Prodrug modulators of the integrated stress pathway and uses thereof

Abstract

This article provides compounds, compositions, and methods for modulating integrated stress response (iSR) and for treating related diseases, symptoms, and conditions.

Description

Prior Technology

[0001] In metazoans, various stress signals converge at a single phosphorylation event at serine 51 of the translation initiation factor eIF2α, a common effector. This process in mammalian cells utilizes four eIF2α kinases: PERK in response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 in response to amino acid starvation and ultraviolet light, PKR in response to viral infection and metabolic stress, and HRI in response to hemoglobin deficiency. This set of signaling pathways is called the "integrated stress response" (ISR) because these pathways converge on the same molecular event. eIF2α phosphorylation attenuates translation and enables cells to resist different stresses (Wek, RC et al., Biochem Soc Trans (2006) 34(Pt 1):7-11).

[0002] eIF2 (containing three subunits, namely α, β, and γ) binds to GTP and initiator Met-tRNA to form a ternary complex (eIF2-GTP-Met-tRNA i). This complex then associates with the 40S ribosomal subunit, scanning the 5'UTR of mRNA to select the initiation AUG codon. After phosphorylation of the α subunit, eIF2 becomes a competitive inhibitor of its GTP exchange factor (GEF), namely eIF2B (Hinnebusch, AG, and Lorsch, JR Cold Spring Harbor Perspect Biol (2012) 4(10)). Phosphorylated eIF2 binds tightly and ineffectively to eIF2B, preventing the eIF2 complex from loading GTP, thereby blocking the formation of the ternary complex and reducing translation initiation (Krishnamoorthy, T. et al., Mol Cell Biol (2001) 21(15):5018-5030). Since the content of eIF2B is lower than that of eIF2, only a small portion of total eIF2 phosphorylation has a significant impact on the activity of eIF2B in cells.

[0003] eIF2B is a complex molecular machine composed of five distinct subunits, eIF2B1 to eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with its partially homologous subunit eIF2B3, forms the "catalytic core" (Williams, DD et al., J Biol Chem (2001) 276:24697-24703). The remaining three subunits (eIF2B1, eIF2B2, and eIF2B4) are also highly homologous and form a "regulatory subcomplex," providing binding sites for the acceptor eIF2B, eIF2 (Dev, K. et al., Mol Cell Biol (2010) 30:5218-5233). The GDP / GTP exchange in eIF2 is catalyzed by its specific guanine nucleotide exchange factor (GEF), eIF2B. eIF2B exists in cells as an octamer (B1 2B2 2B3 2B4 2B5 2) or as a dimer of two pentamers (Gordiyenko, Y. et al., Nat Commun (2014) 5:3902; Wortham, NC et al., FASEB J (2014) 28:2225-2237). Molecules such as ISRIB interact with the eIF2B dimer and stabilize its conformation, thereby enhancing intrinsic GEF activity and making cells insensitive to cellular phosphorylation of eIF2α (Sidrauski, C. et al., eLife (2015) e07314; Sekine, Y. et al., Science (2015) 348:1027-1030). Therefore, small molecule therapeutic agents that modulate eIF2B activity may attenuate the PERK branch of UPR and the entire ISR, and thus may be used to prevent and / or treat a variety of diseases, such as neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, or metabolic diseases. Summary of the Invention

[0004] In one state sample, this paper describes a compound represented by formula (I): (I); Or a pharmaceutically acceptable salt, eutectic, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer, wherein: R1 series is selected from the following groups: -C(O)-C1-4 alkyl, -C(O)-OC1-4 alkyl, -C(O)-N(Ra)-C1-4 alkyl, -C(O)-C1-4 enylalkyl-C1-4 alkoxy, -C(O)-C1-4 enylalkyl-OC1-4 enylalkyl-C1-4 alkoxy, -methylene-OP(O)(OH)2, -C(O)-C1-5 enylalkyl-OP(O)(OH)2, -C(O)-OC1-5 enylalkyl-OP(O)(OH)2, -C(O)-N(Ra)-C1-5 enylalkyl-OP(O)(OH)2, -C(O)-C1-5 enylalkyl-P(O)(OH)2, -C(O)-C1-5 enylalkyl-enylphenyl-OP(O)(OH) 2. -C(O)-C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2) 2. -C(O)-C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2)(OC 1-5 enylalkyl-P(O)(OH) 2), -methylene-OC(O)C 1-5 enylalkyl-enylphenyl-OP(O)(OH) 2, -methylene-OC(O)C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2) 2. -C(O)-OC 1-5 enylalkyl-OC(O)C 1-5 enylalkyl-enylphenyl-OP(O)(OH) 2, -C(O)-N(Ra)-enylaryl-C 1-2 enylalkyl-OP(O)(OH) 2, -P(O)(OH) 2, -SO 3H, -SO 2NR aR b. -C(O)-heteroaryl, -C(O)-C 1-5-alkyl-OC 1-5-alkyl-phenyl and methylene-C 1-5-alkoxide; The -C(O)-C 1-4 alkyl group is substituted with one or two substituents, each of which is independently selected from the group consisting of -NR aR b and -CO 2H; and the substituents include -C(O)-OC 1-4 alkyl, -C(O)-N(Ra)-C 1-4 alkyl, -C(O)-C 1-4 alkyl-C 1-4 alkoxy, -C(O)-C 1-4 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, methylene-OP(O)(OH) 2, -C(O)-C 1-5 alkyl-OP(O)(OH) 2, -C(O)-OC 1-5 alkyl-OP(O)(OH) 2, -C(O)-N(Ra)-C 1-5 alkyl-OP(O)(OH) 2, and -C(O)-C 1-5 alkyl-P(O)(OH) 2. -C(O)-C 1-5 alkyl-phenyl-OP(O)(OH) 2. -C(O)-C 1-5 alkyl-phenyl-(OP(O)(OH) 2) 2. -C(O)-C 1-5 alkyl-phenyl-(OP(O)(OH) 2)(OC 1-5 alkyl-P(O)(OH) 2), -methylene-OC(O)C 1-5 alkyl-phenyl-OP(O)(OH) 2. -methylene-OC(O)C 1-5 alkyl-phenyl-(OP(O)(OH) 2) 2. -C(O)-OC 1-5 alkyl-OC(O)C 1-5 alkyl-phenyl-OP(O)(OH) 2, -C(O)-heteroaryl, -C(O)-C 1-5 alkyl-OC 1-5 alkyl-phenyl and -C(O)-N(R a)-Endonearyl-C1-2-endonel-OP(O)(OH)2 may be substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of: halogens, -CO2H, -NRaRb, and C1-2 alkyl groups (substituting with one, two, or three fluorine groups, depending on the case), and aryl groups; and Ra and Rb are each independently selected from the group consisting of hydrogen and C1-3 alkyl groups each time they appear.

