Modulatoren eines integrierten spannungswegs

Abstract

Provided herein are compounds, compositions, and methods useful for the modulation of elF2B, for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

Description

[0001] MODULATORS OF THE INTEGRATED STRESS PATHWAY

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 580,726, filed November 2, 2017 and U.S. Provisional Application No. 62 / 643,059, filed March 14, 2018, which are incorporated herein by reference in their entirety.

[0004] BACKGROUND

[0005] In metazoa, diverse stress signals converge at a single phosphorylation event at serine 51 of a common effector, the translation initiation factor eIF2a. This step is carried out by four eIF2a kinases in mammalian cells: PERK, which responds to an accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 to amino acid starvation and UV light, PKR to viral infection and metabolic stress, and HRI to heme deficiency. This collection of signaling pathways has been termed the "integrated stress response" (ISR), as they converge on the same molecular event. eIF2a phosphorylation results in an attenuation of translation with

[0006] consequences that allow cells to cope with the varied stresses (Wek, R.C. et al, Biochem Soc Trans (2006) 34(Pt 1):7- 11).

[0007] eIF2 (which is comprised of three subunits, α, β and γ) binds GTP and the initiator Met- tRNA to form the ternary complex (eIF2-GTP-Met-tRNA;), which, in turn, associates with the 40S ribosomal subunit scanning the 5'UTR of mRNAs to select the initiating AUG codon. Upon phosphorylation of its a-subunit, eIF2 becomes a competitive inhibitor of its GTP- exchange factor (GEF), eIF2B (Hinnebusch, A.G. and Lorsch, J.R. Cold Spring Harbor Perspect Biol (2012) 4(10)). The tight and nonproductive binding of phosphorylated eIF2 to eIF2B prevents loading of the eIF2 complex with GTP, thus blocking ternary complex formation and reducing translation initiation (Krishnamoorthy, T. et al, Mol Cell Biol (2001) 21(15):5018-

[0008] 5030). Because eIF2B is less abundant than eIF2, phosphorylation of only a small fraction of the total eIF2 has a dramatic impact on eIF2B activity in cells.

[0009] eIF2B is a complex molecular machine, composed of five different subunits, eIF2B l through eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with a partially homologous subunit eIF2B3, constitutes the "catalytic core" (Williams, D.D. et al, / Biol Chem (2001) 276:24697-24703). The three remaining subunits (eIF2B l , eIF2B2, and eIF2B4) are also highly homologous to one another and form a "regulatory sub-complex" that provides binding sites for eIF2B's substrate eIF2 (Dev, K. et al, Mol Cell Biol (2010) 30:5218- 5233). The exchange of GDP with GTP in eIF2 is catalyzed by its dedicated guanine nucleotide exchange factor (GEF) eIF2B. eIF2B exists as a decamer (BI2 B22 B32 B42 B52) or dimer of two pentamers in cells (Gordiyenko, Y. et al, Nat Commun (2014) 5:3902; Wortham, N.C. et al,

[0010] FASEB J (2014) 28:2225-2237). Molecules such as ISRIB interact with and stabilize the eIF2B dimer conformation, thereby enhancing intrinsic GEF activity and making cells less sensitive to the cellular effects of phosphorylation of eIF2D (Sidrauski, C. et al, eLife (2015) e07314;

[0011] Sekine, Y. et al, Science (2015) 348: 1027-1030). As such, small molecule therapeutics that can modulate eIF2B activity may have the potential to attenuate the PERK branch of the UPR and the overall ISR, and therefore may be used in the prevention and / or treatment of various diseases, such as a neurodegenerative disease, a leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, or a metabolic disease.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention features compounds, compositions, and methods for the modulation of eIF2B (e.g., activation of eIF2B) and the attenuation of 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 Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof. In other embodiments, the present invention features methods of using a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof for the treatment of a disease or disorder, e.g., a neurodegenerative disease, a leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway (e.g., eIF2 pathway).

[0014] In one aspect, (I):

[0015] Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1; L1and L2are each independently Cj-C alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NR , wherein each Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally

[0016] L I 2

[0017] substituted with 1-5 R ; R and R are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy- C2-C6alkyl, hydroxy-C2-C6alkyl, silyloxy-C2-C6alkyl, G1-0-C2-C6alkyl, H02C-d-C6alkyl, or C1-C6 alkyl-C(0)2-Ci-C6 alkyl; each RLis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkoxy, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-d-Ce alkyl, d-C6alkoxy-d-d alkyl, H02C-d-d alkyl, d- alkyl-dO)2-d-d alkyl, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2; or 2 geminal RLgroups together with the carbon to which they are attached form a cyclopropyl moiety; RN1is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, H02C-Ci-C6 alkyl, Q- d alkyl-C(0)2-Ci-C6 alkyl, phenoxy-Ci-C6 alkyl (wherein phenoxy is optionally substituted with 1-3 halogens), -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD; A and W are each independently aryl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY; each Rxis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, C1-C6 alkyl-Ci-C6 alkoxy, C1-C6 alkoxy-Ci-C6 alkoxy, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, =CHC(0)ORD, =CHC(0)OH, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -

[0018] D 2 X

[0019] OS(0)2R , and G ; or 2 geminal R groups together with the carbon to which they are attached form an oxirane moiety; each RYis independently selected from the group consisting of hydrogen, C1-C6 alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkoxy, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, -S(RF)m, -S(0)RD, -S(0)2RD, and G1; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx; each G1and G2is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 Rz; each Rzis independently selected from the group consisting of Ci-C6alkyl, hydroxy-Ci-Ce alkyl, halo-Ci-Ce alkyl, halo, cyano, -ORA, -NRBRC, - NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, and -S(0)2RD; each RAis independently hydrogen, C C6alkyl, halo-Q-Ce alkyl, -C(0)NRBRc, -C(0)RD, or -C(0)ORD;

[0020] B C B C

[0021] each of R and R is independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl; R and R together with the atom to which they are attached form a 3-7-membered heterocyclyl ring

[0022] cc

[0023] optionally substituted with 1-3 R ; each R is independently selected from the group consisting of hydroxy-d-Ce alkyl, halo-Q-Ce alkyl, HChC-Q-Ce alkyl, d-C6alkyl-C(0)2-C1-C6alkyl, (CO)-Ci-Cealkyl-OH, (CO)-Ci-C6alkyl-Ci-C6alkoxy and 4-6 membered heterocyclyl; wherein the heterocyclyl may optionally be substituted with 1-3 Rz: each RDis independently C1-C6 alkyl, 2-7-memberedheteroalkyl, hydroxy-Ci-C6 alkyl, or halo-Ci-C6 alkyl, wherein each Q-C6 alkyl, 2-7-memberedheteroalkyl, hydroxy-Ci-C6 alkyl, or halo-Ci-C6 alkyl is optionally

[0024] G E

[0025] substituted with 1-5 R ; each R is independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl; each R is independently hydrogen, C1-C6 alkyl, or halo; each R is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH; each RHis independently C1-C6 alkyl or halo-Ci-C6 alkyl; m is 1 when RFis hydrogen or C1-C6 alkyl, 3 when RFis C1-C6 alkyl, or 5 when RFis halo; t is 0 or 1; and s is 0 or 1.

[0026] In some embodiments, D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is a bridged 5-8 membered bicyclic cycloalkyl or heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is selected from cubane, bicyclo[l.l.l]pentane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, or 2-azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 R groups. In some embodiments, D is selected from cubane, bicyclo[l.l.l]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or

[0027] bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 Rxgroups. In some

[0028] embodiments, D is substituted with 1 or 2 R . In some embodiments, R is independently C -Ce alkyl, hydroxy-Ci-C6 alkyl, C\-C alkoxy-Ci-C6 alkyl, C\-C alkoxy-Ci-C6 alkoxy, oxo, halo, cyano, -ORA, -OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, =CHC(0)OH, =CHC(0)ORD, NRBRC, NRBRCC, or G2; or 2 geminal Rxgroups together with the carbon to which they are attached form an oxirane moiety. In some embodiments, Rxis independently CH3, -CH2OH, -CH2OCH3, -CH2CH2CH3, -C(CH3)2OH, -O- CH2-0-CH3, CH2CH2OH, oxo, fluoro, bromo, OH, cyano, OCH3, NH2, N(H)CH2CF3,

[0029] N(H)CH2CH2OH, N(CH3)2, N(CH3)CH2CH2OH, N(CH3)CH2C02H N(CH3)CH2CH2C02H, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, C(0)OCH3, OC 0)R , -C(0)CH3, =CHC(0)OH, =CHC(0)OCH2CH3, -SCH3,

[0030] 5and OH . insome embodiments, G is aryl or 5-6 membered heteroaryl. some embodiments, G is oxadiazolyl or tetrazolyl.

[0031] In some embodiments, D is substituted with 0 R . In some embodiments, D is

[0032] In some embodiments, at least one of L and L is independently 2-7-membered

[0033] L 1 2 heteroalkylene optionally substituted by 1-5 R . In some embodiments, one of L and L is

[0034] 1 2

[0035] independently Q-C6 alkylene or C2-C6 alkenylene and the other of L and L is independently 2- 7-membered heteroalkylene, and wherein each C1-C6 alkylene, C2-C6 alkenylene, and 2-7- membered heteroalkylene is optionally substituted by 1-5 RL.

[0036] In some embodiments, each RLis independently C -C alkyl, OH, oxo, -C(0)RD, cyano, HOjC-d-Ce alkyl, CrC6alkyl-C(0)2-C1-C6alkyl, -C(0)OH, -NRBRC, -NRBRCC, - NRBC(0)RD, hydroxy-d-Ce alkyl, or hydroxy-d-C6alkoxy. each RLis independently CH3, oxo, or C(0)CH3.

[0037] In some embodiments, each of L1and L2is independently selected from CH2O-*,

[0038] CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, 0-CH2CH2*, CH2N(CH2C02H)-*, CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*, CH(CN)CH20-*, CH2CH(NH(CH3))-*,CH(OC -*,

[0039] CH2CH(NH(C(0)CH2OH))-*, CH2CH(NH2)CH2*,CH(CH2CH2OH)0-* or

[0040] *" indicates the attachment point to A and W, respectively. In some embodiments, L independently selected from CH20-*, CH2CH20-* or CH=CH-*, L is independently selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*,

[0041] CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, CH2N(CH2C02H)-*, CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*, CH(CN)CH20-*, CH2CH(NH(CH3))-*,CH(OCH2CH2OH)-*,

[0042] (C(0)CH2OH))-*, CH2CH(NH2)CH2*,CH(CH2CH2OH)0-*, CH2C(CH3)20*- or

[0043] , and "-*" indicates the attachment point to A and W, respectively.

[0044] In some embodiments, t is 1 and s is 1. In some embodiments, s is 1 and t is 0. In some embodiments, s is 1 and t is 0.

[0045] 1 2

[0046] In some embodiments, R and R are each independently hydrogen, Cj-C alkyl,

[0047] 1 2

[0048] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. one of R and R is independently hydrogen and

[0049] 1 2

[0050] the other of R and R is independently hydrogen, Cj-C alkyl, C2-C6 hydroxyl-C2-C6 alkyl, silyloxy-C2-C6alkyl, H02C-d-C6alkyl, or C C6alkyl-C(0)2-Ci-C6alkyl. wherein R1and R2are each independently hydrogen, *-CH3, *-CH2CH2OH, *-CH2CH2OSi(CH3)2C(CH3)3, *- CH2C02H, or *-CH2C(0)2C(CH3), and "*-" indicates the attachment point to the nitrogen atom.

[0051] 1 2 1 2

[0052] one of R and R is independently hydrogen and the other of R and R is independently hydrogen, *-CH3, *-CH2CH2OH, *-CH2CH2OSi(CH3)2C(CH3)3, *-CH2C02H, or *-CH2C(0)2C(CH3), and

[0053] 1 2 "*-" indicates the attachment point to the nitrogen atom. In some embodiments, R and R are each independently hydrogen.

[0054] In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, pyrazolyl, pyrimidinyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, pyrimidin-2(lH)-onyl, lH-benzo[d]imidazolyl, pyrazolo[l ,5-a]pyridine, lH-indazolyl or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from: In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Ci-Ce alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy,

[0055] A B C

[0056] hydroxy-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -OR , -NR R , - NRBRCC, — NRBC(0)RD, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, triazinyl, pyrazolyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups.

[0057]

[0058] In some embodiments, W is selected from:

[0059]

[0060]

[0061] In some embodiments, each RYis independently hydrogen, bromo, chloro, fluoro, iodo, cyano, CF3, CHF2, CH2CF3, CH3, CH2CH3, OH, CH2OH, C(CH3)2OH, OCH3, OCH2CH3, OCHF2, OCF3, OCH2CF3, OCH2CH2OH, CH2OCH3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, NH(C(0)CH2OH), NH(CH2CH2OH), NH(CO)CH2OCH3,C(CH)3,

[0062] CH(OH)CH3, C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3,

[0063] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, the 2 RYtogether with the atoms to which they are attached form a phenyl, pyridyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, dioxanyl, dioxolanyl, pyrrolidin-2-onyl, or morpholin-3-onyl ring, each of which is optionally substituted with 1-5 R . In some embodiments, each R is independently Ci-C6alkyl, ORA, or halo. In some embodiments, each Rxis independently CH3ORA, or fluoro.

[0064] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently Q-C6 alkyl or halo.

[0065] In one as a (I-b):

[0066] Formula (I-b)

[0067] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein D is (l,2,3,4,6,7)-cubane, bicyclo[l. l.l]pentane,

[0068] bicyclo[2.2.2] octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1] octane, or 2-azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 Rxgroups; and wherein 2-azabicyclo[2.2.2] octane is substituted on nitrogen by hydrogen or CH3; L1and L2are each independently CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively; R1andR2are each independently hydrogen, CH3, CH2CH2OH, or CH2CH2OSi(CH3)2C(CH3)3; A and W are each independently isoxazolyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups; each Rxis independently selected from CH3, -CH2OH, -C(CH3)2OH, oxo, fluoro, bromo, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, -SCH3, or G2; each RYis independently bromo, chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, OH, CH2OH, C(CH3)2OH, OCH3, OCH2CH3,OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 R ; G and G are cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is optionally substituted with 1-2 Rz; each RDis CH2O optionally substituted with 1-5 RG; each RGis independently pyridyl optionally substituted with 1-5 RH; each RHis independently CF3; each Rzis independently CH3; and t is 0 or 1.

[0069] In some embo of Formula (I-c):

[0070] Formula (I-c)

[0071] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0072] In some embodime d of Formula (I-d)

[0073] Formula (I-d)

[0074] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0075] In some embo Formula (I-e)

[0076] Formula (I-e)

[0077] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0078] In some emb la (I-f)

[0079] Formula (I-f) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0080] In some embo of Formula (I-g):

[0081] Formula (I-g)

[0082] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0083] In some embodi f Formula (I-h):

[0084] Formula (I-h)

[0085] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0086] In some emb la (I-i): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0087] In some embo of Formula (I-j):

[0088] Formula (I-j)

[0089] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0090] In some embodiments, the compound of Formula (I) is a compound of Formula (I-k):

[0091]

[0092] Formula (I-k)

[0093] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0094] In some embodiments, the compound of Formula (I) is a compound of Formula (1-1):

[0095]

[0096] Formula (1-1)

[0097] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0098] Also disclosed herein is a compound of Formula (II):

[0099]

[0100] Formula (II)

[0101] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:

[0102] D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1;

[0103] 1 c

[0104] L is C C alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NR , wherein C -C alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 Rx;

[0105] L2is -(C0-C2 alkylene)-0-(Co-C2alkylene)-; R is hydrogen, C Ce alkyl, alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, and silyloxy-C2-C6 alkyl;

[0106] RN1is selected from the group consisting of hydrogen, Q-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6alkyl, amino-C2-C6alkyl, cyano-C2-C6alkyl, -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD;

[0107] A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;

[0108] each Rxis independently selected from the group consisting of C C alkyl, hydroxy-Ci- C alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, alkoxy-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2;

[0109] each RYis independently selected from the group consisting of hydrogen, C C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -S(RF)m, -S(0)RD, -S(0)2RD, and G1; or

[0110] 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx;

[0111] each G 1 and G 2 is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl is optionally substituted with 1-3 Rz;

[0112] each Rzis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci- C6alkyl, halo-d-C6alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, and -S(0)2RD;

[0113] each RAis independently hydrogen, d-Ce alkyl, halo-C C6alkyl, -C(0)NRBRc, -

[0114] C(0)RD, or -C(0)ORD;

[0115] B C

[0116] each of R and R is independently hydrogen or C1-C6 alkyl; or

[0117] R B and R C together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R ;

[0118] each RDis independently C1-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Ci-C6 alkyl, wherein each Q-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Q-C6 alkyl is optionally substituted with 1-5 RG; each REis independently hydrogen, Ci-Ce alkyl, or halo-Q-Ce alkyl;

[0119] each RFis independently hydrogen, C1-C6 alkyl, or halo;

[0120] each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH;

[0121] each RHis independently Q-C6 alkyl or halo-Ci-C6 alkyl;

[0122] m is 1 when RFis hydrogen or C1-C6 alkyl, 3 when RFis C1-C6 alkyl, or 5 when RFis halo; and; and

[0123] t is 0 or 1.

[0124] . In some

[0125] embodiments, each RAis independently selected from the group consisting of oxo, -ORA(e.g OH or OCH3), -C(0)OH, -C(0)ORD(e.g., -C(0)OCH3), halo, and hydroxy-Cj-Ce alkyl.

[0126] In some embodiments, L1is CH2O-* or CH2OCH2-*; wherein "-*" indicates the attachment point to A. In some embodiments, L is selected from the group consisting of 0-* OCH2-*, CH2O-*, OCH2CH2-*, CH2OCH2-*, and CH2CH2O-*; wherein "-*" indicates the attachment point to W. In some embodiments, R1is hydrogen or C¾

[0127] In some embodiments A is selected from the group consisting of:

[0128]

[0129] In some embodiments, W is selected from the group consisting of:

[0130]

[0131] wherein R is hydrogen or CH3.

[0132] In some embodiments, wherein each RYis independently hydrogen, chloro, fluoro, CF3,

[0133] CHF2, CH3, CH2CH3, CH(CH3)2, OCH3, OCF3, OCH(CH3)2, or CN.

[0134] In some embodiments nd of Formula (Il-a):

[0135] Formula (Il-a)

[0136] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:

[0137] D is bicyclo[l.l. l]pentanyl or bicyclo[2.2.2]octanyl, each of which is optionally substituted with 1-4 Rxgroups;

[0138] L1is CH2O-* or CH2OCH2-*, wherein "-*" indicates the attachment point to A;

[0139] L2is selected from the group consisting of O-*, OCH2-*, CH20-*, OCH2CH2-*,

[0140] CH2OCH2-*, and CH2CH20-*; wherein "-*" indicates the attachment point to W;

[0141] A is phenyl or pyridyl, each of which is optionally substituted with 1-5 RYgroups;

[0142] W is phenyl, pyridyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted on one or more available carbons with 1-5 RYgroups; and wherein pyrazolyl may be optionally substituted on an available nitrogen with hydrogen or CH3;

[0143] each Rxis independently fluoro, oxo, OH, OCH3, C(0)OH, or C(0)OCH3;

[0144] each RYis independently chloro, fluoro, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCH(CH3)2, or CN; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 Rx; and R1is hydrogen.

[0145] In some embodiments, the compound of Formula (I) or (II) is selected from a compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N- oxide or stereoisomer thereof.

[0146] In some embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0147] In another aspect, the present invention features a method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease, or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway (e.g., eIF2 pathway) in a subject, wherein the method comprises administering a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, or a composition thereof, to a subject.

[0148] In some embodiments, the method comprises the treatment of a neurodegenerative disease. In some embodiments, the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain injury (e.g., a traumatic brain injury or toxin induced brain injury). In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo myelination,

[0149] Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia (e.g., HIV- associated dementia or Lewy body dementia), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

[0150] In some embodiments, the method comprises the treatment of cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or a cancer of the secretory cells. In some embodiments, the method comprises the treatment of an inflammatory disease. In some embodiments, the inflammatory disease comprises 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 diabetes mellitus type 1), Guillain-Barre 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, atherosclerosis, or atopic dermatitis.

[0151] In some embodiments, the method comprises the treatment of a musculoskeletal disease. In some embodiments, 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, amyotropic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscle atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado- Joseph disease, cramp fasciculation syndrome, Freidrich's ataxia, a muscle wasting disorder

[0152] (e.g., muscle atrophy, sarcopenia, cachexia), an inclusion body myopathy, motor neuron disease, or paralysis.

[0153] In some embodiments, the method comprises the treatment of a metabolic disease. 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, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0154] In some embodiments, the method comprises the treatment of a mitochondrial disease. In some embodiments, the mitochondrial disease is associated with, or is a result of, or is caused by mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations. In some embodiments, the mitochondrial disease is a mitochondrial myopathy. In some embodiments, the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0155] In another aspect, the present invention features a method of treating a disease or disorder related to modulation (e.g., a decrease) in eIF2B activity or level, modulation (e.g., a decrease) of eIF2a activity or level, modulation (e.g., an increase) in eIF2a phosphorylation, modulation (e.g., an increase) of phosphorylated eIF2a pathway activity, or modulation (e.g., an increase) of ISR activity in a subject, wherein the method comprises administering a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N- oxide or stereoisomer thereof, or a composition thereof, to a subject. In some embodiments, the disease may be caused by a mutation to a gene or protein sequence related to a member of the eIF2 pathway (e.g., the eIF2a signaling pathway or ISR pathway).

