Modulators of integrated stress pathways

Abstract

To provide compounds, compositions and methods useful for modulating the integrated stress response (ISR) and treating related diseases; disorders and conditions.SOLUTION: The present invention features compounds, compositions, and methods for modulation of eIF2B (e.g., activation of eIF2B) and attenuation of ISR signaling pathways. In some embodiments, the invention features an eIF2B modulator (e.g., an eIF2B activator) comprising a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 62 / 332,278, filed May 5, 2016, which is incorporated herein by reference in its entirety. [Background technology]

[0002] In metazoans, diverse stress signals converge on a single phosphorylation event at serine 51 of a common effector, the translation initiation factor eIF2α. 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 collection of signaling pathways has been termed the "integrated stress response" (ISR) because they converge on the same molecular event. eIF2α phosphorylation results in the attenuation of 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 to GTP and the initiation factor Met-tRNA to form a ternary complex (eIF2-GTP-Met-tRNA i), which associates with the 40S ribosomal subunit, which scans the 5'UTR of mRNA to select the initiating AUG codon. Upon phosphorylation of its α-subunit, eIF2 becomes a competitive inhibitor of its GTP-exchange factor (GEF), eIF2B (Hinnebusch, AG and Lorsch, JR Cold Spring Harbor Perspect Biol (2012) 4(10)). The tight and non-productive binding of phosphorylated eIF2 to eIF2B prevents GTP loading into the eIF2 complex, thereby blocking ternary complex formation and reducing translation initiation (Krishnamoorthy, T. et al., Mol Cell Biol (2001) 21(15):5018-5030). Because eIF2B is less abundant than eIF2, phosphorylation of only a small fraction of total eIF2 dramatically affects eIF2B activity in cells. eIF2B is a complex molecular machine composed of five distinct subunits, eIF2B1 through eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with the partially homogeneous subunit eIF2B3, constitutes the "catalytic core" (Williams, D.D. et al., J. Biol. Chem. (2001) 276:24697-24703). The three remaining subunits (eIF2B1, eIF2B2, and eIF2B4) are also highly homogeneous with each other and form a "regulatory subcomplex" that provides a binding site for eIF2, the substrate of eIF2B (Dev, K. et al., Mol. Cell. Biol. (2010) 30:5218-5233). The exchange of GDP for GTP in eIF2 is catalyzed by its dedicated guanine nucleotide exchange factor (GEF), eIF2B. In cells, eIF2B exists as a decamer (B12B22B32B42B52) or a dimer of two pentamers (Gordiyenko, Y. et al., Nat Commun (2014) 5:3902; Wortham, N.C. et al., FASEB J (2014) 28:2225-2237). Molecules such as ISRIB interact with and stabilize the eIF2B dimeric conformation, enhancing its intrinsic GEF activity and reducing cell sensitivity to the cellular effects of eIF2α phosphorylation (Sidrauski, C. et al., eLife (2015) e07314; Sekine, Y. et al., Science (2015) 348:1027-1030). Thus, 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 in the prevention and / or treatment of a variety of diseases, such as neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. [Prior art documents] [Non-patent literature]

[0004] [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: 3902 [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] [Means for Solving the Problems]

[0005] The present invention features compounds, compositions, and methods for modulating eIF2B (e.g., activating eIF2B) and attenuating the ISR signaling pathway. In some embodiments, the present invention features an eIF2B modulator (e.g., an eIF2B activator) comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In other embodiments, the present invention features methods of using a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof for the treatment of a disease or disorder, e.g., a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with impaired function of eIF2B or a component in the ISR pathway (e.g., the eIF2 pathway).

[0006] In one aspect, the present invention provides a compound of formula (I): [ka] wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl, or a cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or a cubanyl is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently C1-C6 alkylene, C2-C6 alkenylene, 2- to 7-membered heteroalkylene, O, or NR C wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2- to 7-membered heteroalkylene is selected from 1 to 5 R X and optionally substituted by R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, silyloxy-C1-C6 alkyl; A and W are each independently aryl or 5-6 membered heteroaryl, where each phenyl or 5-6 membered heteroaryl is selected from the group consisting of 1 to 5 R Yand each R X is C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-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 , -S(O)2R D , -OS(O)R D , -OS(O)2R D , and G 2 each R is independently selected from the group consisting of Y is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, 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 , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or two R on adjacent atoms are independently selected from the group consisting of Y The groups, together with the atoms to which they are attached, consist of 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by 1 and G 2is independently a C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4- 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 and each R Z is 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 each R is independently selected from the group consisting of A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OH, or -C(O)OR D and;R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C together with the atoms to which they are attached, form 1 to 3 R Z forming a 3- to 7-membered heterocyclyl ring optionally substituted by D is independently C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl is selected from 1 to 5 R G and each R E are independently hydrogen, C-C alkyl, or halo-C-C alkyl; each R F are independently hydrogen, C-C alkyl, or halo; each R Gare independently aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R H and each R H is independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0007] In some embodiments, D is a bridged monocyclic cycloalkyl or cycloalkyl, each of which is selected from 1 to 4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cycloalkyl, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1 to 4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1 to 4 R X In some embodiments, D is optionally substituted with a group: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from one R X In some embodiments, R X is C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl, or tetrazolyl).

[0008] In some embodiments, D is 0 R X In some embodiments, D is substituted by [ka] is.

[0009] In some embodiments, L 1 and L 2 At least one of is independently 2 to 7 membered heteroalkylene, O, or NR C wherein the heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 Both of these can be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 are both C1-C6 alkylene or C2-C6 alkenylene, wherein each C1-C6 alkylene and C2-C6 alkenylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 Both have 1 to 5 R X and C2-C6 alkenylene optionally substituted by

[0010] In some embodiments, R X is C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SRE , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl, or tetrazolyl).

[0011] In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- *, CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and CH=CH- * are independently selected from L 2 is CH2O- * , CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2-* , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , -NHC(O)OCH2- * , O- * , NH- * , S(O)2CH2- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from *" indicates the points of attachment to A and W, respectively.

[0012] In some embodiments, t is 1. In some embodiments, t is 0.

[0013] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0014] In some embodiments, A and W each independently represent 1 to 5 R YIn some embodiments, A is phenyl and W is independently phenyl or heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is heteroaryl (e.g., monocyclic heteroaryl or bicyclic heteroaryl).

[0015] In some embodiments, W is a monocyclic heteroaryl. In some embodiments, W is a bicyclic heteroaryl. In some embodiments, W is a 10-membered heteroaryl, a 9-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, W is a nitrogen-containing heteroaryl, an oxygen-containing heteroaryl, or a sulfur-containing heteroaryl.

[0016] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R YIn some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] are independently selected from

[0017] In some embodiments, A and W are each: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0018] In some embodiments, A is: [ka] is selected from.

[0019] In some embodiments, W is: [ka] is selected from.

[0020] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0021] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0022] In some embodiments, each R Yare independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0023] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0024] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Zis independently C1-C6 alkyl (e.g., CH3).

[0025] In one aspect, the present invention provides a compound of formula (Ia): [ka] wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl, or a cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or a cubanyl is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently a C1-C6 alkylene, a C2-C6 alkenylene, or a 2- to 7-membered heteroalkylene, wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2- to 7-membered heteroalkylene is selected from 1 to 5 R X and optionally substituted by R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, silyloxy-C1-C6 alkyl; A and W are each independently phenyl or 5- to 6-membered heteroaryl, wherein each phenyl or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 5 R Y and each R X is 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 each R is independently selected from the group consisting ofY is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, 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 , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or two R on adjacent atoms are independently selected from the group consisting of Y The groups, together with the atoms to which they are attached, consist of 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by 1 is independently a C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4- 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 and each R Z is 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 each R is independently selected from the group consisting of A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C(O)NRB R C , -C(O)R D , -C(O)OH, or -C(O)OR D and;R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C together with the atoms to which they are attached, form 1 to 3 R Z forming a 3- to 7-membered heterocyclyl ring optionally substituted by D is independently C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl is selected from 1 to 5 R G and each R E are independently hydrogen, C-C alkyl, or halo-C-C alkyl; each R F are independently hydrogen, C-C alkyl, or halo; each R G are independently aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R H and each R H is independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0026] In some embodiments, the compound of formula (I) above has formula (Ib): [ka] wherein D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.1]heptane, each of which is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * and "- * " indicate the points of attachment to A and W, respectively; R 1 and R 2are each independently hydrogen, CH, CHCHOH, or CHCHOSi(CH)C(CH); A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y and each R X are CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, -SCH3, or G 2 each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 or two R on adjacent atoms Y groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which contains one to two R X and optionally substituted by G 1 and G 2 is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is selected from the group consisting of 1 to 2 R Z and each R D is 1 to 5 R G CHO optionally substituted by G are independently 1 to 5 RH pyridyl optionally substituted by H is independently CF; each R Z is independently CH3; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0027] In some embodiments, the compound of formula (I) above has the formula (Ic): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0028] In some embodiments, the compound of formula (I) above has the formula (Id): [ka] In the formula, L 1 , L 2 , A, and W are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0029] In some embodiments, the compound of formula (I) above has the formula (Ie): [ka] In the formula, L 2 ,A,W,R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0030] In some embodiments, the compound of formula (I) above has the formula (If): [ka] In the formula, L 2 , W, R Y , R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0031] In some embodiments, the compound of formula (I) above has the formula (Ig): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0032] In some embodiments, the compound of formula (I) above has the formula (Ih): [ka] In the formula, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0033] In some embodiments, the compound of formula (I) above has the formula (Ii): [ka] In the formula, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0034] In some embodiments, the compound of formula (I) above has the formula (Ij): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0035] In some embodiments, the compound of formula (I) above has the formula (Ik): [ka] In the formula, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0036] In some embodiments, the compound of formula (I) above has the formula (Il): [ka] In the formula, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0037] In some embodiments, the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0038] In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il)) or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutically acceptable composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable carrier.

[0039] In another aspect, the invention features a method of treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of a component in the eIF2B or ISR pathway (e.g., the eIF2 pathway) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition thereof.

[0040] In some embodiments, the method comprises treating a neurodegenerative disease. In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, cerebral leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, intellectual disability syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, Parkinson's disease, progressive supranuclear palsy, tauopathy, or prion disease. In some embodiments, the neurodegenerative disease comprises vanishing white matter disease. In some embodiments, the neurodegenerative disease comprises a psychiatric disorder, such as agoraphobia, Alzheimer's disease, anorexia nervosa, memory loss, anxiety disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, delusions, Diogenes syndrome, dyspraxia, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobic disorder, schizophrenia, seasonal affective disorder, schizophrenic personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette's syndrome, or trichotillomania. In some embodiments, the neurodegenerative disease comprises a disease or disorder with symptoms of cognitive impairment or cognitive decline, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, autism, frontotemporal dementia, dementia (e.g., HIV-associated dementia or Lewy body dementia), age-associated dementia, chronic traumatic encephalopathy, HIV-induced neurocognitive dysfunction, HIV-associated neurocognitive disorder, hypoxic injury (e.g., early brain injury, chronic perinatal hypoxia), traumatic brain injury, or postoperative cognitive dysfunction. In some embodiments, the neurodegenerative disease comprises intellectual disability syndrome. In some embodiments, the neurodegenerative disease comprises mild cognitive impairment.

[0041] In some embodiments, the method comprises treating cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells. In some embodiments, the method comprises treating cancer in combination with a chemotherapeutic agent for improving memory (e.g., long-term memory).

[0042] In some embodiments, the method comprises treating an inflammatory disease. In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, traumatic brain injury, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 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, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, or atopic dermatitis.

[0043] In some embodiments, the method comprises treatment of a musculoskeletal disorder, which comprises muscular dystrophy, multiple sclerosis, Friedreich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscle atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, myalgia, repetitive strain injury, or paralysis.

[0044] In some embodiments, the method includes treating a metabolic disease, including nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0045] In another aspect, the invention features a method for treating a disease or disorder associated with modulation (e.g., reduction) of eIF2B activity or levels, modulation (e.g., reduction) of eIF2α activity or levels, modulation (e.g., increase) of eIF2α phosphorylation, modulation (e.g., increase) of phosphorylated eIF2α pathway activity, or modulation (e.g., increase) of ISR activity in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition thereof. In some embodiments, the disease may be caused by a mutation in a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway or the ISR pathway).

[0046] In another aspect, the invention features a method for treating leukodystrophy, such as vanishing white matter disease (VWMD) or childhood ataxia due to central nervous system hypomyelination. In some embodiments, the leukodystrophy is characterized by an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a tRNA synthetase. In some embodiments, administering a compound of Formula (I) improves eIF2B activity in a subject with leukodystrophy, such as vanishing white matter disease (VWMD) or childhood ataxia due to central nervous system hypomyelination.

[0047] In another aspect, the invention features a method of treating a disease or disorder associated with an amino acid mutation (e.g., an amino acid deletion, addition, or substitution) in a gene or gene product (e.g., RNA or protein) that regulates (e.g., reduces) protein synthesis. In some embodiments, administration of a compound of Formula (I) improves the remaining GEF activity of a mutant GEF complex in a subject.

[0048] In another aspect, the invention features a composition for use in treating a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, musculoskeletal disease, or metabolic disease in a subject, the composition including a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0049] In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, cerebral leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, intellectual disability syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, Parkinson's disease, progressive supranuclear palsy, tauopathy, or prion disease. In some embodiments, the neurodegenerative disease comprises vanishing white matter disease. In some embodiments, the neurodegenerative disease comprises a psychiatric disorder, such as agoraphobia, Alzheimer's disease, anorexia nervosa, memory loss, anxiety disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, delusions, Diogenes syndrome, dyspraxia, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobic disorder, schizophrenia, seasonal affective disorder, schizophrenic personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette's syndrome, or trichotillomania. In some embodiments, the neurodegenerative disease comprises a disease or disorder with symptoms of cognitive impairment or cognitive decline, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, autism, frontotemporal dementia, dementia (e.g., HIV-associated dementia or Lewy body dementia), age-associated dementia, chronic traumatic encephalopathy, HIV-induced neurocognitive dysfunction, HIV-associated neurocognitive disorder, hypoxic injury (e.g., early brain injury, chronic perinatal hypoxia), traumatic brain injury, or postoperative cognitive dysfunction. In some embodiments, the neurodegenerative disease comprises intellectual disability syndrome. In some embodiments, the neurodegenerative disease comprises mild cognitive impairment.

[0050] In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells. In some embodiments, the method comprises treating the cancer in combination with a chemotherapeutic agent for improving memory (e.g., long-term memory).

[0051] In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, traumatic brain injury, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 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, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, or atopic dermatitis.

[0052] In some embodiments, the musculoskeletal disorder comprises muscular dystrophy, multiple sclerosis, Friedreich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscle atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, myalgia, repetitive strain injury, or paralysis.

[0053] In some embodiments, the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0054] In another aspect, the invention features a composition for use in treating a disease or disorder associated with modulation (e.g., reduction) of eIF2B activity or levels, modulation (e.g., reduction) of eIF2α activity or levels, modulation (e.g., increase) of eIF2α phosphorylation, modulation (e.g., increase) of phosphorylated eIF2α pathway activity, or modulation (e.g., increase) of ISR activity in a subject, the composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the disease can be caused by a mutation in a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway or the ISR pathway).

[0055] In another aspect, the present invention features a composition for use in treating leukodystrophy, such as vanishing white matter disease (VWMD) or childhood ataxia due to central nervous system hypomyelination. In some embodiments, the leukodystrophy is characterized by an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a tRNA synthetase. In some embodiments, a composition comprising a compound of Formula (I) improves eIF2B activity in a subject with leukodystrophy, such as vanishing white matter disease (VWMD) or childhood ataxia due to central nervous system hypomyelination.