[0005] In one state, this document describes a pharmaceutically acceptable composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0006] In one embodiment, this document describes a method for treating a patient in need of neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinic diseases, kidney diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases, comprising administering to the patient an effective amount of any of the compounds disclosed herein.

[0007] In one embodiment, this article describes a method for treating a patient in need of a disease related to the regulation of the activity or content of eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway, comprising administering to the patient an effective amount of any of the compounds disclosed herein.

[0008] In one embodiment, this article describes a method for treating cancer in a patient in need, comprising administering to the patient a combination of any of the compounds disclosed herein with an immunotherapeutic agent. Implementation

[0009] [Cross-reference to related applications] This application claims priority to U.S. Provisional Application No. 62 / 744,293, filed on October 11, 2018, the contents of which are incorporated herein by reference in their entirety.

[0010] The present invention is characterized by compounds, compositions, and methods for, for example, regulating (e.g., activating) eIF2B and weakening ISR signaling pathways, comprising compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers. In some embodiments, the compound of formula (I) is a prodrug of a bioactive compound that regulates components of eIF2B, eIF2α, or eIF2 or the ISR pathway. In some embodiments, the compound of formula (I) is a prodrug of the compound of formula (II). (II). [definition] [] Chemical definition

[0011] The following describes the definitions of specific functional groups and chemical terms in more detail. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover page, and specific functional groups are generally defined as described therein. Additionally, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following literature: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0012] The abbreviations used in this article have their common meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard chemical valence rules known in the field of chemistry.

[0013] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers may be prepared by methods known to those skilled in the art, including palmar high-performance liquid chromatography (HPLC) and the formation and crystallization of palmar salts from mixtures; or preferably, isomers may 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 sp. 268 (EL Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention also covers compounds described herein in their individual isomer forms, substantially free of other isomers, and alternatively, in mixtures of multiple isomers.

[0014] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., an enantiomeric excess). In other words, the "S" form of the compound substantially does not contain the "R" form of the compound and therefore, the enantiomer in the "R" form is in excess. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of enantiomers. In some embodiments, these weights are the total weight of all enantiomers or stereoisomers of the compound.

[0015] In the compositions provided herein, enantiomerically pure compounds may contain other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compounds. In some embodiments, the enantiomerically pure R-compounds in these compositions may, for example, contain at least about 95% by weight of R-compounds and at most about 5% by weight of S-compounds, based on the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure S-compounds. In some embodiments, the enantiomerically pure S-compounds in these compositions may, for example, contain at least about 95% by weight of S-compounds and at most about 5% by weight of R-compounds, based on the total weight of the compounds. In some embodiments, the active ingredient may be formulated using very little or no excipients or carriers.

[0016] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium) and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C and 14C; O may be in any isotopic form, including 16O and 18O; and the like.

[0017] The article "a species" in this text is used to refer to one or more species (i.e., at least one species) as the grammatical object of the article. For example, "an analogue" means one or more analogues.

[0018] When listing a range of values, it is intended to cover every value and subrange within that range. For example, "C1-C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0019] The following terms are intended to have the meanings presented below and can be used to understand the description and intended scope of the invention.

[0020] "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C1-C12 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tributyl (C4), dibutyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tripentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and similar groups. Alkyl groups may, in each case, be independently substituted as appropriate, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In some embodiments, the alkyl group is an unsubstituted C1-10 alkyl group (e.g., -CH3). In some embodiments, the alkyl group is a substituted C1-6 alkyl group. Commonly used alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3) or i-Bu (-CH2CH(CH3)2).

[0021] Unless otherwise specified, the term "alkylene" alone or as part of another substituent means a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) will have 1 to 24 carbon atoms, and in this invention, such groups preferably have 10 or fewer carbon atoms. Unless otherwise specified, the term "alkenyl" alone or as part of another substituent means a divalent group derived from an olefin. Alkenylenes can be described, for example, C1-C6 alkylene, wherein the term "member" refers to a non-hydrogen atom within that moiety.

[0022] "Alkenyl" refers to a straight-chain or branched hydrocarbon group ("C2-C20 alkenyl") having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no intermediate bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-C10 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butene group). Examples of C2-C4 alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and similar groups. Examples of C2-C6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and similar groups. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octtrienyl (C8), and similar groups. In each case, the alkenyl group may be independently substituted as appropriate, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In some embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl group. In some embodiments, the alkenyl group is a substituted C2-6 alkenyl group.

[0023] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-C 14 aryl"). In some embodiments, the aryl has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has fourteen ring carbon atoms ("C 14 aryl"; e.g., anthracene). Aryl can be described as, for example, C 6-C 10 member aryl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Aryl moieties include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. The aryl group may be substituted independently in each case, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is an unsubstituted C6-C14 aryl. In some embodiments, the aryl group is a substituted C6-C14 aryl.

[0024] In some embodiments, the aryl group is substituted with one or more groups selected from the following: halogen, C1-C8 alkyl, halogen-C1-C8 alkyl, halooxy-C1-C8 alkyl, cyano, hydroxy, alkoxy-C1-C8 alkyl, and amino.

[0025] Representative examples of substituted aryl groups include the following: . One of R56 and R57 may be hydrogen, and at least one of R56 and R57 is independently selected from C1-C8 alkyl, halo-C1-C8 alkyl, 4-10 member heterocyclic, alkoxy, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58COR 59, NR 58SOR 59NR 58SO 2R 59, C(O)O alkyl, C(O)O aryl, CONR 58R 59, CONR 58OR 59, NR 58R 59, SO 2NR 58R 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 can be bonded to form a cyclic ring (saturated or unsaturated) with 5 to 8 atoms, and may contain one or more heteroatoms selected from the groups N, O or S.

