR or a combination thereof. In some embodiments, Y comprises a hydrogen accepting electron withdrawing group (e.g., sulfone, methylsulfone, amide, carboxyl, ester); or an alkyl group optionally substituted with hydroxy, amino, halide, thiol, or a combination thereof, or wherein Y is absent.

[0189] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 is as described above (e.g., aryl, heteroaryl, fused aryl, or fused heteroaryl), substituted with at least one Y, wherein Y comprises: wherein each n independently represents an integer between 0 and 10, between 0 and 1, between 1 and 2, between 2 and 3, between 3 and 5, between 5 and 10, including any range therebetween; and wherein each X' independently comprises or is selected from hydrogen, halogen, hydroxy, -CN, nitro, mercapto, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), amino(C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, -CO2R, -CON(R) 0-2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHC SR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SO2N(R)2, -CO2H or a combination thereof, wherein R is as described above.

[0190] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises wherein A includes a heteroatom selected from N, O, S and P; X' includes hydrogen, halogen, hydroxy, -CN, nitro, mercapto, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), amino(C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, -CO2R, -CON(R') 0-2 , -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -N HCSR', -NHCNR', -NC(=O)OR', -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO2R', -S OR', -SR', -SO2OR', -SON(R')2, -CO2H, or a combination thereof, wherein R' is C1-C6 alkyl; and wherein Cy includes optionally substituted (C5-C6)heterocyclyl, optionally substituted C1-C6 alkyl-(C5-C6)heterocyclyl, optionally substituted alkaryl, optionally substituted (C5-C6)heteroaryl, optionally substituted aryl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic heterocyclyl, optionally substituted cycloalkyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; and wherein n is 0, 1, 2, 3, 4, or 5.

[0191] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises It is optionally replaced by Y, Any one or combination thereof can be substituted.

[0192] In some embodiments, the compounds of the present invention are represented by any one of formulas V-VB, wherein R4 comprises any one of pyridine, phenyl, pyrimidine, pyridazine, pyrazine, triazine, pyrazole, pyrrole, triazole, imidazole, indole, isoindole, indazole, benzimidazole, azaindazole, purine, azaindole and dihydroindole, which is optionally replaced by Y, Any one or combination thereof can be substituted.

[0193] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises any one of isoindolin-1-one, isoindolin-2-one, which is optionally replaced by Y, Any one or combination thereof can be substituted.

[0194] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises any one of the following:

[0195]

[0196] , wherein X 1 is CH or N; and wherein X and Y are as described herein.

[0197] In some embodiments, the compounds of the present invention are represented by any one of Formulas V-VB, wherein R4 comprises any one of the following

[0198]

[0199] It is optional wherein X1 is CH or N; and wherein X is as described herein.

[0200] In some embodiments, the compounds of the present invention are as described above, wherein at least R1 and an additional substituent (eg, any one of R2, R3, and R4) are present in the molecule.

[0201] In some embodiments, the compounds of the present invention are represented by formula V, wherein at least one of R1 and R2, R3 and R4 is a substituent. In some embodiments, the compounds of the present invention are represented by formula V, wherein at least two of R1 and R2, R3 and R4 are substituents. In some embodiments, the compounds of the present invention are represented by formula V, wherein R1, R2 and R4 are substituents, and wherein R3 is H. In some embodiments, the compounds of the present invention are represented by formula V, wherein R1, R2 and R3 are substituents, and wherein R4 is H. In some embodiments, the compounds of the present invention are represented by formula V, wherein R1, R4 and R3 are substituents, and wherein R2 is H. In some embodiments, the compounds of the present invention are represented by formula V, wherein R1 and R4 are substituents, and wherein R2 and R3 are H. In some embodiments, the compounds of the present invention are represented by formula V, wherein R3 or R4 is H.

[0202] In some embodiments, the compounds of the present invention are represented by Formula VI:

[0203]

[0204] wherein R1 is selected from cyano and formamido; wherein R2 is H or selected from C1-C6 haloalkyl (e.g. C1-C2 fluoroalkyl, such as -CF3, -CHF2, -CH2F), optionally substituted alkaryl / heteroaryl, optionally substituted aromatic ring or heteroaromatic ring (e.g. single 5-6 membered ring or bicyclic);

[0205] and wherein R4 is H or selected from halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1- C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, -NH2, -NR2, -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl.

[0206] In some embodiments, the compounds of the present invention are represented by formula VI, wherein R1 is cyano or formamide; R2 is a C1-C3 fluoroalkyl group (such as -CH2F, -CF3), or a 5-6 membered heteroaromatic ring substituted with one or more substituents (such as pyridine, thiazole, furan), wherein at least one of the one or more substituents is selected from -F, amino (such as -NH2), fluoroalkyl (for example, C1-C3 fluoroalkyl, such as -CH2F, optionally deuterated fluoroalkyl) and fluoroalkyl substituted with one or more non-fluorine substituents; R4 is as described above for formula VI.

[0207] In some embodiments, the compounds of the present invention are represented by Formula VI, wherein R1 is cyano or formamide; R2 is C1-C3 fluoroalkyl (such as -CH2F) or a 5-6 membered heteroaromatic ring substituted with -F or C1-C3 fluoroalkyl; and R4 is selected from haloalkyl (such as fluoroalkyl), halo, -OR (such as methoxy), -C(=O)-R (such as ), substituted C3-C6 heterocyclic groups (e.g. ), substituted C3-C6 cycloalkyl (e.g. ) and a substituted C3-C6 heterocyclic group containing an unsaturated bond (e.g. ) and substituted aryl groups (e.g. ), and wherein any one of the substituted C3-C8 heterocyclyl and aryl is substituted by at least one substituent selected from the group consisting of a haloalkyl group, a C1-C6 haloalkyl group, an alkoxy group, a C1-C6 hydroxyalkyl group, an oxo group, an optionally substituted C1-C6 alkyl group, and -C(=O)-R.

[0208] In some embodiments, the compounds of the present invention are represented by Formula VI, wherein R1 is cyano or formamido; R2 is C1-C3 fluoroalkyl (such as -CH2F) or a 5-6 membered heteroaromatic ring substituted with -F or C1-C3 fluoroalkyl; R4 is as described for Formula V; and if R2 is a 5-6 membered heteroaromatic ring, R4 is selected from H, halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; Optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -CO2R; -SO2R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxyl(C1-C6 alkyl); wherein W represents optionally substituted C3-C8 cycloalkyl or optionally substituted C3-C8 heterocyclyl.

[0209] -(C=O)NH2 Non-limiting exemplary compounds of the present invention are shown in Examples 1 and 2.

[0210] As used herein, the term "substituted" or the term "substituent" relates to one or more (e.g., 2, 3, 4, 5, or 6) substituents, wherein each of the one or more substituents is independently selected from hydrogen, halogen, -NO2, -CN, -OH, oxo, amino, thioxo, carbonyl, imino, -(C=O)NH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, NHCOR', -NHCSR', -NHCNR', -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO2R', -SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 halogen alkyl), -NH2, -NR'2-NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​or a combination thereof; wherein each R' independently represents hydrogen, or is selected from optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 30 Alkyl, optionally substituted C1-C 30 Alkenyl, optionally substituted C1-C 30 Alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, hydroxyl, amino, -NH2, -NR'2-NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl(C1-C6 alkyl), hydroxyl(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', or a combination thereof. In some embodiments, the term "substituted" or the term "substituent" includes one or more substituents represented by Y, Y' or Y".

[0211] As used herein, the term "7-10 ring" refers to a cyclic aliphatic or aromatic compound containing 7 to 10 carbon atoms. In some embodiments, the 7-10 ring bicyclic ring contains 7 to 8, 8 to 9, 9 to 10 carbon atoms, including any value therebetween.