[0156] In another aspect, the present invention features a method of treating cancer in a subject, the method comprising administering to the subject a compound of formula (I) or formula (II) in combination with an immunotherapeutic agent.

[0157] DETAILED DESCRIPTION OF THE INVENTION

[0158] The present invention features compounds, compositions, and methods comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof for use, e.g., in the modulation (e.g., activation) of eIF2B and the attenuation of the ISR signaling pathway.

[0159] Definitions

[0160] Chemical Definitions

[0161] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the

[0162] Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and

[0163] rd

[0164] Carruthers, Some Modern Methods of Organic Synthesis, 3 Edition, Cambridge University Press, Cambridge, 1987.

[0165] 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.

[0166] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. ,

[0167] 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 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0168] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91 % by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or

[0169] stereoisomers of the compound.

[0170] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0171] Compound described herein may also comprise one or more isotopic substitutions. For

[0172] 1 2 3

[0173] example, H may be in any isotopic form, including H, H (D or deuterium), and H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including160 and180; and the like.

[0174] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.

[0175] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "C1-C6 alkyl" is intended to encompass, Q, C2, C3, C4, C5, C6, Ci-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-C6alkyl.

[0176] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0177] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C1-C20alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C12 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Cj-Cg alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Q-Cg 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 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 ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6alkyl"). Examples of Ci-Cealkyl groups include methyl (Q), 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), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci_io alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci_6 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (- CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0178] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described as, e.g., a C\-C - membered alkylene, wherein the term "membered" refers to the non-hydrogen atoms within the moiety.

[0179] "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2- C20alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-Cio alkenyl"). 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

[0180] embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some

[0181] embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkenyl") or substituted (a

[0182] "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-6 alkenyl.

[0183] "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 a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-C14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("Cio aryl"; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("CM aryl"; e.g., anthracyl). An aryl group may be described as, e.g., a C6-Cio-membered aryl, wherein 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 instance of an aryl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl.

[0184] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, Ci-C8alkyl, halo-Ci-Cs alkyl, haloxy-Ci-Cs alkyl, cyano, hydroxy, alkoxy Ci-C8alkyl, and amino.

[0185] Exam les of representative substituted aryls include the following

[0186] wherein one of R and R may be hydrogen and at least one of R and R is each independently selected from Ci-C8alkyl, halo-Ci-Cs alkyl, 4-10 membered heterocyclyl, alkanoyl, alkoxy-Ci-Cs alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR3SCOR , CONR OR , NR58R59, S02NR58R59, S-alkyl, S(0)-alkyl, S(0)2-alkyl, S-aryl, S(0)-aryl, S(02)-aryl; or R56and

[0187] R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S.

[0188] erocyclyl group include the following:

[0189] wherein each W is selected from C(R )2, NR , O, and S; and each Y' is selected from carbonyl, NR66, O and S; and R66is independently hydrogen, Ci-C8alkyl, C3-C10cycloalkyl, 4- 10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

[0190] An "arylene" and a "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, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl,

[0191] pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non- limiting examples of heteroarylene.

[0192] "Halo" or "halogen," independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (CI), 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, the halo group is either fluorine or chlorine.

[0193] Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-Ci-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.

[0194] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be 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-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)2, -S(0)-CH3, -S(0)2-CH2,-CH2-CH2-S(0)2- CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, and -O- CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH- OCH3and -CH2-0-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific

[0195] B C

[0196] heteroalkyl groups, such as -CH20, -NR R , or the like, it will be understood that the terms

[0197] B C

[0198] heteroalkyl and -CH20 or -NR R are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be

[0199] B C

[0200] interpreted herein as excluding specific heteroalkyl groups, such as -CH20, -NR R , or the like.

[0201] 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 by, -CH20- and -CH2CH20-. A heteroalkylene group may be described as, e.g., a 2-7- membered heteroalkylene, wherein the term "membered" refers to the non-hydrogen atoms within the moiety. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, 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(0)2R'- may represent both -C(0)2R'- and -R'C(0)2-.

[0202] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term "membered" refers to the non-hydrogen ring atoms within the moiety.

[0203] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0204] 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.

[0205] 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, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0206] Examples of representative heteroaryls include the following formulae:

[0207]

[0208] wherein each Y is selected from carbonyl, N, NR , O, and S; and R is independently hydrogen, Ci-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

[0209] "Cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-Q0cycloalkyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3- Cscycloaikyl"). 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-C10cycloalkyl"). A cycloalkyl group may be described as, e.g., a C C -membered cycloalkyl, wherein the term "membered" refers to the non-hydrogen ring atoms within the moiety.

[0210] Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), cubanyl (Cs), bicyclo[l.l.l]pentanyl (C5), bicyclo[2.2.2]octanyl (Cs), bicyclo[2.1.1]hexanyl (Ce), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (Qo), cyclodecenyl (C10), octahydro- lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10cycloalkyl.

[0211] In some embodiments, "cycloalkyl" is a monocyclic, saturated cycloalkyl group having from 3 to 10 ring carbon atoms ("C3-C10cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8cycloalkyl"). 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-C10cycloalkyl"). Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).

[0212] Examples of C3-C8cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-Q0 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-C10 cycloalkyl.

[0213] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term "membered" refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0214] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0215] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4- membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

[0216] 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, oxasulfuranyl, disulfuranyl, 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, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0217] Particular examples of heterocyclyl groups are shown in the following illustrative examples:

[0218]

[0219] wherein each W is selected from CR , C(R )2, NR , O, and S; and each Y is selected from NR67, O, and S; and R67is independently hydrogen, Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10-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(0)-alkyl, -S(0)-aryl, -S(0)2-alkyl, and -S(0)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

[0220] "Nitrogen-containing heterocyclyl" group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, 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-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0221] 70 71 70 71

[0222] "Amino" refers to the radical -NR R , wherein R and R are each independently hydrogen, Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10- membered heteroaryl. In some embodiments, amino refers to NH2.

[0223] "Cyano" refers to the radical -CN.

[0224] "Hydroxy" refers to the radical -OH.

[0225] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or

[0226] "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or

[0227] "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein that result 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 substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0228] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.

[0229] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F~, CI", Br", Γ), N03", C104", OH", H2P04", HS04", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0230] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds 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 salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

[0231] monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1 -19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in a first buffer, e.g., in 1 mM-50 mM histidine, 0. l -2 sucrose, 2 - 7% mannitol at a pH range of 4.5 to 5.5, that is combined with a second buffer prior to use.

[0232] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+) -tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0233] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0234] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0235] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0236] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0237] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and / or isolate. The present invention is meant to include compounds in racemic and optically pure forms. 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, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0238] The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0239] 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.

[0240] The terms "treating" or "treatment" refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. For example, certain methods herein treat cancer (e.g.

[0241] pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells),

[0242] neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophies (e.g., vanishing white matter disease, childhood ataxia with CNS hypo-myelination), postsurgical cognitive dysfunction, traumatic brain injury, stroke, spinal cord injury, intellectual disability syndromes, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or disorders associated with impaired function of eIF2B or components in a signal transduction or signaling pathway including the ISR and decreased eIF2 pathway activity). For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer; treat neurodegeneration by improving mental wellbeing, increasing mental function, slowing the decrease of mental function, decreasing dementia, delaying the onset of dementia, improving cognitive skills, decreasing the loss of cognitive skills, improving memory, decreasing the degradation of memory, decreasing a symptom of neurodegeneration or extending survival; treat vanishing white matter disease by reducing a symptom of vanishing white matter disease or reducing the loss of white matter or reducing the loss of myelin or increasing the amount of myelin or increasing the amount of white matter; treat childhood ataxia with CNS hypo-myelination by decreasing a symptom of childhood ataxia with CNS hypo-myelination or increasing the level of myelin or decreasing the loss of myelin; treat an intellectual disability syndrome by decreasing a symptom of an intellectual disability syndrome, treat an inflammatory disease by treating a symptom of the inflammatory disease; treat a musculoskeletal disease by treating a symptom of the musculoskeletal disease; or treat a metabolic disease by treating a symptom of the metabolic disease. Symptoms of a disease, disorder, or condition described herein (e.g., cancer a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a condition or disease associated with impaired function of eIF2B or components in a signal transduction pathway including the eIF2 pathway, eIF2D phosphorylation, or ISR pathway) would be known or may be determined by a person of ordinary skill in the art. The term "treating" and conjugations thereof, include prevention of an injury, pathology, condition, or disease (e.g. preventing the development of one or more symptoms of a disease, disorder, or condition described herein).

[0243] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g.

[0244] achieve the effect for which it is administered, 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 a symptom or symptoms of a disease, which could also be referred to as a

[0245] "therapeutically effective amount." A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).

[0246] The term "associated" 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, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a

[0247] musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of eIF2B or components in a signal transduction pathway including the eIF2 pathway, eIF2D phosphorylation, or ISR pathway) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. For example, a symptom of a disease or condition associated with an impaired function of the eIF2B may be a symptom that results (entirely or partially) from a decrease in eIF2B activity (e.g. decrease in eIF2B activity or levels, increase in eIF2a phosphorylation or activity of phosphorylated eIF2a or reduced eIF2 activity or increase in activity of phosphorylated eIF2a signal transduction or the ISR signalling pathway). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a disease associated with decreased eIF2 activity or eIF2 pathway activity, may be treated with an agent (e.g., compound as described herein) effective for increasing the level or activity of eIF2 or eIF2 pathway or a decrease in phosphorylated eIF2a activity or the ISR pathway. For example, a disease associated with phosphorylated eIF2a may be treated with an agent (e.g., compound as described herein) effective for decreasing the level of activity of phosphorylated eIF2a or a downstream component or effector of phosphorylated eIF2a. For example, a disease associated with eIF2a, may be treated with an agent (e.g., compound as described herein) effective for increasing the level of activity of eIF2 or a downstream component or effector of eIF2.

[0248] "Control" or "control experiment" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects.

[0249] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme (e.g. eIF2B, eIF2a, 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 that is involved in a signaling pathway (e.g. eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway).

[0250] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor (e.g., antagonist) interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating 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 pathway or signaling pathway (e.g., eIF2B, eIF2a, or a component of the eIF2 pathway, pathway activated by eIF2a phosphorylation, or ISR pathway). Thus, inhibition may include, at least in part, partially or totally decreasing stimulation, decreasing or reducing activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein increased in a disease (e.g. eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway, wherein each is associated with cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease). Inhibition may include, at least in part, partially or totally decreasing stimulation, decreasing or reducing activation, or deactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein (e.g. eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway) that may modulate the level of another protein or increase cell survival (e.g., decrease in phosphorylated eIF2a pathway activity may increase cell survival in cells that may or may not have an increase in phosphorylated eIF2a pathway activity relative to a non-disease control or decrease in eIF2a pathway activity may increase cell survival in cells that may or may not have an increase in eIF2a pathway activity relative to a non-disease control).

[0251] As defined herein, the term "activation", "activate", "activating" and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g. increasing) the activity or function of the protein (e.g. eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway) relative to the activity or function of the protein in the absence of the activator (e.g. compound described herein). In some embodiments, activation refers to an increase in the activity of a signal transduction pathway or signaling pathway (e.g. eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway). Thus, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease (e.g. level of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway associated with cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease). Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein (e.g., eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway) that may modulate the level of another protein or increase cell survival (e.g., increase in eIF2a activity may increase cell survival in cells that may or may not have a reduction in eIF2a activity relative to a non- disease control).

[0252] 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, eIF2a, or a component of the eIF2 pathway or ISR pathway may result in reduction of the severity of one or more symptoms of a disease associated with eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway (e.g., cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease) or a disease that is not caused by eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway but may benefit from modulation of eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway (e.g., decreasing in level or level of activity of eIF2B, eIF2a or a component of the eIF2 pathway).

[0253] The term "modulator" as used herein refers to modulation of (e.g., an increase or decrease in) the level of a target molecule or the function of a target molecule. In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is an anti- cancer agent. In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is a neuroprotectant. In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is a memory enhancing agent. In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is a memory enhancing agent (e.g., a long term memory enhancing agent). In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is an anti-inflammatory agent. In some embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 pathway or ISR pathway is a pain-relieving agent.

[0254] "Patient" or "subject in need thereof 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, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In some embodiments, a patient is a domesticated animal. In some embodiments, a patient is a dog. In some embodiments, a patient is a parrot. In some embodiments, a patient is livestock animal. In some embodiments, a patient is a mammal. In some embodiments, a patient is a cat. In some embodiments, a patient is a horse. In some embodiments, a patient is bovine. In some embodiments, a patient is a canine. In some embodiments, a patient is a feline. In some embodiments, a patient is an ape. In some embodiments, a patient is a monkey. In some embodiments, a patient is a mouse. In some embodiments, a patient is an experimental animal. In some embodiments, a patient is a rat. In some embodiments, a patient is a hamster. In some embodiments, a patient is a test animal. In some embodiments, a patient is a newborn animal. In some embodiments, a patient is a newborn human. In some embodiments, a patient is a newborn mammal. In some embodiments, a patient is an elderly animal. In some embodiments, a patient is an elderly human. In some

[0255] embodiments, a patient is an elderly mammal. In some embodiments, a patient is a geriatric patient.

[0256] "Disease", "disorder" or "condition" refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, or condition, e.g., through administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.

[0257] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0258] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

[0259] Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0260] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a

[0261] neurodegenerative disease). The compound of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).

[0262] The term "eIF2B" as used herein refers to the heteropentameric eukaryotic translation initiation factor 2B. eIF2B is composed of five subunits: eIF2B l , eIF2B2, eIF2B3, eIF2B4 and eIF2B5. eIF2B l 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.

[0263] eIF2B3 refers to the protein associated with Entrez gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to the protein associated with Entrez gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945.

[0264] eIF2B5 refers to the protein associated with Entrez gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq (protein) NP_003898.

[0265] The terms "eIF2alpha", "eIF2a"or "eIF2a" are interchangeable and refer to the protein "eukaryotic translation initiation factor 2 alpha subunit eIF2S l ". In embodiments, "eIF2alpha", "eIF2a"or "eIF2a" refer to the human protein. Included in the terms eIF2alpha", "eIF2a"or "eIF2a" are the wildtype and mutant forms of the protein. In embodiments, " eIF2alpha", "eIF2a"or "eIF2a" refer to the protein associated with Entrez Gene 1965, OMIM 603907, UniProt P05198, and / or RefSeq (protein) NP_004085. In embodiments, the reference numbers immediately above refer to the protein and associated nucleic acids known as of the date of filing of this application.

[0266] Compounds

[0267] In one aspect, the (I):

[0268] Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1; L1and L2are each independently Cj-C alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NR , wherein each Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally

[0269] L I 2

[0270] substituted with 1-5 R ; R and R are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy- C2-C6alkyl, hydroxy-C2-C6alkyl, silyloxy-C2-C6alkyl, G1-0-C2-C6alkyl, HChC-Q-Ce alkyl, or C1-C6 alkyl-C(0)2-Ci-C6 alkyl; each RLis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkoxy, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-d-Ce alkyl, d-C6alkoxy-d-d alkyl, H02C-d-d alkyl, d- alkyl-C(0)2-C1-C6alkyl, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2; or 2 geminal RLgroups together with the carbon to which they are attached form a cyclopropyl moiety; RN1is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, HO2C-C1-C6 alkyl, Q- d alkyl-C(0)2-Ci-C6 alkyl, phenoxy-Ci-C6 alkyl (wherein phenoxy is optionally substituted with 1-3 halogens), -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD; A and W are each independently aryl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY; each Rxis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, C1-C6 alkyl-Ci-C6 alkoxy, C1-C6 alkoxy-Ci-C6 alkoxy, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, =CHC(0)ORD, =CHC(0)OH, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -

[0271] D 2 X

[0272] OS(0)2R , and G ; or 2 geminal R groups together with the carbon to which they are attached form an oxirane moiety; each RYis independently selected from the group consisting of hydrogen, C1-C6 alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkoxy, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, -S(RF)m, -S(0)RD, -S(0)2RD, and G1; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx; each G1is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 Rz; each Rzis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-Ce alkyl, halo-Ci-Ce alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, - C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, and -S(0)2RD; each RAis independently hydrogen, C C6alkyl, halo-d-Q, alkyl, -C(0)NRBRc, -C(0)RD, or -C(0)ORD; each of RBand

[0273] C B C

[0274] R is independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl; R andR together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1- cc

[0275] 3 R ; each R is independently selected from the group consisting of hydroxy-Ci-C6 alkyl, halo-Ci-Ce alkyl, HC^C-d-Ce alkyl, d-C6alkyl-C(0)2-C1-C6alkyl, (CO)-Ci-C6alkyl-OH, (CO)-Ci-C6alkyl-Ci-C6alkoxy and 4-6 membered heterocyclyl; wherein the heterocyclyl may optionally be substituted with 1-3 Rz: each RDis independently C1-C6 alkyl, 2-7-membered heteroalkyl, hydroxy-Ci-C6 alkyl, or halo-Ci-C6 alkyl, wherein each C1-C6 alkyl, 2-7-membered heteroalkyl, hydroxy-Ci-C6 alkyl, or halo-Ci-C6 alkyl is optionally substituted with 1-5 RG; each REis independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl; each RFis independently hydrogen, C1-C6 alkyl, or halo; each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH; each RHis independently Q-C6 alkyl or halo-Ci-C6 alkyl; m is 1 when RFis hydrogen or C1-C6 alkyl, 3 when RFis C1-C6 alkyl, or 5 when RFis halo; t is 0 or 1; and s is 0 or 1.

[0276] In some embodiments, D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is a bridged 5-8 membered bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is selected from cubane, bicyclo[l.l.l]pentane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,

[0277] bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, or 2- azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is selected from cubane, bicyclo[l. l. l]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R

[0278]

[0279] . in some embodiments, D is selected from:

[0280] elected from: m:

[0281]

[0282] . in some embodiments, D is substituted with 1 or 2 Rx. In some embodiments, Rxis independently Cj-C alkyl, hydroxy-Ci- C alkyl, Cj-C alkoxy-Ci-C6 alkyl, Cj-C alkoxy-Ci-C6 alkoxy, oxo, halo, cyano, -ORA, - OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, =CHC(0)OH, =CHC(0)ORD, NRBRC, NRBRCC, or G2; or 2 geminal Rxgroups together with the carbon to which they are attached form an oxirane moiety. In some embodiments, Rxis independently CH3, -CH2OH, -CH2OCH3, -CH2CH2CH3, -C(CH3)2OH, -0-CH2-0-CH3, CH2CH2OH, oxo, fluoro, bromo, OH, cyano, OCH3, NH2, N(H)CH2CF3, N(H)CH2CH2OH, N(CH3)2, N(CH3)CH2CH2OH, N(CH3)CH2C02H N(CH3)CH2CH2C02H, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, C(0)OCH3,

[0283] OC(0)RD, -C(0)CH3, =CHC(0)OH, =CHC(0)OCH2CH3, -SCH3,

[0284] and OH . in SOme embodiments, Rxis oxo, -ORA, or NR R (e.g., oxo, OH, OCH3, N(CH3)2,

[0285] D 2

[0286] ar OC(0)R"). In some embodiments, G is aryl or 5-6 membered heteroaryl. In some embodiments, G is oxadiazolyl or tetrazolyl. substituted with 0 Rx. In some embodiments, D

[0287] In some embodiments, at least one of L and L is independently 2-7-membered

[0288] C L

[0289] heteroalkylene, O, or NR , wherein heteroalkylene is optionally substituted by 1-5 R . In some embodiments, at least one of L1and L2is independently 2-7-memberedheteroalkylene optionally

[0290] L 1 2

[0291] substituted by 1-5 R . In some embodiments, both L and L are independently 2-7-membered heteroalkylene optionally substituted by 1-5 RL. In some embodiments, one of L1and L2is

[0292] 1 2

[0293] independently Cj-C alkylene or C2-C6 alkenylene and the other of L and L is independently 2- 7-membered heteroalkylene, and wherein each Q-C6 alkylene, C2-C6 alkenylene, and 2-7- membered heteroalkylene is optionally substituted by 1-5 RL. In some embodiments, both of L1and L2are C1-C6 alkylene or C2-C6 alkenylene, and wherein each Q-C6 alkylene, and C2-C6

[0294] L 1 2 alkenylene is optionally substituted by 1-5 R . In some embodiments, both of L and L are C2- C alkenylene, optionally substituted by 1-5 RL.

[0295] In some embodiments, each RLis independently Q-C6 alkyl, hydroxy-Ci-C6 alkyl, oxo, or -C(0)RD(e.g., CH3, OH, oxo, CH2OH, CH2OCH3, or C(0)CH3). In some embodiments, each RLis independently C C6alkyl, OH, oxo, -C(0)RD, cyano, HO2C-Q-C6 alkyl, d-C6alkyl- C(0)2-C C6alkyl, -C(0)OH, -NRBRC, -NRBRCC,— NRBC(0)RD, hydroxy-C C6alkyl, or hydroxy-Ci-C6 alkoxy. In some embodiments, each RLis independently CH3, oxo, or C(0)CH3.