[0056] In another aspect, the invention features compositions for use in treating diseases or disorders associated with amino acid mutations (e.g., amino acid deletions, additions, or substitutions) in genes or gene products (e.g., RNA or proteins) that regulate (e.g., reduce) protein synthesis. In some embodiments, a composition comprising a compound of Formula (I) improves the remaining GEF activity of a mutant GEF complex in a subject. [The present invention 1001] Formula (I): TIFF2026009986000023.tif1982Formula (I) During the ceremony: D is a bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or cubanyl is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently C1-C6 alkylene, C2-C6 alkenylene, 2- to 7-membered heteroalkylene, O, or NR C wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2- to 7-membered heteroalkylene is selected from 1 to 5 R X is optionally substituted by; R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, or silyloxy-C1-C6 alkyl; A and W are each independently phenyl or 5- to 6-membered heteroaryl, wherein each phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R Y is optionally substituted by; Each R X is C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-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 , -S(O)2R D , -OS(O)R D , -OS(O)2R D , and G 2 independently selected from the group consisting of: Each R Y is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, 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 , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 independently selected from the group consisting of: Two R on adjacent atoms Y The groups, together with the atoms to which they are attached, consist of 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by each G 1 and G 2 is independently a C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4- 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 is optionally substituted by; Each R Z is 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 Dindependently selected from the group consisting of: Each R A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OH, or -C(O)OR D and; R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C together with the atoms to which they are attached, form 1 to 3 R Z forming a 3- to 7-membered heterocyclyl ring optionally substituted by Each R D is independently C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl is selected from 1 to 5 R G is optionally substituted by; 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 aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R H is optionally substituted by; Each R H is independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1002] 1001. A compound of this invention wherein D is a bridged monocyclic cycloalkyl or cycloalkyl, each of which is optionally substituted with 1 to 4 Rx groups. [The present invention 1003] D is a bridged 4-6 membered monocyclic cycloalkyl or cycloalkyl, each of which is selected from 1-4 R X 1003. The compound of any one of claims 1001 to 1002, optionally substituted with a group. [The present invention 1004] D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, each of which is selected from 1 to 4 R X The compound of any one of 1001 to 1003, optionally substituted with a group. [The present invention 1005] D is: Any of compounds 1001 to 1004 of the present invention selected from TIFF2026009986000024.tif43151. [The present invention 1006] D is: Any of compounds 1001 to 1005 of the present invention selected from TIFF2026009986000025.tif73155. [The present invention 1007] D is one R X The compound of any one of claims 1001 to 1006, wherein the compound is substituted by: [The present invention 1008] R X C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). [The present invention 1009] G 2 is aryl or 5-6 membered heteroaryl (e.g., oxadiazolyl, or tetrazolyl). [The present invention 1010] D is 0 R X The compound of any one of claims 1001 to 1006, wherein the compound is substituted by: [The present invention 1011] D Any of compounds 1001 to 1006 and 1010 of the present invention, which is TIFF2026009986000026.tif27108. [The present invention 1012] L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X The compound of any one of claims 1001 to 1011, wherein the compound is a 2- to 7-membered heteroalkylene optionally substituted by: [The present invention 1013] L 1 and L 2 Both of these can be independently selected from 1 to 5 R X The compound of any one of claims 1001 to 1012, wherein the compound is a 2- to 7-membered heteroalkylene optionally substituted by: [The present invention 1014] L 1 and L 2 is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 RX The compound of any one of claims 1001 to 1013, optionally substituted by: [The present invention 1015] Each R X are independently C1-C6 alkyl, oxo, or -C(O)R D (e.g., CH3, oxo, or C(O)CH3). [The present invention 1016] L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * 6. The compound of any one of claims 1001 to 1015, wherein "" indicates the points of attachment to A and W, respectively. [The present invention 1017] L 1 But CH2O- * and CH=CH- * are independently selected from L 2 But CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * 1016. The compound of any one of claims 1001 to 1016, wherein "" indicates the points of attachment to A and W, respectively. [The present invention 1018] The compound of any one of claims 1001 to 1017, wherein t is 1. [The present invention 1019] The compound of any one of claims 1001 to 1017, wherein t is 0. [The present invention 1020] R 1 and R 2is each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. [The present invention 1021] R 1 and R 2 is independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. [The present invention 1022] R 1 and R 2 are independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * 22. The compound of any one of claims 1001 to 1021, wherein "-" indicates the point of attachment to the nitrogen atom. [The present invention 1023] R 1 and R 2 is independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The compound of any one of claims 1001 to 1022, wherein "-" indicates the point of attachment to the nitrogen atom. [The present invention 1024] R 1 and R 2 and each independently represent hydrogen. [The present invention 1025] A and W each independently represent 1 to 5 R Y The compound of any one of claims 1001 to 1024, wherein the compound is phenyl or 5-6 membered heteroaryl optionally substituted by a group. [The present invention 1026] A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y 10. The compound of any one of claims 1001 to 1024, optionally substituted with a group. [The present invention 1027] A and W are respectively: Any of compounds 1001 to 1025 of the present invention independently selected from TIFF2026009986000027.tif182164. [The present invention 1028] A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each represent 1 to 5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 The compound of any one of claims 1001 to 1027 of the present invention, [The present invention 1029] A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y 1001-1028. A compound of any one of claims 1001-1028, optionally substituted with: [The present invention 1030] A: Any of compounds 1001 to 1029 of the present invention selected from TIFF2026009986000028.tif74157. [The present invention 1031] W is: Any of compounds 1001 to 1030 of the present invention selected from TIFF2026009986000029.tif180153. [The present invention 1032] Each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 The compound of any one of claims 1001 to 1031 of the present invention, [The present invention 1033] A and W are each two R on adjacent atoms. Y and the two R Y together with the atoms to which they are attached, form 1 to 5 R X 3. The compound of any one of claims 1001 to 1031, wherein the compound forms a 3- to 7-membered fused cycloalkyl, 3- to 7-membered fused heterocyclyl, fused aryl, or 5- to 6-membered fused heteroaryl ring, optionally substituted by: [The present invention 1034] The two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X 1033 compounds of the present invention optionally substituted by: [This invention 1035] Each R Xis independently C1-C6 alkyl or halo (e.g., CH3 or fluoro). [The present invention 1036] G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z 1001-1035. The compound of any one of claims 1001-1035, optionally substituted by: [This invention 1037] Each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). [The present invention 1038] The compound of formula (I) has formula (Ib): TIFF2026009986000030.tif3188 formula: D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, or bicyclo(bicycle)[3.1.1]heptane, each of which contains 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- *, CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * and "- * " indicates the points of attachment to A and W, respectively; R 1 and R 2 are each independently hydrogen, CH3, CH2CH2OH, or CH2CH2OSi(CH3)2C(CH3)3; A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y optionally substituted by a group; Each R X are CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, -SCH3, or G 2 are independently selected from; Each R Yare independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is; or Two R on adjacent atoms Y groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which contains one to two R X is optionally substituted by; G 1 and G 2 is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is selected from the group consisting of 1 to 2 R Z is optionally substituted by; Each R D is 1 to 5 R G CHO optionally substituted by Each R G are independently 1 to 5 R H pyridyl optionally substituted by Each R H are independently CF3; Each R Z are independently CH3; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1039] The compound of formula (I) has formula (Ic): TIFF2026009986000031.tif3491, L 1, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1040] The compound of formula (I) has the formula (Id): TIFF2026009986000032.tif2985, L 1 , L 2 , A, and W are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1041] The compound of formula (I) has formula (Ie): TIFF2026009986000033.tif3491, L 2 ,A,W,R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1042] The compound of formula (I) has the formula (If): TIFF2026009986000034.tif3399, L 2 , W, R Y , R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1043] The compound of formula (I) has the formula (Ig): TIFF2026009986000035.tif3485, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1044] The compound of formula (I) has formula (Ih): TIFF2026009986000036.tif3387, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1045] The compound of formula (I) has the formula (Ii): TIFF2026009986000037.tif35101, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1046] The compound of formula (I) is represented by formula (Ij): TIFF2026009986000038.tif3387, L 1 , L 2 , R 1 , R 2,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1047] The compound of formula (I) has the formula (Ik): TIFF2026009986000039.tif3285, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1048] The compound of formula (I) has the formula (Il): TIFF2026009986000040.tif33100, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1049] A compound of any of the preceding inventions selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1050] A pharmaceutically acceptable composition comprising any of the preceding compounds of the invention and a pharmaceutically acceptable carrier. [This invention 1051] 1. A composition for use in treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, or a metabolic disease in a subject, the composition comprising any compound of formula (I) of the preceding invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [This invention 1052] The composition of the present invention 1051, wherein the neurodegenerative disease comprises cerebral leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction, or brain injury (e.g., traumatic brain injury or toxicant-induced brain injury). [This invention 1053] The composition of any of claims 1051 or 1052, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, multiple sclerosis, Parkinson's disease, or prion disease. [This invention 1054] The composition of any one of claims 1051 to 1053, wherein the neurodegenerative disease includes vanishing white matter disease. [This invention 1055] The composition of claim 1051, wherein said cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells. [This invention 1056] The inflammatory disease is selected from the group consisting of postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, and chlamydia. The compositions of the present invention 1051 include Rohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. [This invention 1057] The composition of the present invention 1051, wherein the musculoskeletal disease comprises muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, or myotonic 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, fasciculations-in-ataxia syndrome, Friedreich's ataxia, muscle wasting diseases (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis. [This invention 1058] The composition of the present invention 1051, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. [This invention 1059] Any of the compositions of inventions 1051 to 1058, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition thereof, in combination with a second agent (e.g., an agent for treating cancer, a neurodegenerative disease, leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway). [The present invention 1060] A composition for use in 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 the ISR pathway, comprising any compound of formula (I) of the preceding invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [The present invention 1061] The composition of claim 1060, wherein said modulation comprises increased eIF2B activity or level, increased eIF2α activity or level, or increased activity or level of a component of the eIF2 pathway or the ISR pathway. [The present invention 1062] The composition of claim 1060, wherein the disease can be caused by a mutation to a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway). DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention features compounds, compositions, and methods including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof for use, for example, in modulating (e.g., activating) eIF2B and attenuating the ISR signaling pathway.

[0058] definition chemical definition Specific functional groups and chemical term definitions are described in more detail below. Chemical elements are defined in Elements, CAS version, Handbook of Chemistry and Physics, 75 th Functional groups are generally defined as described herein. General principles of organic chemistry, as well as specific functional sites and reactivities, are also 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.

[0059] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0060] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as 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-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, 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 additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0061] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" refer to a compound that contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% by weight of an enantiomer. In certain embodiments, weights are based on the combined weight of all enantiomers or stereoisomers of a compound.

[0062] 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 up to 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. 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 up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated without or with little to no excipients or carriers.

[0063] The compounds described herein may contain one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3H (T or tritium) and may be in any isotopic form; 12 C. 13 C, and 14 C may be in any isotopic form, including 16 O and 18 It may be in any isotopic form, including O; and the like.

[0064] The articles "a" and "an" may be used herein to refer to one 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 more than one analog.

[0065] When a range of values ​​is listed, the range is intended to include each value and subrange within the 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.

[0066] The following terms are intended to have the meanings presented together below and are useful in understanding the detailed description and intended scope of the present invention.

[0067] "Alkyl" means a straight-chain or branched saturated hydrocarbon group having 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), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tert-amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, such as from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group can be an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-6 Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0068] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, as exemplified, but not limited to, by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from 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 within the moiety.

[0069] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, 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 10 In 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 (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include ethynyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the above C 2-4Alkenyl groups include 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 of an alkenyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, such as from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group can be an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-6 It is alkenyl.

[0070] "Aryl" refers to an aromatic ring system ("C6-C 14 "C6 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 π electrons shared in the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms, as given in "aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl"; e.g., phenyl). 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracyl). Aryl groups include, for example, C-C 10 aryl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C-C 14In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0071] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, halo-C1-C8 alkyl, haloxy-C1-C8 alkyl, cyano, hydroxy, alkoxyC1-C8 alkyl, and amino.

[0072] Representative examples of substituted aryl include: [ka] In the formula, R 56 and R 57 may be hydrogen, and R 56 and R 57 At least one of the above is C1-C8 alkyl, halo-C1-C8 alkyl, 4- to 10-membered heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 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)-alkyl, S-aryl, S(O)-aryl, S(O)-aryl; or R 56 and R 57 may be connected to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from groups N, O, or S.

[0073] Other representative aryl groups having a fused heterocyclyl group include: [ka] where each W' is C(R 66 )2, NR 66 , O, and S; each Y' is selected from carbonyl, NR 66 , O and S; R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0074] "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, thianaphthalyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, and pyrrolyl. , 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.

[0075] "Halo" or "halogen," independently 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 a fluoride, chloride, bromide, or iodide atom. In certain embodiments, a halo group is either fluorine or chlorine.

[0076] Also, for example, the term "haloalkyl" is meant 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.

[0077] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, 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, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom 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)2-CH 2、Examples include -CH2-CH2-S(O)2-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 to three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. "Heteroalkyl" is listed, followed by a specific heteroalkyl group, such as -CHO, -NR B R C When heteroalkyl and -CHO or -NR are listed, B R C It will be understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Rather, such specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, such as, for example, -CHO, -NR B R C etc. should not be construed herein as being exclusive.

[0078] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as 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 "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene groups, heteroatoms can also 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)-.

[0079] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, if valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring is fused to one or more aryl groups, as defined above, where the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom at the point of attachment (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be in either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety.

[0080] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms attached in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms attached in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms attached in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 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 1 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.

[0081] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, 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.

[0082] Representative heteroaryl examples include the following formulae: [ka] where each Y is a carbonyl, N, NR65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0083] "Cycloalkyl" refers to a group of 3 to 10 ring carbon atoms ("C3-C"). 10 "Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 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 "membered" refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, without limitation, 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, without limitation, 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 includes, but is not limited to, the above C3-C8 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 the above examples illustrate, in certain embodiments, a cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, e.g., a bicyclic ring system ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring is fused to one or more aryl groups, as defined above, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbon atoms is indicated followed by the number of carbon atoms in the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0084] 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-C10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the C5-C6 cycloalkyl groups described above, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the C3-C6 cycloalkyl groups described above, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a 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.

[0085] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, if valence allows. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic ring 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 includes ring systems in which a heterocyclyl ring is fused to one or more cycloalkyl groups, as defined above, where the point of attachment is on the cycloalkyl or heterocyclyl ring, or ring systems in which a heterocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members is indicated followed by the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyls, where the term "membered" 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 ("unsubstituted heterocyclyl") or substituted with one or more substituents ("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 3-10 membered heterocyclyl.

[0086] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 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, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0087] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfanyl, disulfanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0088] Specific examples of heterocyclyl groups are illustrated in the following examples: [ka] Here, each W is 67 , C(R 67 )2, NR 67 , O, and S; each Y is selected from NR 67 , O, and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 and aryl and 5- to 10-membered heteroaryl. These heterocyclyl rings 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.

[0089] 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.

[0090] "Amino" is the radical -NR 70 R 71 where R 70 and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl. In some embodiments, amino refers to NH2.

[0091] "Cyano" refers to the radical -CN.

[0092] "Hydroxy" refers to the radical --OH.

[0093] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted as defined herein (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). 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 a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo a transformation, such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in a given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, e.g., with any substituent described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0094] Two or more substituents may be optionally connected to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found to be attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent ring members of the base structure. For example, two ring-forming substituents attached to adjacent ring members of the cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single ring member of the base structure. For example, two ring-forming substituents attached to a single ring member of the cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent ring members of the base structure.

[0095] A "counterion" or "anionic counterion" is a negatively charged group associated with 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, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0096] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present invention has 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 neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present invention has 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 neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those 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, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginates, 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 that allow the compounds to be converted 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 form. In other cases, the preparation may be a lyophilized powder in a first buffer, e.g., 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH range of 4.5 to 5.5, combined with a second buffer prior to use.

[0097] Thus, the compounds of the present invention may exist as salts with, for example, pharmaceutically acceptable acids. The present invention includes 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 may be prepared by methods known to those skilled in the art.

[0098] 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. Certain physical properties, for example, solubility in polar solvents, differ from the parent form of the compound in the various salt forms.

[0099] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs can also 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 a suitable enzyme or chemical reagent.

[0100] Certain compounds of the present invention can exist in unsolvated form as well as solvated form, including hydrated form. Generally, solvated form is equivalent to unsolvated form and is 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 use contemplated by the present invention and are considered to be within the scope of the present invention.

[0101] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Examples of acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.).

[0102] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-, are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to encompass compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, 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 include both E and Z geometric isomers.

[0103] 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 in the structural arrangement or configuration of the atoms.

[0104] 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.

[0105] 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.

