Substituted cycloalkyls as modulators of integrated stress pathways

Abstract

To provide compounds, compositions and methods useful for modulation of integrated stress response (ISR) and for treatment of related diseases, disorders and conditions.SOLUTION: As the compound of the present invention, for example, (2R) - 6-chloro-N - (3 - {5 - [(3, 5-dimethylphenoxy) methyl] - 2-oxo-1, 3-oxazolidin-3-yl} bicycle [1.1.1] pentan-1-yl) - 4-oxo-3, 4-dihydro - 2H - 1-benzopyran-2-carboxamide is shown.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 840,960, filed April 30, 2019, the contents of which are hereby incorporated by reference in their entirety. [Background technology]

[0002] background In metazoans, diverse stress signals converge on a single common effector, the phosphorylation of the translation initiation factor eIF2α at serine 51. This step is carried out by four eIF2α kinases in mammalian cells: PERK, which responds to the accumulation of unfolded proteins in the endoplasmic reticulum (ER); GCN2, which responds to amino acid starvation and UV light; PKR, which responds to viral infection and metabolic stress; and HRI, which responds to heme depletion. This group of signaling pathways, converging on the same molecular event, has been termed the "integrated stress response" (ISR). Phosphorylation of eIF2α attenuates translation, thereby enabling cells to cope with various stresses (Wek, RC et al., Biochem Soc Trans (2006) 34(Pt 1):7-11).

[0003] eIF2 (consisting of three subunits, α, β, and γ) binds GTP and initiator Met-tRNA to form a ternary complex (eIF2-GTP-Met-tRNA i), which then binds to the 40S ribosomal subunit and scans the 5'UTR of mRNA to select the initiation AUG codon. When its α subunit is phosphorylated, eIF2 becomes a competitive inhibitor of its GTP exchange factor (GEF), eIF2B (Hinnebusch, A.G. and Lorsch, J.R. Cold Spring Harbor Perspect Biol (2012) 4(10) (Non-Patent Document 2)). Strong and unproductive binding of phosphorylated eIF2 to eIF2B prevents the supply of eIF2 GTP complexes, ultimately blocking the formation of the ternary complex and reducing translation initiation (Krishnamoorthy, T. et al., Mol Cell Biol (2001) 21(15):5018-5030 (Non-Patent Document 3)). Because eIF2B is less abundant than eIF2, phosphorylation of only a small fraction of total eIF2 has a dramatic effect on the activity of eIF2B in cells.

[0004] eIF2B is a complex molecular machine composed of five distinct subunits, eIF2B1 to eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with the partially homologous subunit eIF2B3, constitutes the "catalytic core" (Williams, D.D. et al., J. Biol. Chem. (2001) 276:24697-24703 (Non-Patent Document 4)). The remaining three subunits (eIF2B1, eIF2B2, and eIF2B4) are also highly homologous to each other and form a "regulatory subcomplex" that provides a binding site for eIF2B's substrate, eIF2 (Dev, K. et al., Mol. Cell. Biol. (2010) 30:5218-5233 (Non-Patent Document 5)). The exchange of GDP for GTP in eIF2 is catalyzed by its dedicated guanine nucleotide exchange factor (GEF), eIF2B. eIF2B exists in cells as a decamer (B12B22B32B42B52) or a dimer of two pentamers (Gordiyenko, Y. et al., Nat Commun (2014) 5:3902 (Non-Patent Document 6); Wortham, N.C. et al., FASEB J (2014) 28:2225-2237 (Non-Patent Document 7)). Molecules such as ISRIB interact with and stabilize the eIF2B dimeric conformation, thereby enhancing its intrinsic GEF activity and reducing the cell's sensitivity to the cellular effects of eIF2α phosphorylation (Sidrauski, C. et al., eLife (2015) e07314 (Non-Patent Document 8); Sekine, Y. et al., Science (2015) 348:1027-1030 (Non-Patent Document 9)). Therefore, small molecule therapeutics capable of modulating eIF2B activity may have the potential to attenuate the PERK branch of the UPR and the entire ISR, and therefore may be used to prevent and / or treat a variety of diseases, such as neurodegenerative diseases, leukodystrophies, cancer, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Wek, R.C. et al, Biochem Soc Trans (2006) 34(Pt 1):7-11 [Non-Patent Document 2] Hinnebusch, A.G. and Lorsch, J.R. Cold Spring Harbor Perspect Biol (2012) 4(10) [Non-Patent Document 3] Krishnamoorthy, T. et al, Mol Cell Biol (2001) 21(15):5018-5030 [Non-Patent Document 4] Williams, D.D. et al, J Biol Chem (2001) 276:24697-24703 [Non-Patent Document 5] Dev, K. et al, Mol Cell Biol (2010) 30:5218-5233 [Non-Patent Document 6] Gordiyenko, Y. et al, Nat Commun (2014) 5:XXX [Non-Patent Document 7] Wortham, N.C. et al, FASEB J (2014) 28:2225-2237 [Non-Patent Document 8] Sidrauski, C. et al, eLife (2015) e07314 [Non-Patent Document 9] Sekine, Y. et al, Science (2015) 348:1027-1030 [Summary of the Invention]

[0006] The present disclosure relates, at least in part, to compounds, compositions, and methods for modulating eIF2B (e.g., activating eIF2B) and attenuating the ISR signaling pathway. In some embodiments, disclosed herein are eIF2B modulators (e.g., eIF2B activators) comprising a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. In other embodiments, disclosed herein is the use of a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, for the treatment of a disease or disorder, e.g., a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of a component of the eIF2B or ISR pathway (e.g., the eIF2 pathway).

[0007] For example, disclosed herein are compounds of formula (I): TIFF2026009987000001.tif26128 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof; During the ceremony, D is a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, or a cubanyl, wherein each of the 4- to 6-membered monocyclic cycloalkyl, the 4- to 6-membered monocyclic heterocyclyl, the bridged bicyclic cycloalkyl, the bridged bicyclic heterocyclyl, or the cubanyl is optionally substituted on one or more available carbons with one to four R X ; and when the 4- to 6-membered monocyclic heterocyclyl or the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1 and U is -NR 1 C(O)- or -C(O)NR 1 - and E is a bond, -NR 2C(O)-, -C(O)NR 2 -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G and when the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2 or E is TIFF2026009987000002.tif20128, and Y is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R G and when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2 and L 1 is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3 -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1 and optionally substituted by L 2 is a bond, C1-C6 alkylene, a 2- to 7-membered heteroalkylene, or -O-, where the C1-C6 alkylene or the 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2 may be substituted with R 1 is hydrogen or C1-C6 alkyl, R 2 is hydrogen or C1-C6 alkyl, W is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety including a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, where the heterocyclyl has 1 to 4 R W1 The phenyl or heteroaryl may be optionally substituted with 1 to 4 R at one or more available unsaturated carbons. W2 When the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N4 and wherein W is substituted with L through an available saturated carbon or nitrogen atom in the heterocyclyl. 2 binds to A is a C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y When the 5- to 6-membered heteroaryl or 8- to 10-membered bicyclic heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N5 may be substituted with Each R L1 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R L2are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of R N1 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N2 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N3 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N4is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B R C , and -C(O)OR D selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO-C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w C 1-6 alkyl (wherein w is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which independently is selected from the group consisting of halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)NR. B R C selected from the group consisting of R N5is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of Each R W1 are independently hydrogen, C1-C6 alkyl (optionally substituted by -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A , -NR B R C , -NR B R CC , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R W2 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , and -S(O)R Dor selected from the group consisting of Two R on adjacent atoms W2 groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X may be substituted with Each R X are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R Y are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or selected from the group consisting of Two R on adjacent atoms Ygroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be substituted with 1 to 5 R X may be substituted with Each G is independently a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 3 R Z may be substituted with Each R Z are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , and -S(O)R D selected from the group consisting of R A is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B R C , -C(O)R D , or -C(O)OR D and R B and R C are independently hydrogen or C1-C6 alkyl; R B and R C However, together with the atoms to which they are bonded, they form one to three R Z forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CCis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each R E are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F are independently hydrogen, C1-C6 alkyl, or halo; Each R G are independently hydrogen, C1-C6 alkyl, halo, or oxo; and m is R F is 1 when hydrogen or C1-C6 alkyl, and R F is 3 when C1-C6 alkyl, or R F is 5 in the case of halo.

[0008] Also disclosed is a compound of formula (II): TIFF2026009987000003.tif27128 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof; During the ceremony, D IIis a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein each of the bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl is substituted with one to four R X-II and when the 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1-II and U II is -NR 1-II C(O)- or -C(O)NR 1-II - and E II is the bond, -NR 2-II C(O)-, -C(O)NR 2-II -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G-II and when the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2-II or E II teeth, TIFF2026009987000004.tif20128, Y II is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R G-II and when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2-II and L1-II is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3-II -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-II may be substituted with L 2-II is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, -O-, where C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2-II may be substituted with R 1-II is hydrogen or C1-C6 alkyl, R 2-II is hydrogen or C1-C6 alkyl, W II is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R W-II and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N4-II and A II is a C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y-II and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N5-II may be substituted with Each R L1-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)RD-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R L2-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of R N1-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N2-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N3-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-IIR C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N4-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B-II R C-II , and -C(O)OR D-II selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO—C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w-II C 1-6 alkyl (wherein w-II is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)NR B-II R C-II selected from the group consisting of R N5-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of Each R W-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II R CC-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II or selected from the group consisting of: Two R on adjacent atoms W-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with Each R X-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R Y-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -S(R F-II ) m-II , -S(O)R D-II , -S(O)2R D-II , and G 1-II or selected from the group consisting of Two R on adjacent atoms Y-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with each G 1-II are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-II may be substituted with Each R Z-II are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R A-II is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-II R C-II , -C(O)R D-II , or -C(O)OR D-II and R B-II and R C-II are each independently hydrogen or C1-C6 alkyl; R B-II and R C-II together with the atoms to which they are attached, form one to three R Z-II forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-IIis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-II is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each R E-II are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-II are independently hydrogen, C1-C6 alkyl, or halo; and Each R G-II are independently hydrogen, C1-C6 alkyl, halo, or oxo; However, D II When E is a bridged bicyclic five-membered cycloalkyl, II is -NR 2-II It is C(O)-.

[0009] Also disclosed are compounds of formula (IIIa) or formula (IIIb): TIFF2026009987000005.tif29136, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, During the ceremony, D III is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R X-IIIand when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1-III and W III is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein the heterocyclyl is fused to one or more available saturated carbons with one to four R W1-III The phenyl or heteroaryl may be optionally substituted with 1 to 4 R at one or more available unsaturated carbons. W2-III and if the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N2-III and A III is phenyl or a 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl has 1 to 5 R Y-III and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N3-III and R 1-III is hydrogen or C1-C6 alkyl, L 1-III is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-III may be substituted with Each R L1-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NRB-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of R N1-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N2-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N3-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of Each R W1-III are independently hydrogen, C1-C6 alkyl (optionally substituted by -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III RCC-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R W2-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , and -S(O)R D-III or selected from the group consisting of: Two R on adjacent atoms W2-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with Each R X-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III, -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R Y-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , -S(O)2R D-III , and G 1-III or selected from the group consisting of: Two R on adjacent atoms Y-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with each G 1-III are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-III may be substituted with Each R Z-III are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)RD-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R A-III is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-III R C-III , -C(O)R D-III , or -C(O)OR D-III and R B-III and R C-III are each independently hydrogen or C1-C6 alkyl; R B-III and R C-III However, together with the atoms to which they are attached, they form 1 to 3 R Z-III forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-III is independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-III is independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, or halo-C1-C6 alkyl; Each R E-III are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-IIIare independently hydrogen, C1-C6 alkyl, or halo; and m III is R F-III is 1 when R is hydrogen or C1-C6 alkyl; F-III is C1-C6 alkyl, or R F-III is 5 for halo.

[0010] In some embodiments, the compound disclosed herein is selected from the compounds set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

[0011] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are formulated as pharmaceutically acceptable compositions comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0012] In another aspect, the invention features a method for treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject, or a disease or disorder associated with impaired function of a component of the eIF2B or ISR pathway (e.g., the eIF2 pathway), comprising administering to the subject a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, or a composition thereof.

[0013] In another aspect, the invention features a method for treating a disease or disorder associated with modulation (e.g., inhibition) of eIF2B activity or levels, modulation (e.g., inhibition) of eIF2α activity or levels, modulation (e.g., enhancement) of eIF2α phosphorylation, modulation (e.g., enhancement) of phosphorylated eIF2α pathway activity, or modulation (e.g., enhancement) of ISR activity in a subject, the method comprising administering to the subject a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, or a composition thereof. In some embodiments, the disease may be caused by a mutation in the sequence of a gene or protein associated with a component of the eIF2 pathway (e.g., the eIF2α signaling pathway or the ISR pathway).

