Prodrug modulators of the integrated stress pathway

Abstract

To provide novel compounds useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.SOLUTION: The present invention provides a compound represented by a formula (I) or a pharmaceutically acceptable salt thereof, a cocrystal, a solvate, a hydrate, a tautomer, an ester, an N-oxide, or a stereoisomer. [R1 is -C(O)-C1-4 alkyl, -C(O)-O-C1-4 alkyl, -C(O)-N(Ra)-C1-4 alkyl, -C(O)-C1-4 alkylene-C1-4 alkoxy, -C(O)-C1-4 alkylene-O-C1-4 alkylene-C1-4 alkoxy, -methylene-O-P(O)(OH) C2, -C(O)-C1-5 alkylene-O-P(O)(OH)2, -C(O)-O-C1-5 alkylene-O-P(O)(OH)2, -C(O)-N(Ra)-C1-5 alkylene-O-P(O)(OH)2 or the like].SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Application No. 62 / 744,293, filed on October 11, 2018, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background In metazoans, diverse stress signals converge on a single phosphorylation event at serine 51 of the translation initiation factor eIF2α, which is a common effector. This step is carried out by four eIF2α kinases in mammalian cells, namely, PERK that responds to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 that responds to amino acid starvation and UV light, PKR that responds to viral infection and metabolic stress, and HRI that responds to heme deficiency. This group of signaling pathways converges on the same molecular event and is thus called the "integrated stress response" (ISR). Phosphorylation of eIF2α attenuates translation, and as a result, cells can cope with various stresses (Wek, R.C. et al, Biochem Soc Trans (2006) 34(Pt 1):7 - 11 (Non - Patent Document 1)).

[0003] eIF2 (composed of three subunits, α, β, γ) binds GTP and initiator Met - tRNA to form a ternary complex (eIF2 - GTP - Met - tRNA i) is formed, and then the complex binds to the 40S ribosomal subunit and scans the 5’UTR of the mRNA to select the start AUG codon. When the α subunit of eIF2 is phosphorylated, eIF2 becomes a competitive inhibitor of its guanine nucleotide exchange factor (GEF), eIF2B (Hinnebusch, A.G. and Lorsch, J.R. Cold Spring Harbor Perspect Biol (2012) 4(10) (Non-Patent Document 2)). The strong and unproductive binding of phosphorylated eIF2 to eIF2B prevents the supply of the eIF2-GTP complex, thereby blocking the formation of the ternary complex and reducing translation initiation (Krishnamoorthy, T. et al, Mol Cell Biol (2001) 21(15):5018-5030 (Non-Patent Document 3)). Since eIF2B is present in smaller amounts than eIF2, phosphorylation of only a small fraction of the total eIF2 can have a dramatic effect on the activity of eIF2B in the cell.

[0004] eIF2B is a complex molecular machine composed of five different subunits, eIF2B1 to eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with the partially homologous subunit eIF2B3, constitutes the "catalytic core" (Williams, D.D. et al, J Biol Chem (2001) 276:24697-24703 (Non-Patent Document 4)). The remaining three subunits (eIF2B1, eIF2B2, and eIF2B4) are also highly homologous to each other and form a "regulatory subcomplex" that provides the binding site for the substrate eIF2 of eIF2B (Dev, K. et al, Mol Cell Biol (2010) 30:5218-5233 (Non-Patent Document 5)). The exchange of GDP for GTP in eIF2 is catalyzed by its dedicated guanine nucleotide exchange factor (GEF), eIF2B. eIF2B is present as a decamer in the cell (B1 2 B2 2 B3 2 B4 2 B5 2or exist as a dimer of two pentamers (Gordiyenko, Y. et al, Nat Commun (2014) 5:3902; (Non-Patent Document 6) Wortham, N. C. et al, FASEB J (2014) 28:2225-2237 (Non-Patent Document 7)). Molecules such as ISRIB interact with the eIF2B dimer higher-order structure to stabilize the structure, thereby enhancing the intrinsic GEF activity and reducing the cell's sensitivity to the cellular effects of eIF2α phosphorylation (Sidrauski, C. et al, eLife (2015) e07314 (Non-Patent Document 8); Sekine, Y. et al, Science (2015) 348:1027-1030 (Non-Patent Document 9)). Therefore, small molecule therapeutic agents that can regulate eIF2B activity may have the potential to attenuate the PERK branch of the UPR and the entire ISR, and thus may be used for the prevention and / or treatment of various diseases such as neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss, eye diseases, musculoskeletal diseases, or metabolic diseases.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

[0006] In one aspect, as used herein, formula (I): A compound represented by TIFF2025081607000001.tif23128, wherein, R 1 is -C(O)-C 1~4 alkyl, -C(O)-O-C 1~4 alkyl, -C(O)-N(R a )-C 1~4 alkyl, -C(O)-C 1~4 alkylene-C 1~4 alkoxy, -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -methylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-C1~5 Alkylene - P(O)(OH) 2 , -C(O)-C 1~5 Alkylene - phenylene - O - P(O)(OH) 2 , -C(O)-C 1~5 Alkylene - phenylene - (O - P(O)(OH) 2 ) 2 , -C(O)-C 1~5 Alkylene - phenylene - (O - P(O)(OH) 2 )(O - C 1~5 Alkylene - P(O)(OH) 2 ), -methylene - O - C(O)C 1~5 Alkylene - phenylene - O - P(O)(OH) 2 or -methylene - O - C(O)C 1~5 Alkylene - phenylene - (O - P(O)(OH) 2 ) 2 , -C(O)-O - C 1~5 Alkylene - O - C(O)C 1~5 Alkylene - phenylene - O - P(O)(OH) 2 , -C(O)-N(R a ) - heteroarylene - C 1~2 Alkylene - O - P(O)(OH) 2 , -P(O)(OH) 2 , -SO 3 H, -SO 2 NR a R b , -C(O)-heteroaryl, -C(O)-C 1~5 Alkylene - O - C 1~5 Alkylene - phenyl, and methylene - C 1~5 selected from the group consisting of alkoxides, provided that -C(O)-C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a R b and -CO 2 H, and -C(O)-O - C 1~4 alkyl, -C(O)-N(R a ) - C 1~4 alkyl, -C(O)-C 1~4 Alkylene - C1~4 alkoxy, -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, methylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 alkylene-P(O)(OH) 2 ), -methylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 or -methylene-O-C(O)C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-O-C 1~5 alkylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-heteroaryl, -C(O)-C 1~5 alkylene-O-C 1~5 alkylene-phenyl, and -C(O)-N(R a )-heteroarylene-C 1~2 alkylene-O-P(O)(OH) 2 each is independently, halogen, -CO 2 H, -NR a R b , C1~2 One, two, three, or four substituents selected from the group consisting of alkyl (optionally substituted with one, two, or three fluorines) and aryl, which may be optionally substituted, R a and R b are each independently, for their respective presence, selected from the group consisting of hydrogen and C 1~3 alkyl There is described the above compound, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

[0007] In one aspect, described herein is a pharmaceutically acceptable composition comprising any one of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0008] In one aspect, described herein is a method for treating a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, musculoskeletal disease, metabolic disease, or mitochondrial disease in a patient in need of treatment for such a disease, the method comprising administering to the patient an effective amount of any one of the compounds disclosed herein.

[0009] In one aspect, described herein is a method for treating a disease associated with modulation of the activity or level of eIF2B, the activity or level of eIF2α, or the activity or level of a component of the eIF2 pathway or the ISR pathway in a patient in need of treatment for such a disease, the method comprising administering to the patient an effective amount of any one of the compounds disclosed herein.

[0010] In one aspect, described herein is a method for treating cancer in a patient in need thereof, the method comprising administering to the patient any one of the compounds disclosed herein in combination with an immunotherapeutic agent. [Invention 1001] Formula (I): A compound represented by TIFF2025081607000002.tif23128, wherein R 1 is -C(O)-C 1~4 alkyl, -C(O)-O-C 1~4 alkyl, -C(O)-N(R a )-C 1~4 alkyl, -C(O)-C 1~4 alkylene-C 1~4 alkoxy, -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -methylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 alkylene-P(O)(OH) 2 ), -methylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2or -methylene-O-C(O)C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 、-C(O)-O-C 1~5 alkylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 、-C(O)-N(R a )-heteroarylene-C 1~2 alkylene-O-P(O)(OH) 2 、-P(O)(OH) 2 、-SO 3 H、-SO 2 NR a R b 、-C(O)-heteroaryl、-C(O)-C 1~5 alkylene-O-C 1~5 alkylene-phenyl、and methylene-C 1~5 selected from the group consisting of alkoxides, wherein, -C(O)-C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a R b and -CO 2 H, -C(O)-O-C 1~4 alkyl, -C(O)-N(R a )-C 1~4 alkyl, -C(O)-C 1~4 alkylene-C 1~4 alkoxy, -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, methylene-O-P(O)(OH) 2 、-C(O)-C 1~5 alkylene-O-P(O)(OH) 2 、-C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 、-C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 、-C(O)-C 1~5 alkylene-P(O)(OH) 2, -C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 alkylene-P(O)(OH) 2 ), -methylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 or -methylene-O-C(O)C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-O-C 1~5 alkylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-heteroaryl, -C(O)-C 1~5 alkylene-O-C 1~5 alkylene-phenyl, and -C(O)-N(R a )-heteroarylene-C 1~2 alkylene-O-P(O)(OH) 2 is each independently selected from the group consisting of halogen, -CO 2 H, -NR a R b , and C 1~2 alkyl (optionally substituted with 1, 2, or 3 fluorines), and aryl, and may be optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: R a and R b are each independently selected from the group consisting of hydrogen and C 1~3 alkyl, the compound, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Invention 1002] R 1 each independently is -NRa R b and -CO 2 -C(O)-C substituted with one or two substituents selected from the group consisting of 1~4 alkyl, the compound of the present invention 1001. [the present invention 1003] R 1 is selected from the group consisting of TIFF2025081607000003.tif17128, the compound of the present invention 1001 or 1002. [the present invention 1004] R 1 is -C(O)-O-C 1~4 alkyl, the compound of the present invention 1001. [the present invention 1005] R 1 is selected from the group consisting of TIFF2025081607000004.tif11128, the compound of the present invention 1004. [the present invention 1006] R 1 is -C(O)-N(R a )-C 1~4 alkyl, and -C(O)-N(R a )-C 1~4 alkyl is optionally substituted with one or two -CO 2 H groups, the compound of the present invention 1001. [the present invention 1007] R 1 is represented by TIFF2025081607000005.tif22128, the compound of the present invention 1006. [the present invention 1008] R 1 is -C(O)-C 1~4 alkylene -C 1~4 alkoxy, the compound of the present invention 1001. [the present invention 1009] R 1 is selected from the group consisting of TIFF2025081607000006.tif11128, the compound of the present invention 1008. [The present invention 1010] R 1 is -C(O)-C 1~4 alkylene -O-C 1~4 alkylene -C 1~4 is alkoxy, the compound of the present invention 1001. [The present invention 1011] R 1 is represented by TIFF2025081607000007.tif10128, the compound of the present invention 1010. [The present invention 1012] R 1 is -methylene -O -P(O)(OH) 2 is the compound of the present invention 1001. [The present invention 1013] R 1 is represented by TIFF2025081607000008.tif13128, the compound of the present invention 1012. [The present invention 1014] R 1 is -C(O)-C 1~5 alkylene -O -P(O)(OH) 2 is the compound of the present invention 1001. [The present invention 1015] R 1 is selected from the group consisting of TIFF2025081607000009.tif15141, the compound of the present invention 1014. [The present invention 1016] R 1 is -C(O)-O -C 1~5 alkylene -O -P(O)(OH) 2 is the compound of the present invention 1001. [The present invention 1017] R 1 is selected from the group consisting of TIFF2025081607000010.tif15128, the compound of the present invention 1016. [The present invention 1018] R 1 is -C(O)-N(R a )-C 1~5Alkylene - O - P(O)(OH) 2 The compound of the present invention 1001, which is [The present invention 1019] R 1 is The compound of the present invention 1018, which is selected from the group consisting of TIFF2025081607000011.tif15128 [The present invention 1020] R 1 is - C(O) - C 1~5 Alkylene - P(O)(OH) 2 The compound of the present invention 1001, which is [The present invention 1021] R 1 is The compound of the present invention 1020, which is represented by TIFF2025081607000012.tif13128 [The present invention 1022] R 1 is - C(O) - C 1~5 Alkylene - phenylene - O - P(O)(OH) 2 , - C(O) - C 1~5 Alkylene - phenylene - (O - P(O)(OH) 2 ) 2 , or - C(O) - C 1~5 Alkylene - phenylene - (O - P(O)(OH) 2 )(O - C 1~5 Alkylene - P(O)(OH) 2 ) The compound of the present invention 1001, which is [The present invention 1023] R 1 is The compound of the present invention 1022, which is selected from the group consisting of TIFF2025081607000013.tif48131 [The present invention 1024] R 1 is - C(O) - N(R a ) - heteroarylene - C 1~2 Alkylene - O - P(O)(OH) 2 The compound of the present invention 1001, which is [The present invention 1025] R 1 is The compound of the present invention 1024, represented by TIFF2025081607000014.tif21128. [The present invention 1026] R 1 The compound of the present invention 1001, wherein R is -C(O)-heteroaryl. [The present invention 1027] R 1 is The compound of the present invention 1026, selected from the group consisting of TIFF2025081607000015.tif17128. [The present invention 1028] R 1 is -C(O)-C 1~5 alkylene - O - C 1~5 alkylene - phenyl, the compound of the present invention 1001. [The present invention 1029] R 1 is The compound of the present invention 1028, represented by TIFF2025081607000016.tif12128. [The present invention 1030] R 1 is methylene - C 1~5 alkoxide, the compound of the present invention 1001. [The present invention 1031] R 1 is The compound of the present invention 1030, represented by TIFF2025081607000017.tif5128. [The present invention 1032] R 1 is -C(O)-O-C 1~5 alkylene - O - C(O)C 1~5 alkylene - phenylene - O - P(O)(OH) 2 , -methylene - O - C(O)C 1~5 alkylene - phenylene - O - P(O)(OH) 2 , or -methylene - O - C(O)C 1~5 alkylene - phenylene - (O - P(O)(OH) 2 ) 2 the compound of the present invention 1001. [Invention 1033] R 1 is the compound of Invention 1032 represented by TIFF2025081607000018.tif30158. [Invention 1034] R 1 is -P(O)(OH) 2 , -SO 3 H, and -SO 2 NH 2 and is the compound of Invention 1001 selected from the group consisting of. [Invention 1035] a compound selected from the group consisting of TIFF2025081607000019.tif24128TIFF2025081607000020.tif187135TIFF2025081607000021.tif223132TIFF2025081607000022.tif218137TIFF2025081607000023.tif177146, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Invention 1036] a pharmaceutically acceptable composition comprising a compound of any one of Inventions 1001 to 1035 and a pharmaceutically acceptable carrier. [Invention 1037] the composition of Invention 1036 formulated for oral administration. [Invention 1038] A method of treating a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, musculoskeletal disease, metabolic disease, or mitochondrial disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of Inventions 1001 to 1035. [Invention 1039] The method of the present invention 1038, wherein the neurodegenerative disease includes leukodystrophy, leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome (such as fragile X syndrome), cognitive impairment, glial cell dysfunction, or brain injury (such as traumatic brain injury, hypoxia-induced brain injury, or toxin-induced brain injury). [The present invention 1040] The method of the present invention 1038 or 1039, wherein the neurodegenerative disease includes vanishing white matter disease, ataxia-telangiectasia with central nervous system hypomyelination, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker disease, Huntington's disease, dementia (such as HIV-associated dementia or Lewy body dementia), kuru disease, multiple sclerosis, Parkinson's disease, or prion disease. [The present invention 1041] The method of any one of the present inventions 1038 to 1040, wherein the neurodegenerative disease includes vanishing white matter disease. [The present invention 1042] The method of the present invention 1038, wherein the cancer includes pancreatic cancer, breast cancer, multiple myeloma, or cancer of secretory cells. [The present invention 1043] The method of the present invention 1038, wherein the inflammatory disease includes postoperative cognitive dysfunction, arthritis (such as rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (such as juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (such as allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. [The present invention 1044] The method of the present invention 1038, wherein the musculoskeletal disorder is muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, or myotonic dystrophy type 2), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive bulbar spinal muscular atrophy, spinal spasm, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Friedreich's ataxia, muscle wasting disorders (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis. [The present invention 1045] The method of the present invention 1038, wherein the metabolic disorder is 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 syndrome. [The present invention 1046] The method of the present invention 1038, wherein the mitochondrial disorder is related to or a result of mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations. [The present invention 1047] The method of the present invention 1038 or 1046, wherein the mitochondrial disorder is mitochondrial myopathy. [The present invention 1048] The method according to any one of the present inventions 1038, 1046, and 1047, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, i.e., maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome. [The present invention 1049] The autoimmune diseases 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 autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baló disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) i.e. eosinophilic granulomatosis with polyangiitis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler 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 syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (opposite acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing diseases, 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, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren 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,The method of the present invention 1038 selected from the group consisting of palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Persistent-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, rheumatoid polymyalgia, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, autoimmunity to sperm and testis, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)). [The present invention 1050] The method of the present invention 1038, wherein the viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV), and herpes. [The present invention 1051] The method of the present invention 1038, 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), extramammary Paget's disease, simple epidermolysis bullosa, erythropoietic protoporphyria, fungal nail infection, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar wart, polymorphic light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet syndrome, urticaria and angioedema, and vitiligo. [The present invention 1052] The method of the present invention 1038, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrillation, 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. [The present invention 1053] The hemoglobinopathy is "dominant inheritance" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α + -thalassemia (α 0 -thalassemia phenotype), fetal hydrops associated with Hb Bart's disease, sickle cell anemia / sickle cell disease, sickle cell trait, sickle β-thalassemia, α + -thalassemia, α 0 -thalassemia, α-thalassemia associated with myelodysplastic syndrome, α-thalassemia / mental retardation (ATR) syndrome, β0 - Thalassemia, β + - The method of the present invention 1038 selected from the group consisting of thalassemia, δ-thalassemia, γ-thalassemia, severe β-thalassemia, intermediate β-thalassemia, δβ-thalassemia, and εγδβ-thalassemia. [The present invention 1054] The kidney diseases include Abdelhalden-Kaufmann-Lignac syndrome (nephrotic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute kidney injury / acute renal failure, acute lobar nephronia, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infectious diseases, angiomyolipoma, analgesic nephropathy, anorexia nervosa and kidney diseases, angiotensin antibody and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-related glomerulonephritis, APOL1 mutation, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal medicine nephropathy, Balkan endemic nephropathy, arteriovenous malformations and fistulas of the urinary tract, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome, bath salts and acute kidney injury, Beer Potomania, beeturia, β-thalassemia kidney disorder, bile cast nephropathy, BK polyomavirus nephropathy in native kidneys, bladder rupture, detrusor-sphincter dyssynergia, bladder tamponade, Border-Crossers nephropathy, Bourbon virus and acute kidney injury, burning sugarcane harvest and acute renal dysfunction, Byetta and renal failure, C1q nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepsis Laureola poisoning, cannabinoid hyperemesis acute kidney injury, cardio-renal syndrome, carfilzomib-induced kidney injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathy, Chinese herbal medicine and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathy, cocaine and the kidney, cold diuresis, colistin nephrotoxicity, collagenous fibrosing glomerulopathy, collapsing glomerulopathy, CMV-related collapsing glomerulopathy, combined antiretroviral therapy (cART)-related nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, renal pyramid syndrome (Münzer-Sardinia syndrome or Sardinia-Münzer disease), contrast-induced nephropathy, copper sulfate poisoning, renal cortical necrosis, crizotinib-related acute kidney injury, cryoglobulinemic glomerulonephritis, cryoglobulinemia, crystal globulin-induced nephropathy,Crystallization-induced acute kidney injury, crystal accumulation histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced proteinuria in the nephrotic range, dense deposit disease (MPGN type 2), Dent disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis disequilibrium syndrome, diabetes and diabetic kidney disease, diabetes insipidus, nutritional supplements and renal failure, diffuse mesangial sclerosis, diuresis, Djenkol Bean poisoning (Djenkolism), Down syndrome and kidney disease, drug dependence and kidney disease, duplicated ureter, EAST syndrome, Ebola and the kidney, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immunotactoid glomerulopathy, Frey syndrome, fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal complications, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerulotubular reflux, renal glycosuria, Goodpasture syndrome, green smoothie purifying nephropathy, HANAC syndrome, Harvoni (ledipasvir / sofosbuvir combination) -induced kidney injury, hair dye ingestion and acute kidney injury, podocytopathy due to hantavirus infection, heat stress nephropathy, hematuria (blood in urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, hantavirus kidney disease, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), hemosiderinuria, paroxysmal nocturnal hemoglobinuria and hemosiderin deposition related to hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1β-related kidney disease, hepatorenal syndrome, herbal supplements and kidney disease, high altitude nephrotic syndrome, hypertension and kidney disease, HIV-related immune complex kidney disease (HIVICK), HIV-related nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial kidney disease, horseshoe kidney (fused kidney), Hanna ulcer, hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic purpura-like vasculitis syndrome, hypokalemia,Hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in cannabis users, hypertension, monogenic hypertension, ice tea kidney, ifosfamide nephrotoxicity, IgA nephropathy, IgG4-related kidney disease, water diuresis, immune checkpoint therapy-related interstitial nephritis, infliximab-related kidney disease, interstitial cystitis, painful bladder syndrome (questionnaire), interstitial nephritis, karyomegalic interstitial nephritis, IBM syndrome, JC virus nephropathy, Joubert syndrome, ketamine-related bladder dysfunction, kidney stones, nephrolithiasis, Kombucha toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis-related kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipoid nephrosis, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutation, low back pain and hematuria syndrome, lupus, systemic lupus erythematosus, lupus nephritis, lupus nephritis with positive anti-neutrophil cytoplasmic antibody serum, lupus podocytopathy, Lyme disease-related glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malaria nephropathy, malignant tumor-related kidney disease, malignant hypertension, malacoplakia, Mackittrick-Wheelock syndrome, MDMA (molly; ecstasy; 3,4-methylenedioxymethamphetamine) and renal failure, external urethral stricture, medullary cystic kidney disease, uromodulin-related kidney disease, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaureter, melamine toxicity and its kidney, MELAS syndrome, membranoproliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with masked IgGκ deposition, Mesoamerican nephropathy, metabolic acidosis, metabolic alkalosis, methotrexate-related renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammopathy of renal significance, proteinuria, mouse wash 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 glomerulosclerosisNon-gonococcal urethritis, walnut cracking syndrome, oligomeganephronia, orofaciodigital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephrosis, ovarian hyperstimulation syndrome, oxalate nephropathy, page kidney, papillary necrosis, papillary nephropathy syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutation and kidney disease, parvovirus B19 and the kidney, peritoneal-renal syndrome, POEMS syndrome, posterior urethral valve, podocyte infolding glomerulopathy, post-infectious glomerulonephritis, post-streptococcal glomerulonephritis, atypical post-infectious glomerulonephritis, post-infectious glomerulonephritis mimicking IgA nephropathy (IgA-dominant), polyarteritis nodosa, polycystic kidney disease, posterior urethral valve, post-obstructive diuresis, preeclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr disease), propolis (bee resin)-related renal failure, proteinuria (urinary protein), pseudohyperaldosteronism, pseudohypobicarbonatemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, pyridium and renal failure, radiation nephropathy, ranolazine and its kidney, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute kidney injury related to renal arcuate vein microthrombosis, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute kidney injury, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation and autosomal dominant tubulointerstitial kidney disease, renin-secreting tumor (juxtaglomerular cell tumor), reset osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis related to bariatric surgery, rheumatoid arthritis-related kidney disease, sarcoidosis kidney disease, salt wasting in the kidney and brain, schistosomiasis and glomerular disease, Shprintzen immunodeficiency osteogenesis imperfecta, scleroderma renal crisis, serpentine fibula-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure and chronic kidney disease, Sri Lankan farmer's kidney disease, Sjogren syndrome and kidney disease, synthetic cannabinoid use and acute kidney injury, kidney disease after hematopoietic cell transplantation, kidney disease related to stem cell transplantation, TAFRO syndrome, tea and toast hyponatremia,The method of the present invention 1038 selected from the group consisting of tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal immunoglobulinemia-related thrombotic microangiopathy, war nephritis, trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular dysplasia, immune complex tubulointerstitial nephritis caused by autoantibodies against the proximal tubular brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureteral tumor, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin-related cylindroma, vasomotor nephropathy, vesicointestinal fistula, vesicoureteral reflux, VGEF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, von Hippel-Lindau disease, Waldenström macroglobulinemic glomerulonephritis, warfarin-related nephropathy, wasp stings and acute kidney injury, Wegener granulomatosis, polyangiitis with granulomatosis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatorenal syndrome. [The present invention 1055] The method of the present invention 1038, wherein the hearing loss is selected from the group consisting of mitochondrial genetic non-syndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxic agents, disease-induced hearing loss, and trauma-induced hearing loss. [The present invention 1056] The method of the present invention 1038, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy. [The present invention 1057] Any of the compounds of the present invention 1001 to 1035 is administered to the patient in combination with a second agent (for example, a drug for treating cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, or a disease or disorder associated with a dysfunction of a component of the eIF2B, eIF2α, or eIF2 pathway or the ISR pathway), any of the methods of the present invention 1038 to 1056. [The present invention 1058] A method of treating a disease related to the regulation of the activity or level of eIF2B, the activity or level of eIF2α, or the activity or level of a component of the eIF2 pathway or the ISR pathway in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of 1001-1035 of the present invention. [The present invention 1059] The method of the present invention 1058, wherein the regulation includes an increase in the activity or level of eIF2B, an increase in the activity or level of eIF2α, or an increase in the activity or level of a component of the eIF2 pathway or the ISR pathway. [The present invention 1060] The method of the present invention 1058, wherein the disease can be caused by a mutation in the sequence of a gene or protein related to a component of the eIF2 pathway (e.g., the eIF2α signaling pathway). [The present invention 1061] A method of treating cancer in a patient in need thereof, the method comprising administering to the subject a compound of any one of 1001-1035 of the present invention in combination with an immunotherapeutic agent.