[0106] The term "treat" or "treatment" refers to any indication of success in treating or ameliorating an injury, disease, medical condition, or state, including any objective or subjective parameter, such as relief; alleviation; reduction in symptoms or an improvement in the patient's tolerance of the injury, medical condition, or state; slowing the rate of degeneration or decline; reducing wasting at the end point of degeneration; or an improvement in the patient's physical or mental health. 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, cancer of secretory cells), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophy (e.g., vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system), post-operative cognitive dysfunction, traumatic brain injury, intellectual disability syndrome, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with impaired function of eIF2B or components in signal transduction or signaling pathways, including ISR activity and decreased eIF2 pathway activity.For example, certain methods herein treat cancer by reducing or decreasing or preventing the onset, growth, metastasis, or progression of cancer, or reducing the symptoms of cancer; treating neurodegeneration by improving mental health, increasing mental function, delaying the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive ability, reducing loss of cognitive ability, improving memory, reducing memory decline, reducing symptoms of neurodegeneration, or prolonging survival; reducing symptoms of vanishing white matter disease, or reducing white matter loss, or reducing myelin loss. Treating vanishing white matter disease by reducing or increasing the amount of myelin or increasing the amount of white matter; Treating childhood ataxia due to central nervous system hypomyelination by reducing the symptoms of central nervous system hypomyelination or by increasing the level of myelin or by reducing myelin loss; Treating intellectual disability syndrome by reducing the symptoms of intellectual disability syndrome; Treating inflammatory diseases by treating the symptoms of inflammatory diseases; Treating musculoskeletal diseases by treating the symptoms of musculoskeletal diseases; Or Treating metabolic diseases by treating the symptoms of metabolic diseases. Symptoms of the diseases, disorders, or conditions described herein (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or conditions or diseases associated with dysfunction of eIF2B or components in signal transduction pathways, including the eIF2 pathway, eIF2α phosphorylation, or ISR pathway) are known or can be determined by those skilled in the art. The term "treat" and its conjunctions include prevention of injury, condition, state, or disease (e.g., preventing the occurrence of one or more symptoms of a disease, disorder, or condition described herein).

[0107] An "effective amount" is an amount sufficient to achieve the stated purpose (e.g., achieve the effect of administration, treat a disease, reduce enzyme activity, increase enzyme activity, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, and 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, has the intended preventive effect, for example, prevents or delays the onset (or recurrence) of an injury, disease, symptom, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, symptom, or condition, or a symptom thereof. A complete preventive effect does not necessarily occur by administering a single dose, but may occur only after administering a series of doses. Therefore, 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 of ordinary skill 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).

[0108] "Reduction" (and grammatical equivalents of this phrase) of a symptom or symptoms means a decrease in the severity or frequency of the symptom(s), or elimination of the symptom(s).

[0109] The term "associated with" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., a disease or disorder described herein, e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with impaired function of eIF2B or components in a signal transduction pathway, including the eIF2 pathway, eIF2α phosphorylation, or ISR pathway) means that the disease is caused (in whole or in part) or the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function. For example, symptoms of a disease or condition associated with impaired function of eIF2B can be symptoms resulting (in whole or in part) from decreased eIF2B activity (e.g., decreased eIF2B activity or level, increased eIF2α phosphorylation, or activity of phosphorylated eIF2α, or reduced eIF2 activity, or increased activity of phosphorylated eIF2α signal transduction or ISR signaling pathway). As used herein, something described as associated with a disease, when it is a causative agent, can be a target for treating the disease. For example, diseases associated with decreased eIF2 activity or eIF2 pathway activity may be treated with an agent (e.g., a compound described herein) effective for increasing the level or activity of eIF2 or the eIF2 pathway, or phosphorylated eIF2α activity or a decrease in the ISR pathway. For example, diseases associated with phosphorylated eIF2α may be treated with an agent (e.g., a compound described herein) effective for decreasing the level of phosphorylated eIF2α or the activity of downstream components or effectors of phosphorylated eIF2α. For example, diseases associated with eIF2α may be treated with an agent (e.g., a compound described herein) effective for increasing the level of eIF2 or the activity of downstream components or effectors of eIF2.

[0110] "Control" or "control experiment" is used according to its ordinary and accustomed meaning to refer to an experiment in which the experimental subject or agent is treated identically to a parallel experiment except for the omission of the experimental procedure, agent, or variable. In some cases, a control is used as a standard of comparison in evaluating the effectiveness of an experiment.

[0111] "Contacting" is used according to its normal and ordinary meaning and refers to the process of allowing at least two different species (e.g., chemical compounds, including biomolecules, or cells) to come into sufficient proximity to react, interact, or physically come into contact. However, it should be recognized that the resulting reaction product may be produced from a reaction between added reagents or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture. The term "contacting" may include allowing two species to react, interact, or physically come into contact, and the two species may be 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 includes allowing a compound described herein to interact with a protein or enzyme involved in a signaling pathway (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway).

[0112] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, in reference to protein-inhibitor (e.g., antagonist) interaction, refer to negatively affecting (e.g., decreasing) the activity or function of a 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 reduction in the activity of a signal transduction or signaling pathway. As such, inhibition includes, at least in part, partially, or fully, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction or signaling pathway (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway, a pathway activated by eIF2α phosphorylation, or the ISR pathway). Thus, inhibition may include, at least in part, partially or wholly, reducing stimulation, reducing or reducing activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or protein abundance increased in disease (e.g., eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway, each associated with cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease).Inhibition may include, at least in part, partially, or in whole, decreasing stimulation, decreasing or reducing activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity, or the amount of a protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) that may regulate the level of another protein or increase cell survival (e.g., decreasing phosphorylated eIF2α pathway activity may increase cell survival in cells that may or may not have increased phosphorylated eIF2α pathway activity compared to non-disease controls, or decreasing eIF2α pathway activity may increase cell survival in cells that may or may not have increased eIF2α pathway activity compared to non-disease controls).

[0113] As defined herein, the terms "activation," "activate," "activating," and the like, in reference to protein-activator (e.g., agonist) interaction, mean positively affecting (e.g., increasing) the activity or function of a 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 or signaling pathway (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway). Thus, activation may involve, at least in part, partially, or wholly, increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzymatic activity, or protein abundance that is decreased in a 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 may involve, at least in part, partially, or wholly, increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzymatic activity, or protein abundance that may regulate the level of another protein or increase cell survival (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) (e.g., increased eIF2α activity may increase cell survival in cells that may or may not have reduced eIF2α activity compared to non-disease controls).

[0114] 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 can result in a reduction in the severity of one or more symptoms of a disease associated with eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway (e.g., 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 may benefit from modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway (e.g., a decrease in the level or activity of a component of eIF2B, eIF2α, or eIF2 pathway).

[0115] The term "modulator," as used herein, refers to the regulation (e.g., increase or decrease) of the level of a target molecule or the function of a target molecule. In embodiments, the modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an anti-cancer agent. In embodiments, the modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is a neuroprotective agent. In embodiments, the modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is a memory enhancer. In embodiments, the 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, the modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an anti-inflammatory agent. In some embodiments, the modulator of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway is an analgesic.

[0116] A "patient" or "subject" in need refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human. In some embodiments, the patient is a domesticated 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 cow. 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 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 person. In some embodiments, the patient is a geriatric mammal. In some embodiments, the patient is a geriatric patient.

[0117] A "disease," "disorder," or "condition" refers to the condition or state of a patient or subject that may be treated by the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein involve the reduction or elimination of one or more symptoms of a disease, disorder, or condition, e.g., through administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0118] The term "signaling pathway," as used herein, refers to a series of interactions between cellular and optionally extracellular elements (e.g., proteins, nucleic acids, small molecules, ions, lipids) that propagate a change from one element to one or more other elements, which may then propagate the change to additional elements, and optionally be propagated to other signaling pathway elements.

[0119] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate administration of an active agent to a subject and facilitate absorption by the subject, and that can be included in the compositions of the present invention without causing significant toxic side effects in the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, can be mixed with auxiliary substances that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring substances, and / or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0120] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier, such as providing a capsule in which the active ingredient is surrounded by the carrier, either with or without other carriers, thus combining the active ingredient with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0121] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or implantation of a delayed-release device, such as a mini-osmotic pump, to a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration can include, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery forms include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administering," it is meant 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 treatments for neurodegenerative diseases). The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds individually or in combination (more than one compound or agent). Thus, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation) if desired.

[0122] 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 related to Entrez gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq(protein) NP_751945. eIF2B5 refers to a protein related to Entrez gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq(protein) NP_003898.

[0123] The terms "eIF2alpha," "eIF2a," or "eIF2α" are used interchangeably and refer to the protein "eukaryotic translation initiation factor 2 alpha subunit eIF2S1." In embodiments, "eIF2alpha," "eIF2a," or "eIF2α" refers to the human protein. The terms "eIF2alpha," "eIF2a," or "eIF2α" also include 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.

[0124] compound In one aspect, the present invention provides a compound of formula (I): [ka] wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl, or a cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or a cubanyl is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently C1-C6 alkylene, C2-C6 alkenylene, 2- to 7-membered heteroalkylene, O, or NR C wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2- to 7-membered heteroalkylene is selected from 1 to 5 R X and optionally substituted by R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, silyloxy-C1-C6 alkyl; A and W are each independently aryl or 5-6 membered heteroaryl, where each phenyl or 5-6 membered heteroaryl is selected from the group consisting of 1 to 5 R Y and each R X is 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 , -S(O)2R D , -OS(O)R D , -OS(O)2RD and phenyl, and 5- to 6-membered heteroaryl; each R Y is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, 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 , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or two R on adjacent atoms are independently selected from the group consisting of Y The groups, together with the atoms to which they are attached, consist of 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by 1 is independently a C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4- 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 and each R Z is 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 each R is independently selected from the group consisting ofA are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OH, or -C(O)OR D and;R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C together with the atoms to which they are attached, form 1 to 3 R Z forming a 3- to 7-membered heterocyclyl ring optionally substituted by D is independently C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl is selected from 1 to 5 R G and each R E are independently hydrogen, C-C alkyl, or halo-C-C alkyl; each R F are independently hydrogen, C-C alkyl, or halo; each R G are independently aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R H and each R H is independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0125] In some embodiments, D is a bridged monocyclic cycloalkyl or cycloalkyl, each of which is selected from 1 to 4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cycloalkyl, each of which is optionally substituted with 1-4 R XIn some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1 to 4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1 to 4 R X In some embodiments, D is optionally substituted with a group: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from one R X In some embodiments, R X is C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl, or tetrazolyl).

[0126] In some embodiments, D is 0 R X In some embodiments, D is substituted by [ka] is.

[0127] In some embodiments, L 1 and L 2 At least one of is independently 2 to 7 membered heteroalkylene, O, or NR C wherein the heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 Both of these can be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 are both C1-C6 alkylene or C2-C6 alkenylene, wherein each C1-C6 alkylene and C2-C6 alkenylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 Both have 1 to 5 R X and C2-C6 alkenylene optionally substituted by

[0128] In some embodiments, each R X are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, oxo, or -C(O)R D (e.g., CH, OH, oxo, CHOH, CHOCH, or C(O)CH). In some embodiments, each R X are independently C1-C6 alkyl, oxo, or -C(O)R D (e.g., CH3, oxo, or C(O)CH3).

[0129] In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- *, CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and CH=CH-* are independently selected from L 2 is CH2O- * , CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , -NHC(O)OCH2- * , O- * , NH- * , S(O)2CH2- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- *, CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicates the points of attachment to A and W, respectively.

[0130] In some embodiments, t is 1. In some embodiments, t is 0.

[0131] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R1 and R 2 are each independently hydrogen.

[0132] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0133] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The group may be one to five R groups which, together with the atoms to which they are attached, form a bicyclic heteroaryl. X In some embodiments, W is a 10-membered heteroaryl, a 9-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, W is a heteroaryl containing nitrogen, oxygen, or sulfur as allowed by valence.

[0134] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] are independently selected from

[0135] In some embodiments, A and W are each: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0136] In some embodiments, A is: [ka] is selected from.

[0137] In some embodiments, W is: [ka] is selected from.

[0138] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0139] In some embodiments, each R Yare independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0140] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0141] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0142] In some embodiments, G 1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0143] In another aspect, the present invention provides a compound of formula (Ia): [ka] wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl, or a cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or a cubanyl is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently a C1-C6 alkylene, a C2-C6 alkenylene, or a 2- to 7-membered heteroalkylene, wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2- to 7-membered heteroalkylene is selected from 1 to 5 R X and optionally substituted by R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, silyloxy-C1-C6 alkyl; A and W are each independently phenyl or 5- to 6-membered heteroaryl, wherein each phenyl or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 5 R Y and each R Xis 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 each R is independently selected from the group consisting of Y is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, 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 , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 or two R on adjacent atoms are independently selected from the group consisting of Y The groups, together with the atoms to which they are attached, consist of 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by 1 is independently a C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4- to 7-membered heterocyclyl, an aryl, or a 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 3 R Zand each R Z is 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 each R is independently selected from the group consisting of A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C(O)NR B R C , -C(O)R D , -C(O)OH, or -C(O)OR D and;R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C together with the atoms to which they are attached, form 1 to 3 R Z forming a 3- to 7-membered heterocyclyl ring optionally substituted by D is independently C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2- to 7-membered heteroalkyl, or halo-C1-C6 alkyl is selected from 1 to 5 R G and each R E are independently hydrogen, C-C alkyl, or halo-C-C alkyl; each R F are independently hydrogen, C-C alkyl, or halo; each R G are independently aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R H and each R His independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0144] In some embodiments, D is a bridged monocyclic cycloalkyl or cycloalkyl, each of which is selected from 1 to 4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cycloalkyl, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1 to 4 R X In some embodiments, D is optionally substituted with a group: [ka] In some embodiments, D is selected from: [ka] In some embodiments, D is selected from one R X In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, D is 0 R X In some embodiments, D is substituted by [ka] is.

[0145] In some embodiments, L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 Both of these can be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 R X In some embodiments, each R X are independently C1-C6 alkyl, oxo, or -C(O)R D (e.g., CH3, oxo, or C(O)CH3). In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- *are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicates the points of attachment to A and W, respectively.

[0146] In some embodiments, t is 1. In some embodiments, t is 0.

[0147] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3,* -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0148] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0149] In some embodiments, A is: [ka] In some embodiments, W is selected from: [ka] is selected from.

[0150] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0151] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0152] In some embodiments, G 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0153] In some embodiments, the compound of formula (I) above has formula (Ib): [ka] wherein D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.1]heptane, each of which is selected from 1 to 4 R X optionally substituted by a group; L 1 and L 2 are each independently CH2O- *, CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * and "- * " indicate the points of attachment to A and W, respectively; R 1 and R 2 are each independently hydrogen, CH, CHCHOH, or CHCHOSi(CH)C(CH); A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y and each R Xare CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, -SCH3, or G 2 each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 or two R on adjacent atoms Y groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which contains one to two R X and optionally substituted by G 1 and G 2 is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is selected from the group consisting of 1 to 2 R Z and each R D is 1 to 5 R G CHO optionally substituted by G are independently 1 to 5 R H pyridyl optionally substituted by H is independently CF; each R Z is independently CH3; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0154] In some embodiments, the compound of formula (I) above has the formula (Ic): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0155] In some embodiments, R X is C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl, or tetrazolyl).

[0156] In some embodiments, L 1 and L 2 At least one of is independently 2 to 7 membered heteroalkylene, O, or NR C wherein the heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 Both of these can be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 are both C1-C6 alkylene or C2-C6 alkenylene, and each C1-C6 alkylene and C2-C6 alkenylene is selected from 1 to 5 R X In some embodiments, L 1 and L 2 Both have 1 to 5 R X and C2-C6 alkenylene optionally substituted by

[0157] In some embodiments, R X is C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R.B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , —C(O)CH3, or —SCH3). In some embodiments, R X is oxo, -OR A , or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl, or tetrazolyl).

[0158] In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- *, CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and CH=CH- * are independently selected from L 2 is CH2O- * , CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- *, CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , -NHC(O)OCH2- * , O- * , NH- * , S(O)2CH2- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from *" indicates the points of attachment to A and W, respectively.

[0159] In some embodiments, t is 1. In some embodiments, t is 0.

[0160] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0161] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0162] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The group may be one to five R groups which, together with the atoms to which they are attached, form a bicyclic heteroaryl. X In some embodiments, W is a 10-membered heteroaryl, a 9-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, W is a heteroaryl containing nitrogen, oxygen, or sulfur as allowed by valence.

[0163] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] are independently selected from

[0164] In some embodiments, A and W are each: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0165] In some embodiments, A is: [ka] is selected from.

[0166] In some embodiments, W is: [ka] is selected from.