[0212] As used herein, the term "C1-C6 alkyl" includes any C1-C6 alkyl related compound and refers to any linear or branched alkyl chain containing 1 to 6, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6 carbon atoms, including any range therebetween. In some embodiments, the C1-C6 alkyl includes any one or any combination of methyl, ethyl, propyl, butyl, pentyl, isopentyl, hexyl, and tert-butyl. In some embodiments, the C1-C6 alkyl as described herein further includes an unsaturated bond, wherein the unsaturated bond is located at position 1, 2, 3, 4, 5, or 6 of the C1-C6 alkyl.

[0213] As used herein, the term "(C3-C 10 )cycloalkyl" refers to an optionally substituted C3, C4, C5, C6, C7, C8, C9 or C 10 In some embodiments, (C3-C 10 ) ring includes optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane or cycloheptane.

[0214] As used herein, the term "(C3-C8)cycloalkyl" refers to an optionally substituted C3, C4, C5, C6, C7, or C8 ring. In some embodiments, (C3-C 10 ) ring includes optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane or cycloheptane.

[0215] As used herein, the term "(C6-C 12 ) ring" refers to an optionally substituted C6, C7, C8, C9, C 10 、C 11 or C 12 In some embodiments, (C6-C 12 ) ring refers to a bicyclic ring (eg, a fused ring, a spiro ring, or a biaryl ring).

[0216] As used herein, the term "bicyclic heteroaryl" refers to (C6-C 12 ) bicyclic heteroaromatic ring, wherein the bicyclic (C6-C 10 ) ring as described herein.

[0217] As used herein, the term "bicyclic aryl" refers to (C6-C 12 ) bicyclic aryl ring, wherein the bicyclic (C6-C 12 ) ring as described herein.

[0218] As used herein, the term "bicyclic heterocyclyl" refers to (C6-C 12 ) bicyclic heterocycle, wherein (bicyclic (C6-C 12 ))ring as described herein.

[0219] As used herein, the term "bicycloalkyl" refers to a (C6-C 12 ) bicycloalkyl ring, wherein the bicyclo (C6-C 12 ) ring as described herein.

[0220] In some embodiments, the compounds described herein are pharmaceutically pure compounds having a chemical purity greater than 95%, greater than 97%, or greater than 99%, including any ranges therebetween.

[0221] In some embodiments, the compounds described herein are chiral compounds (i.e., having an asymmetric carbon atom). In some embodiments, diastereomers, geometric isomers, and individual isomers are encompassed within the scope of the present invention. In some embodiments, the chiral compounds described herein are in the form of racemic mixtures. In some embodiments, the chiral compounds are in the form of single enantiomers, having an asymmetric carbon atom in the R configuration. In some embodiments, the chiral compounds are in the form of single enantiomers, having an asymmetric carbon atom in the S configuration, as described above.

[0222] In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity greater than 70%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity greater than 80%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity greater than 90%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity greater than 95%.

[0223] In some embodiments, compounds of the invention containing unsaturated bonds are in the form of trans or cis isomers. In some embodiments, compositions of the invention contain a mixture of cis and trans isomers, as described above.

[0224] In some embodiments, compositions of the invention comprise a compound of the invention, a mixture of enantiomers (eg, a racemic mixture), or enriched in an enantiomer of interest.

[0225] In some embodiments, the compounds of the present invention include any of the compounds disclosed herein, including any enantiomers thereof. In some embodiments, the compounds of the present invention include mixtures of enantiomers (e.g., racemic mixtures). In some embodiments, the compounds of the present invention include any of the compounds disclosed herein, including any salts thereof. In some embodiments, the salts of the compounds are pharmaceutically acceptable salts.

[0226] Pharmaceutical composition

[0227] In another aspect of the invention disclosed herein, there is a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, or both.

[0228] Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (e.g., bromide, chloride, iodide, fluoride), tartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, oxalate tetraacetate, fumarate, gluconate, and lactate, or any combination thereof.

[0229] In some embodiments, the pharmaceutical composition comprises a compound of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0230] For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans. In some embodiments, the compound of the invention is referred to herein as an active ingredient in a pharmaceutical composition.

[0231] In some embodiments, the pharmaceutical compositions described herein are topical compositions. In some embodiments, the pharmaceutical compositions are oral compositions. In some embodiments, the pharmaceutical compositions are injectable compositions. In some embodiments, the pharmaceutical compositions are for systemic use.

[0232] In some embodiments, the pharmaceutical composition is any one of an emulsion, liquid solution, gel, paste, suspension, dispersion, ointment, cream, or foam.

[0233] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient or solvent with which the active ingredient is administered. Such carriers can be sterile liquids, such as water-based and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., polyethylene glycol, glycerol, propylene glycol or other synthetic solvents.

[0234] Other non-limiting examples of carriers include, but are not limited to, terpenes derived from cannabis or a total terpene extract from the cannabis plant, terpenes from coffee or cocoa, mint extract, eucalyptus extract, citrus extract, tobacco extract, anis extract, any plant oil, peppermint oil, d-limonene, b-myrcene, a-pinene, linalool, anethole, a-bisabolol, camphor, b-caryophyllene and caryophyllene oxide, 1,8-cineole, citral, citronellal, delta-3-carene, farnesol, geraniol, indomethacin, pulegol, linalool, nonyl acetate, b-myristene, myrcenol, l-menthol, menthone, menthol and neomenthol / Russiconidine, a-pinene, diclofenac, nepafenac, bromfenac, phytol, terpineol, pinene-4-ol, thymol, and thymoquinone. Those skilled in the art will appreciate that the particular carrier employed in the pharmaceutical compositions of the present invention may vary depending on the route of administration.

[0235] In some embodiments, the carrier improves the stability of the active ingredient in vivo. In some embodiments, the carrier improves the stability of the active ingredient in the pharmaceutical composition. In some embodiments, the carrier improves the bioavailability of the active ingredient.

[0236] Water can be used as a carrier, for example, when the active ingredient is sufficiently water-soluble for intravenous injection. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions.

[0237] In some embodiments, the carrier is a liquid carrier. In some embodiments, the carrier is an aqueous carrier.

[0238] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. If desired, the composition may also contain a small amount of a wetting agent or emulsifier, or a pH buffer such as acetate, citrate, or phosphate. Antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; and agents for adjusting tonicity such as sodium chloride or glucose are also contemplated. The carrier may comprise a total of 0.1% to 99.99999% by weight of the composition and / or pharmaceutical composition described herein.

[0239] In some embodiments, the pharmaceutical composition comprises any active ingredient incorporated into or on a granular formulation of a polymeric compound, such as polylactic acid, polyglycolic acid, a hydrogel, or the like, or incorporated into liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroids. Such composition may affect the physical state, solubility, stability, in vivo release rate, and in vivo clearance rate.

[0240] In some embodiments, the pharmaceutical composition is a liquid at a temperature of 15 to 45°C. In some embodiments, the pharmaceutical composition is a solid at a temperature of 15 to 45°C. In some embodiments, the pharmaceutical composition is a semi-liquid at a temperature of 15 to 45°C. It should be understood that the term "semi-liquid" refers to a material that can flow under pressure and / or shear forces. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials and other similar materials. In some embodiments, the pharmaceutical composition is a semi-liquid composition characterized by a viscosity in the range of 31,000-800,000 cps.

[0241] Non-limiting examples of carriers for pharmaceutical compositions in the form of creams include, but are not limited to, nonionic surfactants (e.g., glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, lanolin alcohol, lecithin mono- and diglycerides, poloxamers, polyoxyethylene 50 stearate, and sorbitan trioleate stearate), anionic surfactants (e.g., pharmaceutically acceptable salts of fatty acids such as stearic acid, oleic acid, palmitic acid, and lauric acid), cationic surfactants (e.g., pharmaceutically acceptable quaternary ammonium salts such as benzalkonium chloride, phenethonium chloride, and cetylpyridinium chloride), or any combination thereof.

[0242] In some embodiments, the pharmaceutical composition in the form of a cream further comprises a thickening agent.