[0026] Other representative aryl groups with fused heterocyclic groups include the following: , Each W' group is selected from C(R 66) 2, NR 66, O and S; and each Y' group 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, 4-10 member heterocyclic, C 6-C 10 aryl and 5-10 member heteroaryl.

[0027] "Phenaryl" and "heteraryl" alone or as part of another substituent refer to divalent groups derived from aryl and heteroaryl groups, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxanepentenyl, benzodioxane, thianaphthyl, pyrrolopyridinyl, indazole, quinolinyl, quinoxalinyl, pyridinopyrazinyl, quinazolinoneyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothiopheneyl, and benzo[…]. Thiophane, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazoleyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanothiopheneyl, pyridyl, pyrimidinyl, benzothiazolyl, purineyl, benzimidazolyl, isoquinolinyl, thiadiazolyl, oxiadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolinyl. The above examples may be substituted or unsubstituted, and the divalent groups in the above heteroaryl examples are non-limiting examples of heteroaryl groups.

[0028] Unless otherwise specified, "halogen" or "halogen" alone or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halogen" alone or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. In some embodiments, the halogen is fluorine or chlorine.

[0029] Additionally, terms such as "haloalkyl" are intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and similar groups.

[0030] Unless otherwise specified, the term "heteroalkyl" alone or in combination with another term means a noncyclic stable straight or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be oxidized, and the nitrogen heteroatom may 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 rest of the molecule. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)2, -S(O)-CH3, -S(O)2-CH2, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. At most two or three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When the term "heteroalkyl" is used, followed by a specific heteroalkyl group such as -CH₂O, -NRBRC, or a similar group, it should be understood that the term heteroalkyl and -CH₂O or -NRBRC are not redundant or mutually exclusive. In fact, the specific heteroalkyl group is stated for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding a specific heteroalkyl group such as -CH₂O, -NRBRC, or a similar group.

[0031] Similarly, unless otherwise specified, the term "hexaalkyl" alone or as part of another substituent means a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH₂O- and -CH₂CH₂O-. Hexaalkyl groups can be described, for example, as 2-7 member hexaalkyl groups, where the term "member" refers to a non-hydrogen atom within that part. For hexaalkyl groups, the heteroatom may also occupy any one or both chain ends (e.g., hexaalkyloxy, hexaalkyldioxy, hexaalkylamino, hexaalkyldiamino, and similar groups). Furthermore, for hexaalkyl and hexaalkyl linking groups, the direction in which the chemical formula of the linking group is written does not indicate the orientation of the linking group. For example, the formula -C(O)₂R'- can represent -C(O)₂R'- and -R'C(O)₂-.

[0032] "Heteroaryl" refers to a group having a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system (e.g., a ring array with 6 or 10 π electrons) with a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom, if the valence state allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems fused with one or more aryl rings as defined above, wherein the bonding point is on the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazoleyl, and similar groups) that does not contain a heteroatom in one ring, the linkage can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). Heteroaryl groups can be described, for example, as 6-10-membered heteroaryl groups, where the term "member" refers to the non-hydrogen ring atom within that part.

[0033] In some embodiments, the heteroaryl group is a 5-10 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heteroaryl"). In some embodiments, the 5-6 member heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be substituted independently in each case, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl group is an unsubstituted 5-14 member heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 member heteroaryl group.

[0034] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadimonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0035] Representative examples of heteroaryl groups include the following: Each Y group is selected from carbonyl, N, NR 65, O and S; and R 65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 member heterocyclic, C6-C10 aryl and 5-10 member heteroaryl.

[0036] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group ("C3-C10 cycloalkyl") having 3 to 10 ring carbon atoms and zero heteroatoms in a non-aromatic ring system. In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms ("C5-C10 cycloalkyl"). Cycloalkyl can be described, for example, as a C4-C7 member cycloalkyl, where the term "member" refers to the non-hydrogen ring atom within that portion. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and similar groups. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubic alkyl (C8), bicyclo[1.1.1]pentyl (C5), bicyclo[2.2.2]octyl (C8), bicyclo[2.1.1]hexyl (C6), bicyclo[3.1.1]heptyl (C7), and similar groups. Exemplary C3-C10 cycloalkyl groups include, but are not limited to, the aforementioned C3-C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthyl (C10), spiro[4.5]decyl (C10), and similar groups. As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or partially unsaturated. “Cycloalkyl” also includes a cycloalkyl ring fused with one or more aryl groups as defined above, wherein the connecting point is on the cycloalkyl ring and in such cases, the number of carbon atoms still specifies the number of carbon atoms in the cycloalkyl ring system. The cycloalkyl group may be substituted independently in each case, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, the cycloalkyl group is an unsubstituted C3-C10 cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl group. [, , ]

[0037] In some embodiments, "cycloalkyl" refers to a monocyclic saturated cycloalkyl group having 3 to 10 cyclic carbon atoms ("C3-C10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms ("C5-C10 cycloalkyl"). Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, the cycloalkyl group in each case is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C3-C10 cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl group. [, , ]

[0038] "Heterocyclic group" or "heterocycle" refers to a 3- to 10-membered non-aromatic ring system group having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom, if the valence state allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. Bicyclic heterocyclic systems may include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system fused with one or more cycloalkyl groups as defined above, wherein the linking point is on the cycloalkyl or heterocyclic ring; or a ring system fused with one or more aryl or heteroaryl groups as defined above, wherein the linking point is on the heterocyclic ring, and in such cases, the number of ring members also specifies the number of ring members in the heterocyclic ring system. A heterocyclic group can be described, for example, as a 3-7 member heterocyclic group, where the term "member" refers to the non-hydrogen ring atom within that part, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In each case, the heterocyclic group may be independently substituted as appropriate, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-10 member heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 member heterocyclic group. [, , ]

[0039] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclic group"). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. [, , ]

[0040] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxeteropropyl, and thiohexacyclopropyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrobutyl, oxeterobutyl, and thiohexacyclobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxeteropentyl, oxeteropentane, dithiopentane, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropiperanyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, and similar groups. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and similar groups.