[0167] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0168] In some embodiments, each R Yare independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0169] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0170] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0171] In some embodiments, G 1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0172] In some embodiments, the compound of formula (I) above has the formula (Id): [ka] In the formula, L 1 , L 2 , A, and W are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0173] In some embodiments, the compound of formula (I) above has the formula (Ie): [ka] In the formula, L 2 ,A,W,R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0174] In some embodiments, L 2 is 1 to 5 R XIn some embodiments, L is C1-C6 alkylene, C2-C6 alkenylene, or 2-7 membered heteroalkylene optionally substituted by 2 is CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , NH- * , S(O)2CH- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0175] C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, or -SCH3).

[0176] In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W. In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0177] In some embodiments, t is 1. In some embodiments, t is 0.

[0178] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0179] In some embodiments, A and W each independently represent 1 to 5 R Y In some embodiments, A and W are each independently 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Yare independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] are independently selected from

[0180] In some embodiments, A and W are each: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2RD , or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0181] In some embodiments, A is: [ka] is selected from.

[0182] In some embodiments, W is: [ka] is selected from.

[0183] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0184] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0185] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0186] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro).

[0187] In some embodiments, the compound of formula (I) above has the formula (If): [ka] In the formula, L 2 , W, R Y , R 1 , R 2 and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0188] In some embodiments, L 2is 1 to 5 R X In some embodiments, L is C1-C6 alkylene, C2-C6 alkenylene, or 2-7 membered heteroalkylene optionally substituted by 2 is a 2- to 7-membered heteroalkylene, O, or NR C and 1 to 5 R X In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0189] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -OR A, -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, or -SCH3).

[0190] In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W. In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2-* , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0191] In some embodiments, t is 1. In some embodiments, t is 0.

[0192] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0193] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] In some embodiments, A and W are each independently selected from: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0194] In some embodiments, A is: [ka] is selected from.

[0195] In some embodiments, W is: [ka] is selected from.

[0196] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Yare independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0197] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0198] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0199] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R XIn some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0200] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0201] In some embodiments, the compound of formula (I) above has the formula (Ig): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0202] In some embodiments, the compound of formula (I) above has the formula (Ih): [ka] In the formula, L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0203] In some embodiments, the compound of formula (I) above has the formula (Ii): [ka] In the formula, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0204] In some embodiments, L 2 is 1 to 5 R X In some embodiments, L is C1-C6 alkylene, C2-C6 alkenylene, or 2-7 membered heteroalkylene optionally substituted by 2 is a 2- to 7-membered heteroalkylene, O, or NR C and 1 to 5 R X In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2CH2CH2- * , CH2- * , CH2C(O)- *, CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , NHCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , CH(OH)- * , CH(OH)CH2CH2- * , CH2CH(OH)- * , CH2NHC(O)- * , NHC(O)OCH2- * , O- * , NH- * , S(O)2CH- * , S(O)2CH2CH2- * , S(O)2CH2CH2O- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0205] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D , -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, or -SCH3).

[0206] In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W. In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2-* , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0207] In some embodiments, t is 1. In some embodiments, t is 0.

[0208] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0209] In some embodiments, A and W each independently represent 1 to 5 R Yand each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] In some embodiments, A and W are each independently selected from: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Yare independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0210] In some embodiments, A is: [ka] is selected from.

[0211] In some embodiments, W is: [ka] is selected from.

[0212] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D, -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0213] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0214] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0215] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R XIn some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0216] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0217] In some embodiments, the compound of formula (I) above has the formula (Ij): [ka] In the formula, L 1 , L 2 , R 1 , R 2 ,A,W,R X , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0218] In some embodiments, the compound of formula (I) above has the formula (Ik): [ka] In the formula, L 2 , R 1 , R 2 ,A,W,R X, and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0219] In some embodiments, the compound of formula (I) above has the formula (Il): [ka] In the formula, L 2 , R 1 , R 2 , W, R X , R Y , and t are each as defined for formula (I); or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0220] In some embodiments, L 1 and L 2 At least one of the following may be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 Both of these can be independently selected from 1 to 5 R X In some embodiments, L is a 2- to 7-membered heteroalkylene optionally substituted by 1 and L 2 is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 and the other is independently a 2- to 7-membered heteroalkylene, wherein each C-C alkylene, C-C alkenylene, and 2- to 7-membered heteroalkylene is selected from 1 to 5 R X In some embodiments, each R X are independently C1-C6 alkyl, oxo, or -C(O)R D (e.g., CH3, oxo, or C(O)CH3). In some embodiments, L1 and L 2 are respectively CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicate the points of attachment to A and W, respectively. In some embodiments, L 1 is CH2O- * and L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * are selected independently from * " indicates the points of attachment to A and W, respectively.

[0221] In some embodiments, L2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W. In some embodiments, L 2 is CH2O- * , CH2CH2- * , CH2C(O)- * , CH=CH- * , CH2CH2O- * , CH2OCH2- * , CH2OCH2CH2- * , CH2CH2CH2O- * , CH2CH2OCH2- * , CH2NH- * , CH2N(CH3)- * , CH2N(CH3)C(O)- * , CH2N(C(O)CH3)- * , CH2CH(OH)- * , NHC(O)OCH2- * , or CH2C(O)- * Selected from "- * " indicates the point of attachment to W.

[0222] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -OR A , -OS(O)2R D, -S(O)2R D , -SR E , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, NR B R C , or G 2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3, or -SCH3).

[0223] In some embodiments, t is 1. In some embodiments, t is 0.

[0224] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxyl-C1-C6 alkyl, or silyloxy-C1-C6 alkyl. 1 and R 2 are independently hydrogen, and R 1 and R 2 and the other is independently hydrogen, C-C alkyl, C-C hydroxyl-C-C alkyl, or silyloxy-C-C alkyl. 1 and R 2 are each independently hydrogen, * -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are independently hydrogen, and R 1 and R 2 the other is independently hydrogen,* -CH3, * -CH2CH2OH, or * -CH2CH2OSi(CH3)2C(CH3)3, and * The "-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0225] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0226] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The group may be one to five R groups which, together with the atoms to which they are attached, form a bicyclic heteroaryl. X In some embodiments, W is a 10-membered heteroaryl, a 9-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, W is a heteroaryl containing nitrogen, oxygen, or sulfur as allowed by valence.

[0227] In some embodiments, A and W each independently represent 1 to 5 R Y and each R is phenyl or 5-6 membered heteroaryl optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D, -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y In some embodiments, A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1 to 5 R Y In some embodiments, A and W are each optionally substituted by a group: [ka] In some embodiments, A and W are each independently selected from: [ka] In some embodiments, A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each are independently selected from 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Y is optionally replaced by

[0228] In some embodiments, A is: [ka] is selected from.

[0229] In some embodiments, W is: [ka] is selected from.

[0230] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, A and W each contain 1-5 R Y and each R is optionally substituted by Y are independently 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 , -NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)2R D , or G 1 is.

[0231] In some embodiments, each R Yare independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0232] In some embodiments, each R Y are independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 is.

[0233] In some embodiments, A and W each represent two R on adjacent atoms. Y and the two R Y These, together with the atoms to which they are bonded, form 1 to 5 R X In some embodiments, two R Y together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from the group consisting of 1 to 5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (e.g., CH3 or fluoro).

[0234] In some embodiments, G 1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, G is optionally substituted with 1 is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is selected from 1 to 5 R Z In some embodiments, each R Z is independently C-C alkyl (e.g., CH) or halo (e.g., chloro). In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3).

[0235] In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il)) or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutically acceptable composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable carrier.

[0236] In some embodiments, the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 [Table 1-58] [Table 1-59] [Table 1-60] [Table 1-61] [Table 1-62] [Table 1-63] [Table 1-64] [Table 1-65] [Table 1-66] [Table 1-67] [Table 1-68] [Table 1-69]

[0237] 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 the 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 Schemes 1-24, but are not limited thereto. The variables A, D, W, L 1 , L 2 , R 1 , and R 2is defined as detailed herein, for example, in the Summary of the Invention.

[0238] [ka] As shown in Scheme 1, compounds of formula (3) can be prepared by reacting A and W with each other. 1 and L 2are the same, are representative of compounds of formula (I) and can be prepared from compounds of formula (1). Carboxylic acids of formula (2A) can be coupled with amines of formula (1) under amide bond forming conditions to give compounds of formula (3). Examples of conditions known to produce amides from a mixture of carboxylic acids and amines include, but are not limited to, coupling reagents such as, but not limited to, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC, or EDCI) or the corresponding hydrochlorides, 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-azabenzotriazole- Examples of suitable coupling reagents include the addition of 1-(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 (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) (HBTU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®). The coupling reagents may be added as solids or solutions, or as reagents bound to solid support resins.

[0239] In addition to the coupling reagent, an auxiliary coupling reagent can facilitate the coupling reaction. Auxiliary coupling reagents often used in coupling reactions include, but are not limited to, (dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT), and 1-hydroxybenzotriazole (HOBT). The reaction may optionally be carried out in the presence of a base, such as, but not limited to, triethylamine, N,N-diisopropylethylamine, or pyridine. The coupling reaction may 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. The reaction may be carried out at ambient temperature or with heating. Heating can be achieved either conventionally or by microwave irradiation.

[0240] Alternatively, an acid chloride of formula (2B) can be reacted with an amine of formula (1) in a solvent such as, but not limited to, dichloromethane, optionally in the presence of a base, such as a tertiary amine base, for example, but not limited to, triethylamine or N,N-diisopropylethylamine, or an aromatic base, for example, pyridine, at room temperature or with heating to provide an amide of formula (3). An amine of formula (1) can also be coupled with an acid chloride of formula (2B) in a mixture of water and dichloromethane in the presence of a base, for example, but not limited to, sodium hydroxide.

[0241] [ka] As shown in Scheme 2, compounds of formula (3) can be prepared by reacting A and W with each other, or with W being the same or different, and L 1 and L 2When are the same or different, they are representative of compounds of formula (I) and can be prepared from compounds of formula (1). The amine of formula (1) can be protected with a suitable protecting group (PG) to give compounds of formula (4). For example, the amine of formula (1) can be treated with di-tert-butyl bicarbonate in a solvent such as, but not limited to, tetrahydrofuran at ambient temperature to give compounds of formula (4) where PG is C(O)OC(CH). A carboxylic acid of formula (2A) or an acid chloride of formula (2B) can be coupled with an amine of formula (4) under the amide bond forming conditions described in Scheme 1 to give compounds of formula (5). The protecting group (PG) in formula (5) can be removed to give compounds of formula (6). For example, a BOC protecting group can be removed using an acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid in a solvent such as, but not limited to, methanol, 1,4-dioxane, or dichloromethane, or a mixture thereof. The reaction may be carried out at ambient or elevated temperature. Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (6) under amide bond forming conditions described in Scheme 1 to give compounds of formula (3), which are representative of compounds of formula (I).

[0242] [ka] As shown in Scheme 3, compounds of formula (9) are representative of compounds of formula (I) when t is 0 and can be prepared from compounds of formula (6). Compounds of formula (6) can be prepared as described in Scheme 2, where R 100 is absent or is alkylene or heteroalkylene with an aldehyde of formula (8), in the presence of a reducing agent such as, but not limited to, sodium triacetoxyborohydride or sodium cyanoborohydride, to provide a compound of formula (9). The reaction is typically carried out in a solvent such as, but not limited to, 1,2-dichloroethane, dichloromethane, methanol, ethanol, tetrahydrofuran, acetonitrile, or a mixture thereof at ambient temperature.

[0243] [ka] Alternatively, compounds of formula (9), which are representative of compounds of formula (I) when t is 0, can be prepared from compounds of formula (6) as shown in Scheme 4. Amines of formula (6) can be reacted with bromides of formula (10) in the presence of a base, such as, but not limited to, potassium carbonate, to give compounds of formula (9). The reaction is typically carried out in a solvent, such as, but not limited to, N,N-dimethylformamide or dimethyl sulfoxide, at elevated temperatures.

[0244] [ka] Compounds of formula (13) and (14) are representative of compounds of formula (I) where t is 1 and can be prepared as shown in Scheme 5. Amines of formula (6) can be prepared as described in Scheme 2 and can be reacted with 2-chloroacetyl chloride in the presence of a base, such as, but not limited to, potassium carbonate, to give compounds of formula (11). The addition is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, water, or a mixture thereof, at a low temperature before warming to ambient temperature. Alcohols of formula (12A) can be reacted with compounds of formula (11) in the presence of a strong base, such as, but not limited to, sodium hydride, to give compounds of formula (13). The reaction is typically carried out in a solvent, such as, but not limited to, N,N-dimethylformamide, at ambient temperature. Alternatively, an alcohol of formula (12A) can be reacted with a compound of formula (11) in the presence of a base, such as, but not limited to, potassium carbonate, optionally with the addition of a catalytic amount of potassium iodide, to give a compound of formula (13). The reaction is typically carried out at elevated temperature in a solvent, such as, but not limited to, acetonitrile, acetone, or a mixture thereof, optionally in a microwave. An alcohol of formula (12B) where n is 1-6 can be reacted with a compound of formula (11) in the presence of a strong base, such as, but not limited to, sodium hydride, to give a compound of formula (14). The reaction is typically carried out at ambient temperature in a solvent, such as, but not limited to, N,N-dimethylformamide.

[0245] [ka] As shown in Scheme 6, compounds of formula (15) can be prepared when t is 1 and L 2 is a C2-C7 heteroalkylene and can be prepared from a compound of formula (6). The amine of formula (6) can be treated with bis(trichloromethyl) carbonate followed by an alcohol of formula (12B) to give a compound of formula (15). The reaction is typically carried out in a solvent such as, but not limited to, tetrahydrofuran at ambient temperature.

[0246] [ka] Compounds of formula (18) are those in which t is 1 and R 2 is C-C alkyl, C-C alkoxy-C-C alkyl, hydroxy-C-C alkyl, or silyloxy-C-C alkyl, and can be prepared from compounds of formula (6) as shown in Scheme 7. Amines of formula (6) can be alkylated with alkylating agents of formula (16) where X is a halide in the presence of a base, such as, but not limited to, potassium carbonate, to give compounds of formula (17). The reaction is typically carried out in a solvent, such as, but not limited to, N,N-dimethylformamide, at elevated temperatures. Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (17) under the amide bond forming conditions described in Scheme 1 to give compounds of formula (18).

[0247] [ka] As shown in Scheme 8, compounds of formula (20) are representative of compounds of formula (I) where t is 1 and can be prepared from amines of formula (6). The amines of formula (6) can be reacted with chloroformates of formula (19) in the presence of a base, such as, but not limited to, N,N-diisopropylethylamine, to provide compounds of formula (20). The reaction is typically carried out at ambient temperature in a solvent, such as, but not limited to, toluene, dichloromethane, or mixtures thereof.

[0248] [ka] R 1Compounds of formula (I) where X is C-C alkyl, C-C alkoxy-C-C alkyl, hydroxy-C-C alkyl, or silyloxy-C-C alkyl can be prepared from compounds of formula (5) as shown in Scheme 9. Amines of formula (5) can be prepared as described in Scheme 2 and alkylated with an alkylating agent of formula (21) where X is a halide in the presence of a base, such as, but not limited to, sodium hydride, to provide compounds of formula (22). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, or mixtures thereof, at ambient temperature. After removal of the protecting group (PG), compounds of formula (22) can be reacted with carboxylic acids of formula (7A) or acid chlorides of formula (7B) under the amide bond-forming conditions described in Scheme 2 to provide compounds of formula (I).

[0249] [ka] As shown in Scheme 10, compounds of formula (25) are representative of compounds of formula (I) where t is 1 and can be prepared from compounds of formula (6). Amines of formula (6) can be prepared as described in Scheme 2 and can be reacted with 2-hydroxyacetic acid under the amide bond forming conditions described in Scheme 2 to give compounds of formula (23). Compounds of formula (23) can be alkylated with alkylating agents of formula (24), where X is a halide and n is 0-5, in the presence of a base, such as, but not limited to, sodium hydride, to give compounds of formula (25). The reaction is typically carried out at elevated temperatures in a solvent, such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, or mixtures thereof.

[0250] [ka] Compounds of formula (28) are representative of compounds of formula (I) where t is 1 and can be prepared from compounds of formula (23) as shown in Scheme 11. Compounds of formula (23), which can be prepared as described in Scheme 10, can be reacted with 2-bromomethyl acetate in the presence of a base, such as, but not limited to, cesium carbonate, to provide compounds of formula (26). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, at ambient temperature. Compounds of formula (26) can be treated with aqueous lithium hydroxide to provide compounds of formula (27). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, methanol, or mixtures thereof, at ambient temperature. Compounds of formula (27) can be treated with N-hydroxyacetimidamide in the presence of a coupling agent, such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), and a base, such as, but not limited to, triethylamine, to give compounds of formula (28). The reaction is typically carried out in a solvent, such as, but not limited to, acetonitrile, at elevated temperatures.