[0014] In another aspect, the invention features a method of treating cancer in a subject, the method including administering to the subject a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b) in combination with an immunotherapeutic agent. [The present invention 1001] Formula (I): The compound of TIFF2026009987000006.tif27128, During the ceremony, D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein each of the bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl is substituted with one to four R X and when the 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1 and U is -NR 1 C(O)-, -C(O)NR 1- or 5- to 6-membered heteroaryl; E is a bond, -NR 2 C(O)-, -C(O)NR 2 -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted with R N2 or E is TIFF2026009987000007.tif20128, and Y is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R G and when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted with R N2 and L 1 is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3 -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1 and optionally substituted by L 2 is a bond, C1-C6 alkylene, a 2- to 7-membered heteroalkylene, or -O-, where the C1-C6 alkylene or the 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2 may be substituted with R 1 is hydrogen or C1-C6 alkyl, R 2 is hydrogen or C1-C6 alkyl, W is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein the heterocyclyl has 1 to 4 R W1 and the phenyl or heteroaryl may be substituted with 1 to 4 R at one or more available unsaturated carbons. W2 When the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N4 and W is optionally substituted with L through an available saturated carbon or nitrogen atom in the heterocyclyl. 2 binds to A is a C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y and when said 5- to 6-membered heteroaryl or 8- to 10-membered bicyclic heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R N5 may be substituted with Each R L1 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each RL2 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of R N1 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N2 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N3 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N4is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B R C , and -C(O)OR D selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO—C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w C 1-6 alkyl (wherein w is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)-NR B R C selected from the group consisting of R N5is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of Each R W1 are independently hydrogen, C1-C6 alkyl (optionally substituted by -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A , -NR B R C , -NR B R CC , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R W2 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , and -S(O)R Dor selected from the group consisting of Two R on adjacent atoms W2 groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X may be substituted with Each R X are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R Y are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or selected from the group consisting of Two R on adjacent atoms Ygroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X may be substituted with each G 1 are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z may be substituted with Each R Z are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , and -S(O)R D selected from the group consisting of R A is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B R C , -C(O)R D , or -C(O)OR D and R B and R C are independently hydrogen or C1-C6 alkyl; R B and R C However, together with the atoms to which they are bonded, they form one to three R Z forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CCis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each R E are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F are independently hydrogen, C1-C6 alkyl, or halo; Each R G are independently hydrogen, C1-C6 alkyl, halo, or oxo; and m is R F is 1 when hydrogen or C1-C6 alkyl, and R F is 3 when C1-C6 alkyl, or R F is 5 for halo, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. [The present invention 1002] D is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from the group consisting of 1 to 4 R X The compound of the present invention 1001, which may be substituted with a group. [The present invention 1003] D is, Any of compounds 1001 to 1002 of the present invention selected from the group consisting of TIFF2026009987000008.tif38148. [The present invention 1004] D is, Any of compounds 1001 to 1003 of the present invention selected from the group consisting of TIFF2026009987000009.tif63146. [The present invention 1005] D is 0 R x 1005. The compound of any one of claims 1001 to 1004, substituted with: [The present invention 1006] D is, Any of compounds 1001 to 1005 of the present invention selected from the group consisting of TIFF2026009987000010.tif57143. [The present invention 1007] D is, Any of compounds 1001 to 1006 of the present invention, which is TIFF2026009987000011.tif18128. [The present invention 1008] D is one R X 1006. The compound of any one of claims 1001 to 1005, substituted with [The present invention 1009] D is, Any of compounds 1001 to 1005 and 1008 of the present invention, which is TIFF2026009987000012.tif20128. [The present invention 1010] R X The compound of any of claims 1008 or 1009, wherein is -OH. [The present invention 1011] U is -NHC(O)-, -C(O)NH-, and Any of compounds 1001 to 1010 of the present invention selected from the group consisting of TIFF2026009987000013.tif19128. [The present invention 1012] 1012. The compound of any one of claims 1001 to 1011, wherein U is -NHC(O)-. [The present invention 1013] L 1 is a bond or C1-C6 alkylene, and the C1-C6 alkylene is selected from 1 to 5 R L1 Optionally, the compound of any of claims 1001 to 1012 is substituted with [The present invention 1014] L 1 is a bond or C1-C6 alkylene, and the C1-C6 alkylene is not present in any of the groups represented by R L1 10. The compound of any one of claims 1001 to 1013, wherein the compound is substituted with [The present invention 1015] L 1 The compound of any one of claims 1001 to 1014, wherein is a bond or -CH2-. [The present invention 1016] R 1 Any of compounds 1001 to 1015 of the present invention, wherein is hydrogen or CH3. [The present invention 1017] W is the formula (Wa): Represented by TIFF2026009987000014.tif23128, During the ceremony, X is NR N4 or C(R X1 )(R X2 ) and R N4 is hydrogen or C1-C6 alkyl, R X1 is hydrogen or hydroxyl, R X2 is hydrogen or hydroxyl, or R X1 and R X2 together form an oxo moiety, Any of the compounds of 1001 to 1016 of the present invention. [The present invention 1018] W is, Any of compounds 1001 to 1017 of the present invention selected from the group consisting of TIFF2026009987000015.tif44128. [The present invention 1019] W is, Any of compounds 1001 to 1016 of the present invention, which is TIFF2026009987000016.tif18128. [The present invention 1020] W is one R W2 1001-1019. The compound of any of claims 1001-1019, wherein the compound is substituted with [The present invention 1021] R W2 The compound of the present invention 1020, wherein is chloro. [The present invention 1022] W, two R W2 1001-1019. The compound of any of claims 1001-1019, wherein the compound is substituted with [The present invention 1023] Each R W2 is independently chloro or fluoro. [The present invention 1024] E is a bond, -NR 2 C(O)-, -C(O)NR 2 - and Any of compounds 1001 to 1023 of the present invention selected from the group consisting of TIFF2026009987000017.tif20128. [The present invention 1025] E is, Any of compounds 1001 to 1021 of the present invention selected from the group consisting of TIFF2026009987000018.tif51151. [The present invention 1026] E is, Any of compounds 1001 to 1021 of the present invention selected from the group consisting of TIFF2026009987000019.tif70141. [The present invention 1027] E is a bond, -NR 2 C(O)-, -C(O)NR 2 -, Any of compounds 1001 to 1026 of the present invention selected from the group consisting of TIFF2026009987000020.tif82151. [The present invention 1028] E is, Any of compounds 1001 to 1017 of the present invention selected from the group consisting of TIFF2026009987000021.tif14128. [The present invention 1029] R 2 1028. The compound of any one of claims 1001 to 1028, wherein is hydrogen. [The present invention 1030] L 2 is a bond, -O-, C1-C6 alkylene, or 2- to 7-membered heteroalkylene. [The present invention 1031] L 2 is a bond, -CH2-, -CH2O- * , -(CH2)2O- * , -(CH2)3O- * or -O-, wherein "- * " indicates the point of attachment to A. [The present invention 1032] A, Any of compounds 1001 to 1031 of the present invention selected from the group consisting of TIFF2026009987000022.tif95142. [The present invention 1033] A, Any of compounds 1001 to 1032 of the present invention selected from the group consisting of TIFF2026009987000023.tif53148. [The present invention 1034] Each R Y is independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxyl, phenyl, CHF2, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH3)2, CH2OCF3, and CN. [This invention 1035] Formula (II): The compound of TIFF2026009987000024.tif27128, During the ceremony, D II is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein the bridged bicyclic cycloalkyl, the bridged bicyclic heterocyclyl, the 4- to 6-membered monocyclic cycloalkyl, the 4- to 6-membered monocyclic heterocyclyl, or the cubanyl each has one to four R X-II and when the 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1-II and U II is -NR 1-II C(O)- or -C(O)NR 1-II - and E II is the bond, -NR 2-II C(O)-, -C(O)NR 2-II -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G-II and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted with R N2-II or E II teeth, TIFF2026009987000025.tif20128, Y II is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein said 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R G-IIand when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted with R N2-II and L 1-II is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3-II -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-II may be substituted with L 2-II is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, -O-, and the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2-II may be substituted with R 1-II is hydrogen or C1-C6 alkyl, R 2-II is hydrogen or C1-C6 alkyl, W II is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R W-II and when said 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R N4-II and A II is a C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y-II and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N5-II may be substituted with Each R L1-IIare independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R L2-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of R N1-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N2-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NRB-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N3-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N4-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B-II R C-II , and -C(O)OR D-II selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO—C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w-II C 1-6alkyl (wherein w-II is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)NR B-II R C-II selected from the group consisting of R N5-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of Each R W-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II R CC-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II or selected from the group consisting of Two R on adjacent atoms W-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with Each R X-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R Y-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -S(R F-II ) m-II , -S(O)R D-II , -S(O)2R D-II , and G 1-II or selected from the group consisting of Two R on adjacent atoms Y-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with each G 1-II are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-II may be substituted with Each R Z-II are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R A-II is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-II R C-II , -C(O)R D-II , or -C(O)OR D-II and R B-II and R C-II are each independently hydrogen or C1-C6 alkyl; R B-II and R C-II together with the atoms to which they are attached, form one to three R Z-II forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-IIis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-II is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each R E-II are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-II are independently hydrogen, C1-C6 alkyl, or halo; and Each R G-II are independently hydrogen, C1-C6 alkyl, halo, or oxo; However, D II When E is a bridged bicyclic five-membered cycloalkyl, II is -NR 2-II C(O)-, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. [The present invention 1036] D II is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from 1 to 4 R X-II The compound of the present invention 1035, which may be substituted with a group. [This invention 1037] DII but, Any of compounds 1035 to 1036 of the present invention selected from the group consisting of TIFF2026009987000026.tif61139. [The present invention 1038] D II But there are 0 R X-II 8. The compound of any one of claims 1035 to 1037, wherein the compound is substituted with: [This invention 1039] D II but, Any of compounds 1035 to 1038 of the present invention selected from the group consisting of TIFF2026009987000027.tif19128. [The present invention 1040] D II But one R X-II 8. The compound of any one of claims 1035 to 1037, wherein the compound is substituted with: [The present invention 1041] D II but, Any of compounds 1035 to 1037 and 1040 of the present invention, which is TIFF2026009987000028.tif24128. [The present invention 1042] R X-II The compound of invention 1040 or 1041, wherein is -OH. [This invention 1043] L 1-II is C1-C6 alkylene or 2- to 7-membered heteroalkylene, and the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-II Optionally, the compound of any one of 1035 to 1042 of the present invention is substituted with [This invention 1044] L 1-II but, 0 R L1-II C1-C6 alkylene or 2- to 7-membered heteroalkylene substituted with Any of compounds 1035 to 1043 of the present invention, [This invention 1045] L 1-IIis -CH2- or CH2O- * In the formula, "- * " indicates the point of attachment to WII. [The present invention 1046] R 1-II Any of compounds 1035 to 1045 of the present invention, wherein is hydrogen or CH3. [This invention 1047] W II but, Any of compounds 1035 to 1046 of the present invention selected from the group consisting of TIFF2026009987000029.tif78149. [This invention 1048] W II but, Any of compounds 1035 to 1047 of the present invention, which is TIFF2026009987000030.tif15128. [This invention 1049] Each R Y-II is independently chloro, fluoro, or CF3. [The present invention 1050] E II But, -NR 2-II C(O)-, -C(O)NR 2-II - and Any of compounds 1035 to 1049 of the present invention selected from the group consisting of TIFF2026009987000031.tif20128. [This invention 1051] E II but, Any of compounds 1035 to 1049 of the present invention selected from the group consisting of TIFF2026009987000032.tif35128. [This invention 1052] E II But, -NR 2-II C(O)-, Any of compounds 1035 to 1051 of the present invention selected from the group consisting of TIFF2026009987000033.tif21128. [This invention 1053] D II but If it is TIFF2026009987000034.tif17128, then E II But, -NR 2-II Any of compounds 1035 to 1050 and 1052 of the present invention, which is C(O)-. [This invention 1054] R 2-II The compound of any one of claims 1035 to 1053, wherein is hydrogen or methyl. [This invention 1055] L 2-II is a bond, -O-, or 2- to 7-membered heteroalkylene. [The present invention 1056] L 2-II is the bond, -CH2O- * , -(CH2)2O- * , -(CH2)3O- * or -O-, wherein "- * " is A II 10. A compound of any one of claims 1035 to 1055, showing the point of attachment to [This invention 1057] A II but, Any of compounds 1035 to 1056 of the present invention selected from the group consisting of TIFF2026009987000035.tif79149. [This invention 1058] A II but, Any of compounds 1035 to 1057 of the present invention, which is TIFF2026009987000036.tif15128. [This invention 1059] Each R Y-II Any of compounds 1035 to 1058 of the present invention, wherein is chloro or OCF3. [The present invention 1060] Formula (IIIa) or Formula (IIIb): A compound represented by TIFF2026009987000037.tif29136, During the ceremony, D III is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein said 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R X-III and when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted with R N1-III and W III is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein the heterocyclyl has 1 to 4 R W1-III and the phenyl or heteroaryl may be substituted with 1 to 4 R at one or more available unsaturated carbons. W2-III and if said heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R N2-III and A III is phenyl or a 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl has 1 to 5 R Y-III When the five- to six-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N3-III and R 1-III is hydrogen or C1-C6 alkyl, L 1-III is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-III may be substituted with Each R L1-IIIare independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of R N1-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N2-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N3-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of Each R W1-IIIare independently hydrogen, C1-C6 alkyl (optionally substituted with -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III R CC-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R W2-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , and -S(O)R D-III or selected from the group consisting of Two R on adjacent atoms W2-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with Each R X-IIIare independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R Y-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , -S(O)2R D-III , and G 1-III or selected from the group consisting of: Two R on adjacent atoms Y-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with each G 1-IIIare independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-III may be substituted with Each R Z-III are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R A-III is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-III R C-III , -C(O)R D-III , or -C(O)OR D-III and R B-III and R C-III are each independently hydrogen or C1-C6 alkyl; R B-III and R C-III However, together with the atoms to which they are attached, they form 1 to 3 R Z-III forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-IIIis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-III are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, or halo-C1-C6 alkyl; Each R E-III are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-III are independently hydrogen, C1-C6 alkyl, or halo; and m III is R F-III is 1 when R is hydrogen or C1-C6 alkyl; F-III is C1-C6 alkyl, or R F-III is 5 for halo, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. [This invention 1061] D III is an azetidine, pyrrolidine, piperidine, piperazine, or 2-azaspiro[3.3]heptane moiety, each of which is substituted with one to four R W-III groups, and each R W-III are independently C1-C6 alkyl, halo-C1-C6 alkyl, halo, oxo, cyano, or -OR A-III where piperazine has R N2-III The compound of the present invention 1060, optionally substituted with [The present invention 1062] D III is selected from the group consisting of: N1-III is hydrogen or C1-C3 alkyl; TIFF2026009987000038.tif18144. [The present invention 1063] D III but, TIFF2026009987000039.tif17128, compound of the present invention 1062. [The present invention 1064] W III But the formula (Wb): Represented as TIFF2026009987000040.tif23128, During the ceremony, X III is NR N4-III or C(R X1-III )(R X2-III ) and R N4-III is hydrogen or C1-C6 alkyl, R X1-III is hydrogen or hydroxyl, R X2-III is hydrogen or hydroxyl, or R X1-III and R X2-III together form an oxo moiety, Any compound of 1060 to 1063 of the present invention. [This invention 1065] W III but, Any of compounds 1060 to 1064 of the present invention selected from the group consisting of TIFF2026009987000041.tif20164. [The present invention 1066] W III But one R W2-III 1060. The compound of any one of claims 1060 to 1065, substituted with [This invention 1067] R W2-IIIThe compound of the present invention 1066, wherein is chloro. [The present invention 1068] L 1-III But 1-5 R L1-III The compound of any one of claims 1060 to 1067, wherein the compound is a 2- to 7-membered heteroalkylene optionally substituted with [The present invention 1069] L 1-III But there are 0 R L1 1068. The compound of any one of claims 1060 to 1068, wherein the compound is a 2- to 7-membered heteroalkylene substituted with [The present invention 1070] L 1-III But CH2O- * or CH2OCH2- * wherein "-" is selected from the formula: * " is A III 1098. A compound of any of claims 1060 to 1098, showing the point of attachment to [This invention 1071] R 1-III Any of compounds 1060 to 1070 of the present invention, wherein is hydrogen or CH3. [This invention 1072] A III but, Any of the compounds of claims 1060 to 1071 selected from the group consisting of TIFF2026009987000042.tif45143. [This invention 1073] Each R Y-III is independently selected from the group consisting of hydrogen, chloro, fluoro, CHF2, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH3)2, and CN. [This invention 1074] A compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, N-oxides, or stereoisomers thereof: TIFF2026009987000043.tif137128TIFF2026009987000044.tif219113TIFF2026009987000045.tif221113TIFF2026009987000046.tif198113 TIFF2026009987000047.tif206113TIFF2026009987000048.tif203113TIFF2026009987000049.tif204113TIFF2026009987000050.tif223113 TIFF2026009987000051.tif201113TIFF2026009987000052.tif206113TIFF2026009987000053.tif216113TIFF2026009987000054.tif213113 TIFF2026009987000055.tif200113TIFF2026009987000056.tif219113TIFF2026009987000057.tif21063TIFF2026009987000058.tif138128. [This invention 1075] A pharmaceutically acceptable composition comprising any one of the compounds of the present invention 1001 to 1074 and a pharmaceutically acceptable carrier. [This invention 1076] A method for treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of any of compounds 1001 to 1074 of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. [This invention 1077] 1076. The method of claim 1076, wherein said neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive disorder, a glial cell dysfunction, or a brain injury. [This invention 1078] 1078. The method of claim 1076 or 1077, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with central nervous system dysmyelination, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia, kuru, multiple sclerosis, Parkinson's disease, or prion disease. [This invention 1079] 1079. The method of any one of claims 1076 to 1078, wherein the neurodegenerative disease comprises vanishing white matter disease. [The present invention 1080] 1076. The method of claim 1076, wherein said cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells. [This invention 1081] 1076. The method of claim 1076, wherein the inflammatory disease comprises postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. [This invention 1082] The method of claim 1076, wherein the musculoskeletal disease comprises muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal-bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Friedrich's ataxia, muscle wasting disorder, inclusion body myositis, motor neuron disease, or paralysis. [This invention 1083] The method of claim 1076, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. [This invention 1084] 1077. The method of claim 1076, wherein said mitochondrial disease is associated with or results from mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations. [This invention 1085] The method of any one of claims 1076 to 1084, wherein the mitochondrial disease is a mitochondrial myopathy. [The present invention 1086] Any of methods 1076 and 1084 to 1085 of the present invention, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, i.e., maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome. [This invention 1087] The autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Barro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castle disease, and the like. Mann's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia , Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS,Paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, The method of the present invention 1076, wherein the disease is selected from the group consisting of restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)). [This invention 1088] 1076. The method of claim 1076, wherein said viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV), and herpes. [This invention 1089] The skin disease may be acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infection of the nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, piscine The method of the present invention 1076 is selected from the group consisting of leprosy, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts, polymorphous light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo. [The present invention 1090] 1076. The method of claim 1076, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, interstitial pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling. [This invention 1091] The hemoglobinopathy may be "dominant" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α + - Thalassemia (α 0 -thalassemia phenotype), hydrops fetalis with Hb Bartz disease, sickle cell anemia / sickle cell disease, sickle cell trait, sickle beta-thalassemia disease, α + - Thalassemia, α 0 -Thalassemia, α-thalassemia with myelodysplastic syndrome, α-thalassemia / mental retardation (ATR) syndrome, β 0- Thalassemia, beta + 1076. The method of claim 1076, wherein the β-thalassemia is selected from the group consisting of εγδβ-thalassemia, δ-thalassemia, γ-thalassemia, β-thalassemia major, β-thalassemia intermedia, δβ-thalassemia, and εγδβ-thalassemia. [This invention 1092] The kidney disease may be Abderhalden-Kaufmann-Lignac syndrome (nephropathic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephrosis, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, vasculitis Myolipoma, analgesic nephropathy, anorexia nervosa and kidney disease, angiotensin antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-associated glomerulonephritis, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal medicine nephropathy, Balkan endemic nephropathy, arteriovenous malformations and fistulas of the urinary tract, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome, bath salts and acute kidney injury, polydipsia Potomania, beet urine, β-thalassemia nephropathy, bile cast nephropathy, BK polyomavirus nephropathy in the native kidney, bladder rupture, bladder sphincter dystonia, bladder tamponade, Border-Crosser's nephropathy, bourbon virus and acute kidney injury, burned sugarcane harvest and acute renal dysfunction, Byetta and renal failure, C1q nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepsis laureola Laureola) intoxication, cannabinoid hyperemesis acute renal failure, cardiorenal syndrome, carfilzomib-induced kidney injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathy, Chinese herbal medicines and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathies, cocaine and the kidney, cold diuresis, colistin nephrotoxicity, collagenous glomerulopathy, collapsing glomerulopathy, CMV-associated collapsing glomerulopathy, combined antiretroviral therapy (cART)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, renal pyramidal syndrome (Mainzer-Sardino syndrome or Sardino-Mainzer disease), contrast nephropathy, copper sulfate toxicity, renal cortical necrosis, crizotinib-associated acute kidney injury, crystal cryoglobulinemia, cryoglobulinemia, crystal globulin-induced nephropathyCrystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (MPGN type 2), Dent's disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes and diabetic kidney disease, diabetes insipidus, nutritional supplements and renal failure, diffuse mesangial sclerosis, diuretics, Zhilin bean (Djenkol) Bean poisoning (Djenkolism), Down syndrome and kidney disease, addictive drugs and kidney disease, ureter duplication, EAST syndrome, Ebola and the kidney, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immunotactoid glomerulopathy, Frehley syndrome, fluid overload, hypervolemia, Focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal complications, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerular tubular reflux, renal diabetes, Goodpasture syndrome, green smoothie-purifying nephropathy, HANAC syndrome, Harvoni (ledipasvir / sofosbuvir combination)-induced kidney injury, hair dye ingestion and acute kidney injury, hantavirus-associated podocytopathy, heat stress nephropathy, hematuria (Blood in the urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus kidney disease, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), brown urine, paroxysmal nocturnal hemoglobinuria and hemosiderinosis associated with hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1β-related kidney disease, hepatorenal syndrome, herbal supplements and kidney disease, high blood pressure High-grade renal syndrome, hypertension and renal disease, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial kidney disease, horseshoe kidney (fused kidney), Hunner's ulcer, hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic urticarial vasculitis syndrome, hypokalemia,Hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in cannabis users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, water diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated kidney disease, interstitial cystitis, bladder pain syndrome (questionnaire), interstitial nephritis, karyomegalic interstitial nephritis, Ivmark syndrome, JC virus nephropathy, Joubert syndrome, Ke Calcium-related bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirotic kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutations, lower back pain and hematuria, lupus, systemic lupus erythematosus, lupus kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody Lupus nephritis with systemic seropositivity, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated kidney disease, malignant hypertension, malakoplakia, McKittrick-Wheelock syndrome, MDMA (Molly, Ecstasy, 3,4-methylenedioxymethamphetamine) and renal failure, urethral meatal stenosis, medullary cystic kidney disease, uromodulin-associated nephropathy, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaureter, melamine toxicity and its kidney, MELAS syndrome, membranoproliferative glomerulonephritis, membranous Nephropathy, Membranous Glomerulopathy with Masked IgGκ Deposition, Mesoamerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate-Associated Renal Failure, Microscopic Polyangiitis, Milk-Alkali Syndrome, Minimal Change Disease, Monoclonal Gammopathy with Nephropathy, Dysproteinemia, Mouthwash Toxicity, MUC1 Nephropathy, Polycystic Dysplastic Kidney, Multiple Myeloma, Myeloproliferative Neoplasia and Glomerulopathy, Nail-Patella Syndrome, NARP Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Wandering Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, 9 / 11 and Renal DiseaseNodular glomerulosclerosis, Nongonococcal urethritis, Nutcracker syndrome, Oligomegalic glomerulopathy, Orofacial-Digital syndrome, Orotic aciduria, Orthostatic hypotension, Orthostatic proteinuria, Osmotic diuresis, Osmotic nephrosis, Ovarian hyperstimulation syndrome, Oxalate nephropathy, Page kidney, Papillary necrosis, Papillary-renal syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutations and kidney disease, Parvovirus B19 and the kidney, Peritoneal-renal syndrome, POEMS syndrome, Posterior urethral valve, Podocyte invagination glomerulopathy, Post-infectious glomerulonephritis, Post-streptococcal glomerulonephritis, Atypical post-infectious glomerulonephritis, Post-infectious glomerulonephritis (IgA-Dominant) Mimicking IgA Nephropathy, polyarteritis nodosa, polycystic kidney disease, posterior urethral valve, post-obstructive diuresis, pre-eclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr's disease), propolis (bee resin)-associated renal failure, proteinuria (protein in the urine), pseudohyperaldosteronism, pseudohypobicarbonatemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (renal infection), pyonephrosis, pyridium and renal failure, radiation nephropathy, ranolazine and its effects on the kidneys, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, renal arcuate vein microthrombus-associated Acute kidney injury, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation, autosomal dominant tubulointerstitial kidney disease, renin-secreting tumor (juxtaglomerular cell tumor), reset osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, bariatric surgery-related rhabdomyolysis, rheumatoid arthritis-associated kidney disease, sarcoidosis nephropathy, renal and cerebral salt wasting, schistosomiasis and glomerular disease, Schimke's immune dyskinesia, scleroderma renal crisis, serpentine fibula and polycystic kidney disease Fibula-Polycystic Kidney Syndrome, Exner's Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Kidney Disease in Sri Lankan Farmers, Sjogren's Syndrome and Kidney Disease, Synthetic Cannabis Use and Acute Kidney Injury, Kidney Disease After Hematopoietic Cell Transplantation, Kidney Disease Associated with Stem Cell Transplantation, TAFRO Syndrome, Tea and Toast Hyponatremia,Tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal gammopathy-associated thrombotic microangiopathy, war nephritis, bladder trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular hypoplasia, immune complex-mediated tubulointerstitial nephritis caused by autoantibodies against the proximal tubule brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocele, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin The method of the present invention 1076 is selected from the group consisting of: associated cast nephropathy, vasomotor nephropathy, vesicoenteric fistula, vesicoureteral reflux, VEGF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, von Hippel-Lindau disease, Waldenstrom's macroglobulinemic glomerulonephritis, warfarin-associated nephropathy, bee sting and acute kidney injury, Wegener's granulomatosis, granulomatosis with polyangiitis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatic-renal syndrome. [This invention 1093] The method of claim 1076, wherein the hearing loss is selected from the group consisting of mitochondrial genetic non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or inherited hearing loss, hearing loss resulting from exposure to ototoxins, disease-induced hearing loss, and trauma-induced hearing loss. [This invention 1094] 1076. The method of claim 1076, wherein said eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy. [This invention 1095] The method of any of claims 1076 to 1094, further comprising a second agent for treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway. [This invention 1096] A method for treating a disease associated with modulation of eIF2B activity or level, eIF2α activity or level, or activity or level of a component of the eIF2 pathway or ISR pathway in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of any one of inventions 1001 to 1074, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof. [This invention 1097] 1096. The method of claim 1096, wherein said modulation comprises an increase in the activity or level of eIF2B, an increase in the activity or level of eIF2α, or an increase in the activity or level of a component of the eIF2 pathway or the ISR pathway. [This invention 1098] 1096. The method of claim 1096, wherein said disease can be caused by a mutation in the sequence of a gene or protein associated with a component of said eIF2 pathway. [This invention 1099] A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds of the present invention 1001 to 1074, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, in combination with an immunotherapeutic agent. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention The present invention features compounds, compositions, and methods including a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, for use, for example, in modulating (e.g., activating) eIF2B and attenuating the ISR signaling pathway.