[0296] 1 2

[0297] In some embodiments, each of L and L is independently selected from CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*,

[0298] CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, 0-CH2CH2*, CH2N(CH2C02H)-*, CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*, CH(CN)CH20-*, CH2CH(NH(CH3))-*,CH(OC -*,

[0299] CH2CH(NH(C(0)CH2OH))-*, CH2CH(NH2)CH2*,CH(CH2CH2OH)0-* or and "- *" indicates the attachment point to A and W, respectively. In some embodiments, each of L1 and is independently selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20- *, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively. In some embodiments, L1is independently selected from CH20-* and CH=CH-*, L is independently selected from CH20-*, CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*,

[0300] CH2NHC(0)-*, -NHC(0)OCH2-*, O-*, NH-*, S(0)2CH2-*, S(0)2CH2CH2-*, S(0)2CH2CH20- *, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively. In some

[0301] 1 2 embodiments, L is independently selected from CH20-*, CH2CH20-* or CH=CH-*, L is independently selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH- *, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, CH2N(CH2C02H)-*, CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*, CH(CN)CH20-*, CH2CH(NH(CH3))-*,CH(OCH2CH2OH)-*,

[0302] (C(0)CH2OH))-*, CH2CH(NH2)CH2*,CH(CH2CH2OH)0-*, CH2C(CH3)20*- or

[0303] , and "-*" indicates the attachment point to A and W, respectively.

[0304] In some embodiments, t is 1 and s is 1. In some embodiments, s is 1 and t is 0. In some embodiments, s is 0 and t is 0.

[0305] 1 2

[0306] In some embodiments, R and R are each independently hydrogen, C\-Ce alkyl,

[0307] 1 2 hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one of R1and R" is independently hydrogen and the other of R1and R2is independently hydrogen, C\-Ce alkyl, C2- C6hydroxyl-C2-C6alkyl, silyloxy-C2-C6alkyl, H02C-C C6alkyl, or d-C6alkyl-C(0)2-C C6 alkyl. In some embodiments, R1and R2are each independently hydrogen, *-CH3, *-CH2CH2OH, *-CH2CH2OSi(CH3)2C(CH3)3, *-CH2C02H, or *-CH2C(0)2C(CH3), and "*-" indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R2is independently

[0308] 1 2

[0309] hydrogen and the other of R and R is independently hydrogen, *-CH3, *-CH2CH2OH, or *- CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the nitrogen atom, one of

[0310] 1 2 1 2

[0311] R and R is independently hydrogen and the other of R and R is independently hydrogen, *- CH3, *-CH2CH2OH, *-CH2CH2OSi(CH3)2C(CH3)3, *-CH2C02H, or *-CH2C(0)2C(CH3), and

[0312] 1 2

[0313] "*-" indicates the attachment point to the nitrogen atom. In some embodiments, R and R are each independently hydrogen.

[0314] In some embodiments, A is phenyl and W is independently phenyl or 5-6-membered heteroaryl. In some embodiments, each A and W is independently phenyl. In some

[0315] embodiments, A is phenyl and W is 5-6-membered heteroaryl.

[0316] In some embodiments, W is a monocyclic 5-6-membered heteroaryl. In some embodiments, 2 RYgroups on adjacent atoms of W, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl or heterocyclyl optionally substituted with 1-5 Rxforming 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 heteroaryl containing nitrogen, oxygen or sulfur as allowed by valence.

[0317] In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY, and each RYis independently Cj-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, pyrazolyl, pyrimidinyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, pyrimidin-2(lH)-onyl, lH-benzo[d]imidazolyl, pyrazolo[l ,5-a]pyridine, 1H- indazolyl or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0318]

[0319] . In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Cj-C alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci- C alkoxy, hydroxy-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, - NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0320] pyridazinonyl, pyrimidinyl, triazinyl, pyrazolyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups.

[0321]

[0322] In some embodiments, W is selected from:

[0323]

[0324] In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl. In embodiments, each of A and W is optionally substituted with 1-5 RY, and each RYis independently C -Ce alkyl, hydroxy-Q-Ce alkyl, halo-Q-Ce alkyl, halo-Q-Ce alkoxy, amino-Cj-

[0325] C6alkyl, cyano-d-C6alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1.

[0326] In some embodiments, each RYis independently hydrogen, bromo, chloro, fluoro, iodo, cyano, CF3, CHF2, CH2CF3, CH3, CH2CH3, OH, CH2OH, C(CH3)2OH, OCH3, OCH2CH3, OCHF2, OCF3, OCH2CF3, OCH2CH2OH, CH2OCH3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, NH(C(0)CH2OH), NH(CH2CH2OH), NH(CO)CH2OCH3,C(CH)3,

[0327] CH(OH)CH3, C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3,

[0328] some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3

[0329] OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0330] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, the 2 RYtogether with the atoms to which they are attached form a phenyl, pyridyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, dioxanyl, dioxolanyl, pyrrolidin-2-onyl, or morpholin-3-onyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently C C6alkyl, OR , or halo, (e.g., CH3or fluoro). In some embodiments, each R is independently CH3, OHor fluoro.

[0331] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently Q-C6 alkyl or halo. In some embodiments, each Rzis independently Q-C6 alkyl (e.g., CH3).

[0332] In another aspect, the present invention features a compound of Formula (I-a):

[0333] Formula (I-a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl is optionally substituted with 1-4 Rxgroups; L1and L2are each independently C\-Ce alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene, wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 Rx; R1and R2are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, silyloxy-C2-C6 alkyl; A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY; each Rxis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-

[0334] A B C

[0335] C1-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -OR , -NR R , - NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, -SRE, -S(0)RD, and -S(0)2RD; each RYis independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy- C1-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m, -S(0)RD, -S(0)2RD, and G1; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx; each G1is independently C3-C6 cycloalkyl, 4- 7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4- 7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 Rz; each Rzis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Q-Ce alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, - C(0)OH, -C(0)ORD, and -S(0)2RD; each RAis independently hydrogen, d-C6alkyl, halo-d- C6alkyl, -C(0)NRBRc, -C(0)RD, -C(0)OH, or -C(0)ORD; each of RBand Rcis independently

[0336] B C

[0337] hydrogen or C1-C6 alkyl; or R and R together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 Rz; each RDis independently Q- C(, alkyl, 2-7-membered heteroalkyl, or halo-Ci-C6 alkyl, wherein each C1-C6 alkyl, 2-7-

[0338] G E

[0339] membered heteroalkyl, or halo-Ci-C6 alkyl is optionally substituted with 1-5 R ; each R is independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl; each RFis independently hydrogen, C1-C6 alkyl, or halo; each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH; each RHis independently C Ce alkyl or halo-Q-Ce alkyl; m is 1 when RFis hydrogen or C Ce alkyl, 3 when RFis C -Ce alkyl, or 5 when RFis halo; and; and t is 0 or 1.

[0340] In some embodiments, D is a bridged bicyclic cycloalkyl or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is a bridged 5-8 membered bicyclic cycloalkyl or cubanyl, each of which is optionally substituted with 1-4 Rxgroups. In some embodiments, D is selected from cubane, bicyclo[l.l. l]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4

[0341] R em o ments, D s se ecte rom: o- , or embodiments, D is

[0342] me embodiments, D is substituted with 1

[0343] Rx. In some embodiments, Rxis oxo, -ORA, or NRBRC(e.g., oxo, OH, OCH3, N(CH3)2, or D). In some embodiments, D is substituted with 0 Rx. In some embodiments, D is

[0344] In some embodiments, at least one of L and L is independently 2-7-membered heteroalkylene optionally substituted by 1-5 Rx. In some embodiments, both L1and L2are independently 2-7-membered heteroalkylene optionally substituted by 1-5 Rx. In some embodiments, one of L 1 and L 2 is independently Cj-C alkylene or C2-C6 alkenylene and the other of L1and L2is independently 2-7-membered heteroalkylene, and wherein each C1-C6 alkylene, C2-C6 alkenylene, and 2-7-membered heteroalkylene is optionally substituted by 1-5 Rx. In some embodiments, each Rxis independently C1-C6 alkyl, oxo, or -C(0)RD(e.g., CH3, oxo, or C(0)CH3). In some embodiments, each of L and L is independently selected from CH2O-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0345] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2 is independently selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively.

[0346] In some embodiments, t is 1. In some embodiments, t is 0.

[0347] In some embodiments, R 1 and R 2 are each independently hydrogen, Q-C6 alkyl,

[0348] 1 2 hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one ofR1and R" is independently hydrogen and the other of R 1 and R 2 is independently hydrogen, Q-C6alkyl, hydroxyl or silyloxy iments, R 1 and R 2

[0349] -C2-C6 alkyl, -C2-C6 alkyl. In some embod are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the nitrogen atom. In some embodiments, one of R 11andR 2" is independently hydrogen and the other of R 1 and R 2 is independently hydrogen, *-CH3, *- CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the nitrogen atom. In some embodiments, R 1 andR 2 are each independently hydrogen.

[0350] In some embodiments, each A and W is independently a phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RYgroups, and each RYis independently C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0351] some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 R , and each R is independently C\-Ce alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0352] pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 Y

[0353]

[0354] R , and

[0355] In some embodiments In some embodiments W is selected from:

[0356]

[0357] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, C¾, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0358] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently Q-C6 alkyl or halo (e.g., CH3or fluoro).

[0359] In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3).

[0360] In some embo of Formula (I-b):

[0361] Formula (I-b)

[0362] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof,

[0363] wherein D is (l ,2,3,4,6,7)-cubane, bicyclo[l . l . l]pentane, bicyclo[2.2.2]octane,

[0364] bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, or 2- azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 R groups; and wherein

[0365] 2-azabicyclo[2.2.2]octane is substituted on nitrogen by hydrogen or CH3; L 1 and V 2 are each independently CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20- *, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*,

[0366] CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively; R1and R2are each independently hydrogen, CH3, CH2CH2OH, or

[0367] CH2CH2OSi(CH3)2C(CH3)3; A and W are each independently isoxazolyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups; each Rxis independently selected from CH3, -CH2OH, -C(CH3)2OH, oxo, fluoro, bromo, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, -SCH3, or G2; each RYis independently bromo, chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, OH, CH2OH, C(CH3)2OH, OCH3, OCH2CH3,OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1; or 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 Rx; G1and G2are cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is optionally substituted with 1-2 Rz; each RDis CH20 optionally substituted with 1-5 RG; each RGis independently pyridyl optionally substituted with 1-5 RH; each RHis independently CF3; each Rzis independently CH3; and t is 0 or 1.

[0368] In some embodiments la (I-c):

[0369] Formula (I-c)

[0370] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L1, L2, R1, R2, A, W, Rx, and t is defined as for Formula (I). In some embodiments, Rxis Cj-Cg alkyl, oxo, halo, cyano, -ORA, -OS(0)2RD, - S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, - S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3). In some embodiments, Rxis oxo, -ORA, or NRBRC(e.g., oxo, OH, OCH3, N(CH3)2, or OC(0)RD). In some

[0371] embodiments, G is aryl or 5-6 membered heteroaryl (e.g., oxadiazolyl, or tetrazolyl).

[0372] 1 2

[0373] In some embodiments, at least one of L and L is independently 2-7-membered heteroalkylene, O, or NRC, wherein heteroalkylene is optionally substituted by 1-5 Rx. In some

[0374] 1 2

[0375] embodiments, at least one of L and L is independently 2-7-memberedheteroalkylene optionally substituted by 1-5 Rx. In some embodiments, both L1and L2are independently 2-7-membered heteroalkylene optionally substituted by 1-5 Rx. In some embodiments, one of L1and L2is

[0376] 1 2

[0377] independently Q-C6 alkylene or C2-C6 alkenylene and the other of L and L is independently 2- 7-membered heteroalkylene, and wherein each Q-C6 alkylene, C2-C6 alkenylene, and 2-7- membered heteroalkylene is optionally substituted by 1-5 Rx. In some embodiments, both of L1and L are C1-C6 alkylene or C2-C6 alkenylene, and wherein each Q-C6 alkylene, and C2-C6 alkenylene is optionally substituted by 1-5 Rx. In some embodiments, both of L1and L2are C2- C alkenylene, optionally substituted by 1-5 Rx.

[0378] In some embodiments, Rxis C1-C6 alkyl, oxo, halo, cyano, -ORA, -OS(0)2RD, - S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, - S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3). In some embodiments, Rxis oxo, -ORA, or NRBRC(e.g., oxo, OH, OCH3, N(CH3)2, or OC(0)RD). In some

[0379] embodiments, G is aryl or 5-6 membered heteroaryl (e.g., oxadiazolyl, or tetrazolyl).

[0380] In some embodiments, each of L1and L2is independently selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*,

[0381] CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W,

[0382] 1 2

[0383] respectively. In some embodiments, each of L and L is independently selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*,

[0384] CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively. In some embodiments, L1is independently selected from CH20-* and CH=CH-*, L2is independently selected from CH20-*, CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, - NHC(0)OCH2-*, O-*, NH-*, S(0)2CH2-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively. In some embodiments, L1is CH20-*, L2is independently selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively.

[0385] In some embodiments, t is 1. In some embodiments, t is 0.

[0386] 1 2

[0387] In some embodiments, R and R are each independently hydrogen, Cj-C alkyl,

[0388] 1 2 hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one of R1and R" is

[0389] 1 2

[0390] independently hydrogen and the other of R and R is independently hydrogen, Cj-C alkyl,

[0391] 1 2

[0392] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, R and R are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-"

[0393] 1 2 indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R" is independently hydrogen and the other of R1and R2is independently hydrogen, *-CH3, *-

[0394] CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the nitrogen atom. In some embodiments, R1and R2are each independently hydrogen.

[0395] In some embodiments, A is phenyl and W is independently phenyl or 5-6-membered heteroaryl. In some embodiments, each A and W is independently phenyl. In some embodiments, A is phenyl and W is 5-6-membered heteroaryl.

[0396] In some embodiments, W is a monocyclic 5-6-membered heteroaryl. In some embodiments, 2 R groups on adjacent atoms of W, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl or heterocyclyl optionally substituted with 1-5 R forming 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 heteroaryl containing nitrogen, oxygen or sulfur as allowed by valence. In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY, and each RYis independently Ci-Ce alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0397]

[0398]

[0399] In some embodiments, each of A and W is independently selected from:

[0400] . In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Cj-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0401] pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RY

[0402]

[0403] In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl. In some embodiments, each of A and W is optionally substituted with 1-5 RY, and each RYis independently alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci- C6alkyl, cyano-d-C6alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1.

[0404] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3,

[0405] C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0406] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0407] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently C1-C6 alkyl or halo {e.g., CH3or fluoro).

[0408] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3).

[0409] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):

[0410] Formula (I-d)

[0411] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or

[0412] 1 2

[0413] stereoisomer thereof, wherein each of L , L , A, and W, is defined as for Formula (I).

[0414] In some embo Formula (I-e):

[0415] Formula (I-e)

[0416] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or

[0417] 2 1 2

[0418] stereoisomer thereof, wherein each of L , A, W, R , R and t is defined as for Formula (I).

[0419] In some embodiments, L is Ci-Ce alkylene, C2-C6 alkenylene, or 2-7-membered

[0420] X 2

[0421] heteroalkylene optionally substituted by 1-5 R . In some embodiments, L is selected from CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*,

[0422] CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, NH-*, S(0)2CH-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0423] Cj-Ce alkyl, oxo, halo, cyano, -ORA, -OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, - C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3).

[0424] In some embodiments, L2is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*,

[0425] CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W. In some embodiments, L is selected from CH2O-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0426] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0427] In some embodiments, t is 1. In some embodiments, t is 0. In some embodiments, R and R are each independently hydrogen, C -Ce alkyl,

[0428] 1 2 hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one of R1and R" is

[0429] 1 2

[0430] independently hydrogen and the other of R and R is independently hydrogen, Cj-C alkyl,

[0431] 1 2

[0432] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, R and R are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-"

[0433] 1 2 indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R" is

[0434] 1 2

[0435] independently hydrogen and the other of R and R is independently hydrogen, *-CH3, *- CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the

[0436] 1 2

[0437] nitrogen atom. In some embodiments, R and R are each independently hydrogen.

[0438] In some embodiments, each A and W is independently a phenyl or heteroaryl optionally substituted with 1-5 RYgroups. In some embodiments, each A and W is independently a phenyl or 5-6-membered heteroaryl optionally substituted with 1 -5 RYgroups, and each RYis independently C\-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci- C6alkyl, cyano-Q-Q, alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0439]

[0440]

[0441] In some embodiments, each of A and W is independently selected from:

[0442]

[0443] . In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl,

[0444] Y Y

[0445] each of A and W is optionally substituted with 1-5 R , and each R is independently Cj-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5

[0446] RY

[0447]

[0448] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CHF2,

[0449] CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1. In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0450] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently Q-C6 alkyl or halo (e.g., CH3or fluoro).

[0451] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro).

[0452] In some emb la (I-f):

[0453] Formula (I-f)

[0454] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L2, W, RY, R1, R2and t is defined as for Formula (I).

[0455] In some embodiments, L is Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered

[0456] X 2

[0457] heteroalkylene optionally substituted by 1-5 R . In some embodiments, L is 2-7-membered

[0458] C X 2 heteroalkylene, O, or NR , optionally substituted by 1-5 R . In some embodiments, L is selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-* CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*,

[0459] CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0460] In some embodiments, each Rxis independently C1-C6 alkyl, oxo, halo, cyano, -ORA, - OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2 (e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3).

[0461] In some embodiments, L2is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W. In some embodiments, L is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0462] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0463] In some embodiments, t is 1. In some embodiments, t is 0.

[0464] 1 2

[0465] In some embodiments, R and R are each independently hydrogen, Cj-C alkyl,

[0466] 1 2 hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one of R1and R" is

[0467] 1 2

[0468] independently hydrogen and the other of R and R is independently hydrogen, Cj-C alkyl,

[0469] 1 2

[0470] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, R and R are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-"

[0471] 1 2 indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R" is

[0472] 1 2

[0473] independently hydrogen and the other of R and R is independently hydrogen, *-CH3, *- CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the nitrogen atom. In some embodiments, R1and R2are each independently hydrogen.

[0474] In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY, and each RYis independently C C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R groups In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R groups. In some embodiments, each of A and W is independently selected from: some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 R , and each R is independently C\-Ce alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0475] pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 Y

[0476]

[0477] R , and

[0478]

[0479]

[0480] In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl. In some embodiments, each of A and W is optionally substituted with 1-5 RY, and each RYis independently C\-Ce alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci- C6alkyl, cyano-Q-Q, alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1.

[0481] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3,OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3,

[0482] C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0483] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1. In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently Cj-C alkyl or halo (e.g., CH3or fluoro).

[0484] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3).

[0485] In some embo of Formula (I-g):

[0486] Formula (I-g)

[0487] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L1, L2, R1, R2, A, W, Rx, and t is defined as for Formula (I)·

[0488] In some embodi f Formula (I-h):

[0489] Formula (I-h)

[0490] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L2, R1, R2, A, W, Rx, and t is defined as for Formula (I).

[0491] In some emb la (I-i):

[0492] Formula (I-i) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L2, R1, R2, W, Rx, RY, and t is defined as for Formula (I).

[0493] In some embodiments, L is Cj-C alkylene, C2-C6 alkenylene, or 2-7-membered

[0494] X 2

[0495] heteroalkylene optionally substituted by 1-5 R . In some embodiments, L is 2-7-membered

[0496] C X 2

[0497] heteroalkylene, O, or NR , optionally substituted by 1-5 R . In some embodiments, L is selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*,

[0498] CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0499] In some embodiments, each Rxis independently Q-C6 alkyl, oxo, halo, cyano, -ORA, - OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3).

[0500] In some embodiments, L2is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W. In some embodiments, L is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0501] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0502] In some embodiments, t is 1. In some embodiments, t is 0.

[0503] 1 2

[0504] In some embodiments, R and R are each independently hydrogen, Q-C6 alkyl,

[0505] 1 2

[0506] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, one of R1and R" is

[0507] 1 2

[0508] independently hydrogen and the other of R and R is independently hydrogen, Q-C6 alkyl,

[0509] 1 2

[0510] hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl. In some embodiments, R and R are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-"

[0511] 1 2 indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R" is

[0512] 1 2

[0513] independently hydrogen and the other of R and R is independently hydrogen, *-CH3, *- CH2CH2OH, or and "*-" indicates the attachment point to the

[0514] 1 2

[0515] nitrogen atom. In some embodiments, R and R are each independently hydrogen.

[0516] In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY, and each RYis independently Ci-Ce alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0517]

[0518]

[0519] In some embodiments, each of A and W is independently selected from:

[0520] . In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Cj-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0521] pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RY

[0522]

[0523] In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl. In some embodiments, each of A and W is optionally substituted with 1-5 RY, and each RYis independently alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci- C6alkyl, cyano-d-C6alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1.

[0524] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3,

[0525] C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0526] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0527] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently C1-C6 alkyl or halo {e.g., CH3or fluoro).

[0528] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3).

[0529] In some embodiments, the compound of Formula (I) is a compound of Formula (I-j):

[0530] Formula (I-j)

[0531] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein each of L1, L2, R1, R2, A, W, Rx, and t is defined as for Formula (I).

[0532] In some embodiments, the compound of Formula (I) is a compound of Formula (I-k):

[0533]

[0534] Formula (I-k)

[0535] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or

[0536] 2 1 2 X

[0537] stereoisomer thereof, wherein each of L , R , R A, W, R , and t is defined as for Formula (I).