[0243] Non-limiting examples of thickening agents include, but are not limited to, microcrystalline cellulose, starch, modified starch, gum tragacanth, gelatin, and polymeric thickeners (eg, polyvinylpyrrolidone), or any combination thereof.

[0244] In some embodiments, the pharmaceutical composition comprising the compounds of the invention is in unit dosage form. In some embodiments, the pharmaceutical composition is prepared by any method known in the pharmaceutical art. In some embodiments, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial, or prefilled syringe.

[0245] In addition, in vitro tests can be optionally used to help determine the optimal dosage range. The exact dosage used in the formulation also depends on the route of administration and the nature of the disease or disorder, and should be determined based on the doctor's judgment and the circumstances of each patient. The effective dose can be inferred from a dose-response curve derived from an in vitro or in vivo animal model test bioassay or system. In some embodiments, the effective dose is determined as described above.

[0246] In another embodiment, the pharmaceutical composition of the present invention is administered in any conventional oral, parenteral or transdermal dosage form.

[0247] As used herein, the terms "administering," "administration," and like terms refer to any method within sound medical practice for delivering a composition containing an active agent to a subject in a manner that provides a therapeutic effect.

[0248] In some embodiments, the pharmaceutical composition is administered by oral (i.e., enteral), rectal, vaginal, topical, sublingual, oral, nasal, ophthalmic, transdermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, or intravenous administration. The route of administration of the pharmaceutical composition will depend on the disease or condition to be treated. Suitable routes of administration include, but are not limited to, parenteral injection, such as intradermal, intravenous, intramuscular, intralesional, subcutaneous, intrathecal, and any other injection known in the art. In addition, it may be desirable to introduce the pharmaceutical composition of the present invention by any suitable route, including intraventricular and intrathecal injection; intraventricular injection can be facilitated by a ventricular catheter connected to a reservoir. Pulmonary administration can also be employed, such as by using an inhaler or nebulizer.

[0249] In some embodiments, the pharmaceutical composition is in the form of, for example, but not limited to, an ointment, cream, gel, paste, foam, aerosol, suppository, pad, or gel stick.

[0250] In some embodiments, for oral administration, the pharmaceutical composition is in the form of a tablet or capsule, which may contain any of the following ingredients or compounds of similar properties: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it may contain, in addition to the types of materials described above, a liquid carrier such as a fatty oil. Furthermore, the dosage unit form may contain various other materials that may modify the physical form of the dosage unit, such as a coating of sugar, shellac, or other enteric solvents. In some embodiments, the tablets of the present invention are further film-coated. In some embodiments, the oral administration of the pharmaceutical composition or kit is in the form of a drinkable liquid. In some embodiments, the oral administration of the pharmaceutical composition or kit is in the form of an edible product.

[0251] For parenteral administration, sesame or peanut oil or aqueous solutions of propylene glycol may be used, as well as sterile aqueous solutions of the corresponding water-soluble salts. If necessary, such aqueous solutions may be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection.

[0252] In some embodiments, the pharmaceutical composition is used to inhibit protein kinase-R (PKR). In some embodiments, inhibiting PKR comprises inhibiting the cellular activity of PKR, wherein the inhibition is as described herein. In some embodiments, the inhibition comprises selective inhibition of PKR activity.

[0253] In some embodiments, the compound has an IC of 100 for PKR compared to other eIF2α phosphorylating kinases, such as PKR-like ER kinase (PERK), general control non-derepressed-2 (GCN2), or heme-regulated inhibitor (HRI). 50 In some embodiments, the compound has substantially no inhibitory activity against non-PKR kinases (e.g., eIF2α phosphorylating kinases).

[0254] In some embodiments, compounds of the invention (e.g., as shown in Example 1) inhibit PKR activity by 50% at a concentration (e.g., IC50) of less than 10,000 nM, less than 5,000 nM, less than 2,000 nM, less than 1,000 nM, less than 200 nM, less than 500 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM. In some embodiments, inhibition of PKR activity is assessed in vitro (e.g., in a cell-free biochemical assay, as shown in the Examples section).

[0255] In some embodiments, the pharmaceutical composition is used to prevent or inhibit PKR-related cytotoxicity. In some embodiments, the pharmaceutical composition is used to prevent or inhibit eIF2α phosphorylation. In some embodiments, the pharmaceutical composition is used to prevent or inhibit TAU ​​phosphorylation. In some embodiments, the pharmaceutical composition is used to prevent or inhibit PKR-related cytotoxicity. In some embodiments, the pharmaceutical composition is used to inhibit PKR. In some embodiments, the pharmaceutical composition is used to inhibit eIF2α phosphorylation. In some embodiments, the pharmaceutical composition is used to inhibit TAU ​​phosphorylation (directly, through GSK3β or other pathways). In some embodiments, the pharmaceutical composition is used to prevent cytotoxicity. In some embodiments, the pharmaceutical composition is used to induce or enhance anti-inflammatory effects by PKR inhibition (e.g., inhibiting the NfKB pathway and / or inhibiting inflammasome activation). In some embodiments, the pharmaceutical composition is used to reduce amyloid β aggregates, wherein amyloid β aggregates are as described herein.

[0256] In some embodiments, the cell is a neural cell. In some embodiments, the cell is a neuron. In some embodiments, the cell is a glial cell. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell expresses PKR. In some embodiments, the cell is characterized by elevated expression of PKR. In some embodiments, the cell is characterized by elevated activation of PKR.

[0257] In some embodiments, the cell is a cancer cell. In some embodiments, the cancer is a PKR-related cancer. In some embodiments, the cancer is associated with abnormal expression of PKR.

[0258] In some embodiments, the cancer cell is selected from a breast cancer cell, a colon cancer cell, a skin cancer cell, a hematopoietic cancer cell, or any combination thereof.

[0259] In some embodiments, the pharmaceutical composition is for preventing or treating abnormal cell growth and / or metastasis of cells expressing PKR in a subject in need thereof. In some embodiments, the pharmaceutical composition is for preventing or treating abnormal proliferation of cells expressing PKR.

[0260] In some embodiments, the pharmaceutical composition is used to prevent or treat a neurodegenerative disorder, a neuroinflammatory disorder, a metabolic disease, a cardiovascular disease, a proliferative disease, or any combination thereof.

[0261] In some embodiments, the pharmaceutical composition is used to prevent or treat cognitive impairment. In some embodiments, the pharmaceutical composition is used to improve symptoms associated with cognitive impairment.

[0262] In some embodiments, the pharmaceutical composition is used to prevent or treat hypoxia (e.g., hypoxia of muscle tissue, such as myocardial tissue) in a subject in need thereof. In some embodiments, the pharmaceutical composition is used to prevent or treat ischemia (e.g., ischemia of muscle tissue, such as myocardial tissue) in a subject in need thereof.

[0263] method

[0264] In another aspect, provided herein is a method for preventing or treating a disease or disorder associated with abnormal or normal activity of PKR in a subject, or improving its condition, comprising administering a pharmaceutical composition of the present invention to a subject, thereby (i) preventing or treating a disease or disorder associated with abnormal or normal expression and / or activation of PKR in the subject; or (ii) improving its condition. In another aspect, provided herein is a method for preventing or treating a disease or disorder associated with abnormal or normal activity of PKR in a subject, or improving its condition, comprising administering a pharmaceutical composition of the present invention to a subject, thereby preventing or treating a disease or disorder. In some embodiments, there is a method for preventing or treating a disease or disorder comprising a neurodegenerative disorder, a neuroinflammatory disorder, a metabolic disease, a cardiovascular disease, a proliferative disease, or any combination thereof.

[0265] In some embodiments, there is a method for preventing or treating cancer (e.g., a cancer associated with abnormal or normal PKR activity) comprising administering a pharmaceutical composition or compound of the present invention to a subject. In some embodiments, the method is used to prevent or treat a cancer characterized by cells expressing PKR. In some embodiments, the method is used to prevent or inhibit cell mitosis, wherein the cells are as described above.