[0041] Specific examples of heterocyclic groups are shown in the following illustrative examples: Each W series is selected from CR 67, C(R 67) 2, NR 67, O and S; and each Y series is selected from NR 67, O and S; and R 67 is independently hydrogen, C 1-C 8 alkyl, C 3-C 10 cycloalkyl, 4-10 member heterocyclic, C 6-C 10 aryl and 5-10 member heteroaryl. These heterocyclic rings may be substituted, as appropriate, with one or more groups selected from the group consisting of: acetyl, acetylamino, acetoxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., acetylamino), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, halogen, hydroxyl, ketone, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituents include carbonyl or thiocarbonyl groups that provide, for example, lactamines and urea derivatives.

[0042] "Nitrogen-containing heterocyclic group" means a non-aromatic cyclic group of 4 to 7 members containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azacyclic butane, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine, such as N-methylpiperazine. Specific examples include azacyclic butane, piperidinone, and piperazineone.

[0043] "Amino" refers to the group -NR 70R 71, wherein R 70 and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 member heterocyclic, C6-C10 aryl, and 5-10 member heteroaryl. In some embodiments, amino refers to NH 2.

[0044] "Cyano" refers to the -CN group.

[0045] "Hydroxy group" refers to the -OH group.

[0046] As defined herein, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are substituted as appropriate (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted," whether preceded by the phrase "as appropriate," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, such as one that does not spontaneously transform by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is intended to include substitution with all permissible organic compound substituents, such as any substituents described herein that will form a stable compound. This invention covers any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein, such substituents satisfying the valence state of the heteroatom and causing the formation of a stable moiety. [, , ]

[0047] Two or more substituents may, as appropriate, combine to form aryl, heteroaryl, cycloalkyl, or heterocyclic groups. Such so-called cyclic substituents are typically, but not necessarily, attached to a cyclic base structure. In one embodiment, the cyclic substituent is attached to an adjacent member of the base structure. For example, two cyclic substituents attached to adjacent members of the cyclic base structure create a fused ring structure. In another embodiment, the cyclic substituent is attached to a single member of the base structure. For example, two cyclic substituents attached to a single member of the cyclic base structure create a spirocyclic structure. In yet another embodiment, the cyclic substituent is attached to a non-adjacent member of the base structure.

[0048] "Counter ions" or "anionic counter ions" are negatively charged groups that associate with cationic quaternary amine groups to maintain electroneutrality. Exemplary counter ions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, ClO4-, OH-, H2PO4-, HSO4-, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate and similar ions), and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate and similar ions). [, , ]

[0049] The term "medically acceptable salt" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases based on specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired base in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired acid in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid and similar acids, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and similar acids. Also included are salts of amino acids such as arginine and similar amino acids, and salts of organic acids such as glucuronic acid or galacturonic acid and similar acids (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of this invention contain basic and acidic functional groups that enable the compounds to be converted into basic addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in this invention. Salts tend to be more soluble in aqueous or other protic solvents that are the corresponding free base forms. In other cases, the formulation may be a lyophilized powder in a first buffer solution, for example, in a pH range of 4.5 to 5.5 containing 1 mM-50 mM histidine, 0.1%-2% sucrose, and 2%-7% mannitol, which is combined with a second buffer solution before use.

[0050] Therefore, the compounds of the present invention can exist in salt form, such as salts formed with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobroms, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts formed with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0051] The neutral form of these compounds is better regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. Certain physical properties of the parent form of the compound, such as its solubility in polar solvents, differ from those of the various salt forms.

[0052] The term "prodrug" can be used to describe the compounds of the present invention that readily undergo chemical changes under physiological conditions to provide bioactive compounds that regulate the eIF2B, eIF2α, or eIF2 or ISR pathways. Furthermore, the prodrug compounds of the present invention can be converted into bioactive compounds that regulate the eIF2B, eIF2α, or eIF2 or ISR pathways in an in vitro environment by chemical or biochemical methods. For example, the prodrug compounds of the present invention, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, can be slowly converted into bioactive compounds that regulate the eIF2B, eIF2α, or eIF2 or ISR pathways.

[0053] The term "medically 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 exists in a neutral (unionized) crystalline solid form, wherein one of the two or more compounds is an active pharmaceutical ingredient (e.g., compound of formula (I)) and wherein 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 exist independently in solid form under ambient conditions. In some embodiments, the two or more compounds interact via nonionic intermolecular interactions.

[0054] Some of the compounds of this invention may exist in unsolvated and solvated forms, including hydrated forms. Generally, the solvated form is equivalent to the unsolvated form and is covered within the scope of this invention.

[0055] Some of the compounds of this invention may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses covered by this invention and are intended to be within the scope of this invention.

[0056] As used herein, the term "salt" refers to an acid or base salt of a compound used in the methods of the present invention. Exemplary examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid and similar acids) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and similar acids) salts, and quaternary ammonium (iodomethane, iodoethane and similar) salts.

[0057] Some of the compounds of this invention have asymmetric carbon atoms (optically or diametrically opposed centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers defined by absolute stereochemistry, such as (R)- or (S)-, or (D)- or (L)- for amino acids, and individual isomers are all covered within the scope of this invention. The compounds of this invention do not include compounds known in this art to be too unstable to synthesize and / or isolate. This invention intends to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using diametrically opposed synthons or diametrically opposed reagents, or resolved using known techniques. When the compounds described herein contain alkene bonds or other geometrically asymmetric centers, and unless otherwise stated, such compounds are expected to include E and Z geometric isomers.

[0058] As used herein, the term "isomer" refers to compounds that have the same atomic number and type and therefore the same molecular weight, but whose atoms have different structural arrangements or configurations.

[0059] 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.

[0060] Those skilled in the art will readily recognize that some of the compounds of this invention can exist in tautomeric forms, and all such tautomeric forms of these compounds are within the scope of this invention.