Mode for Carrying Out the Invention

[0011] Detailed Description of the Invention The present invention features compounds, compositions, and methods for use, for example, in the regulation (e.g., activation) of eIF2B and attenuation of the ISR signaling pathway, and includes compounds of formula (I), or pharmaceutically acceptable salts, co-crystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof. In some embodiments, the compound of formula (I) is a prodrug of a biologically active compound that regulates eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway. In some embodiments, the compound of formula (I) is a compound of formula (II): TIFF2025081607000024.tif22128's prodrug.

[0012] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Elements are specified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75 th Ed., and are identified by reference. Specific functional groups are generally defined as described in the above Handbook. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0013] The abbreviations used herein have their conventional meanings within the scope of the chemical and biological arts. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valency known in the chemical arts.

[0014] The compounds described herein may contain one or more asymmetric centers and, accordingly, may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be isolated from the mixture 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 the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0015] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., is enantiomerically pure). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus enantiomerically pure with respect to the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% of the enantiomer. In certain embodiments, the weight is based on all enantiomers or stereoisomers of the compound.

[0016] In the compositions provided herein, an enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% R-compound and at most about 5% S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound, based on the total weight of the compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% S-compound and at most about 5% R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

[0017] The compounds described herein may also contain one or more isotope substitutions. For example, H may be 1 H,2 H (D or deuterium), and 3 any isotope that may contain H (T or tritium), C is 12 C, 13 C, and 14 any isotope that may contain C, O is 16 O and 18 any isotope that may contain O, and so on.

[0018] In this specification, the articles "a" and "an" can be used to refer to one or more (i.e., at least 1) of the grammatical objects of the article. By way of example, "a kind of analog" means one kind of analog or two or more kinds of analogs.

[0019] When a range of values is recited, the range is intended to include each value and sub-range within the range. For example, "C 1 ~C 6 alkyl" means C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 3 ~C 6 , C 3 ~C 5 , C 3 ~C 4 , C 4 ~C 6 , C 4 ~C 5 , and C 5 ~C 6It is intended to include alkyl.

[0020] The following terms are intended to have the meanings set forth below as indicated by those terms and are useful for understanding the description and intended scope of the present invention.

[0021] "Alkyl" means a radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1 ~C 20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1 ~C 12 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1 ~C 8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1 ~C 6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1 ~C 5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1 ~C 4 alkyl"). The alkyl group has 1 to 3 carbon atoms ("C 1 ~C 3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1 ~C 2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C 1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2 ~C 6 alkyl"). Examples of C 1 ~C 6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanil (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ) are mentioned. Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), etc. Each example of an alkyl group is independently optionally substituted, that is, it may be unsubstituted (unsubstituted alkyl) or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ( "substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1 ~C 10 alkyl (for example, -CH 3 ). In certain embodiments, the alkyl group is substituted C 1 ~C 6 alkyl. Common abbreviations for alkyl include Me (-CH 3 ), Et (-CH 2 CH 3 ), iPr (-CH(CH 3 )) 2 ), nPr (-CH 2 CH 2 CH 3 ), n-Bu (-CH 2 CH 2 CH 2 CH 3 ), or i-Bu (-CH 2 CH(CH 3 )) 2 ) are mentioned.

[0022] The term "alkylene", alone or as part of another substituent, unless otherwise expressly stated, is -CH 2 CH2 CH 2 CH 2 - as an example, but not limited thereto, means a divalent radical derived from alkyl. Generally, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, and in the present invention, those groups having 10 or fewer carbon atoms are preferred. The term "alkenylene", alone or as part of another substituent, means a divalent radical derived from alkene, unless otherwise expressly stated. An alkylene group may be described, for example, as C 1 ~C 6 member alkylene, where the term "member" refers to non-hydrogen atoms within that portion.

[0023] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds and no triple bonds ("C 2 ~C 20 alkenyl"). In some embodiments, the alkenyl group has from 2 to 10 carbon atoms ("C 2 ~C 10 alkenyl"). In some embodiments, the alkenyl group has from 2 to 8 carbon atoms ("C 2 ~C 8 alkenyl"). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms ("C 2 ~C 6 alkenyl"). In some embodiments, the alkenyl group has from 2 to 5 carbon atoms ("C 2 ~C 5 alkenyl"). In some embodiments, the alkenyl group has from 2 to 4 carbon atoms ("C 2 ~C 4 alkenyl"). In some embodiments, the alkenyl group has from 2 to 3 carbon atoms ("C 2 ~C 3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C 2"Alkenyl"). The one or more carbon-carbon double bonds may be internal double bonds (such as 2-butenyl) or terminal double bonds (such as 1-butenyl). C 2 ~C 4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like. C 2 ~C 6 Examples of alkenyl groups include the above-mentioned C 2 ~C 4 alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrieneyl (C 8 ), and the like. Each example of an alkenyl group is independently optionally substituted, that is, it may be unsubstituted (unsubstituted alkenyl) or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ( "substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~6 alkenyl

[0024] "Aryl" refers to 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 arrangement), having 6 to 14 ring carbon atoms present in the aromatic ring system and no heteroatoms, a radical of the above aromatic ring system ("C 6~14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C 6"Aryl", for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 "Aryl", for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl", for example, anthracyl). The aryl group is, for example, C 6 ~C 10 member aryl and may be described as such, where the term "member" refers to non-hydrogen ring atoms within that portion. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of each aryl group are independently optionally substituted, that is, they may be unsubstituted (unsubstituted aryl) or may be substituted with one or more substituents ("substituted aryl"). In certain embodiments, the above aryl group is unsubstituted C 6 ~C 14 aryl. In certain embodiments, the above aryl group is substituted C 6 ~C 14 aryl.

[0025] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C 1 ~C 8 alkyl, halo-C 1 ~C 8 alkyl, halooxy-C 1 ~C 8 alkyl, cyano, hydroxy, alkoxy-C 1 ~C 8 alkyl, and amino.

[0026] Examples of representative substituted aryls include the following, namely TIFF2025081607000025.tif18128, wherein R 56 and R 57 one of which may be hydrogen, and R 56 and R 57 at least one of each is independently C 1 ~C 8Alkyl, halo-C 1 ~C 8 Alkyl, 4- to 10-membered heterocyclyl, alkanoyl, alkoxy-C 1 ~C 8 Alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 、NR 58 SOR 59 、NR 58 SO 2 R 59 、C(O)Oalkyl, C(O)Oaryl, CONR 58 R 59 、CONR 58 OR 59 、NR 58 R 59 、SO 2 NR 58 R 59 、S-alkyl, S(O)-alkyl, S(O) 2 -alkyl, S-aryl, S(O)-aryl, S(O 2 )-aryl, or R 56 and R 57 together may form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms containing one or more heteroatoms optionally selected from the group consisting of N, O, or S.

[0027] Other representative aryl groups having a fused heterocyclyl group include, for example TIFF2025081607000026.tif12128, wherein each W’ is selected from C(R 66 ) 2 、NR 66 、O, and S, each Y’ is selected from carbonyl, NR 66 、O, and S, and R 66 is independently hydrogen, C 1 ~C 8 alkyl, C 3 ~C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6 ~C 10It is aryl and 5- to 10-membered heteroaryl.

[0028] "Arylene" and "heteroarylene" each mean a divalent radical derived from aryl and heteroaryl, respectively, either alone or as part of another substituent. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolinyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolinyl. The above examples may be substituted or unsubstituted, and the divalent radicals of each of the above heteroaryl examples are non-limiting examples of heteroarylene.

[0029] "Halo" or "halogen" independently or as part of another substituent, unless otherwise expressly indicated, means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide" refers to fluoride, chloride, bromide, or iodide, either by itself or as part of another substituent. In certain embodiments, the halo group is either fluorine or chlorine.

[0030] Also, terms such as "haloalkyl" are intended to encompass monohaloalkyl and polyhaloalkyl. For example, "halo-C 1 ~C 6As used herein, the term "alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0031] As used herein, the term "heteroalkyl" means an acyclic stable straight or branched chain, or combinations thereof, which alone or in combination with another term, includes at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, with the proviso that the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heteroatoms O, N, P, S, and Si may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 -S(O) 2 、-S(O)-CH 3 、-S(O) 2 -CH 2 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、-O-CH 3 、and -O-CH 2 -CH3 include, but are not limited to, for example, -CH 2 -NH-OCH 3 and CH 2 -O-Si(CH 3 ) 3 up to two or three heteroatoms may be consecutive, such as. The term "heteroalkyl" is described, followed by -CH 2 O, -NR B R C etc., when specific heteroalkyl groups are described, the terms heteroalkyl and CH 2 O or -NR B R C are not overlapping or mutually exclusive. Instead, specific heteroalkyl groups are described for clarity. Thus, in this specification, the term "heteroalkyl" should not be construed to exclude specific heteroalkyl groups such as -CH 2 O, -NR B R C .

[0032] Similarly, the term "heteroalkylene", alone or as part of another term, unless otherwise expressly stated, refers to a divalent radical derived from heteroalkyl, exemplified by (but not limited to) -CH 2 O- and -CH 2 CH 2 O-. A heteroalkylene group may be described, for example, as a 2- to 7-membered heteroalkylene, where the term "member" refers to non-hydrogen atoms within the moiety. For a heteroalkylene group, the heteroatom(s) may occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylenamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- may represent both -C(O) 2 R'- and -R'C(O) 2 -.

[0033] "Heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement), having ring carbon atoms and 1 to 4 ring heteroatoms present in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur, and refers to a radical of the above aromatic ring system ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom as long as the valence is allowed. The bicyclic heteroaryl ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes a ring system in which the heteroaryl ring defined above is condensed with one or more aryl groups and the bonding point is present on either the aryl ring or the heteroaryl ring. In such a case, the ring member number indicates the ring member number of the condensed (aryl / heteroaryl) ring system. In a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bonding point may be present on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). The heteroaryl group may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to non-hydrogen ring atoms within that portion.

[0034] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each example of the heteroaryl group is independently optionally substituted, i.e., it may be unsubstituted (unsubstituted heteroaryl) or substituted with one or more substituents (a "substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0035] Examples of 5-membered heteroaryl groups containing one exemplary heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two exemplary heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three exemplary heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. An example of a 5-membered heteroaryl group containing four exemplary heteroatoms is tetrazolyl, but is not limited thereto. An example of a 6-membered heteroaryl group containing one exemplary heteroatom is pyridinyl, but is not limited thereto. Examples of 6-membered heteroaryl groups containing two exemplary heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four exemplary heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one exemplary heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-fused heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-fused heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0036] Examples of representative heteroaryls include the following formulas, namely TIFF2025081607000027.tif54128 is mentioned, where each Y is selected from carbonyl, N, NR 65 , O, and S, and R 65 is independently hydrogen, C 1 ~C 8 alkyl, C 3 ~C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6 ~C 10 aryl, and 5- to 10-membered heteroaryl.

[0037] "Cycloalkyl" refers to a radical of a non-aromatic cyclic group having 3 to 10 ring carbon atoms ("C 3 ~C 10 cycloalkyl") that does not have a heteroatom in the non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 ~C 8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 ~C 6 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 ~C 6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5 ~C 10 cycloalkyl"). The cycloalkyl group may be described, for example, as C 4 ~C 7 -membered cycloalkyl, where the term "membered" refers to the non-hydrogen ring atoms within that portion. Exemplary C 3 ~C 6 cycloalkyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc., but are not limited thereto. Exemplary C 3 ~C 8 Examples of the cycloalkyl group include the above-mentioned C 3 ~C 6 cycloalkyl group, and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), cubanyl (C 8 ), bicyclo[1.1.1]pentanyl (C 5 ), bicyclo[2.2.2]octanyl (C 8 ), bicyclo[2.1.1]hexanyl (C 6 ), bicyclo[3.1.1]heptanyl (C 7 ), etc., but are not limited thereto. Exemplary C 3 ~C 10 Examples of the cycloalkyl group include the above-mentioned C 3 ~C 6 cycloalkyl group, and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10) include, but are not limited to, the above. As described in the above examples, in certain embodiments, the cycloalkyl group is monocyclic ("monocyclic cycloalkyl"), or contains a fused ring system such as a bicyclic system ("bicyclic cycloalkyl"), a bridged ring system, or a spiro ring system, and may be saturated or partially unsaturated. "Cycloalkyl" also includes a ring system in which the cycloalkyl ring defined above is fused to one or more aryl groups and the bonding point is on the cycloalkyl ring. In such a case, the number of carbon atoms continues to indicate the number of carbon atoms in the cycloalkyl ring system. Each example of the cycloalkyl group is independently optionally substituted, that is, it may be unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3 ~C 10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3 ~C 10 cycloalkyl.

[0038] In some embodiments, "cycloalkyl" is a monocyclic, saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C 3 ~C 10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 ~C 8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 ~C 6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 ~C 6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5 ~C 10 cycloalkyl"). C 5 ~C 6Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 6 ). C 3 ~C 6 Examples of cycloalkyl groups include the above-mentioned C 5 ~C 6 cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). C 3 ~C 8 Examples of cycloalkyl groups include the above-mentioned C 3 ~C 6 cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted (``unsubstituted cycloalkyl'') or substituted with one or more substituents (``substituted cycloalkyl''). In certain embodiments, the cycloalkyl group is unsubstituted C 3 ~C 10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3 ~C 10 cycloalkyl.

[0039] "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 each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence is permitted. The heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), or a fused ring system such as a bicyclic system ("bicyclic heterocyclyl"), a bridged ring system, or a spiro ring system, and may be saturated or partially unsaturated. The bicyclic heterocyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring defined above is fused with one or more cycloalkyl groups and the point of attachment is present on either the cycloalkyl ring or the heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused with one or more aryl groups or heteroaryl groups and the point of attachment is present on the heterocyclyl ring. In such a case, the ring member number continues to indicate the ring member number of the above heterocyclyl ring system. The heterocyclyl group may be described, for example, as 3- to 7-membered heterocyclyl, where the term "member" refers to non-hydrogen ring atoms within that portion, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of heterocyclyl may independently be optionally substituted, i.e., may be unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0040] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system (a "5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system (a "5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system (a "5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary, C 6Examples of the 5-membered heterocyclyl group fused to an aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, 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, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0042] Specific examples of the heterocyclyl group are for the purpose of the following description, namely, shown in TIFF2025081607000028.tif45128, wherein each W is CR 67 , C(R 67 ), 2 NR 67 , O, and S, each Y is selected from NR 67 , O, and S, and R 67 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. These heterocyclic rings are 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., amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O) 2 -alkyl, and S(O) 2 -aryl. Substituents include, for example, carbonyl or thiocarbonyl that gives lactam and urea derivatives.

[0043] The term "nitrogen-containing heterocyclyl" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine, but is not limited thereto. Specific examples include azetidine, piperidone, and piperazone.

[0044] "Amino" refers to the radical -NR 70 R 71 wherein, in the formula, R 70 and R 71 are each independently hydrogen, C 1 ~C 8 alkyl, C 3 ~C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6 ~C 10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, amino refers to NH 2 .

[0045] "Cyano" refers to the radical -CN.

[0046] "Hydroxy" refers to the radical -OH.