[0538] In some embodiments, the compound of Formula (I) is a compound of Formula (1-1):

[0539]

[0540] Formula (1-1)

[0541] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or

[0542] 2 1 2 X Y

[0543] stereoisomer thereof, wherein each of L , R , R W, R , R , and t is defined as for Formula (I).

[0544] 1 2

[0545] In some embodiments, at least one of L and L is independently 2-7-membered

[0546] X 1 2 heteroalkylene optionally substituted by 1-5 R . In some embodiments, both L and L are independently 2-7-membered heteroalkylene optionally substituted by 1-5 Rx. In some

[0547] 1 2

[0548] embodiments, one of L and L is independently C -Ce alkylene or C2-C6 alkenylene and the

[0549] 1 2

[0550] other of L and L is independently 2-7-membered heteroalkylene, and wherein each C1-C6 alkylene, C2-C6 alkenylene, and 2-7-membered heteroalkylene is optionally substituted by 1 -5 Rx. In some embodiments, each Rxis independently C1-C6 alkyl, oxo, or -C(0)RD(e.g., CH3,

[0551] 1 2

[0552] oxo, or C(0)CH3). In some embodiments, each of L and L is independently selected from CH2O-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0553] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the

[0554] 1 2

[0555] attachment point to A and W, respectively. In some embodiments, L is CH20-*, L is independently selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively.

[0556] In some embodiments, L2is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W. In some embodiments, L is selected from CH20-*, CH2CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*,

[0557] CH2N(C(0)CH3)-*, CH2CH(OH)-*, NHC(0)OCH2-*, or CH2C(0)-*, and "-*" indicates the attachment point to W.

[0558] In some embodiments, each Rxis independently Q-C6 alkyl, oxo, halo, cyano, -ORA, - OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, NRBRC, or G2(e.g., CH3, oxo, fluoro, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, or -SCH3).

[0559] In some embodiments, t is 1. In some embodiments, t is 0.

[0560] 1 2

[0561] In some embodiments, R and R are each independently hydrogen, Q-C6 alkyl, hydroxyl-Ci-C6 alkyl, or silyloxy-Ci-C6 alkyl. In some embodiments, one of R1and R2is

[0562] 1 2

[0563] independently hydrogen and the other of R and R is independently hydrogen, Q-C6 alkyl, Ci- C hydroxyl-Ci-C6 alkyl, or silyloxy-Ci-C6 alkyl. In some embodiments, R1and R2are each independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-"

[0564] 1 2 indicates the attachment point to the nitrogen atom. In some embodiments, one of R1and R" is

[0565] 1 2

[0566] independently hydrogen and the other of R and R is independently hydrogen, *-CH3, *- CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the attachment point to the

[0567] 1 2

[0568] nitrogen atom. In some embodiments, R and R are each independently hydrogen.

[0569] In some embodiments, A is phenyl and W is independently phenyl or 5-6-membered heteroaryl. In some embodiments, each A and W is independently phenyl. In some embodiments, A is phenyl and W is 5-6-membered heteroaryl. In some embodiments, W is a monocyclic 5-6-membered heteroaryl. In some embodiments, 2 RYgroups on adjacent atoms of W, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl or heterocyclyl optionally substituted with 1-5 Rxforming 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 heteroaryl containing nitrogen, oxygen or sulfur as allowed by valence.

[0570] In some embodiments, each A and W is independently phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RY, and each RYis independently C C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups. In some embodiments, each of A and W is independently selected from:

[0571]

[0572]

[0573] In some embodiments, each of A and W is independently selected from:

[0574] . In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Cj-C alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m,-S(0)2RD, or G1. In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl,

[0575] pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RY

[0576]

[0577] In some embodiments, A is phenyl and W is phenyl or 5-6-membered heteroaryl. In some embodiments, each of A and W is optionally substituted with 1-5 RY, and each RYis independently alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci- C6alkyl, cyano-d-C6alkyl, halo, cyano, -ORA, -NRBRC, -C(0)RD, -C(0)OH, -C(0)ORD, - S(RF)m,-S(0)2RD, or G1.

[0578] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3,

[0579] C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0580] In some embodiments, each RYis independently chloro, fluoro, iodo, CF3, CH3, CH2CH3, OCH3, S(0)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1.

[0581] In some embodiments, each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx. In some embodiments, 2 RYtogether with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 Rx. In some embodiments, each Rxis independently C1-C6 alkyl or halo {e.g., CH3or fluoro).

[0582] In some embodiments, G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, G1is cyclopropyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz. In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). In some embodiments, each Rzis independently C1-C6 alkyl (e.g., CH3). In some embodiments, the compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k) or (I-l)) or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0583] In some embodiments, the compound of Formula (I) (e.g., a compound of Formula (I-a),

[0584] (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k) or (I-l)) is selected from a compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0585] Also disclosed herein

[0586] Formula (II)

[0587] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:

[0588] D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1;

[0589] 1 c L is C1-C6 alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NR , wherein Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 R ;

[0590] L2is -(C0-C2 alkylene)-0-(Co-C2alkylene)-;

[0591] R1is hydrogen, Ci-C6alkyl, Ci-C6alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, and silyloxy-C2-C6 alkyl;

[0592] RN1is selected from the group consisting of hydrogen, Ci-C6alkyl, hydroxy-C2-C6alkyl, halo-C2-C6alkyl, amino-C2-C6alkyl, cyano-C2-C6alkyl, -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD;

[0593] A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY; each R is independently selected from the group consisting of C -Ce alkyl, hydroxy-Q- Ce alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2;

[0594] each RYis independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -S(RF)m, -S(0)RD, -S(0)2RD, and G1; or

[0595] 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx;

[0596] 1 2

[0597] each G and G is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl is optionally substituted with 1-3 Rz;

[0598] each Rzis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-

[0599] C6alkyl, halo-Ci-Q alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, and -S(0)2RD;

[0600] each RAis independently hydrogen, d-C6alkyl, halo-C C6alkyl, -C(0)NRBRc, - C(0)RD, or -C(0)ORD;

[0601] each of RBand Rcis independently hydrogen or C1-C6 alkyl; or

[0602] B C

[0603] R and R together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 Rz;

[0604] each RDis independently C1-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Ci-C6 alkyl, wherein each C1-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Ci-C6 alkyl is optionally substituted with 1-5 RG;

[0605] each REis independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl;

[0606] each RFis independently hydrogen, C1-C6 alkyl, or halo;

[0607] each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH;

[0608] each RHis independently C1-C6 alkyl or halo-Ci-C6 alkyl;

[0609] m is 1 when RFis hydrogen or Q-C6 alkyl, 3 when RFis alkyl, or 5 when RFis halo; and; and t is 0 or 1.

[0610] In some embodiments D is selected from the group consisting of

[0611]

[0612] embodiments, each R is independently selected from the group consisting of oxo, -OR (e.g., OH or OCH3), -C(0)OH, -C(0)ORD(e.g., -C(0)OCH3), halo, and hydroxy-Cj-Ce alkyl.

[0613] In some embodiments, L1is C¾0-* or CH2OCH2-*; wherein "-*" indicates the attachment point to A. In some embodiments, L2is selected from the group consisting of O-*, OCH2-*, CH2O-*, OCH2CH2-*, CH2OCH2-*, and CH2CH2O-*; wherein "-*" indicates the attachment point to W. In some embodiments, R1is hydrogen or C¾

[0614] In some embodiments A is selected from the group consisting of:

[0615]

[0616] In some embodiments, W is selected from the group consisting of:

[0617] wherein R is hydrogen or CH3.

[0618] In some embodiments, each RYis independently hydrogen, chloro, fluoro, CF3, CHF2,

[0619] CH3, CH2CH3, CH(CH3)2, OCH3, OCF3, OCH(CH3)2, or CN.

[0620] some embodiments nd of Formula (Il-a)

[0621] Formula (Il-a)

[0622] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:

[0623] D is bicyclo[l.l. l]pentanyl or bicyclo[2.2.2]octanyl, each of which is optionally substituted with 1-4 Rxgroups;

[0624] L1is CH20-* or CH2OCH2-*, wherein "-*" indicates the attachment point to A;

[0625] L is selected from the group consisting of O-*, OCH2-*, CH20-*, OCH2CH2-*, CH2OCH2-*, and CH2CH20-*; wherein "-*" indicates the attachment point to W;

[0626] A is phenyl or pyridyl, each of which is optionally substituted with 1-5 RYgroups;

[0627] W is phenyl, pyridyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted on one or more available carbons with 1-5 RYgroups; and wherein pyrazolyl may be optionally substituted on an available nitrogen with hydrogen or CH3;

[0628] each Rxis independently fluoro, oxo, OH, OCH3, C(0)OH, or C(0)OCH3;

[0629] each RYis independently chloro, fluoro, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCH(CH3)2, or CN; or

[0630] 2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 R ; and

[0631] R1is hydrogen.

[0632] In some embodiments, the compound of Formula (II) (e.g., a compound of Formula (Il-a) or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0633] In some embodiments, the compound of Formula (II) (e.g., a compound of Formula (Il-a) is selected from a compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof. Table 1: Exemplary compounds of the invention

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685] Methods of Making Exemplary Compounds

[0686] The compounds of the invention may be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared. The compounds of this invention can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in, but not limited to, Schemes 1-29. The

[0687] 1 2 1 2

[0688] variables A, D, W, L , If , R , and R" are defined as detailed herein, e.g., in the Summary Scheme 1 : Represe the invention.

[0689]

[0690] As shown in Scheme 1 , compounds of formula (3), when A and W are the same and L and L are the same, and which are representative of compounds of formula (I), 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 provide compounds of formula (3). Examples of conditions known to generate amides from a mixture of a carboxylic acid and an amine include, but are not limited to, adding a coupling reagent such as, but not limited to, N-(3- dimethylaminopropyl)-N-ethylcarbodiimide or 1 -(3-dimethylaminopropyl)-3-ethylcarbodiirnide (EDC, ED AC or EDCI) or the corresponding hydrochloride salt, 1 ,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1), N-[(dimethylamino)-lH-l ,2,3- triazolo-[4,5-¾]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide or 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1- [bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 2-(lH- benzo [d] [ 1 ,2, 3] triazol- 1 -yl)- 1 , 1 ,3 , 3 -tetr amethylisouronium hexafluorophosphate( V) (ΗΒ TU) , and 2,4,6-tripropyl-l ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®). The coupling reagents may be added as a solid, a solution, or as the reagent bound to a solid support resin.

[0691] In addition to the coupling reagents, auxiliary-coupling reagents may facilitate the coupling reaction. Auxiliary coupling reagents that are often used in the coupling reactions include but are not limited to (dimethylamino)pyridine (DMAP), l-hydroxy-7-azabenzotriazole (ΗΟΑΤ) and 1-hydroxybenzotriazole (ΗΟΒΤ). The reaction may be carried out optionally 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 solvents such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate. The reactions may be carried out at ambient temperature or heated. The heating can be accomplished either conventionally or with microwave irradiation.

[0692] Alternatively, acid chlorides of formula (2B) can be reacted with amines of formula (1), optionally in the presence of a base for example, a tertiary amine base such as, but not limited to, triethylamine or N,N-diisopropylethylamine or an aromatic base such as pyridine, at room temperature or heated in a solvent such as, but not limited to, dichloromethane to provide amides of formula (3). Amines of formula (1) can also be coupled with acid chlorides of formula (2B) in a mixture of water and dichloromethane in the presence of a base such as but not limited to sodium hydroxide. Scheme 2: ion.

[0693]

[0694] As shown in Scheme 2, compounds of formula (3), when A and W are the same or

[0695] 1 2

[0696] different and L and L are the same or different, and which are representative of compounds of formula (I), can be prepared from compounds of formula (1). Amines of formula (1) can be protected with a suitable protecting group (PG) to provide compounds of formula (4). For example, amines of formula (1) can be treated with di-teri-butyl dicarbonate at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran to provide compounds of formula (4) wherein PG is C(0)OC(CH3)3. Carboxylic acids of formula (2A) or acid chlorides of formula (2B) can be coupled with amines of formula (4) under amide bond forming conditions described in Scheme 1 to provide compounds of formula (5). The protecting group (PG) in formula (5) can be removed to provide compounds of formula (6). For example, BOC protecting groups 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

[0697] dichloromethane, or mixtures thereof. The reaction may be performed at ambient or an elevated temperature. Carboxylic acids of formula (7 A) or acid chlorides of formula (7B) can be coupled with amines of formula (6) under amide bond forming conditions described in Scheme 1 to provide compounds of formula (3), which are representative of compounds of formula (I). Scheme 3: Representative scheme for synthesis of exemplary compounds of the invention.

[0698]

[0699] As shown in Scheme 3, compounds of formula (9), which are representative of compounds of formula (I) when t is 0, can be prepared from compounds of formula (6).

[0700] Compounds of formula (6), which can be prepared as described in Scheme 2, can be reacted with an aldehyde of formula (8), wherein R100is absent or is alkylene or heteroalkylene, in the presence of a reducing agent such as, but not limited to, sodium triacetoxyborohydride or sodium cyanoborohydride, to provide compounds of formula (9). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, 1,2-dichloroethane,

[0701] dichloromethane, methanol, ethanol, tetrahydrofuran, acetonitrile, or mixtures thereof.

[0702] Scheme 4: Re ention.

[0703]

[0704] 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 provide compounds of formula (9). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, N,N-dimethylformamide or dimethyl sulfoxide. Scheme n.

[0705]

[0706] Compounds of formula (13) and compounds of formula (14), which are representative of compounds of formula (I) wherein t is 1, can be prepared as shown in Scheme 5. Amines of formula (6), which can be prepared as described in Scheme 2, can be treated with 2-chloroacetyl chloride in the presence of a base such as, but not limited to, potassium carbonate, to provide compounds of formula (11). The addition is typically performed at low temperature before warming up to ambient temperature in a solvent such as, but not limited to, tetrahydrofuran, water, or mixtures thereof. 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 provide compounds of formula (13). The reaction is typically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide. Alternatively, alcohols of formula (12A) can be reacted with compounds 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 provide compounds of formula (13). The reaction is typically performed at an elevated temperature, optionally in a microwave, and in a solvent such as, but not limited to, acetonitrile, acetone, or mixtures thereof. Alcohols of formula (12B), wherein n is 1-6, can be reacted with compounds of formula (11) in the presence of a strong base, such as but not limited to sodium hydride, to provide compounds of formula (14). The reaction is typically performed at ambient temperature in a solvent, such as but not limited to, N,N-dimethylformamide. Scheme 6: Re ention.

[0707]

[0708] A shown in Scheme 6, compounds of formula (15), which are representative of compounds of formula (I) wherein t is 1 and L is C2-C7 heteroalkylene, can be prepared from compounds of formula (6). Amines of formula (6) can be treated with bis(trichloromethyl) carbonate, followed by alcohols of formula (12B), to provide compounds of formula (15). The reaction is typically performed at ambient temperature in a solvent such as but not limited to tetrahydrofuran.

[0709]

[0710] Compounds of formula (18), which are representative of compounds of formula (I) wherein t is 1 and R is C1-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, silyloxy- C1-C6 alkyl, or Q-C6 alkyl-C(0)2-Ci-C6 alkyl can be prepared from compounds of formula (6) as shown in Scheme 7. Amines of formula (6) can be alkylated with an alkylating agent of formula (16) wherein X is a halide, in the presence of a base such as, but not limited to, potassium carbonate, to provide compounds of formula (17). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, N,N-dimethylformamide. Carboxylic acids of formula (7 A) or acid chlorides of formula (7B) can be coupled with amines of formula (17) under amide bond forming conditions described in Scheme 1 to provide compounds of formula (18). Scheme 8: tion.

[0711]

[0712] As shown in Scheme 8, compounds of formula (20), which are representative of compounds of formula (I) wherein t is 1 , can be prepared from amines of formula (6). 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 performed at ambient temperature in a solvent such as but not limited to toluene, dichloromethane, or mixtures thereof. Sche ary compounds of the invention.

[0713] Formula (I)

[0714] Compounds of formula (I), wherein R is Cj-C alkyl, Cj-C alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, or silyloxy-C2-C6 alkyl, can be prepared from compounds of formula (5) as shown in Scheme 9. Amines of formula (5), which can be prepared as described in Scheme 2, can be alkylated with an alkylating agent of formula (21), wherein 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 performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, or mixtures thereof. After removal of the protecting group (PG), compounds of formula (22) can be reacted with carboxylic acids of formula (7 A) or acid chlorides of formula (7B) under amide bond forming conditions described in Scheme 2 to provide compounds of formula (I). Sche

[0715]

[0716] As shown in Scheme 10, compounds of formula (25), which are representative of compounds of formula (I) wherein t is 1, can be prepared from compounds of formula (6). Amines of formula (6), which can be prepared as described in Scheme 2, can be reacted with 2- hydroxyacetic acid to provide compounds of formula (23) under amide bond forming conditions described in Scheme 2. Compounds of formula (23) can be alkylated with an alkylating agent of formula (24), wherein X is a halide and n is 0-5, in the presence of a base such as but not limited to sodium hydride, to provide compounds of formula (25). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, tetrahydrofuran N,N- dimethylformamide, or mixtures thereof.

[0717] Scheme on.

[0718]

[0719] Compounds of formula (28), which are representative of compounds of formula (I),wherein t is 1, 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 methyl 2-bromoacetate in the presence of a base such as, but not limited to, cesium carbonate to provide compounds of formula (26). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran. Compounds of formula (26) can be treated with aqueous lithium hydroxide to provide compounds of formula (27). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran, methanol, or mixtures thereof. 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]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and a base such as, but not limited to, triethylamine, to provide compounds of formula (28). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to acetonitrile.

[0720]

[0721] As shown in Scheme 12, compounds of formula (30), which are representative of compounds of formula (I), can be prepared from compounds of formula (26). Compounds of formula (26), which can be prepared as described in Scheme 11, can be treated with hydrazine monohydrate, to provide compounds of formula (29). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, ethanol. Compounds of formula (29) can be treated with Ι ,Γ-carbonyldiimidazole, to provide compounds of formula (30). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to 1 ,4-dioxane. Scheme 13: Representative scheme for synthesis of exemplary compounds of the invention.

[0722]

[0723] Scheme 13 describes the synthesis of compounds of formula (I) wherein D is a 2- oxobicyclo[2.2.2]octan-l-yl core. Ethyl 4-amino-2-oxobicyclo[2.2.2]octane-l-carboxylate, which can be prepared as described herein, can be reacted with carboxylic acids of formula (2A) or acid chlorides of formula (2B) under amide bond forming conditions described in Scheme 1 to provide compounds of formula (31). Compounds of formula (31) can be treated with a methanolic solution of sodium hydroxide at ambient temperature to provide 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 treatment with tert- butanol, to provide compounds of formula (33). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, toluene. Compounds of formula (33) can be treated with an acid such as, but not limited to, hydrochloric acid at ambient temperature in a solvent such as, but not limited to, 1 ,4-dioxane, to provide compounds of formula (34). Compounds of formula (34) can be reacted with carboxylic acids of formula (7 A) or acid chlorides of formula (7B) under amide bond forming conditions described in Scheme 2 to provide compounds of formula (I). Scheme 14: Representative scheme for synthesis of exemplary compounds of the invention.

[0724]

[0725] Scheme 14 describes the synthesis of carboxylic acids (37), (42), and (45), which are representative of acids of formula (2A) and formula (7 A).

[0726] Compounds of formula (35) can be reacted with ethyl 2-hydroxyacetate in the presence of a strong base such as, but not limited to, potassium teri-butoxide to provide compounds of formula (36). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran. Compounds of formula (36) can be treated with aqueous lithium hydroxide to provide compounds of formula (37). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.

[0727] Alcohols 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 provide compounds of formula (39). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, N,N-dimethylformamide. Compounds of formula (39) can be treated with an acid such as, but not limited to, hydrochloric acid to provide compounds of formula (37). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, 1,4-dioxane. Compounds 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 provide compounds of formula (41). The addition is typically performed at low temperature before warming to ambient temperature, in a solvent such as, but not limited to, tetrahydrofuran. Compounds of formula (41) can be treated with aqueous sodium hydroxide to provide compounds of formula (42). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.

[0728] Carboxylic acids of formula (43) can be reacted with sarcosine methyl ester, under amide bond forming conditions as described in Scheme 1, to provide compounds of formula (44). Compounds of formula (44) can be treated with aqueous sodium hydroxide to provide compounds of formula (45). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, ethanol.

[0729] Scheme 15: Represent nds of the invention.

[0730] As shown in Scheme 15, bromides of formula (47), which are representative of compounds of formula (10) and (24), can be prepared from alcohols of formula (46).

[0731] 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 provide compounds of formula (47). The reaction is typically performed at elevated temperature in a solvent such as, but not limited to, acetonitrile.

[0732] Scheme 16: Representative scheme for synthesis of exemplary compounds of the invention.

[0733]

[0734] As shown in Scheme 16, compounds of formula (49), wherein A and W are the same or different and L 1 and L 2 are the same or different, and which are representative of compounds of formula (I), can be prepared from compounds of formula (48). Carboxylic acids of formula (7 A) or acid chlorides of formula (7B) can be coupled with amines of formula (48) under amide bond forming conditions described in Scheme 1 to provide 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 solvents such as a mixture of methanol and dichloromethane to give alcohols of formula (50). Carboxylic acids of formula (7 A) or acid chlorides of formula (7B) can be coupled with amines of formula (50) under amide bond forming conditions described in Scheme 1 to provide 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 solvents such as a mixture of methanol and dichloromethane to give alcohols of formula (51).