[0251] [ka] As shown in Scheme 12, compounds of formula (30) are representative of compounds of formula (I) and can be prepared from compounds of formula (26). Compounds of formula (26) can be prepared as described in Scheme 11 and treated with hydrazine monohydrate to give compounds of formula (29). The reaction is typically carried out in a solvent such as, but not limited to, ethanol at elevated temperatures. Compounds of formula (29) can be treated with 1,1'-carbonyldiimidazole to give compounds of formula (30). The reaction is typically carried out in a solvent such as, but not limited to, 1,4-dioxane at elevated temperatures.

[0252] [ka] Scheme 13 describes the synthesis of compounds of Formula (I) where D is a 2-oxobicyclo[2.2.2]octan-1-yl core. Ethyl 4-amino-2-oxobicyclo[2.2.2]octane-1-carboxylate can be prepared as described herein and reacted with a carboxylic acid of Formula (2A) or an acid chloride of Formula (2B) under the amide bond-forming conditions described in Scheme 1 to give compounds of Formula (31). Compounds of Formula (31) can be treated with a methanolic solution of sodium hydroxide at ambient temperature to give compounds of Formula (32). Acids of Formula (32) can be treated with diphenylphosphoryl azide in the presence of a base, such as, but not limited to, triethylamine, followed by tert-butanol to give compounds of Formula (33). The reaction is typically carried out in a solvent, such as, but not limited to, toluene, at elevated temperatures. The compound of formula (33) can be treated with an acid, such as, but not limited to, hydrochloric acid, in a solvent, such as, but not limited to, 1,4-dioxane, at ambient temperature to provide a compound of formula (34). The compound of formula (34) can be reacted with a carboxylic acid of formula (7A) or an acid chloride of formula (7B) under amide bond forming conditions described in Scheme 2 to provide a compound of formula (I).

[0253] [ka] Scheme 14 describes the synthesis of carboxylic acids (37), (42), and (45), which are representative of acids of formula (2A) and formula (7A).

[0254] The compound of formula (35) can be reacted with ethyl 2-hydroxyacetate in the presence of a strong base, such as, but not limited to, potassium tert-butoxide, to give a compound of formula (36). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, at ambient temperature. The compound of formula (36) can be treated with aqueous lithium hydroxide to give a compound of formula (37). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, at ambient temperature.

[0255] The alcohol of formula (38) can be reacted with tert-butyl 2-bromoacetate in the presence of a base, such as, but not limited to, potassium carbonate, to give a compound of formula (39). The reaction is typically carried out in a solvent, such as, but not limited to, N,N-dimethylformamide, at elevated temperature. The compound of formula (39) can be treated with an acid, such as, but not limited to, hydrochloric acid, to give a compound of formula (37). The reaction is typically carried out in a solvent, such as, but not limited to, 1,4-dioxane, at ambient temperature.

[0256] The compound of formula (40) can be reacted with ethyl 3-bromopropanoate in the presence of a strong base, such as, but not limited to, sodium hydride, to give a compound of formula (41). The addition is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, at a low temperature before warming to ambient temperature. The compound of formula (41) can be treated with aqueous sodium hydroxide to give a compound of formula (42). The reaction is typically carried out in a solvent, such as, but not limited to, tetrahydrofuran, at ambient temperature.

[0257] Carboxylic acids of formula (43) can be reacted with sarcosine methyl ester under amide bond forming conditions described in Scheme 1 to give compounds of formula (44). Compounds of formula (44) can be treated with aqueous sodium hydroxide to give compounds of formula (45). The reaction is typically carried out at ambient temperature in a solvent such as, but not limited to, ethanol.

[0258] [ka] As shown in Scheme 15, bromides of formula (47), representative of compounds of formulas (10) and (24), can be prepared from alcohols of formula (46). Compounds of formula (46) can be reacted with 1,2-dibromoethane in the presence of a base, such as, but not limited to, potassium carbonate, to give compounds of formula (47). The reaction is typically carried out in a solvent, such as, but not limited to, acetonitrile, at elevated temperatures.

[0259] [ka] As shown in Scheme 16, A and W may be the same or different, and L 1 and L 2 Compounds of formula (49), which are representative of compounds of formula (I), can be prepared from compounds of formula (48), where R is the same or different. Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (48) under the amide bond forming conditions described in Scheme 1 to give compounds of formula (49). Ketones of formula (48) can also be reduced in the presence of a reducing agent, such as, but not limited to, sodium borohydride, in a solvent such as a mixture of methanol and dichloromethane to give alcohols of formula (50). Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (50) under the amide bond forming conditions described in Scheme 1 to give compounds of formula (51). Ketones of formula (49) can also be reduced in the presence of a reducing agent, such as, but not limited to, sodium borohydride, in a solvent such as a mixture of methanol and dichloromethane to give alcohols of formula (51). Compounds of formula (48), formula (49), formula (50) and formula (51) can be further derivatized as shown in the examples below.

[0260] [ka] As shown in Scheme 17, compounds of formula (52) can be converted to compounds of formula (6), which can then be converted to compounds of formula (I) via the methods described in Schemes 2-8 and 10. Thus, carboxylic acids of formula (2A) or acid chlorides of formula (2B) can be coupled with amines of formula (50) under the amide bond forming conditions described in Scheme 1, followed by ester hydrolysis using conditions known to those skilled in the art, to provide compounds of formula (53). Compounds of formula (53) can be treated with Curtius reaction conditions, such as diphenylphosphoryl azide and triethylamine in heated toluene, followed by acid hydrolysis, to provide compounds of formula (6).

[0261] [ka] As shown in Scheme 18, compounds of formula (6) can be converted to compounds of formula (57), which are representative of compounds of formula (I). Thus, compounds of formula (6) can be coupled with protected amino acids of formula (54), where PG is a suitable amine protecting group, using the amide bond coupling conditions described in Scheme 1 to provide compounds of formula (55). The protecting group PG in compounds of formula (55) can be removed under conditions known to those skilled in the art to expose primary amines that can be coupled with carboxylic acids of formula (56) using the amide bond coupling conditions described in Scheme 1 to provide compounds of formula (57).

[0262] [ka] As shown in Scheme 19, compounds of formula (6) can be converted to compounds of formula (59), which are representative of compounds of formula (I). Compounds of formula (6) can be reacted with sulfonyl chlorides of formula (58) in the presence of a base, such as, but not limited to, triethylamine, in a solvent, such as, but not limited to, N,N-dimethylformamide, optionally at elevated temperature, to provide compounds of formula (59).

[0263] [ka] As shown in Scheme 20, compounds of formula (6) can be converted to compounds of formula (61), which are representative of compounds of formula (I). Compounds of formula (6) can be reacted with isocyanates of formula (60) in the presence of pyridine to give compounds of formula (61).

[0264] [ka] As shown in Scheme 21, compounds of formula (6) can be converted to compounds of formula (63), which are representative of compounds of formula (I). Compounds of formula (6) can be reacted with carbonochloridates of formula (62) in the presence of a base, such as N,N-diisopropylethylamine, in a solvent, such as tetrahydrofuran, to provide compounds of formula (63).

[0265] [ka] As shown in Scheme 22, compounds of formula (64) can be converted to compounds of formula (65), which are representative of compounds of formula (I). Compounds of formula (64) can be reduced with indium(III) bromide and triethylsilane (EtSiH) in warm dichloromethane to give compounds of formula (65).

[0266] [ka] As shown in Scheme 23, a compound of formula (66) can be converted to a compound of formula (1). Accordingly, the ester moiety of a compound of formula (66) can be hydrolyzed under conditions known to those skilled in the art to provide the corresponding carboxylic acid. The carboxylic acid can be treated under Curtius reaction conditions to complete the conversion to a compound of formula (67). The compound of formula (67) can be reacted with di-tert-butyl dicarbonate in the presence of a base to provide an orthogonally protected bis-amine (68). The compound of formula (68) can be converted to a compound of formula (1) using catalytic hydrogenation conditions in the presence of an acid, such as 4 M hydrochloric acid, in a solvent, such as warm dioxane. The compound of formula (1) can be used as described in Scheme 1 or Scheme 2.

[0267] [ka] As shown in Scheme 24, compounds of formula (68) can be converted to compounds of formula (71). Compounds of formula (68) can be converted to compounds of formula (71) by the reaction of R 2b is an optionally substituted C1-C6 alkyl. Compounds of formula (69) can be reductively aminated to compounds of formula (69) under acidic conditions known to those skilled in the art to selectively remove the tert-butoxycarbonyl protecting group, and the exposed amine can then be coupled with compounds of formula (2A) using the amide bond forming reaction conditions described in Scheme 1 to provide compounds of formula (70). Alternatively, acid chlorides of formula (2B) can be coupled with amines also described in Scheme 1. The benzyl protecting group of compounds of formula (70) can be removed under catalytic hydrogenation conditions, and the exposed amine can then be coupled with a carboxylic acid of formula (7A) to provide compounds of formula (71). Compounds of formula (71) can also be obtained by reaction of the above exposed amine with the corresponding acid chloride under conditions also described in Scheme 1. Compounds of formula (71) are representative of compounds of formula (I).

[0268] Pharmaceutical Composition The present invention features a pharmaceutical composition comprising a compound of Formula (I) 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) 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.

[0269] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparation methods include combining a compound of formula (I) ("active ingredient") with the carrier and / or one or more other accessory ingredients, and then, as necessary and / or desired, shaping and / or packaging the product into a desired single or multiple dosage unit. 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 generally equal to the dosage of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0270] The relative amounts of the compound of formula (I), pharmaceutically acceptable excipient, and / or any additional components in the pharmaceutical compositions of the present invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain between 0.1% and 100% (w / w) of the compound of formula (I).

[0271] 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 pharmaceutical compositions of the present invention are any of those 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 preparation of pharmaceutical compositions of the present invention include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycerol mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0272] Compositions of the invention may 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 are administrable intravenously and / or orally.

[0273] 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 oily suspensions. These suspensions may 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 saline solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media.

[0274] The pharmaceutically acceptable compositions of the present invention may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets 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 provided oral formulations 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) may also be in microencapsulated form.

[0275] The compositions of the present invention can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and can be delivered transdermally or topically. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. 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 may further 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 may also be delivered as microspheres for delayed release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for subcutaneous delayed release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the invention can be delivered by the use of liposomes that fuse with or are internalized by the cell membrane, i.e., by using receptor ligands attached to the liposomes that bind to surface membrane protein receptors of the cell, triggering endocytosis.Liposomes can be used to concentrate the delivery of the composition of the present invention to target cells in vivo, especially when the liposome surface carries receptor ligands specific to target cells, or in other cases, when it is selectively targeted to specific organs (see, for example, 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 composition of the present invention can also be delivered as nanoparticles.

[0276] 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 comprises areas or organs that are easily accessible by topical application, including diseases of the eye, skin or lower gastrointestinal tract.Suitable topical formulations can be easily prepared for each of these areas or organs.

[0277] 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 low water solubility. The rate of absorption of the drug then depends on the dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0278] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all classes of animals. Modifications of pharmaceutical compositions that are suitable for administration to humans to make them suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications by routine experimentation.

[0279] The compounds provided herein, such as compounds of formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers, are typically formulated in dosage unit form, for example, single unit dosage form, for ease of administration and uniformity of dosage. However, it will be understood that the total daily use amount of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The therapeutically effective dose level specific to any particular subject or organism will depend on various factors, including the severity of the disease and disorder being treated; 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, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination or simultaneously with the specific active ingredient used; and similar factors well known in the medical field.

[0280] 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 the side effect or disorder, the attributes of the particular compound(s), the mode of administration, etc. A desired dosage may be delivered three times per day, twice per day, once per day, every other day, every third day, once per week, once every two weeks, once per three weeks, or once per four weeks. In certain embodiments, a desired dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0281] In certain embodiments, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof for administration one or more times daily may contain 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.

[0282] In certain embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof may be at a dosage level sufficient to deliver from about 0.001 mg / kg to about 1000 mg / kg, 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 of body weight of the subject per day, one or more times per day, to obtain the desired therapeutic effect.

[0283] It will be appreciated that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents can be determined by a physician or person skilled in the art and may be less than or the same as the amount administered to adults.

[0284] It will also be recognized that the compounds or compositions described herein, such as compounds of Formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers, can be administered in combination with one or more additional agents. The compounds or compositions can be administered in combination with additional agents that improve bioavailability, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in the body. It will also be recognized that the treatments used can achieve the desired effect for the same disorder and / or can achieve different effects.

[0285] The compound or composition may be administered simultaneously with, before, or after one or more additional agents that may be useful, for example, as a combination therapy. The agents include therapeutically active agents. The agents also include prophylactically active agents. Each additional agent may be administered at a dose and / or time schedule determined for that agent. The additional agents may also 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 compound of the present invention with the additional agents and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that additional agents used in combination will be used at levels that do not exceed the levels used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

[0286] Exemplary additional drugs include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Drugs include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the US Food and Drug Administration as provided by the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0287] Pharmaceutical compositions provided by the present invention include compositions containing a therapeutically effective amount of an active ingredient (e.g., a compound described herein, including embodiments or examples), 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 will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule (e.g., an element of the eIF2B, eIF2, or eIF2α signal transduction pathway, or a phosphorylated component of the eIF2α or ISR pathway) and / or reducing, eliminating, or delaying the progression of a disease symptom (e.g., a symptom of 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 or ISR pathway). Determining a therapeutically effective amount of a compound of the present invention is well within the capabilities of one skilled in the art, especially in light of the detailed disclosure herein.

[0288] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, such as 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 concurrent treatment, and complications from the disease or other health-related problem being treated. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds of Applicant's invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the capabilities of one of ordinary skill in the art.

[0289] 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) obtainable by the methods described herein, as measured using methods described herein or known in the art.

[0290] As is well known in the art, therapeutically effective amounts for human use can also be determined from animal models. For example, dosages for humans can be formulated to achieve concentrations found to be effective in animals. Dosages for humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above. Adjusting dosages to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0291] Dosage may vary depending on the patient's needs and the compound being used. The dosage administered to a patient should be sufficient to induce a beneficial therapeutic response in the patient over time, in accordance with the present invention. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the dosage appropriate for a particular situation is also within the skill of the artisan. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Dosage amount and interval can be individually adjusted to provide an administered compound level effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0292] Utilizing the techniques provided herein, effective prophylactic or therapeutic treatment regimens can be designed that do not cause substantial toxicity but are effective in treating the clinical symptoms demonstrated 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, patient weight, the presence and severity of adverse side effects, preferred dosage form, and the toxicity profile of the selected agent.

[0293] Kits (e.g., pharmaceutical packs) are also encompassed by the present invention. The kits of the present invention may be useful for preventing and / or treating diseases (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or other diseases or conditions described herein).

[0294] The provided kits may 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 may optionally further include a second container containing a pharmaceutical excipient for dilution or suspension of 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.

[0295] Thus, in one aspect, a kit is also provided that includes a first container containing a compound of Formula (I), 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 the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof to a subject to prevent and / or treat a disease described herein.

[0296] Treatment method The present invention features compounds, compositions, and methods comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, 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, musculoskeletal diseases, or metabolic diseases.

[0297] 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 involving 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) nervous system cell 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.

[0298] In some embodiments, the disease may be caused by a mutation in a gene or protein sequence related to a member 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, such as conformational or steric changes, that affect the function of the protein. For example, in some embodiments, amino acids in or 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 to affect the activity of the protein. In some cases, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) may be conservative and may not substantially affect the structure or function of the protein. For example, in certain cases, the substitution of a serine residue with a threonine residue may not substantially affect the function of the protein. In other cases, the amino acid mutation may be larger, for example, a substitution of a charged amino acid (e.g., aspartic acid or lysine) with a large nonpolar amino acid (e.g., phenylalanine or tryptophan), and thus may substantially affect protein function. The nature of mutations that affect the structure or function of a gene or protein can be easily identified using standard sequencing techniques, such as deep sequencing techniques that are well known in the art. In some embodiments, mutations in members of the eIF2 pathway may affect the binding or activity of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, thereby modulating the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0299] 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.