[0266] In some embodiments, the method comprises administering a compound as described herein to a subject having cancer. In some embodiments, the method comprises administering a compound as described herein to a subject having cancer, wherein the cancer is characterized by expression of PKR and / or highly expressing cancer cells of PKR. In some embodiments, the method comprises administering a compound as described herein to a subject having cancer, wherein the cancer is characterized by expression of activated PKR cancer cells. In some embodiments, the method further comprises selecting a subject having cancer, wherein the subject comprises cancer cells that express PKR and / or highly express PKR.

[0267] In some embodiments, administration is by oral administration, topical administration, systemic administration, or a combination thereof.

[0268] In some embodiments, the neurological disorder treated with the compounds and / or compositions described herein is selected from the group consisting of multiple sclerosis, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), dystonia, and prion disease, or any combination thereof, and acquired and inherited neurological diseases of the peripheral nervous system. In some embodiments, the neurological disorder is multiple sclerosis. In some embodiments, the neurological disorder is Alzheimer's disease.

[0269] In some embodiments, the method comprises ameliorating a condition associated with abnormal or normal PKR activity in a subject, wherein the improvement comprises (i) enhancing cognitive function, or (ii) inhibiting cognitive dysfunction in the subject.

[0270] As used herein, the term "cognitive function" is well known in the art and refers to a variety of mental abilities, including learning, thinking, reasoning, memory, problem solving, decision-making, and attention.

[0271] In some embodiments, the method is used to induce neuroprotection in neural cells and / or glial cells in a subject.

[0272] In some embodiments, the method is used to prevent or reduce inflammation of neural cells and / or glial cells in a subject. In some embodiments, the method is used to prevent or reduce inflammation of neural tissue.

[0273] In some embodiments, the method is used to prevent or reduce apoptosis of neural cells and / or glial cells in a subject.

[0274] In some embodiments, the method is used to prevent or reduce the accumulation of amyloid beta aggregates in a subject in need thereof. In some embodiments, amyloid beta aggregates include intracellular aggregates, extracellular aggregates, aggregates in neural tissue, and aggregates in the nervous system, or any combination thereof. In some embodiments, intracellular and / or extracellular aggregates refer to cells selected from nerve cells, glial cells, cancer cells, epithelial cells, or muscle cells, or any combination thereof. In some embodiments, the method is used to prevent or reduce the accumulation of amyloid beta aggregates in neural tissue.

[0275] In some embodiments, the method is used to prevent or reduce the accumulation of tau protein aggregates. In some embodiments, the tau protein aggregates are located in the subject's neural cells and / or glial cells. In some embodiments, the tau protein aggregates are located in the subject's neural tissue and / or nervous system.

[0276] In some embodiments, the method is used to prevent or treat frontotemporal dementia, frontotemporal lobar degeneration. In some embodiments, the method is used to prevent or reduce a tauopathy selected from the group consisting of corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, and Pick's disease, including any combination thereof.

[0277] In some embodiments, the method is used to prevent or treat a disease or disorder associated with abnormal or normal accumulation of amyloid beta aggregates, wherein amyloid beta aggregates are as described herein. In some embodiments, the method is used to prevent or treat a disease or disorder associated with abnormal or normal accumulation of tau protein. In some embodiments, the accumulation of tau protein is extracellular and / or intracellular accumulation. In some embodiments, the accumulation of tau protein is in the cells and / or tissues of the subject.

[0278] The therapeutic effect and identity of subjects who may benefit from the compounds and / or compositions described herein can be monitored / identified by methods including MRI, PET, PET-CT, etc. The therapeutic effect can be assessed by monitoring physiological parameters and / or disease-associated biomarkers of the subject. These physiological parameters are well known in the art.

[0279] In some embodiments, the method comprises administering pharmaceutical composition of the present invention at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 7 times or at least 10 times every day or every week or every month, or any value and scope therebetween.Every possibility all represents a separate embodiment of the present invention.In some embodiments, the method comprises administering composition of the present invention or combination every day or every week or every month 1-2 times, every day or every week or every month 1-3 times, every day or every week or every month 1-4 times, every day 1-5 times, every day or every week or every month 1-7 times, every day or every week or every month 2-3 times, every day or every week or every month 2-4 times, every day or every week or every month 2-5 times, every day or every week or every month 3-4 times, every day or every week or every month 3-5 times or every day or every week or every month 5-7 times.Every possibility all represents a separate embodiment of the present invention.

[0280] In some embodiments, the method comprises administering to the subject a pharmaceutical composition of the present invention at a daily, weekly, or monthly dose of 0.05 to 20 mg / kg, 0.05 to 0.1 mg / kg, 0.1 to 0.3 mg / kg, 0.3 to 0.5 mg / kg, 0.5 to 0.8 mg / kg, 0.8 to 1 mg / kg, 1 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, 10 to 15 mg / kg, 15 to 20 mg / kg, including any range or value therebetween.

[0281] Those skilled in the art will appreciate that, for example, in vitro and in vivo assays may optionally be employed to help determine the optimal dosage range. The exact dosage used in the formulation also depends on the route of administration and the nature of the disease or disorder and should be determined based on the physician's judgment and individual patient circumstances. The effective dose may be inferred from dose-response curves derived from in vitro or in vivo animal model test bioassays or systems.

[0282] In some embodiments, the subject is a mammal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a farm animal. In some embodiments, the subject is a human subject.

[0283] In some embodiments, the compositions of the present invention are administered in a therapeutically safe and effective amount. As used herein, the term "safe and effective amount" refers to an amount of a component sufficient to produce the desired therapeutic response without excessive adverse side effects, commensurate with a reasonable benefit / risk ratio when used in the manner currently described, with adverse side effects including, but not limited to, toxicity, such as calcium poisoning, irritation, or allergic reactions. The actual amount applied, the rate of administration, and the time course will depend on the nature and severity of the condition being treated. The treatment prescription, such as the determination of dosage, time, etc., is the responsibility of a general practitioner or specialist, and will generally take into account the disorder to be treated, the condition of the individual patient, the delivery site, the method of administration, and other factors known to the doctor. Examples of techniques and protocols can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, Philadelphia, Pa., (2005).

[0284] In some embodiments, effective amounts or doses of active ingredients can be estimated initially from in vitro assays. In one embodiment, a dose can be formulated in animal models, and this information can be used to more accurately determine useful doses in humans.

[0285] In one embodiment, the toxicity and therapeutic effect of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, cell culture or experimental animals. In one embodiment, the data obtained from these in vitro and cell culture experiments and animal studies can be used to formulate a dosage range for human use. In one embodiment, the dosage can vary depending on the dosage form used and the route of administration used. In one embodiment, the exact formulation, route of administration and dosage can be selected by an individual physician based on the patient's condition. [See, for example, The Pharmacological Basis of Therapeutics by Goodman and Gilman, 13th edition, McGraw-Hill / Education, New York, NY (2017)].

[0286] In some embodiments, the subject has a disease or disorder associated with PKR expression and / or activation. In some embodiments, the subject has a disease or disorder selected from breast cancer, colon cancer, skin cancer, basal cell carcinoma, leukemia, lymphoma.

[0287] In some embodiments, the subject suffers from a neurological disease or disorder selected from multiple sclerosis, Alzheimer's disease, multiple sclerosis, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), dystonia and prion disease or any combination thereof, and acquired and inherited neurological diseases in the peripheral nervous system. In some embodiments, the neurological disorder is multiple sclerosis. In some embodiments, the neurological disorder is frontotemporal dementia, frontotemporal lobar degeneration and / or any other tauopathy, as described herein.

[0288] In some embodiments, the method is used to reduce or inhibit abnormal cell proliferation, tumor growth, malignancy, or any combination thereof in a subject in need thereof. In some embodiments, the method is used to reduce or inhibit the proliferation of cells expressing PKR. In some embodiments, the method is used to selectively reduce or inhibit the proliferation of cells expressing PKR.