[0735] Compounds of formula (48), formula (49), formula (50) and formula (51) can be further derivatized as illustrated in the Examples below. S ention.

[0736] Formula (I)

[0737] As shown in Scheme 17, compounds of formula (52) can be transformed to compounds of formula (6) which in turn through the methods described in Schemes 2-8 and 10 can be converted to compounds of formula (I). Accordingly, carboxylic acids of formula (2A) or acid chlorides of formula (2B) can be coupled with amines of formula (50) under amide bond forming conditions described in Scheme 1 followed by ester hydrolysis using conditions known to one of skill in the art to provide compounds of formula (53). Compounds of formula (53) can be reacted under Curtius reaction conditions such as treatment with diphenylphosphoryl azide and triethylamine in heated toluene followed by acid hydrolysis to give compounds of formula (6).

[0738] Scheme 18: nvention.

[0739]

[0740] 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). Accordingly, compounds of formula (6) can be coupled with protected amino acids of formula (54), wherein PG is suitable amine protecting group, using the amide bond coupling conditions described in Scheme 1 to give compounds of formula (55). The protecting group, PG, in compounds of formula (55) can be removed under conditions known to one of skill in the art to expose a primary amine that can be coupled with carboxylic acids of formula (56) using the amide bond coupling conditions described in Scheme 1 to give compounds of formula (57).

[0741] Scheme 19: Represent ds of the invention.

[0742]

[0743] 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 triethylamine, in an optionally warmed solvent, such as but not limited to N,N- dimethylformamide, to give compounds of formula (59).

[0744] Scheme 20: Representat nds of the invention.

[0745]

[0746] 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).

[0747] Scheme 21 : Representat nds of the invention.

[0748]

[0749] 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 carbanochloridates of formula (62) in the presence of a base, such as N,N- diisopropylethylamine, in a solvent, such as tetrahydrofuran, to give compounds of formula (63).

[0750] Scheme 22: Representative scheme for synthesis of exemplary compounds of the invention.

[0751]

[0752] As shown in Scheme 22, compounds of formula (64) can be transformed 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 (EtsSiH) in warmed

[0753] dichloromethane to give compounds of formula (65). Scheme 23: Representative scheme for synthesis of exemplary compounds of the invention. di-ferf-butyl dicarbonate base

[0754]

[0755]

[0756] As shown in Scheme 23, compounds of formula (66) can be converted to compounds of formula (1). Accordingly, the ester moiety of compounds of formula (66) can be hydrolyzed under conditions known to one of skill in the art to give the corresponding carboxylic acids. The carboxylic acids can be treated under Curtius reaction conditions to complete the transformation to compounds of formula (67). Compounds of formula (67) can be reacted with di-teri-butyl dicarbonate in the presence of a base to give the orthogonally protected bis-amine, (68).

[0757] Compounds of formula (68) can be converted to compounds of formula (1) under catalytic hydrogenation conditions in the presence of an acid, such as 4 M hydrochloric acid, in a solvent such as warmed dioxane. Compounds of formula (1) can be used as described in Scheme 1 or Scheme 2.

[0758] Scheme 24: Representative scheme for synthesis of exemplary compounds of the invention.

[0759]

[0760] As shown in Scheme 24, compounds of formula (68) can be converted to compounds of formula (71). Compounds of formula (68) can be reductively aminated to compounds of formula (69), wherein R2bis optionally substituted C1-C6 alkyl. Compounds of formula (69) can be treated under acidic conditions known to one of skill in the art to selectively remove the tert- butoxy carbonyl protecting group and then couple the exposed amine with compounds of formula (2A) using amide bond forming reaction conditions described in Scheme 1 to give compounds of formula (70). Alternatively, acid chlorides of formula (2B) can be coupled with the amines also as described in Scheme 1. The benzyl protecting group of compounds of formula (70) can be removed under catalytic hydrogenation conditions, and then the revealed amine can be coupled with carboxylic acids of formula (7 A) to give compounds of formula (71). Compounds of formula (71) can also be obtained by reaction with the corresponding acid chloride with the previously mentioned revealed amine using conditions also described in Scheme 1. Compounds of formula (71) are representative of compounds of formula (I).

[0761] Scheme 25: Representative scheme for synthesis of exemplary compounds of the invention.

[0762]

[0763] As shown in Scheme 25, compounds of formula (72) can be converted to compounds of formula (75). Carboxylic acids of formula (2A) can be coupled with amines of formula (72) under amide bond forming conditions as discussed for Scheme 1 to provide compounds of formula (73). Compounds of formula (73) can be reacted with compounds of formula (74), wherein LG1is a leaving group, e.g., halogen or sulfonate, under nucleophilic substitution reaction conditions to give compounds of formula (75). Compounds of formula (73) can be reacted with compounds of formula (74) in the presence of a tertiary amine base, such as 2,6-di- teri-butylpyridine, in a solvent such as dichloromethane to give compounds of formula (75).

[0764] When LG1is a halogen, a silver reagent such as silver trifluoromethanesulfonate may be used to increase the reactivity of the halide during nucleophilic substitution compounds of formula (74) such as benzyl halides, for example. Compounds of formula (75) are representative of compounds of Formula (I). the invention.

[0765]

[0766] (77)

[0767] As shown in Scheme 26, compounds of formula (4) can be transformed to compounds of formula (77) which in turn through the last two steps described in Schemes 2 can be converted to compounds of formula (I). Compounds of formula (4), wherein PG is suitable amine protecting group, can be reacted with 2-chloroacetic acid under the amide bond forming conditions described in Scheme 1 to give compound of formula (76). Compounds of formula (76) can be reacted with compounds of formula (38) in the presence of potassium iodide and a base such as potassium carbonate in a heated solvent such as but not limited to acetone to give compounds of formula (77). The heating may be achieved conventionally or with microwave irradiation. After removal of the protecting group (PG) under conditions known to one of skill in the art and dependent upon the particular protecting group from compounds of formula (77), reaction of the resultant amine with carboxylic acids of formula (7A) or acid chlorides of formula (7B) under amide bond forming conditions described in Scheme 1 can provide compounds of formula (I). Scheme 27: Re resentative scheme for synthesis of exemplary compounds of the invention.

[0768]

[0769] As shown in Scheme 27, compounds of formula (4) can be transformed to compounds of formula (79) which in turn through the last two steps described in Schemes 2 can be converted to compounds of formula (I). Compounds of formula (4), wherein PG is suitable amine protecting group, can be reacted with compounds of formula (10) in the presence of a base such as but not limited to cesium carbonate in an optionally warmed solvent such as but not limited to N,N- dimethylformamide to give compounds of formula (78). Compounds of formula (78) can be reacted with aldehydes, R2c-CHO, wherein R2cis hydrogen, C1-C5 alkyl, C1-C6 alkoxy-C2-Cs alkyl, hydroxy-C2-C5alkyl, silyloxy-C2-C5alkyl, or d-C5alkyl-C(0)2-Ci-C6alkyl; under reductive amination conditions such as in the presence of an acid such as trifluoroacetic acid in the presence of sodium borohydride in a solvent such as methanol to give compounds of formula (79). After removal of the protecting group (PG) under conditions known to one of skill in the art and dependent upon the particular protecting group from compounds of formula (79), reaction of the resultant amine with carboxylic acids of formula (2A) or acid chlorides of formula (2B) under amide bond forming conditions described in Scheme 1 can provide compounds of formula (I). nds of the invention.

[0770]

[0771] As shown in Scheme 28, compounds of formula (6) can be converted to compounds of formula (3) in one step. Accordingly, amines of formula (6) can be reacted with esters of formula (79) in a heated solvent such as but not limited to toluene to give compounds of formula (3). Compounds of formula (3) are representative of compounds of Formula (I).

[0772] the invention.

[0773]

[0774] As shown in Scheme 29, compounds of formula (6) can be converted to compounds of formula (81). Accordingly, amines of formula (6) can be reacted with alcohols of formula (80) and 4-nitrophenyl carbonochloridate in a heated solvent such as but not limited to acetonitrile in the presence of a tertiary amine base such as Hunig' s base and an aromatic amine base such as pyridine to give compounds of formula (81). The heating may be accomplished conventionally or through microwave irradiation. Compounds of formula (81) are representative of compounds of Formula (I).

[0775] Pharmaceutical Compositions

[0776] The present invention features pharmaceutical compositions comprising a compound of

[0777] Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, 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.

[0778] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of Formula (I) or Formula (II), (the "active ingredient") into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose 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 the 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 which 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.

[0779] Relative amounts of a compound of Formula (I) or Formula (II), the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) of a compound of Formula (I) or Formula (II).

[0780] 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 the manufacture of the pharmaceutical compositions of the invention are any of those that are well known in the art of pharmaceutical formulation and include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0781] Compositions of the present invention may be administered orally, parenterally

[0782] (including subcutaneous, intramuscular, intravenous and intradermal), 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.

[0783] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, 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 this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0784] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A compound of Formula (I) or Formula (II) may also be in micro-encapsulated form.

[0785] The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., 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, for example, water or water / propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Patent Nos. 4,911 ,920; 5,403,841 ; 5,212, 162; and 4,861 ,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (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, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0786] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0787] In some embodiments, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0788] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0789] Compounds provided herein, e.g., a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0790] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g. , two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0791] In certain embodiments, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof for administration one or more times a day may comprise about 0.0001 mg to about 5000 mg, e.g., from about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0792] In certain embodiments, a compound of Formula (I) or Formula (II), or a

[0793] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 1000 mg / kg, e.g., about 0.001 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 250 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 50 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0794] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0795] It will be also appreciated that a compound or composition, e.g., a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N- oxide or stereoisomer thereof as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0796] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g. , combination therapies. Pharmaceutical agents include therapeutically active agents.

[0797] Pharmaceutical agents also include prophylactically active agents. Each additional

[0798] pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0799] Exemplary additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and pain-relieving agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient (e.g., compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in 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 methods to treat 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. eIF2B, eIF2 or component of eIF2a signal transduction pathway or component of phosphorylated eIF2a pathway or the ISR pathway), and / or reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of cancer a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of eIF2B, eIF2a or a component of the eIF2 pathway or ISR pathway). Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0800] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g. a symptom of cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with impaired function of eIF2B, eIF2 a, or a component of the eIF2 pathway or ISR pathway), kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

[0801] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0802] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0803] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0804] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0805] Also encompassed by the invention are kits (e.g. , pharmaceutical packs). The inventive kits may be useful for preventing and / or treating a disease (e.g. , cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or other disease or condition described herein).

[0806] The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g. , a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful in preventing and / or treating a proliferative disease in a subject. In certain embodiments, the kits further include instructions for administering a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject to prevent and / or treat a disease described herein. Methods of Treatment

[0807] The present invention features compounds, compositions, and methods comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof. In some embodiments, the compounds, compositions, and methods are used in the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a disease with mutations that leads to UPR induction, a malaria infection, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease.

[0808] In some embodiments, the disease, disorder, or condition is related to (e.g., caused by) modulation of (e.g., a decrease in) eIF2B activity or level, eIF2a activity or level, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder, or condition is related to modulation of a signaling pathway related to 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 related to (e.g., caused by) neurodegeneration. In some embodiments, the disease, disorder, or condition is related to (e.g., caused by) neural cell death or dysfunction. In some embodiments, the disease, disorder, or condition is related to (e.g., caused by) glial cell death or dysfunction. In some embodiments, the disease, disorder, or condition is related to (e.g., caused by) an increase in the level or activity of eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder, or condition is related to (e.g., caused by) a decrease in the level or activity of eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway.

[0809] In some embodiments, the disease may be caused by a mutation to a gene or protein sequence related to a member of the eIF2 pathway (e.g., eIF2B, eIF2a, or other component). Exemplary mutations include an amino acid mutation in the eIF2B l , eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, an amino acid mutation (e.g., an amino acid substitution, addition, or deletion) in a particular protein that may result in a structural change, e.g., a conformational or steric change, that affects the function of the protein. For example, in some embodiments, amino acids in and around the active site or close to a binding site (e.g., a phosphorylation site, small molecule binding site, or protein-binding site) may be mutated such that the activity of the protein is impacted. In some instances, the amino acid mutation (e.g., an amino acid substitution, addition, or deletion) may be conservative and may not substantially impact the structure or function of a protein. For example, in certain cases, the substitution of a serine residue with a threonine residue may not significantly impact the function of a protein. In other cases, the amino acid mutation may be more dramatic, such as the substitution of a charged amino acid (e.g., aspartic acid or lysine) with a large, nonpolar amino acid (e.g., phenylalanine or tryptophan) and therefore may have a substantial impact on protein function. The nature of the mutations that affect the structure of function of a gene or protein may be readily identified using standard sequencing techniques, e.g., deep sequencing techniques that are well known in the art. In some embodiments, a mutation in a member of the eIF2 pathway may affect binding or activity of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof and thereby modulate treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0810] In some embodiments, an 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, an 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, an 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. In some embodiments, an eIF2 protein may comprise 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.

[0811] 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 the eIF2B l , eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. 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,

[0812] phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2B l , eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. 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,

[0813] phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2B l , eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, the eIF2 protein may comprise an amino acid deletion at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine,

[0814] phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2B l , eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. Exemplary mutations include V183F (eIF2B l subunit), H341Q (eIF2B3), I346T (eIF2B3), R483W (eIF2B4), R113H (eIF2B5), and R195H (eIF2B5).

[0815] In some embodiments, an amino acid mutation (e.g., an amino acid substitution, addition, or deletion) in a member of the eIF2 pathway (e.g., an eIF2B protein subunit) may affect binding or activity of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof and thereby modulate treatment of a particular disease, disorder, or condition, or a symptom thereof. Neurodegenerative Disease

[0816] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0817] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a neurodegenerative disease. As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of a subject's nervous system becomes impaired. Examples of a neurodegenerative disease that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, Dystonia, frontotemporal dementia (FTD), Gerstmann- Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple system atrophy, Multisystem proteinopathy, Narcolepsy,

[0818] Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics, e.g., Spinocerebellar ataxia type 2 or Spinocerebellar ataxia type 8), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X- linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzbacher Disease, Krabbe disease, leukodystrophy due to mutation in DARS2 gene (sometimes known as lukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

[0819] (LBSL), DARS2-related spectrum disorders, or Tabes dorsalis.

[0820] In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo-myelination, a leukodystrophy, a

[0821] leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome (e.g., Fragile X syndrome), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia (e.g., HIV-associated dementia or Lewy body dementia), kuru, multiple sclerosis, Parkinson's disease, or a prion disease. In some embodiments, the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo-myelination, a leukodystrophy, a

[0822] leukoencephalopathy, a hypomyelinating or demyelinating disease, or an intellectual disability syndrome (e.g., Fragile X syndrome).

[0823] In some embodiments, the neurodegenerative disease comprises a psychiatric disease such as agoraphobia, Alzheimer's disease, anorexia nervosa, amnesia, anxiety disorder, attention deficit disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, delusions, Diogenes syndrome, dyspraxia, insomnia, Munchausen' s syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobic disorder, schizophrenia, seasonal affective disorder, schizoid personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania.

[0824] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0825] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide 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 a symptom of vanishing white matter disease, reducing the loss of white matter, reducing the loss of myelin, increasing the amount of myelin, or increasing the amount of white matter in a subject.

[0826] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0827] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat childhood ataxia with CNS hypo-myelination. Exemplary methods of treating childhood ataxia with CNS hypo-myelination include, but are not limited to, reducing or eliminating a symptom of childhood ataxia with CNS hypo-myelination, increasing the level of myelin, or decreasing the loss of myelin in a subject.

[0828] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0829] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat an intellectual disability syndrome (e.g., Fragile X syndrome). Exemplary methods of treating an intellectual disability syndrome include, but are not limited to, reducing or eliminating a symptom of an intellectual disability syndrome.

[0830] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0831] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat neurodegeneration. Exemplary methods of treating neurodegeneration include, but are not limited to, improvement of mental wellbeing, increasing mental function, slowing the decrease of mental function, decreasing dementia, delaying the onset of dementia, improving cognitive skills, decreasing the loss of cognitive skills, improving memory, decreasing the degradation of memory, or extending survival.

[0832] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0833] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a leukoencephalopathy or demyelinating disease. Exemplary

[0834] leukoencephalopathies include, but are not limited to, progressive multifocal

[0835] leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with vanishing white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior

[0836] leukoencephalopathy syndrome, hypertensive leukoencephalopathy, megalencephalic leukoencephalopathy with subcortical cysts, Charcot-Marie-Tooth disorder, and Devic' s disease. A leukoencephalopathy may comprise a demyelinating disease, which may be inherited or acquired. In some embodiments, an acquired demyelinating disease may be an inflammatory demyelinating disease (e.g., an infectious inflammatory demyelinating disease or a 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 a symptom of a leukoencephalopathy or demyelinating disease, reducing the loss of myelin, increasing the amount of myelin, reducing the loss of white matter in a subject, or increasing the amount of white matter in a subject.

[0837] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0838] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a traumatic injury or a toxin-induced injury to the nervous system (e.g., the brain). Exemplary traumatic brain injuries include, but are not limited to, a brain abscess, concussion, ischemia, brain bleeding, cranial fracture, diffuse axonal injury, locked-in syndrome, or injury relating to a traumatic force or blow to the nervous system or brain that causes damage to an organ or tissue. Exemplary toxin-induced brain injuries include, but are 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), Guillan-Barre syndrome, Sydenham's chorea, rabies, leprosy, neurosyphilis, a prion disease, or exposure to a chemical (e.g., arsenic, lead, toluene, ethanol, manganese, fluoride, dichlorodiphenyltrichloroe thane (DDT), dichlorodiphenyldichloroethylene (DDE), tetrachloroethylene, a polybrominated diphenyl ether, a pesticide, a sodium channel inhibitor, a potassium channel inhibitor, a chloride channel inhibitor, a calcium channel inhibitor, or a blood brain barrier inhibitor).

[0839] In other embodiments, the compound of Formula (I) or Formula (II), or a

[0840] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to improve memory in a subject. Induction of memory has been shown to be facilitated by decreased and impaired by increased eIF2a phosphorylation. Regulators of translation, such as compounds disclosed herein (e.g. a compound of Formula (I) or Formula (II)), could serve as therapeutic agents that 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 and thus could have negative effects on memory consolidation such as Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis (ALS) and prion diseases. In addition, a mutation in eIF2y that disrupts complex integrity linked intellectual disability (intellectual disability syndrome or ID) to impaired translation initiation in humans. Hence, two diseases with impaired eIF2 function, ID and VWM, display distinct phenotypes but both affect mainly the brain and impair learning. In some embodiments, the disease or condition is unsatisfactory memory (e.g., working memory, long term memory, short term memory, or memory consolidation).

[0841] In still other embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used in a method to improve memory in a subject (e.g., working memory, long term memory, short term memory, or memory consolidation). In some embodiments, the subject is 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

[0842] embodiments, the patient is a bovine. In some embodiments, the subject is a primate.

[0843] Cancer

[0844] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0845] pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof is used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In some further instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, 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.

[0846] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemia, lymphoma, carcinomas and sarcomas.

[0847] Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, 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 carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma (e.g., WNT-dependent pediatric

[0848] medulloblastoma), Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget' s Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

[0849] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy- cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0850] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial 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, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0851] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding- Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0852] 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 with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0853] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0854] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells. For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer. In some embodiments, the methods described herein may be used to treat cancer by decreasing or eliminating a symptom of cancer. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a cancer described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells).

[0855] In some embodiments, the compounds (compounds described herein, e.g. , a compound of Formula (I) or Formula (II)) and compositions (e.g. , compositions comprising a compound described herein, e.g. , a compound of Formula (I) or Formula (II))) are used with a cancer immunotherapy (e.g. , a checkpoint blocking antibody) to treat a subject (e.g. , a human subject), e.g. , suffering from a disease or disorder described herein (e.g. , abnormal cell growth, e.g. , cancer (e.g. , a cancer described herein)). The methods described herein comprise administering a compound described herein, e.g., a compound of Formula (I) or Formula (II) and an

[0856] immunotherapy to a subject having abnormal cell growth such as cancer. Exemplary

[0857] immunotherapies include, but are not limited to the following.

[0858] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits the immune checkpoint blockade pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that agonizes the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three groups of immunotherapy used to treat cancer include cell-based, antibody-based, and cytokine therapies. All groups exploit cancer cells' display of subtly different structures (e.g., molecular structure; antigens, proteins, molecules, carbohydrates) on their surface that can be detected by the immune system. Cancer immunotherapy (i.e., anti-tumor immunotherapy or antitumor immunotherapeutics) includes but is not limited to, immune checkpoint antibodies (e.g. , PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (i.e., anti-tumor vaccines or vaccines based on neoantigens such as a peptide or RNA vaccine).

[0859] Cell-based therapies (e.g., cancer vaccines), usually involve the removal of immune cells from a subject suffering from cancer, either from the blood or from a tumor. Immune cells specific for the tumor will be activated, grown, and returned to a subject suffering from cancer where the immune cells provide an immune response against the cancer. Cell types that can be used in this way are e.g., natural killer cells, lymphokine-activated killer cells, cytotoxic T-cells, dendritic cells, CAR-T therapies (i.e., chimeric antigen receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (i.e., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy is Provenge. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0860] Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system.