[0300] In some embodiments, the eIF2 protein may include 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 the eIF2B1, eIF2B2, eIF2B3, eIF2B4, or eIF2B5 subunit. In some embodiments, the eIF2 protein may contain amino acid substitutions at alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, or eIF2B5 subunits. In some embodiments, the eIF2 protein may include 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 in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, or eIF2B5 subunit. In some embodiments, the eIF2 protein may contain 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 in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, or eIF2B5 subunit. Exemplary mutations include V183F (eIF2B1 subunit), H341Q (eIF2B3), I346T (eIF2B3), R483W (eIF2B4), R113H (eIF2B5), and R195H (eIF2B5).

[0301] In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in members of the eIF2 pathway (e.g., the eIF2B protein subunit) may affect the binding or activity of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, thereby modulating the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0302] Neurodegenerative diseases In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat a neurodegenerative disease. As used herein, the term "neurodegenerative disease" refers to a disease or condition resulting in loss of function in a subject's nervous system. Examples of neurodegenerative diseases that may be treated by the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, and Huntington's disease. , HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar degeneration type 3), multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, pernicious anemia secondary subacute combined spinal degeneration, schizophrenia, spinocerebellar ataxia (various variants with different features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0303] In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, cerebral leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, intellectual disability syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

[0304] In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, cerebral leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, or intellectual disability syndrome.

[0305] In some embodiments, the neurodegenerative disease comprises a psychiatric disorder, such as agoraphobia, Alzheimer's disease, anorexia nervosa, memory loss, anxiety disorder, attention deficit disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, delusions, Diogenes syndrome, dyspraxia, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobic disorder, schizophrenia, seasonal affective disorder, schizophrenic personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette's syndrome, or trichotillomania.

[0306] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat vanishing white matter disease. Exemplary methods of treating vanishing white matter disease include, but are not limited to, reducing or eliminating symptoms of vanishing white matter disease, reducing white matter loss, reducing myelin loss, increasing the amount of myelin, or increasing the amount of white matter in a subject.

[0307] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat childhood ataxia due to central nervous system hypomyelination. Exemplary methods of treating childhood ataxia due to central nervous system hypomyelination include, but are not limited to, reducing or eliminating symptoms of childhood ataxia due to central nervous system hypomyelination, increasing myelin levels, or reducing myelin loss in a subject.

[0308] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat intellectual disability syndrome. Exemplary methods of treating intellectual disability syndrome include, but are not limited to, reducing or eliminating the symptoms of intellectual disability syndrome.

[0309] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer is used to treat neurodegeneration. Exemplary methods of treating neurodegeneration include, but are not limited to, improving mental health, increasing mental function, delaying the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive ability, reducing cognitive loss, improving memory, reducing memory decline, or prolonging survival.

[0310] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat leukoencephalopathy or demyelinating diseases. Exemplary leukoencephalopathy include, but are not limited to, progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with white matter loss, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, hypertensive leukoencephalopathy, macrocephalic leukoencephalopathy with subcortical cysts, Charcot-Marie-Tooth disease, and Devic's disease. Leukoencephalopathy may include demyelinating diseases that can be genetic or acquired. In some embodiments, the acquired demyelinating disease may be an inflammatory demyelinating disease (e.g., infectious or non-infectious inflammatory demyelinating disease), a toxic demyelinating disease, a metabolic demyelinating disease, a hypoxic demyelinating disease, a traumatic demyelinating disease, or an ischemic demyelinating disease (e.g., Binswanger's disease). Exemplary methods of treating a leukoencephalopathy or demyelinating disease include, but are not limited to, reducing or eliminating symptoms of the leukoencephalopathy or demyelinating disease in a subject, reducing myelin loss, increasing the amount of myelin, reducing white matter loss, or increasing the amount of white matter in a subject.

[0311] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat traumatic or toxic injury to the nervous system (e.g., brain). Exemplary traumatic brain injuries include, but are not limited to, brain abscess, concussion, ischemia, cerebral hemorrhage, skull fracture, diffuse axonal injury, locked-in syndrome, or injury related to a traumatic force or blow to the nervous system or brain that causes organ or tissue damage. Exemplary toxin-induced brain damage includes, but is not limited to, toxic encephalopathy, meningitis (e.g., bacterial meningitis or viral meningitis), meningoencephalitis, encephalitis (e.g., Japanese encephalitis, Eastern equine encephalitis, West Nile encephalitis), Guillain-Barré syndrome, Sydenham's chorea, rabies, leprosy, neurosyphilis, prion diseases, or exposure to chemicals (e.g., arsenic, lead, toluene, ethanol, manganese, fluorides, dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), tetrachloroethylene, polybrominated diphenyl ethers, pesticides, sodium channel blockers, potassium channel blockers, chloride channel blockers, calcium channel blockers, or blood-brain barrier blockers).

[0312] In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to improve memory in a subject. It has been shown that memory induction is promoted by the reduction and loss of eIF2α due to increased phosphorylation. Translation regulators, such as compounds disclosed herein (e.g., compounds of Formula (I)), can function as therapeutic agents to improve memory in human disorders associated with memory loss, such as Alzheimer's disease, and in other neurological disorders that activate the UPR or ISR in neurons, thereby negatively impacting memory consolidation, such as Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis, and prion diseases. Additionally, mutations in eIF2γ that disrupt complex integrity have been linked to intellectual disability (intellectual disability syndrome or ID) in humans due to loss of translation initiation. Thus, while ID and VWM, two diseases caused by loss of eIF2 function, exhibit distinct phenotypes, both primarily affect the brain and impair learning. In some embodiments, the disease or condition is poor memory (eg, working memory, long-term memory, short-term memory, or memory consolidation).

[0313] In still other embodiments, an aspect of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used in a method of improving memory (e.g., working memory, long-term memory, short-term memory, or memory consolidation) in a subject. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a bird. In some embodiments, the subject is a horse. In embodiments, the patient is a bovine. In some embodiments, the subject is a primate.

[0314] cancer In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, including solid and lymphatic cancers, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver cancer (including hepatocellular carcinoma), B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), lymphomas including Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma, sarcoma, adenocarcinoma, lymphoma, leukemia, melanoma, etc. In some further instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, osteosarcoma, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0315] As used herein, the term "cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, osteosarcoma, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung cancer, melanoma, mesothelioma, ovary, sarcoma, stomach, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant leukemia, and malignant leukemia. thyroid cancer, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of the pancreatic stellate cells, carcinoma of hepatic stellate cells, or prostate cancer.

[0316] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs, generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are commonly classified clinically based on (1) the duration and character of the disease—acute or chronic; (2) the type of cells involved—myeloid (myeloid), lymphatic (lymphoid), or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood—leukemic or nonleukemic (subleukemic). Exemplary leukemias that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, These include acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryotrophic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogenous granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0317] The term "sarcoma" generally refers to a tumor made up of a substance like embryonic connective tissue, and is generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated by the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, and fascial sarcoma. sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0318] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0319] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchoalveolar carcinoma, bronchiolocarcinoma, bronchiocarcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, uterine carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, compact carcinoma durum, embryonal carcinoma, encephalooid carcinoma, epithelioid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in situ, Krompecher carcinoma, Kurticycky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma carcinoma, melanoma, soft carcinoma, mucinous carcinoma, myxomatous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma (carcinoma mucosum), mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, supplementary cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinomacarcinoma, spheroidal cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, angioectatic carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0320] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat pancreatic cancer, breast cancer, multiple myeloma, or secretory cell cancer. For example, certain methods herein treat cancer by reducing, reducing, or preventing the onset, growth, metastasis, or progression of cancer. In some embodiments, the methods described herein may be used to treat cancer by reducing or eliminating the symptoms of cancer. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof can be used as a single agent in a composition or in combination with another agent in the composition to treat a cancer described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, or secretory cell cancer).

[0321] inflammatory diseases In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat an inflammatory disease. As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control, e.g., a healthy person not afflicted with the disease). Examples of inflammatory diseases include postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 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, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis. Proteins associated with inflammation and inflammatory diseases (e.g., whose aberrant expression is a symptom or cause or marker of the disease) include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), TNF-α (tumor necrosis factor-alpha), and C-reactive protein (CRP).

[0322] In some embodiments, the inflammatory disease is selected from the group consisting of postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, and the like. In some embodiments, the term "inflammatory bowel disease" includes inflammatory bowel disease, including ulcerative colitis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

[0323] In some embodiments, the inflammatory disease includes postoperative cognitive dysfunction, which refers to a decline in cognitive function (e.g., memory or executive function (e.g., working memory, reasoning, task adaptability, processing speed, or problem solving)) after surgery.

[0324] In other embodiments, the method of treatment is a method of prevention.For example, the method of treating postoperative cognitive dysfunction can include administering the compound described herein before surgery to prevent postoperative cognitive dysfunction or the symptoms of postoperative cognitive dysfunction, or reduce the severity of the symptoms of postoperative cognitive dysfunction.

[0325] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat an inflammatory disease (e.g., an inflammatory disease described herein) by reducing or eliminating symptoms of the disease. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof may be used as the sole agent in a composition for treating an inflammatory disease (e.g., an inflammatory disease described herein) or in combination with another agent in the composition.

[0326] musculoskeletal disorders In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat a musculoskeletal disorder. As used herein, the term "musculoskeletal disorder" refers to a disease or condition that results in loss of function of a subject's musculoskeletal system (e.g., muscles, ligaments, tendons, cartilage, or bone). Exemplary musculoskeletal disorders that can be treated with a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof include muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, or myotonic muscular dystrophy), polyarteritis, muscular dystrophy (e.g., muscular dystrophy ... Examples of conditions that may be present include: atherosclerosis, 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, fasciculations and contractions syndrome, Friedreich's ataxia, muscle wasting diseases (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

[0327] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat a musculoskeletal disorder (e.g., a musculoskeletal disorder described herein) by reducing or eliminating symptoms of the disorder. In some embodiments, the method of treatment includes treating muscle pain or stiffness associated with a musculoskeletal disorder. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof can be used as the sole agent in a composition or in combination with another agent in the composition to treat a musculoskeletal disorder (e.g., a musculoskeletal disorder described herein).

[0328] metabolic disease In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat a metabolic disease. As used herein, the term "metabolic disease" refers to a disease or condition that affects metabolic processes in a subject. Exemplary metabolic diseases that can be treated with a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0329] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat a metabolic disease (e.g., a metabolic disease described herein) by reducing or eliminating symptoms of the disease. In some embodiments, the method of treatment includes reducing or eliminating symptoms including high blood pressure, high blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, etc. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof can be used as the sole agent in a composition or in combination with another agent in the composition to treat a metabolic disease (e.g., a musculoskeletal disease described herein).

[0330] Methods for increasing protein production In another aspect, the compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof may be useful in applications where it is desirable to increase the output of protein production, for example, in vitro cell-free systems for protein production.

[0331] In some embodiments, the invention features a method for increasing protein expression in a cell or an in vitro expression system, comprising administering to the cell or expression system an effective amount of a compound, wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the method is a method for increasing protein expression by a cell, comprising administering to the cell an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof). In other embodiments, the method is a method for increasing protein expression by an in vitro protein expression system, comprising administering to the in vitro (e.g., cell-free) protein expression system an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof).

[0332] In some embodiments, the invention features methods of increasing protein expression in diseases, disorders, or conditions characterized by abnormal or reduced levels of protein production (e.g., leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating diseases, muscle wasting diseases, or sarcopenia).

[0333] In some embodiments, the compounds described herein are provided as pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. In embodiments of the methods, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is co-administered with a second agent (e.g., a therapeutic agent). In other embodiments of the methods, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is co-administered with a second agent (e.g., a therapeutic agent) administered in a therapeutically effective amount. In embodiments, the second agent is an agent for improving memory.

[0334] Combination therapy In one aspect, the invention features a pharmaceutical composition including a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a second agent (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the second agent (e.g., the second therapeutic agent). In some embodiments, the second agent is an agent for treating cancer, a neurodegenerative disease, leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

[0335] The compounds described herein may be used in combination with other active agents known to be useful in treating cancer, neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or disorders associated with dysfunction of eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway, or with each other and adjunct agents that may not be effective alone but may contribute to the efficacy of the active agent.

[0336] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In other embodiments, the active agents and / or adjunct agents can be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with treatments for cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or disorders associated with dysfunction of eIF2B, eIF2α, or components of the eIF2 pathway or the ISR pathway.

[0337] In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic agent. In embodiments, the second agent is an agent for improving memory. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In embodiments, the second agent is an agent for treating leukodystrophy. In embodiments, the second agent is an agent for treating vanishing white matter disease. In embodiments, the second agent is an agent for treating childhood ataxia due to hypomyelination of the central nervous system. In embodiments, the second agent is an agent for treating intellectual disability syndrome. In embodiments, the second agent is an agent for treating pancreatic cancer. In embodiments, the second agent is an agent for treating breast cancer. In embodiments, the second agent is an agent for treating multiple myeloma. In embodiments, the second agent is an agent for treating myeloma. In embodiments, the second agent is an agent for treating cancer of secretory cells. In embodiments, the second agent is an agent for reducing eIF2α phosphorylation. In an embodiment, the second agent is an agent for inhibiting a pathway activated by eIF2α phosphorylation. In an embodiment, the second agent is an agent for inhibiting a pathway activated by eIF2α. In an embodiment, the second agent is an agent for inhibiting the integrated stress response. In an embodiment, the second agent is an anti-inflammatory agent. In an embodiment, the second agent is an agent for treating postoperative cognitive dysfunction. In an embodiment, the second agent is an agent for treating traumatic brain injury. In an embodiment, the second agent is an agent for treating a musculoskeletal disease. In an embodiment, the second agent is an agent for treating a metabolic disease. In an embodiment, the second agent is an antidiabetic agent.

[0338] anticancer drugs Gonadotropins (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), antitoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., U1 ln, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™) , panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF29 9804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0339] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its normal and accustomed meaning to refer to a chemical composition or compound having anti-neoplastic properties or the ability to inhibit cell growth or proliferation.

[0340] The compounds described herein also may be used in combination with other therapeutic agents, including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), antitoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugates, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugates, etc.), and radioimmunotherapy (e.g., m In, 90 Y, or 131 The antibody may be co-administered with conventional immunotherapeutics, including anti-CD20 monoclonal antibodies conjugated to I or the like.

[0341] In further embodiments, the compounds described herein are optionally conjugated to an antibody directed against a tumor antigen, such as, but not limited to, a radionuclide. 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 It may be co-administered with conventional radiotherapeutic agents, including Bi.

[0342] Further agents In some embodiments, the second agent for use in combination with a compound described herein (e.g., a compound of Formula (I)) or a composition thereof is an agent for use in treating a neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease. In some embodiments, the second agent for use in combination with a compound described herein (e.g., a compound of Formula (I)) or a composition thereof is an agent approved by the FDA or a similar regulatory agency in a country other than the USA to treat a disease, disorder, or condition described herein.

[0343] In some embodiments, second agents for use in treating a neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease include, but are not limited to, antipsychotics, antidepressants, anti-anxiety agents, analgesics, stimulants, sedatives, analgesics, anti-inflammatory agents, benzodiazepines, cholinesterase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, MAO inhibitors, beta-blockers, calcium channel blockers, antacids, or other agents.Exemplary second agents include donepezil, galantamine, rivastigmine, memantine, levodopa, dopamine, pramipexole, ropinirole, rotigotine, doxapram, oxazepam, quetiapine, selegiline, rasagiline, entacapone, benztropine, trihexyphenidyl, riluzole, diazepam, chlorodiazepoxide, lorazepam, alprazolam, buspirone, gepirone, ipsapirone, hydroxyzine, and propranolol. , hydroxyzine, midazolam, trifluoperazine, methylphenidate, atomoxetine, methylphenidate, pemoline, perphenazine, divalproex, valproic acid, sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, trazodone, desvenlafaxine, duloxetine, venlafaxine, amitriptyline, amoxapine, clomipramine, desipramine, imipramine, Nortriptyline, protriptyline, trimipramine, maprotiline, bupropion, nefazodone, vortioxetine, lithium, clozapine, fluphenazine, haloperidol, paliperidone, loxapine, thiothixene, pimozide, thioridazine, risperidone, aspirin, ibuprofen, naproxen, acetaminophen, azathioprine, methotrexate, mycophenolate, leflunomide, dibenzoylmethane, cilostazol-13 Examples of such anti-inflammatory drugs include benzodiazepines, benzodiazepines, benzodiazepines (e.g., benzodiazepines), ...