[0047] As used herein, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl groups, "substituted" or "unsubstituted" alkenyl groups, "substituted" or "unsubstituted" alkynyl groups, "substituted" or "unsubstituted" cycloalkyl groups, "substituted" or "unsubstituted" heterocyclyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that, whether or not the term "optionally" is present before it, at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, i.e., a substituent that results in a stable compound, e.g., a compound that does not spontaneously convert, such as by rearrangement, cyclization, elimination, or other reactions, upon substitution. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position may be the same or different. The term "substitution" is intended to encompass substitution with any and all acceptable substituents of an organic compound, 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 for arriving at a stable compound. For the purposes of the present invention, a heteroatom such as nitrogen may have any and appropriate substituents described herein that satisfy the hydrogen substituents and / or the valence of the heteroatom, resulting in the formation of a stable moiety.

[0048] Optionally, two or more substituents may combine together to form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocyclyl group. Such so-called ring-forming substituents generally, but not necessarily, include those attached to the cyclic basic structure. In one embodiment, the ring-forming substituent is attached to adjacent ring atoms of the basic structure. For example, two ring-forming substituents attached to adjacent ring atoms of the cyclic basic structure form a fused ring structure. In another embodiment, the ring-forming substituent is attached to a single ring atom of the basic structure. For example, two ring-forming substituents attached to a single ring atom of the cyclic basic structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituent is attached to non-adjacent ring atoms of the basic structure.

[0049] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , OH - , H 2 PO 4 - , HSO 4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonate-5-sulfonate ion, ethane-1-sulfonate-2-sulfonate ion, etc.), and carboxylate ions (e.g., acetate ion, ethanoate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0050] The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds made using relatively non-toxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, without solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, without solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, hydrogen carbonic, phosphoric, hydrogen phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, hydroiodic, or phosphorous acids, and salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic acids, and salts of amino acids such as arginate, and salts of organic acids such as glucuronic or galacturonic acids (see, for example, Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups capable of converting the compound into either a base addition salt or an acid addition salt. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protic solvents in the form of their corresponding free base. In other cases, the formulation may be a lyophilized powder in a first buffer, for example, 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol in a pH range of 7.5 to 5.5, and is mixed with a second buffer prior to use.

[0051] Accordingly, the compounds of the present invention may exist as salts such as salts with pharmaceutically acceptable acids. The present invention encompasses such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0052] The neutral form of the present compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the present compound has certain physical properties, such as solubility in polar solvents, that differ from those of the various salt forms.

[0053] The term "prodrug" can be used to represent the compounds of the present invention that are readily chemically transformed under physiological conditions to give biologically active compounds that modulate eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway. Furthermore, the prodrug compounds of the present invention can be converted to biologically active compounds that modulate eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug compounds of the present invention are placed in a transdermal patch reservoir together with a suitable enzyme or chemical reactant, they can be slowly converted to biologically active compounds that modulate eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

[0054] The term "pharmaceutically acceptable cocrystal" can be defined as a crystalline solid comprising two or more different compounds, wherein at least one of the two or more compounds is present in the crystalline solid in a neutral state (not ionized), one of the two or more compounds is an active pharmaceutical ingredient (e.g., a compound of formula (I)), and the one or more other compounds present in the crystalline solid are also pharmaceutically acceptable. In some embodiments, at least two of the two or more compounds independently exist as a solid under ambient conditions. In some embodiments, the two or more compounds interact via non-ionic intermolecular interactions.

[0055] Certain compounds of the present invention may exist not only in the unsolvated form but also in solvated forms including hydrated forms. Generally, the solvated forms are equivalent to the unsolvated form and are encompassed within the scope of the present invention.

[0056] Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent with respect to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0057] As used herein, the term "salt" refers to an acid or base salt of the compound used in the methods of the present invention. Examples for the description of acceptable salts include salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.).

[0058] Certain compounds of the present invention have an asymmetric carbon atom (optical or chiral center) or a double bond, and from the perspective of absolute stereochemistry, enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomers that can be defined as (R)- or (S)- or (D)- or (L)- of an amino acid, and the individual isomers are included within the scope of the present invention. The compounds of the present invention do not include compounds known in the art that are difficult to synthesize and / or isolate due to being overly unstable. The present invention is intended to include the compounds in racemic and optically pure forms. The optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral starting materials or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0059] As used herein, the term "isomer" refers to compounds having the same number and types of atoms, and thus the same molecular weight, but differing with respect to the structural arrangement or constitution of the atoms.

[0060] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another.

[0061] It will be apparent to those skilled in the art that certain compounds of the present invention may exist as tautomers, and that all such tautomers of the compounds are within the scope of the present invention.

[0062] The terms "treating" or "treatment" refer to evidence of success in the treatment or amelioration of an injury, disease, pathology, or disorder, including reduction; remission; making a disorder, pathology, or disease more tolerable to the patient; slowing degeneration or decline; making the end point of degeneration less debilitating; improving the physical or mental health of the patient, and the like, including objective or subjective parameters. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods herein treat cancer (e.g., pancreatic cancer, breast cancer, multiple myeloma, secretory cell carcinoma), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophies (e.g., vanishing white matter disease, ataxia-telangiectasia with central nervous system hypomyelination), postoperative cognitive dysfunction, traumatic brain injury, hypoxic ischemic brain injury, stroke, spinal cord injury, intellectual disability syndromes, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or disorders associated with dysfunction of components of a signal transduction pathway, i.e., a signaling pathway, including eIF2B or ISR.For example, a particular method of the present specification treats cancer by reducing, decreasing, or preventing the occurrence, growth, metastasis, or progression of cancer, or by reducing the symptoms of cancer; treats neurodegeneration by improving mental health, enhancing mental function, decelerating the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive ability, reducing the loss of cognitive ability, improving memory, reducing the decline of memory, reducing the symptoms of neurodegeneration, or extending survival; treats leukodystrophy by reducing the symptoms of leukodystrophy, reducing the loss of white matter, reducing the loss of myelin, increasing the amount of myelin, or increasing the amount of white matter; treats childhood ataxia with central nervous system hypomyelination by reducing the symptoms of childhood ataxia with central nervous system hypomyelination, increasing the level of myelin, or reducing the loss of myelin; treats intellectual disability syndrome by reducing the symptoms of intellectual disability syndrome; treats inflammatory diseases by treating the symptoms of inflammatory diseases; treats musculoskeletal diseases by treating the symptoms of musculoskeletal diseases; treats metabolic diseases by treating the symptoms of metabolic diseases; treats autoimmune diseases by treating the symptoms of autoimmune diseases; treats viral infections by treating the symptoms of viral infections; treats skin diseases by treating the symptoms of skin diseases; treats fibrotic diseases by treating the symptoms of fibrotic diseases; treats hemoglobinopathies by treating the symptoms of hemoglobinopathies; treats hearing loss by improving the hearing of a subject in need thereof; or treats eye diseases by treating the symptoms of eye diseases or by improving the vision of a subject in need thereof. The symptoms of the diseases, disorders, or illnesses described herein (e.g., cancer, neurodegenerative diseases, leukodystrophies, inflammatory diseases, musculoskeletal diseases, metabolic diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss, eye diseases, or diseases or disorders associated with a dysfunction of a component of a signal transduction pathway including the eIF2B or eIF2 pathway, phosphorylation of eIF2α, or the ISR pathway) are known or can be determined by one of ordinary skill in the art.The term "treating" and its conjugations include the prevention of injury, pathology, disease, or disorder (e.g., prevention of the onset of one or more symptoms of a disease, disorder, or illness described herein).

[0063] "Effective amount" means an amount sufficient to achieve a stated purpose (e.g., achieve an effect for which a drug is administered, treat a disease, reduce enzyme activity, increase enzyme activity, or reduce one or more symptoms of a disease or disorder). Examples of "effective amount" are amounts sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, and may also be referred to as a "therapeutically effective amount". A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will, for example, prevent or delay the onset (or recurrence) of an injury, disease, pathology, or disorder, or reduce the likelihood of the onset (or recurrence) of an injury, disease, pathology, or disorder, or its symptoms, resulting in the intended prophylactic effect. A complete prophylactic effect does not necessarily occur with a single administration and may occur only after a series of administrations. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the particular treatment objective and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0064] "Reduction" of one or more symptoms (and grammatical equivalents of this expression) means a decrease in the severity or frequency of the symptom(s) or the elimination of the symptom(s).

[0065] In the context of a substance or the activity or function of a substance related to a disease (e.g., a disease or disorder described herein, such as cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, or a disease or disorder related to a dysfunction of a component of a signal transduction pathway including the eIF2B or eIF2 pathway, phosphorylation of eIF2α, or the ISR pathway), the terms "related to" or "associated with" mean that the disease is caused (in whole or in part) by the substance or the activity or function of the substance, or that the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance. For example, the symptoms of a disease or disorder related to a dysfunction of eIF2B may be due (in whole or in part) to a decrease in eIF2B activity (e.g., a decrease in the activity or level of eIF2B, an increase in the phosphorylation of eIF2α or the activity of phosphorylated eIF2α, or a decrease in eIF2 activity or an increase in the activity of the phosphorylated eIF2α signaling pathway or the ISR signaling pathway). As used herein, a substance described as related to a disease (if it is a causative agent) can be a target for the treatment of the disease. For example, a disease related to a decrease in eIF2 activity or the activity of the eIF2 pathway can be treated with an agent (e.g., a compound described herein) effective to increase the level or activity of eIF2 or the eIF2 pathway, or to decrease the activity of phosphorylated eIF2α or the ISR pathway. For example, a disease related to phosphorylated eIF2α can be treated with an agent (e.g., a compound described herein) effective to decrease the level of the activity of phosphorylated eIF2α or a downstream component or effector of phosphorylated eIF2α. For example, a disease related to eIF2α can be treated with an agent (e.g., a compound described herein) effective to increase the level of the activity of a downstream component or effector of eIF2 or an eIF2 agent.

[0066] "Control" or "control experiment" is used in accordance with its plain and ordinary meaning and refers to an experiment in which the subject or reagent of the experiment is treated in the same manner as a parallel experiment, except that the experimental procedure, reagent, or variable element is omitted. Optionally, the control is used as a reference for comparison when evaluating the effect of the experiment.

[0067] "Contacting" is used in accordance with its plain and ordinary meaning and refers to the process of bringing at least two different species (e.g., chemical compounds including biomolecules, or cells) into close proximity sufficient to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be directly generated from the reaction between the added reactants, or may be generated from intermediates derived from one or more of the added reactants that are generated in the reaction mixture. The term "contacting" means reacting, interacting, or physically contacting two species, and may include reacting, interacting, or contacting the two species with the compounds, and proteins or enzymes described herein (e.g., eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway). In some embodiments, contacting includes interacting a compound described herein with a protein or enzyme involved in a signaling pathway (e.g., eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway).

[0068] As used herein, terms such as "inhibit", "inhibiting", "inhibition" with respect to protein-inhibitor (e.g., antagonist) interactions mean having an adverse effect (e.g., reducing) on the activity or function of the protein as compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway, i.e., a signal transmission pathway. Thus, inhibition includes, at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or the enzymatic activity or amount of a protein. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway, i.e., a signal transmission pathway (e.g., the eIF2B, eIF2α, or eIF2 pathway, a pathway activated by phosphorylation of eIF2α, or a component of the ISR pathway). Thus, inhibition may include, at least in part, partially or completely reducing a stimulus, reducing or decreasing activation, or inactivating, desensitizing, or downregulating signal transduction or the enzymatic activity or amount of a protein that is increased in a disease (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway or the ISR pathway, each of which is associated with cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, musculoskeletal disease, or metabolic disease).Inhibition may, at least in part, include reducing the stimulus partially or completely, reducing or decreasing activation, or inactivating, desensitizing, or downregulating the enzymatic activity or amount of a protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway) that can modulate signal transduction or the level of another protein, or increase the cell lifespan (e.g., a decrease in the activity of the phosphorylated eIF2α pathway may increase cell lifespan in cells where the activity of the phosphorylated eIF2α pathway may or may not increase compared to a non-diseased control, or a decrease in the activity of the eIF2α pathway may increase cell lifespan in cells where the activity of the eIF2α pathway may or may not increase compared to a non-diseased control).

[0069] "Activation", "activate", "activating", etc. with respect to protein-activator (e.g., agonist) interactions as defined herein refer to a positive effect (e.g., an increase) on the activity or function of the above-mentioned protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) compared to the activity or function of the above-mentioned protein in the absence of the above-mentioned activator (e.g., a compound described herein). In some embodiments, activation refers to an increase in the activity of a signal transduction pathway, i.e., a signaling pathway (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway). Thus, activation may include increasing a stimulus, at least in part, partially, or completely, increasing or enabling activation, or activating, sensitizing, or upregulating the enzymatic activity or amount of a protein (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway associated with cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, or metabolic disease) that is decreased in signal transduction or disease. Activation may include increasing a stimulus, at least in part, partially, or completely, increasing or enabling activation, or activating, sensitizing, or upregulating the enzymatic activity or amount of a protein (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway) that may regulate the level of signal transduction or another protein, or increase the cell survival period (e.g., an increase in the activity of eIF2α may increase the cell survival period in cells where the activity of eIF2α may or may not be decreased compared to non-diseased controls).

[0070] The term "modulation" refers to an increase or decrease in the level of a target molecule or the function of a target molecule. In some embodiments, modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway may reduce the severity of one or more symptoms of a disease associated with eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway (cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobinopathy, kidney disease, hearing loss, eye disease, musculoskeletal disease, or metabolic disease), or a disease that does not result from but may benefit from modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway (e.g., reducing the level or activity level of a component of eIF2B, eIF2α, or the eIF2 pathway).

[0071] As used herein, the term "modulator" refers to modulation (e.g., increase or decrease) of the level of a target molecule or the function of a target molecule. In embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is an anti-cancer agent. In embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is a neuroprotective agent. In embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is a memory enhancer. In embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is a memory enhancer (e.g., a long-term memory enhancer). In embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is an anti-inflammatory agent. In some embodiments, a modulator of a component of eIF2B, eIF2α, or the eIF2 pathway or the ISR pathway is an analgesic.

[0072] The term "patient" or "subject" in need thereof refers to a living organism that has or is susceptible to a disease or disorder that can be treated by administering the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a pet animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a cow. In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a human newborn. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an aged animal. In some embodiments, the patient is an aged human. In some embodiments, the patient is an elderly patient.

[0073] "Disease", "disorder", or "ailment" refers to a condition or state of health of a patient or subject that can be treated by the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein include, for example, reduction or elimination of one or more symptoms of the above diseases, disorders, or ailments by administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0074] As used herein, the term "signaling pathway" refers to a series of interactions between cellular components and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that convey a change in one component to one or more other components, whereupon the other components may then convey the change to additional components, and the change is optionally propagated to components of other signaling pathways.

[0075] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that assist in the administration of the active agent to a subject and its absorption by the subject, without producing a significant adverse toxicological effect on the patient, and that can be included in the compositions of the present invention. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, lactose, amylose, or carbohydrates such as starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such formulations may be sterilized and, if desired, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffering agents, coloring agents, and / or aromatic substances that do not react with the compounds of the present invention in a harmful manner. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0076] The term "formulation" is intended to include formulations of active compounds having an encapsulating material as a carrier for forming capsules, wherein the active compound is surrounded by the carrier in the capsule, either with or without other carriers, such that the carrier coexists with the active compound. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0077] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject. Administration can be by any route including parenteral and transmucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intracerebroventricular, and intracranial administration. Other delivery forms include, but are not limited to, use of liposomal formulations, intravenous infusion, transdermal patches, etc. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., an anti-cancer agent, a chemotherapeutic agent, or a therapeutic agent for a neurodegenerative disease). The compounds of the invention may be administered alone or co-administered to the patient. Co-administration is intended to include administering the compounds individually or in combination (multiple compounds or agents) simultaneously or sequentially. Thus, the formulations may also, if desired, be combined with other active substances (e.g., to reduce degradation by metabolism).

[0078] As used herein, the term "eIF2B" refers to the heteropentameric eukaryotic translation initiation factor 2B. eIF2B is composed of five subunits: eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. eIF2B1 refers to a protein associated with Entrez Gene 1967, OMIM 606686, Uniprot Q14232, and / or RefSeq (protein) NP_001405. eIF2B2 refers to a protein associated with Entrez Gene 8892, OMIM 606454, Uniprot P49770, and / or RefSeq (protein) NP_055054. eIF2B3 refers to a protein associated with Entrez Gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to a protein associated with Entrez Gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945. eIF2B5 refers to a protein associated with Entrez Gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq (protein) NP_003898.

[0079] The terms "eIF2 alpha", "eIF2a", or "eIF2α" are synonymous and refer to the protein "eukaryotic translation initiation factor 2 alpha subunit eIF2S1". In embodiments, "eIF2 alpha", "eIF2a", or "eIF2α" refers to the above human protein. "eIF2 alpha", "eIF2a", or "eIF2α" includes wild-type and mutant forms of the protein. In embodiments, "eIF2 alpha", "eIF2a", or "eIF2α" refers to a protein associated with Entrez Gene 1965, OMIM 603907, UniProt P05198, and / or RefSeq (protein) NP_004085. In embodiments, the immediately preceding reference numbers refer to the protein and related nucleic acids known as of the filing date of the present application.

[0080] Compound In one aspect, as used herein, formula (I): A compound represented by TIFF2025081607000029.tif23128, wherein, R 1 is -C(O)-C 1~4 alkyl, -C(O)-O-C 1~4 alkyl, -C(O)-N(R a )-C 1~4 alkyl, -C(O)-C 1~4 alkylene-C 1~4 alkoxy, -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -methylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 alkylene-P(O)(OH) 2 ), -methylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 or -methylene-O-C(O)C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 , -C(O)-O-C1~5 alkylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 ,-C(O)-N(R a )-heteroarylene-C 1~2 alkylene-O-P(O)(OH) 2 ,-P(O)(OH) 2 ,-SO 3 H,-SO 2 NR a R b ,-C(O)-heteroaryl,-C(O)-C 1~5 alkylene-O-C 1~5 alkylene-phenyl,and methylene-C 1~5 selected from the group consisting of alkoxides, provided that,-C(O)-C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a R b and -CO 2 H,and -C(O)-O-C 1~4 alkyl,-C(O)-N(R a )-C 1~4 alkyl,-C(O)-C 1~4 alkylene-C 1~4 alkoxy,-C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy,methylene-O-P(O)(OH) 2 ,-C(O)-C 1~5 alkylene-O-P(O)(OH) 2 ,-C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 ,-C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 ,-C(O)-C 1~5 alkylene-P(O)(OH) 2 ,-C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 ,-C(O)-C 1~5Alkylene-phenylene-(O-P(O)(OH) 2 ) 2 、-C(O)-C 1~5 Alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 Alkylene-P(O)(OH) 2 )、-Methylene-O-C(O)C 1~5 Alkylene-phenylene-O-P(O)(OH) 2 Or -Methylene-O-C(O)C 1~5 Alkylene-phenylene-(O-P(O)(OH) 2 ) 2 、-C(O)-O-C 1~5 Alkylene-O-C(O)C 1~5 Alkylene-phenylene-O-P(O)(OH) 2 、-C(O)-Heteroaryl、-C(O)-C 1~5 Alkylene-O-C 1~5 Alkylene-phenyl, and -C(O)-N(R a )-Heteroarylene-C 1~2 Alkylene-O-P(O)(OH) 2 Is each independently selected from the group consisting of halogen, -CO 2 H, -NR a R b 、C 1~2 Alkyl (optionally substituted with 1, 2, or 3 fluorines), and aryl, and may be optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of R a And R b Are each independently selected from the group consisting of hydrogen and C 1~3 Alkyl The above compound, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is provided.

[0081] In some embodiments, R 1 Are each independently -NR a R b And -CO 2-C(O)-C substituted with one or two substituents selected from the group consisting of H 1~4 is alkyl.

[0082] In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000030.tif17128.

[0083] In some embodiments, R 1 is -C(O)-O-C 1~4 alkyl. In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000031.tif11128.

[0084] In some embodiments, R 1 is one or two -CO 2 H groups, optionally substituted -C(O)-N(R a )-C 1~4 alkyl. In some embodiments, R 1 is represented by TIFF2025081607000032.tif22128.

[0085] In some embodiments, R 1 is -C(O)-C 1~4 alkylene-C 1~4 alkoxy. In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000033.tif11128.

[0086] In some embodiments, R 1 is -C(O)-C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy. In some embodiments, R 1 is It is represented by TIFF2025081607000034.tif10128.

[0087] In some embodiments, R 1 is -methylene-O-P(O)(OH) 2 In some embodiments, R 1 is It is represented by TIFF2025081607000035.tif13128.

[0088] In some embodiments, R 1 is -C(O)-C 1~5 alkylene-O-P(O)(OH) 2 In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000036.tif16144.