[0289] In some embodiments, the reduction comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% reduction in cell proliferation, including any values ​​therebetween.

[0290] In some embodiments, the reduction comprises at least 10%, 20%, 30%, 40%, 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% reduction in PKR activity, including any values ​​therebetween.

[0291] In some embodiments, the IC of the compounds of the present invention in inhibiting PKR activity is 50 0.1 to 1 nM, 1 to 5 nM, 5 to 10 nM, 10 to 50 nM, 50 to 100 nM, 100 to 500 nM, 500 to 1 uM, 1 to 5 uM, 5 to 10 uM, including any value therebetween.

[0292] In some embodiments, the PKR IC of the compound is greater than that of other eIF2α phosphorylating kinases, such as PKR-like ER kinase (PERK), general control non-derepressed-2 (GCN2), or heme-regulated inhibitor (HRI). 50Reduced by at least 2-fold, 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 30-fold, at least 30-fold, at least 50-fold, at least 80-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 700-fold, at least 1000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold.

[0293] definition

[0294] The term "one or more" refers to any number selected from 1, 2, 3, 4, 5 or 6.

[0295] As used herein, the term "alkyl" describes aliphatic hydrocarbons including straight and branched chain groups. Alkyl groups have 1 to 20, 1 to 10, 1 to 15, 1 to 5, 1 to 3, 2 to 20, 2 to 10, 2 to 5, or 1, 2, 3, 4, 5, or 6 carbon atoms, including any range or value therebetween. Whenever a numerical range is mentioned herein, such as "1-20," this means that the group, in this case an alkyl group, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 20 carbon atoms. Alkyl groups can be substituted or unsubstituted, as defined herein. "Alkyl" also includes "heteroalkyl," i.e., an alkyl group containing one or more heteroatoms (e.g., O, S, N, or NH) within the backbone of the alkyl chain.

[0296] As used herein, the term "alkyl" also includes saturated or unsaturated hydrocarbons, and thus the term also includes alkenyl and alkynyl groups.

[0297] The term "alkenyl" describes an unsaturated alkyl group as defined herein having at least two carbon atoms and at least one carbon-carbon double bond. As noted above, an alkenyl group may be unsubstituted or substituted with one or more substituents.

[0298] The term "alkynyl" as defined herein is an unsaturated alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be substituted or unsubstituted with one or more substituents, as described above.

[0299] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (i.e., rings that share a pair of adjacent carbon atoms) group in which one or more rings do not have a completely conjugated pi electron system. Cycloalkyl groups can be substituted or unsubstituted, saturated, or contain at least one unsaturated bond, as described herein.

[0300] The term "cyclyl" describes an aryl, polycyclic, heteroaryl, cycloalkyl or heterocyclyl group or any combination thereof.

[0301] The term "polycyclic ring" or "polycyclic radical" includes multiple (e.g., 2, 3, 4, 5 or 6) fused or adjacent rings (e.g., biaryl or dicyclohexyl), wherein each ring is independently selected from aryl, heteroaryl, optionally unsaturated cycloalkyl, optionally unsaturated heterocyclic radical or any combination thereof. In some embodiments, the term "polycyclic radical" includes polycyclic aromatic rings, polycyclic aliphatic rings or mixed polycyclic rings. The term "polycyclic ring" or "polycyclic radical" includes fused rings (e.g., fused aliphatic rings, fused aromatic rings and / or heteroaromatic rings), spirocycles, bridged rings, bicyclic rings (two aromatic rings and / or aliphatic rings connected by a single carbon-carbon bond), as shown below: wherein each B independently comprises any of the following: (i) an optionally substituted aliphatic ring, optionally containing one or more heteroatoms, (ii) an optionally substituted aromatic or heteroaromatic ring; (iii) an optionally substituted bicyclic aliphatic, bicyclic aromatic / heteroaromatic or bicyclic mixed aromatic / heteroaromatic aliphatic ring, wherein each ring optionally contains one or more heteroatoms; (iv) a polycyclic aromatic ring, a polycyclic heteroaromatic ring or a polycyclic alicyclic ring, or a mixed polycyclic ring.

[0302] The term "mixed polycyclic" refers to any multiple rings (e.g., fused rings, bicyclic rings, spirocyclic rings, etc.) covalently bonded to each other, including at least one aromatic ring (aryl or heteroaryl) and at least one aliphatic ring or non-aromatic ring (optionally heterocyclic and / or unsaturated).

[0303] The term "bicyclic" includes fused rings (fused aromatic and / or heteroaromatic rings), spiro rings, bridged rings, and bicyclic rings (two aromatic and / or aliphatic rings connected by a single carbon-carbon bond). The terms "bicyclyl" and "bicyclic" are used interchangeably herein.

[0304] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a completely conjugated pi electron system. As described herein, an aryl group can be substituted or unsubstituted.

[0305] The term "alkoxy" describes O-alkyl and -O-cycloalkyl groups as defined herein.

[0306] The term "aryloxy" describes an -O-aryl group, as defined herein.

[0307] Each of the alkyl, cycloalkyl, and aryl groups in the general formula herein may be substituted with one or more substituents, wherein each substituent may independently be, for example, halogen, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxy, thiol, thioalkoxy, carboxyl, amide, aryl, and aryloxy, depending on the substituted group and its position in the molecule. Other substituents are also contemplated.

[0308] The terms "halide," "halogen," or "halo" describe fluorine, chlorine, bromine, or iodine. The term "haloalkyl" describes an alkyl group as defined herein, further substituted with one or more halides. The term "haloalkoxy" describes an alkoxy group as defined herein, further substituted with one or more halides. The term "hydroxyl" or "hydroxy" describes an -OH group. The term "mercapto" or "thiol" describes an -SH group. The term "thioalkoxy" describes an -S-alkyl and -S-cycloalkyl group, as defined herein. The term "thioaryloxy" describes an -S-aryl and -S-heteroaryl group, as defined herein. The term "amino" describes an -NR'R" group or a salt thereof, wherein R' and R" are as described herein.

[0309] The term "heterocyclyl" describes a monocyclic or fused ring group having one or more atoms (such as nitrogen, -NH-, oxygen, and sulfur) in the ring. The ring may also have one or more double bonds. However, these rings do not have a completely conjugated π electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, etc.

[0310] The term "heteroatom" describes O, S, N, NH, NH2, or N(R') as allowed by valence. 1-2 .

[0311] The term "carboxy" or "carboxylate" describes a -C(O)OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon), or heterocyclyl (bonded through a ring carbon), as defined herein. The term "carboxy" describes a -C(O)OR' group or a carboxylate salt thereof, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon), or heterocyclyl (bonded through a ring carbon), as defined herein.

[0312] The term "carbonyl" describes a -C(O)R' group, where R' is as defined above.

[0313] The above terms also include the thio derivatives thereof (thiocarboxy and thiocarbonyl).

[0314] The term "thiocarbonyl" describes a -C(S)R' group, where R' is as defined above.

[0315] "Thiocarboxy" refers to a -C(S)OR' group where R' is as defined herein.

[0316] "Sulfinyl" describes a -S(O)R' group, where R' is as defined herein.

[0317] "Sulfonyl" or "sulfonic acid" describes a -S(O)2R' group, where R' is as defined herein.

[0318] "Carbamoyl" or "carbamoyl" describes a -OC(O)NR'R' group where R' is as defined herein and R" is as defined for R'.

[0319] "Nitro" refers to a -NO2 group.

[0320] As used herein, the term "amide" includes C-amides and N-amides.

[0321] The term "C-amide" describes a -C(O)NR'R" terminal group or a -C(O)NR'- linking group, as these phrases are defined above, where R' and R" are as defined herein.

[0322] The term "N-amide" describes a terminal -NR"C(O)R' group or a -NR'C(O)- linking group, as these phrases are defined above, where R' and R" are as defined herein.