[0344] Naturally derived agents or dietary supplements can also be used in conjunction with the compound of formula (I) or its composition to treat neurodegenerative, inflammatory, musculoskeletal, or metabolic diseases. Exemplary naturally derived agents or dietary supplements include omega-3 fatty acids, carnitine, citicoline, curcumin, ginkgo, vitamin E, vitamin B (e.g., vitamin B5, vitamin B6, or vitamin B12), huperzine A, phosphatidylserine, rosemary, caffeine, melatonin, chamomile, St. John's wort, tryptophan, etc. [Example]

[0345] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any way.

[0346] Synthesis protocol The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthetic protocols described that would be known to those skilled in the art. It will be recognized that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. General schemes relating to methods for making exemplary compounds of the present invention are further described in the section entitled "Methods of Making the Compounds."

[0347] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, many protecting groups, and their introduction and removal, are described in Greene et al., "Protecting Groups in Organic Synthesis," Second Edition, Wiley, New York, 1991, and the references cited therein.

[0348] Abbreviation APCI for atmospheric pressure chemical ionization; DCI for desorption chemical ionization; DMSO for dimethyl sulfoxide; ESI for electrospray ionization; HPLC for high performance liquid chromatography; LC / MS for liquid chromatography / mass spectrometry; MS for mass spectrum; NMR for nuclear magnetic resonance; psi for pounds per square inch; TLC for thin layer chromatography.

[0349] Example 1: N,N'-(bicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide] (Compound 100) A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with bicyclo[2.2.2]octane-1,4-diamine dihydrochloride (PharmaBlock, CAS No. 2277-93-2, 100 mg, 0.455 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (205 mg, 1.001 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU®, 485 mg, 1.092 mmol). The contents of the flask were placed under a dry nitrogen atmosphere, and then N,N-dimethylformamide (10 mL) was added via syringe. The stirred suspension was cooled to 0°C, and then N,N-diisopropylethylamine (0.66 mL, 3.78 mmol) was introduced dropwise via syringe (the reaction mixture turned bright yellow). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was diluted with water, and the white insoluble solid was collected by filtration. The solid was treated with methanol and then collected by filtration. The title compound was thus obtained as a white solid (93.5 mg, 40% yield). 1 H NMR (DMSO-d6) δ ppm 7.51-7.44 (m, 4H), 7.02 (dd, J = 11.4, 2.9 Hz, 2H), 6.81 (ddd, J = 9.0, 2.8, 1.2 Hz, 2H), 4.43 (s, 4H), 1.90 (s, 12H). MS (+ESI) m / z 513 (M+H) + ,MS(-ESI)m / z 511(MH) - .

[0350] Example 2: 2-(4-chloro-3-fluorophenoxy)-N-[4-(2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide (Compound 101) Example 2A: tert-Butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate Bicyclo[2.2.2]octane-1,4-diamine dihydrochloride (PharmaBlock, CAS No. 2277-93-2, 200 mg, 1.43 mmol) was dissolved in methanol (5 mL). The solution was basified with 50% aqueous sodium hydroxide. After stirring for 15 minutes (slightly exothermic), the mixture was diluted with water and brine and extracted with dichloromethane (3 × 150 mL). The combined organic layers were dried (NaSO) and filtered. The filtrate was concentrated under reduced pressure to give the free base as a white solid. The free base, bicyclo[2.2.2]octane-1,4-diamine (176 mg, 1.255 mmol), di-tert-butyl dicarbonate (274 mg, 1.255 mmol), and tetrahydrofuran (100 mL) were stirred at ambient temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The organic layer was washed with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title intermediate as an off-white solid (258 mg, 86% yield). 1 H NMR (methanol-d4) δ ppm 1.91-1.85 (m, 7H), 1.65-1.60 (m, 2H), 1.40 (s, 12H). MS (DCI-NH3) m / z 241 (M+H) + .

[0351] Example 2B: tert-Butyl (4-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octan-1-yl)carbamate A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with 2-(4-chloro-3-fluorophenoxy)acetic acid (234 mg, 1.144 mmol), tert-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate (Example 2A, 250 mg, 1.040 mmol), and COMU® (535 mg, 1.248 mmol). The contents of the flask were placed under a dry nitrogen atmosphere, and N,N-dimethylformamide (4 mL) was introduced via syringe. N,N-diisopropylethylamine (0.545 mL, 3.12 mmol) was then added dropwise via syringe. The reaction mixture was stirred at ambient temperature for 19 hours. The reaction mixture was diluted with water (pH = 10). The insoluble beige solid was collected by filtration and rinsed thoroughly with water. The material was purified by column chromatography on an Analogix® IntelliFlash™-310 (Isco RediSep® 40 g silica gel cartridge, 70:30 to 0:100 heptane / ethyl acetate). Fractions 15-31 were combined and concentrated under reduced pressure to give the title intermediate as a white solid (69.5 mg, 15.65% yield). 1 H NMR (CDCl3) δ□ppm 7.31 (t, J = 8.6 Hz, 1H), 6.73 (dd, J = 10.3, 2.9 Hz, 1H), 6.64 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 6.07 (s, 1H), 4.32 (s, 1H), 4.31 (s, 2H), 2.05-1.91 (m, 12H), 1.42 (s, 9H). MS (+ESI)m / z 426(M+H) + , m / z 853 (2M+H) + MS(-ESI) m / z 425(MH) - .

[0352] Example 2C: N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride A 4 mL vial equipped with a magnetic stir bar was charged with tert-butyl (4-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octan-1-yl)carbamate (Example 2B, 69 mg, 0.162 mmol). Methanol (1 mL) was added, and the resulting solution was stirred at ambient temperature while 4 M HCl in dioxane (1.2 mL, 4.80 mmol) was added via syringe. The reaction mixture was stirred at ambient temperature for 89 hours. The volatiles were removed under reduced pressure to provide the title intermediate as a white solid (58.3 mg, 99% yield). 1 H NMR (methanol-d4) δ ppm 7.36 (t, J = 8.7 Hz, 1H), 6.89 (dd, J = 11.0, 2.9 Hz, 1H), 6.79 (ddd, J = 9.0, 2.9, 1.3 Hz, 1H), 4.43 (s, 2H), 2.15-2.08 (m, 6H), 1.94-1.87 (m, 6H). MS(+ESI) m / z 327(M+H) + MS(-ESI) m / z 325(MH) - .

[0353] Example 2D: 2-(4-chloro-3-fluorophenoxy)-N-[4-(2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide A 4 mL vial equipped with a magnetic stir bar was charged with N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride (Example 2C, 25 mg, 0.069 mmol), 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid (18.26 mg, 0.083 mmol), and COMU™ (41.3 mg, 0.096 mmol). The vial was sealed with a septum screw cap. The cap was sealed and the contents were placed under a dry nitrogen atmosphere. N,N-Dimethylformamide (0.5 mL) was introduced via syringe, and the stirred reaction mixture was treated dropwise with N,N-Diisopropylethylamine (0.1 mL, 0.573 mmol). The reaction mixture was stirred at ambient temperature for 19 hours. An aliquot was partitioned between water and ethyl acetate. The organic layer was checked by TLC (80:20 ethyl acetate / heptane). The R was higher than either starting material. f A major new spot high in HCl was evident. LC / MS confirmed that this major new material had the exact mass of the title compound. The reaction bulk was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid. This crude solid was purified by column chromatography on an Analogix® IntelliFlash™-310 (Isco RediSep® 12 g silica gel cartridge, 70:30 heptane / ethyl acetate) to give a white solid, which was stirred with tert-butyl methyl ether. The solvent was decanted off, and the solid was dried on a rotary evaporator to give the title compound as a white solid (11.0 mg, 30.2% yield). 1H NMR (CDCl3) δ□ppm 8.43 (d, J = 2.9 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.34-7.28 (m, 2H), 6.73 (dd, J = 10.3, 2.9 Hz, 1H), 6.65 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 6.10 (d, J = 2.8 Hz, 2H), 4.45 (s, 2H), 4.33 (s, 2H), 2.08 (s, 12H).MS(+ESI)m / z 530(M+H) + MS(-ESI) m / z 528(MH) - .

[0354] Example 3: N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-(4-chlorophenyl)propanamide (Compound 102) Example 3A: 3-(4-chlorophenyl)propanoyl chloride A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with white crystals of 3-(4-chlorophenyl)propanoic acid (Aldrich, CAS No. 2019-34-3, 100 mg, 0.542 mmol). The flask was sealed with a septum attached to a bubbler. Anhydrous dichloromethane (2 mL) was introduced via syringe to give a solution, which was stirred at ambient temperature. Oxalyl chloride (0.142 mL, 1.625 mmol) was added via syringe, followed by N,N-dimethylformamide (0.042 μL, 0.542 μmol), at which point gas evolution was evident. The reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under reduced pressure to give a pale yellow oil, which was used in the next step.

[0355] Example 3B: N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-(4-chlorophenyl)propanamide Example 3A was redissolved in dichloromethane (3 mL), and then a suspension of N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride (Example 112A, 174 mg, 0.542 mmol) in dichloromethane (10 mL) was added to the reaction mixture. The mixture was stirred at ambient temperature under a dry nitrogen atmosphere, and triethylamine (0.302 mL, 2.167 mmol) was introduced via syringe. The reaction mixture was stirred at ambient temperature for 20.5 hours. The reaction mixture was treated with aqueous citric acid. The organic layer was washed with brine, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to give a beige solid, which was treated with tert-butyl methyl ether. The insoluble cream-colored solid was collected by filtration and purified by column chromatography on an Analogix® IntelliFlash™-310 (Isco RediSep® 24 g silica gel cartridge, 90:10 to 85:15 dichloromethane / acetone, monitoring wavelength: 220 nm) to give the title compound as a white solid (97.9 mg, 40% yield). 1 H NMR (DMSO-d6) δ□ppm 8.68 (s, 1H), 8.40 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.34-7.30 (m, 2H), 7.23-7.19 (m, 2H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.47 (s, 2H), 2.77 (dd, J = 8.6, 6.9 Hz, 2H), 2.31 (dd, J = 8.5, 7.1 Hz, 2H), 2.20 (s, 6H).MS(+ESI)m / z 451(M+H) + MS(-ESI) m / z 449(MH) - .

[0356] Example 4: N,N'-(pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7]octane-1,4-diyl)bis[2-(4-chlorophenoxy)-acetamide] (Compound 103) Example 4A: Cubane-1,4-diamine dihydrochloride A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with cubane-1,4-dicarboxylic acid (Aldrich, CAS No. 32846-66-5, 800 mg, 4.16 mmol), triethylamine (1.16 mL, 8.32 mmol), diphenylphosphoryl azide (1.8 mL, 8.35 mmol), and t-butanol (12.8 mL). The flask was fitted with a reflux condenser equipped with a calcium sulfate drying tube, and the reaction mixture was stirred at reflux for 16 hours. The reaction mixture was allowed to cool to ambient temperature and then poured into saturated aqueous sodium bicarbonate (50 mL). The precipitate was collected by filtration and washed with water. The solid was dissolved in a hot mixture of dichloromethane, tetrahydrofuran, ethyl acetate, and ethanol. The warm solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a beige solid, which was treated with ether and collected by filtration. The crude bis-(tert-butoxy-carbonyl)-protected intermediate was suspended in methanol (30 mL) and treated with 4 M HCl in dioxane (30 mL, 120 mmol, 47.4 equiv.). The reaction mixture was stirred at ambient temperature for 4 hours. The volatiles were removed under reduced pressure to give a light brown solid, which was treated with diethyl ether and then ethyl acetate. The solid was dissolved in hot methanol and treated with acetone to induce precipitation. The title intermediate solid was collected by filtration (125 mg, 14.5% yield). 1 H NMR (methanol-d4) δ ppm 4.23 (s, 6H). MS (DCI-NH3) m / z 135 (M+H) + , m / z 152 (M+NH4) + , m / z 169 (M+NH4+NH3) + .

[0357] Example 4B: N,N'-(pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 ]octane-1,4-diyl)bis[2-(4-chlorophenoxy)acetamide] A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with cubane-1,4-diamine dihydrochloride (Example 4A, 77 mg, 0.372 mmol). The contents of the flask were placed under a dry nitrogen atmosphere, and then a solution of 2-(4-chlorophenoxy)acetyl chloride (Aldrich, CAS No. 4122-68-3, 160 mg, 0.781 mmol) in dichloromethane (4 mL) was introduced via syringe. The stirred suspension was treated with triethylamine (0.4 mL, 2.87 mmol). The reaction mixture was stirred at ambient temperature under a dry nitrogen atmosphere for 17 hours. The volatiles were removed under reduced pressure, and the solid residue was partitioned between tert-butyl methyl ether and ice water. The material insoluble in either layer was considered the product and collected by filtration. The crude beige solid was dissolved in a warm mixture of tetrahydrofuran and ethanol. Silica gel (1.2 g) was added, and the solvent was removed in vacuo. The silica gel-adsorbed mixture was placed on top of a Practichem 4 g silica gel cartridge from which the top 1.6 g of silica gel had been removed. The cartridge was reassembled and connected to the top of an Isco RediSep® 24 g silica gel cartridge. The assembly was eluted with 100:0 to 90:10 dichloromethane / acetone on an Analogix® IntelliFlash™-310 (monitoring wavelength: 220 nm) to give the title compound as a white solid (25.6 mg, 14.6% yield). 1 H NMR (DMSO-d6) δ□ppm 8.82 (s, 2H), 7.40-7.30 (m, 4H), 6.98 (d, J = 8.9 Hz, 4H), 4.49 (s, 4H), 3.96 (s, 6H).MS(+ESI)m / z 471(M+H) + MS(-ESI) m / z 469(MH) - .

[0358] Example 5: N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanamide (Compound 104) Example 5A: Methyl 3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanoate A 50 mL round-bottom flask equipped with a magnetic stir ...

Claims

1. Formula (I): 【Chem.99】 Formula (I) During the ceremony: D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl, or a cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or cubanyl is selected from 1 to 4 R Ｘ optionally substituted by a group; L １ and L ２ are each independently C １ -C ６ Alkylene, C ２ -C ６ Alkenylene, 2- to 7-membered heteroalkylene, O, or NR Ｃ where each C １ -C ６ Alkylene, C ２ -C ６ Alkenylene or 2- to 7-membered heteroalkylene is 1 to 5 R Ｘ and optionally substituted by R １ and R ２ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy-C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, silyloxy-C １ -C ６ is alkyl; A and W are each independently phenyl or 5- to 6-membered heteroaryl, wherein each phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R Ｙ and optionally substituted by Each R Ｘ is 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, C １ -C ６ Alkoxy-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 , -S(O) ２ R Ｄ , -OS(O)R Ｄ , -OS(O) ２ R Ｄ , and G ２ are independently selected from the group consisting of: Each R Ｙ is 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, 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 , -S(R Ｆ ) ｍ , -S(O)R Ｄ , -S(O) ２ R Ｄ , and G １ or Two R on adjacent atoms Ｙ The groups, together with the atoms to which they are attached, are composed of 1 to 5 R Ｘ forming a fused 3-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted by Each G １ and G ２ are independently ３ -C ６ cycloalkyl, 4- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, wherein each C ３ -C ６ cycloalkyl, 4- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is selected from 1 to 3 R Ｚ and optionally substituted by Each R Ｚ is C 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 are independently selected from the group consisting of: Each R Ａ are independently hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , —C(O)OH, or —C(O)OR Ｄ and R Ｂ and R Ｃ are each independently hydrogen or C １ -C ６ is alkyl; or R Ｂ and R Ｃ together with the atoms to which they are attached, form 1 to 3 R Ｚ forming a 3- to 7-membered heterocyclyl ring optionally substituted by Each R Ｄ are independently １ -C ６ alkyl, 2- to 7-membered heteroalkyl, or halo-C １ -C ６ alkyl, where each C １ -C ６ alkyl, 2- to 7-membered heteroalkyl, or halo-C １ -C ６ alkyl is 1 to 5 R Ｇ and optionally substituted by 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 aryl or 5- to 6-membered heteroaryl, and each aryl or 5- to 6-membered heteroaryl is selected from 1 to 5 R Ｈ and optionally substituted by Each R Ｈ are independently １ -C ６ Alkyl or halo-C １ -C ６ is alkyl; m is 1, 3, or 5; t is 0 or 1; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

2. 2. The compound of claim 1, wherein D is a bridged monocyclic cycloalkyl or cubanyl, each of which is optionally substituted with 1 to 4 RX groups.

3. D is a bridged 4-6 membered monocyclic cycloalkyl or cycloalkyl, each of which is selected from 1-4 R Ｘ The compound of any one of claims 1 to 2, optionally substituted by a group.