[0089] In some embodiments, R 1 is -C(O)-O-C 1~5 alkylene-O-P(O)(OH) 2 In some embodiments, R 1 is, selected from the group consisting of TIFF2025081607000037.tif15128.

[0090] In some embodiments, R 1 is -C(O)-N(R a )-C 1~5 alkylene-O-P(O)(OH) 2 In some embodiments, R 1 is, selected from the group consisting of TIFF2025081607000038.tif15128

[0091] In some embodiments, R 1 is -C(O)-C 1~5 alkylene-P(O)(OH) 2 In some embodiments, R 1is represented by TIFF2025081607000039.tif13128.

[0092] In some embodiments, R 1 is -C(O)-C 1~5 alkylene-phenylene-O-P(O)(OH) 2 or -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 or -C(O)-C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 )(O-C 1~5 alkylene-P(O)(OH) 2 ) In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000040.tif48131.

[0093] In some embodiments, R 1 is -C(O)-N(R a )-heteroarylene-C 1~2 alkylene-O-P(O)(OH) 2 In some embodiments, R 1 is represented by TIFF2025081607000041.tif21128.

[0094] In some embodiments, R 1 is -C(O)-heteroaryl. In some embodiments, R 1 is selected from the group consisting of TIFF2025081607000042.tif17128.

[0095] In some embodiments, R 1 is -C(O)-C 1~5 alkylene-O-C 1~5 alkylene-phenyl. In some embodiments, R 1 is It is represented by TIFF2025081607000043.tif12128.

[0096] In some embodiments, R 1 is methylene-C 1~5 alkoxide. In some embodiments, R 1 is represented by TIFF2025081607000044.tif5128.

[0097] In some embodiments, R 1 is -C(O)-O-C 1~5 alkylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , -methylene-O-C(O)C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , or -methylene-O-C(O)C 1~5 alkylene-phenylene-(O-P(O)(OH) 2 ) 2 . In some embodiments, R 1 is represented by TIFF2025081607000045.tif30156.

[0098] In some embodiments, R 1 is -P(O)(OH) 2 , -SO 3 H, and -SO 2 NH 2 selected from the group consisting of.

[0099] In some embodiments, the compound of formula (I) is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof.

[0100] (Table 1) Exemplary compounds of the present invention TIFF2025081607000046.tif40155TIFF2025081607000047.tif219155TIFF2025081607000048.tif203155TIFF2025081607000049.tif202155TIFF2025081607000050.tif131155

[0101] Method for producing exemplary compounds The compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods that illustrate the means by which the compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in Schemes 1-5. The variable elements R 1 、R a 、and R b are defined herein as detailed, for example, in the summary of the invention.

[0102] Scheme 1: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF2025081607000051.tif98151As shown in Scheme 1, the compounds of formula (1-3), formula (1-5), and formula (1-7) can be prepared from the compound of formula (1-1).

[0103] The compound of formula (1-1) is optionally heated in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethane, but not limited thereto, in the presence of an acetonitrile solution of 1H-tetrazole, and reacted with a phosphoramidite of formula (1-2) (wherein PG 1 is a protecting group such as t-butyl or optionally substituted benzyl). Subsequently, the phosphorus moiety is oxidized by treatment with an oxidizing agent such as hydrogen peroxide. Then the protecting group PG 1It can be removed using conditions known to those skilled in the art and depending on the individual protecting groups. For example, a benzyl protecting group can be removed by treatment with catalytic hydrogenation or treatment with an acid such as, but not limited to, trifluoroacetic acid, to give the compound of formula (1-3). In the case of a t-butyl protecting group, treatment with trifluoroacetic acid in a solvent such as dichloromethane gives the compound of formula (1-3). The compound of formula (1-3) is a representative compound of formula (I).

[0104] The compound of formula (1-1) can be reacted with chloroformate C of formula (1-4) in optionally warmed pyridine to give the compound of formula (1-5). The compound of formula (1-5) is a representative compound of formula (I). 1~3 The compound of formula (1-5) is a representative compound of formula (I).

[0105] The compound of formula (1-1) is reacted with a compound of formula (1-6) (wherein R 1-a is OH or NR a R b and when R 1-a is OH, in a solvent such as dichloromethane, and when R 1-a is NR a R b in a solvent such as N,N-dimethylacetamide, to give the compound of formula (1-7). The compound of formula (1-7) is a representative compound of formula (I).

[0106] Scheme 2: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF2025081607000052.tif42145 As shown in Scheme 2, the compound of formula (2-2) can be prepared from the compound of formula (1-1). It is necessary to couple the compound of formula (1-1) with the carboxylic acid of formula (2-1) and then, if necessary, remove the protecting group by deprotection to obtain the compound of formula (2-2). Examples of conditions known for forming an ester from a mixture of the carboxylic acid of formula (2-1) and the alcohol of formula (1-1) include the addition of coupling reagents such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and bis(tetramethylene)fluoroformamidinium hexafluorophosphate, but are not limited thereto. The above coupling reagents can be added as solids, as solutions, or as reagents bound to solid support resins. In addition to the above coupling reagents, auxiliary coupling reagents may accelerate this coupling reaction. Examples of auxiliary coupling reagents commonly used in this coupling reaction include, but are not limited to, (dimethylamino)pyridine (DMAP). This reaction may be carried out optionally in the presence of a base such as triethylamine or N,N-diisopropylethylamine. This coupling reaction can be carried out in a solvent such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethane. This coupling reaction can be carried out at ambient temperature or by heating, and the heating can be carried out conventionally or by microwave irradiation. R 2-a is -C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OPG 1 ) 2 、-C 1~5Alkylene-P(O)(OPG 1 ) 2 , -C 1~5 Alkylene-phenylene-O-P(O)(OPG 1 ) 2 , and -heteroaryl, provided that -C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a PG 2 and -CO 2 H, and -C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OPG 1 ) 2 , -C 1~5 alkylene-P(O)(OPG 1 ) 2 , -C 1~5 alkylene-phenylene-O-P(O)(OPG 1 ) 2 , and -heteroaryl are each independently optionally substituted with one, two, three, or four substituents selected from the group consisting of halogen, -CO 2 H 、 C 1~2 alkyl (optionally substituted with one, two, or three fluorines), and aryl. The protecting group PG 1 is as defined in Scheme 1. The protecting group PG 2 is an amine protecting group such as, but not limited to, t-butoxycarbonyl. The protecting groups PG 1 and PG 2 are known to those skilled in the art and can be removed using conditions appropriate for the individual protecting groups. For example, a benzyl protecting group (PG 1 ) can be removed by treatment with catalytic hydrogenation or treatment with an acid such as, but not limited to, trifluoroacetic acid, to give the compound of formula (2-2). A t-butyl protecting group (PG 1) or a t-butoxycarbonyl protecting group (PG 2 ) in the case of treatment with trifluoroacetic acid in a solvent such as dichloromethane, a compound of formula (2-2) is obtained. Coupling or coupling followed by removal of the protecting group gives a compound of formula (2-2), wherein R 2-a is -C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OH) 2 , -C 1~5 alkylene-P(O)(OH) 2 , -C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , and -heteroaryl, provided that -C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a and -CO 2 H, and -C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OH) 2 , -C 1~5 alkylene-P(O)(OH) 2 , -C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , and -heteroaryl are each independently halogen, -CO 2 H 、 C 1~2 alkyl (substituted with 1, 2, or 3 fluorines, optionally substituted), and aryl, and may be optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of. The compound of formula (2-2) is a representative compound of formula (I).

[0107] Scheme 3: Representative Scheme for the Synthesis of Exemplary Compounds of the Present Disclosure TIFF2025081607000053.tif42145 As shown in Scheme 3, the compound of formula (3-2) can be prepared from the compound of formula (1-1). The compound of formula (1-1) is coupled with the carboxylic acid chloride or chloroformate of formula (3-1), and then, if necessary, deprotected to remove the protecting group to obtain the compound of formula (3-2). The above carboxylic acid chloride can be obtained from a commercial source or from the corresponding carboxylic acid by treatment with oxalyl chloride and a catalytic amount of N,N-dimethylformamide, thionyl chloride, cyanuric chloride, PCl 3 , or PCl 5 . Examples of conditions known to produce esters or carbonates from a mixture of the carboxylic acid chloride or chloroformate of formula (3-1) and the alcohol of formula (1-1) include the addition of a base such as triethylamine or N,N-diisopropylethylamine, and optionally an auxiliary coupling reagent such as, but not limited to, (dimethylamino)pyridine (DMAP). This coupling reaction can be carried out in a solvent such as, but not limited to, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethane. R 3-a is -C 1~4 alkyl, -O-C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OH) 2 , -C 1~5 alkylene-O-P(O)(OPG 1 ) 2 , -O-C 1~5 alkylene-O-P(O)(OPG 1 ) 2 , -C 1~5Alkylene-P(O)(OPG 1 ) 2 , -C 1~5 Alkylene-phenylene-O-P(O)(OPG 1 ) 2 , and -heteroaryl, provided that -C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of -NR a PG 2 and -CO 2 H, -O-C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OH) 2 , -C 1~5 alkylene-O-P(O)(OPG 1 ) 2 , -O-C 1~5 alkylene-O-P(O)(OPG 1 ) 2 , -C 1~5 alkylene-P(O)(OPG 1 ) 2 , -C 1~5 alkylene-phenylene-O-P(O)(OPG 1 ) 2 , and heteroaryl is each independently optionally substituted with one, two, three, or four substituents selected from the group consisting of halogen, -CO 2 H, -NR a R b , C 1~2 alkyl (optionally substituted with one, two, or three fluorines), and aryl. The protecting group PG 1 is as defined in Scheme 1, and the protecting group PG 2 is defined in Scheme 2. The protecting groups PG 1 and PG 2As described in the above scheme, it is known to those skilled in the art and can be removed using conditions according to individual protecting groups. Coupling or coupling and subsequently removing the protecting group gives a compound of formula (3-2), wherein R 3-a is, each being optionally substituted as described above, -C 1~4 alkyl, -O-C 1~4 alkyl, -C 1~4 alkylene-C 1~4 alkoxy, -C 1~4 alkylene-O-C 1~4 alkylene-C 1~4 alkoxy, -C 1~5 alkylene-O-P(O)(OH) 2 , -O-C 1~5 alkylene-O-P(O)(OH) 2 , -C 1~5 alkylene-P(O)(OH) 2 , -C 1~5 alkylene-phenylene-O-P(O)(OH) 2 , and -heteroaryl. In some examples, the esters or carbonates formed by the above coupling may be further modified using methods known to those skilled in the art. The compound of formula (3-2) is a representative compound of formula (I).

[0108] Scheme 4: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF2025081607000054.tif108153 As shown in Scheme 4, the compound of formula (4-2) can be prepared from the compound of formula (1-1). The compound of formula (1-1) is reacted with triphosgene or N,N'-disuccinimidyl carbonate in optionally pyridine or a mixture of pyridine and dichloromethane to obtain a compound of formula (4-1). The compound of formula (4-1) is reacted in a solvent such as tetrahydrofuran or ethyl acetate in the presence of an optionally base such as triethylamine or N,N-diisopropylethylamine or sodium bicarbonate, and an optionally auxiliary coupling reagent such as (dimethylamino)pyridine (DMAP), but not limited thereto, with a nucleophile R4-b -X 1 -H (wherein X 1 is O or NR a and R 4-b is C 1~4 alkyl, -C 1~5 alkylene - O - P(O)(OPG 1 ) 2 , - heteroarylene - C 1~2 alkylene - O - P(O)(OPG 1 ) 2 wherein, -C 1~4 alkyl is each independently substituted with one or two substituents selected from the group consisting of bromine and -CO 2 H), and can be reacted with. The protecting group PG 1 , when present, is known to those skilled in the art as described in Scheme 1 and can be removed using conditions according to the individual protecting groups. In some examples, the carbonates or carbamates formed by the above coupling may be further modified using methods known to those skilled in the art. For example, when R 4-b is alkyl bromide, bromine can be substituted in a nucleophilic substitution reaction. The compound of formula (4 - 2) is a representative compound of formula (I), wherein R 4-c is -C 1~4 alkyl, -C 1~5 alkylene - O - P(O)(OH) 2 , - heteroarylene - C 1~2 alkylene - O - P(O)(OH) 2 wherein, -C 1~4 alkyl is substituted with one or two -CO 2 H. The compound of formula (4 - 2) is a representative compound of formula (I).

[0109] Scheme 5: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF2025081607000055.tif As shown in Scheme 5, the compounds of formula (5-2) and formula (5-3) can be prepared from the compound of formula (1-1). The compound of formula (1-1) can be reacted with chloromethyl methyl sulfide in a solvent such as tetrahydrofuran in the presence of a base such as iodine and sodium hydride to obtain the compound of formula (5-1). The compound of formula (5-1) is first treated with solid H 3 PO 4 and activated 5 Å molecular sieves, and then treated with N-iodosuccinimide to obtain the compound of formula (5-2). Alternatively, the compound of formula (5-1) is first treated with solid H 3 PO 4 and activated 5 Å molecular sieves, then with N-iodosuccinimide, and subsequently treated with C 1~5 alcohol to obtain the compound of formula (5-3). The compounds of formula (5-2) and formula (5-3) are representative compounds of formula (I).

[0110] Pharmaceutical composition The present invention features a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, 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 a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is provided in an effective amount in the above pharmaceutical composition. In some embodiments, the above effective amount is a therapeutically effective amount. In certain embodiments, the above effective amount is a prophylactically effective amount.

[0111] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such a preparation method involves combining a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof (the "active ingredient") with a carrier and / or one or more auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dose units. The pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit doses, and / or as multiple single unit doses. As used herein, a "unit dose" is an individual quantity of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that is considered to be administered to the subject and / or a convenient fraction of such a dosage (e.g., half or one-third of such a dosage).

[0112] The relative amounts of the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, a pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions of the present invention will vary depending on the identity, profile, and / or condition of the subject to be treated, and also depending on the route used to administer the composition. By way of example, the composition can contain from 0.1% to 100% (w / w) of the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

[0113] 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 formulated therewith. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the present invention are any excipients well known in the field of pharmaceutical formulations and include inert diluents, dispersing agents and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0114] The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. In some embodiments, the compounds or compositions provided are administrable intravenously and / or orally.

[0115] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intramedullary, intraliver, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Also, the sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil has conventionally been used as a solvent or suspending medium.

[0116] The pharmaceutically acceptable compositions of the present invention can be administered orally 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, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Optionally, certain sweetening, flavoring, or coloring agents may be added. In some embodiments, the oral formulations provided are formulated for immediate release or extended release / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration including tablets, lozenges, and troches. The compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, may be in microencapsulated form.

[0117] The composition of the present invention can be delivered transdermally, via a topical route, and can be formulated as an applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, coating agent, powder, and aerosol. Oral formulations include tablets, pills, powders, dragees, capsules, solutions, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by patients. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water / propylene glycol solutions. The composition of the present invention can additionally contain components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimicking polymers, gelling polysaccharides, and micronized drug carrier matrices. These components are discussed in more detail in U.S. Pat. Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are hereby incorporated by reference in their entirety for all purposes. The composition of the present invention can also be delivered as microspheres for sustained release in the body. For example, microspheres can be delivered via intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable injectable gel formulations (e.g., see Gao, Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (e.g., see Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulation of the composition of the present invention can be delivered by the use of liposomes that fuse with or are phagocytosed by cell membranes, and phagocytosis is brought about, i.e., by using a receptor ligand bound to the liposome, as a result of the binding of the ligand to the surface membrane protein receptor of the cell.By using liposomes, the compositions of the present invention can be focused on delivering to target cells in vivo, especially when the liposome surface bears receptor ligands specific for the target cells or is preferentially directed to a particular organ (see, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0118] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target of treatment includes a site or organ that is readily accessible by topical application (including diseases of the eye, skin, or lower intestinal tract). Suitable topical formulations can be readily prepared for each of such sites or organs.

[0119] In some embodiments, it is often desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to extend the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. In that case, the absorption rate of the drug depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, the absorption delay of a parenterally administered drug form is effected by dissolving or suspending the drug in an oily vehicle.

[0120] The description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are also widely suitable for administration to all kinds of animals. It is well understood that modifications can be made to adapt pharmaceutical compositions suitable for administration to humans to be suitable for administration to various animals, and a veterinary pharmacologist with ordinary skill can design and / or implement such modifications using ordinary experiments.

[0121] The compounds described in this specification, such as the compounds of formula (I), or pharmaceutically acceptable salts, co-crystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof are typically formulated in dosage unit form, e.g., in a single unit dosage form, to facilitate administration and to provide uniform dosage. However, it will be understood that the total daily usage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject or organism will depend upon a variety of factors including the disorder being treated, the severity of the disorder, the activity of the specific active ingredient being employed, the specific composition being utilized, the age, weight, general health status, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion of the specific active ingredient being employed, the duration of the treatment, drugs used in combination with or concurrently with the specific active ingredient being employed, and like factors well known in the medical arts.

[0122] The exact amount of the compound necessary to achieve an effective amount will vary depending on the subject, e.g., the species, age, and general condition of the subject, the severity of the side effects or disorder, what the specific compound(s) is / are, the mode of administration, etc. The desired dosage can be delivered once, twice, or three times daily; every two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve days; once, twice, or three times weekly; every two, three, or 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).

[0123] In certain embodiments, an effective amount for once or more daily administration of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be from about 0.0001 mg to about 5000 mg per unit dosage form, such as, for example, from about 0.0001 mg to about 4000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound.

[0124] In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be at a dosage level sufficient to deliver from about 0.001 mg / kg to about 1000 mg / kg, such as, for example, from about 0.001 mg / kg to about 500 mg / kg, from about 0.01 mg / kg to about 250 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.1 mg / kg to about 25 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, or from about 1 mg / kg to about 50 mg / kg of the subject's body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0125] It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount to be administered to a pediatric or adolescent can be determined by a medical practitioner or one of ordinary skill in the art, and this amount can be less than or the same as the amount administered to an adult.

[0126] Also, it will be understood that a compound or composition, e.g., a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be administered in combination with one or more additional pharmaceutical agents. The above compound or composition may be administered in combination with an additional pharmaceutical agent that improves its bioavailability, reduces and / or modifies its metabolism, inhibits its excretion, and / or modifies its distribution in the body. Also, it will be understood that the therapies used may achieve the desired effect for the same disease and / or may achieve different effects.

[0127] The above compound or composition can be administered simultaneously with, before, or after one or more additional pharmaceutical agents, which can be useful (e.g., as combination therapy). Pharmaceutical agents include therapeutically active agents. Also, pharmaceutical agents include prophylactically active agents. Each additional pharmaceutical agent can be administered at the dosage and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents can be administered together in a single dose, or separately at different doses, with each other and / or with the compounds or compositions described herein. The particular combination used in the regimen takes into account the compatibility of the additional pharmaceutical agents with the compounds of the invention and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the additional pharmaceutical agents used in combination will be used at levels that do not exceed those at which they are used individually. In some embodiments, the levels used in combination are lower than those used individually.

[0128] Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressive agents, and analgesics. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0129] The pharmaceutical compositions provided by the present invention include compositions in which the active ingredient (e.g., the compounds described herein including embodiments or examples) is included in a therapeutically effective amount, i.e., an amount effective to achieve the intended purpose. The actual amount effective for a particular application depends, inter alia, on the condition being treated. When administered in a method for treating a disease, such compositions are effective to achieve a desired result, such as modulation of the activity of a target molecule (e.g., a component of the eIF2B, eIF2, or eIF2α signaling pathway, or a component of the phosphorylated eIF2α pathway or the ISR pathway), and / or reduction, elimination, or delay in the progression of a disease symptom (e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with a dysfunction of a component of the eIF2B, eIF2α, or eIF2 pathway or the ISR pathway), and contain an amount of the active ingredient effective to achieve such. The determination of a therapeutically effective amount for the compounds of the present invention is well within the skill of the art, particularly in view of the detailed disclosure herein.

[0130] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, such as whether the mammal has another disease, and the route of administration; the subject's profile, age, gender, health status, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or the symptoms of a disease or disorder associated with a dysfunction of eIF2B, eIF2α, or a component of the eIF2 or ISR pathway), the type of combination therapy, complications or other health-related problems from the disease being treated. Other treatment regimens or agents can also be used in combination with the methods and compounds of the applicant's invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the skill of the art.

[0131] For any compound described herein, a therapeutically effective amount can first be determined from cell culture assays. The target concentration is the concentration of the active compound(s) capable of achieving the methods described herein, measured using the methods described herein or methods known in the art.

[0132] As is known in the art, a therapeutically effective amount for use in humans can also be determined from animal models. For example, a dosage for humans can be formulated to achieve a concentration found to be effective in animals. The dosage in humans can be adjusted, as described above, by monitoring the effectiveness of the compound and adjusting the dosage up or down. Adjusting the dosage to achieve maximum efficacy in humans, based on the methods described above and other methods, is well within the skill of the art.