[0016] definition chemical definition The following provides a more detailed explanation of the definitions of certain functional groups and chemical terms. Elements are listed in the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75 th Ed., endpapers, and specific functional groups are generally defined as described in the Handbook. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0017] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0018] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0019] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the enantiomer. In certain embodiments, weights are based on all enantiomers or stereoisomers of the compound.

[0020] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S-compound, based on the total weight of the compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredients may be formulated with few or no excipients or carriers.

[0021] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1H, 2 H (D or deuterium), and 3 H (T or tritium) and C can be any isotope, 12 C. 13 C, and 14 It can be any isotope including C, and O 16 O and 18 It can be any isotope including O, etc.

[0022] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or two or more analogs.

[0023] When a range of values ​​is listed, the range is intended to include each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0024] The following terms are intended to have the meanings set forth below and are helpful in understanding the description and intended scope of the present invention.

[0025] "Alkyl" means a radical of a straight- or branched-chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C-C 12In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each exemplary alkyl group can independently be substituted, i.e., unsubstituted (unsubstituted alkyl) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl groups are unsubstituted C1-C 10 In certain embodiments, the alkyl group is a substituted C-C alkyl. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0026] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, for example, but not limited to, -CHCHCHCH-. Generally, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described, for example, as a C-C membered alkylene, where the term "membered" refers to a non-hydrogen atom in the moiety.

[0027] "Alkenyl" means a radical of a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds and no triple bonds ("C2-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C-C"). 10In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal double bonds (such as in 2-butenyl) or terminal double bonds (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the C2-C4 alkenyl groups mentioned above, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example alkenyl group can independently be substituted, i.e., unsubstituted (unsubstituted alkenyl) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group can be an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-6 It is alkenyl.

[0028] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and no heteroatoms present in the aromatic ring system ("C 6-14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 Aryl, e.g., anthracyl). Aryl groups include, for example, C-C 10

[0023] The term "membered" refers to a non-hydrogen ring atom in the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each exemplary aryl group can independently be substituted, i.e., unsubstituted (unsubstituted aryl) or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C6-C 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0029] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, halo-C1-C8 alkyl, halooxy-C1-C8 alkyl, cyano, hydroxy, alkoxy-C1-C8 alkyl, and amino.

[0030] Representative examples of substituted aryl include the following: TIFF2026009987000059.tif17128, in which R 56 and R 57 may be hydrogen, and R 56 and R 57 At least one of the groups independently represents C1-C8 alkyl, halo-C1-C8 alkyl, 4- to 10-membered heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , C(O)O alkyl, C(O)O aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, S(O)-alkyl, S(O)2-alkyl, S-aryl, S(O)-aryl, S(O2)-aryl, wherein R58 and R59 are independently hydrogen or C1-C8 alkyl, or R 56 and R 57 may together form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S.

[0031] Other representative aryl groups having a fused heterocyclyl group include the following: TIFF2026009987000060.tif12128, wherein each W' is C(R 66 )2, NR 66 , O, and S, and each Y' is selected from carbonyl, NR 66 , O, and S; R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0032] The terms "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalenyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, and pyrrolidinyl. Heteroaryl includes, for example, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The above examples may be substituted or unsubstituted, and the divalent radical of each of the above heteroaryl examples is a non-limiting example of heteroarylene.

[0033] "Halo" or "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," by itself or as part of another substituent, refers to fluoride, chloride, bromide, or iodine. In certain embodiments, the halo group is either fluorine or chlorine.

[0034] Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0035] The term "heteroalkyl," by itself or in combination with another term, unless otherwise indicated, means an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)2, -S(O)-CH3, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and CH2-O-Si(CH3)3. When the term "heteroalkyl" is followed by -CHO, -NR B R C When a specific heteroalkyl group is mentioned, such as heteroalkyl and CHO or -NR B R C The terms "heteroalkyl" and "heteroalkyl-" are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are described for clarity. Thus, as used herein, the term "heteroalkyl" includes -CHO, -NR B R C This should not be construed as excluding certain heteroalkyl groups such as:

[0036] Similarly, the term "heteroalkylene," unless otherwise stated, by itself or as part of another substituent, means a divalent radical derived from heteroalkyl, exemplified, but not limited to, by -CHO- and -CHCHO-. A heteroalkylene group may be described, for example, as a 2- to 7-membered heteroalkylene, where the term "member" refers to a non-hydrogen atom within the moiety. For heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- can represent both -C(O)R'- and -R'C(O)-.

[0037] "Heteroaryl" refers to a radical of a five- to ten-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and one to four ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("five- to ten-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., on the ring with the heteroatom (e.g., 2-indolyl) or on the ring that does not contain the heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom in the moiety.

[0038] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group can independently be optionally substituted, i.e., unsubstituted (unsubstituted heteroaryl) or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0039] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thipinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0040] Representative examples of heteroaryls include those of the formula: TIFF2026009987000061.tif64128, wherein each Y is a carbonyl, N, NR65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0041] "Cycloalkyl" refers to a radical of a non-aromatic cyclic group having 3 to 10 ring carbon atoms ("C3-C 10 "Cycloalkyl" refers to the above radicals having no heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups described above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C 10The cycloalkyl group may be any of the above-mentioned C3-C6 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As illustrated in the examples above, in certain embodiments, the cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also encompasses ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the cycloalkyl ring system. Each instance of a cycloalkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0042] In some embodiments, "cycloalkyl" is a monocyclic, saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-C6 cycloalkyl groups include the C5-C6 cycloalkyl groups mentioned above, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the C3-C6 cycloalkyl groups mentioned above, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group can independently be unsubstituted (an "unsubstituted cycloalkyl") or substituted with one or more substituents (a "substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C3-C6 cycloalkyl group. 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0043] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("3- to 10-membered heterocyclyl") having ring carbon atoms and from 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0044] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system ("5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system ("5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system ("5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0045] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary five-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0046] Particular examples of heterocyclyl groups are given below in the illustrative examples: TIFF2026009987000062.tif43128, where each W′′ is a CR 67 , C(R 67 )2, NR 67 , O, and S, and each Y″ is selected from NR 67 , O, and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The heterocyclyl ring may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and S(O)2-aryl. Substituents include, for example, carbonyl or thiocarbonyl, which give lactam and urea derivatives.

[0047] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0048] "Amino" is the radical -NR 70 R 71 In the formula, R 70 and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, amino refers to NH2.

[0049] "Cyano" refers to the radical -CN.

[0050] "Hydroxy" refers to the radical --OH.

[0051] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be substituted as defined herein (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" cycloalkyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that is not spontaneously transformed, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents at each position can be the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any and all suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0052] Two or more substituents may optionally join together to form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, present attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent ring atoms of the base structure. For example, two ring-forming substituents attached to adjacent ring atoms of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single ring atom of the base structure. For example, two ring-forming substituents attached to a single ring atom of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent ring atoms of the base structure.

[0053] A "counterion" or "anionic counterion" is a negatively charged group that accompanies a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonate-5-sulfonate ion, ethane-1-sulfonate-2-sulfonate ion, etc.), and carboxylate ions (e.g., acetate ion, ethanoate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0054] The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)).Certain specific compounds of the present invention contain both basic and acidic functional groups, which can convert the compounds into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation may be a lyophilized powder in a first buffer solution, e.g., 1 mM to 50 mM histidine, 0.1% to 2% sucrose, and 2 to 7% mannitol at a pH range of 4.5 to 5.5, which is mixed with a second buffer solution before use.

[0055] Therefore, the compounds of the present invention may exist as salts, such as salts with pharmaceutically acceptable acids. The present invention encompasses such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0056] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0057] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reactant.

[0058] Certain compounds of the present invention may exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0059] As used herein, the term "salt" refers to an acid or base salt of the compound used in the method of the present invention. Illustrative examples of acceptable salts include salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.).

[0060] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; stereoisomers that can be defined in terms of absolute stereochemistry as enantiomers, racemates, diastereomers, tautomers, geometric isomers, (R)- or (S)- or (D)- or (L)- of amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include compounds known in the art to be difficult to synthesize and / or isolate due to excessive instability. The present invention is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral starting materials or chiral reactants, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to encompass both E- and Z-geometric isomers.

[0061] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0062] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0063] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0064] The term "treat" or "treatment" refers to evidence of successful treatment or amelioration of an injury, disorder, pathology, or disease, and includes objective or subjective parameters such as relief; remission; reduction of symptoms or making the disorder, pathology, or disease more tolerable to the patient; slowing degeneration or decline; making the end point of degeneration less debilitating; improving the patient's physical or mental health, etc. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods herein treat cancer (e.g., pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophies (e.g., vanishing white matter disease, childhood ataxia with central nervous system dysmyelination), post-operative cognitive dysfunction, traumatic brain injury, stroke, spinal cord injury, intellectual disability syndrome, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with impaired function of components of signal transduction or signal transduction pathways involving eIF2B or the ISR and decreased activity of the eIF2 pathway.For example, certain methods herein treat cancer by reducing, reducing, or preventing the occurrence, growth, metastasis, or progression of cancer, or by reducing the symptoms of cancer; treat neurodegeneration by improving mental health, enhancing mental function, slowing the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive ability, reducing cognitive loss, improving memory, reducing memory decline, reducing symptoms of neurodegeneration, or prolonging survival; treat vanishing white matter disease by reducing the symptoms of vanishing white matter disease or reducing white matter loss or reducing myelin loss or increasing the amount of myelin or increasing the amount of white matter; treat childhood ataxia with central nervous system hypomyelination by reducing the symptoms of childhood ataxia with central nervous system hypomyelination or increasing the level of myelin or reducing myelin loss; treat intellectual disability syndrome by reducing the symptoms of intellectual disability syndrome; treat an inflammatory disease by treating a symptom of an inflammatory disease; treat a musculoskeletal disease by treating a symptom of a musculoskeletal disease; or treat a metabolic disease by treating a symptom of a metabolic disease. Symptoms of a disease, disorder, or condition described herein (e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or disease or condition associated with impaired function of components of signal transduction pathways, including the eIF2B or eIF2 pathway, phosphorylation of eIF2α, or the ISR pathway) are known or can be determined by one of skill in the art. The term "treat" and its conjugations encompass prevention of injury, pathology, disease, or condition (e.g., preventing the onset of one or more symptoms of a disease, disorder, or condition described herein).

[0065] An "effective amount" is an amount sufficient to achieve the stated purpose (e.g., achieving the effect for which the drug is administered, treating a disease, decreasing enzyme activity, increasing enzyme activity, or reducing one or more symptoms of a disease or disorder). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, will produce the intended preventive effect, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or disorder, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or disorder, or a symptom thereof. A complete preventive effect does not necessarily occur with a single administration, but may occur only after a series of administrations. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the purpose of the treatment, and can be ascertained by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0066] "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptom(s) in question, or the elimination of the symptom(s).

[0067] The term "associated with" or "associated with" in the context of a substance or activity or function of a substance associated with a disease (e.g., a disease or disorder described herein, e.g., a cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of a component of a signal transduction pathway, including the eIF2B or eIF2 pathway, phosphorylation of eIF2α, or the ISR pathway) means that the disease in question is caused (in whole or in part) by the activity or function of the substance or substance in question, or that a symptom of the disease in question is caused (in whole or in part) by the activity or function of the substance or substance in question. For example, a disease or disorder symptom associated with impaired eIF2B function can be a symptom attributable (in whole or in part) to decreased eIF2B activity (e.g., decreased activity or levels of eIF2B, increased eIF2α phosphorylation or phosphorylated eIF2α activity or decreased eIF2 activity, or increased activity of the phosphorylated eIF2α signaling pathway or the ISR signaling pathway. Anything described herein as being associated with a disease (if it is a causative agent) can be a target for treating that disease. For example, a disease associated with decreased eIF2 activity or activity of the eIF2 pathway can be a symptom attributable (in whole or in part) to decreased levels of eIF2 or the eIF2 pathway. or activity, or can be treated by an agent (e.g., a compound described herein) effective in decreasing the activity of phosphorylated eIF2α or the ISR pathway. For example, diseases associated with phosphorylated eIF2α can be treated by an agent (e.g., a compound described herein) effective in decreasing the level of phosphorylated eIF2α or the activity of downstream components or effectors of phosphorylated eIF2α. For example, diseases associated with eIF2α can be treated by an agent (e.g., a compound described herein) effective in increasing the level of eIF2 or the activity of downstream components or effectors of eIF2.

[0068] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subjects or reagents are treated identically to a parallel experiment, except that the experimental procedure, reagent, or variable is omitted. A control is sometimes used as a standard of comparison in evaluating the effectiveness of an experiment.

[0069] "Contacting" is used according to its plain and ordinary meaning to refer to the process of bringing at least two different species (e.g., chemical compounds, including biomolecules, or cells) into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reactants or may be produced from an intermediate derived from one or more added reactants that may be produced in the reaction mixture. The term "contacting" may also encompass reacting, interacting, or physically contacting two species, where the two species are a compound described herein and a protein or enzyme (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway). In some embodiments, contacting encompasses interacting a compound described herein with a protein or enzyme involved in a signal transduction pathway (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway).

[0070] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to protein-inhibitor (e.g., antagonist) interaction, refer to adversely affecting (e.g., decreasing) the activity or function of the protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway, i.e., a signal transduction pathway. Thus, inhibition encompasses, at least in part, partially or completely blocking a stimulus; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating the signal transduction or enzymatic activity or amount of a protein. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway, i.e., a signal transduction pathway (e.g., the eIF2B, eIF2α, or eIF2 pathway, a pathway activated by phosphorylation of eIF2α, or a component of the ISR pathway). Thus, inhibition may involve, at least in part, partially or completely reducing stimulation, reducing or diminishing activation, or inactivating, desensitizing, or downregulating signal transduction or the enzymatic activity or amount of a protein that is increased in a disease (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway, each of which is associated with cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease).Inhibition may encompass, at least in part, partially or completely reducing stimulation, reducing or diminishing activation, or inactivating, desensitizing, or downregulating signal transduction or the enzymatic activity or amount of a protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) that may modulate the level of another protein or increase cell survival (e.g., reduced activity of the phosphorylated eIF2α pathway may increase cell survival in cells that may or may not have increased activity of the phosphorylated eIF2α pathway compared to non-disease controls, or reduced activity of the eIF2α pathway may increase cell survival in cells that may or may not have increased activity of the eIF2α pathway compared to non-disease controls).

[0071] As defined herein, "activation," "activate," "activating," and the like, with respect to protein-activator (e.g., agonist) interaction, means positively affecting (e.g., increasing) the activity or function of the protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) compared to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). In some embodiments, activation refers to an increase in the activity of a signal transduction pathway or signaling pathway (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway). Thus, activation can include at least partially, partially, or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating the enzymatic activity or amount of a protein decreased in signaling or disease (e.g., levels of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway associated with cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease). Activation can also include at least partially, partially, or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating the enzymatic activity or amount of a protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) that may modulate signaling or the level of another protein or increase cell survival (e.g., increased activity of eIF2α may increase cell survival in cells that may or may not have decreased eIF2α activity compared to non-diseased controls).

[0072] The term "modulation" refers to an increase or decrease in the level of a target molecule or the function of a target molecule. In some embodiments, modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway may reduce the severity of one or more symptoms of a disease associated with eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway (such as cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease), or a disease that is not caused by eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway but would benefit from modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway (e.g., decreasing the level or activity of a component of eIF2B, eIF2α, or eIF2 pathway).

[0073] The term "modulator," as used herein, refers to modulation (e.g., increase or decrease) of the level of a target molecule or the function of a target molecule. In embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an anti-cancer agent. In embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is a neuroprotective agent. In embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is a memory enhancer. In embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is a memory enhancer (e.g., a long-term memory enhancer). In embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an anti-inflammatory agent. In some embodiments, a modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an analgesic agent.

[0074] The term "patient" or "subject" in need thereof refers to a living organism suffering from or susceptible to a disease or disorder that can be treated by administering a compound or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a domestic animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a bovine. In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a human neonate. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly human. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is a geriatric patient.

[0075] "Disease," "disorder," or "condition" refers to a physical condition or state of health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein include the reduction or elimination of one or more symptoms of the disease, disorder, or condition, e.g., by administration of a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt thereof.

[0076] The term "signal transduction pathway," as used herein, refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which may then transmit the change to further components, which optionally are propagated to components of other signal transduction pathways.

[0077] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of an active agent to a subject and its absorption by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such formulations may be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0078] The term "preparation" is intended to include a preparation of an active compound with an encapsulating material as a carrier to form a capsule, in which the active compound is surrounded by the carrier with or without other carriers, and thus the carrier is coextensive with the active compound.Similarly, cachets and lozenges are also included.Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0079] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, into a subject. Administration is by any route, including parenteral administration and transmucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal administration). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer agents, chemotherapeutic agents, or agents for treating neurodegenerative diseases). The compounds of the present invention may be administered alone or simultaneously to the patient. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (multiple compounds or agents). Thus, the formulations may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0080] The term "eIF2B" as used herein refers to the heteropentameric eukaryotic translation initiation factor 2B. eIF2B is composed of five subunits: eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. eIF2B1 refers to the protein associated with Entrez Gene 1967, OMIM 606686, Uniprot Q14232, and / or RefSeq (protein) NP_001405. eIF2B2 refers to the protein associated with Entrez Gene 8892, OMIM 606454, Uniprot P49770, and / or RefSeq (protein) NP_055054. eIF2B3 refers to the protein associated with Entrez Gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to a protein associated with Entrez Gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945. eIF2B5 refers to a protein associated with Entrez Gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq (protein) NP_003898.

[0081] The terms "eIF2alpha," "eIF2a," or "eIF2α" are synonymous and refer to the protein "eukaryotic translation initiation factor 2 alpha subunit eIF2S1." In embodiments, "eIF2alpha," "eIF2a," or "eIF2α" refers to the human protein described above. "eIF2alpha," "eIF2a," or "eIF2α" includes wild-type and mutant forms of the protein. In embodiments, "eIF2alpha," "eIF2a," or "eIF2α" refers to proteins related to Entrez Gene 1965, OMIM 603907, UniProt P05198, and / or RefSeq(protein) NP_004085. In embodiments, the immediately preceding reference numbers refer to proteins and related nucleic acids known as of the filing date of this application.