[0061] The term "treatment" refers to any indication of successful treatment or improvement of an injury, disease, lesion, or condition, including any objective or subjective parameters such as the elimination, relief, or reduction of symptoms, or making the patient more tolerant of the injury, lesion, or condition; slowing the rate of degeneration or worsening; making the final outcome of degeneration less likely to result in debilitating symptoms; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examinations, neuropsychiatric examinations, and / or psychiatric evaluations. For example, some of the methods described in this article are used to treat cancers (e.g., pancreatic cancer, breast cancer, multiple myeloma, secretory cell carcinoma), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophy (e.g., leukoablation encephalopathy, childhood ataxia with CNS myelination insufficiency), postoperative cognitive impairment, traumatic brain injury, stroke, spinal cord injury, intellectual disability syndrome, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with reduced function of eIF2B or components of signal transduction or signaling pathways, including ISR and reduced eIF2 pathway activity). For example, some of the methods described in this article treat cancer by reducing or preventing its occurrence, growth, metastasis, or progression, or by alleviating its symptoms; neurodegeneration by improving mental health, increasing mental function, slowing the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive skills, reducing cognitive skill loss, improving memory, reducing memory decline, reducing symptoms of neurodegeneration, or prolonging survival; leukoabrasion by reducing symptoms of white matter ablation encephalopathy, or reducing white matter loss, or reducing myelin loss, or increasing myelin levels, or increasing white matter levels; childhood ataxia with CNS myelin deficiency by reducing symptoms of CNS myelination in children, or increasing myelin content, or reducing myelin loss; and intellectual disability syndrome by reducing symptoms of CNS myelination in children. To treat intellectual disability syndrome; to treat inflammatory diseases by treating symptoms of inflammatory diseases; to treat musculoskeletal diseases by treating symptoms of musculoskeletal diseases; to treat metabolic diseases by treating symptoms of metabolic diseases; to treat autoimmune diseases by treating symptoms of autoimmune diseases; to treat viral infections by treating symptoms of viral infections; to treat skin diseases by treating symptoms of skin diseases; to treat fibrotic diseases by treating symptoms of fibrotic diseases; to treat hemoglobinopathic diseases by treating symptoms of hemoglobinopathic diseases; to treat hearing loss by improving hearing in subjects in need; or to treat eye diseases by treating symptoms of eye diseases or improving vision in subjects in need.The diseases, symptoms, or conditions described herein (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinic disorders, kidney diseases, hearing loss, eye diseases, or symptoms associated with impaired function of components of eIF2B or signal transduction pathways, including the eIF2 pathway, eIF2α phosphorylation, or ISR pathways) will be known or can be determined by a person generally skilled in the art. The term "treatment" and related expressions include prevention of disease, lesion, condition, or illness (e.g., prevention of the development of one or more symptoms of the diseases, symptoms, or conditions described herein).

[0062] An "effective dose" is a quantity sufficient to achieve a specified purpose (e.g., to achieve the effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to reduce one or more symptoms of a disease or condition). Examples of "effective doses" are quantities sufficient to induce treatment, prevention, or reduction of one or more symptoms of a disease; these may also be called "therapeutic effective doses." A "preventive effective dose" is a quantity of drug that, when administered to a subject, will have the expected preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition, or its symptoms. A single dose may not produce a complete preventive effect, and it may only occur after a series of doses. Therefore, preventive effective doses can be administered in one or more doses. The exact dosage will depend on the therapeutic purpose and can be determined by someone skilled in the technique using known techniques (see, for example, 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 ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0063] The "reduction" of one or more symptoms (and the grammatical equivalent of the phrase) means to reduce the severity or frequency of the symptoms, or to eliminate the symptoms.

[0064] In the context of a substance or its activity or function being associated with a disease (such as the diseases or conditions described herein, such as cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobin disorders, kidney diseases, hearing loss, eye diseases, or diseases or conditions related to the impaired function of components in eIF2B or signal transduction pathways, including the eIF2 pathway, eIF2α phosphorylation, or the ISR pathway), the terms "associated" or "associated with" mean that the disease is (wholly or partially) caused by, or that the symptoms of the disease are (wholly or partially) caused by, the substance or its activity or function. For example, symptoms of diseases or conditions associated with reduced eIF2B function may be ( wholly or partially) caused by decreased eIF2B activity (e.g., decreased eIF2B activity or content, increased eIF2α phosphorylation or phosphorylated eIF2α activity, decreased eIF2 activity, or increased activity of phosphorylated eIF2α signaling or ISR signaling pathways). As used herein, if a pathogenic factor is described as being associated with a disease, it can be a target for treating that disease. For example, diseases associated with decreased eIF2 activity or eIF2 pathway activity can be treated with agents that effectively increase the content or activity of eIF2 or the eIF2 pathway, or reduce phosphorylated eIF2α activity or the ISR pathway (e.g., the compounds described herein). For example, diseases associated with phosphorylated eIF2α can be treated with agents that effectively reduce the activity levels of phosphorylated eIF2α or its downstream components or effectors (e.g., the compounds described herein). For example, diseases related to eIF2α can be treated with agents (such as the compounds described herein) that effectively increase the activity levels of eIF2 or its downstream components or effectors.

[0065] "Control" or "controlled experiment" is used in its general sense and refers to an experiment in which subjects or reagents are treated as in a parallel experiment, but with the experimental procedures, reagents, or variables omitted. In some cases, a control is used as a comparative standard for evaluating the effects of an experiment.

[0066] "Contact" is used in its general sense to refer to a process in which at least two different species (e.g., compounds, including biomolecules or cells) are brought close enough to react, interact, or physically contact. However, it should be understood that the resulting reaction product may be generated directly from a reaction between added reagents or from an intermediate obtained from one or more added reagents that produce a reaction mixture. The term "contact" can include causing two species to react, interact, or physically touch, wherein the two species may be compounds as described herein and proteins or enzymes (e.g., eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway). In some embodiments, contact includes causing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway (e.g., eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway).