[0133] The dosage of the drug can vary depending on the requirements of the patient and the compound being used. In the context of the present invention, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response over time in the patient. Also, the size of the dosage is also determined by the presence, nature, and extent of any adverse side effects. The determination of the appropriate dosage of the drug in a particular situation is within the skill of the art. Generally, treatment is initiated at a dosage of the drug in an amount less than the optimal dosage of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is reached. The dosage and interval can be adjusted individually to provide a level of the compound being administered that is effective for the particular clinical indication being treated. This results in a treatment regimen that is tailored to the severity of the individual's disease state.

[0134] Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and is also effective in treating the clinical symptoms exhibited by a particular patient. This planning should involve a careful selection of the active compound by taking into account factors such as the potency of the compound, relative bioavailability, patient body weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0135] The present invention also encompasses kits (e.g., pharmaceutical packs). The kits of the present invention can be useful for the prevention and / or treatment of diseases (e.g., cancer, neurodegenerative diseases, leukodystrophies, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or other diseases or disorders described herein).

[0136] The provided kit can include the pharmaceutical composition or compound of the present invention and a container (e.g., vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the provided kit can optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the pharmaceutical composition or compound of the present invention provided in the container and the second container are adapted to form one unit dosage form.

[0137] Accordingly, in one aspect, there is provided a kit comprising a first container containing a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit is useful for the prevention and / or treatment of proliferative diseases in a subject. In certain embodiments, the kit further comprises instructions for administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, or a pharmaceutical composition thereof, for the prevention and / or treatment of the diseases described herein.

[0138] Method of treatment The present invention features compounds, compositions, and methods comprising a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, 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 illness. Exemplary diseases, disorders, or illnesses include, but are not limited to, neurodegenerative diseases, leukodystrophies, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss, eye diseases, diseases having mutations leading to UPR induction, malaria infections, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases.

[0139] In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) a modulation (e.g., decrease) of eIF2B activity or level, eIF2α activity or level, or a regulator of a component of the eIF2 pathway or the ISR pathway. In some embodiments, a disease, disorder, or illness is associated with a modulation of a signaling pathway associated with a component of the eIF2 pathway or the ISR pathway (e.g., phosphorylation of a component of the eIF2 pathway or the ISR pathway). In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) neurodegeneration. In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) neuronal cell death or dysfunction. In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) glial cell death or dysfunction. In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) an increase in the level or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway. In some embodiments, a disease, disorder, or illness is associated with (e.g., caused by) a decrease in the level or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

[0140] In some embodiments, the disease can be caused by mutations in genes or protein sequences related to components of the eIF2 pathway (e.g., eIF2B, eIF2α, or other components). Exemplary mutations include amino acid mutations in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in specific proteins that can result in structural changes (e.g., conformational or steric changes) that affect the function of the protein. For example, in some embodiments, amino acids in and around the active site, or in the vicinity of a binding site (e.g., a phosphorylation site, a small molecule binding site, or a protein binding site) can be mutated such that the activity of the protein is affected. In some instances, the amino acid mutations (e.g., amino acid substitutions, additions, or deletions) may be conservative and may not substantially affect the structure or function of the protein. For example, in certain cases, substituting a serine residue with a threonine residue may not have a significant impact on the function of the protein. In other cases, the amino acid mutations may be more dramatic, such as substituting a charged amino acid (e.g., aspartic acid or lysine) with a large nonpolar amino acid (e.g., phenylalanine or tryptophan), and thus may have a substantial impact on protein function. The nature of the mutations that affect the structure of the function of a gene or protein can be readily identified using standard sequencing techniques (e.g., deep sequencing techniques well known in the art). In some embodiments, mutations in components of the eIF2 pathway affect the binding or activity of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, and thus can modulate the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0141] In some embodiments, the eIF2 protein can include an amino acid variation (e.g., an amino acid substitution, addition, or deletion) at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein can include an amino acid substitution at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein can include an amino acid addition at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein can include 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.

[0142] In some embodiments, the eIF2 protein may include amino acid mutations (e.g., amino acid substitutions, additions, or deletions) at alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues within the eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. In some embodiments, the eIF2 protein may include amino acid substitutions at alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues within the eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. In some embodiments, the eIF2 protein may include amino acid additions at alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues within the eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. In some embodiments, the eIF2 protein may include amino acid deletions at alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues within the eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. Exemplary mutations include V183F (eIF2B1 subunit), H341Q (eIF2B3), I346T (eIF2B3), R483W (eIF2B4), R113H (eIF2B5), and R195H (eIF2B5).

[0143] In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in components of the eIF2 pathway (e.g., eIF2B protein subunits) affect the binding or activity of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, and thus can modulate the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0144] Neurodegenerative disease In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating neurodegenerative diseases. As used herein, the term "neurodegenerative disease" refers to a disease or disorder in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases that can be treated using the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Kuru disease, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple system proteinopathy, narcolepsy, neurosyphilis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with various features, such as spinocerebellar ataxia type 2 or spinocerebellar ataxia type 8), spinal muscular atrophy, Steele-Richardson-Olszewski syndrome, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzbächer disease, Krabbe disease, leukodystrophy due to mutations in the DARS2 gene (optionally, known as leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL)), DARS2-related spectrum disorder, or spinal cord gangrene.

[0145] In some embodiments, the neurodegenerative disease includes leukoencephalopathy, ataxia-telangiectasia, leukodystrophy, leukoencephalopathy, hypomyelination or demyelinating disease, 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 disease, multiple sclerosis, Parkinson's disease, or prion disease.

[0146] In some embodiments, the neurodegenerative disease includes leukoencephalopathy, ataxia-telangiectasia, leukodystrophy, leukoencephalopathy, hypomyelination or demyelinating disease, or intellectual disability syndrome (e.g., fragile X syndrome).

[0147] In some embodiments, the neurodegenerative disease includes mental disorders such as agoraphobia, Alzheimer's disease, anorexia nervosa, amnesia, anxiety disorder, attention deficit disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, delusion, Diogenes syndrome, movement disorder, insomnia, Münchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, mental disorder, phobic disorder, schizophrenia, seasonal affective disorder, schizoid personality disorder, sleepwalking disorder, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania.

[0148] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat leukoencephalopathy. Exemplary methods of treating leukoencephalopathy include, but are not limited to, reducing or eliminating symptoms of leukoencephalopathy in a subject, reducing white matter loss, reducing myelin loss, increasing the amount of myelin, or increasing the amount of white matter.

[0149] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating childhood ataxia with central nervous system hypomyelination. Exemplary methods for treating childhood ataxia with central nervous system hypomyelination include, but are not limited to, reducing or eliminating symptoms of childhood ataxia with central nervous system hypomyelination in a subject, increasing myelin levels, or decreasing myelin loss.

[0150] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating an intellectual disability syndrome (such as, for example, fragile X syndrome). Exemplary methods for treating an intellectual disability syndrome include, but are not limited to, reducing or eliminating symptoms of the intellectual disability syndrome.

[0151] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating neurodegeneration. Exemplary methods for treating neurodegeneration include, but are not limited to, improving mental health, increasing mental function, slowing mental function decline, reducing dementia, delaying dementia onset, improving cognitive ability, reducing cognitive ability loss, improving memory, reducing memory decline, or extending lifespan.

[0152] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat leukodystrophy or demyelinating disease. Exemplary leukodystrophies include, but are not limited to, progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with vanishing white matter, leukoencephalopathy with axonal spheroids, reversible posterior leukoencephalopathy syndrome, hypertensive leukoencephalopathy, megalencephalic leukoencephalopathy with subcortical cysts, Charcot-Marie-Tooth disorder, and Devic's disease. Leukodystrophy may include demyelinating disease, which can be either hereditary or acquired. In some embodiments, the acquired demyelinating disease can 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 leukodystrophy or demyelinating disease include, but are not limited to, reducing or eliminating symptoms of leukodystrophy or demyelinating disease in a subject, reducing myelin loss, increasing the amount of myelin, reducing white matter loss in a subject, or increasing the amount of white matter.

[0153] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat traumatic or toxin-induced injury to the nervous system (e.g., the brain). Exemplary traumatic brain injuries include, but are not limited to, brain abscess, concussion, ischemia, cerebral hemorrhage, skull fracture, diffuse axonal injury, closed head syndrome, or injury related to traumatic force or impact 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), Guillain-Barré syndrome, Sydenham chorea, rabies, leprosy, neurosyphilis, prion disease, or exposure to a chemical substance (e.g., arsenic, lead, toluene, ethanol, manganese, fluoride, dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), tetrachloroethylene, polybrominated diphenyl ether, pesticides, sodium channel inhibitors, potassium channel inhibitors, chloride channel inhibitors, calcium channel inhibitors, or blood-brain barrier inhibitors).

[0154] In other embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to improve memory in a subject. Memory induction has been shown to be facilitated by a decrease in eIF2α phosphorylation and impaired by an increase in eIF2α phosphorylation. Translation regulators such as the compounds disclosed herein (e.g., compounds of formula (I)) are thought to act as therapeutic agents for improving memory in human disorders associated with memory loss such as Alzheimer's disease, and memory in other neurological disorders that can have an adverse effect on memory fixation to activate the UPR or ISR within neurons, such as Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), and prion diseases. In addition, mutations in eIF2γ that disrupt the integrity of the complex have been associated in humans with intellectual disability (intellectual disability syndrome or ID) related to defects in translation initiation. Thus, two disorders with defects in eIF2 function, ID and VWM, exhibit distinct phenotypes but both primarily affect the brain and impair learning. In some embodiments, the disorder or disease is insufficient memory (e.g., working memory, long-term memory, short-term memory, or memory fixation).

[0155] In yet other embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used in a method for improving memory (e.g., working memory, long-term memory, short-term memory, or memory fixation) in a subject. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domestic animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a bird. In some embodiments, the subject is a horse. In embodiments, the patient is a cow. In some embodiments, the subject is a primate.

[0156] Cancer In some embodiments, the compounds disclosed herein, e.g., compounds of formula (I), formula (II), or formula (III), are used for treating cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc., and cancers include solid and lymphatic cancers, cancers of the kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver (including hepatocellular carcinoma), lymphomas (including acute B lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt, small cell, and large cell lymphoma), Hodgkin lymphoma), leukemias (including AML, ALL, and CML), and / or multiple myeloma. Further in some additional cases, "cancer" refers to lung cancer, breast cancer, ovarian cancer, ovarian epithelial cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, cancer of the oral cavity or pharynx, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of hematological tissues, small intestine cancer or appendiceal 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.

[0157] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated using the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenström macroglobulinemia, benign monoclonal gammopathy, 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 cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid tumor, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, epithelioma, oligodendroglioma, meningioma, glioma, or melanoma. Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urothelial cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0158] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs, generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease (acute or chronic), (2) the cell type involved: myeloid (myelogenous), lymphoid (lymphoblastic), or monocytic, and (3) the presence or absence of an increased number of abnormal cells in leukemic or non-leukemic (sub-leukemic) blood. Exemplary leukemias that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute non-lymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia, hairy cell leukemia, erythroblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphoblastic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelocytic granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, sub-leukemic leukemia, or undifferentiated cell leukemia.

[0159] The term "sarcoma" generally refers to tumors composed of substances such as fetal connective tissue and is generally composed of densely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated using the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanoma, myxosarcoma, osteosarcoma, avanecy sarcoma, liposarcoma, lipoma, alveolar soft part sarcoma, ameloblastic sarcoma, sarcoma botryoides, chloroma, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, endotheliosarcoma, interstitial sarcoma, Ewing sarcoma, fasciitis sarcoma, fibroblast sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen sarcoma, Kaposi sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, osteosarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0160] The term "melanoma" is interpreted to mean tumors arising from the melanocyte system of the skin and other organs. Melanomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigo-derived melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0161] The term "cancer" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary cancers that can be treated using the compounds, pharmaceutical compositions, or methods described herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, bronchioloalveolar carcinoma, bronchioloalveolar cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cervical cancer, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, colloid carcinoma, colon cancer, comedocarcinoma, corpus cancer, cribriform carcinoma, scirrhous carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, medullary carcinoma, endometroid carcinoma, epidermoid carcinoma, epithelial carcinoma, adenocarcinoma, exophytic carcinoma, ulcerating carcinoma, fibrosarcoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, adenocarcinoma, granulosa cell carcinoma, trichoblastoma, sarcoma, hepatocellular carcinoma, hepatoma, Hurthle cell carcinoma, hyaline carcinoma, adrenocortical carcinoma, pediatric embryonal carcinoma, intraepithelial carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, chromophobe carcinoma, Kultschitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, liposarcoma-like carcinoma, lobular carcinoma, lung cancer, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucin-secreting carcinoma, mucinous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucosal carcinoma, myxosarcoma-like carcinoma, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, osteoidcarcinoma), ovarian cancer, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, acanthocytic carcinoma, encephaloid carcinoma, renal cell carcinoma of the kidney, residual cell carcinoma, sarcomatoid carcinoma, Schnyder carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous gland carcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, valerianoid carcinoma, globular cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, squamous cell carcinoma, bead-like carcinoma, angiiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, undifferentiated carcinoma, verrucous carcinoma, or villous carcinoma.

[0162] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat pancreatic cancer, breast cancer, multiple myeloma, cancer of secretory cells. For example, certain methods herein treat cancer by reducing or decreasing or preventing the occurrence, growth, metastasis, or progression of cancer. In some embodiments, the methods described herein can be used to treat cancer by reducing or eliminating the symptoms of cancer. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof can be used as a single agent in a composition or in combination with another agent in a composition to treat the cancers described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, cancer of secretory cells).

[0163] In some embodiments, the compounds (compounds described herein, e.g., compounds of formula (I)) and compositions (e.g., compositions comprising a compound described herein, e.g., a compound of formula (I)) are used in combination with cancer immunotherapies (e.g., checkpoint blockade antibodies) to treat a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer described herein)). The methods described herein involve administering a compound described herein, e.g., a compound of formula (I), and an immunotherapy to a subject having abnormal cell growth such as cancer. Exemplary immunotherapies include, but are not limited to, the following.

[0164] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits an 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 activates the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. The three groups of immunotherapies used to treat cancer include cell-based therapies, antibody-based therapies, and cytokine therapies. All groups utilize the presentation of slightly different structures (e.g., molecular structures; antigens, proteins, molecules, carbohydrates) on the surface of cancer cells that can be detected by the immune system. Cancer immunotherapies (i.e., antitumor immunotherapies or anti-tumor immunotherapies) include, but are not limited to, immune checkpoint antibodies (e.g., PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, TIGIT antibody); and cancer vaccines (i.e., antitumor vaccines, or vaccines based on neoantigens such as peptide or RNA vaccines).

[0165] Cell-based therapies (e.g., cancer vaccines) typically involve the removal of immune cells from a subject with cancer, either from the blood or the tumor. Tumor-specific immune cells are activated, grown, and returned to the subject with cancer, where the immune cells elicit an immune response against the cancer within the subject. Cell types that can be used in this method include, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapy (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 CAR-T therapy.

[0166] Interleukin-2 and interferon-alpha are examples of proteins, cytokines, that regulate and coordinate the behavior of the immune system.

[0167] Cancer vaccines using neoantigens Neoantigens are antigens encoded by tumor-specific mutant genes. Technological innovations have made it possible to examine immune responses against patient-specific neoantigens resulting from tumor-specific mutations, and the data being obtained suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapy. Such findings indicate that neoantigen load may form a biomarker in cancer immunotherapy. Many new therapeutic approaches have been developed to selectively enhance the reactivity of T cells against this class of antigens. One approach to targeting neoantigens is via cancer vaccines. These vaccines can be developed using peptides or RNA, e.g., synthetic peptides or synthetic RNA.

[0168] Antibody therapy involves antibody proteins produced by the immune system that bind to target antigens on the cell surface. Antibodies are typically encoded by immunoglobulin gene(s), or fragments thereof. In normal physiological functions, antibodies are used by the immune system to fight pathogens. Each antibody is specific for one or several proteins, and antibodies that bind to cancer antigens are used, for example, in the treatment of cancer. Antibodies can specifically bind to an antigen or an 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 biologic agents. Specific binding of an antibody is shown by binding to the target antigen or epitope with a considerably higher affinity than binding to unrelated antigens. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, and most often at least 100% greater. The relative difference can be, for example, at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least -fold, at least 50-fold, at least 100-fold, or at least 1000-fold.

[0169] Exemplary types of antibodies include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single-chain, antibody binding fragments, and diabodies. Once an antibody binds to a cancer antigen, it can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand, or deliver a chemotherapy or radiation payload, all of which can lead to cell death. Exemplary antibodies for treating cancer include, but are not limited to, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, nivolumab, pembrolizumab, avelumab, durvalumab, and pidilizumab.

[0170] Checkpoint blockade antibody The methods described herein, in some embodiments, include treating a human subject having 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 an antibody) that inhibits an immune checkpoint blockade pathway. Immune checkpoint proteins maintain self-tolerance under normal physiological conditions (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding to, for example, a 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 (e.g., immune checkpoint proteins) or antagonists of inhibitory signals result in amplification of antigen-specific T cell responses. Antibodies that block immune checkpoints do not directly target tumor cells and typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0171] Exemplary checkpoint blockade antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (i.e., an antibody against lymphocyte activation gene 3), and anti-TIM3 (i.e., an antibody 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). 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. Also, exemplary checkpoint blockade antibodies include, but are not limited to, IMP321 and MGA271.

[0172] Furthermore, regulatory T cells (e.g., CD4+, CD25+, or T-reg) are also involved in the discrimination between self-antigens and non-self (e.g., foreign) antigens and may correspond to an important mechanism for suppressing the immune response in many cancers. T-reg cells may develop from the thymus (i.e., "natural T-reg") or may differentiate from mature T cells under conditions of peripheral tolerance induction (i.e., "induced T-reg"). Therefore, a strategy to minimize the action of T-reg cells is expected to promote the immune response against tumors. (Sutmuller, van Duivernvoorde et al., 2001)

[0173] IDO pathway inhibitor The IDO pathway regulates the 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, consequently, the mobilization of antigen-specific T cell energy and regulatory T cells. Some tumors even express IDO to shield themselves from the immune system. Compounds that inhibit IDO or the IDO pathway, thereby activating the immune system to attack cancer (e.g., tumors in a subject). Exemplary IDO pathway inhibitors include indoximod, epacadostat, and EOS200271.

[0174] STING pathway agonist Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytoplasmic nucleic acid ligands. Evidence has shown the involvement of the STING pathway in the induction of anti-tumor immune responses. Activation of the STING-dependent pathway in cancer cells has been shown to result in tumor infiltration by immune cells and the regulation of anti-cancer immune responses. STING agonists are being developed as a type of cancer therapeutic agent. Exemplary STING agonists include MK-1454 and ADU-S100.

[0175] Costimulatory antibody In some embodiments, the methods described herein include treating a human subject suffering from a disease or disorder described herein, the method including administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a costimulatory inhibitor or antibody. In some embodiments, the methods described herein include depleting or activating anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, and anti-CD40, and variants thereof.

[0176] The method of the present invention contemplates single and multiple administrations of a therapeutically effective amount of a compound as described herein. The compound, for example, a compound as described herein, can be administered at regular intervals depending on the nature, severity, and extent of the disease of the subject. In some embodiments, the compounds described herein are administered as a single dose. In some embodiments, the compounds described herein are administered as multiple doses.

[0177] Inflammatory disease In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating an inflammatory disease. As used herein, the term "inflammatory disease" refers to a disease or disorder characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control such as a healthy subject not suffering from the disease). Examples of inflammatory diseases include postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet'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., abnormal expression of which is a symptom or cause or marker of the disease) include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), TNF-α (tumor necrosis factor-alpha), and C-reactive protein (CRP).

[0178] In some embodiments, the inflammatory disease includes postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, 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.

[0179] In some embodiments, the inflammatory disease includes postoperative cognitive impairment, which refers to a decline in postoperative cognitive function (e.g., memory or executive function (e.g., working memory, reasoning, flexibility in tasks, processing speed, or problem-solving)).

[0180] In other embodiments, the method of treatment is a method of prevention. For example, a method of treating postoperative cognitive impairment may include preventing postoperative cognitive impairment or symptoms of postoperative cognitive impairment, or reducing the severity of symptoms of postoperative cognitive impairment, by administering a compound described herein before surgery.

[0181] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat an inflammatory disease (e.g., an inflammatory disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can 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).