[0082] compound Disclosed herein are, for example, compounds of formula (I): TIFF2026009987000063.tif27128 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof; During the ceremony, D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl is substituted with 1 to 4 R X and when the 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is R N1 may be replaced by U is -NR 1 C(O)-, -C(O)NR 1 - or 5- to 6-membered heteroaryl; E is a bond, -NR 2 C(O)-, -C(O)NR 2 -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G and when the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2 or E is TIFF2026009987000064.tif20128, and Y is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R at one or more available carbons. G and when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2 and L 1 is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3 -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1 and optionally substituted by L 2 is a bond, C1-C6 alkylene, a 2- to 7-membered heteroalkylene, or -O-, where the C1-C6 alkylene or the 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2 may be substituted with R 1 is hydrogen or C1-C6 alkyl, R 2 is hydrogen or C1-C6 alkyl, W is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety including a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, where the heterocyclyl is fused to one or more available carbons with one to four R W1 The phenyl or heteroaryl may be optionally substituted with 1 to 4 R at one or more available unsaturated carbons. W2 When the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N4 and W may be substituted with L through an available saturated carbon or nitrogen atom in the heterocyclyl. 2 binds to A is a C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y and when the 5- to 6-membered heteroaryl or 8- to 10-membered bicyclic heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N5 may be substituted with Each R L1 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R L2 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of R N1 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N2 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N3 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of R N4 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B R C , and -C(O)OR D selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO—C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w C 1-6 alkyl (wherein w is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)-NR B R C selected from the group consisting of R N5 is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OR D , and -S(O)R D selected from the group consisting of Each R W1 are independently hydrogen, C1-C6 alkyl (optionally substituted by -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -ORA , -NR B R C , -NR B R CC , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R W2 are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , and -S(O)R D or selected from the group consisting of Two R on adjacent atoms W2 groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X may be substituted with Each R X are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NRB C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D selected from the group consisting of Each R Y are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or selected from the group consisting of Two R on adjacent atoms Y groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X may be substituted with each G 1 are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z may be substituted with Each R Zare independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , and -S(O)R D selected from the group consisting of R A is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B R C , -C(O)R D , or -C(O)OR D and R B and R C are independently hydrogen or C1-C6 alkyl; R B and R C However, together with the atoms to which they are bonded, they form one to three R Z forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC is independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each RE are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F are independently hydrogen, C1-C6 alkyl, or halo; Each R G are independently hydrogen, C1-C6 alkyl, halo, or oxo; and m is R F is 1 when hydrogen or C1-C6 alkyl, and R F is 3 when C1-C6 alkyl, or R F is 5 in the case of halo.

[0083] In some embodiments, D is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from 1 to 4 R X In some embodiments, D is optionally substituted with a group. TIFF2026009987000065.tif38148.

[0084] For example, in some embodiments, D is TIFF2026009987000066.tif64149.

[0085] In some embodiments, D is 0 R X For example, in some embodiments, D is substituted with TIFF2026009987000067.tif56135. For example, in some embodiments, D is selected from the group consisting of: TIFF2026009987000068.tif18128.

[0086] In other embodiments, D is selected from one R X For example, in some embodiments, D is substituted with TIFF2026009987000069.tif20128. In certain embodiments, R X is -OH.

[0087] In some embodiments, U is —NHC(O)—, —C(O)NH—, and TIFF2026009987000070.tif19128. For example, in certain embodiments, U is -NHC(O)-.

[0088] In other embodiments, L 1 is a bond or C1-C6 alkylene, where C1-C6 alkylene is a group consisting of 1 to 5 R L1 For example, in some embodiments, L 1 is a bond or C1-C6 alkylene, where C1-C6 alkylene is L1 In certain embodiments, L 1 is, for example, a bond or -CH-. In certain other embodiments, R 1 is hydrogen or CH3.

[0089] In a further embodiment, W has the formula (Wa): Represented as TIFF2026009987000071.tif23128, During the ceremony, X is NR N4 or C(R X1 )(R X2 ) and R N4 is hydrogen or C1-C6 alkyl, R X1 is hydrogen or hydroxyl, R X2 is hydrogen or hydroxyl, or R X1 and R X2together form an oxo moiety.

[0090] For example, in some embodiments, W is TIFF2026009987000072.tif41128. In certain embodiments, W is selected from the group consisting of, for example, The file is TIFF2026009987000073.tif18128.

[0091] In some embodiments, W is one R W2 For example, in certain embodiments, R W2 In another embodiment, W is a group selected from two R W2 For example, in certain embodiments, each R W2 is independently chloro or fluoro.

[0092] In some embodiments, E is a bond, —NR 2 C(O)-, -C(O)NR 2 - and TIFF2026009987000074.tif20128.

[0093] In other embodiments, E is TIFF2026009987000075.tif58142.

[0094] In a further embodiment, E is TIFF2026009987000076.tif87144.

[0095] In still further embodiments, E is a bond, —NR 2 C(O)-, -C(O)NR 2 -, TIFF2026009987000077.tif85141.

[0096] For example, in certain embodiments, E is TIFF2026009987000078.tif13128.

[0097] In some embodiments, R 2 is hydrogen. 2 is a bond, —O—, C1-C6 alkylene, or 2- to 7-membered heteroalkylene. For example, in certain embodiments, L 2 is a bond, -CH2-, -CH2O- * , -(CH2)2O- * , -(CH2)3O- * , or -O-, where "- * " indicates the point of attachment to A.

[0098] In some embodiments, A is selected from the group consisting of: TIFF2026009987000079.tif94143.

[0099] For example, in certain embodiments, A is selected from the group consisting of: TIFF2026009987000080.tif53149.

[0100] In some embodiments, each R Y are independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxyl, phenyl, CHF2, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH3)2, CH2OCF3, and CN.

[0101] Also disclosed herein is a compound of formula (II): TIFF2026009987000081.tif27128 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof; During the ceremony, D IIis a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein each of the bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl is substituted with one to four R X-II and when the 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1-II and U II is -NR 1-II C(O)- or -C(O)NR 1-II - and E II is the bond, -NR 2-II C(O)-, -C(O)NR 2-II -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or the 5- to 6-membered heterocyclyl has 1 to 5 R G-II and when the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2-II or E II teeth, TIFF2026009987000082.tif20128, Y II is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R G-II and when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N2-II and L1-II is a bond, C1-C6 alkylene, 2- to 7-membered heteroalkylene, -NR N3-II -, or -O-, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-II may be substituted with L 2-II is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, -O-, where C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L2-II may be substituted with R 1-II is hydrogen or C1-C6 alkyl, R 2-II is hydrogen or C1-C6 alkyl, W II is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R W-II and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N4-II and A II is a C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is substituted with 1 to 5 R at one or more available carbons. Y-II and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N5-II may be substituted with Each R L1-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)RD-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R L2-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of R N1-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N2-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N3-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-IIR C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R N4-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkyl-C1-C6 cycloalkyl, C1-C6 alkenyl, -C(O)-C1-C6 alkyl, -C(O)-C1-C6 cycloalkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, -C(O)-C1-C3 alkyl-O-C1-C3 alkyl-O-C1-C3 alkyl, -C(O)-phenyl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -S(O)2-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-heteroaryl, -C(O)NR B-II R C-II , and -C(O)OR D-II selected from the group consisting of wherein C-C alkyl, hydroxy-C-C alkyl, C-C alkyl-C-C cycloalkyl, C-C alkenyl, C(O)-C-C alkyl, —C(O)-C-C cycloalkyl, C-C alkyl-COH, C-C alkyl-CO—C-C alkyl, —C(O)-heterocyclyl, and —S(O)-C-C alkyl may be optionally substituted with one or more substituents, each of which is independently fluoro, hydroxyl, C-C alkoxy, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) w-II C 1-6 alkyl (wherein w-II is 0, 1, or 2); and wherein -C(O)-phenyl, -C(O)-heteroaryl, -S(O)-phenyl, and -S(O)-heteroaryl may be optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, C-C alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C-C alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O)NR B-II R C-II selected from the group consisting of R N5-II is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of Each R W-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II R CC-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II or selected from the group consisting of Two R on adjacent atoms W-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with Each R X-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -SR E-II , -S(O)R D-II , and -S(O)R D-II selected from the group consisting of Each R Y-II are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , -S(R F-II ) m-II , -S(O)R D-II , -S(O)2R D-II , and G 1-II or selected from the group consisting of Two R on adjacent atoms Y-IIgroups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-II may be substituted with each G 1-II are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-II may be substituted with Each R Z-II are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-II , -NR B-II R C-II , -NR B-II C(O)R D-II , -C(O)NR B-II R C-II , -C(O)R D-II , -C(O)OH, -C(O)OR D-II , and -S(O)R D-II selected from the group consisting of R A-II is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-II R C-II , -C(O)R D-II , or -C(O)OR D-II and R B-II and R C-II are each independently hydrogen or C1-C6 alkyl; R B-II and R C-II together with the atoms to which they are attached, form one to three R Z-II forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-IIis independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-II is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each R E-II are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-II are independently hydrogen, C1-C6 alkyl, or halo; and Each R G-II are independently hydrogen, C1-C6 alkyl, halo, or oxo; However, D II When E is a bridged bicyclic five-membered cycloalkyl, II is -NR 2-II It is C(O)-.

[0102] In some embodiments, D II is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from one to four R X-II It may be substituted with a group.

[0103] For example, in some embodiments, D II teeth, TIFF2026009987000083.tif61137.

[0104] In some embodiments, D II 0 R X-II For example, in some embodiments, D II teeth, TIFF2026009987000084.tif19128.

[0105] In other embodiments, D II is one R X-II For example, in certain embodiments, D II teeth, TIFF2026009987000085.tif24128. In some embodiments, R X-II is -OH.

[0106] In a further embodiment, L 1-II is C1-C6 alkylene or 2- to 7-membered heteroalkylene, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-II For example, in some embodiments, L 1-II 0 R L1-II In certain embodiments, for example, L 1-II is -CH2- or CH2O- * In the formula, "- * " is W II indicates the attachment point to

[0107] In some embodiments, R 1-II is hydrogen or CH. In other embodiments, W II teeth, TIFF2026009987000086.tif78150. For example, in certain embodiments, W II teeth, TIFF2026009987000087.tif15128. In another embodiment, R Y-II is independently chloro, fluoro, or CF3.

[0108] In some embodiments, E II is -NR 2-II C(O)-, -C(O)NR 2-II - and TIFF2026009987000088.tif20128.

[0109] In other embodiments, E II teeth, TIFF2026009987000089.tif56151.

[0110] For example, in certain embodiments, E II is -NR 2-II C(O)-, TIFF2026009987000090.tif21128. In a further embodiment, E II is D II but If it is TIFF2026009987000091.tif17128, -NR 2-II It is C(O)-.

[0111] In some embodiments, R 2-II is hydrogen or methyl. 2-II is a bond, —O—, or 2- to 7-membered heteroalkylene. For example, in certain embodiments, L 2-II is the bond, -CH2O- * , -(CH2)2O- * , -(CH2)3O- * or -O-, wherein "- * " is A II indicates the attachment point to

[0112] In some embodiments, A IIis selected from the group consisting of: TIFF2026009987000092.tif80150. For example, in one particular embodiment, A II teeth, TIFF2026009987000093.tif14128. In another embodiment, each R Y-II is chloro or OCF3.

[0113] Also disclosed are compounds of formula (IIIa) or formula (IIIb): TIFF2026009987000094.tif29136, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, During the ceremony, D III is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein the 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R X-III and when a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N1-III and W III is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein the heterocyclyl is fused to one or more available saturated carbons with one to four R W1-III The phenyl or heteroaryl may be optionally substituted with 1 to 4 R at one or more available unsaturated carbons. W2-III and if the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R N2-III and A IIIis phenyl or a 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl has 1 to 5 R Y-III and when the 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen is optionally substituted with R N3-III and R 1-III is hydrogen or C1-C6 alkyl, L 1-III is a bond, C1-C6 alkylene, or 2- to 7-membered heteroalkylene, wherein the C1-C6 alkylene or 2- to 7-membered heteroalkylene is selected from 1 to 5 R L1-III may be substituted with Each R L1-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of R N1-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N2-IIIis hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R N3-III is hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of Each R W1-III are independently hydrogen, C1-C6 alkyl (optionally substituted by -CO2H), hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, C=N-OH, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III R CC-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R W2-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkyl-O-, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III RC-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , and -S(O)R D-III or selected from the group consisting of Two R on adjacent atoms W2-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with Each R X-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , -SR E-III , -S(O)R D-III , and -S(O)R D-III selected from the group consisting of Each R Y-III are independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III, -C(O)OH, -C(O)OR D-III , -S(R F-III ) m-III , -S(O)R D-III , -S(O)2R D-III , and G 1-III or selected from the group consisting of Two R on adjacent atoms Y-III groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R X-III may be substituted with each G 1-III are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Z-III may be substituted with Each R Z-III are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A-III , -NR B-III R C-III , -NR B-III C(O)R D-III , -C(O)NR B-III R C-III , -C(O)R D-III , -C(O)OH, -C(O)OR D-III , and -S(O)R D-III selected from the group consisting of R A-III is, in each occurrence, independently hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B-III R C-III , -C(O)R D-III , or -C(O)OR D-III and R B-III and R C-III are each independently hydrogen or C1-C6 alkyl; R B-IIIand R C-III However, together with the atoms to which they are attached, they form 1 to 3 R Z-III forming an optionally substituted 3- to 7-membered heterocyclyl ring, Each R CC-III is independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyl-CO2H, C1-C6 alkyl-CO2-C1-C6 alkyl, C(O)C1-C6 alkyl, S(O)2-C1-C6 alkyl, and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl, halo, and —C(O)OH; Each R D-III is independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, or halo-C1-C6 alkyl; Each R E-III are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F-III are independently hydrogen, C1-C6 alkyl, or halo; and m III is R F-III is 1 when R is hydrogen or C1-C6 alkyl; F-III is C1-C6 alkyl, or R F-III is 5 for halo.

[0114] In some embodiments, D III is an azetidine, pyrrolidine, piperidine, piperazine, or 2-azaspiro[3.3]heptane moiety, each of which is a 2-azaspiro[3.3]heptane moiety having one to four R W-III groups, and each R W-III are independently C1-C6 alkyl, halo-C1-C6 alkyl, halo, oxo, cyano, or -OR A-IIIand piperazine has R at the substitutable nitrogen. N2-III may be substituted by:

[0115] For example, in some embodiments, D III is the following: TIFF2026009987000095.tif18144, wherein R N1-III is hydrogen or C1-C3 alkyl. For example, in certain embodiments, D III teeth, The file is TIFF2026009987000096.tif17128.

[0116] In some embodiments, W III is the formula (Wb): Represented as TIFF2026009987000097.tif23128, During the ceremony, X III is NR N4-III or C(R X1-III )(R X2-III ) and R N4-III is hydrogen or C1-C6 alkyl, R X1-III is hydrogen or hydroxyl, R X2-III is hydrogen or hydroxyl, or R X1-III and R X2-III together form an oxo moiety.

[0117] For example, in some embodiments, W III teeth, TIFF2026009987000098.tif40128.

[0118] In some embodiments, W III is one R W2-III For example, in certain embodiments, R W2-III is chloro.

[0119] In some embodiments, L 1-III is 1 to 5 R L1-III In another embodiment, L is a 2- to 7-membered heteroalkylene optionally substituted by 1-III 0 R L1 For example, in certain embodiments, L 1-III is CH2O- * or CH2OCH2- * wherein "-" is selected from the formula: * " is A III In another embodiment, R 1-III is hydrogen or CH3.

[0120] In some embodiments, A III is selected from the group consisting of: TIFF2026009987000099.tif44144.

[0121] In some embodiments, each R Y-III are independently selected from the group consisting of hydrogen, chloro, fluoro, CHF2, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCHF2, OCF3, OCH2CF3, OCH(CH3)2, and CN.

[0122] In some embodiments, the disclosed compounds comprise: (2R)-6-chloro-N-(3-{5-[(3,5-dimethylphenoxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{(1R,3r,5S)-8-[3-(4-chlorophenoxy)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-((1r,4R)-4-{[(4-chloro-3-fluorophenoxy)acetyl](methyl)amino}cyclohexyl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 3-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[(6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; 3-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[(6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-[(2S)-2-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide; 6-chloro-4-oxo-N-[3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-hydroxy-N-[3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chlorophenoxy)-N-[4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide; (2R,4R)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (1s,3s)-N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-(trifluoromethoxy)cyclobutane-1-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-{rac-(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}acetamide; 6-chloro-4-hydroxy-N-[rac-(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-{rac-(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; rac-(2R,4R)-6-chloro-4-hydroxy-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-(2-hydroxy-4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)acetamide; (2R,4R)-6-chloro-N-{(1R,3r,5S)-8-[3-(4-chlorophenoxy)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-((1r,4r)-4-{[(6-chloro-1H-benzimidazol-2-yl)methyl]carbamoyl}cyclohexyl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-(3-{[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{[(1s,3S)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; N-[(6-chloro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentane-1-carboxamide; 6-chloro-N-{(1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-(rac-(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-(3-{[(1s,3S)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-(3-{[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-((1r,4r)-4-{3-[5-(difluoromethyl)pyrazin-2-yl]-2-oxoimidazolidin-1-yl}cyclohexyl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-[rac-(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-((1r,4r)-4-{[(6-chloro-1H-benzimidazol-2-yl)methyl]carbamoyl}cyclohexyl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-{rac-(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-(rac-(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-{(1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-(3-{5-[(3,5-dimethylphenoxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{2-[(4-chloro-3-fluorophenoxy)acetyl]-2-azaspiro[3.3]heptan-6-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-[2-(rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[2-(6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]acetamide; 6-chloro-N-((3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl)-4-oxo-4H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-((3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide and (2R,4R)-6-chloro-4-hydroxy-N-((3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; rac-(2R,4R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-(4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-(3-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-((3R,6S)-6-{5-[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-((3R,6S)-6-{5-[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)acetamide; (2R,4R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}bicyclo[2.2.2]octane-1-carboxamide; (1r,4r)-4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclohexane-1-carboxamide; rac-(2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; rac-(2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2RS,4RS)-6-chloro-4-hydroxy-N-((3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-oxo-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-{3-[5-(rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-1-yl}acetamide; 6-chloro-4-oxo-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-(rac-(1R,2S,4R,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl)acetamide; (2R,4R)-6-chloro-4-hydroxy-N-((3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-((3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; rac-(2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-[trans-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S)-6-chloro-4-oxo-N-((3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-(3-phenylazetidine-1-carbonyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-((3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-((1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-((1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-((1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-((1r,4R)-4-{2-oxo-3-[3-(trifluoromethoxy)cyclobutyl]imidazolidin-1-yl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6,7-Difluoro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6,7-difluoro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.1.1]hexan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-((1r,4R)-4-{2-oxo-3-[3-(trifluoromethoxy)cyclobutyl]imidazolidin-1-yl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4S)-6-chloro-4-hydroxy-N-[trans-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(1-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-(1-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{trans-4-[3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[(1R * ,2S * ,4R *,5S * )-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[(1S * ,2R * ,4S * ,5R * )-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[trans-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(trans-4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-(3-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-((1RS,2SR,4RS,5SR)-5-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-7-oxabicyclo[2.2.1]heptan-2-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-[(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[(3R * )-3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[(3S * )-3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-{3-[5-(cis-3-hydroxycyclobutyl)-4,5-dihydro-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-{3-[5-(cis-3-hydroxycyclobutyl)-4,5-dihydro-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-[3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; 2-(4-chloro-3-fluorophenoxy)-N-{3-[5-((2R * ,4R *)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-1-yl}acetamide; 2-(4-chloro-3-fluorophenoxy)-N-{3-[5-((2S * ,4S * )-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-1-yl}acetamide; (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[1-(4-chlorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[1-(4-chlorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[4-(4-chloro-3-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[trans-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; N-{3-[((2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl)amino]bicyclo[1.1.1]pentan-1-yl}-2-phenyl-1,3-oxazole-5-carboxamide; (2R,4R)-6-chloro-N-(3-{2-[(cis-3-cyanocyclobutyl)oxy]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-[3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-[3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-((3R,6S)-6-{5-[3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}oxan-3-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4S)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4S)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R)-6-chloro-4-oxo-N-[3-({(1RS,2SR)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[3-({(1RS,2SR)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1,3-thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[3-({4-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-2-yl}oxy)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-[trans-4-{3-[5-(difluoromethyl)pyrazin-2-yl]-2-oxoimidazolidin-1-yl}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{(1R,2S,4R,5S)-5-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[2.2.1]heptan-2-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[2-(4-chloro-3-fluorophenyl)-1,3-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-N-(3-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2S,4R)-6-chloro-4-hydroxy-N-(trans-4-{2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(trans-4-{2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-N-(3-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide; and pharmaceutically acceptable salts, solvates, hydrates, tautomers, N-oxides, or stereoisomers thereof; is selected from the group consisting of:

[0123] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are formulated as pharmaceutically acceptable compositions comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0124] In some embodiments, the disclosed compounds are selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

[0125] Table 1: Exemplary compounds of the present invention TIFF2026009987000100.tif201155TIFF2026009987000101.tif206155TIFF2026009987000102.tif226155TIFF20260099870 00103.tif222155TIFF2026009987000104.tif207155TIFF2026009987000105.tif222155TIFF2026009987000106.tif206155 TIFF2026009987000107.tif212155TIFF2026009987000108.tif214155TIFF2026009987000109.tif219155TIFF20260099870 00110.tif203155TIFF2026009987000111.tif226155TIFF2026009987000112.tif213155TIFF2026009987000113.tif119155

[0126] In some embodiments, the disclosed compounds are selected from the compounds set forth in Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

[0127] Table 2: Exemplary compounds of the present invention TIFF2026009987000114.tif57128TIFF2026009987000115.tif222115TIFF2026009987000116.tif218115TIFF20260099870 00117.tif198115TIFF2026009987000118.tif214115TIFF2026009987000119.tif221115TIFF2026009987000120.tif87128

[0128] Methods of Making Exemplary Compounds The compounds of the present invention can be better understood in connection with the following synthetic schemes and methods which illustrate the means by which such compounds can be prepared. The compounds of the present invention can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in the following schemes, but are not limited thereto. The variables A, D, E, W, X, Y, L 1 , L 2 , R 1 , R 2 , R W2 , A II , D II , W II , Y II , L 1-II , L 2-II , R 1-II , R 2-II , A III , D III , W III , L 1-III , L 2-III , R 1-III , and R 2-III is defined herein, for example, as detailed in the Summary of the Invention.

[0129] Scheme 1: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 1, compounds of formula (1-3) can be prepared from compounds of formula (1-1). Compounds of formula (1-1) can be coupled under amide bond forming conditions with carboxylic acids of formula (1-2A) or acid chlorides of formula (1-2B) to provide amides of formula (1-3).Examples of conditions known to produce amides from a mixture of a carboxylic acid of formula (1-2A) and an amine of formula (1-1) include, but are not limited to, the addition of a coupling reagent, such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC, or EDCI), 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), ), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide or 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(3H-[1,2,3]triazolo Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) or 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V), Coupling reagents include the addition of tetramethylisouronium hexafluorophosphate (V) (HBTU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU®), and fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate. Coupling reagents can be added as solids, solutions, or as reagents bound to solid support resins.

[0130] In addition to the coupling reagent, auxiliary coupling reagents can also facilitate the coupling reaction. Examples of auxiliary coupling reagents often used in coupling reactions include, but are not limited to, 4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT), and 1-hydroxybenzotriazole (HOBT). The coupling reaction can optionally be carried out in the presence of a base such as triethylamine or diisopropylethylamine. The coupling reaction can be carried out in a solvent such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate.

[0131] Alternatively, the carboxylic acid of formula (1-2A) can be converted to the corresponding acid chloride of formula (1-2B) by reaction with thionyl chloride, PCl3, PCl5, cyanuric chloride, Ghosez's reagent, or oxalyl chloride. The reaction with thionyl chloride and oxalyl chloride can be catalyzed by N,N-dimethylformamide in a solvent such as dichloromethane at ambient temperature. The resulting acid chloride of formula (1-2B) can then be coupled with an amine of formula (1-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine or an aromatic base such as pyridine, to give an amide of formula (1-3). The compound of formula (1-3) is representative of the compound of formula (I).

[0132] Scheme 2: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 2 of TIFF2026009987000122.tif73141, compounds of formula (2-3) can be prepared from compounds of formula (1-1). Compounds of formula (1-1) can be coupled with compounds of formula (2-1) under amide bond-forming conditions described in Scheme 1 to give compounds of formula (2-2). Compounds of formula (2-2) can be reduced to compounds of formula (2-3) using a reducing agent such as sodium cyanoborohydride in the presence of zinc chloride in a solvent such as methanol, optionally with heating, or using sodium borohydride in a solvent such as methanol. Compounds of formula (2-2) and formula (2-3) are representative of compounds of formula (I).

[0133] Alternatively, compounds of formula (1-1) can be coupled with compounds of formula (2-4) under amide bond forming conditions described in Scheme 1 to give compounds of formula (2-3).

[0134] Scheme 3. Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 3, the compound of formula (3-5) can be prepared from the compound of formula (3-1). 1 is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with a carboxylic acid of formula (3-2A) or, alternatively, with an acid chloride of formula (3-2B) under amide bond forming conditions to give an amide of formula (3-3). Examples of conditions known to produce amides from a mixture of a carboxylic acid of formula (3-2A) and an amine of formula (3-1) are described in Scheme 1.

[0135] Alternatively, the carboxylic acid of formula (3-2A) can be converted to the corresponding acid chloride of formula (3-2B) by the reaction described in Scheme 1. The resulting acid chloride of formula (3-2B) can then be coupled with an amine of formula (3-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a base such as a tertiary amine base such as triethylamine or diisopropylethylamine, or an aromatic base such as pyridine, to provide the amide of formula (3-3).

[0136] The compound of formula (3-3) can be prepared by removing the protecting group (PG 1 The compound of formula (3-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (3-4) can be coupled with carboxylic acids of formula (1-2A), or alternatively with acid chlorides of formula (1-2B), to give compounds of formula (3-5). Compounds of formula (3-5) are representative of compounds of formula (I).

[0137] Scheme 4: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 4, compounds of formula (4-3) can be prepared from compounds of formula (3-4). Compounds of formula (3-4) can be coupled with compounds of formula (4-1) under amide bond forming conditions described in Scheme 1 to give compounds of formula (4-2). Compounds of formula (4-2) can be reduced to compounds of formula (4-3) using conditions described in Scheme 2. Compounds of formula (4-2) and formula (4-3) are representative of compounds of formula (I).

[0138] Alternatively, compounds of formula (3-4) can be coupled with compounds of formula (4-5) under amide bond forming conditions described in Scheme 1 to give compounds of formula (4-3).

[0139] Scheme 5: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 5, the compound of formula (3-5) can be prepared from the compound of formula (5-1). 1 is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with a carboxylic acid of formula (1-2A) or, alternatively, with an acid chloride of formula (1-2B) under amide bond forming conditions to provide an amide of formula (5-2). Examples of conditions known to generate amides from a mixture of a carboxylic acid of formula (1-2A) and an amine of formula (5-1) are described in Scheme 1.

[0140] Alternatively, the carboxylic acid of formula (1-2A) can be converted to the corresponding acid chloride of formula (1-2B) by the reaction described in Scheme 1. The resulting acid chloride of formula (1-2B) can then be coupled with an amine of formula (5-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a base such as a tertiary amine base such as triethylamine or diisopropylethylamine, or an aromatic base such as pyridine, to provide the amide of formula (5-2).

[0141] The compound of formula (5-2) can be obtained by removing the protecting group (PG 1 ), can be deprotected using conditions known to those skilled in the art. Compounds of formula (5-3) can be coupled with carboxylic acids of formula (3-2A) or alternatively with acid chlorides of formula (3-2B) under amide bond forming conditions as discussed above to give compounds of formula (3-5). Compounds of formula (3-5) are representative of compounds of formula (I).

[0142] Scheme 6: Representative scheme for synthesizing exemplary compounds of the present invention. TIFF2026009987000126.tif69143 Compounds of formula (6-1) can be reacted with compounds of formula (6-2) in heated phosphorus oxychloride to give compounds of formula (6-3). Alternatively, compounds of formula (6-1) can be reacted with compounds of formula (6-2) under the amide bond coupling conditions described to give compounds of formula (1-3). After coupling, the intermediate can be cyclized and dehydrated using 4-methylbenzene-1-sulfonyl chloride in the presence of a tertiary amine base such as N,N-diisopropylethylamine in acetonitrile, optionally with heating, to give compounds of formula (6-3). Compounds of formula (6-3) can be free of the protecting group (PG) used to give compounds of formula (6-4). 1 ) can be deprotected using conditions known to those skilled in the art. Compounds of formula (6-4) can be coupled with carboxylic acids of formula (1-2A) or alternatively with acid chlorides of formula (1-2B) under amide bond forming conditions as discussed above to give compounds of formula (6-5). Compounds of formula (6-5) are representative of compounds of formula (I).

[0143] Scheme 7: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 7a), the compound of formula (7-4) can be prepared from the compound of formula (6-1). 1 is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with an amine of formula (7-1) under amide bond forming conditions to give an amide of formula (7-2). Examples of conditions known to produce amides from a mixture of a carboxylic acid of formula (6-1) and an amine of formula (7-1) are described in Scheme 1.

[0144] The compound of formula (7-2) can be obtained by removing the protecting group (PG 1), can be deprotected using conditions known to those skilled in the art. Compounds of formula (7-3) can be coupled with carboxylic acids of formula (1-2A) or alternatively with acid chlorides of formula (1-2B) under amide bond forming conditions as discussed above to give compounds of formula (7-4). Compounds of formula (7-4) are representative of compounds of formula (I). As shown in Scheme 7b), compounds of formula (7-7) can be prepared from compounds of formula (6-1) and amines of formula (7-5) using the reaction conditions described in Scheme 7a. Compounds of formula (7-7) are representative of compounds of formula (I).

[0145] Scheme 8: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 8, compounds of formula (8-2) or (8-3) can be prepared from compounds of formula (7-3) and formula (7-8), respectively. Compounds of formula (7-3) or (7-8) can be coupled with compounds of formula (8-1) under amide bond forming conditions described in Scheme 1 to give compounds of formula (8-2) or (8-3). Compounds of formula (8-2) and (8-3) are representative of compounds of formula (I).

[0146] Scheme 9: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 9, a compound of formula (9-9) can be prepared from a compound of formula (9-1). The compound of formula (9-1) can be converted to a compound of formula (9-2) (wherein PG 1 is a suitable amine protecting group) to give compounds of formula (9-3). The amine protecting group of compounds of formula (9-3) can be replaced with a protecting group (PG 1), using conditions known to those skilled in the art, to give compounds of formula (9-4), which can then be cyclized via imidazolinone-forming conditions utilizing the primary and secondary amine groups to give compounds of formula (9-5). Compounds of formula (9-4) can be treated with a carbonylating reagent such as N,N'-carbonyldiimidazole in the presence of a tertiary amine base such as 1,8-diazabicyclo[5.4.0]undec-7-ene. Compounds of formula (9-5) can be prepared by nucleophilic substitution (L 2 is a bond), a compound of formula (9-6) 1 is a leaving group, such as a halogen or sulfonate group, to give compounds of formula (9-7). 2 When is a bond, compounds of formula (9-5) and compounds of formula (9-6) can also be converted to compounds of formula (9-7) using nucleoaromatic substitution reaction conditions, such as palladium-catalyzed cross-coupling reaction conditions. Examples of palladium cross-coupling reaction conditions include, but are not limited to, palladium catalysts (e.g., tris(dibenzylideneacetone)dipalladium(0)), ligands (e.g., 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos)), and bases (e.g., cesium carbonate) under an inert atmosphere in a solvent (e.g., dioxane). Compounds of formula (9-9) are representative of compounds of formula (I).

[0147] Scheme 10: Representative scheme for synthesizing exemplary compounds of the present invention. Alternatively, as shown in Scheme 10, compounds of formula (10-4) can be prepared from compounds of formula (3-1). Amine of formula (3-1) can be reacted with bromide of formula (10-1) in the presence of a base, such as, but not limited to, N,N-diisopropylethylamine or potassium carbonate, to give compounds of formula (10-2). The reaction is typically carried out at elevated temperature in a solvent, such as, but not limited to, N,N-dimethylformamide or dimethyl sulfoxide.

[0148] The compound of formula (10-2) can be obtained by removing the protecting group (PG 1 ), can be deprotected using conditions known to those skilled in the art. Compounds of formula (10-3) can be coupled with carboxylic acids of formula (1-2A) or alternatively with acid chlorides of formula (1-2B) under amide bond forming conditions as discussed above to give compounds of formula (10-4). Compounds of formula (10-4) are representative of compounds of formula (I).

[0149] Scheme 11: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 11, compounds of formula (11-2) can be prepared from compounds of formula (11-1), where Ar is a fused aryl or heteroaryl ring, by reduction to compounds of formula (11-2) using a reducing agent such as sodium borohydride in a solvent such as methanol, optionally at elevated temperature. Compounds of formula (11-2) are representative of compounds of formula (I).

[0150] Scheme 12: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 12, compounds of formula (12-1) can be prepared from compounds of formula (11-2). Compounds of formula (11-2), where Ar is a fused aryl or heteroaryl ring, can be converted to compounds of formula (12-1) by treatment with trifluoroacetic acid, optionally with warming, for 0.5-4 hours, followed by aqueous ammonium hydroxide. Similarly, compounds of formula (12-2) can be converted to compounds of formula (12-3) under the same conditions. Compounds of formula (12-3) are intermediates for preparing compounds of formula (I). Compounds of formula (12-1) are representative of compounds of formula (I).

[0151] Scheme 13: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 13, compounds of formula (13-4) can be prepared from compounds of formula (13-1). Compounds of formula (13-1) can be coupled with carboxylic acids of formula (13-2) under amide bond forming conditions described in Scheme 1 to give compounds of formula (13-3). Compounds of formula (13-3) can then be cyclized to give oxadiazoles of formula (13-4) using conditions described in Scheme 6 or Scheme 2-3. Compounds of formula (13-4) are representative of compounds of formula (I).

[0152] Scheme 14: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 14, compounds of formula (14-3) can be prepared from compounds of formula (14-1). Under photoredox conditions, compounds of formula (14-1) (wherein X 1is O, NH, or CH / CH2) can be reacted with a compound of formula (6-1) to give a compound of formula (14-2). Compounds of formula (14-2) can be deprotected and then coupled with compounds of formula (1-2A), or alternatively, with compounds of formula (1-2B), under amide bond forming conditions as described in Scheme 1, to give compounds of formula (14-3). Compounds of formula (14-3) are representative of compounds of formula (I).

[0153] Scheme 15: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 15, compounds of formula (15-4) can be prepared from compounds of formula (15-1). Under photoredox conditions, compounds of formula (15-1), where Het is a heteroaryl or heterocycle containing an NH moiety, are converted to compounds of formula (15-2), where R 15-1 is methyl or ethyl) to give compounds of formula (15-3). Compounds of formula (15-3) can be converted to compounds of formula (15-4) in a four-step process. Step 1 is saponification of the ester of compound of formula (15-3), followed by a Curtius rearrangement in step 2. Removal of the amine protecting group introduced in the Curtius rearrangement is the third step, followed by coupling with a compound of formula 1-2A or 1-2B in step 4 to complete the sequence. Compounds of formula (15-4) are representative of compounds of formula (I).

[0154] Scheme 16: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 16, compounds of formula (16-5) can be prepared from compounds of formula (16-1). Compounds of formula (16-1) can be treated with hydroxylamine to give compounds of formula (16-2). Compounds of formula (16-2) can be coupled with compounds of formula (6-1) under the amide bond-forming conditions described in Scheme 1 to give compounds of formula (16-3). Compounds of formula (16-3) can be treated with tetrabutylammonium fluoride to give compounds of formula (16-4). The oxadiazole of formula (16-4) can be deprotected and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (16-5). Compounds of formula (16-5) are representative of compounds of formula (I).

[0155] Scheme 17: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 17, compounds of formula (17-4) can be prepared from compounds of formula (17-1). Compounds of formula (17-1) can be treated with N-chlorosuccinimide. Subsequent treatment with an alkene or alkyne of formula (17-2) in the presence of a base such as triethylamine provides compounds of formula (17-3). Deprotection of the oxazoline or oxazole of formula (17-3) followed by coupling with compounds of formula (1-2A) or (1-2B) under conditions described above can provide compounds of formula (17-4). Compounds of formula (17-4) are representative of compounds of formula (I).

[0156] Scheme 18: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 18, compounds of formula (18-4) can be prepared from compounds of formula (18-1). Compounds of formula (18-1) can be treated with N-chlorosuccinimide. Subsequent treatment with an alkene or alkyne of formula (18-2) in the presence of a base such as triethylamine provides compounds of formula (18-3). Deprotection of the oxazoline or oxazole of formula (18-3) followed by coupling with compounds of formula (1-2A) or (1-2B) under conditions described above can provide compounds of formula (18-4). Compounds of formula (18-4) are representative of compounds of formula (I).

[0157] Scheme 19: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 19 of TIFF2026009987000139.tif66142, compounds of formula (19-5) can be prepared from compounds of formula (19-1). Compounds of formula (19-1) can be treated with 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene and sodium cyanide to give compounds of formula (19-2). Compounds of formula (19-2) can be reacted with compounds of formula (19-3) in heated xylene to give compounds of formula (19-4). Compounds of formula (19-4) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (19-5). Compounds of formula (19-5) are representative of compounds of formula (I).

[0158] Scheme 20: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 20, compounds of formula (20-5) can be prepared from compounds of formula (20-1). Compounds of formula (20-1) can be treated with 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene and sodium cyanide to give compounds of formula (20-2). Compounds of formula (20-2) can be reacted with compounds of formula (20-3) in heated xylene to give compounds of formula (20-4). Compounds of formula (20-4) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (20-5). Compounds of formula (20-5) are representative of compounds of formula (I).

[0159] Scheme 21: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 21 (TIFF2026009987000141.tif65140), compounds of formula (21-5) can be prepared from compounds of formula (21-1). Compounds of formula (21-1) can be treated with sodium nitrite and then cyclized in the presence of heated acetic anhydride to give compounds of formula (21-2). Compounds of formula (21-2) can be reacted with compounds of formula (21-3) in the presence of 4,7-diphenyl-1,10-phenanthroline, copper(II) sulfate, and a base such as triethylamine to give compounds of formula (21-4). Compounds of formula (21-4) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (21-5). Compounds of formula (21-5) are representative of compounds of formula (I).