[0067] As defined herein, the terms "inhibition / inhibit / inhibiting" and similar expressions relating to protein inhibitors (e.g., antagonists) mean adversely affecting (e.g., reducing) the activity or function of a protein relative to its activity or function in the absence of an inhibitor. In some embodiments, inhibition refers to reducing disease or disease symptoms. In some embodiments, inhibition refers to reducing the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes at least partially or completely blocking stimulation; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating the activity, amount, or quantity of signal transduction or enzyme activity or protein. In some embodiments, inhibition refers to reducing the activity of a signal transduction pathway or signaling pathway (e.g., the eIF2B, eIF2α, or eIF2 pathway, the pathway activated by eIF2α phosphorylation, or a component of the ISR pathway). Therefore, inhibition can at least partially or completely include reducing stimulation; reducing or decreasing activation; or inactivating, desensitizing, or downregulating the amount of signal transduction or enzyme activity or protein (e.g., components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway, each of which is associated with cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinic diseases, kidney diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, or metabolic diseases) that are increased in a disease. Inhibition may include at least partially or completely reducing stimulation; reducing or decreasing activation; or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or protein quantity (e.g., components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway) that can regulate the content of another protein or increase cell survival (e.g., reduced activity of the phosphorylated eIF2α pathway may increase cell survival, and such cells may or may not show an increase in phosphorylated eIF2α pathway activity relative to disease-free controls, or reduced activity of the eIF2α pathway may increase cell survival, and such cells may or may not show an increase in eIF2α pathway activity relative to disease-free controls).

[0068] As defined herein, the term "activation" and similar expressions relating to protein-activator (e.g., agonist) interactions mean, advantageously, (e.g., increasing), the activity or function of a protein (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway, or ISR pathway) relative to the activity or function of a protein in the absence of an activator (e.g., the compounds described herein). In some embodiments, activation refers to increasing the activity of a signal transduction pathway or signaling pathway (e.g., a component of the eIF2B, eIF2α, or eIF2 pathway, or ISR pathway). Thus, activation can at least partially or completely include partially or completely increasing stimulation; increasing or achieving activation; or activating, sensitizing, or upregulating the reduced activity of signal transduction or enzymes or the amount of proteins (e.g., the levels of eIF2B, eIF2α, or components of the eIF2 pathway, or ISR pathway associated with cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, or metabolic diseases). Activation can include at least partially or completely increasing stimulation; increasing or achieving activation; or activating, sensitizing, or upregulating the activity or amount of a signal transduction or enzyme that regulates the content of another protein or increases cell survival (e.g., components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway). For example, increased eIF2α activity can increase cell survival, and these cells may or may not show reduced eIF2α activity compared to disease-free controls.

[0069] The term "modulation" refers to an increase or decrease in the content or function of a target molecule. In some embodiments, modulation of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway may alleviate the severity of one or more symptoms of diseases associated with components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, or metabolic diseases) or diseases not caused by components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway but which may benefit from modulation of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway (e.g., reducing the content or activity level of components of the eIF2B, eIF2α, or eIF2 pathway).

[0070] As used herein, the term "modulator" refers to a modulator (e.g., one that modulates the level or function of a target molecule). In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are anticancer agents. In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are neuroprotective agents. In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are memory enhancers. In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are memory enhancers (e.g., long-term memory enhancers). In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are anti-inflammatory agents. In embodiments, modulators of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway are pain relievers.

[0071] "Patient" or "subject" in need refers to a living organism that suffers from or is susceptible to a disease or condition treatable by administration of the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, the patient is a human. In some embodiments, the patient is a domesticated animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a bovine animal. In some embodiments, the patient is a canine animal. In some embodiments, the patient is a feline animal. 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 newborn mammal. In some embodiments, the patient is an aged animal. In some embodiments, the patient is an elderly person. In some embodiments, the patient is an aged mammal. In some embodiments, the patient is an elderly patient.

[0072] "Disease," "symptom," or "condition" means the state or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein involve reducing or eliminating one or more symptoms of the disease, symptom, or condition, for example, by administering a compound of formula (I) or a medically acceptable salt thereof.

[0073] As used herein, the term "signaling pathway" refers to a series of interactions between a cell and, as appropriate, extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids), which transfer a change in one component to one or more other components, which in turn transfer the change to yet another component, which in turn propagates to other signaling pathway components.

[0074] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration of the active agent to a subject and the subject's absorption of the active agent, and can be included in the compositions of this invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard physiological saline solutions, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and colorants, and the like. Such formulations may be sterilized and, if necessary, mixed with adjuvants that do not adversely react with the compounds of this invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances and the like. Those skilled in this art will recognize that other pharmaceutical excipients can also be used in this invention.

[0075] The term "formulation" is intended to include a mixture of an active compound and a sealing material serving as a carrier for providing a capsule, wherein the active ingredient is associated with the carrier, whether in the presence or absence of other carriers. Similarly, this includes flat capsules and sugar tablets. Tablets, powders, capsules, pills, flat capsules, and sugar tablets can be used as solid dosage forms suitable for oral administration.

[0076] As used herein, the term "administration" means administration to a subject orally, as a suppository, via surface contact, intravenously, non-enterically, intraperitoneally, intramuscularly, intralesionally, intrathecally, intracranially, intranasally, or subcutaneously, or via implantation of a slow-release device, such as a micro-osmotic pump. Administration is carried out via any route, including non-enteric and mucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Non-enteric administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusion, and percutaneous patches. "Co-administration" means that the composition described herein is administered simultaneously with, immediately before, or immediately after one or more other therapies (e.g., treatment of an anticancer agent, chemotherapy agent, or neurodegenerative disease). The compounds of this invention can be administered to a patient alone or in combination. Co-administration is intended to include simultaneous or sequential administration of individual compounds or combinations of compounds (more than one compound or agent). Therefore, if necessary, these formulations can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0077] As used herein, the term "eIF2B" refers to heteropentauri eukaryotic translation initiation factor 2B. eIF2B consists of five subunits: eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. eIF2B1 refers to proteins associated with Entrez gene 1967, OMIM 606686, Uniprot Q14232, and / or RefSeq (protein) NP_001405. eIF2B2 refers to proteins associated with Entrez gene 8892, OMIM 606454, Uniprot P49770, and / or RefSeq (protein) NP_055054. eIF2B3 refers to proteins associated with Entrez gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to proteins associated with Entrez gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945. eIF2B5 refers to proteins associated with Entrez gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq (protein) NP_003898.