[0323] As used herein, the term "carboxylic acid derivative" includes carboxyl, amide, carbonyl, anhydride, carbonate, and carbamate.

[0324] "Cyano" or "nitrile" refers to a -CN group.

[0325] The term "azo" or "diazo" describes a terminal -N=NR' group or a linking -N=N- group, as these phrases are defined above, where R' is as defined above.

[0326] The term "guanidine" describes a -R'NC(N)NR"R"' terminal group or a -R'NC(N)NR"- linking group, as these phrases are defined above, where R', R", and R'" are as defined herein.

[0327] As used herein, the term "azide" refers to a -N3 group.

[0328] The term "sulfonamide" refers to a -S(O)2NR'R" group, where R' and R" are as defined herein.

[0329] The term "phosphono" or "phosphonic acid" describes a -OP(O)-(OR')2 group, where R' is as defined above.

[0330] The term "phosphinyl" describes a -PR'R" group, where R' and R" are as defined above.

[0331] The term "alkaryl" describes an alkyl group, as defined herein, substituted with an aryl group, as described herein. An exemplary alkaryl group is benzyl.

[0332] The term "heteroaryl" describes a monocyclic (e.g., C5-C6 heteroaromatic) or fused ring (i.e., a ring that shares a pair of adjacent atoms) group having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring, and in addition having a completely conjugated π electron system. In some embodiments, the terms "heteroaryl" and "C5-C6 heteroaryl" are used interchangeably herein. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. As described above, heteroaryl groups may be substituted or unsubstituted with one or more substituents. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine, and the like. In some embodiments, heteroaryl is selected from pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridyl (pyridinyl), In some embodiments, the heteroaryl group may be substituted with any of the following: inyl) (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienothiphenyl, 1,8-naphthyridinyl, other naphthyridinyl, pteridinyl or phenothiazinyl. When the heteroaryl group contains more than one ring, each additional ring is saturated (perhydro) or partially unsaturated (e.g., dihydro or tetrahydro), or maximally unsaturated (non-aromatic). Thus, the term heteroaryl includes bicyclic radicals in which both rings are aromatic and bicyclic radicals in which only one ring is aromatic.Examples of such heteroaryl groups include 3H-dihydroindolinyl, 2(1H)-quinolinyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4-chromenyl, oxindolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo[g]isoquinolinyl, 1,2,3,4-tetrahydro-benzo[g]isoquinolinyl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzo-dioxanyl, 1,2,3-4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolinyl, 5,6-dihydroisoquinolinyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazole quinolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1,4-naphthoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolinyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydro-benzoxazolyl, 1H-4-oxa-1,5-diaza-naphthalen-2-one, 1,3-dihydroimidazo-[4,5]-pyridin-2-one, 2, 3-Dihydro-1,4-dinaphthoquinone, 2,3-dihydro-1H-pyrrolo[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthopyridinyl, 1,2,3,4-tetrahydrobenzo[b][1,6]-naphthopyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo[3,4-b]indolyl, 1H-2,3,4,5-tetrahydro-azepine. [3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepine -[4,3-b]indolyl, 1H-2,3,4,5-tetrahydro-aza [4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[2,7]-naphthyridinyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro[1,4]-dioxino[2,3-b]79escry79, 3,4-dihydro-2H-1-oxa[4,6]naphthyridinyl, 4,5 ,6,7-tetrahydro-3H-imidazole-[4,5-c]pyridinyl, 6,7-dihydro[5,8]naphthyridinyl, 1,2,3,4-tetrahydro[1,5]-naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl, 1,2,3,4-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl or 1,2,3,4-tetrahydro[2,6]naphthyridinyl. In some embodiments, heteroaryl is optionally substituted. In one embodiment, one or more substituents are each independently selected from halo, hydroxy, amino, cyano, nitro, alkylamino, acyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkylamino, alkylthiooxy, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl.

[0333] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, benzoxazole, oxadiazole, benzopyrazole, quinolinazine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, OC 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl and amino-C 1-6 alkyl.

[0334] As used herein, the terms "halo" and "halide" refer interchangeably herein to a halogen atom, ie, fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0335] The term "haloalkyl" describes an alkyl group as described above that is further substituted with one or more halides.

[0336] Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36Cl, and 125I, respectively. In one embodiment, isotopically labeled compounds can be used for metabolic studies (using 14C), reaction kinetic studies (using, for example, 2H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug and substrate tissue distribution assays, or for radiotherapy of patients. In particular, 18F-labeled compounds may be particularly suitable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by performing the procedures disclosed herein, using readily available isotopically labeled reagents instead of non-isotopically labeled reagents.

[0337] As a general example and not limitation, isotopes of hydrogen, such as deuterium (D) and tritium (3H), can optionally be used anywhere in the structure to achieve the desired result. Alternatively or in addition, isotopes of carbon, such as 13C and 14C, can be used. In one embodiment, isotopic substitution is the replacement of hydrogen with deuterium at one or more positions on the molecule to improve the performance of the molecule as a drug, such as pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can be bound to carbon in the distribution of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or it can be bound adjacent to or near the bond cleavage site (β-deuterium kinetic isotope effect).

[0338] Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched by 80%, 85%, 90%, 95%, or 99% or more of the isotope at any position of interest. In some embodiments, deuterium is enriched by 80%, 85%, 90%, 95%, or 99% at the desired position. Unless otherwise indicated, enrichment at any time is above natural abundance and, in one embodiment, is sufficient to alter the detectable properties of the compound as a drug in humans.

[0339] The compounds of the present disclosure can form solvates with solvents (including water). Therefore, in one embodiment, the present invention includes solvated forms of active compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salt) and one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising the disclosed compound and water. Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent can be isotopically substituted, such as D2O, d6-acetone or d6-DMSO. The solvate can be in liquid or solid form.

[0340] General Description

[0341] As used herein, the terms "treatment" or "treating" a disease, disorder, or condition include alleviating at least one symptom thereof, reducing its severity, or inhibiting its progression. Treatment does not necessarily mean that the disease, disorder, or condition is completely cured. To be an effective treatment method, the useful compositions herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, or improve the quality of life of the patient or subject.

[0342] As used herein, the term "prevention" of a disease, disorder, or condition includes delaying, preventing, suppressing, or inhibiting the onset of the disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a preventative process in which a subject is exposed to the presently described active ingredients prior to the induction or onset of the disease / disorder process. This can be done in situations where an individual has a genetic pedigree indicating a susceptibility to the onset of the disease / disorder to be prevented. For example, this may be true for someone whose ancestors showed a predisposition to certain types of inflammatory disorders.

[0343] The term "suppression" is used to describe a situation where a disease / disorder process has begun but no overt symptoms have yet appeared. Thus, an individual's cells may be affected by a disease / disorder but no outward signs of the disease / disorder may be clinically detected. In either case, the term prevention is used to encompass both prevention and suppression.

[0344] In some embodiments, the term "reduce" or "enhance" (including any grammatical forms thereof) refers to a decrease / enhancement (e.g., enzyme activity) of at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99%, including any ranges therebetween, compared to a control or baseline.

[0345] In contrast, the term "treatment" refers to the clinical application of an active agent to combat an existing condition, the clinical manifestation of which has been achieved in the patient.

[0346] In the discussion, unless otherwise indicated, adjectives such as "substantially" and "approximately" modifying conditions or relationship characteristics of one or more features of an embodiment of the present invention are understood to mean that the condition or feature is defined within an acceptable tolerance range for the operation of the embodiment for its intended application. Unless otherwise indicated, the word "or" in the specification and claims is considered to be inclusive "or" rather than exclusive "or" and means at least one or any combination of the items it connects.

[0347] It should be understood that the terms "a" and "an" as used above and elsewhere herein refer to "one or more" of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless otherwise specifically stated. Therefore, the terms "a," "an," and "at least one" may be used interchangeably in this application.

[0348] As used herein, the term "about" refers to ±10%.