[0861] Cancer Vaccines with Neoantigens

[0862] Neoantigens are antigens encoded by tumor-specific mutated genes. Technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer

[0863] immunotherapy. Many novel therapeutic approaches are being developed that selectively enhance T cell reactivity against this class of antigens. One approach to target neoantigens is via cancer vaccine. These vaccines can be developed using peptides or RNA, e.g., synthetic peptides or synthetic RNA. Antibody therapies are antibody proteins produced by the immune system and that bind to a target antigen on the surface of a cell. Antibodies are typically encoded by an

[0864] immunoglobulin gene or genes, or fragments thereof. In normal physiology antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or a few proteins, and those that bind to cancer antigens are used, e.g., for the treatment of cancer. Antibodies are capable of specifically binding an antigen or epitope. (Fundamental Immunology, 3 rd Edition, W.E., Paul, ed., Raven Press, N.Y. (1993). Specific binding occurs to the corresponding antigen or epitope even in the presence of a heterogeneous population of proteins and other biologies. Specific binding of an antibody indicates that it binds to its target antigen or epitope with an affinity that is substantially greater than binding to irrelevant antigens. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, most often at least 100% greater. The relative difference can be at least 2-fold, at least 5-fold, at least 10-fold, at least 25- fold, at least 50-fold, at least 100-fold, or at least 1000-fold, for example.

[0865] Exemplary types of antibodies include without limitation human, humanized, chimeric, monoclonal, polyclonal, single chain, antibody binding fragments, and diabodies. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor interacting with its ligand or deliver a payload of chemotherapy or radiation, all of which can lead to cell death. Exemplary antibodies for the treatment of cancer include but are not limited to, Alemtuzumab, Bevacizumab, Bretuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab,

[0866] Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab,

[0867] Pembrolizumab, Avelumab, durvalumab and pidilizumab.

[0868] Checkpoint blocking antibodies

[0869] The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits the immune checkpoint blockade pathway. Immune checkpoint proteins, under normal physiological conditions, maintain self-tolerance (e.g. , prevent autoimmunity) and protect tissues from damage when the immune system is responding to e.g. , pathogenic infection. Immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism. (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of co- stimulatory receptors or antagonists of inhibitory signals (e.g. , immune checkpoint proteins), provide an amplification of antigen-specific T-cell responses. Antibodies that block immune checkpoints do not target tumor cells directly but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0870] Exemplary checkpoint blocking antibodies include but are not limited to, anti-CTLA-4, anti-PD-1 , anti-LAG3 (i.e., antibodies against lymphocyte activation gene 3), and anti-TIM3 (i.e., antibodies against T-cell membrane protein 3). Exemplary anti-CTLA-4 antibodies include but are not limited to, ipilimumab and tremelimumab. Exemplary anti-PD-1 ligands include but are not limited to, PD-L1 (i.e., B7-H1 and CD274) and PD-L2 (i.e., B7-DC and CD273).

[0871] Exemplary anti-PD-1 antibodies include but are not limited to, nivolumab (i.e., MDX-1106, BMS-936558, or ONO-4538)), CT-011 , AMP-224, pembrolizumab (trade name Keytruda), and MK-3475. Exemplary PD-L1 -specific antibodies include but are not limited to, BMS936559 (i.e., MDX- 1105), MEDI4736 and MPDL-3280A. Exemplary checkpoint blocking antibodies also include but are not limited to, IMP321 and MGA271.

[0872] T-regulatory cells (e.g. , CD4+, CD25+, or T-reg) are also involved in policing the distinction between self and non-self (e.g. , foreign) antigens, and may represent an important mechanism in suppression of immune response in many cancers. T-reg cells can either emerge from the thymus (i.e., "natural T-reg") or can differentiate from mature T-cells under circumstances of peripheral tolerance induction (i.e., "induced T-reg"). Strategies that minimize the action of T-reg cells would therefore be expected to facilitate the immune response to tumors. (Sutmuller, van Duivernvoorde et al., 2001).

[0873] IDO pathway inhibitors

[0874] The IDO pathway regulates immune response by suppressing T cell function and enabling local tumor immune escape. IDO expression by antigen-presenting cells (APCs) can lead to tryptophan depletion, and resulting antigen-specific T cell energy and regulatory T cell recruitment. Some tumors even express IDO to shield themselves from the immune system. A compound that inhibits IDO or the IDO pathway thereby activating the immune system to attack the cancer (e.g., tumor in a subject). Exemplary IDO pathway inhibitors include indoximod, epacadostat and EOS200271. STING pathway agonists

[0875] Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence indicates involvement of the STING pathway in the induction of antitumor immune response. It has been shown that activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response. STING agonists are being developed as a class of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.

[0876] Co-stimulatory antibodies The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g. , an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a co-stimulatory inhibitor or antibody. In some embodiments, the methods described herein comprise depleting or activating anti-4-lBB, anti- OX40, anti-GITR, anti-CD27 and anti-CD40, and variants thereof.

[0877] Inventive methods of the present invention contemplate single as well as multiple administrations of a therapeutically effective amount of a compound as described herein.

[0878] Compounds, e.g., a compound as described herein, can be administered at regular intervals, depending on the nature, severity and extent of the subject's condition. In some embodiments, a compound described herein is administered in a single dose. In some embodiments, a compound described herein is administered in multiple doses.

[0879] Inflammatory Disease

[0880] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0881] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide 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 aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus

[0882] erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1 , Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune 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. aberrant expression being a symptom or cause or marker of the disease) include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin- 18 (IL-18), TNF-a (tumor necrosis factor-alpha), and C-reactive protein (CRP).

[0883] In some embodiments, the inflammatory disease comprises 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 diabetes mellitus type 1), Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune 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, atherosclerosis, or atopic dermatitis.

[0884] In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, which refers to a decline in cognitive function (e.g. memory or executive function (e.g. working memory, reasoning, task flexibility, speed of processing, or problem solving)) following surgery.

[0885] In other embodiments, the method of treatment is a method of prevention. For example, a method of treating postsurgical cognitive dysfunction may include preventing postsurgical cognitive dysfunction or a symptom of postsurgical cognitive dysfunction or reducing the severity of a symptom of postsurgical cognitive dysfunction by administering a compound described herein prior to surgery. In some embodiments, the compound of Formula (I) or Formula (II), or a

[0886] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat an inflammatory disease (e.g., an inflammatory disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat an inflammatory disease (e.g., an inflammatory disease described herein). Musculoskeletal Diseases

[0887] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0888] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a musculoskeletal disease. As used herein, the term "musculoskeletal disease" refers to a disease or condition in which the function of a subject's musculoskeletal system (e.g., muscles, ligaments, tendons, cartilage, or bones) becomes impaired. Exemplary musculoskeletal diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide 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, myotonic muscular dystrophy type 1, or myotonic muscular dystrophy type 2), limb girdle muscular dystrophy, multisystem

[0889] proteinopathy, rhizomelic chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-HUnermann syndrome, Autosomal dominant chondrodysplasia punctata, stress induced skeletal disorders (e.g., stress induced osteoporosis), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscle atrophy, myasthenia gravis, neuralgia,

[0890] fibromyalgia, Machado-Joseph disease, Paget' s disease of bone, cramp fasciculation syndrome, Freidrich's ataxia, a muscle wasting disorder (e.g., muscle atrophy, sarcopenia, cachexia), an inclusion body myopathy, motor neuron disease, or paralysis.

[0891] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0892] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a musculoskeletal disease (e.g., a musculoskeletal disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the method of treatment comprises treatment of muscle pain or muscle stiffness associated with a musculoskeletal disease. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a musculoskeletal disease (e.g., a musculoskeletal disease described herein).

[0893] Metabolic Diseases

[0894] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0895] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat metabolic disease. As used herein, the term "metabolic disease" refers to a disease or condition affecting a metabolic process in a subject. Exemplary metabolic diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0896] In some embodiments, the compound of Formula (I) or Formula (II), or a

[0897] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the method of treatment comprises decreasing or eliminating a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, NT- oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a metabolic disease (e.g., a musculoskeletal disease described herein). Mitochondrial Diseases

[0898] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0899] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat mitochondrial disease. As used herein, the term "mitochondrial disease" refers to a disease or condition affecting the mitochondria in a subject. In some embodiments, the mitochondrial disease is associated with, or is a result of, or is caused by mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations. In some embodiments, the mitochondrial disease is a mitochondrial myopathy. In some embodiments, mitochondrial diseases, e.g., the mitochondrial myopathy, that may be treated with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include, e.g., Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0900] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0901] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a mitochondrial disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a mitochondrial disease described herein.

[0902] Hearing Loss

[0903] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0904] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat hearing loss. As used herein, the term "hearing loss" or "hearing loss condition" may broadly encompass any damage to the auditory systems, organs, and cells or any impairment of an animal subject's ability to hear sound, as measured by standard methods and assessments known in the art, for example otoacoustic emission testing, pure tone testing, and auditory brainstem response testing. Exemplary hearing loss conditions that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include, but are not limited to, mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or inherited hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, and hearing loss resulting from trauma. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness is a MT-RNR1- related hearing loss. In some embodiments, the MT-RNR1 -related hearing loss is the result of amino glycoside ototoxicity. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness is a MT-TS1 -related hearing loss. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness is characterized by sensorineural hearing loss.

[0905] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0906] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a hearing loss condition described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a hearing loss condition described herein.

[0907] Ocular Disease

[0908] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0909] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat eye disease. As used herein, the term "ocular disease" may refer to a disease or condition in which the function of a subject's eye becomes impaired. Exemplary ocular diseases and conditions that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0910] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0911] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat an ocular disease or condition described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat an ocular disease or condition described herein.

[0912] Kidney Diseases

[0913] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0914] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat kidney disease. As used herein, the term "kidney disease" may refer to a disease or condition in which the function of a subject's kidneys becomes impaired. Exemplary kidney diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include Abderhalden-Kaufmann-Lignac syndrome (Nephropathic Cystinosis), Abdominal Compartment Syndrome, Acetaminophen-induced Nephrotoxicity, Acute Kidney Failure / Acute Kidney Injury, Acute Lobar Nephronia, Acute Phosphate Nephropathy, Acute Tubular Necrosis, Adenine Phosphoribosyltransferase Deficiency, Adenovirus Nephritis, Alagille Syndrome, Alport Syndrome, Amyloidosis, ANCA Vasculitis Related to Endocarditis and Other Infections, Angiomyolipoma, Analgesic Nephropathy, Anorexia Nervosa and Kidney Disease, Angiotensin Antibodies and Focal Segmental Glomerulosclerosis, Antiphospholipid Syndrome, Anti-TNF-a Therapy-related Glomerulonephritis, APOL1 Mutations, Apparent Mineralocorticoid Excess Syndrome, Aristolochic Acid Nephropathy, Chinese Herbal

[0915] Nephropathy, Balkan Endemic Nephropathy, Arteriovenous Malformations and Fistulas of the Urologic Tract, Autosomal Dominant Hypocalcemia, Bardet-Biedl Syndrome, Bartter

[0916] Syndrome, Bath Salts and Acute Kidney Injury, Beer Potomania, Beeturia, β-Thalassemia Renal Disease, Bile Cast Nephropathy, BK Polyoma Virus Nephropathy in the Native Kidney, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Tamponade, Border-Crossers' Nephropathy, Bourbon Virus and Acute Kidney Injury, Burnt Sugarcane Harvesting and Acute Renal Dysfunction, Byetta and Renal Failure, Clq Nephropathy, C3 Glomerulopathy, C3

[0917] Glomerulopathy with Monoclonal Gammopathy, C4 Glomerulopathy, Calcineurin Inhibitor Nephrotoxicity, Callilepsis Laureola Poisoning, Cannabinoid Hyperemesis Acute Renal Failure, Cardiorenal syndrome, Carfilzomib-Indiced Renal Injury, CFHR5 nephropathy, Charcot-Marie- Tooth Disease with Glomerulopathy, Chinese Herbal Medicines and Nephrotoxicity, Cherry Concentrate and Acute Kidney Injury, Cholesterol Emboli, Churg-Strauss syndrome, Chyluria, Ciliopathy, Cocaine and the Kidney, Cold Diuresis, Colistin Nephrotoxicity, Collagenofibrotic Glomerulopathy, Collapsing Glomerulopathy, Collapsing Glomerulopathy Related to CMV, Combination Antiretroviral (cART) Related-Nephropathy, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), Congenital Nephrotic Syndrome, Congestive Renal Failure, Conorenal syndrome (Mainzer-Saldino Syndrome or Saldino-Mainzer Disease), Contrast Nephropathy, Copper Sulphate Intoxication, Cortical Necrosis, Crizotinib-related Acute Kidney Injury, Cryocrystalglobulinemia, Cryoglobuinemia, Crystalglobulin-Induced Nephropathy, Crystal-Induced Acute Kidney injury, Crystal-Storing Histiocytosis, Cystic Kidney Disease, Acquired, Cystinuria, Dasatinib-Induced Nephrotic-Range Proteinuria, Dense Deposit Disease (MPGN Type 2), Dent Disease (X-linked Recessive Nephrolithiasis), DHA Crystalline

[0918] Nephropathy, Dialysis Disequilibrium Syndrome, Diabetes and Diabetic Kidney Disease, Diabetes Insipidus, Dietary Supplements and Renal Failure, Diffuse Mesangial Sclerosis, Diuresis, Djenkol Bean Poisoning (Djenkolism), Down Syndrome and Kidney Disease, Drugs of Abuse and Kidney Disease, Duplicated Ureter, EAST syndrome, Ebola and the Kidney, Ectopic Kidney, Ectopic Ureter, Edema, Swelling, Erdheim-Chester Disease, Fabry's Disease, Familial Hypocalciuric Hypercalcemia, Fanconi Syndrome, Fraser syndrome, Fibronectin

[0919] Glomerulopathy, Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy, Fraley syndrome, Fluid Overload, Hypervolemia, Focal Segmental Glomerulosclerosis, Focal Sclerosis, Focal Glomerulosclerosis, Galloway Mowat syndrome, Giant Cell (Temporal) Arteritis with Kidney Involvement, Gestational Hypertension, Gitelman Syndrome, Glomerular Diseases, Glomerular Tubular Reflux, Glycosuria, Goodpasture Syndrome, Green Smoothie Cleanse Nephropathy, HANAC Syndrome, Harvoni (Ledipasvir with Sofosbuvir)-Induced Renal Injury, Hair Dye Ingestion and Acute Kidney Injury, Hantavirus Infection Podocytopathy, Heat Stress Nephropathy, Hematuria (Blood in Urine), Hemolytic Uremic Syndrome (HUS), Atypical Hemolytic Uremic Syndrome (aHUS), Hemophagocytic Syndrome, Hemorrhagic Cystitis, Hemorrhagic Fever with Renal Syndrome (HFRS, Hantavirus Renal Disease, Korean

[0920] Hemorrhagic Fever, Epidemic Hemorrhagic Fever, Nephropathis Epidemica), Hemosiderinuria, Hemosiderosis related to Paroxysmal Nocturnal Hemoglobinuria and Hemolytic Anemia, Hepatic Glomerulopathy, Hepatic Veno-Occlusive Disease, Sinusoidal Obstruction Syndrome, Hepatitis C- Associated Renal Disease, Hepatocyte Nuclear Factor Ιβ-Associated Kidney Disease, Hepatorenal Syndrome, Herbal Supplements and Kidney Disease, High Altitude Renal Syndrome, High Blood Pressure and Kidney Disease, HIV-Associated Immune Complex Kidney Disease (HIVICK), HIV-Associated Nephropathy (HIVAN), HNFlB-related Autosomal Dominant Tubulointerstitial Kidney Disease, Horseshoe Kidney (Renal Fusion), Hunner's Ulcer, Hydroxychloroquine-induced Renal Phospholipidosis, Hyperaldosteronism, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hyperoxaluria, Hyperphosphatemia, Hypocalcemia, Hypocomplementemic Urticarial Vasculitic Syndrome, Hypokalemia,

[0921] Hypokalemia-induced renal dysfunction, Hypokalemic Periodic Paralysis, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Hypophosphatemia in Users of Cannabis, Hypertension, Hypertension, Monogenic, Iced Tea Nephropathy, Ifosfamide Nephrotoxicity, IgA Nephropathy, IgG4 Nephropathy, Immersion Diuresis, Immune-Checkpoint Therapy-Related Interstitial Nephritis, Infliximab-Related Renal Disease, Interstitial Cystitis, Painful Bladder Syndrome (Questionnaire), Interstitial Nephritis, Interstitial Nephritis, Karyomegalic, Ivemark's syndrome, JC Virus Nephropathy, Joubert Syndrome, Ketamine-Associated Bladder Dysfunction, Kidney Stones, Nephrolithiasis, Kombucha Tea Toxicity, Lead Nephropathy and Lead-Related

[0922] Nephrotoxicity, Lecithin Cholesterol Acyltransferase Deficiency (LCAT Deficiency),

[0923] Leptospirosis Renal Disease, Light Chain Deposition Disease, Monoclonal Immunoglobulin Deposition Disease, Light Chain Proximal Tubulopathy, Liddle Syndrome, Lightwood-Albright Syndrome, Lipoprotein Glomerulopathy, Lithium Nephrotoxicity, LMX1B Mutations Cause Hereditary FSGS, Loin Pain Hematuria, Lupus, Systemic Lupus Erythematosis, Lupus Kidney Disease, Lupus Nephritis, Lupus Nephritis with Antineutrophil Cytoplasmic Antibody

[0924] Seropositivity, Lupus Podocytopathy, Lyme Disease-Associated Glomerulonephritis, Lysinuric Protein Intolerance, Lysozyme Nephropathy, Malarial Nephropathy, Malignancy-Associated Renal Disease, Malignant Hypertension, Malakoplakia, McKittrick-Wheelock Syndrome, MDMA (Molly; Ecstacy; 3,4-Methylenedioxymethamphetamine) and Kidney Failure, Meatal Stenosis, Medullary Cystic Kidney Disease, Urolodulin- Associated Nephropathy, Juvenile

[0925] Hyperuricemic Nephropathy Type 1 , Medullary Sponge Kidney, Megaureter, Melamine Toxicity and the Kidney, MELAS Syndrome, Membranoproliferative Glomerulonephritis, Membranous Nephropathy, Membranous-like Glomerulopathy with Masked IgG Kappa Deposits,

[0926] MesoAmerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate-related Renal Failure, Microscopic Polyangiitis, Milk-alkalai syndrome, Minimal Change Disease,

[0927] Monoclonal Gammopathy of Renal Significance, Dysproteinemia, Mouthwash Toxicity, MUC1 Nephropathy, Multicystic dysplastic kidney, Multiple Myeloma, Myeloproliferative Neoplasms and Glomerulopathy, Nail-patella Syndrome, NARP Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Floating Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, 9 / 11 and Kidney Disease, Nodular Glomerulosclerosis, Non-Gonococcal Urethritis, Nutcracker syndrome, Oligomeganephronia, Orofaciodigital Syndrome, Orotic Aciduria, Orthostatic Hypotension, Orthostatic Proteinuria, Osmotic Diuresis, Osmotic

[0928] Nephrosis, Ovarian Hyperstimulation Syndrome, Oxalate Nephropathy, Page Kidney, Papillary Necrosis, Papillorenal Syndrome (Renal-Coloboma Syndrome, Isolated Renal Hypoplasia), PARN Mutations and Kidney Disease, Parvovirus B 19 and the Kidney, The Peritoneal-Renal Syndrome, POEMS Syndrome, Posterior Urethral Valve, Podocyte Infolding Glomerulopathy, Post-infectious Glomerulonephritis, Post-streptococcal Glomerulonephritis, Post-infectious

[0929] Glomerulonephritis, Atypical, Post-Infectious Glomerulonephritis (IgA-Dominant), Mimicking IgA Nephropathy, Polyarteritis Nodosa, Polycystic Kidney Disease, Posterior Urethral Valves, Post-Obstructive Diuresis, Preeclampsia, Propofol infusion syndrome, Proliferative

[0930] Glomerulonephritis with Monoclonal IgG Deposits (Nasr Disease), Propolis (Honeybee Resin) Related Renal Failure, Proteinuria (Protein in Urine), Pseudohyperaldosteronism,

[0931] Pseudohypobicarbonatemia, Pseudohypoparathyroidism, Pulmonary-Renal Syndrome,

[0932] Pyelonephritis (Kidney Infection), Pyonephrosis, Pyridium and Kidney Failure, Radiation Nephropathy, Ranolazine and the Kidney, Refeeding syndrome, Reflux Nephropathy, Rapidly Progressive Glomerulonephritis, Renal Abscess, Peripnephric Abscess, Renal Agenesis, Renal Arcuate Vein Microthrombi- Associated Acute Kidney Injury, Renal Artery Aneurysm, Renal Artery Dissection, Spontaneous, Renal Artery Stenosis, Renal Cell Cancer, Renal Cyst, Renal Hypouricemia with Exercise-induced Acute Renal Failure, Renal Infarction, Renal

[0933] Osteodystrophy, Renal Tubular Acidosis, Renin Mutations and Autosomal Dominant

[0934] Tubulointerstitial Kidney Disease, Renin Secreting Tumors (Juxtaglomerular Cell Tumor), Reset Osmostat, Retrocaval Ureter, Retroperitoneal Fibrosis, Rhabdomyolysis, Rhabdomyolysis related to Bariatric Sugery, Rheumatoid Arthritis-Associated Renal Disease, Sarcoidosis Renal Disease, Salt Wasting, Renal and Cerebral, Schistosomiasis and Glomerular Disease, Schimke immuno-osseous dysplasia, Scleroderma Renal Crisis, Serpentine Fibula-Polycystic Kidney Syndrome, Exner Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Sri Lankan Farmers' Kidney Disease, Sjogren's Syndrome and Renal Disease, Synthetic Cannabinoid Use and Acute Kidney Injury, Kidney Disease Following Hematopoietic Cell Transplantation, Kidney Disease Related to Stem Cell Transplantation, TAFRO Syndrome, Tea and Toast Hyponatremia, Tenofovir-Induced Nephrotoxicity, Thin Basement Membrane Disease, Benign Familial Hematuria, Thrombotic Microangiopathy Associated with Monoclonal Gammopathy, Trench Nephritis, Trigonitis, Tuberculosis, Genitourinary, Tuberous Sclerosis, Tubular Dysgenesis, Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the Proximal Tubule Brush Border, Tumor Lysis Syndrome, Uremia, Uremic Optic Neuropathy, Ureteritis Cystica, Ureterocele, Urethral Caruncle, Urethral Stricture, Urinary Incontinence, Urinary Tract Infection, Urinary Tract Obstruction, Urogenital Fistula, Uromodulin-Associated Kidney Disease, Vancomycin- Associated Cast Nephropathy, Vasomotor Nephropathy,

[0935] Vesicointestinal Fistula, Vesicoureteral Reflux, VGEF Inhibition and Renal Thrombotic Microangiopathy, Volatile Anesthetics and Acute Kidney Injury, Von Hippel-Lindau Disease, Waldenstrom's Macroglobulinemic Glomerulonephritis, Warfarin-Related Nephropathy, Wasp Stings and Acute Kidney Injury, Wegener's Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus and Chronic Kidney Disease, Wunderlich syndrome, Zellweger Syndrome, or Cerebrohepatorenal Syndrome.