[0182] Musculoskeletal disorders In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating a musculoskeletal disorder. As used herein, the term "musculoskeletal disorder" refers to a disease or disorder in which the function of the subject's musculoskeletal system (e.g., muscle, ligament, tendon, cartilage, or bone) is impaired. Exemplary musculoskeletal diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, or myotonic dystrophy type 2), limb-girdle muscular dystrophy, multi-system proteinopathy, rhizomelic chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-Hünermann 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 bulbar spinal muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, Paget's disease of bone, myospasm-fasciculation syndrome, Friedreich's ataxia, muscle wasting disorders (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

[0183] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat a musculoskeletal disorder (e.g., a musculoskeletal disorder described herein) by reducing or eliminating the symptoms of the disorder. In some embodiments, the method of treatment includes treating muscle pain or muscle stiffness associated with a musculoskeletal disorder. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof can be used as a single agent in a composition or in combination with another agent in a composition to treat a musculoskeletal disorder (e.g., a musculoskeletal disorder described herein).

[0184] Metabolic disorder In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat a metabolic disorder. As used herein, the term "metabolic disorder" refers to a disease or disorder that affects the metabolic processes in a subject. Exemplary metabolic disorders that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof include 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.

[0185] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat a metabolic disorder (e.g., a metabolic disorder described herein) by reducing or eliminating the symptoms of the disorder. In some embodiments, the method of treatment includes reducing or eliminating symptoms including hypertension, hyperglycemia, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition to treat a metabolic disorder (e.g., a musculoskeletal disorder described herein).

[0186] Mitochondrial disease In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat a mitochondrial disease. As used herein, the term "mitochondrial disease" refers to a disease or disorder that affects the mitochondria in a subject. In some embodiments, the mitochondrial disease is associated with, a result of, or caused by mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations. In some embodiments, the mitochondrial disease is mitochondrial myopathy. In some embodiments, mitochondrial diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, such as mitochondrial myopathy, include, for example, Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome.

[0187] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat a mitochondrial disease described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can 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.

[0188] Hearing loss In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, 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 disorder” broadly encompasses any damage to the auditory system, auditory organs, and auditory cells, or any impairment of the ability of an animal subject to hear sounds, as measured by standard methods and assessments known in the art, such as otoacoustic emission testing, pure tone testing, and auditory brainstem response testing. Exemplary hearing loss disorders that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, 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 hereditary hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss due to disease, and hearing loss due to trauma. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness are MT-RNR1-related hearing loss. In some embodiments, MT-RNR1-related hearing loss is the result of aminoglycoside ototoxicity. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness are MT-TS1-related hearing loss. In some embodiments, mitochondrial nonsyndromic hearing loss and deafness are characterized by sensorineural hearing loss.

[0189] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the hearing loss disorders described herein by reducing or eliminating the symptoms of the disorder. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition for treating the hearing loss disorders described herein.

[0190] Eye diseases In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat eye diseases. As used herein, the term "eye disease" can refer to a disease or disorder in which the function of the subject's eye is impaired. Exemplary eye diseases and disorders that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0191] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the eye diseases or disorders described herein by reducing or eliminating the symptoms of the disorder. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition for treating the eye diseases or disorders described herein.

[0192] Kidney diseases In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating renal diseases. As used herein, the term "renal disease" can refer to a disease or disorder in which the function of the subject's kidney is impaired. Exemplary renal diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include Abdelhalden-Kaufmann-Lignac syndrome (nephrotic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephronia, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenoviral nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa and renal diseases, angiotensin antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-related glomerulonephritis, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herb nephropathy, Balkan endemic nephropathy, arteriovenous malformations and fistulas of the urinary tract, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome, Bassolt and acute kidney injury, beer potomania, beeturia, β-thalassemia renal disease, bile cast nephropathy, BK polyomavirus nephropathy in native kidneys, bladder rupture, detrusor-sphincter dyssynergia, bladder tamponade, Border-Crossers nephropathy, Bourbon virus and acute kidney injury, sugarcane bagasse and acute kidney dysfunction, Byetta and renal failure, C1q nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy of undetermined significance, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepsis laureola poisoning, cannabinoid hyperemesis acute renal failure, cardio-renal syndrome, carfilzomib-induced kidney injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathy, Chinese herbs and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, galactosuria, ciliopathy,Cocaine and the kidney, cold diuresis, colistin nephrotoxicity, collagen fibrillary glomerulopathy, collapsing glomerulopathy, CMV-related collapsing glomerulopathy, combination antiretroviral therapy (cART)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, conorenal syndrome (Münzer-Saldino syndrome or Saldino-Münzer disease), contrast-induced nephropathy, copper sulfate poisoning, renal cortical necrosis, crizotinib-related acute kidney injury, crystal cryoglobulinemia, cryoglobulinemia, crystal globulin-induced nephropathy, crystal-induced acute kidney injury, crystal deposition histiocytosis, acquired cystic kidney disease, 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, drug dependence and kidney disease, duplicated ureter, EAST syndrome, Ebola and the kidney, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immunotactoid glomerulopathy, Frey syndrome, fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal complications, gestational hypertension, Gitelman syndrome, glomerular disease, glomerulotubular reflux, renal glycosuria, Goodpasture syndrome, green smoothie purifying nephropathy, HANAC syndrome, Harvoni (ledipasvir / sofosbuvir combination) -induced kidney injury, hair dye ingestion and acute kidney injury, podocytopathy due to hantavirus infection, heat stress nephropathy, hematuria (blood in the urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, hantavirus kidney disease, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), hemosiderinuria, paroxysmal nocturnal hemoglobinuria and hemosiderin deposition related to hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1β-related kidney disease, hepatorenal syndrome,Herbal supplements and kidney diseases, advanced nephrotic syndrome, hypertension and kidney diseases, HIV-related immune complex kidney disease (HIVICK), HIV-related nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial kidney disease, horseshoe kidney (fused kidney), Hunter ulcer, hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic urticarial vasculitis syndrome, hypokalemia, hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in cannabis users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4-related kidney disease, water diuresis, immune checkpoint therapy-related interstitial nephritis, infliximab-related kidney disease, interstitial cystitis, painful bladder syndrome (questionnaire), interstitial nephritis, karyomegalic interstitial nephritis, IBM syndrome, JC virus nephropathy, Joubert syndrome, ketamine-related bladder dysfunction, kidney stones, nephrolithiasis, Kombucha toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis-related kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipotoxin glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutation, low back pain and hematuria, lupus, systemic lupus erythematosus, lupus nephritis, lupus nephritis with anti-neutrophil cytoplasmic antibody serum positivity, lupus podocytopathy, Lyme disease-related glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malaria nephropathy, malignant tumor-related kidney disease, malignant hypertension, malacoplakia, Mackittrick-Wheelock syndrome, MDMA (molly; ecstasy; 3,4-methylenedioxymethamphetamine) and renal failure, external urethral stricture, medullary cystic kidney disease, uromodulin-related nephropathy, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaloureter, melamine toxicity and its kidney, MELAS syndrome, membranoproliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with masked IgGκ deposition, Mesoamerican nephropathy, metabolic acidosis, metabolic alkalosisMethotrexate-related renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammopathy of renal significance, proteinuria, mouse wash 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, oro-facio-digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephrosis, ovarian hyperstimulation syndrome, oxalate nephropathy, page kidney, papillary necrosis, papillary renal syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutations and kidney disease, parvovirus B19 and the kidney, peritoneo-renal syndrome, POEMS syndrome, posterior urethral valve, podocyte infolding glomerulopathy, post-infectious glomerulonephritis, post-streptococcal glomerulonephritis, atypical post-infectious glomerulonephritis, post-infectious glomerulonephritis mimicking IgA nephropathy (IgA-dominant), polyarteritis nodosa, polycystic kidney disease, posterior urethral valve, post-obstructive diuresis, pre-eclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr disease), propolis (bee resin)-related renal failure, proteinuria (urinary protein), pseudohyperaldosteronism, pseudohypobicarbonatemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, pyridium and renal failure, radiation nephropathy, ranolazine and the kidney, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, renal arcuate vein microthrombosis-related acute kidney injury, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute kidney injury, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutations and autosomal dominant tubulointerstitial kidney disease, renin-secreting tumor (juxtaglomerular cell tumor), reset osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis associated with bariatric surgery, rheumatoid arthritis-related kidney disease, sarcoidosis kidney disease,Salt loss in the kidney and brain, schistosomiasis and glomerular diseases, Shprintzen immunodeficiency osteogenesis imperfecta, scleroderma renal crisis, serpentine fibula-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure and chronic kidney disease, kidney disease in Sri Lankan farmers, Sjogren's syndrome and kidney disease, synthetic cannabinoid use and acute kidney injury, kidney disease after hematopoietic cell transplantation, kidney disease associated with stem cell transplantation, TAFRO syndrome, tea and toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal immunoglobulinemia-related thrombotic microangiopathy, war nephritis, trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular dysgenesis, immune complex tubulointerstitial nephritis due to autoantibodies against the proximal tubular brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureteral tumor, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin-related cylindroma, vasomotor nephropathy, vesicointestinal fistula, vesicoureteral reflux, VGEF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, von Hippel-Lindau disease, Waldenström macroglobulinemic glomerulonephritis, warfarin-related nephropathy, wasp sting and acute kidney injury, Wegener granulomatosis, polyangiitis with granulomatosis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatorenal syndrome may be mentioned.,

[0193] Infectious diseases In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used for treating infectious diseases. Exemplary infectious diseases that can be treated with the compounds disclosed herein, such as the compounds of formula (I), include bacterial infections, viral infections (e.g., herpes, shingles, influenza, colds, encephalitis), and parasitic infections.

[0194] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used to treat an infectious disease (e.g., an infectious disease described herein) by reducing or eliminating the symptoms of the infectious disease. In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), can be used as a single agent in a composition or in combination with another agent in a composition for treating an infectious disease.

[0195] Parasitic infection In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used to treat a parasitic infection.

[0196] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used to treat a parasitic infection by reducing or eliminating the symptoms of the infection. In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), can be used as a single agent in a composition or in combination with another agent in a composition for treating a parasitic infection.

[0197] Immunosuppressive disease In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used to treat an immunosuppressive disease.

[0198] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), are used to treat an immunosuppressive disease by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), can be used as a single agent in a composition or in combination with another agent in a composition for treating an immunosuppressive disease.

[0199] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the kidney diseases described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof can be used as a single agent in a composition or in combination with another agent in a composition to treat the kidney diseases described herein.

[0200] Skin diseases In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat skin diseases. As used herein, the term "skin disease" can refer to a disease or disorder that affects the skin. Exemplary skin diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic keratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts, polymorphic light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo.

[0201] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the skin diseases described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition to treat the skin diseases described herein.

[0202] Fibrotic disease In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat fibrotic diseases. As used herein, the term "fibrotic disease" can refer to a disease or disorder defined by the accumulation of excessive extracellular matrix components. Exemplary fibrotic diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrillation, 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, silicosis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

[0203] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat a fibrotic disease described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can 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.

[0204] Hemoglobin disorder In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat hemoglobinopathy. As used herein, the terms “hemoglobinopathy” or “hemoglobin disorder” can refer to a disease or disorder characterized by abnormal production or structure of the hemoglobin protein. Exemplary hemoglobinopathies that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include “dominant genetic” β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α + -thalassemia (α 0 -thalassemia phenotype), hydrops fetalis with Hb Bart's disease, sickle cell anemia / sickle cell trait, sickle cell phenotype, sickle β-thalassemia disorder, α + -thalassemia, α 0 -thalassemia, α-thalassemia with myelodysplastic syndrome, α-thalassemia / mental retardation (ATR) syndrome, β 0 -thalassemia, β + -thalassemia, δ-thalassemia, γ-thalassemia, severe β-thalassemia, intermediate β-thalassemia, δβ-thalassemia, and εγδβ-thalassemia.

[0205] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the hemoglobinopathies described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition to treat the hemoglobinopathies described herein.

[0206] Autoimmune disease In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating an autoimmune disease. As used herein, the term "autoimmune disease" can refer to a disease or disorder in which the immune system of a subject attacks the subject's tissues and causes damage. Exemplary kidney diseases that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include acralasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune vitiligo, axonal and neuronal neuropathy (AMAN), bullous pemphigoid, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) i.e., eosinophilic granulomatosis with polyangiitis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler 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 syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (opposite type acne), 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, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren 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), Personege-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular autoimmune syndrome type I, polyglandular autoimmune syndrome type II, polyglandular autoimmune syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, autoimmunity to semen and testis, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Suzaku syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombotic 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 granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0207] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat an autoimmune disease described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition for treating an autoimmune disease described herein.

[0208] Viral infection In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat viral infections. Exemplary viral infections that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include influenza, human immunodeficiency virus (HIV), and herpes.

[0209] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat a viral infection described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition for treating a viral infection described herein.

[0210] Malaria infection In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat malaria. As used herein, the term "malaria" can refer to a parasitic disease of protozoa of the genus Plasmodium that causes infection of red blood cells (RBCs). Exemplary malaria infections that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, or stereoisomer thereof, include infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum. In some embodiments, the malaria infection that can be treated with the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is resistant / relapsing malaria.

[0211] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used to treat the malaria infections described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition to treat the malaria infections described herein.

[0212] Diseases with mutations leading to the induction of the unfolded protein response (UPR) In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating a disease having a mutation leading to UPR induction. Exemplary diseases having a mutation leading to UPR induction include Marinesco-Sjögren syndrome, neuropathic pain, painful diabetic neuropathy, noise-induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier-White disease, Ascher syndrome, collagen abnormality, thin basement membrane nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia Schmid type, and pseudoachondroplasia.

[0213] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, is used for treating a disease having a mutation leading to UPR induction as described herein by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition for treating a disease having a mutation leading to UPR induction as described herein.

[0214] Method for regulating protein production In another aspect, provided herein is a method of modulating the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a 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 a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, thereby modulating the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof decreases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell.

[0215] In another aspect, provided herein is a method of preventing or treating a disease, disorder, or condition in a patient in need of such prevention or treatment, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, modulates the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, by the patient's cells, thereby treating the disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is characterized by aberrant expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, by the patient's cells. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, increases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, by the patient's cells, thereby treating the disease, disorder, or condition. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, decreases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, by the patient's cells, thereby treating the disease, disorder, or condition.

[0216] In another aspect, provided herein is a method of modulating the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a 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 a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, thereby modulating the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof decreases the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell.

[0217] In another aspect, provided herein is a method of preventing or treating a disease, disorder, or condition in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, modulates the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in patient cells, thereby treating the disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is characterized by aberrant activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in patient cells. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, increases the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in patient cells, thereby treating the disease, disorder, or condition. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, decreases the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in patient cells, thereby treating the disease, disorder, or condition.

[0218] In some embodiments, administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, modulates both the expression and activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in patient cells, thereby treating a disease, disorder, or impairment.

[0219] In some embodiments, the compound of formula (I) is chemically modified before (ex vivo) or after (in vivo) contacting the cell to form a biologically active compound that modulates the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, the compound of formula (I) is metabolized by a patient to form a biologically active compound that modulates the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in patient cells, thereby treating a disease, disorder, or impairment disclosed herein. In some embodiments, the biologically active compound is a compound of formula (II).

[0220] In one aspect, the present disclosure provides a method for treating a disease associated with modulation of eIF2B activity or level, eIF2α activity or level, or the activity or level of a component of the eIF2 pathway or the ISR pathway in a patient in need of treatment for the following diseases, the method comprising administering to the patient an effective amount of a compound of formula (I). In some embodiments, the modulation comprises an increase in eIF2B activity or level, an increase in eIF2α activity or level, or an increase in the activity or level of a component of the eIF2 pathway or the ISR pathway. In some embodiments, the disease can be caused by a mutation in a gene or protein sequence associated with a component of the eIF2 pathway (e.g., the eIF2α signaling pathway).

[0221] Method for increasing protein activity and production In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, may be useful in an application where it is desirable to increase the production amount of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, such as an in vitro cell-free system for protein production.

[0222] In some embodiments, the present invention is a method of increasing the expression of eIF2B, eIF2α, a constituent factor of the eIF2 pathway, a constituent factor of the ISR pathway, or any combination thereof by a cell or an in vitro expression system, the method comprising contacting the cell or the in vitro expression system with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, the above method is a method of increasing the expression of eIF2B, eIF2α, a constituent factor of the eIF2 pathway, a constituent factor of the ISR pathway, or any combination thereof by a cell, the method comprising contacting the cell with an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof). In other embodiments, the above method is a method of increasing the expression of eIF2B, eIF2α, a constituent factor of the eIF2 pathway, a constituent factor of the ISR pathway, or any combination thereof by an in vitro protein expression system, the method comprising contacting the in vitro protein expression system with an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof). In some embodiments, by contacting the cell or the in vitro expression system with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the expression of eIF2B, eIF2α, a constituent factor of the eIF2 pathway, a constituent factor of the ISR pathway, or any combination thereof in the cell or the in vitro expression system is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%.In some embodiments, contacting a cell or an in vitro expression system with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell or in vitro expression system by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 10000-fold, about 100000-fold, or about 1000000-fold.

[0223] In some embodiments, the present invention is a method of increasing the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof by patient cells, comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, disorder, or illness disclosed herein, and the disease, disorder, or illness is characterized by abnormal expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof (e.g., leukodystrophy, leukoencephalopathy, hypomyelination or demyelinating disease, muscle wasting disease, or sarcopenia). In some embodiments, by administering to the patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof by patient cells is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, thereby treating the disease, disorder, or illness.In some embodiments, administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, increases the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 10000-fold, about 100000-fold, or about 1000000-fold, thereby treating a disease, disorder, or illness.

[0224] In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, may be useful in an application where it is desirable to increase the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof.

[0225] In some embodiments, the present invention is a method of increasing the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in a cell, comprising contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, by contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, by contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell is increased by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 10000-fold, about 100000-fold, or about 1000000-fold.

[0226] In some embodiments, the present invention is a method of increasing the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in a patient in need of increased activity, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, disorder, or illness disclosed herein, and the disease, disorder, or illness is characterized by a decrease in the level of protein activity. In some embodiments, by administering to the patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the patient is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, thereby treating the disease, disorder, or illness. In some embodiments, by administering to the patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the patient is increased by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 10000-fold, about 100000-fold, or about 1000000-fold, thereby treating the disease, disorder, or illness.

[0227] In some embodiments, the compounds of formula (I) are chemically modified before (ex vivo) or after (in vivo) contact with a cell or an in vitro expression system to form a biologically active compound that increases the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell and / or in vitro expression system. In some embodiments, the compounds of formula (I) are metabolized by a patient to form a biologically active compound that increases the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the patient's cells, thereby treating a disease, disorder, or condition disclosed herein. In some embodiments, the biologically active compound is a compound of formula (II).

[0228] Method for reducing protein activity and production In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, may be useful in an application where it is desirable to increase the production amount of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof.

[0229] In some embodiments, the invention is a method of reducing the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a 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 a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0230] In some embodiments, the invention is a method of reducing the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in a patient in need of such a reduction in expression, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, disorder, or condition described herein, and the disease, disorder, or condition is characterized by an increased level of protein production. In some embodiments, by administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, the expression of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof, in the patient is reduced by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, thereby treating the disease, disorder, or condition.

[0231] In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, may be useful in an application where it is desirable to reduce the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof.

[0232] In some embodiments, the present invention is a method of reducing the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in a cell, comprising contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, thereby treating a disease, disorder, or illness.

[0233] In some embodiments, the invention is a method of reducing the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in a patient in need of such a reduction in activity, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, disorder, or illness described herein, and the disease, disorder, or illness is characterized by an increased level of protein activity. In some embodiments, administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, to a patient in need thereof reduces the activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the patient by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%, thereby treating the disease, disorder, or illness.

[0234] In some embodiments, the compound of formula (I) is chemically modified before (ex vivo) or after (in vivo) contacting the cell to form a biologically active compound that reduces the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the cell. In some embodiments, the compound of formula (I) is metabolized by the patient to form a biologically active compound that reduces the expression and / or activity of eIF2B, eIF2α, a component of the eIF2 pathway, a component of the ISR pathway, or any combination thereof in the patient's cells, thereby treating a disease, disorder, or illness disclosed herein. In some embodiments, the biologically active compound is the compound of formula (I).

[0235] Combination therapy In one aspect, the present invention features a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, and a second agent (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent (e.g., a second therapeutic agent). In some embodiments, the second agent is an agent for treating cancer, a neurodegenerative disease, leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or disorder associated with a dysfunction of a component of the eIF2B, eIF2α, or eIF2 or ISR pathway.

[0236] The compounds described herein can each be used in combination with other active agents known to be useful for treating cancer, neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or disorders associated with a dysfunction of a component of the eIF2B, eIF2α, or eIF2 or ISR pathway, or with adjuvant agents that may not be effective alone but can contribute to the effectiveness of the active agent.