4. D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, each of which is selected from 1 to 4 R Ｘ The compound of any one of claims 1 to 3, optionally substituted by a group.

5. D: 【Chemistry 100】 The compound according to any one of claims 1 to 4, selected from:

6. D: 【Chemistry 101】 The compound according to any one of claims 1 to 5, selected from:

7. D is one R Ｘ The compound of any one of claims 1 to 6, substituted by:

8. R Ｘ But C １ -C ６ Alkyl, oxo, halo, cyano, -OR Ａ , -OS(O) ２ R Ｄ , -S(O) ２ R Ｄ , -SR Ｅ , N.R. Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH,NR Ｂ R Ｃ , or G ２ (For example, CH ３ , oxo, fluoro, OH, cyano, OCH ３ , N.H. ２ , N(CH ３ ) ２ , NHC(O)CH ３ , OC(O)CH ３ , C(O)NH ２ , OS(O) ２ CH ３ , -S(O) ２ CH ３ , -S(O) ２ CH ２ CH ３ , C(O)OH, OC(O)R Ｄ , —C(O)CH ３ , or -SCH ３ 8. The compound according to claim 1, wherein

9. G ２ The compound of claim 8, wherein is aryl or 5-6 membered heteroaryl (e.g., oxadiazolyl, or tetrazolyl).

10. D is 0 R Ｘ The compound of any one of claims 1 to 6, substituted by:

11. D is 【Chemical Engineering 102】 The compound according to any one of claims 1 to 6 and 10,

12. L １ and L ２ At least one of the following is independently 1 to 5 R Ｘ 12. The compound of any one of claims 1 to 11, which is a 2- to 7-membered heteroalkylene optionally substituted by:

13. L １ and L ２ and each independently represent 1 to 5 R Ｘ 13. The compound of any one of claims 1 to 12, which is a 2- to 7-membered heteroalkylene optionally substituted by:

14. L １ and L ２ One of them is independently C １ -C ６ Alkylene or C ２ -C ６ alkenylene, and L １ and L ２ and the other is independently 2- to 7-membered heteroalkylene, wherein each C １ -C ６ Alkylene, C ２ -C ６ Alkenylene and 2- to 7-membered heteroalkylene are each a group consisting of 1 to 5 R Ｘ The compound of any one of claims 1 to 13, optionally substituted by:

15. Each R Ｘ But independently, C １ -C ６ Alkyl, oxo, or —C(O)R Ｄ (For example, CH ３ , oxo, or C(O)CH ３ 15. The compound according to any one of claims 12 to 14, wherein

16. L １ and L ２ are each CH ２ O− ＊ CH ２ CH ２ − ＊ CH ２ CH ２ CH ２ − ＊ CH ２ − ＊ CH ２ C(O)− ＊ CH=CH− ＊ CH ２ CH ２ O− ＊ CH ２ OCH ２ − ＊ CH ２ OCH ２ CH ２ − ＊ CH ２ CH ２ CH ２ O− ＊ CH ２ CH ２ OCH ２ − ＊ NHCH ２ − ＊ CH ２ NH− ＊ CH ２ N(CH<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, S(O) ２ CH- ＊ , S(O) ２ CH ２ CH ２ - ＊ , S(O) ２ CH ２ CH ２ O- ＊ , or C.H. ２ C(O)- ＊ are selected independently from ＊ 16. The compound of any one of claims 1 to 15, wherein "" indicates the points of attachment to A and W, respectively.

17. L １ が、CH ２ O- ＊ &CH=CH- ＊ からますましてててまする、L ２ が、CH ２ O- ＊ 、H ２ CH ２ - ＊ 、H ２ CH ２ CH ２ - ＊ 、H ２ - ＊ 、H ２ C(O)- ＊ 、CH=C- ＊ 、H ２ CH ２ O- ＊ 、H ２ OCH ２ - ＊ 、H ２ OCH ２ CH ２ - ＊ 、H ２ CH ２ CH ２ O- ＊ 、H ２ CH ２ OCH ２ - ＊ 、NHCH ２ - ＊ 、H ２ NH- ＊ 、H ２ N(CH) ３ )- ＊ 、H ２ N(CH) ３ )C(O)- ＊ 、H ２ N(C(O)CH ３ )- ＊ 、H ２ \H (OH)- ＊ ,\H (OH)- ＊ , CH (OH) CH ２ CH ２ - ＊ ,H ２ \H (OH)- ＊ 、H ２ NHC(O)- ＊ 、NHC(O)OCH ２ - ＊ , O- ＊ , NH- ＊ , S(O) ２ CH- ＊ , S(O) ２ CH ２ CH ２ - ＊ , S(O) ２ CH ２ CH ２ O- ＊ , or C.H. ２ C(O)- ＊ are selected independently from ＊ 17. The compound of any one of claims 1 to 16, wherein "" indicates the points of attachment to A and W, respectively.

18. The compound according to any one of claims 1 to 17, wherein t is 1.

19. The compound according to any one of claims 1 to 17, wherein t is 0.

20. R １ and R ２ are each independently hydrogen, C １ -C ６ Alkyl, Hydroxyl-C １ -C ６ Alkyl, or silyloxy-C １ -C ６ The compound of any one of claims 1 to 19, which is alkyl.

21. R １ and R ２ is independently hydrogen, and R １ and R ２ The other is independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Hydroxyl-C １ -C ６ Alkyl, or silyloxy-C １ -C ６ The compound of any one of claims 1 to 20, which is alkyl.

22. R １ and R ２ are independently hydrogen, ＊ -CH ３ , ＊ -CH ２ CH ２ OH, or ＊ -CH ２ CH ２ OSi(CH ３ ) ２ C(CH ３ ) ３ And " ＊ 22. The compound of any one of claims 1 to 21, wherein "-" indicates the point of attachment to the nitrogen atom.

23. R １ and R ２ is independently hydrogen, and R １ and R ２ the other is independently hydrogen, ＊ -CH ３ , ＊ -CH ２ CH ２ OH, or ＊ -CH ２ CH ２ OSi(CH ３ ) ２ C(CH ３ ) ３ And " ＊ 23. The compound of any one of claims 1 to 22, wherein "-" indicates the point of attachment to the nitrogen atom.

24. R １ and R ２ The compound according to any one of claims 1 to 23, wherein each is independently hydrogen.

25. A and W each independently represent 1 to 5 R Ｙ The compound of any one of claims 1 to 24, which is phenyl or 5-6 membered heteroaryl optionally substituted by a group.

26. A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Ｙ The compound of any one of claims 1 to 24, optionally substituted by a group.

27. A and W are each: 【Chemistry 103】 26. The compound of any one of claims 1 to 25, independently selected from:

28. A is phenyl, W is phenyl or 5-6 membered heteroaryl, and A and W each represent 1-5 R Ｙ and each R Ｙ But independently, 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 , -NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OH, -C(O)OR Ｄ , -S(R Ｆ ) ｍ , -S(O) ２ R Ｄ , or G １ The compound according to any one of claims 1 to 27,

29. A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Ｙ 29. The compound of any one of claims 1 to 28, optionally substituted by:

30. A: 【Chemical 104】 The compound according to any one of claims 1 to 29, selected from:

31. W is: 【Chemistry 105】 The compound according to any one of claims 1 to 30, selected from:

32. Each R Ｙ are independently chloro, fluoro, iodo, CF ３ , CHF ２ , C.H. ２ CF ３ , C.H. ３ , C.H. ２ CH ３ , C(CH ３ ) ２ OH, OCH ３ , OCH ２ CH ３ , OCF ３ , S(O) ２ CH ３ , S(O) ２ CH ２ CH ２ CH ３ , CN, N(CH ３ ) ２ , SF ５ , S.C.H. ３ , N.H. ２ , C(CH) ３ , CH(CH ３ ) ２ , C.H. ２ C.N., C.H. ２ NH ２ , CH(OH)CH ３ , C(OH)(CH ３ )CF ３ , S(O) ２ CH ３ , C(O)CH ３ , C(O)OCH ３ , C(O)OH, OCHF ２ or G １ The compound according to any one of claims 1 to 31,

33. A and W are each two R on adjacent atoms. Ｙ and the two R Ｙ together with the atoms to which they are attached, form 1 to 5 R Ｘ 32. The compound of any one of claims 1 to 31, wherein the compound forms a 3- to 7-membered fused cycloalkyl, 3- to 7-membered fused heterocyclyl, fused aryl or 5- to 6-membered fused heteroaryl ring optionally substituted by

34. The two R Ｙ together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is selected from 1 to 5 R Ｘ 34. The compound of claim 33, optionally substituted by:

35. Each R Ｘ But independently, C １ -C ６ Alkyl or halo (e.g., CH ３ or fluoro).

36. G １ is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is selected from 1 to 5 R Ｚ 36. The compound of any one of claims 1 to 35, optionally substituted by:

37. Each R Ｚ But independently, C １ -C ６ Alkyl (e.g., CH ３ 37. The compound of claim 36, wherein the aryl group is aryl, ...

38. The compound of formula (I) is represented by formula (I-b): 【Chemistry 106】 During the ceremony: D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, or bicycle[3.1.1]heptane, each of which contains 1 to 4 R Ｘ optionally substituted by a group; L １ and L ２ are each independently CH ２ O− ＊ CH ２ CH ２ − ＊ CH ２ CH ２ CH ２ − ＊ CH ２ − ＊ CH ２ C(O)− ＊ CH=CH− ＊ CH ２ CH ２ O− ＊ CH ２ OCH ２ − ＊ CH ２ OCH ２ CH ２ − ＊ CH ２ CH ２ CH ２ O− ＊ CH ２ CH ２ OCH ２ − ＊ NHCH ２ − ＊ CH ２ NH− ＊ CH ２ N(CH ３ )− ＊ CH<00�0549>N(CH ３ )C(O)− ＊ CH ２ N(C(O)CH ３ )− ＊ CH ２ CH(OH)− ＊ CH(OH)− ＊ CH(OH)CH ２ CH ２ − ＊ CH ２ CH(OH)− ＊ CH ２ NHC(O)− ＊ NHC(O)OCH ２ − ＊ O− ＊ NH− ＊ , S(O) ２ CH- ＊ , S(O) ２ CH ２ CH ２ - ＊ , S(O) ２ CH ２ CH ２ O- ＊ , or C.H. ２ C(O)- ＊ And "- ＊ " indicates the points of attachment to A and W, respectively; R １ and R ２ are each independently hydrogen, CH ３ , C.H. ２ CH ２ OH, or CH ２ CH ２ OSi(CH ３ ) ２ C(CH ３ ) ３ and A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is selected from 1 to 5 R Ｙ optionally substituted by a group; Each R Ｘ is CH ３ , oxo, fluoro, OH, cyano, OCH ３ , N.H. ２ , N(CH ３ ) ２ , NHC(O)CH ３ , OC(O)CH ３ , C(O)NH ２ , OS(O) ２ CH ３ , -S(O) ２ CH ３ , -S(O) ２ CH ２ CH ３ , C(O)OH, OC(O)R Ｄ , —C(O)CH ３ , -SCH ３ , or G ２ are independently selected from Each R Ｙ are independently chloro, fluoro, iodo, CF ３ , CHF ２ , C.H. ２ CF ３ , C.H. ３ , C.H. ２ CH ３ , C(CH ３ ) ２ OH, OCH ３ , OCH ２ CH ３ , OCF ３ , S(O) ２ CH ３ , S(O) ２ CH ２ CH ２ CH ３ , CN, N(CH ３ ) ２ , SF ５ , S.C.H. ３ , N.H. ２ , C(CH) ３ , CH(CH ３ ) ２ , C.H. ２ C.N., C.H. ２ NH ２ , CH(OH)CH ３ , C(OH)(CH ３ )CF ３ , S(O) ２ CH ３ , C(O)CH ３ , C(O)OCH ３ , C(O)OH, OCHF ２ Or G １ or Two R on adjacent atoms Ｙ groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which may contain one to two R Ｘ and optionally substituted by G １ and G ２ is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is selected from 1 to 2 R Ｚ and optionally substituted by Each R Ｄ is 1 to 5 R Ｇ CH optionally substituted by ２ is O; Each R Ｇ are independently 1 to 5 R Ｈ pyridyl optionally substituted by Each R Ｈ are independently ３ and Each R Ｚ are independently CH ３ and t is 0 or 1; 38. The compound of any one of claims 1 to 37, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

39. The compound of formula (I) is represented by formula (I-c): 【Chemistry 107】 In the ceremony, L １ , L ２ , R １ , R ２ , A.W.,R. Ｘ , and t are each as defined for formula (I); 39. The compound of any one of claims 1 to 38, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

40. The compound of formula (I) is represented by formula (I-d): 【Chemistry 108】 In the ceremony, L １ , L ２ , A, and W are each as defined for formula (I); 40. The compound of any one of claims 1 to 39, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

41. The compound of formula (I) is represented by formula (I-e): 【Chemistry 109】 In the ceremony, L ２ , A.W.,R. １ , R ２ and t are each as defined for formula (I); 40. The compound of any one of claims 1 to 39, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

42. The compound of formula (I) is represented by formula (If): 【Chemical 110】 In the ceremony, L ２ ,W.,R. Ｙ , R １ , R ２ and t are each as defined for formula (I); 42. The compound of any one of claims 1 to 39 and 41, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

43. The compound of formula (I) is represented by formula (I-g): 【Chemistry 111】 In the ceremony, L １ , L ２ , R １ , R ２ , A.W.,R. Ｘ , and t are each as defined for formula (I); 39. The compound of any one of claims 1 to 38, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

44. The compound of formula (I) is represented by formula (I-h): 【Chemistry 112】 In the ceremony, L ２ , R １ , R ２ , A.W.,R. Ｘ , and t are each as defined for formula (I); 44. The compound of any one of claims 1 to 38 and 43, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

45. The compound of formula (I) is represented by formula (I-i): 【Chemistry 113】 In the ceremony, L ２ , R １ , R ２ ,W.,R. Ｘ , R Ｙ , and t are each as defined for formula (I); 45. The compound of any one of claims 1 to 38 and 43 to 44, wherein the compound is:

46. The compound of formula (I) is represented by formula (I-j): 【Chemistry 114】 In the ceremony, L １ , L ２ , R １ , R ２ , A.W.,R. Ｘ , and t are each as defined for formula (I); 39. The compound of any one of claims 1 to 38, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

47. The compound of formula (I) is represented by formula (I-k): 【Chemical 115】 In the ceremony, L ２ , R １ , R ２ , A.W.,R. Ｘ , and t are each as defined for formula (I); 47. The compound of any one of claims 1 to 38 and 46, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

48. The compound of formula (I) is represented by formula (I-l): 【Chemistry 116】 In the ceremony, L ２ , R １ , R ２ ,W.,R. Ｘ , R Ｙ , and t are each as defined for formula (I); 48. The compound of any one of claims 1 to 38 and 46 to 47, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

49. 10. The compound of any one of the preceding claims, selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

50. 10. A pharmaceutically acceptable composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier.

51. 1. A composition for use in treating a neurodegenerative disease, leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, or a metabolic disease in a subject, the composition comprising a compound of formula (I) as defined in any of the preceding claims or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

52. 52. The composition of claim 51, wherein the neurodegenerative disease comprises leukodystrophy, leukoencephalopathy, hypomyelinating or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction, or brain injury (e.g., traumatic brain injury or toxicant-induced brain injury).

53. 53. The composition of any one of claims 51 or 52, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia due to hypomyelination of the central nervous system, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

54. 54. The composition of any one of claims 51 to 53, wherein the neurodegenerative disease comprises vanishing white matter disease.

55. 52. The composition of claim 51, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells.

56. The inflammatory disease may be postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, chloasma, cholangitis ...

52. The composition of claim 51, comprising an agent selected from the group consisting of: Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

57. 52. The composition of claim 51, wherein the musculoskeletal disorder comprises muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, or myotonic 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, fasciculations, Friedreich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

58. 52. The composition of claim 51, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

59. 59. The composition of any one of claims 51 to 58, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition thereof, in combination with a second agent (e.g., an agent for treating cancer, a neurodegenerative disease, leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway).

60. A composition for use in 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 the ISR pathway, comprising a compound of formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

61. The composition of claim 60, wherein the modulation comprises increased eIF2B activity or level, increased eIF2α activity or level, or increased activity or level of a component of the eIF2 pathway or ISR pathway.

62. 61. The composition of claim 60, wherein the disease can be caused by a mutation in a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway).

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