[0936] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0937] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a kidney disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a kidney disease described herein.

[0938] Skin Diseases

[0939] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0940] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a skin disease. As used herein, the term "skin disease" may refer to a disease or condition affecting the skin. Exemplary skin diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extra-mammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infections of nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (verrucas), polymorphic light eruption, psoriasis, plaque psoriasis, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, sweet's syndrome, urticaria and angioedema and vitiligo.

[0941] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0942] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a skin disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a skin disease described herein.

[0943] Fibrotic Diseases

[0944] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0945] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a fibrotic disease. As used herein, the term "fibrotic disease" may refer to a disease or condition that is defined by the accumulation of excess extracellular matrix components. Exemplary fibrotic diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include adhesive capsulitis, arterial stiffness, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis,

[0946] Dupuytren's contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, non-alcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis and ventricular remodeling. In some embodiments, the compound of Formula (I) or Formula (II) or a

[0947] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a fibrotic disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a fibrotic disease described herein.

[0948] Hemoglobin Disorders

[0949] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0950] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a hemoglobin disease. As used herein, the terms "hemoglobin disease" or "hemoglobin disorder" may refer to a disease or condition characterized by an abnormal production or structure of the hemoglobin protein. Exemplary hemoglobin diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include "dominant" β- thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / -thalassemia, HbE / -thalassemia, HbSC disease, homozygous a+-thalassemia (phenotype of a°-thalassemia), Hydrops fetalis with Hb Bart's, sickle cell anemia / disease, sickle cell trait, sickle β-thalassemia disease, a+-thalassemia, a°- thalassemia, a-Thalassemia associated with myelodysplastic syndromes, a-Thalassemia with mental retardation syndrome (ATR), °-Thalassemia,+-Thalassemia, δ- Thalassemia, γ- Thalassemia, β-Thalassemia major, β-Thalassemia intermedia, δβ-Thalassemia, and εγδβ- Thalassemia.

[0951] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0952] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a hemoglobin disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a hemoglobin disease described herein. Autoimmune Diseases

[0953] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0954] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat an autoimmune disease. As used herein, the term "autoimmune disease" may refer to a disease or condition in which the immune system of a subject attacks and damages the tissues of said subject. Exemplary kidney diseases that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti- TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AM AN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis he etiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa),

[0955] Hypogammaglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus,

[0956] Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MP A), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome,, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndrome type I, Polyglandular syndrome type II, Polyglandular syndrome type III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRC A), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

[0957] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0958] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat an autoimmune disease described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat an autoimmune disease described herein.

[0959] Viral Infections

[0960] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0961] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a viral infection. Exemplary viral infections that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include influenza, human immunodeficiency virus (HIV) and herpes.

[0962] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0963] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a viral infection described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a viral infection described herein.

[0964] Malaria Infection

[0965] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0966] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a malaria. As used herein, the term "malaria" may refer to a parasitic disease of protozoan of the Plasmodium genus that causes infection of red blood cells (RBCs). Exemplary forms of malaria infection that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof include infection caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum. In some embodiments, the malaria infection that may be treated with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is

[0967] resistant / recrudescent malaria.

[0968] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0969] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a malaria infection described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a malaria infection described herein.

[0970] Diseases with Mutations Leading to Unfolded Protein Response (UPR) Induction In some embodiments, the compound of Formula (I) or Formula (II) or a

[0971] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a disease with mutations that leads to UPR induction. Exemplary disease with mutations that lead to UPR induction include Marinesco-Sjogren syndrome, neuropathic pain, diabetic neuropathic pain, noise induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier White disease, Usher syndrome, collagenopathies, Thin basement nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid, and Pseudochondrodysplasia.

[0972] In some embodiments, the compound of Formula (I) or Formula (II) or a

[0973] pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof is used to treat a disease with mutations that leads to UPR induction described herein by decreasing or eliminating a symptom of the disease. In some embodiments, the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat a disease with mutations that leads to UPR induction described herein.

[0974] Methods of Modulating Protein Production

[0975] In another aspect, disclosed herein is a method of modulating the expression of eIF2B, eIF2a, a component of the eIF2 pathway, component of the ISR pathway or any combination thereof in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, thereby modulating the expression of eIF2B, eIF2a, a component of the eIF2 pathway, component of the ISR pathway or any combination thereof in the cell. In some embodiments, contacting the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof with the cell increases the expression of eIF2B, eIF2a, a component of the eIF2 pathway, component of the ISR pathway or any combination thereof in the cell. In some embodiments, contacting the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof with the cell decreases the expression of eIF2B, eIF2a, a component of the eIF2 pathway, com...

Claims

CLAIMSWe claim:

1. A compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclicheterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1;1 2L and L are each independently Ci-C alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NR , wherein each Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 RL;1 2R and R" are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, hydroxy-C2-C6alkyl, silyloxy-C2-C6alkyl, G1-0-C2-C6alkyl, HChC-Q-Ce alkyl, or C C6alkyl-C(0)2-C1-C6alkyl;each RLis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci-C alkyl, hydroxy-Ci-C6 alkoxy, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, C1-C6 alkoxy-d-Ce alkyl, HC^C-d-Ce alkyl, d-C6alkyl-dO)2-d-d alkyl, oxo, halo, cyano, - ORA, -NRBRC, -NRBRCC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2; or2 geminal RLgroups together with the carbon to which they are attached form a cyclopropyl moiety;RN1is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, H(¾C-d-d alkyl, C1-C6 alkyl-C(0)2-Ci-C6 alkyl, phenoxy-Ci-C6 alkyl (wherein phenoxy is optionally substituted with 1-3 halogens), -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD;A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;each Rxis independently selected from the group consisting of Ci-C alkyl, hydroxy-Ci- Ce alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, Ci-Ce alkoxy-Ci-C6 alkyl, Ci- C6alkyl-d-Ce alkoxy, C C6alkoxy-C C6alkoxy, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, =CHC(0)ORD, =CHC(0)OH, - SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2; or2 geminal Rxgroups together with the carbon to which they are attached form an oxirane moiety;each RYis independently selected from the group consisting of hydrogen, Ci-C alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkoxy, halo- C1-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, -S(RF)m, - S(0)RD, -S(0)2RD, and G1; or2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx;1 2each G and G is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl is optionally substituted with 1-3 Rz;each Rzis independently selected from the group consisting of C1-C6 alkyl, hydroxy-Ci- C6alkyl, halo-Ci-Q alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, -C(0)ORD, and -S(0)2RD;each RAis independently hydrogen, d-C6alkyl, halo-C C6alkyl, -C(0)NRBRc, - C(0)RD, or -C(0)ORD;B Ceach of R and R is independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl;B CR and R together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 Rz;cceach R is independently selected from the group consisting of hydroxy-Ci-C6 alkyl, halo-Ci-Ce alkyl, H02C-C C6alkyl, d-C6alkyl-C(0)2-C!-C6alkyl, (CO)-Ci-C6alkyl-OH, (CO)-C1-C6alkyl-C1-C6alkoxy and 4-6 membered heterocyclyl; wherein the heterocyclyl may optionally be substituted with 1-3 Rz:each R is independently Ci-Ce alkyl, 2-7-memberedheteroalkyl, hydroxy-Q-Ce alkyl, or halo-Ci-C6 alkyl, wherein each C1-C6 alkyl, 2-7-memberedheteroalkyl, hydroxy-Ci-C6 alkyl, or halo-Ci-C6 alkyl is optionally substituted with 1-5 RG;each REis independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl;each RFis independently hydrogen, C1-C6 alkyl, or halo;each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH;each RHis independently Q-C6 alkyl or halo-Ci-C6 alkyl;m is 1 when RFis hydrogen or C1-C6 alkyl, 3 when RFis C1-C6 alkyl, or 5 when RFis halo;t is 0 or 1 ; ands is 0 or 1.

2. The compound of claim 1 , wherein D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups.

3. The compound of any one of claims 1-2, wherein D is a bridged 5-8 membered bicyclic cycloalkyl or heterocyclyl, or cubanyl, each of which is optionally substituted with 1-4 Rxgroups.

4. The compound of any one of claims 1-3, wherein D is selected from cubane,bicyclo[l . l . l]pentane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, or 2-azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 Rxgroups.

5. The compound of any one of claims 1-4, wherein D is selected from:

7. The compound of any one of claims 1-6, wherein D is substituted with 1 or 2 R .

8. The compound of any one of claims 1-7, wherein R is independentlyalkyl, hydroxy-Ci-C6 alkyl, C\-C alkoxy-Ci-C6 alkyl, C\-C alkoxy-Ci-C6 alkoxy, oxo, halo, cyano, - ORA, -OS(0)2RD, -S(0)2RD, -SRE, NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, =CHC(0)OH, =CHC(0)ORD, NRBRC, NRBRCC, or G2; or 2 geminal Rxgroups together with the carbon to which they are attached form an oxirane moiety.

9. The compound of claim 8, wherein Rxis independently C¾, -CH2OH, -CH2OCH3, - CH2CH2CH3, -C(CH3)2OH, -O-CH2-O-CH3, CH2CH2OH, oxo, fluoro, bromo, OH, cyano,OCH3, NH2, N(H)CH2CF3, N(H)CH2CH2OH, N(CH3)2, N(CH3)CH2CH2OH, N(CH3)CH2C02H N(CH3)CH2CH2C02H, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2D, -C(0)CH3, =CHC(0)OH, =CHC(0)OCH2CH3, -The compound of claim 8, wherein G is aryl or 5-6 membered heteroaryl. The compound of claim 8, wherein G is oxadiazolyl, or tetrazolyl.

14. The compound of any one of claims 1- 13, wherein at least one of L and L is independently 2-7-membered heteroalkylene optionally substituted by 1-5 RL.1 215. The compound of any one of claims 1- 14, wherein one of L and L is independently Q-1 2Ce alkylene or C2-C6 alkenylene and the other of L and L is independently 2-7-membered heteroalkylene, and wherein each C1-C6 alkylene, C2-C6 alkenylene, and 2-7-membered heteroalkylene is optionally substituted by 1-5 RL.

16. The compound of any one of claims 14-15, wherein each RLis independently C1-C6 alkyl, OH, oxo, -C(0)RD, cyano, H02C-d-C6alkyl, d-C6alkyl-C(0)2-Ci-C6alkyl, -C(0)OH, -NRBRC, -NRBRCC,— NRBC(0)RD, hydroxy-Q-Ce alkyl, or hydroxy-d-Ce alkoxy.

17. The compound of any one of claims 14-16, wherein each RLis independently CH3, oxo, or C(0)CH3.

18. The compound of any one of claims 1-17, wherein each of L and L is independently selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*,CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, 0-CH2CH2*, CH2N(CH2C02H)-*,CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*, CH(CN)CH20-*, CH2CH(NH(CH3))-*,2OH)-*, CH2CH(NH(C(0)CH2OH))-*, CH2CH(NH2)CH2*,CH(CH2CH2OH)0-*or, and "-*" indicates the attachment point to A and W, respectively.

19. The compound of any one of claims 1-18, wherein L1is independently selected from CH20-*, CH2CH20-* or CH=CH-*, L2is independently selected from CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)-*, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*,CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, CH2C(0)-*, CH2N(CH2C02H)-*, CH(C02H)CH2CH20-*, CH2N(CH2C02C(CH3)3)-*,CH(CN)CH20-*, CH2CH(NH(CH3))-*,CH(OCH2CH2OH)-*, (C(0)CH2OH))-*,CH2CH(NH2)CH2*,CH(CH2CH2OH)0-*, CH2C(CH3)20*- or, and "-*" indicates the attachment point to A and W, respectively.

20. The compound of any one of claims 1-19, wherein t is 1 and s is 1.

21. The compound of any one of claims 1-19, wherein s is 1 and t is 0.

22. The compound of any one of claims 1- 19, wherein s is 0 and t is 0.1 223. The compound of any one of claims 1-22, wherein R and R are each independently hydrogen, C\-Ce alkyl, hydroxyl-C2-C6 alkyl, or silyloxy-C2-C6 alkyl.1 224. The compound of any one of claims 1-23, wherein one of R and R is independently hydrogen and the other of R1and R2is independently hydrogen, C\-Ce alkyl, C2-C6hydroxyl-C2- C6alkyl, silyloxy-C2-C6alkyl, HChC-Q-Ce alkyl, or d-C6alkyl-C(0)2-Ci-C6alkyl.1 225. The compound of any one of claims 1-24, wherein R and R are each independently hydrogen, *-CH3, *-CH2CH2OH, *-CH2CH2OSi(CH3)2C(CH3)3, *-CH2C02H, or *- CH2C(0)2C(CH3), and "*-" indicates the attachment point to the nitrogen atom.1 226. The compound of any one of claims 1-25, wherein one of R and R is independently1 2hydrogen and the other of R and R is independently hydrogen, *-CH3, *-CH2CH20H, *- CH2CH2OSi(CH3)2C(CH3)3, *-CH2C02H, or *-CH2C(0)2C(CH3), and "*-" indicates the attachment point to the nitrogen atom.

27. The compound of any one of claims 1-26, wherein R1and R2are each independently hydrogen.

28. The compound of any one of claims 1-27, wherein each A and W is independently a phenyl or 5-6-membered heteroaryl optionally substituted with 1-5 RYgroups.

29. The compound of any one of claims 1-27, wherein each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, pyrazolyl, pyrimidinyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, pyrimidin-2(lH)-onyl, 1H- benzo[d]imidazolyl, pyrazolo[l ,5-a]pyridine, lH-indazolyl or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups.

30. The compound of any one of claims 1-28, wherein each of A and W is independently selected from:

31. The compound of any one of claims 1-30, wherein A is phenyl and W is phenyl or 5-6- membered heteroaryl, each of A and W is optionally substituted with 1-5 RY, and each RYis independently Ci-Ce alkyl, O-C3-C6 cycloalkyl, C1-C6 alkoxy-Ci-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, hydroxy-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, halo, cyano, -ORA, -NRBRC, -NRBRCC, — NRBC(0)RD, -C(0)RD, -C(0)OH, -C(0)ORD, -SiR WVr G1.

32. The compound of any one of claims 1-31 , wherein A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, triazinyl, pyrazolyl, triazolyl, oxadiazolyl, oxadiazolonyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is optionally substituted with 1-5 RYgroups.The com ound of any one of claims 1-32, wherein A is selected from:

34. The compound of any one of claims 1-33, wherein W is selected from:

35. The compound of any one of claims 1-34, wherein each RYis independently hydrogen, bromo, chloro, fluoro, iodo, cyano, CF3, CHF2, CH2CF3, CH3, CH2CH3, OH, CH2OH,C(CH3)2OH, OCH3, OCH2CH3, OCHF2, OCF3, OCH2CF3, OCH2CH2OH, CH2OCH3, S(0)2CH3S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, NH(C(0)CH2OH), NH(CH2CH2OH), NH(CO)CH2OCH3,C(CH)3, CH(CH3)2, CH2CN, CH2NH2,3, C(OH)(CH3)CF3,S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2, G , or36. The compound of any one of claims 1-35, wherein each A and W is independently substituted with 2 RYon adjacent atoms, and the 2 RY, together with the atoms to which they areattached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6-membered fused heteroaryl ring optionally substituted with 1-5 Rx.

37. The compound of claim 36, wherein the 2 RYtogether with the atoms to which they are attached form a phenyl, pyridyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, dioxanyl, dioxolanyl, pyrrolidin-2-onyl, or morpholin-3-onyl ring, each of which is optionally substituted with 1-5 Rx38. The compound of any one of claims 36-37, wherein each Rxis independently Cj-C alkyl, ORA, or halo.

39. The compound of any one of claims 36-38, wherein each Rxis independently C¾, OH or fluoro.

40. The compound of any one of claims 1-39, wherein G1is cyclopropyl, isoxazolyl, piperidinyl, phenyl, or pyrazolyl, each of which is optionally substituted with 1-5 Rz.

41. The compound of claim 40, wherein each Rzis independently Cj-C alkyl or halo.

42. The compound of any one of claims 1-41 , wherein the compound of Formula (I) is a compound of Formula (I-b):Formula (I-b)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof,wherein:D is (l ,2,3,4,6,7)-cubane, bicyclo[l . l . l]pentane, bicyclo[2.2.2]octane,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, or 2- azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 Rxgroups; and wherein 2-azabicyclo[2.2.2]octane is substituted on nitrogen by hydrogen or CH3;L and are each independently CH20-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(0)- *, CH=CH-*, CH2CH20-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH20-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(0)-*, CH2N(C(0)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(0)-*, NHC(0)OCH2-*, O-*, NH-*, S(0)2CH-*, S(0)2CH2CH2-*, S(0)2CH2CH20-*, or CH2C(0)-*, and "-*" indicates the attachment point to A and W, respectively.R 1 andR 2" are each independently hydrogen, CH3, CH2CH2OH, orCH2CH2OSi(CH3)2C(CH3)3;A and W are each independently isoxazolyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, triazinyl, thiazolyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 RYgroups;each Rxis independently selected from CH3, -CH2OH, -C(CH3)2OH, oxo, fluoro, bromo, OH, cyano, OCH3, NH2, N(CH3)2, NHC(0)CH3, OC(0)CH3, C(0)NH2, OS(0)2CH3, -S(0)2CH3, -S(0)2CH2CH3, C(0)OH, OC(0)RD, -C(0)CH3, -SCH3, or G2;each RYis independently bromo, chloro, fluoro, iodo, CF3, CHF2, CH2CF3, CH3,CH2CH3, OH, CH2OH, C(CH3)2OH, OCH3, OCH2CH3,OCF3, S(0)2CH3, S(0)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3,C(OH)(CH3)CF3, S(0)2CH3, C(0)CH3, C(0)OCH3, C(0)OH, OCHF2or G1; or2 RYgroups on adjacent atoms, together with the atoms to which they are attached form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 Rx;G1and G2are cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl, or tetrazolyl, or pyrazolyl, each of which is optionally substituted with 1-2 Rz;each RDis CH20 optionally substituted with 1-5 RG;each R G is independently pyridyl optionally substituted with 1-5 R H ;each RHis independently CF3;each R is independently CH3; andt is 0 or 1.

43. The compound of any one of claims 1-42, wherein the compound of Formula (I) is a compound of Formula (I-c):Formula (I-c)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

44. The compound of any one of claims 1-43, wherein the compound of Formula (I) is a compound of Formula (I-d):Formula (I-d)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

45. The compound of any one of claims 1-43, wherein the compound of Formula (I) isFormula (I-e)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

46. The compound of any one of claims 1-43 and 45, wherein the compound of Formula (I) is a compound of Formula (I-f):Formula (I-f)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

47. The compound of any one of claims 1-42, wherein the compound of Formula (I) is a compound of Formula (I-g):Formula (I-g)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

48. The compound of any one claims 1-42 and 47, wherein the compound of Formula (I) is a compound of Formula (I-h):Formula (I-h)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide stereoisomer thereof.