[0237] In some embodiments, co - administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co - administration includes administering two active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co - administration can be accomplished by co - formulation, i.e., preparing a single pharmaceutical composition comprising both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active and / or auxiliary agents may be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with a treatment for cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or disorder associated with a dysfunction of a component of the eIF2B, eIF2α, or eIF2 pathway or the ISR pathway.

[0238] In an embodiment, the second agent is an anti-cancer agent. In an embodiment, the second agent is a chemotherapeutic agent. In an embodiment, the second agent is an agent for improving memory. In an embodiment, the second agent is an agent for treating neurodegenerative diseases. In an embodiment, the second agent is an agent for treating leukodystrophy. In an embodiment, the second agent is an agent for treating vanishing white matter disease. In an embodiment, the second agent is an agent for treating ataxia telangiectasia with central nervous system hypomyelination. In an embodiment, the second agent is an agent for treating intellectual disability syndromes (such as fragile X syndrome). In an embodiment, the second agent is an agent for treating pancreatic cancer. In an embodiment, the second agent is an agent for treating breast cancer. In an embodiment, the second agent is an agent for treating multiple myeloma. In an embodiment, the second agent is an agent for treating myeloma. In an embodiment, the second agent is an agent for treating cancer of secretory cells. In an embodiment, the second agent is an agent for reducing eIF2α phosphorylation. In an embodiment, the second agent is an agent for inhibiting a pathway activated by eIF2α phosphorylation. In an embodiment, the second agent is an agent for inhibiting a pathway activated by eIF2α. In an embodiment, the second agent is an agent for inhibiting the integrated stress response. In an embodiment, the second agent is an anti-inflammatory agent. In an embodiment, the second agent is an agent for treating postoperative cognitive dysfunction. In an embodiment, the second agent is an agent for treating traumatic brain injury. In an embodiment, the second agent is an agent for treating musculoskeletal diseases. In an embodiment, the second agent is an agent for treating metabolic diseases. In an embodiment, the second agent is an anti-diabetic agent.

[0239] Anti-cancer agent Sarcophytol A; Sargramostim; Sdi 1 mimetic; Semustine; Aging-derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction regulator; Single-chain antigen-binding protein; Schizophyllan; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solverol; Somatomedin-binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiroxostin; Sprenopentin; Spongistatin 1; Squaramine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromelysin inhibitor; Sulfinosine; Superactive vasoactive intestinal peptide antagonist; Suradista; Suramine; Swainsonine; Synthetic glycosaminoglycan; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Sodium tecogalan; Tegafur; Tellurapyrylium; Telomerase inhibitor; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocholic acid; Thrombopoietin; Thrombopoietin mimetic; Timalphasin; Thymopoietin receptor agonist; Timotrinan; Thyroid-stimulating hormone; Tin ethyl etiopurpurin; Tirapazamine; Titanocene dichloride; Topsecentin; Toremifene; Pluripotent stem cell factor; Translation inhibitor; Tretinoin; Triacetyluridine; Triciribine; Trimethoprexate; Triptorelin; Tropisetron; Tursteride; Tyrosine kinase inhibitor; Tilostatin; UBC inhibitor; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor antagonist; Bapreotide; Variolin B; Vector system, erythrocyte gene therapy; Veraresol; Veramine; Verdin; Verteporfin; Vinorelbine; Vincaescin; Vitaxin; Borozole; Zanolteron; Zenoplatin; Dirascolb; Dinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,Asibicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adzelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisfanid Dimethyl Sulfate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Broxuridine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbethimer; Carboplatin; Carmustine; Carvicine Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diazquone; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Zuazomycin; Edatrexate; Efloxatin Hydrochloride; Elsamitrucin; Enloplatin; Empromate; Epipropidine; Epirubicin Hydrochloride; Elbuzole; Esorubicin Hydrochloride; Estramustine; Estramustine Sodium Phosphate; Ethanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Fluroxyridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Hosquidone; Hostacarcin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Iimofosine; Interleukin II (including recombinant interleukin II, or rlL.sub.2),Interferon alpha-2a; Interferon alpha-2b; Interferon alpha-nl; Interferon alpha-n3; Interferon beta-1a; Interferon gamma-1b; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Rialoxazole hydrochloride; Romidepsin sodium; Romustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melenegestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Methopterin; Metsuredepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitospur; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentostatin; Pepromycin sulfate; Parfosfamide; Pipobroman; Piposulfan; Pyroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Riboprine; Logretimide; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiro mustine; Spiroplatin; Streptozocin; Streptozotocin; Slofenur; Talisomycin; Tegafur sodium; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazofurin; Tirabazamine; Toremifene citrate; Trenbolone acetate; Trisciribine phosphate; Trimetrexate; Glucuronate trimetrexate; Triptorelin; Tubulozole hydrochloride; Uracil mustard; Uredepa; Bapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vincoglycin sulfate; Vinrolosin sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Boroazole; ZenipLatin; Dinostatin; Zorubicin hydrochloride; Arrest cells at the G2-M phase,and / or an agent that modulates the formation or stability of microtubules (e.g., taxol (i.e., paclitaxel), taxotere, a compound containing a taxane skeleton, eribulin (i.e., R-55104), laulastatin 10 (i.e., DLS-10 and NSC-376128), mivobulin isethionate (i.e., CI-980), vincristine, NSC-639829, discodermolide (i.e., NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altretamine (e.g., altretamine A and altretamine C), spongistatin (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), semadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilone (e.g., epothilone A, epothilone B, epothilone C (i.e., desoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), sobuzoxane (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-1 12378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651),SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Bicirubinamide, Tubulysin A, Canadensol, Centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Physanolide B, Laurimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), Narcosin (also known as NSC-5366), Noscapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanosine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine),A-204197 (Abbott), T-607 (Tularik, i.e., T-900607), RPR-115781 (Aventis), ellipticine (e.g., desmethyl ellipticine, desacetyl ellipticine, isoellipticine A, and Z-ellipticine), calycosin, calycosin-7-O-β-D-glucoside, halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), takanonolide A, TUB-245 (Aventis), A-259754 (Abbott), gezosatin, (-)-phenylahistin (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zenta, ris), SC-12983 (NCI), sodium resveratrol phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), e.g., goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., U1 ln, 90 Y, or 131An anti-CD20 monoclonal antibody conjugated to I, etc.), tripterid, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, an EGFR inhibitor, an epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agent (e.g., gefitinib (Iressa (trademark)), erlotinib (Tarceva (trademark)), cetuximab (Erbitux (trademark)), lapatinib (Tykerb (trademark)), panitumumab (Vectibix (trademark)), vandetanib (Caprelsa (trademark)), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0240] "Chemotherapeutic agent" or "chemotherapeutic drug" is used according to its ordinary meaning and refers to a chemical composition or compound having anti-neoplastic properties or the ability to inhibit cell growth or proliferation.

[0241] In addition, the compounds described herein include, but are not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g.,m In, 90 Y, or 131 It can be co-administered with a conventional immunotherapeutic agent including an anti-CD20 monoclonal antibody conjugated to I, etc.

[0242] In a further embodiment, the compounds described herein are conjugated, but not limited to, with an antibody optionally directed against a tumor antigen, 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 It can be co-administered with a conventional radiotherapeutic agent including radionuclides such as Bi.

[0243] Additional agent In some embodiments, the second agent for use in combination with the compounds described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof), or a composition thereof, is an agent for use in the treatment of neurodegenerative diseases, leukodystrophies, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. In some embodiments, the second agent for use in combination with the compounds described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof), or a composition thereof, is an agent for the treatment of the diseases, disorders, or illnesses described herein, approved by the FDA or similar regulatory agencies in countries other than the United States.

[0244] In some embodiments, second agents for treating neurodegenerative diseases, leukodystrophies, inflammatory diseases, musculoskeletal diseases, or metabolic diseases include, but are not limited to, antipsychotics, antidepressants, anxiolytics, analgesics, stimulants, sedatives, pain relievers, anti-inflammatory agents, benzodiazepines, cholinesterase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, MAO inhibitors, beta blockers, calcium channel blockers, antacids, or other agents.Exemplary second agents may include donepezil, galantamine, rivastigmine, memantine, levodopa, dopamine, pramipexole, ropinirole, rotigotine, doxapram, oxazepam, ketiapiine, selegiline, rasagiline, entacapone, benztropine, trihexyphenidyl, riluzole, diazepam, chlordiazepoxide, lorazepam, alprazolam, buspirone, gepirone, ipsapirone, hydroxyzine, propranolol, hydroxyzine, midazolam, trifluoperazine, methylphenidate, atomoxetine, methylphenidate, pemoline, perphenazine, divalproex, valproic acid, sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, trazodone, desvenlafaxine, duloxetine, venlafaxine, amitriptyline, amoxapine, clomipramine, desipramine, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, bupropion, nefazodone, vortioxetine, lithium, clozapine, fluphenazine, haloperidol, paliperidone, loxapine, thiothixene, pimozide, thioridazine, risperidone, aspirin, ibuprofen, naproxen, acetaminophen, azathioprine, methotrexate, mycophenolic acid, leflunomide, dibenzoylmethane, cilostazol, pentoxifylline, duloxetine, cannabinoid (e.g., nabiximols), simeticone, magnesium trisilicate, aluminum salts, calcium salts, sodium salts, magnesium salts, alginic acid, acarbose, albiglutide,alogliptin, metformin, insulin, lisinopril, atenolol, atorvastatin, fluvastatin, lovastatin, pitavastatin, simvastatin, rosuvastatin, and the like.

[0245] In addition, for treating neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, or metabolic diseases, natural - derived drugs or supplements can also be used in combination with the compounds of formula (I), or pharmaceutically acceptable salts, co - crystals, solvates, hydrates, tautomers, esters, N - oxides, or stereoisomers thereof, or compositions thereof. Exemplary natural - derived drugs or supplements include omega - 3 fatty acids, carnitine, citicoline, curcumin, ginkgo, vitamin E, vitamin B (e.g., vitamin B5, vitamin B6, or vitamin B12), fupenzi A, phosphatidylserine, rosemary, caffeine, melatonin, chamomile, St. John's wort, tryptophan, and the like.

Examples

[0246] To better understand the present invention described herein, the following examples are provided. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed in any way as limiting their scope.

[0247] Synthetic protocol The compounds provided herein can be prepared from readily available starting materials using modified forms of the following specific synthetic protocols well - known to those skilled in the art. When general or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, it will be understood that other process conditions can be used unless otherwise explicitly stated. Optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures. In addition, a general scheme for the preparation method of exemplary compounds of the present invention is described in the section entitled Preparation Method of Compounds.

[0248] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of appropriate protecting groups for specific functional groups, as well as the appropriate conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0249] Abbreviations APCI refers to atmospheric pressure chemical ionization, Boc refers to tert-butoxycarbonyl, t-Bu refers to tert-butyl, DCI refers to desorption chemical ionization, DMSO refers to dimethyl sulfoxide, ESI refers to electrospray ionization, HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HPLC refers to high performance liquid chromatography, LC refers to liquid chromatography, LC / MS refers to liquid chromatography / mass spectrometry, MS refers to mass spectrum, NMR refers to nuclear magnetic resonance, psi refers to pounds per square inch, SFC refers to supercritical fluid chromatography, and UV refers to ultraviolet light.

[0250] Example 1: (2S)-1,4-Bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl acetate (Compound 100) Example 1A: Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2-diol (12.29 mL, 220 mmol), and p-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) in toluene (200 mL) was stirred at 120 °C for 180 minutes using a Dean-Stark trap apparatus. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and then concentrated under reduced pressure. The residue was purified on silica gel (0 - 30% ethyl acetate / heptane) to give 12.77 g of the title compound as a clear oil. TIFF2025081607000056.tif18151

[0251] Example 1B: Ethyl 8-acetyl-1,4-dioxaspiro[4.5]decane-8-carboxylate To a solution of diisopropylamine (5.19 mL, 36.4 mmol) in tetrahydrofuran (25 mL) at 0 °C, n-butyllithium was slowly added while maintaining the internal temperature below 5 °C. After stirring for 30 minutes, the solution was cooled to -78 °C under nitrogen, and a solution of Example 1A (6.0 g, 28.0 mmol) in tetrahydrofuran (3 mL) was slowly added, and the resulting mixture was stirred at the same temperature for 30 minutes. Then acetyl chloride (2.59 mL, 36.4 mmol) was slowly added while maintaining the temperature below -60 °C, and the mixture was stirred at -70 °C for 2 hours. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on silica gel (0 - 70% ethyl acetate / heptane) to give 6.78 g of the title compound as a clear oil. TIFF2025081607000057.tif18145

[0252] Example 1C: Ethyl 1-acetyl-4-oxocyclohexanecarboxylate A mixture of Example 1B (6.5 g, 25.4 mmol) and HCl (21.13 mL, 127 mmol) in acetone (60 mL) was stirred overnight at ambient temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 5.46 g of the title compound as a clear oil, which was used without further purification. TIFF2025081607000058.tif11128

[0253] Example 1D: Ethyl 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylate A mixture of Example 1C (9.7 g, 45.7 mmol), benzylamine (14.98 mL, 137 mmol), and p-toluenesulfonic acid monohydrate (0.087 g, 0.457 mmol) in toluene (100 mL) was stirred overnight at reflux using a Dean-Stark trap apparatus. The mixture was concentrated under reduced pressure, and the residue was stirred with a mixture of ethyl acetate (50 mL) and 3N HCl (100 mL) for 30 minutes. The precipitate was collected by filtration, washed with a mixture of ethyl acetate / heptane, and air-dried to give 11.3 g of the title compound as the hydrochloride salt. The filtrate was neutralized with 6N NaOH and extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered under reduced pressure. The residue was purified on silica gel (0 - 70% ethyl acetate / heptane) to give an additional 0.77 g of the title compound as a yellow solid. TIFF2025081607000059.tif18146

[0254] Example 1E: Ethyl 4-amino-2-oxobicyclo[2.2.2]octane-1-carboxylate To a mixture of Example 1D (11.2 g, 33.2 mmol) in tetrahydrofuran (110 mL) in a 50 mL pressure bottle, 20% Pd(OH) 2 / C, Moisture (2.2 g, 1.6 mmol) was added and the reaction mixture was shaken at 50 °C for 22 h under 50 psi of hydrogen. The reaction mixture was cooled to ambient temperature, the solid was filtered off and washed with methanol (1 L). The filtrate and washings were concentrated under reduced pressure to give 7.9 g of the title compound as the hydrochloride salt. TIFF2025081607000060.tif11150

[0255] Example 1F: Ethyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-oxobicyclo[2.2.2]octane-1-carboxylate To a suspension of Example 1E (7.8 g, 31.5 mmol), N-ethyl-N-isopropylpropan-2-amine (22.00 mL, 126 mmol), and 2-(4-chloro-3-fluorophenoxy)acetic acid (7.41 g, 36.2 mmol) in N,N-dimethylformamide (200 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (14.97 g, 39.4 mmol) and the resulting brown solution was stirred at ambient temperature for 16 h. Water was added and the mixture was stirred for 15 min. The precipitate was collected by filtration, washed with water and air dried to give 12.1 g of the title compound as an off-white solid. TIFF2025081607000061.tif24150

[0256] Example 1G: 4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-oxobicyclo[2.2.2]octane-1-carboxylic acid A suspension of Example 1F (11.37 g, 28.6 mmol) and sodium hydroxide (7.15 mL, 57.2 mmol, 8 M solution) in methanol (100 mL) was stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure and the residue was acidified with 1 N HCl. The precipitate was collected by filtration and dried in a vacuum oven to give 9.9 g of the title compound as a white solid. TIFF2025081607000062.tif18148

[0257] Example 1H: N-(4-Amino-3-oxobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide A mixture of Example 1G (3.24 g, 8.76 mmol), diphenylphosphoryl azide (2.84 mL, 13.14 mmol), and triethylamine (3.66 mL, 26.3 mmol) in toluene (100 mL) was heated at 110 °C for 2 hours. The solution was cooled to ambient temperature and poured into 150 mL of 3N HCl solution. The mixture was stirred for 16 hours to obtain a suspension. The precipitate was filtered, washed with ethyl acetate, and air-dried to give the title compound (1.63 g) as the HCl salt, a white solid. The filtrate was then basified with solid sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified on silica gel (0 - 10% methanol / dichloromethane) to give the title compound (0.6 g) as the free base. TIFF2025081607000063.tif18150

[0258] Example 1I: N-(4-Amino-3-hydroxybicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride A mixture of Example 1H (2.5 g, 6.63 mmol) and sodium borohydride (1.254 g, 33.1 mmol) in a 1:1 mixture of methanol / dichloromethane (50 mL) was stirred for 24 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic fraction was separated, dried (MgSO 4 ), and concentrated. The residue was then treated with 4N HCl dioxane solution. The suspension was sonicated and concentrated. The residue was dried under vacuum to give 2.82 g of the title compound as a pale yellow solid. TIFF2025081607000064.tif24148

[0259] Example 1J: N,N'-(2-Oxobicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide] A mixture of Example 1H (0.5 g, 1.325 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (0.339 g, 1.657 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.157 mL, 6.63 mmol) in N,N-dimethylformamide (20 mL) was treated with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.756 g, 1.988 mmol), and the reaction mixture was stirred at ambient temperature for 30 minutes, whereupon it was confirmed that the conversion was complete. Water was added, and the resulting mixture was stirred for 15 minutes. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven at 50 °C for 2 hours to give 0.64 g of the title compound as a white solid. TIFF2025081607000065.tif24149

[0260] Example 1K: N,N'-(2-hydroxybicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide] Sodium borohydride (0.226 g, 5.97 mmol) was added portionwise to a solution of Example 1J (0.63 g, 1.195 mmol) in dichloromethane (10 mL) and methanol (10 mL), and the mixture was stirred at ambient temperature for 4 hours. The volatiles were removed, and the residue was triturated with dichloromethane / methanol to give 0.32 g of the title compound as a white solid. The filtrate was concentrated, and the residue was purified on silica gel (10 - 100% ethyl acetate / heptane) to give 0.21 g of the title compound. TIFF2025081607000066.tif31149

[0261] Example 1L: N,N'-[(2S)-2-hydroxybicyclo[2.2.2]octane-1,4-diyl]bis[2-(4-chloro-3-fluorophenoxy)acetamide] The labeled compound was isolated as the second peak eluting from the column by chiral preparative SFC (supercritical fluid chromatography) of Example 1K. The preparative SFC was carried out on a THAR / Waters SFC 80 system operating under the control of SuperChrom (trademark) software. The preparative SFC system was equipped with an 8-way preparative column switcher, a CO 2 pump, a conditioning pump, an automatic back pressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase was ultrapure dry uncertified CO 2 supplied at a flow rate of 70 g / min by a dewar of CO 2 pressurized to 350 psi and containing methanol as a modifier. The column temperature was ambient temperature, and the back pressure regulator was set to maintain 100 bar. The sample was dissolved in a mixture of methanol / dichloromethane (1:1) at a concentration of 10 mg / mL. The sample was loaded into the modifier stream as an injection of 1 mL (10 mg). The mobile phase was held at a constant composition of 30% methanol:CO 2 . Fraction collection was time-driven. A Chiralpak (registered trademark) AD-H column packed with 5 μm particles and having dimensions of 21 mm inner diameter × 250 mm length was attached to this apparatus. TIFF2025081607000067.tif31148

[0262] Example 1M: (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl acetate To a suspension of the product of Example 1K (7.80 g, 14.73 mmol), N,N-dimethylpyridin-4-amine (1.88 g, 15.4 mmol), and triethylamine (2.70 mL, 19.4 mmol) in CH 2 Cl 2 (80 mL) at 0 °C was added acetyl chloride (1.35 mL, 19 mmol). The ice bath was removed, the mixture was stirred for 30 minutes, and concentrated under reduced pressure. The residue was diluted with ethyl acetate. The mixture was washed with 1N HCl (40 mL), water (25 mL), saturated NaHCO 3It was washed with an aqueous solution (25 mL) and saturated brine (25 mL). The organic fraction was dehydrated over anhydrous Na 2 SO 4 and adsorbed onto silica gel, and purified on silica gel (25 - 30% ethyl acetate / dichloromethane) to obtain 7.78 g of the racemic substance as a white solid. The enantiomers were separated by chiral preparative SFC (supercritical fluid chromatography). The preparative SFC was performed on a THAR / Waters SFC 80 system operating under the control of SuperChrom (trademark) software. The preparative SFC system was equipped with an 8-way preparative column switcher, a CO 2 pump, a conditioning pump, an automatic back pressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase was supercritical CO 2 pressurized to 350 psi and supplied at a flow rate of 80 mL / min by a dewar of anhydrous, uncertified CO 2 containing methanol as a modifier. The column temperature was ambient temperature, and the back pressure regulator was set to maintain 100 bar. The sample was dissolved in a mixture of methanol / dichloromethane (1:1) at a concentration of 10 mg / mL. The sample was loaded into the modifier stream with an injection volume of 1 mL (10 mg). The mobile phase was held at a constant composition of 40% methanol:CO 2 . Fraction collection was time-driven. A Chiralpak (registered trademark) AD-H column packed with 5-μm particles having dimensions of inner diameter 21 mm × length 250 mm was attached to this apparatus.