[0160] Scheme 22: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 22, compounds of formula (22-4) can be prepared from compounds of formula (19-3). Compounds of formula (19-3) can be treated with 2,5-dimethoxytetrahydrofuran in a heated mixture of acetic acid and water to give compounds of formula (22-1). Compounds of formula (22-1) can be brominated with N-bromosuccinimide (NBS) and then cross-coupled under Suzuki reaction conditions with a boronic acid or other suitable coupling partner of formula (22-2) (where Ar-A is an optionally substituted aryl or optionally substituted heteroaryl moiety on the A ring) to give compounds of formula (22-3). Compounds of formula (22-3) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (22-4). Compounds of formula (22-4) are representative of compounds of formula (I).

[0161] Scheme 23: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 23, compounds of formula (23-3) can be prepared from compounds of formula (23-1). 23-1 is hydrogen or methyl) with heated sulfuric acid or phosphorus oxychloride to cyclize the starting material and protect the PG 1 Compounds of formula (23-2) can be coupled with compounds of formula (1-2A) or (1-2B) under the conditions described above to give compounds of formula (23-3). Compounds of formula (23-3) are representative of compounds of formula (I).

[0162] Scheme 24: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 24, compounds of formula (24-3) can be prepared from compounds of formula (24-1). 23-1 is hydrogen or methyl) with heated sulfuric acid to cyclize the starting material and protect the protecting group PG 1 Compounds of formula (24-2) can be coupled with compounds of formula (1-2A) or (1-2B) under the conditions described above to give compounds of formula (24-3). Compounds of formula (24-3) are representative of compounds of formula (I).

[0163] Scheme 25: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 25, compounds of formula (25-4) can be prepared from compounds of formula (25-1). Compounds of formula (25-1) can be oxidized with m-chloroperoxybenzoic acid to give an intermediate epoxide, which is ring-opened by treatment with compounds of formula (19-3) to give compounds of formula (25-2). Compounds of formula (25-2) can be reacted with 1,1'-carbonyldiimidazole to give compounds of formula (25-3). Compounds of formula (25-3) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (25-4). Compounds of formula (25-4) are representative of compounds of formula (I).

[0164] Scheme 26: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 26, compounds of formula (26-4) can be prepared from compounds of formula (6-1). Compounds of formula (6-1) can be converted to compounds of formula (26-1) in a three-step process. In the first step, compounds of formula (6-1) are coupled with N,O-dimethylhydroxylamine using the amide bond-forming reaction conditions described in Scheme 1. In the second step, the resulting N-methoxy-N-(methyl)amide moiety is reacted with methylmagnesium bromide to give a methyl ketone. In the third step, the methyl ketone is brominated with phenyltrimethylammonium tribromide to give compounds of formula (26-1). Compounds of formula (26-1) can be reacted with a thioamide of formula (26-2) to give compounds of formula (26-3). Compounds of formula (26-3) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (26-4), which are representative of compounds of formula (I).

[0165] Scheme 27: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 27 of TIFF2026009987000147.tif80140, compounds of formula (27-1) can be converted to compounds of formula (27-5). Compounds of formula (27-1) can be reacted with di(1H-imidazol-1-yl)methanethione in the presence of N,N-dimethylpyridin-4-amine, followed by reaction with ammonium hydroxide, to give compounds of formula (27-2). Compounds of formula (27-2) can be reacted with compounds of formula (27-3) in the presence of a tertiary amine base to give compounds of formula (27-4). Compounds of formula (27-4) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (27-5). Compounds of formula (27-5) are representative of compounds of formula (I).

[0166] Scheme 28: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 28, compounds of formula (23-1) can be converted to compounds of formula (28-2). Compounds of formula (23-1) can be reacted with ammonium acetate in heated xylene to give compounds of formula (28-1). Compounds of formula (28-1) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (28-2). Compounds of formula (28-2) are representative of compounds of formula (I).

[0167] Scheme 29: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 29, compounds of formula (29-1) can be converted to compounds of formula (29-4). Compounds of formula (29-1) can be reacted with hydrazines of formula (29-2) in a warm solvent such as methanol or ethanol to give compounds of formula (29-3). Compounds of formula (29-3) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (29-4). Compounds of formula (29-4) are representative of compounds of formula (I).

[0168] Scheme 30: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 30, compounds of formula (9-5) can be converted to compounds of formula (30-3). Compounds of formula (9-5) can be converted to compounds of formula (30-1), where LG 2is a leaving group, such as chlorine, bromine, iodine, or sulfonate, and Ar-A is an A ring consisting of an optionally substituted aryl or an optionally substituted heteroaryl moiety, to give compounds of formula (30-2). Compounds of formula (30-2) can be deprotected under the conditions described above and then coupled with compounds of formula (1-2A) or (1-2B) to give compounds of formula (30-3). Compounds of formula (30-3) are representative of compounds of formula (I).

[0169] Scheme 31: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 31, compounds of formula (31-1) can be converted to compounds of formula (31-4). Compounds of formula (31-1) can be reacted with azides of formula (31-2) under click chemistry reaction conditions to give compounds of formula (31-3). Compounds of formula (31-3) can be deprotected and then coupled with compounds of formula (1-2A) or (1-2B) under the conditions described above to give compounds of formula (31-4). Compounds of formula (31-4) are representative of compounds of formula (I).

[0170] Scheme 2-1: A representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 2-1, the compound of formula (2-1-6) can be prepared from the compound of formula (2-1-1). 1-II is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with a carboxylic acid of formula (2-1-2A) or, alternatively, with an acid chloride of formula (2-1-2B) under amide bond forming conditions to provide an amide of formula (2-1-3). Examples of conditions known to produce an amide from a mixture of a carboxylic acid of formula (2-1-2A) and an amine of formula (2-1-1) are described in Scheme 1.

[0171] Alternatively, the carboxylic acid of formula (2-1-2A) can be converted to the corresponding acid chloride of formula (2-1-2B) by the reaction described in Scheme 1. The resulting acid chloride of formula (2-1-2B) can then be coupled with an amine of formula (2-1-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a base such as a tertiary amine base such as triethylamine or diisopropylethylamine, or an aromatic base such as pyridine, to provide the amide of formula (2-1-3).

[0172] The compound of formula (2-1-3) can be obtained by removing the protecting group (PG 1-II The compound of formula (2-1-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (2-1-4) can be coupled with carboxylic acids of formula (2-1-5A), or alternatively with acid chlorides of formula (2-1-5B), to give compounds of formula (2-1-6). Compounds of formula (2-1-6) are representative of compounds of formula (II).

[0173] Scheme 2-2: Representative scheme for synthesizing exemplary compounds of the present invention. TIFF2026009987000153.tif80144 Scheme 2-2: As shown in Scheme 2-2, the compound of formula (2-2-5) can be prepared from the compound of formula (2-2-1). The compound of formula (2-2-1) can be prepared from PG 1-II is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with an amine of formula (2-2-2) under amide bond forming conditions to give an amide of formula (2-2-3). Examples of conditions known to produce amides from a mixture of a carboxylic acid of formula (2-2-1) and an amine of formula (2-2-2) are described in Scheme 1.

[0174] The compound of formula (2-2-3) can be obtained by removing the protecting group (PG1-II The compound of formula (2-2-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (2-2-4) can be coupled with carboxylic acids of formula (2-1-5A), or alternatively with acid chlorides of formula (2-1-5B), to give compounds of formula (2-2-5). Compounds of formula (2-2-5) are representative of compounds of formula (II).

[0175] Schemes 2-3: Representative schemes for synthesizing exemplary compounds of the present invention. As shown in Scheme 2-3, compound of formula (2-3-1) can be reacted with compound of formula (2-3-2) in heated phosphorus oxychloride to give compound of formula (2-3-3). Alternatively, compound of formula (2-3-1) can be reacted with compound of formula (2-3-2) under the described amide bond coupling conditions to give compound of formula (1-3). After coupling, the intermediate can be cyclized and dehydrated using 4-methylbenzene-1-sulfonyl chloride in heated acetonitrile in the presence of a tertiary amine base such as N,N-diisopropylethylamine to give compound of formula (2-3-3). Compound of formula (2-3-3) can be free of the protecting group (PG) used to give compound of formula (2-3-4). 1-II The compound of formula (2-3-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (2-3-4) can be coupled with carboxylic acids of formula (2-1-2A), or alternatively with acid chlorides of formula (2-1-2B), to give compounds of formula (2-3-5). Compounds of formula (2-3-5) are representative of compounds of formula (II).

[0176] Scheme 3-3: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 3-3, the compound of formula (3-3-5) can be prepared from the compound of formula (3-3-1).1-II is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with an amine of formula (3-3-2) under amide bond forming conditions to give an amide of formula (3-3-3). Examples of conditions known to produce amides from a mixture of a carboxylic acid of formula (3-3-1) and an amine of formula (3-3-2) are described in Scheme 1.

[0177] The compound of formula (3-3-3) can be obtained by removing the protecting group (PG 1-II The compound of formula (3-3-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (3-3-4) can be coupled with carboxylic acids of formula (2-1-5A), or alternatively with acid chlorides of formula (2-1-5B), to give compounds of formula (3-3-5). Compounds of formula (3-3-5) are representative of compounds of formula (II).

[0178] Scheme 3-1: A representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 3-1, the compound of formula (3-1-6) can be prepared from the compound of formula (3-1-1). 1-III is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with a carboxylic acid of formula (3-1-2A) or, alternatively, with an acid chloride of formula (3-1-2B) under amide bond forming conditions to provide an amide of formula (3-1-3). Examples of conditions known to generate amides from a mixture of a carboxylic acid of formula (3-1-2A) and an amine of formula (3-1-1) are described in Scheme 1.

[0179] Alternatively, the carboxylic acid of formula (3-1-2A) can be converted to the corresponding acid chloride of formula (3-1-2B) by the reaction described in Scheme 1. The resulting acid chloride of formula (3-1-2B) can then be coupled with an amine of formula (3-1-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a base such as a tertiary amine base such as triethylamine or diisopropylethylamine, or an aromatic base such as pyridine, to provide the amide of formula (3-1-3).

[0180] The compound of formula (3-1-3) can be obtained by removing the protecting group (PG 1-III The compound of formula (3-1-4) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (3-1-4) can be coupled with carboxylic acids of formula (3-1-5A), or alternatively with acid chlorides of formula (3-1-5B), to give compounds of formula (3-1-6). Compounds of formula (3-1-6) are representative of compounds of formula (III-a).

[0181] Scheme 3-2: Representative scheme for synthesizing exemplary compounds of the present invention. As shown in Scheme 3-2, the compound of formula (3-2-4) can be prepared from the compound of formula (3-2-1). 1-III is an amine protecting group (e.g., tert-butoxycarbonyl or benzyloxycarbonyl), which can be coupled with a carboxylic acid of formula (3-1-2A) or, alternatively, with an acid chloride of formula (3-1-2B) under amide bond forming conditions to provide an amide of formula (3-2-2). Examples of conditions known to generate amides from a mixture of a carboxylic acid of formula (3-1-2A) and an amine of formula (3-2-1) are described in Scheme 1.

[0182] Alternatively, a carboxylic acid of formula (3-1-2A) can be converted to the corresponding acid chloride of formula (3-1-2B) by the reaction described in Scheme 1. The resulting acid chloride of formula (3-1-2B) can then be coupled with an amine of formula (3-2-1) in a solvent such as dichloromethane at room temperature, optionally in the presence of a base such as a tertiary amine base such as triethylamine or diisopropylethylamine, or an aromatic base such as pyridine, to provide an amide of formula (3-2-2).

[0183] The compound of formula (3-2-2) can be obtained by removing the protecting group (PG 1-III The compound of formula (3-2-3) can be deprotected using conditions known to those skilled in the art, depending on the amide bond forming conditions discussed above. Compounds of formula (3-2-3) can be coupled with carboxylic acids of formula (3-1-5A), or alternatively with acid chlorides of formula (3-1-5B), to give compounds of formula (3-2-4). Compounds of formula (3-2-4) are representative of compounds of formula (III-b).

[0184] Pharmaceutical Compositions The present invention features a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0185] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparation methods include the step of combining a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof ("active ingredient") with the carrier and / or one or more other accessory ingredients, and then shaping and / or packaging the product into a desired single- or multi-dose unit, as necessary and / or desired. Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single-unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is approximately equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage (e.g., one-half or one-third of such a dosage).

[0186] The relative amounts of the compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), pharmaceutically acceptable excipient, and / or any additional components in the pharmaceutical compositions of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route used to administer the composition. By way of example, the composition can contain 0.1% to 100% (w / w) of a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0187] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in preparing the pharmaceutical compositions of the present invention are any excipients well known in the art of pharmaceutical formulation, including inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0188] Compositions of the invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0189] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media.

[0190] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets intended for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavoring agents, or coloring agents may be added. In some embodiments, the oral preparations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration, including tablets, lozenges, and troches. The compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, may be in microencapsulated form.

[0191] The compositions of the present invention can be delivered transdermally or topically as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, liniments, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for patient ingestion. Solid-form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid-form preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention can additionally contain components for sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered via intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as a biodegradable injectable gel formulation (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present invention can be delivered by the use of liposomes that fuse with the cell membrane or are phagocytosed, i.e., by using a receptor ligand attached to the liposome as a result of the ligand binding to a surface membrane protein receptor of the cell.Liposomes can be used to target the delivery of the compositions of the present invention to target cells in vivo, particularly if the liposome surface carries specific receptor ligands for the target cells or is preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, J. Hosp. Pharm. 46:1576-1587, 1989.) The compositions of the present invention can also be delivered as nanoparticles.

[0192] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration.The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application (including diseases of the eyes, skin, or lower intestinal tract).Suitable topical formulations can be easily prepared for each of these areas or organs.

[0193] In some embodiments, in order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the drug depends on its dissolution rate, which may depend on crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0194] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are also broadly suitable for administration to animals of all kinds. Modifications to pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and such modifications can be designed and / or implemented by a veterinary pharmacologist of ordinary skill, using routine experimentation.

[0195] The compounds described herein, e.g., compounds of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. However, it will be understood that the total daily usage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the disease being treated, the severity of the disorder, the activity of the specific active ingredient used, the specific composition used, the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the excretion rate of the specific active ingredient used, the duration of treatment, drugs used in combination with or contemporaneously with the specific active ingredient used, and similar factors well known in the medical field.

[0196] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of any side effects or disorders, the identity of the particular compound(s), the mode of administration, etc. The desired dosage can be delivered three times daily, twice daily, once daily, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0197] In certain embodiments, an effective amount of a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, for one or more daily administration may include from about 0.0001 mg to about 5000 mg, e.g., from about 0.0001 mg to about 4000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0198] In certain embodiments, a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, may be administered at a dosage level sufficient to deliver from about 0.001 mg / kg to about 1000 mg / kg of subject body weight per day, e.g., from about 0.001 mg / kg to about 500 mg / kg, from about 0.01 mg / kg to about 250 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.1 mg / kg to about 25 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, or from about 1 mg / kg to about 50 mg / kg, one or more times per day to achieve the desired therapeutic effect.

[0199] It will be understood that the dosage ranges as provided herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount to be administered to a child or adolescent can be determined by a medical practitioner or person skilled in the art, and may be less than or the same as the amount administered to an adult.

[0200] It will also be understood that a compound or composition, e.g., a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, can be administered in combination with one or more additional pharmaceutical agents. The compound or composition may be administered in combination with additional pharmaceutical agents that improve its bioavailability, reduce and / or alter its metabolism, inhibit its excretion, and / or alter its distribution in the body. It will also be understood that the therapies used may achieve the desired effect for the same disease and / or may achieve different effects.

[0201] The compounds or compositions can be administered simultaneously with, before, or after one or more additional pharmaceutical agents, which can be useful (e.g., as combination therapy). Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent can be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents can be administered together with each other and / or with the compounds or compositions described herein in a single dose or separately in different doses. The particular combination to use in a regimen will take into account the compatibility of the compounds of the present invention with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that additional pharmaceutical agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0202] Exemplary additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0203] Pharmaceutical compositions provided by the present invention include compositions containing an active ingredient (e.g., a compound described herein, including embodiments or examples) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in a method for treating a disease, such compositions contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule (eIF2B, eIF2, or eIF2α signaling pathway component, or a phosphorylated eIF2α pathway or ISR pathway component) and / or reducing, eliminating, or delaying the progression of disease symptoms (e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway). Determining a therapeutically effective amount of a compound of the present invention is well within the skill of those in the art, especially in light of the detailed disclosure herein.

[0204] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, including whether the mammal is suffering from another disease and the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or symptoms of a disease or disorder associated with dysfunction of eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway); the type of concomitant treatment; and complications from the disease or other health-related problems being treated. Other therapeutic regimens or agents can also be used with the methods and compounds of Applicant's invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the skill of one of ordinary skill in the art.

[0205] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound(s) achievable by the methods described herein, as measured using the methods described herein or methods known in the art.

[0206] As is known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a human dose can be formulated to achieve a concentration found to be effective in animals. The human dosage can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the methods described above and other methods is well within the skill of one of ordinary skill in the art.

[0207] Dosage may vary depending on the requirements of the patient and the compound being used. In the context of the present invention, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. Generally, treatment is initiated with small dosages that are less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached. Dosage and interval can be individually adjusted to provide a level of the administered compound that is effective for the specific clinical indication being treated. This results in a treatment regimen that is tailored to the severity of the individual's disease state.

[0208] The teachings provided herein can be used to design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity yet are effective in treating the clinical symptoms exhibited by a particular patient. This design should involve careful selection of an active compound by considering factors such as the compound's potency, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0209] The present invention also encompasses kits (e.g., pharmaceutical packs) that may be useful for the prevention and / or treatment of diseases (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or other diseases or conditions described herein).

[0210] The provided kits can include a pharmaceutical composition or compound of the invention and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the provided kits can optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the invention. In some embodiments, the container and the pharmaceutical composition or compound of the invention provided in the second container are combined to form a single unit dosage form.

[0211] Thus, in one aspect, a kit is provided that includes a first container containing a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit is useful for preventing and / or treating a proliferative disease in a subject. In certain embodiments, the kit further includes instructions for administering to a subject a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof to prevent and / or treat a disease described herein.

[0212] Treatment method The present invention features compounds, compositions, and methods comprising a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, the compounds, compositions, and methods are used in the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to, neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss, eye diseases, diseases with mutations that lead to UPR induction, malarial infections, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases.

[0213] In some embodiments, the disease, disorder, or condition is associated with (e.g., caused by) modulation (e.g., decrease) of eIF2B activity or levels, eIF2α activity or levels, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder, or condition is associated with modulation of a signaling pathway associated with a component of the eIF2 pathway or ISR pathway (e.g., phosphorylation of a component of the eIF2 pathway or ISR pathway). In some embodiments, the disease, disorder, or condition is associated with (e.g., caused by) neurodegeneration. In some embodiments, the disease, disorder, or condition is associated with (e.g., caused by) neuronal death or dysfunction. In some embodiments, the disease, disorder, or condition is associated with (e.g., caused by) glial cell death or dysfunction. In some embodiments, the disease, disorder, or condition is associated with (e.g., caused by) increased levels or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder, or condition is associated with (eg, caused by) a decrease in the level or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

[0214] In some embodiments, the disease may be caused by a mutation in a gene or protein sequence associated with a component of the eIF2 pathway (e.g., eIF2B, eIF2α, or other component). Exemplary mutations include amino acid mutations in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in a particular protein may result in structural changes (e.g., conformational or steric changes) that affect the function of the protein. For example, in some embodiments, amino acids in and around the active site or near a binding site (e.g., a phosphorylation site, a small molecule binding site, or a protein binding site) may be mutated such that the activity of the protein is affected. In some instances, the amino acid mutations (e.g., amino acid substitutions, additions, or deletions) may be conservative and not substantially affect the structure or function of the protein. For example, in certain cases, substituting a serine residue with a threonine residue may not significantly affect the function of the protein. In other cases, the amino acid mutations may be more dramatic, such as substituting a charged amino acid (e.g., aspartic acid or lysine) with a large, nonpolar amino acid (e.g., phenylalanine or tryptophan), thereby substantially affecting protein function. The nature of mutations that affect the structure of a gene or protein function can be readily identified using standard sequencing techniques (e.g., deep sequencing techniques well known in the art). In some embodiments, mutations in eIF2 pathway components affect the binding or activity of a compound of Formula (I), Formula (II), Formula (III-a), or Formula (III-b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, and thus can modulate the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0215] In some embodiments, the eIF2 protein may comprise an amino acid mutation (e.g., an amino acid substitution, addition, or deletion) at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein may comprise an amino acid substitution at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein may comprise an amino acid addition at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue, or an amino acid deletion at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue.