49. The compound of any one of claims 1-42 and 47-48, wherein the compound of Formula (I) is a compound of Formula (I-i):Formula (I-i)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

50. The compound of any one of claims 1-42, wherein the compound of Formula (I) is a compound of Formula (I-j):Formula (I-j)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

51. The compound of any one of claims 1-42 and 50, wherein the compound of Formula (I) is a compound of Formula (I-k):Formula (I-k)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

52. The compound of any one of claims 1-42 and 50-51, wherein the compound of Formula (I) is a compound of Formula (1-1):Formula (1-1)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

53. A compound of Formula (II):Formula (II)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl is optionally substituted with 1-4 Rxgroups; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1;L1is C C alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NRC, wherein Q-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 Rx;L2is -(C0-C2 alkylene)-0-(Co-C2alkylene)-;R1is hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, and silyloxy-C2-C6 alkyl;RN1is selected from the group consisting of hydrogen, Q-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6alkyl, amino-C2-C6alkyl, cyano-C2-C6alkyl, -C(0)NRBRc, -C(0)RD, -C(0)ORD, and -S(0)2RD;A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;each Rxis independently selected from the group consisting of Q-C6 alkyl, hydroxy-Ci- C alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, C1-C6 alkoxy-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -SRE, -S(0)RD, -S(0)2RD, -OS(0)RD, -OS(0)2RD, and G2;each RYis independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RD, -C(0)OH, - C(0)ORD, -S(RF)m, -S(0)RD, -S(0)2RD, and G1; or2 R groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 Rx;each G 1 and G 2 is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5- 6-membered heteroaryl is optionally substituted with 1-3 Rz;each Rzis independently selected from the group consisting ofalkyl, hydroxy-Cj- C6alkyl, halo-Ci-Ce alkyl, halo, cyano, -ORA, -NRBRC,— NRBC(0)RD, -C(0)NRBRc, -C(0)RE-C(0)OH, -C(0)ORD, and -S(0)2RD;each RAis independently hydrogen, Ci-C6alkyl, halo-Ci-C6alkyl, -C(0)NRBRc, - C(0)RD, or -C(0)ORD;B Ceach of R and R is independently hydrogen or C1-C6 alkyl; orB CR and R together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 Rz;each RDis independently C1-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Ci-C6 alkyl, wherein each Q-C6 alkyl, 2-7-memberedheteroalkyl, or halo-Ci-C6 alkyl is optionally substituted with 1-5 RG;each REis independently hydrogen, C1-C6 alkyl, or halo-Ci-C6 alkyl;each RFis independently hydrogen, C1-C6 alkyl, or halo;each RGis independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH;each RHis independently Q-C6 alkyl or halo-Ci-C6 alkyl;m is 1 when RFis hydrogen or Q-C6alkyl, 3 when RFis C1-C6 alkyl, or 5 when RFis halo; andt is 0 or 1.

54. The compound of claim 53, wherein D is selected from the group consisting of55. The compound of claim 53 or 54, wherein each R is independently selected from the group consisting of oxo, -ORA(e.g., OH or OCH3), -C(0)OH, -C(0)ORD(e.g., -C(0)OCH3), halo, and hydroxy-Ci-C6 alkyl.

56. The compound of any one of claims 53-55, wherein L1is CH20-* or CH2OCH -*; wherein "-*" indicates the attachment point to A.

57. The compound of any one of claims 53-56, wherein L2is selected from the group consisting of O-*, OCH2-*, CH20-*, OCH2CH2-*, CH2OCH2-*, and CH2CH20-*; wherein " *" indicates the attachment point to W.

58. The compound of any one of claims 53-57, wherein R1is hydrogen or C¾59. The compound of any one of claims 53-58, wherein A is selected from the group consistin of:

60. The compound of any one of claims 53-59, wherein W is selected from the group consistin of:wherein R is hydrogen or CH361. The compound of any one of claims 53-60, wherein each RYis independently hydrogen, chloro, fluoro, CF3, CHF2, CH3, CH2CH3, CH(CH3)2, OCH3, OCF3, OCH(CH3)2, or CN.

62. The compound of any one of claims 53-61 , wherein the compound of Formula (II) is a compound of Formula (Il-a):Formula (Il-a)or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:D is bicyclo[l.l. l]pentanyl or bicyclo[2.2.2]octanyl, each of which is optionally substituted with 1-4 Rxgroups;L1is CH20-* or CH2OCH2-*, wherein "-*" indicates the attachment point to A;L2is selected from the group consisting of O-*, OCH2-*, CH20-*, OCH2CH2-*, CH2OCH2-*, and CH2CH20-*; wherein "-*" indicates the attachment point to W;A is phenyl or pyridyl, each of which is optionally substituted with 1-5 RYgroups;W is phenyl, pyridyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted on one or more available carbons with 1-5 RYgroups; and wherein pyrazolyl may be optionally substituted on an available nitrogen with hydrogen or CH3;each Rxis independently fluoro, oxo, OH, OCH3, C(0)OH, or C(0)OCH3;each RYis independently chloro, fluoro, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCH(CH3)2, or CN; or2 R groups on adjacent atoms, together with the atoms to which they are attached form furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 Rx; andR1is hydrogen.

63. The compound of any one of claims 1-62, wherein the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

64. A pharmaceutically acceptable composition comprising a compound of claims 1-63 and a pharmaceutically acceptable carrier.

65. A composition for use in treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject, wherein the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof as described in any one claims 1-63.

66. The composition of claim 65, wherein the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain injury (e.g., a traumatic brain injury or toxin induced brain injury).

67. The composition of any one of claims 65 or 66, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo myelination, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia (e.g., HIV- associated dementia or Lewy body dementia), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

68. The composition of any one of claims 65-67, wherein the neurodegenerative disease comprises vanishing white matter disease.

69. The composition of claim 65, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or a cancer of the secretory cells.

70. The composition of claim 65, wherein the inflammatory disease comprises 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 diabetes mellitus type 1), Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune 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, atherosclerosis, or atopic dermatitis.

71. The composition of claim 65, 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, amyotropic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscle atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Freidrich's ataxia, a muscle wasting disorder (e.g., muscle atrophy, sarcopenia, cachexia), an inclusion body myopathy, motor neuron disease, or paralysis.

72. The composition of claim 65, 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 I diabetes, Type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

73. The composition of claim 65, wherein the mitochondrial disease is associated with or is a result of mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations.

74. The composition of claim 65 or 73, wherein the mitochondrial disease is a mitochondrial myopathy.

75. The composition of any one of claims 65 and 73-74, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive externalophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

76. The composition of claim 65, wherein the autoimmune disease is selected from the group consisting of Achalasia, Addison' s disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia,Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressier' s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto' s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes),Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MP A), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis,Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy,Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndrome type I, Polyglandular syndrome type II, Polyglandular syndrome type III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome,Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

77. The composition of claim 65, wherein the viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV) and herpes.

78. The composition of claim 65, wherein the skin disease is selected from the group consisting of acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extra-mammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infectionsof nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism,hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (verrucas), polymorphic light eruption, psoriasis, plaque psoriasis, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, sweet's syndrome, urticaria and angioedema and vitiligo.

79. The composition of claim 65, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arterial stiffness, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, non-alcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis and ventricular remodeling.

80. The composition of claim 65, wherein the hemoglobin disease is selected from the group consisting of "dominant" β-thalassemia, acquired (toxic) methemoglobinemia,carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β- thalassemia, HbE^-thalassemia, HbSC disease, homozygous a+-thalassemia (phenotype of a°- thalassemia), Hydrops fetalis with Hb Bart's, sickle cell anemia / disease, sickle cell trait, sickle β- thalassemia disease, a+-thalassemia, a°-thalassemia, a- Thalassemia associated withmyelodysplastic syndromes, a-Thalassemia with mental retardation syndrome (ATR), β°- Thalassemia,+-Thalassemia, δ-Thalassemia, γ-Thalassemia, β-Thalassemia major, β- Thalassemia intermedia, δβ-Thalassemia, and εγδβ-Thalassemia.

81. The composition of claim 65, wherein the kidney disease is selected from the group consisting of Abderhalden-Kaufmann-Lignac syndrome (Nephropathic Cystinosis), Abdominal Compartment Syndrome, Acetaminophen-induced Nephrotoxicity, Acute Kidney Failure / Acute Kidney Injury, Acute Lobar Nephroma, Acute Phosphate Nephropathy, Acute Tubular Necrosis,Adenine Phosphoribosyltransferase Deficiency, Adenovirus Nephritis, Alagille Syndrome, Alport Syndrome, Amyloidosis, ANCA Vasculitis Related to Endocarditis and Other Infections, Angiomyolipoma, Analgesic Nephropathy, Anorexia Nervosa and Kidney Disease, Angiotensin Antibodies and Focal Segmental Glomerulosclerosis, Antiphospholipid Syndrome, Anti-TNF-a Therapy-related Glomerulonephritis, APOL1 Mutations, Apparent Mineralocorticoid Excess Syndrome, Aristolochic Acid Nephropathy, Chinese Herbal Nephropathy, Balkan Endemic Nephropathy, Arteriovenous Malformations and Fistulas of the Urologic Tract, Autosomal Dominant Hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, Bath Salts and Acute Kidney Injury, Beer Potomania, Beeturia, β-Thalassemia Renal Disease, Bile Cast Nephropathy, BK Polyoma Virus Nephropathy in the Native Kidney, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Tamponade, Border-Crossers' Nephropathy, Bourbon Virus and Acute Kidney Injury, Burnt Sugarcane Harvesting and Acute Renal Dysfunction, Byetta and Renal Failure, Clq Nephropathy, C3 Glomerulopathy, C3 Glomerulopathy with MonoclonalGammopathy, C4 Glomerulopathy, Calcineurin Inhibitor Nephrotoxicity, Callilepsis Laureola Poisoning, Cannabinoid Hyperemesis Acute Renal Failure, Cardiorenal syndrome, Carfilzomib- Induced Renal Injury, CFHR5 nephropathy, Charcot-Marie-Tooth Disease withGlomerulopathy, Chinese Herbal Medicines and Nephrotoxicity, Cherry Concentrate and Acute Kidney Injury, Cholesterol Emboli, Churg-Strauss syndrome, Chyluria, Ciliopathy, Cocaine and the Kidney, Cold Diuresis, Colistin Nephrotoxicity, Collagenofibrotic Glomerulopathy, Collapsing Glomerulopathy, Collapsing Glomerulopathy Related to CMV, CombinationAntiretroviral (cART) Related-Nephropathy, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), Congenital Nephrotic Syndrome, Congestive Renal Failure, Conorenal syndrome (Mainzer- Saldino Syndrome or Saldino-Mainzer Disease), Contrast Nephropathy, Copper Sulphate Intoxication, Cortical Necrosis, Crizotinib-related Acute Kidney Injury, Cryocrystalglobulinemia, Cryoglobuinemia, Crystalglobulin-Induced Nephropathy, Crystal- Induced Acute Kidney injury, Crystal-Storing Histiocytosis, Cystic Kidney Disease, Acquired, Cystinuria, Dasatinib-Induced Nephrotic-Range Proteinuria, Dense Deposit Disease (MPGN Type 2), Dent Disease (X-linked Recessive Nephrolithiasis), DHA Crystalline Nephropathy, Dialysis Disequilibrium Syndrome, Diabetes and Diabetic Kidney Disease, Diabetes Insipidus, Dietary Supplements and Renal Failure, Diffuse Mesangial Sclerosis, Diuresis, Djenkol Bean Poisoning (Djenkolism), Down Syndrome and Kidney Disease, Drugs of Abuse and Kidney Disease, Duplicated Ureter, EAST syndrome, Ebola and the Kidney, Ectopic Kidney, EctopicUreter, Edema, Swelling, Erdheim-Chester Disease, Fabry's Disease, Familial Hypocalciuric Hypercalcemia, Fanconi Syndrome, Fraser syndrome, Fibronectin Glomerulopathy, Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy, Fraley syndrome, Fluid Overload, Hypervolemia, Focal Segmental Glomerulosclerosis, Focal Sclerosis, Focal Glomerulosclerosis, Galloway Mowat syndrome, Giant Cell (Temporal) Arteritis with Kidney Involvement, Gestational Hypertension, Gitelman Syndrome, Glomerular Diseases, Glomerular Tubular Reflux, Glycosuria, Goodpasture Syndrome, Green Smoothie Cleanse Nephropathy, HANAC Syndrome, Harvoni (Ledipasvir with Sofosbuvir)-Induced Renal Injury, Hair Dye Ingestion and Acute Kidney Injury, Hantavirus Infection Podocytopathy, Heat Stress Nephropathy, Hematuria (Blood in Urine), Hemolytic Uremic Syndrome (HUS), Atypical Hemolytic Uremic Syndrome (aHUS), Hemophagocytic Syndrome, Hemorrhagic Cystitis, Hemorrhagic Fever with Renal Syndrome (HFRS, Hantavirus Renal Disease, Korean Hemorrhagic Fever, EpidemicHemorrhagic Fever, Nephropathis Epidemica), Hemosiderinuria, Hemosiderosis related to Paroxysmal Nocturnal Hemoglobinuria and Hemolytic Anemia, Hepatic Glomerulopathy, Hepatic Veno-Occlusive Disease, Sinusoidal Obstruction Syndrome, Hepatitis C-Associated Renal Disease, Hepatocyte Nuclear Factor Ιβ-Associated Kidney Disease, Hepatorenal Syndrome, Herbal Supplements and Kidney Disease, High Altitude Renal Syndrome, High Blood Pressure and Kidney Disease, HIV-Associated Immune Complex Kidney Disease (HIVICK), HIV-Associated Nephropathy (HIVAN), HNFlB-related Autosomal Dominant Tubulointerstitial Kidney Disease, Horseshoe Kidney (Renal Fusion), Hunner's Ulcer,Hydroxychloroquine-induced Renal Phospholipidosis, Hyperaldosteronism, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hyperoxaluria, Hyperphosphatemia, Hypocalcemia, Hypocomplementemic Urticarial Vasculitic Syndrome, Hypokalemia,Hypokalemia-induced renal dysfunction, Hypokalemic Periodic Paralysis, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Hypophosphatemia in Users of Cannabis, Hypertension,Hypertension, Monogenic, Iced Tea Nephropathy, Ifosfamide Nephrotoxicity, IgA Nephropathy, IgG4 Nephropathy, Immersion Diuresis, Immune-Checkpoint Therapy-Related Interstitial Nephritis, Infliximab-Related Renal Disease, Interstitial Cystitis, Painful Bladder Syndrome (Questionnaire), Interstitial Nephritis, Interstitial Nephritis, Karyomegalic, Ivemark's syndrome, JC Virus Nephropathy, Joubert Syndrome, Ketamine- Associated Bladder Dysfunction, Kidney Stones, Nephrolithiasis, Kombucha Tea Toxicity, Lead Nephropathy and Lead-RelatedNephrotoxicity, Lecithin Cholesterol Acyltransferase Deficiency (LCAT Deficiency),Leptospirosis Renal Disease, Light Chain Deposition Disease, Monoclonal Immunoglobulin Deposition Disease, Light Chain Proximal Tubulopathy, Liddle Syndrome, Lightwood-Albright Syndrome, Lipoprotein Glomerulopathy, Lithium Nephrotoxicity, LMX1B Mutations Cause Hereditary FSGS, Loin Pain Hematuria, Lupus, Systemic Lupus Erythematosis, Lupus Kidney Disease, Lupus Nephritis, Lupus Nephritis with Antineutrophil Cytoplasmic AntibodySeropositivity, Lupus Podocytopathy, Lyme Disease-Associated Glomerulonephritis, Lysinuric Protein Intolerance, Lysozyme Nephropathy, Malarial Nephropathy, Malignancy-Associated Renal Disease, Malignant Hypertension, Malakoplakia, McKittrick-Wheelock Syndrome, MDMA (Molly; Ecstacy; 3,4-Methylenedioxymethamphetamine) and Kidney Failure, Meatal Stenosis, Medullary Cystic Kidney Disease, Urolodulin-Associated Nephropathy, JuvenileHyperuricemic Nephropathy Type 1 , Medullary Sponge Kidney, Megaureter, Melamine Toxicity and the Kidney, MELAS Syndrome, Membranoproliferative Glomerulonephritis, Membranous Nephropathy, Membranous-like Glomerulopathy with Masked IgG Kappa Deposits,MesoAmerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate-related Renal Failure, Microscopic Polyangiitis, Milk-alkalai syndrome, Minimal Change Disease,Monoclonal Gammopathy of Renal Significance, Dysproteinemia, Mouthwash Toxicity, MUCl Nephropathy, Multicystic dysplastic kidney, Multiple Myeloma, Myeloproliferative Neoplasms and Glomerulopathy, Nail-patella Syndrome, NARP Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Floating Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, 9 / 11 and Kidney Disease, Nodular Glomerulosclerosis, Non-Gonococcal Urethritis, Nutcracker syndrome, Oligomeganephronia, Orofaciodigital Syndrome, Orotic Aciduria, Orthostatic Hypotension, Orthostatic Proteinuria, Osmotic Diuresis, OsmoticNephrosis, Ovarian Hyperstimulation Syndrome, Oxalate Nephropathy, Page Kidney, Papillary Necrosis, Papillorenal Syndrome (Renal-Coloboma Syndrome, Isolated Renal Hypoplasia), PARN Mutations and Kidney Disease, Parvovirus B 19 and the Kidney, The Peritoneal-Renal Syndrome, POEMS Syndrome, Posterior Urethral Valve, Podocyte Infolding Glomerulopathy, Post-infectious Glomerulonephritis, Post-streptococcal Glomerulonephritis, Post-infectious Glomerulonephritis, Atypical, Post-Infectious Glomerulonephritis (IgA-Dominant), Mimicking IgA Nephropathy, Polyarteritis Nodosa, Polycystic Kidney Disease, Posterior Urethral Valves, Post-Obstructive Diuresis, Preeclampsia, Propofol infusion syndrome, ProliferativeGlomerulonephritis with Monoclonal IgG Deposits (Nasr Disease), Propolis (Honeybee Resin) Related Renal Failure, Proteinuria (Protein in Urine), Pseudohyperaldosteronism,Pseudohypobicarbonatemia, Pseudohypoparathyroidism, Pulmonary-Renal Syndrome,Pyelonephritis (Kidney Infection), Pyonephrosis, Pyridium and Kidney Failure, Radiation Nephropathy, Ranolazine and the Kidney, Refeeding syndrome, Reflux Nephropathy, Rapidly Progressive Glomerulonephritis, Renal Abscess, Peripnephric Abscess, Renal Agenesis, Renal Arcuate Vein Microthrombi- Associated Acute Kidney Injury, Renal Artery Aneurysm, Renal Artery Dissection, Spontaneous, Renal Artery Stenosis, Renal Cell Cancer, Renal Cyst, Renal Hypouricemia with Exercise-induced Acute Renal Failure, Renal Infarction, RenalOsteodystrophy, Renal Tubular Acidosis, Renin Mutations and Autosomal DominantTubulointerstitial Kidney Disease, Renin Secreting Tumors (Juxtaglomerular Cell Tumor), Reset Osmostat, Retrocaval Ureter, Retroperitoneal Fibrosis, Rhabdomyolysis, Rhabdomyolysis related to Bariatric Sugery, Rheumatoid Arthritis-Associated Renal Disease, Sarcoidosis Renal Disease, Salt Wasting, Renal and Cerebral, Schistosomiasis and Glomerular Disease, Schimke immuno-osseous dysplasia, Scleroderma Renal Crisis, Serpentine Fibula-Polycystic Kidney Syndrome, Exner Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Sri Lankan Farmers' Kidney Disease, Sjogren's Syndrome and Renal Disease, Synthetic Cannabinoid Use and Acute Kidney Injury, Kidney Disease Following Hematopoietic Cell Transplantation, Kidney Disease Related to Stem Cell Transplantation, TAFRO Syndrome, Tea and Toast Hyponatremia, Tenofovir-Induced Nephrotoxicity, Thin Basement Membrane Disease, Benign Familial Hematuria, Thrombotic Microangiopathy Associated with Monoclonal Gammopathy, Trench Nephritis, Trigonitis, Tuberculosis, Genitourinary, Tuberous Sclerosis,Tubular Dysgenesis, Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the Proximal Tubule Brush Border, Tumor Lysis Syndrome, Uremia, Uremic Optic Neuropathy, Ureteritis Cystica, Ureterocele, Urethral Caruncle, Urethral Stricture, Urinary Incontinence, Urinary Tract Infection, Urinary Tract Obstruction, Urogenital Fistula, Uromodulin-Associated Kidney Disease, Vancomycin- Associated Cast Nephropathy, Vasomotor Nephropathy,Vesicointestinal Fistula, Vesicoureteral Reflux, VGEF Inhibition and Renal Thrombotic Microangiopathy, Volatile Anesthetics and Acute Kidney Injury, Von Hippel-Lindau Disease, Waldenstrom's Macroglobulinemic Glomerulonephritis, Warfarin-Related Nephropathy, Wasp Stings and Acute Kidney Injury, Wegener's Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus and Chronic Kidney Disease, Wunderlich syndrome, Zellweger Syndrome, or Cerebrohepatorenal Syndrome.

82. The composition of claim 65, wherein the hearing loss condition is selected from the group consisting of mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age- related hearing loss, noise-induced hearing loss, genetic or inherited hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, and hearing loss resulting from trauma.

83. The composition of claim 65, wherein the ocular disease cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

84. The composition of any one of claims 65-83, comprising administering a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, or a composition thereof, to a subject in combination with a second agent (e.g., agent for treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway).

85. A composition for use in treating a disease related to a modulation of eIF2B activity or levels, eIF2a activity or levels, or the activity or levels of a component of the eIF2 pathway or the ISR pathway, wherein the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof as described in any one of claims 1-63.

86. The composition of claim 85, wherein the modulation comprises an increase in eIF2B activity or levels, increase in eIF2a activity or levels, or increase in activity or levels of a component of the eIF2 pathway or the ISR pathway.

87. The composition of claim 85, wherein the disease may be caused by a mutation to a gene or protein sequence related to a member of the eIF2 pathway (e.g., the eIF2a signaling pathway).

88. A method of treating cancer in a subject, the method comprising administering to the subject a compound of formula (I) or formula (II) in combination with an immunotherapeutic agent.