[0263] The second eluted compound from this chiral separation was the title compound (2.97 g, 5.19 mmol, 35% yield). TIFF2025081607000068.tif31146

[0264] Example 2: (2S)-1,4-Bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl dihydrogen phosphate (Compound 101) Example 2A: (S)-1,4-Bis(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octan-2-yl di-tert-butyl phosphate To a solution of the product of Example 1L (0.200 g, 0.378 mmol) in N,N-dimethylformamide (1.1 mL) was added a 0.45 M acetonitrile solution of lH-tetrazole (2.1 mL, 0.945 mmol), followed by di-tert-butyldiethylphosphoramidite (0.21 mL, 0.76 mmol). The mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Hydrogen peroxide (0.39 mL, 3.82 mmol) was added to the reaction mixture at room temperature, and then it was stirred for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 aqueous solution and saturated brine, and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified on silica gel (3% ethanol / dichloromethane). This substance still containing impurities was repurified on silica gel (40% ethyl acetate / dichloromethane) to give the title compound (0.124 g, 0.172 mmol, 46% yield), which was then carried on without further purification. LC / MS (APCI + ) m / z 721 (M+H) + .

[0265] Example 2B: (2S)-1,4-Bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl dihydrogen phosphate A solution of Example 2A (0.1244 g, 0.172 mmol) in CH 2 Cl 2 (0.60 mL) and 2,2,2-trifluoroacetic acid (0.20 mL, 2.61 mmol) was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Phenomenex® Luna® 250×30 mm 10 μm C18 column, 60 mL / min, gradient of 15 - 95% acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to give the title compound (0.035 g, 0.058 mmol, 34% yield). TIFF2025081607000069.tif31150

[0266] Example 3: (2S)-2-Amino-4-({(2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl}oxy)-4-oxobutanoic acid (Compound 102) A suspension of the product of Example 1L (30 mg, 0.057 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (0.025 mL, 0.142 mmol) was treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolium 3-oxide hexafluorophosphate (24 mg, 0.062 mmol) and (S)-2-((tert-butoxycarbonyl)amino)succinic acid (20 mg, 0.086 mmol). The reaction mixture was stirred at 25 °C for 20 h and then concentrated under reduced pressure. The residue was diluted with trifluoroacetic acid (0.2 mL) and purified by HPLC (Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column 250 mm × 21.2 mm, flow rate 25 mL / min, gradient of 0 - 60% acetonitrile / buffer (0.1% aqueous tri...

Claims

1. Formula (I): A compound represented by the formula: During the ceremony, R １ is -C(O)-C １～４ Alkyl, —C(O)—O—C １～４ Alkyl, —C(O)—N(R ａ ) -C １～４ Alkyl, —C(O)—C １～４ Alkylene-C １～４ Alkoxy, —C(O)—C １～４ Alkylene -O-C １～４ Alkylene-C １～４ Alkoxy, -methylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-O-C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-N(R ａ ) -C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ , -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) (O-C １～５ Alkylene-P(O)(OH) ２ ), -methylene-O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ or -methylene-O-C(O)C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ , -C(O)-O-C １～５ Alkylene -O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , -C(O)-N(R ａ )-heteroarylene-C １～２ Alkylene-O-P(O)(OH) ２ , -P(O)(OH) ２ , -SO ３ H, -SO ２ N.R. ａ R ｂ , —C(O)-heteroaryl, —C(O)-C １～５ Alkylene -O-C １～５ Alkylene-phenyl and methylene-C １～５ alkoxides, Here, -C(O)-C １～４ Each alkyl is independently -NR ａ R ｂ and -CO ２ H; and １～４ Alkyl, —C(O)—N(R ａ ) -C １～４ Alkyl, —C(O)—C １～４ Alkylene-C １～４ Alkoxy, —C(O)—C １～４ Alkylene -O-C １～４ Alkylene-C １～４ Alkoxy, methylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-O-C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-N(R ａ ) -C １～５ Alkylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ , -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) (O-C １～５ Alkylene-P(O)(OH) ２ ), -methylene-O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ or -methylene-O-C(O)C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ , -C(O)-O-C １～５ Alkylene -O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , —C(O)-heteroaryl, —C(O)-C １～５ Alkylene -O-C １～５ Alkylene-phenyl, and —C(O)—N(R ａ )-heteroarylene-C １～２ Alkylene-O-P(O)(OH) ２ each independently represents a halogen, —CO ２ H, -NR ａ R ｂ , and C １～２ optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl (optionally substituted with 1, 2, or 3 fluorines), and aryl; R ａ and R ｂ is independently for each occurrence hydrogen and C １～３ selected from the group consisting of alkyl, The compound, or a pharma- ceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

2. R １ However, each is independently -NR ａ R ｂ and -CO ２ -C(O)-C substituted with 1 or 2 substituents selected from the group consisting of H １～４ The compound of claim 1 , wherein the aryl group is an alkyl group.

3. R １ but, 3. The compound according to claim 1 or 2, selected from the group consisting of:

4. R １ -C(O)-O-C １～４ The compound of claim 1 , wherein the aryl group is an alkyl group.

5. R １ but, 5. The compound of claim 4 selected from the group consisting of:

6. R １ is -C(O)-N(R ａ ) -C １～４ alkyl, —C(O)—N(R ａ ) -C １～４ The alkyl group has one or two -CO ２ The compound of claim 1, optionally substituted with H groups.

7. R １ but, The compound of claim 6, represented by:

8. R １ -C(O)-C １～４ Alkylene-C １～４ The compound of claim 1 which is alkoxy.

9. R １ but, 9. The compound of claim 8 selected from the group consisting of:

10. R １ -C(O)-C １～４ Alkylene -O-C １～４ Alkylene-C １～４ The compound of claim 1 which is alkoxy.

11. R １ but, 11. The compound of claim 10, represented by:

12. R １ Ga-methylene-O-P(O)(OH) ２ 2. The compound of claim 1,

13. R １ but, 13. The compound of claim 12, represented by:

14. R １ -C(O)-C １～５ Alkylene-O-P(O)(OH) ２ 2. The compound of claim 1,

15. R １ but, 15. The compound of claim 14, selected from the group consisting of:

16. R １ -C(O)-O-C １～５ Alkylene-O-P(O)(OH) ２ 2. The compound of claim 1 ,

17. R １ but, 17. The compound of claim 16, selected from the group consisting of:

18. R １ is -C(O)-N(R ａ ) -C １～５ Alkylene-O-P(O)(OH) ２ 2. The compound of claim 1 ,

19. R １ but, 20. The compound of claim 18, selected from the group consisting of:

20. R １ -C(O)-C １～５ Alkylene-P(O)(OH) ２ 2. The compound of claim 1 ,

21. R １ but, 21. The compound of claim 20, represented by:

22. R １ But -C(O)-C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ or -C(O)-C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) (O-C １～５ Alkylene-P(O)(OH) ２ 2. The compound of claim 1, wherein

23. R １ but, 23. The compound of claim 22, selected from the group consisting of:

24. R １ is -C(O)-N(R ａ )-heteroarylene-C １～２ Alkylene-O-P(O)(OH) ２ 2. The compound of claim 1,

25. R １ but 25. The compound of claim 24, represented by:

26. R １ The compound of claim 1 , wherein is —C(O)-heteroaryl.

27. R １ but, 27. The compound of claim 26, selected from the group consisting of:

28. R １ -C(O)-C １～５ Alkylene -O-C １～５ The compound of claim 1 which is alkylene-phenyl.

29. R １ but, 29. The compound of claim 28, represented by:

30. R １ Methylene-C １～５ The compound of claim 1 which is an alkoxide.

31. R １ but, 31. The compound of claim 30, represented by:

32. R １ But -C(O)-O-C １～５ Alkylene -O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ , -methylene-O-C(O)C １～５ Alkylene-phenylene-O-P(O)(OH) ２ or -methylene-O-C(O)C １～５ Alkylene-phenylene-(O-P(O)(OH) ２ ) ２ 2. The compound of claim 1 ,

33. R １ but, 33. The compound of claim 32, represented by:

34. R １ But -P(O)(OH) ２ , -SO ３ H, and -SO ２ N.H. ２ 2. The compound of claim 1 selected from the group consisting of:

35. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt, co-crystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

36. A pharma- ceutically acceptable composition comprising a compound according to any one of claims 1 to 35 and a pharma- ceutically acceptable carrier.

37. 37. The composition of claim 36, formulated for oral administration.

38. 36. 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 hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 35.

39. 39. The method of claim 38, wherein the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome (e.g., fragile X syndrome), a cognitive disorder, a glial cell dysfunction, or a brain injury (e.g., a traumatic brain injury, a hypoxia-induced brain injury, or a toxin-induced brain injury).

40. 40. The method of claim 38 or 39, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with central nervous system dysmyelination, 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 dementia with Lewy bodies), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

41. 41. The method of any one of claims 38 to 40, wherein the neurodegenerative disease comprises vanishing white matter disease.

42. 39. The method of claim 38, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or cancer of a secretory cell.

43. 39. The method of claim 38, 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 type 1 diabetes), 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.

44. The musculoskeletal disease is selected from the group consisting of 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, and myotonic muscular dystrophy type 2), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal-bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, muscle spasms and fasciculations (cramps, fasciculations, and the like).

40. The method of claim 38, wherein the condition is a muscle wasting disorder (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

45. 39. The method of claim 38, wherein the metabolic disease comprises nonalcoholic steatohepatitis (NASH), nonalcoholic 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 syndrome.

46. 39. The method of claim 38, wherein the mitochondrial disease is associated with or is the result of mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DNA mutations.

47. 47. The method of claim 38 or 46, wherein the mitochondrial disease is a mitochondrial myopathy.

48. 48. The method of any one of claims 38, 46, and 47, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, i.e., maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

49. The autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid Small pox, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (I C), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis,Palindromic rheumatism (PR), PANDA, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, recurrent polyarthritis, 39. The method of claim 38, wherein the disease is selected from the group consisting of myeloarthritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, autoimmunity against sperm and testes, stiff-persons syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

50. 39. The method of claim 38, wherein the viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV), and herpes.

51. 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), extramammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infection of the nail, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, and ichthyosis.

39. The method of claim 38, wherein the skin ulcer is selected from the group consisting of psoriasis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoidis, pityriasis rubra pilaris, plantar warts, polymorphous light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo.

52. 39. The method of claim 38, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, liver cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scar, Hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

53. The hemoglobinopathy may be "dominant" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α ＋ - Thalassemia (α 0 -thalassemia phenotype), hydrops fetalis with Hb Bartz disease, sickle cell anemia / disease, sickle cell trait, sickle beta-thalassemia, α ＋ - Thalassemia, alpha 0 - Thalassemia, α-thalassemia with myelodysplastic syndrome, α-thalassemia / mental retardation (ATR) syndrome, β ０ - Thalassemia, beta ＋ 39. The method of claim 38, wherein the thalassemia is selected from the group consisting of β-thalassemia major, β-thalassemia intermedia, δβ-thalassemia, γ-thalassemia, β-thalassemia major, β-thalassemia intermedia, δβ-thalassemia, and εγδβ-thalassemia.

54. The kidney disease may be Abderhalden-Kaufmann-Lignac syndrome (nephropathic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / injury, acute lobar nephronia, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, vascular Myolipoma, analgesic nephropathy, anorexia nervosa and kidney disease, angiotensin antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-associated glomerulonephritis, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, herbal medicine nephropathy, Balkan endemic nephropathy, arteriovenous malformations and fistulas of the urinary tract, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome, bath salts and acute kidney injury, beer polydipsia Potomania), beet urine, β-thalassemia nephropathy, bile cast nephropathy, BK polyomavirus nephropathy in native kidney, bladder rupture, bladder sphincter dyssynergia, bladder tamponade, Border-Crossers nephropathy, bourbon virus and acute kidney injury, burnt sugarcane harvest and acute renal dysfunction, Byetta and renal failure, C1q nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepsis laureola Laureola poisoning, cannabinoid hyperemesis acute renal failure, cardiorenal syndrome, carfilzomib-induced renal injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathy, Chinese herbal medicines and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathy, cocaine and the kidney, cold diuresis, colistin nephrotoxicity, collagen fibrotic glomerulopathy, collapsing glomerulopathy, CMV associated collapsing glomerulopathy, combination antiretroviral therapy (cART)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, renal pyramidal syndrome (Mainzer-Sardino syndrome or Sardino-Mainzer disease), contrast nephropathy, copper sulfate poisoning, renal cortical necrosis, crizotinib-associated acute kidney injury, crystal cryoglobulinemia, cryoglobulinemia, crystal globulin-induced nephropathy,Crystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (MPGN2), Dent's disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes and diabetic kidney disease, diabetes insipidus, nutritional supplements and renal failure, diffuse mesangial sclerosis, diuresis, Djenkol bean Bean poisoning (Djenkolism), Down's syndrome and kidney disease, Addictive drugs and kidney disease, Duplication of ureter, EAST syndrome, Ebola and kidneys, Ectopic kidney, Ectopic ureter, Edema, Swelling, Erdheim-Chester disease, Fabry disease, Familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, Fibronectin glomerulopathy, Fibrillary glomerulonephritis and immunotactoid glomerulopathy, Frehley syndrome, Fluid overload, Hypervolemia, Focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal complications, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerular tubular reflux, renal glycosuria, Goodpasture's syndrome, green smoothie-purifying nephropathy, HANAC syndrome, Harvoni (ledipasvir / sofosbuvir combination drug)-induced kidney injury, hair dye ingestion and acute kidney injury, hantavirus infection-induced podocytopathy, heat stress nephropathy, hematuria (urinary hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus kidney disease, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), hemosiderinuria, paroxysmal nocturnal hemoglobinuria and hemosiderinosis associated with hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1β-related kidney disease, hepatorenal syndrome, herbal supplements and kidney disease, high Severe renal syndrome, hypertension and renal disease, HIV-associated immune complex kidney disease (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-associated autosomal dominant tubulointerstitial kidney disease, horseshoe kidney (fused kidney), Hunner's ulcer, hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic urticarial vasculitis syndrome, hypokalemia,Hypokalemia-induced renal dysfunction, Hypokalemic periodic paralysis, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Hypophosphatemia in cannabis users, Hypertension, Monogenic hypertension, Ice tea nephropathy, Ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, Water diuresis, Immune checkpoint therapy-associated interstitial nephritis, Infliximab-associated kidney disease, Interstitial cystitis, Bladder pain syndrome (questionnaire), Interstitial nephritis, Karyomegalic interstitial nephritis, Ivemark syndrome, JC virus nephropathy, Joubert syndrome, Ketamine-related bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutations, lower back pain and hematuria, lupus, systemic lupus erythematosus, lupus kidney disease, lupus nephritis, antineutrophil cytoplasmic antibodies Lupus nephritis with seropositivity, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated kidney disease, malignant hypertension, malakoplakia, McKittrick-Wheelock syndrome, MDMA (Molly; Ecstasy; 3,4-methylenedioxymethamphetamine) and renal failure, meatal stenosis, medullary cystic kidney disease, uromodulin-associated nephropathy, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaureter, melamine toxicity and its kidney, MELAS syndrome, membranoproliferative glomerulonephritis, membranous Nephropathy, Membranous glomerulopathy with masked IgGkappa deposition, Mesoamerican nephropathy, Metabolic acidosis, Metabolic alkalosis, Methotrexate-associated renal failure, Microscopic polyangiitis, Milk-alkali syndrome, Minimal change disease, Monoclonal gammopathy with nephropathy, Dysproteinemia, Mouthwash toxicity, MUC1 nephropathy, Polycystic dysplastic kidney, Multiple myeloma, Myeloproliferative neoplasms and glomerulopathies, Nail-patella syndrome, NARP syndrome, Nephrocalcinosis, Nephrogenic systemic fibrosis, Nephroptosis (wandering kidney, Renal ptosis), Nephrotic syndrome, Neurogenic bladder, 9 / 11 and renal disease, Nodular glomerulosclerosis,Non-gonococcal urethritis, Nutcracker syndrome, Oligomegalic glomerulopathy, Orofacial-digital syndrome, Orotic aciduria, Orthostatic hypotension, Orthostatic proteinuria, Osmotic diuresis, Osmotic nephrosis, Ovarian hyperstimulation syndrome, Oxalate nephropathy, Page kidney, Papillary necrosis, Papillary-renal syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutation and kidney disease, Parvovirus B19 and kidney, Peritoneal-renal syndrome, POEMS syndrome, Posterior urethral valve, Podocyte invagination glomerulopathy, Post-infectious glomerulonephritis, Post-streptococcal post-infectious glomerulonephritis, Atypical post-infectious glomerulonephritis, Post-infectious glomerulonephritis (IgA-Dominant) Mimicking IgA nephropathy), polyarteritis nodosa, polycystic kidney disease, posterior urethral valves, post-obstructive diuresis, pre-eclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr disease), propolis (bee resin)-associated renal failure, proteinuria (protein in the urine), pseudoaldosteronism, pseudohypobicarbonatemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, pyridium and renal failure, radiation nephropathy, ranolazine and its kidneys, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute renal disease associated with renal arcuate vein microthrombosis Injury, Renal Artery Aneurysm, Spontaneous Renal Artery Dissection, Renal Artery Stenosis, Renal Cell Carcinoma, Renal Cyst, Renal Hypouricemia with Exercise-Induced Acute Renal Failure, Renal Infarction, Renal Osteodystrophy, Renal Tubular Acidosis, Renin Mutations and Autosomal Dominant Tubulointerstitial Kidney Disease, Renin-Secreting Tumors (Juxtaglomerular Cell Tumors), Reset Osmostat, Retrocaval Ureter, Retroperitoneal Fibrosis, Rhabdomyolysis, Rhabdomyolysis Associated with Bariatric Surgery, Rheumatoid Arthritis-Associated Kidney Disease, Sarcoidosis Kidney Disease, Renal and Cerebral Salt Loss, Schistosomiasis and Glomerular Disease, Schimke's Immune Osteogenesis Imperfecta, Scleroderma Renal Crisis, Serpentine Polycystic Kidney Disease Fibula-Polycystic Kidney Syndrome, Exner Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Kidney Disease in Sri Lankan Farmers, Sjogren's Syndrome and Kidney Disease, Synthetic Cannabis Use and Acute Kidney Injury, Kidney Disease Following Hematopoietic Cell Transplantation, Kidney Disease Associated with Stem Cell Transplantation, TAFRO Syndrome, Tea and Toast Hyponatremia,Tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal gammopathy-associated thrombotic microangiopathy, war nephritis, bladder trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular dysplasia, immune complex tubulointerstitial nephritis caused by autoantibodies against proximal tubule brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocele, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin-related 39. The method of claim 38, wherein the disease is selected from the group consisting of cast nephropathy, vasomotor nephropathy, vesicoenteric fistula, vesicoureteral reflux, VGEF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, von Hippel-Lindau disease, Waldenstrom's macroglobulinemic glomerulonephritis, warfarin-associated nephropathy, yellow bee sting and acute kidney injury, Wegener's granulomatosis, granulomatosis with polyangiitis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatic-renal syndrome.

55. 39. The method of claim 38, wherein the hearing loss is selected from the group consisting of mitochondrial genetic non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxins, disease-induced hearing loss, and trauma-induced hearing loss.

56. 39. The method of claim 38, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

57. 57. The method of any one of claims 38 to 56, comprising administering to the patient a compound of any one of claims 1 to 35 in combination with a second agent (e.g., an agent for treating cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, hearing loss, an eye disease, a musculoskeletal disease, a metabolic disease, a mitochondrial disease, or a disease or disorder associated with dysfunction of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway).

58. A method of treating a disease associated with modulation of eIF2B activity or levels, eIF2α activity or levels, or activity or levels of a component of the eIF2 pathway or the ISR pathway in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 35.

59. 59. The method of claim 58, wherein the modulation comprises an increase in eIF2B activity or level, an increase in eIF2α activity or level, or an increase in the activity or level of a component of the eIF2 pathway or the ISR pathway.

60. 59. The method of claim 58, wherein the disease can be caused by a mutation in the sequence of a gene or protein associated with a component of the eIF2 pathway (e.g., the eIF2α signaling pathway).

61. 36. A method of treating cancer in a patient in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 35 in combination with an immunotherapeutic agent.

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