[0349] The terms "comprises," "comprising," "includes," "including," "having" and variations thereof mean "including but not limited to."

[0350] For a better understanding of the present teachings, and not to limit the scope of the teachings in any way, all numbers expressing quantities, percentages or ratios, as well as other numerical values ​​used in the specification and claims, unless otherwise indicated, should be understood in all instances as being modified by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximate and may vary depending upon the desired properties sought. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0351] In the specification and claims of this application, each verb "comprise", "include" and "have" and its variations are used to indicate that one or more objects of the verb are not necessarily a complete list of constituents, elements or parts of the one or more subjects of the verb.

[0352] Other terms used herein are meant to be defined by their commonly understood meanings in the art.

[0353] Unless otherwise stated or clear from the context, the term "or" as used herein should be understood to be inclusive.

[0354] In this specification and claims, the word "comprise" or variations such as "comprises" or "comprising" means the inclusion of any recited integer or group of integers but not the exclusion of any other integer or combination of integers.

[0355] As used herein, the term "consisting essentially of" or variations such as "consist essentially of" or "consisting essentially of" as used throughout the specification and claims means including any recited integer or group of integers, and optionally including any shown integer or group of integers, which does not materially change the basic or novel property of the specified method, structure, or composition.

[0356] As used herein, the terms "comprises," "comprising," "containing," "having," and the like may mean "includes," "including," and the like; "consisting essentially of" or "consists essentially of" also have the meanings specified in U.S. patent law, and the terms are open-ended, allowing for more than what is described, as long as the basic or novel features of the described content are not changed by the more than what is described, but excluding prior art embodiments. In one embodiment, the terms "comprises," "comprising," and "having" may be interchangeable with "consisting of."

[0357] Although the present invention has been described in conjunction with specific embodiments of the present invention, it is apparent that many alternatives, modifications and variations will be apparent to those skilled in the art. Therefore, the present invention is intended to encompass all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0358] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated as incorporated by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. Where section headings are used, they should not be construed as necessarily limiting.

[0359] Example

[0360] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical and microbiological techniques. These techniques are fully explained in the literature.

[0361] Example 1

[0362] In vitro PKR inhibitors

[0363] Several compounds of the present invention exhibit significant PKR inhibition in vitro, showing micromolar and submicromolar IC 50 IC values ​​for some compounds 50 Values ​​range from 1 to 10 nM (e.g. in cell-free biochemical assays).

[0364] Specific representative examples of potent PKR inhibitors of formula VII:

[0365] These are shown in Table 1. The inventors have synthesized other potent PKR compounds of the present invention.

[0366] Table 1: Exemplary PKR inhibitors represented by Formula VII

[0367]

[0368] In addition, compounds of formula VII, wherein R3 is pyridine, or R2 is pyridine substituted with an electron-donating group, and / or a substituted aromatic ring, a heteroaromatic substituted / unsubstituted ring, or a fused heteroaromatic ring at position R4, are also potent PKR inhibitors.

[0369] Example 2

[0370] In vitro PKR inhibitors

[0371] Other exemplary compounds of the present invention exhibit significant PKR inhibition in vitro, showing micromolar and submicromolar IC 50 In addition to the compounds disclosed in Example 1, the inventors have synthesized about 120 other compounds that exhibit significant PKR inhibitory effects in vitro.

[0372] Figure 4 Non-limiting examples of other PKR inhibitors represented by Formula VII or VIIA are shown:

[0373]

[0374] Figure 4 Some of the compounds shown in were tested in cell-based assays and showed significant cell-based potency.

[0375] An exemplary cell-based assay is as follows: The assay used to determine the cellular activity of compounds is the In-cell Western (ICW) assay, a cellular quantitative immunofluorescence assay that measures p-PKR levels in human cell lines. The assay is performed in 384-well plates and measures p-PKR levels after induction of the PKR pathway with Poly I:C (with or without varying concentrations of the test compound). The data generated are used to plot dose-response inhibition curves and calculate the IC of the test compound. 50 .

[0376] Surprisingly, closely related compounds not of the present invention showed negligible PKR inhibition in a cell-free enzyme assay (IC 50 higher than 1uM).

[0377] The general synthesis scheme is as follows Figure 1-3 shown.

[0378] Although the present invention has been described in detail, it will be appreciated by those skilled in the art that many variations and modifications may be made. Therefore, the present invention should not be construed as being limited to the specifically described embodiments, and the scope and concept of the present invention will be more readily understood by reference to the claims.

Claims

1. A compound represented by or comprising Formula IA or Formula IB: in: Indicates a single or double bond: Each L is absent or independently includes optionally substituted C1-C6 alkyl, N, NH, S and O, -S(O)2-, -C(O)-, -(C1-C6)-O-(C1-C6) 0-1 -、-(C1-C6)-S-(C1-C6) 0-1 -、-(C1-C6)-NH-(C1-C6) 0-1 - or any combination thereof; Each X1 is independently selected from CH, C or N, and at least one X1 is N; X includes S, O, N or NH; Each R1 independently represents hydrogen, or includes the following substituents: halogen, -NO2, -CN, -OH, -(C=O)NH2, HCONH-, oxo, carbonyl, amino, imino, thio, -OR, -(C=O)NH2, -CO2R, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SON(R)2, -NHNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy R1 represents a substituent; Any one of R2, R3 and R4 is independently H or represents a substituent including the following: halogen, -NO2, -CN, -OH, -OR, -SR, -(C=O)NH2, -CONR2, -C02R, -S02R, oxo, carbonyl, amino, C1-C6 mercaptoalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, imino, thio, carbonyl, aminoalkyl, fluoroalkyl, optionally substituted alkaryl / heteroaryl, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, -NR2, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated and cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -C(═O)—R, —S—C1-C6 haloalkyl, —NH—C1-C6 haloalkyl, —NR2, —NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof; or any of R2, R3, and R4 is absent; wherein at least one of R2 and R3 is not H or does not exist; wherein M is selected from -O-, -S-, -NH-, -C(=O)-, -CONR-, -CNNR-, -CSNR-, -CONH-O-, -CONH-NH-, -NHCO-, -NHCSR-, -NHCN-, -NC(=O)O-, -NC(=O)N-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SO2O-, -SO2NR-, -NHNR-, -CO2-, -OCO-, -OC(=O)O-, -OC(=O)N-, -OC(=S)O- and -OC(=S)N-; wherein W represents an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 heterocyclyl, an optionally substituted aryl, an optionally substituted alkaryl / heteroaryl or an optionally substituted heteroaryl; wherein each R independently represents hydrogen, or is selected from the group consisting of optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl / alkynyl, hydroxy, amino, -NH2, -NR2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, -OR, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR2, C1-C6 alkyl-SR, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C1-C 10 Alkaryl (eg benzyl), optionally substituted C1-C 10 Alkyl-C3-C 10 Cycloalkyl, optionally substituted C3-C 10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; or a salt thereof, wherein the compound includes any tautomer, any isotope, or any salt thereof.

2. The compound according to claim 1, wherein the compound is represented by or comprises Formula III or Formula IIIA: wherein R1 is selected from halo, cyano and formamide; and wherein R2 represents H or a substituent comprising C1-C6 haloalkyl, C1-C6 fluoroalkyl, -NR2, C1-C6 alkyl-NR2, C1-C6 alkyl-OR, C1-C6 alkyl-CONR2, C1-C6 alkyl-COOR, C1-C6 alkyl-CNNR2, C1-C6 alkyl-CSNR2, optionally substituted C5 or C6 heteroaryl; and if R2 is H, then R3 is not H.

3. The compound according to claim 1 or 2, wherein the compound is represented by or includes formula IV: wherein R1 is selected from halo (e.g. fluoro), cyano and carboxamido; wherein R2 represents H or a substituent comprising C1-C6 fluoroalkyl, -NR2 or optionally substituted C5 or C6 heteroaryl; and if R2 is H, then R3 is not H.