[0078] The terms "eIF2alpha", "eIF2a", or "eIF2α" are interchangeable and refer to the protein "eIF2S1, a subunit of eukaryotic translation initiation factor 2α". In embodiments, "eIF2alpha", "eIF2a", or "eIF2α" refers to a human protein. The terms "eIF2alpha", "eIF2a", or "eIF2α" include both wild-type and mutant forms of the protein. In embodiments, "eIF2alpha", "eIF2a", or "eIF2α" refers to proteins associated with Entrez gene 1965, OMIM 603907, UniProt P05198, and / or RefSeq (protein) NP_004085. In embodiments, the reference numbers mentioned above refer to proteins and related nucleic acids known as of the date of filing of this application. [Compound] []

[0079] In one state sample, this paper provides a compound represented by formula (I): (I); Or a pharmaceutically acceptable salt, eutectic, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer, wherein: R1 series is selected from the following groups: -C(O)-C1-4 alkyl, -C(O)-OC1-4 alkyl, -C(O)-N(Ra)-C1-4 alkyl, -C(O)-C1-4 enylalkyl-C1-4 alkoxy, -C(O)-C1-4 enylalkyl-OC1-4 enylalkyl-C1-4 alkoxy, -methylene-OP(O)(OH)2, -C(O)-C1-5 enylalkyl-OP(O)(OH)2, -C(O)-OC1-5 enylalkyl-OP(O)(OH)2, -C(O)-N(Ra)-C1-5 enylalkyl-OP(O)(OH)2, -C(O)-C1-5 enylalkyl-P(O)(OH)2, -C(O)-C1-5 enylalkyl-enylphenyl-OP(O)(OH) 2. -C(O)-C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2) 2. -C(O)-C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2)(OC 1-5 enylalkyl-P(O)(OH) 2), -methylene-OC(O)C 1-5 enylalkyl-enylphenyl-OP(O)(OH) 2, -methylene-OC(O)C 1-5 enylalkyl-enylphenyl-(OP(O)(OH) 2) 2. -C(O)-OC 1-5 enylalkyl-OC(O)C 1-5 enylalkyl-enylphenyl-OP(O)(OH) 2, -C(O)-N(Ra)-enylaryl-C 1-2 enylalkyl-OP(O)(OH) 2, -P(O)(OH) 2, -SO 3H, -SO 2NR aR b. -C(O)-heteroaryl, -C(O)-C 1-5-alkyl-OC 1-5-alkyl-phenyl and methylene-C 1-5-alkoxide; The -C(O)-C 1-4 alkyl group is substituted with one or two substituents, each of which is independently selected from the group consisting of -NR aR b and -CO 2H; and the substituents include -C(O)-OC 1-4 alkyl, -C(O)-N(Ra)-C 1-4 alkyl, -C(O)-C 1-4 alkyl-C 1-4 alkoxy, -C(O)-C 1-4 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, methylene-OP(O)(OH) 2, -C(O)-C 1-5 alkyl-OP(O)(OH) 2, -C(O)-OC 1-5 alkyl-OP(O)(OH) 2, -C(O)-N(Ra)-C 1-5 alkyl-OP(O)(OH) 2, and -C(O)-C 1-5 alkyl-P(O)(OH) 2. -C(O)-C 1-5 alkyl-phenyl-OP(O)(OH) 2. -C(O)-C 1-5 alkyl-phenyl-(OP(O)(OH) 2) 2. -C(O)-C 1-5 alkyl-phenyl-(OP(O)(OH) 2)(OC 1-5 alkyl-P(O)(OH) 2), -methylene-OC(O)C 1-5 alkyl-phenyl-OP(O)(OH) 2 or -methylene-OC(O)C 1-5 alkyl-phenyl-(OP(O)(OH) 2) 2. -C(O)-OC 1-5 alkyl-OC(O)C 1-5 alkyl-phenyl-OP(O)(OH) 2, -C(O)-heteroaryl, -C(O)-C 1-5 alkyl-OC 1-5 alkyl-phenyl and -C(O)-N(R a)-Endonearyl-C1-2-endonel-OP(O)(OH)2 may be substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of: halogens, -CO2H, -NRaRb, and C1-2 alkyl groups (substituting with one, two, or three fluorine groups, depending on the case), and aryl groups; and Ra and Rb are each independently selected from the group consisting of hydrogen and C1-3 alkyl groups each time they appear.

[0080] In some embodiments, R1 is a -C(O)-C1-4 alkyl group; wherein the -C(O)-C1-4 alkyl group is substituted with one or two substituents, each of which is independently selected from the group consisting of -NR aR b and -CO 2H.

[0081] In some embodiments, R1 is selected from the group consisting of: , , , and .

[0082] In some embodiments, R1 is a C(O)-OC1-4 alkyl group. In some embodiments, R1 is selected from... and A group that makes up the group.

[0083] In some embodiments, R1 is a -C(O)-N(Ra)-C1-4 alkyl group, wherein the -C(O)-N(Ra)-C1-4 alkyl group may be substituted with one or two –CO2H groups, depending on the situation. In some embodiments, R1 is composed of… , and express.

[0084] In some embodiments, R1 is a C(O)-C1-4 alkyl-C1-4 alkoxy group. In some embodiments, R1 is selected from... and A group that makes up the group.

[0085] In some embodiments, R1 is a C(O)-C1-4 alkyl-OC1-4 alkyl-C1-4 alkoxy group. In some embodiments, R1 is composed of... express.

[0086] In some embodiments, R1 is a methylene-OP(O)(OH)2. In some embodiments, R1 is composed of... express.

[0087] In some embodiments, R1 is a C(O)-C1-5 alkyl-OP(O)(OH)2. In some embodiments, R1 is selected from the group consisting of: , , and .

[0088] In some embodiments, R1 is a C(O)-OC1-5-alkyl-OP(O)(OH)2. In some embodiments, R1 is selected from the group consisting of: , and .

[0089] In some embodiments, R1 is a C(O)-N(Ra)-C1-5 alkyl-OP(O)(OH)2. In some embodiments, R1 is selected from... and A group that makes up the group.

[0090] In some embodiments, R1 is a C(O)-C1-5 alkyl-P(O)(OH)2. In some embodiments, R1 is composed of... express.