[0216] In some embodiments, the eIF2 protein may include an amino acid mutation (e.g., an amino acid su...

Claims

1. Formula (I): A compound of the formula: During the ceremony, D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, or a cubanyl, wherein each of the bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl is substituted with one to four R Ｘ and when said 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted by R Ｎ１ and U is -NR １ C(O)-, -C(O)NR １ - or 5- to 6-membered heteroaryl; E is a bond, -NR ２ C(O)-, -C(O)NR ２ -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl has 1 to 5 R Ｇ and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ２ or E is, and Y is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R Ｇ and when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted by R Ｎ２ and L １ is a bond, C １ -C ６ Alkylene, 2- to 7-membered heteroalkylene, —NR Ｎ３ - or -O-, where C １ -C ６ The alkylene or 2- to 7-membered heteroalkylene is one to five R Ｌ１ and optionally substituted by L ２ is a bond, C １ -C ６ alkylene, 2- to 7-membered heteroalkylene, or —O—, where C １ -C ６ The alkylene or 2- to 7-membered heteroalkylene is one to five R Ｌ２ may be substituted with R １ is hydrogen or C １ -C ６ is alkyl, R ２ is hydrogen or C １ -C ６ is alkyl, W is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein said heterocyclyl has 1 to 4 R Ｗ１ and the phenyl or heteroaryl may be substituted with 1 to 4 R at one or more available unsaturated carbons. Ｗ２ When the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be substituted with R Ｎ４ and W is optionally substituted with L through an available saturated carbon or nitrogen atom in the heterocyclyl. ２ binds to A is C ３ -C ６ cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein C ３ -C ６ Cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl may have 1 to 5 R Ｙ and when said 5- to 6-membered heteroaryl or 8- to 10-membered bicyclic heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ５ may be substituted with Each R Ｌ１ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -SR Ｅ , -S(O)R Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of Each R Ｌ２ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -SR Ｅ , -S(O)R Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of R Ｎ１ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of R Ｎ２ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of R Ｎ３ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of R Ｎ４ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, C １ -C ６ Alkyl-C １ -C ６ Cycloalkyl, C １ -C ６ Alkenyl, —C(O)—C １ -C ６ Alkyl, —C(O)—C １ -C ６ Cycloalkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, —C(O)—C １ -C ３ Alkyl-O-C １ -C ３ Alkyl-O-C １ -C ３ Alkyl, —C(O)-phenyl, —C(O)-heteroaryl, —C(O)-heterocyclyl, —S(O) ２ -C １ -C ６ Alkyl, —S(O) ２ -phenyl, -S(O) ２ -heteroaryl, -C(O)NR Ｂ R Ｃ , and —C(O)OR Ｄ selected from the group consisting of Here, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, C １ -C ６ Alkyl-C １ -C ６ Cycloalkyl, C １ -C ６ Alkenyl, C(O)—C １ -C ６ Alkyl, —C(O)—C １ -C ６ Cycloalkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, —C(O)-heterocyclyl, and —S(O) ２ -C １ -C ６ The alkyl can be optionally substituted with one or more substituents, each of which independently includes fluoro, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) ｗ C １－６ alkyl, wherein w is 0, 1, or 2; and where —C(O)-phenyl, —C(O)-heteroaryl, —S(O) ２ -phenyl, and -S(O) ２ The heteroaryl may be optionally substituted with one or more substituents, each of which may independently be halogen, hydroxyl, C １ -C ６ alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C １ -C ６ Alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) ２ -NR Ｂ R Ｃ selected from the group consisting of R Ｎ５ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of Each R Ｗ１ are independently hydrogen, C １ -C ６ Alkyl (-CO ２ H), hydroxy-C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl-O-, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, C═N—OH, halo, cyano, —OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ R ＣＣ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -SR Ｅ , -S(O)R Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of Each R Ｗ２ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl-O-, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -S(R Ｆ ) ｍ , -S(O)R Ｄ , and -S(O) ２ R Ｄ or selected from the group consisting of Two R on adjacent atoms Ｗ２ groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ may be substituted with Each R Ｘ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -SR Ｅ , -S(O)R Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of Each R Ｙ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, halo-C １ -C ６ Alkoxy-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -S(R Ｆ ) ｍ , -S(O)R Ｄ , -S(O) ２ R Ｄ , and G １ or selected from the group consisting of Two R on adjacent atoms Ｙ The groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ may be substituted with Each G １ is independently a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, the 3- to 7-membered heterocyclyl, the aryl, or the 5- to 6-membered heteroaryl is selected from 1 to 3 R Ｚ may be substituted with Each R Ｚ are independently １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , and -S(O) ２ R Ｄ selected from the group consisting of R Ａ is independently, in each occurrence, hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and R Ｂ and R Ｃ Each of is independently hydrogen or C １ -C ６ is alkyl, R Ｂ and R Ｃ together with the atoms to which they are attached, form one to three R Ｚ forming an optionally substituted 3- to 7-membered heterocyclyl ring; Each R ＣＣ are independently hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, C(O)C １ -C ６ Alkyl, S(O) ２ -C １ -C ６ and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ selected from the group consisting of alkyl, hydroxyl, halo, and —C(O)OH; Each R Ｄ are independently １ -C ６ Alkyl or halo-C １ -C ６ is alkyl, Each R Ｅ are independently hydrogen, C １ -C ６ Alkyl, or halo-C １ -C ６ is alkyl, Each R Ｆ are independently hydrogen, C １ -C ６ alkyl, or halo; Each R Ｇ are independently hydrogen, C １ -C ６ alkyl, halo, or oxo; and m is R Ｆ is hydrogen or C １ -C ６ 1 for alkyl, and R Ｆ is C １ -C ６ 3 for alkyl, or R Ｆ is 5 for halo, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

2. D is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from 1 to 4 R Ｘ The compound of claim 1, which may be substituted with a group.

3. D is, 3. The compound according to any one of claims 1 to 2, selected from the group consisting of:

4. D is, 4. The compound of claim 1, selected from the group consisting of:

5. D is 0 R ｘ 5. The compound of claim 1 , substituted with:

6. D is, 6. The compound of any one of claims 1 to 5, selected from the group consisting of:

7. D is, 7. The compound of claim 1, wherein

8. D is one R Ｘ 6. The compound of claim 1 , substituted with:

9. D is, 9. The compound of any one of claims 1 to 5 and 8, wherein

10. R Ｘ The compound of any one of claims 8 or 9, wherein is -OH.

11. U is —NHC(O)—, —C(O)NH—, and 11. The compound of any one of claims 1 to 10, selected from the group consisting of:

12. 12. The compound of any one of claims 1 to 11, wherein U is -NHC(O)-.

13. L １ is a bond or C １ -C ６ alkylene, and C １ -C ６ The alkylene is 1 to 5 R Ｌ１ 13. The compound of any one of claims 1 to 12, optionally substituted with:

14. L １ is a bond or C １ -C ６ alkylene, and C １ -C ６ The alkylene is selected from the group consisting of 0 R Ｌ１ 14. The compound of any one of claims 1 to 13, substituted with:

15. L １ is a bond or -CH ２ The compound according to any one of claims 1 to 14, wherein

16. R １ is hydrogen or CH ３ 16. The compound of any one of claims 1 to 15, wherein

17. W is a compound represented by the formula (W-a): is represented by During the ceremony, X is NR Ｎ４ or C(R Ｘ１ ) (R Ｘ２ ) and R Ｎ４ is hydrogen or C １ -C ６ is alkyl, R Ｘ１ is hydrogen or hydroxyl, R Ｘ２ is hydrogen or hydroxyl, or R Ｘ１ and R Ｘ２ together form an oxo moiety, 17. A compound according to any one of claims 1 to 16.

18. W is, 18. The compound of any one of claims 1 to 17, selected from the group consisting of:

19. W is, 17. The compound of any one of claims 1 to 16, wherein

20. W is one R Ｗ２ 20. The compound of any one of claims 1 to 19, substituted with:

21. R Ｗ２ 21. The compound of claim 20, wherein is chloro.

22. W is two R Ｗ２ 20. The compound of any one of claims 1 to 19, substituted with:

23. Each R Ｗ２ 23. The compound of claim 22, wherein is independently chloro or fluoro.

24. E is a bond, -NR ２ C(O)-, -C(O)NR ２ - and 24. The compound of any one of claims 1 to 23, selected from the group consisting of:

25. E, 22. The compound of any one of claims 1 to 21, selected from the group consisting of:

26. E, 22. The compound of any one of claims 1 to 21, selected from the group consisting of:

27. E is a bond, -NR ２ C(O)-, -C(O)NR ２ -, 27. The compound of any one of claims 1 to 26, selected from the group consisting of:

28. E, 18. The compound of any one of claims 1 to 17, selected from the group consisting of:

29. R ２ 29. The compound of any one of claims 1 to 28, wherein is hydrogen.

30. L ２ is a bond, -O-, C １ -C ６ 30. The compound of any one of claims 1 to 29, which is alkylene or 2- to 7-membered heteroalkylene.

31. L ２ is a bond, -CH ２ -, -CH ２ O- ＊ , -(CH ２ ) ２ O- ＊ , -(CH ２ ) ３ O- ＊ or —O—, wherein “— ＊ 31. The compound of any one of claims 1 to 30, wherein "" indicates the point of attachment to A.

32. A is, 32. The compound of any one of claims 1 to 31, selected from the group consisting of:

33. A is, 33. The compound of any one of claims 1 to 32, selected from the group consisting of:

34. Each R Ｙ are independently hydrogen, chloro, fluoro, hydroxyl, phenyl, CHF ２ , C.F. ３ , C.H. ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , OCH ３ , OCHF ２ , OCF ３ , OCH ２ CF ３ , OCH(CH ３ ) ２ , C.H. ２ OCF ３ 34. The compound of any one of claims 1 to 33, wherein the compound is selected from the group consisting of:

35. Formula (II): A compound of the formula: During the ceremony, D ＩＩ is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl, wherein the bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or cubanyl each has one to four R Ｘ－ＩＩ and when said 4- to 6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted by R Ｎ１－ＩＩ and U ＩＩ is -NR １－ＩＩ C(O)- or -C(O)NR １－ＩＩ - and E ＩＩ is a bond, -NR ２－ＩＩ C(O)-, -C(O)NR ２－ＩＩ -, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl has 1 to 5 R Ｇ－ＩＩ and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ２－ＩＩ or E ＩＩ teeth, and Y ＩＩ is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein said 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R Ｇ－ＩＩ and when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted by R Ｎ２－ＩＩ and L １－ＩＩ is a bond, C １ -C ６ Alkylene, 2- to 7-membered heteroalkylene, —NR Ｎ３－ＩＩ - or -O-, where C １ -C ６ The alkylene or 2- to 7-membered heteroalkylene is one to five R Ｌ１－ＩＩ may be substituted with L ２－ＩＩ is a bond, C １ -C ６ alkylene, or 2- to 7-membered heteroalkylene, —O—; １ -C ６ The alkylene or 2- to 7-membered heteroalkylene is one to five R Ｌ２－ＩＩ may be substituted with R １－ＩＩ is hydrogen or C １ -C ６ is alkyl, R ２－ＩＩ is hydrogen or C １ -C ６ is alkyl, W ＩＩ is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R Ｗ－ＩＩ and when said 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ４－ＩＩ and A ＩＩ is C ３ -C ６ cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, where C ３ -C ６ Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl may have 1 to 5 R Ｙ－ＩＩ and when said 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ５－ＩＩ may be substituted with Each R Ｌ１－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , -SR Ｅ－ＩＩ , -S(O)R Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of Each R Ｌ２－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , -SR Ｅ－ＩＩ , -S(O)R Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of R Ｎ１－ＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OR Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of R Ｎ２－ＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OR Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of R Ｎ３－ＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OR Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of R Ｎ４－ＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, C １ -C ６ Alkyl-C １ -C ６ Cycloalkyl, C １ -C ６ Alkenyl, —C(O)—C １ -C ６ Alkyl, —C(O)—C １ -C ６ Cycloalkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, —C(O)—C １ -C ３ Alkyl-O-C １ -C ３ Alkyl-O-C １ -C ３ Alkyl, —C(O)-phenyl, —C(O)-heteroaryl, —C(O)-heterocyclyl, —S(O) ２ -C １ -C ６ Alkyl, —S(O) ２ -phenyl, -S(O) ２ -heteroaryl, -C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , and —C(O)OR Ｄ－ＩＩ selected from the group consisting of Here, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, C １ -C ６ Alkyl-C １ -C ６ Cycloalkyl, C １ -C ６ Alkenyl, C(O)—C １ -C ６ Alkyl, —C(O)—C １ -C ６ Cycloalkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, —C(O)-heterocyclyl, and —S(O) ２ -C １ -C ６ The alkyl can be optionally substituted with one or more substituents, each of which independently includes fluoro, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O) ｗ－ＩＩ C １－６ alkyl (wherein w-II is 0, 1, or 2); and where —C(O)-phenyl, —C(O)-heteroaryl, —S(O) ２ -phenyl, and -S(O) ２ The heteroaryl may be optionally substituted with one or more substituents, each of which may independently be halogen, hydroxyl, C １ -C ６ alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), C １ -C ６ Alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms), and S(O ２ ) NR Ｂ－ＩＩ R Ｃ－ＩＩ selected from the group consisting of R Ｎ５－ＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OR Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of Each R Ｗ－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl-O-, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, C═N—OH, halo, cyano, —OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ R ＣＣ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , -SR Ｅ－ＩＩ , -S(O)R Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ or selected from the group consisting of Two R on adjacent atoms Ｗ－ＩＩ groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ－ＩＩ may be substituted with Each R Ｘ－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , -SR Ｅ－ＩＩ , -S(O)R Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of Each R Ｙ－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, halo, cyano, -OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , -S(R Ｆ－ＩＩ ) ｍ－ＩＩ , -S(O)R Ｄ－ＩＩ , -S(O) ２ R Ｄ－ＩＩ , and G １－ＩＩ or selected from the group consisting of Two R on adjacent atoms Ｙ－ＩＩ groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ－ＩＩ may be substituted with Each G １－ＩＩ is independently a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, the 3- to 7-membered heterocyclyl, the aryl, or the 5- to 6-membered heteroaryl is selected from 1 to 3 R Ｚ－ＩＩ may be substituted with Each R Ｚ－ＩＩ are independently １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo, cyano, -OR Ａ－ＩＩ , -NR Ｂ－ＩＩ R Ｃ－ＩＩ , -NR Ｂ－ＩＩ C(O)R Ｄ－ＩＩ , —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩ , and -S(O) ２ R Ｄ－ＩＩ selected from the group consisting of R Ａ－ＩＩ is independently, in each occurrence, hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩ R Ｃ－ＩＩ , -C(O)R Ｄ－ＩＩ , or —C(O)OR Ｄ－ＩＩ and R Ｂ－ＩＩ and R Ｃ－ＩＩ are each independently hydrogen or C １ -C ６ is alkyl, R Ｂ－ＩＩ and R Ｃ－ＩＩ together with the atoms to which they are attached, form one to three R Ｚ－ＩＩ forming an optionally substituted 3- to 7-membered heterocyclyl ring; Each R ＣＣ－ＩＩ are independently hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, C(O)C １ -C ６ Alkyl, S(O) ２ -C １ -C ６ and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ selected from the group consisting of alkyl, hydroxyl, halo, and —C(O)OH; Each R Ｄ－ＩＩ are independently １ -C ６ Alkyl or halo-C １ -C ６ is alkyl, Each R Ｅ－ＩＩ are independently hydrogen, C １ -C ６ Alkyl, or halo-C １ -C ６ is alkyl, Each R Ｆ－ＩＩ are independently hydrogen, C １ -C ６ alkyl, or halo, and Each R Ｇ－ＩＩ are independently hydrogen, C １ -C ６ alkyl, halo, or oxo; However, D ＩＩ When is a bridged bicyclic five-membered cycloalkyl, E ＩＩ is -NR ２－ＩＩ C(O)—; The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

36. D ＩＩ is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, cyclohexyl, or tetrahydro-2H-pyranyl, each of which is selected from 1 to 4 R Ｘ－ＩＩ 36. The compound of claim 35, optionally substituted with a group.

37. D ＩＩ but, 37. The compound of any one of claims 35 to 36, selected from the group consisting of:

38. D ＩＩ But there are 0 R Ｘ－ＩＩ 38. The compound of any one of claims 35 to 37, substituted with:

39. D ＩＩ but, 39. The compound of any one of claims 35 to 38, selected from the group consisting of:

40. D ＩＩ But one R Ｘ－ＩＩ 38. The compound of any one of claims 35 to 37, substituted with:

41. D ＩＩ but, 41. The compound of any one of claims 35 to 37 and 40, wherein:

42. R Ｘ－ＩＩ The compound of claim 40 or 41, wherein is -OH.

43. L １－ＩＩ But C １ -C ６ alkylene or 2- to 7-membered heteroalkylene, １ -C ６ Alkylene or 2- to 7-membered heteroalkylene is 1 to 5 R Ｌ１－ＩＩ 43. The compound of any one of claims 35 to 42, optionally substituted with:

44. L １－ＩＩ but, 0 R Ｌ１－ＩＩ C substituted with １ -C ６ Alkylene or 2- to 7-membered heteroalkylene 44. The compound of any one of claims 35 to 43, wherein

45. L １－ＩＩ But -CH ２ - or CH ２ O- ＊ In the formula, "- ＊ 45. The compound of any one of claims 35 to 44, wherein "" indicates the point of attachment to WII.