4. The compound according to any one of claims 1 to 3, wherein R3 is H, and R2 represents any one of the following: wherein Y is hydrogen or represents one or more substituents, each substituent being independently selected from halo, C1-C6 fluoroalkyl, -NO2, -NH2, -O(C1-C6 alkyl), -OME, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -(C=O)NH2, -CONR2, -CNNR2, -CSNR2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, -SO2R, -SOR, -SR, -SO2OR, -SO2N(R)2, -NHNR2, -NNR, -(C1-C6)-OH, or a combination thereof.

5. The compound of any one of claims 1 to 4, wherein R is selected from halogen, -NO, -CN, -OH, -OR, -(C=O)NH, -CONR, -SR, -C0R, -S0R, optionally substituted C1-C6 alkyl, amino, oxo, imino, thioxo, carbonyl, aminoalkyl, -NH, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 mercaptoalkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl, optionally substituted bicyclic cycloalkyl, or a combination thereof.

6. The compound according to any one of claims 1 to 5, wherein the compound is represented by or comprises Formula V or Formula VA: in: R1 is selected from halo, cyano and formamide; R3 is H or selected from (i) halogen, -NO2, -CN, -OH, -OR, -(C=O)NH2, -CONR2, -SR, -C02R, -S02R, optionally substituted C1-C6 alkyl, amino, oxo, imino, thioxo, carbonyl, aminoalkyl, -NH2, -NH(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 mercaptoalkyl, C1-C6 haloalkyl and (ii) optionally substituted C3-C8 cycloalkyl, any wherein R is an optionally substituted C3-C8 heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, or a combination thereof; if R3 is H or (i), then R2 is selected from C1-C6 fluoroalkyl and heteroaryl optionally substituted with one or more substituents, optionally wherein the substituents are linked to form a 5- or 6-membered aliphatic, unsaturated or aromatic ring; If R3 or R4 is H, then R2 is not H; If R3 is (ii), then R2 is C1-C6 fluoroalkyl.

7. The compound of claim 6, wherein R3 is H, R2 is selected from C1-C6 fluoroalkyl and a heteroaromatic ring optionally substituted with one or more substituents, optionally wherein the substituents are linked to each other to form a 5- or 6-membered aliphatic, unsaturated or aromatic ring.

8. A compound according to any one of claims 1 to 7, wherein R4 is H or selected from halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R ; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; CONR2; -C02R; -S02R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl.

9. The compound according to any one of claims 1 to 8, wherein R2 is C1-C3 fluoroalkyl, or a 5-6 membered heteroaromatic ring substituted with one or more substituents selected from -F and C1-C3 fluoroalkyl.

10. The compound according to any one of claims 6 to 8, which is represented by formula VB: wherein X is N or CH; wherein each Y' is independently hydrogen or one or more substituents selected from optionally substituted C1-C6 alkyl, -OR, -NR2, -O(C1-C6 alkyl), -OME, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CN, -OH, -NHCOR, -NHNR2, -NNR, C1-C6 haloalkyl, -(C1-C6)OH, or wherein two Y' are linked to each other to form a ring; and wherein R2 is selected from H and C1-C6 fluoroalkyl; and wherein R4 is H or selected from halogen; -OR; -O-C1-C6 haloalkyl; -OC(R)2-C1-C6 haloalkyl; C1-C6 haloalkyl; optionally substituted C1-C6 alkyl; -MW; optionally substituted C3-C8 saturated / unsaturated heterocyclyl; optionally substituted C3-C8 saturated / unsaturated cycloalkyl; optionally substituted C2-C6 alkenyl; -CN; optionally substituted C2-C6 alkynyl; -C(=O)-R; -SR; -S-C1-C6 haloalkyl; -NH-C1-C6 haloalkyl; -NO2; -OH; -(C=O)NH2; -CONR2; -CO2R; -SO2R; -NH2; -NR2; -NH(C1-C6 alkyl); hydroxy(C1-C6 alkyl); optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted bicyclic heteroaryl; optionally substituted bicyclic aryl; optionally substituted bicyclic heterocyclyl; and optionally substituted bicyclic cycloalkyl.

11. The compound according to any one of claims 1 to 10, which is represented by formula VI: wherein R1 is selected from cyano and formamide; R2 is selected from C1-C6 haloalkyl, optionally substituted alkaryl / heteroaryl, and a 5-6 membered heteroaromatic ring optionally substituted with at least one of -F and C1-C3 fluoroalkyl; R4 is H or selected from halogen, -OR, -O-C1-C6 haloalkyl, -OC(R)2-C1-C6 haloalkyl, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -MW, optionally substituted C3-C8 saturated / unsaturated heterocyclyl, optionally substituted C3-C8 saturated / unsaturated cycloalkyl, optionally substituted C2-C6 alkenyl, -CN, optionally substituted C2-C6 alkynyl, -C(=O)-R, -SR, -S-C1-C 6-haloalkyl, -NH-C1-C6-haloalkyl, -NO2, -OH, -(C=O)NH2, -CONR2, -C02R, -S02R, -NH2, -NR2, -NH(C1-C6-alkyl), hydroxy(C1-C6-alkyl), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted bicyclic heteroaryl, optionally substituted bicyclic aryl, optionally substituted bicyclic heterocyclyl and optionally substituted bicyclic cycloalkyl.

12. The compound according to claim 11, wherein R2 is selected from -CH2F and a 5-6 membered heteroaryl ring substituted with at least one of -F and C1-C3 fluoroalkyl.

13. A compound according to any one of claims 11 to 12, wherein R2 is selected from -CH2F and pyridine substituted with at least one of -F and C1-C3 fluoroalkyl; and wherein R4 is selected from fluoroalkyl, halo, -OR, -C(=O)-R, substituted C3-C6 cycloalkyl, substituted C3-C6 heterocyclyl containing an unsaturated bond, and substituted aryl.

14. The compound of claim 13, wherein the substituted comprises at least one substituent selected from the group consisting of haloalkyl, C1-C6 haloalkyl, alkoxy, C1-C6 hydroxyalkyl, oxo, optionally substituted C1-C6 alkyl, and -C(=O)-R.

15. The compound according to any one of claims 1 to 14, wherein the compound is or includes any one of the compounds in Table 1 or Figure 4, including any salt, any isotope or any tautomer thereof.

16. The compound of any one of claims 1 to 15, wherein the compound is stable in aqueous solution for at least 1 hour.

17. A pharmaceutical composition comprising the compound of any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17, for inhibiting protein kinase-R (PKR) cellular activity.

19. The pharmaceutical composition of any one of claims 17 to 18, wherein the cells are neural cells, glial cells, or both.

20. A method for preventing or treating a disease or disorder associated with PKR activity in a subject or ameliorating the condition thereof, comprising administering to the subject the pharmaceutical composition of claim 17, thereby (i) preventing or treating the disease or disorder; or (ii) ameliorating the condition associated with abnormal expression and / or activation of the PKR in the subject.

21. The method of claim 20, wherein the disease or disorder comprises a neurodegenerative disorder, a neuroinflammatory disorder, a metabolic disease, a cardiovascular disease, a proliferative disease, or any combination thereof.

22. The method of claim 21, wherein the neurodegenerative disorder is selected from Alzheimer's disease, multiple sclerosis, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), dystonia, and prion disease, or any combination thereof.

23. The method of any one of claims 20 to 22, wherein said preventing or said treating comprises inhibiting said PKR function in said cell.

24. The method of any one of claims 20 to 23, wherein the administering is by oral administration, topical administration, nasal administration, sublingual administration, buccal administration, systemic administration, or any combination thereof.

25. The method of any one of claims 20 to 24, wherein the improvement comprises (i) enhancing cognitive function, or (ii) inhibiting cognitive dysfunction in the subject.

26. The method of any one of claims 20 to 25, wherein the subject comprises a human subject, an animal subject, or both.

27. A method for enhancing or improving cognition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 17, thereby enhancing or improving cognition in the subject in need thereof.

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