46. R １－ＩＩ is hydrogen or CH ３ 46. ​​The compound of any one of claims 35 to 45, wherein:

47. W ＩＩ but, 47. The compound of any one of claims 35 to 46, selected from the group consisting of:

48. W ＩＩ but, 48. The compound of any one of claims 35 to 47, wherein:

49. Each R Ｙ－ＩＩ are independently chloro, fluoro, or CF ３ 49. The compound of any one of claims 35 to 48, wherein:

50. E ＩＩ But, -NR ２－ＩＩ C(O)-, -C(O)NR ２－ＩＩ - and 50. The compound of any one of claims 35 to 49, selected from the group consisting of:

51. E ＩＩ but, 50. The compound of any one of claims 35 to 49, selected from the group consisting of:

52. E ＩＩ But, -NR ２－ＩＩ C(O)-, 52. The compound of any one of claims 35 to 51, selected from the group consisting of:

53. D ＩＩ but If E ＩＩ But, -NR ２－ＩＩ 53. The compound of any one of claims 35 to 50 and 52, which is C(O)-.

54. R ２－ＩＩ 54. The compound of any one of claims 35 to 53, wherein is hydrogen or methyl.

55. L ２－ＩＩ 55. The compound of any one of claims 35 to 54, wherein is a bond, -O-, or 2- to 7-membered heteroalkylene.

56. L ２－ＩＩ is a bond, -CH ２ O- ＊ , -(CH ２ ) ２ O- ＊ , -(CH ２ ) ３ O- ＊ or —O—, wherein “— ＊ " is A ＩＩ 56. The compound of any one of claims 35 to 55, showing a point of attachment to:

57. A ＩＩ but, 57. The compound of any one of claims 35 to 56, selected from the group consisting of:

58. A ＩＩ but, 58. The compound of any one of claims 35 to 57, wherein:

59. Each R Ｙ－ＩＩ but chloro or OCF ３ 59. The compound of any one of claims 35 to 58, wherein:

60. Formula (IIIa) or Formula (IIIb): A compound represented by the formula: During the ceremony, D ＩＩＩ is a 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl, wherein said 4- to 9-membered monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl has 1 to 5 R Ｘ－ＩＩＩ and when said 4- to 9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic, or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen is optionally substituted by R Ｎ１－ＩＩＩ and W ＩＩＩ is an 8- to 10-membered partially unsaturated fused bicyclic ring moiety comprising a 5- to 6-membered heterocyclyl fused to a phenyl or a 5- to 6-membered heteroaryl, wherein said heterocyclyl has 1 to 4 R Ｗ１－ＩＩＩ and the phenyl or heteroaryl may be substituted with 1 to 4 R at one or more available unsaturated carbons. Ｗ２－ＩＩＩ and if said heterocyclyl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ２－ＩＩＩ and A ＩＩＩ is phenyl or a 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl has 1 to 5 R Ｙ－ＩＩＩ When said 5- to 6-membered heteroaryl contains a substitutable nitrogen moiety, said substitutable nitrogen may be substituted with R Ｎ３－ＩＩＩ and R １－ＩＩＩ is hydrogen or C １ -C ６ is alkyl, L １－ＩＩＩ is a bond, C １ -C ６ alkylene, or 2- to 7-membered heteroalkylene, wherein C １ -C ６ The alkylene or 2- to 7-membered heteroalkylene is one to five R Ｌ１－ＩＩＩ may be substituted with Each R Ｌ１－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , -SR Ｅ－ＩＩＩ , -S(O)R Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of R Ｎ１－ＩＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OR Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of R Ｎ２－ＩＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OR Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of R Ｎ３－ＩＩＩ is hydrogen, C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl, halo-C ２ -C ６ Alkyl, amino-C ２ -C ６ Alkyl, cyano-C ２ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OR Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of Each R Ｗ１－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl (-CO ２ H), hydroxy-C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl-O-, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, C═N—OH, halo, cyano, —OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ R ＣＣ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , -SR Ｅ－ＩＩＩ , -S(O)R Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of Each R Ｗ２－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, hydroxy-C ２ -C ６ Alkyl-O-, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, halo, cyano, -OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , -S(R Ｆ－ＩＩＩ ) ｍ－ＩＩＩ , -S(O)R Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ or selected from the group consisting of Two R on adjacent atoms Ｗ２－ＩＩＩ groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ－ＩＩＩ may be substituted with Each R Ｘ－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , -SR Ｅ－ＩＩＩ , -S(O)R Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of Each R Ｙ－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo-C １ -C ６ Alkoxy, amino-C １ -C ６ Alkyl, cyano-C １ -C ６ Alkyl, halo, cyano, -OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , -S(R Ｆ－ＩＩＩ ) ｍ－ＩＩＩ , -S(O)R Ｄ－ＩＩＩ , -S(O) ２ R Ｄ－ＩＩＩ , and G １－ＩＩＩ or selected from the group consisting of: Two R on adjacent atoms Ｙ－ＩＩＩ groups, together with the atoms to which they are attached, form a 3- to 7-membered fused cycloalkyl, a 3- to 7-membered fused heterocyclyl, a fused aryl, or a 5- to 6-membered fused heteroaryl, each of which may be joined by 1 to 5 R Ｘ－ＩＩＩ may be substituted with Each G １－ＩＩＩ is independently a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each of the 3- to 7-membered cycloalkyl, the 3- to 7-membered heterocyclyl, the aryl, or the 5- to 6-membered heteroaryl is selected from 1 to 3 R Ｚ－ＩＩＩ may be substituted with Each R Ｚ－ＩＩＩ are independently １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, halo, cyano, -OR Ａ－ＩＩＩ , -NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -NR Ｂ－ＩＩＩ C(O)R Ｄ－ＩＩＩ , —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , -C(O)OH, -C(O)OR Ｄ－ＩＩＩ , and -S(O) ２ R Ｄ－ＩＩＩ selected from the group consisting of R Ａ－ＩＩＩ is independently, in each occurrence, hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, —C(O)NR Ｂ－ＩＩＩ R Ｃ－ＩＩＩ , -C(O)R Ｄ－ＩＩＩ , or —C(O)OR Ｄ－ＩＩＩ and R Ｂ－ＩＩＩ and R Ｃ－ＩＩＩ are each independently hydrogen or C １ -C ６ alkyl, or R Ｂ－ＩＩＩ and R Ｃ－ＩＩＩ together with the atoms to which they are attached, form one to three R Ｚ－ＩＩＩ forming an optionally substituted 3- to 7-membered heterocyclyl ring; Each R ＣＣ－ＩＩＩ are independently hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C １ -C ６ Alkyl-CO ２ H, C １ -C ６ Alkyl-CO ２ -C １ -C ６ Alkyl, C(O)C １ -C ６ Alkyl, S(O) ２ -C １ -C ６ and 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 4- to 6-membered heterocyclyl can be optionally substituted with one or more substituents, each of which is independently selected from the group consisting of C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, halo-C １ -C ６ selected from the group consisting of alkyl, hydroxyl, halo, and —C(O)OH; Each R Ｄ－ＩＩＩ is independently C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, or halo-C １ -C ６ is alkyl, Each R Ｅ－ＩＩＩ are independently hydrogen, C １ -C ６ Alkyl, or halo-C １ -C ６ is alkyl, Each R Ｆ－ＩＩＩ are independently hydrogen, C １ -C ６ alkyl, or halo, and m ＩＩＩ is R Ｆ－ＩＩＩ is hydrogen or C １ -C ６ For alkyl, it is 1, and R Ｆ－ＩＩＩ is C １ -C ６ 3 for alkyl, or R Ｆ－ＩＩＩ is 5 for halo, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

61. D ＩＩＩ is an azetidine, pyrrolidine, piperidine, piperazine, or 2-azaspiro[3.3]heptane moiety, each of which is selected from 1 to 4 R Ｗ－ＩＩＩ groups, and each R Ｗ－ＩＩＩ But independently, C １ -C ６ Alkyl, halo-C １ -C ６ alkyl, halo, oxo, cyano, or -OR Ａ－ＩＩＩ where the piperazine has R Ｎ２－ＩＩＩ 61. The compound of claim 60, optionally substituted with:

62. D ＩＩＩ is selected from the group consisting of: Ｎ１－ＩＩＩ is hydrogen or C １ -C ３ 62. The compound of any one of claims 60 or 61, wherein: 。

63. D ＩＩＩ but, 63. The compound of claim 62, wherein:

64. W ＩＩＩ is expressed by the formula (W-b): is expressed as During the ceremony, X ＩＩＩ is NR Ｎ４－ＩＩＩ or C(R Ｘ１－ＩＩＩ ) (R Ｘ２－ＩＩＩ ) and R Ｎ４－ＩＩＩ is hydrogen or C １ -C ６ is alkyl, R Ｘ１－ＩＩＩ is hydrogen or hydroxyl, R Ｘ２－ＩＩＩ is hydrogen or hydroxyl, or R Ｘ１－ＩＩＩ and R Ｘ２－ＩＩＩ together form an oxo moiety, 64. A compound according to any one of claims 60 to 63.

65. W ＩＩＩ but, 65. The compound of any one of claims 60 to 64, selected from the group consisting of:

66. W ＩＩＩ But one R Ｗ２－ＩＩＩ 66. The compound of any one of claims 60 to 65, substituted with:

67. R Ｗ２－ＩＩＩ 67. The compound of claim 66, wherein is chloro.

68. L １－ＩＩＩ But 1-5 R Ｌ１－ＩＩＩ 68. The compound according to any one of claims 60 to 67, wherein the heteroalkylene is a 2- to 7-membered heteroalkylene optionally substituted with:

69. L １－ＩＩＩ But there are 0 R Ｌ１ 69. The compound of any one of claims 60 to 68, which is a 2- to 7-membered heteroalkylene substituted with:

70. L １－ＩＩＩ But CH ２ O- ＊ or CH ２ OCH ２ - ＊ wherein "-" is selected from the formula: ＊ " is A ＩＩＩ 99. The compound of any one of claims 60 to 98, showing a point of attachment to:

71. R １－ＩＩＩ is hydrogen or CH ３ 71. The compound of any one of claims 60 to 70, wherein

72. A ＩＩＩ but, 72. The compound of any one of claims 60 to 71, selected from the group consisting of:

73. Each R Ｙ－ＩＩＩ are independently hydrogen, chloro, fluoro, CHF ２ , C.F. ３ , C.H. ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , OCH ３ , OCHF ２ , OCF ３ , OCH ２ CF ３ , OCH(CH ３ ) ２ 73. The compound of any one of claims 60 to 72, wherein the compound is selected from the group consisting of:

74. A compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, N-oxides, or stereoisomers thereof: 。

75. 75. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 to 74 and a pharmaceutically acceptable carrier.

76. 75. A method of treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

77. 77. The method of claim 76, wherein the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive disorder, a glial cell dysfunction, or a brain injury.

78. 78. The method of claim 76 or 77, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with central nervous system hypomyelination, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia, kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

79. 79. The method of any one of claims 76 to 78, wherein the neurodegenerative disease comprises vanishing white matter disease.

80. 77. The method of claim 76, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells.

81. 77. The method of claim 76, wherein the inflammatory disease comprises postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

82. 77. The method of claim 76, wherein the musculoskeletal disorder comprises muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal-bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Friedrich's ataxia, muscle wasting disorder, inclusion body myositis, motor neuron disease, or paralysis.

83. 77. The method of claim 76, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

84. 77. The method of claim 76, wherein the mitochondrial disease is associated with or results from mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations.

85. 85. The method of claim 76 or 84, wherein the mitochondrial disease is a mitochondrial myopathy.

86. 86. The method of any one of claims 76 and 84-85, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, i.e., maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

87. The autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Barro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castle disease, and the like. Mann's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia , Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS,Paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, 77. The method of claim 76, wherein the disease is selected from the group consisting of restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

88. 77. The method of claim 76, wherein the viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV), and herpes.

89. The skin disease may be acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infection of the nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, ichthyosis, 77. The method of claim 76, wherein the skin condition is selected from the group consisting of scabies, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (verrucae), polymorphous light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo.

90. 77. The method of claim 76, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, interstitial pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

91. The hemoglobinopathy may be "dominant" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α ＋ - Thalassemia (α ０ -thalassemia phenotype), hydrops fetalis with Hb Barth's disease, sickle cell anemia / sickle cell disease, sickle cell trait, sickle beta-thalassemia disease, alpha ＋ - Thalassemia, alpha ０ - Thalassemia, α-thalassemia with myelodysplastic syndrome, α-thalassemia / mental retardation (ATR) syndrome, β ０ - Thalassemia, beta ＋ 77. The method of claim 76, wherein the thalassaemia is selected from the group consisting of εγδβ-thalassemia, δ-thalassemia, γ-thalassemia, β-thalassemia major, β-thalassemia intermedia, δβ-thalassemia, and εγδβ-thalassemia.

92. The kidney disease may be Abderhalden-Kaufmann-Lignac syndrome (nephropathic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephronia, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, vasculitis Myolipoma, analgesic nephropathy, anorexia nervosa and kidney disease, angiotensin antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-associated glomerulonephritis, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, herbal medicine nephropathy, Balkan endemic nephropathy, arteriovenous malformations and fistulas of the urinary tract, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome, bath additives and acute kidney injury, polydipsia Potomania), beet urine, β-thalassemia nephropathy, bile cast nephropathy, BK-type polyomavirus nephropathy in the native kidney, bladder rupture, bladder sphincter dystonia, bladder tamponade, Border-Crosser's nephropathy, bourbon virus and acute kidney injury, burned sugarcane harvest and acute renal dysfunction, Byetta and renal failure, C1q nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepsis laureola Laureola poisoning, cannabinoid hyperemesis acute renal failure, cardiorenal syndrome, carfilzomib-induced kidney injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathy, Chinese herbal medicines and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathies, cocaine and the kidney, cold diuresis, colistin nephrotoxicity, collagenous glomerulopathy, collapsing glomerulopathy, CMV-related collapsing glomerulopathy associated with cART (combined antiretroviral therapy)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, renal pyramidal syndrome (Mainzer-Sardino syndrome or Sardino-Mainzer disease), contrast nephropathy, copper sulfate poisoning, renal cortical necrosis, crizotinib-associated acute kidney injury, crystal cryoglobulinemia, cryoglobulinemia, crystal globulin-induced nephropathy,Crystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (MPGN2), Dent's disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes and diabetic kidney disease, diabetes insipidus, nutritional supplements and renal failure, diffuse mesangial sclerosis, diuretics, Zhilin bean (Djenkol) Bean poisoning (Djenkolism), Down syndrome and kidney disease, addictive drugs and kidney disease, ureter duplication, EAST syndrome, Ebola and the kidney, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immunotactoid glomerulopathy, Frehley syndrome, fluid overload, hypervolemia, Focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal complications, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerular tubular reflux, renal diabetes, Goodpasture syndrome, green smoothie-purifying nephropathy, HANAC syndrome, Harvoni (ledipasvir / sofosbuvir combination)-induced kidney injury, hair dye ingestion and acute kidney injury, hantavirus-associated podocytopathy, heat stress nephropathy, hematuria (blood in urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus kidney disease, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), brown urine, paroxysmal nocturnal hemoglobinuria and hemosiderinosis associated with hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1β-related kidney disease, hepatorenal syndrome, herbal supplements and kidney disease, high blood pressure High blood pressure renal syndrome, hypertension and kidney disease, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial kidney disease, horseshoe kidney (fused kidney), Hunner's ulcer, hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic urticarial vasculitis syndrome, hypokalemia,Hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in cannabis users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, water diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated kidney disease, interstitial cystitis, bladder pain syndrome (questionnaire), interstitial nephritis, karyomegalic interstitial nephritis, Ivemark syndrome, JC virus nephropathy, Joubert syndrome, Ke Calcium-related bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirotic kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutations, lower back pain and hematuria, lupus, systemic lupus erythematosus, lupus kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody Lupus nephritis with systemic seropositivity, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated kidney disease, malignant hypertension, malakoplakia, McKittrick-Wheelock syndrome, MDMA (Molly, Ecstasy, 3,4-methylenedioxymethamphetamine) and renal failure, urethral meatal stenosis, medullary cystic kidney disease, uromodulin-associated nephropathy, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaureter, melamine toxicity and its kidney, MELAS syndrome, membranoproliferative glomerulonephritis, membranous Nephropathy, Membranous Glomerulopathy with Masked IgGκ Deposition, Mesoamerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate-Associated Renal Failure, Microscopic Polyangiitis, Milk-Alkali Syndrome, Minimal Change Disease, Monoclonal Gammopathy with Nephropathy, Dysproteinemia, Mouthwash Toxicity, MUC1 Nephropathy, Polycystic Dysplastic Kidney, Multiple Myeloma, Myeloproliferative Neoplasia and Glomerulopathy, Nail-Patella Syndrome, NARP Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Wandering Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, 9 / 11 and Renal Disease,Nodular glomerulosclerosis, Nongonococcal urethritis, Nutcracker syndrome, Oligomegalic glomerulopathy, Orofacial-Digital syndrome, Orotic aciduria, Orthostatic hypotension, Orthostatic proteinuria, Osmotic diuresis, Osmotic nephrosis, Ovarian hyperstimulation syndrome, Oxalate nephropathy, Page kidney, Papillary necrosis, Papillary-renal syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutations and kidney disease, Parvovirus B19 and the kidney, Peritoneal-renal syndrome, POEMS syndrome, Posterior urethral valve, Podocyte invagination glomerulopathy, Post-infectious glomerulonephritis, Post-streptococcal glomerulonephritis, Atypical post-infectious glomerulonephritis, Pseudo-IgA nephropathy Post-infectious glomerulonephritis (IgA dominant) (Post-infectious glomerulonephritis) (IgA-Dominant) Mimicking IgA Nephropathy, Polyarteritis nodosa, Polycystic Kidney Disease, Posterior Urethral Valve, Post-Obstructive Diuresis, Preeclampsia, Propofol Infusion Syndrome, Proliferative Glomerulonephritis with Monoclonal IgG Deposition (Nasr Disease), Propolis (Bee Resin)-Associated Renal Failure, Proteinuria (Protein in the Urinary Urine), Pseudohyperaldosteronism, Pseudohypobicarbonatemia, Pseudohypoparathyroidism, Pulmonary-Renal Syndrome, Pyelonephritis (Kidney Infection), Pyonephrosis, Pyridium and Renal Failure, Radiation Nephropathy, Ranolazine and Its Kidneys, Refeeding Syndrome, Reflux Nephropathy, Rapidly Progressive Glomerulonephritis, Renal Abscess, Perinephric Abscess, Renal Agenesis, Renal Arcuate Vein Microthrombosis Acute kidney injury, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation, autosomal dominant tubulointerstitial kidney disease, renin-secreting tumors (juxtaglomerular cell tumors), reset osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, bariatric surgery-related rhabdomyolysis, rheumatoid arthritis-associated kidney disease, sarcoidosis nephropathy, renal and cerebral salt wasting, schistosomiasis and glomerular disease, Schimke's immune dysplasia, scleroderma renal crisis, serpentine polycystic kidney disease (Serpentine) Fibula-Polycystic Kidney Syndrome, Exner Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Kidney Disease in Sri Lankan Farmers, Sjogren's Syndrome and Kidney Disease, Synthetic Cannabis Use and Acute Kidney Injury, Kidney Disease After Hematopoietic Cell Transplantation, Kidney Disease Associated with Stem Cell Transplantation, TAFRO Syndrome, Tea and Toast Hyponatremia,Tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal gammopathy-associated thrombotic microangiopathy, war nephritis, bladder trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular hypoplasia, immune complex-mediated tubulointerstitial nephritis caused by autoantibodies against the proximal tubule brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocele, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin-related 77. The method of claim 76, wherein the condition is selected from the group consisting of: tubular cast nephropathy, vasomotor nephropathy, vesicoenteric fistula, vesicoureteral reflux, VGEF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, von Hippel-Lindau disease, Waldenstrom's macroglobulinemic glomerulonephritis, warfarin-associated nephropathy, bee sting and acute kidney injury, Wegener's granulomatosis, granulomatosis with polyangiitis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatic-renal syndrome.

93. 77. The method of claim 76, wherein the hearing loss is selected from the group consisting of mitochondrial genetic non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or inherited hearing loss, hearing loss resulting from exposure to ototoxins, disease-induced hearing loss, and trauma-induced hearing loss.

94. 77. The method of claim 76, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

95. 95. The method of any one of claims 76-94, further comprising a second agent for treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

96. 75. A method of treating a disease associated with modulation of eIF2B activity or levels, eIF2α activity or levels, or the activity or levels of a component of the eIF2 pathway or ISR pathway in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of any one of claims 1 to 74, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.

97. 97. The method of claim 96, wherein the modulation comprises an increase in the activity or level of eIF2B, an increase in the activity or level of eIF2α, or an increase in the activity or level of a component of the eIF2 pathway or the ISR pathway.

98. 97. The method of claim 96, wherein the disease can be caused by a mutation in the sequence of a gene or protein associated with a component of the eIF2 pathway.

99. 75. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-74, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, in combination with an immunotherapeutic agent.

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