[0091] In some embodiments, R1 is a C(O)-C1-5 alkyl-phenyl-OP(O)(OH)2, a C(O)-C1-5 alkyl-phenyl-(OP(O)(OH)2)2, or a C(O)-C1-5 alkyl-phenyl-(OP(O)(OH)2)(OC1-5 alkyl-P(O)(OH)2). In some embodiments, R1 is selected from the group consisting of: , , , and .

[0092] In some embodiments, R1 is a C(O)-N(Ra)-acrylaryl-C1-2-alkyl-OP(O)(OH)2. In some embodiments, R1 is composed of... express.

[0093] In some embodiments, R1 is a -C(O)-heteroaryl group. In some embodiments, the R1 group is selected from... and A group that makes up the group.

[0094] In some embodiments, R1 is a C(O)-C1-5 alkyl-OC1-5 alkyl-phenyl group. In some embodiments, R1 is composed of... express.

[0095] In some embodiments, R1 is a methylene-C1-5 alkoxide. In some embodiments, R1 is composed of... express.

[0096] In some embodiments, R1 is derived from -C(O)-OC1-5-alkyl-OC(O)C1-5-alkyl-phenyl-OP(O)(OH)2, -methylene-OC(O)C1-5-alkyl-phenyl-OP(O)(OH)2, or -methylene-OC(O)C1-5-alkyl-phenyl-(OP(O)(OH)2)2. In some embodiments, R1 is derived from... , and express.

[0097] In some embodiments, R1 is selected from the group consisting of -P(O)(OH)2, -SO3H and -SO2NH2.

[0098] In some embodiments, the compound of formula (I) is selected from the compounds described in Table 1 or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers or stereoisomers. [, , ] [] [surface] [1]: Exemplary compounds of the present invention [Compound Number] [structure] [Compound Number] [structure]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] [Methods for preparing exemplary compounds] []

[0099] The compounds disclosed herein can be better understood by referring to the following synthetic procedures and methods, which illustrate ways in which these compounds can be prepared. The compounds disclosed herein can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in, but not limited to, procedures 1-5. Variables R1, Ra, and Rb are as defined in detail herein, for example, in the summary of the invention. Procedure 1: A representative procedure for synthesizing exemplary compounds disclosed herein.

[0100] As shown in process 1, the compounds of formulas (1-3), (1-5) and (1-7) can be prepared from the compound of formula (1-1).

[0101] The compound of formula (1-1) can be reacted with an aminophosphate of formula (1-2) (wherein PG 1 is a protecting group, such as tert-butyl or, where appropriate, a substituted benzyl group) in the presence of a 1 H-tetrazole acetonitrile solution in a solvent heated, where appropriate, such as, but not limited to, N,N-dimethylformamide, dimethylacetamide, or dichloromethane. Subsequently, the phosphorus moiety is oxidized by treatment with an oxidizing agent, such as hydrogen peroxide. Then, the protecting group PG 1 can be removed using conditions known to those skilled in the art and according to the specific protecting group. For example, the benzyl protecting group can be removed by catalytic hydrogenation or by treatment with an acid, such as, but not limited to, trifluoroacetic acid, thereby yielding the compound of formula (1-3). For the tert-butyl protecting group, treatment with trifluoroacetic acid in a solvent such as dichloromethane also provides the compound of formula (1-3). The compounds of formula (1-3) are representative of the compounds of formula (I).

[0102] The compound of formula (1-1) can be reacted with the C1-3 alkyl chloroformate of formula (1-4) in pyridine under appropriate heating to give the compound of formula (1-5). The compound of formula (1-5) is representative of the compound of formula (I).

[0103] The compound of formula (1-1) can be reacted with the compound of formula (1-6) (where R 1-a is OH or NR aR b) in a solvent such as dichloromethane or N,N-dimethylacetamide to give the compound of formula (1-7). The compound of formula (1-7) is representative of the compound of formula (I). Procedure 2: A representative procedure for the exemplary compounds used in the cost disclosure case.

[0104] As shown in process 2, the compound of formula (2-2) can be prepared from the compound of formula (1-1). The compound of formula (1-1) can be coupled with the carboxylic acid of formula (21) and subsequently deprotected, if necessary, to remove the protecting group, to obtain the compound of formula (2-2). Examples of conditions known for producing esters from a mixture of the carboxylic acid of formula (2-1) and the alcohol of formula (1-1) include, but are not limited to, the addition of coupling agents, 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. These coupling agents can be added in solid, solution, or as agents bound to a solid supporting resin. In addition to coupling agents, auxiliary coupling agents can promote the coupling reaction. Commonly used auxiliary coupling agents in coupling reactions include, but are not limited to, (dimethylamino)pyridine (DMAP). The reaction can be carried out, depending on the circumstances, in the presence of a base such as triethylamine or N,N-diisopropylethylamine. The coupling reaction can be carried out in solvents such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethane. The coupling reaction can be carried out at ambient temperature or under heating, which can be achieved by conventional methods or by microwave irradiation. R 2a is selected from the group consisting of: -C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, C 14 alkyl-OC 14 alkyl-C 1-4 alkoxy, -C 1-5 alkyl-OP(O)(OPG 1) 2, C 15 alkyl-P(O)(OPG 1) 2, -C 15 alkyl-phenyl-OP(O)(OPG 1) 2, and -heteroaryl; wherein the C 1-4 alkyl is substituted by one or two substituents, each of which is independently selected from the group consisting of –NR aPG 2 and -CO 2H; and wherein -C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, C 14 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, C 15 alkyl-OP(O)(OPG 1) 2, C The 15-alkyl P(O)(OPG 1) 2, -C 1-5 alkyl-phenyl-OP(O)(OPG 1) 2, and -heteroaryl groups may be substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of halogens, -CO 2H, C 1-2 alkyl groups (substituted with one, two, or three fluorine groups, depending on the case), and aryl groups. Protecting group PG 1 is as defined in Procedure 1. Protecting group PG 2 is an amine protecting group, such as, but not limited to, a tert-butoxycarbonyl group. Protecting groups PG 1 and PG 2 may be removed using conditions known to those skilled in the art and depending on the specific protecting group.For example, the benzyl protecting group (PG 1) can be removed by catalytic hydrogenation or by treatment with an acid, such as but not limited to trifluoroacetic acid, thereby obtaining the compound of formula (2-2). For the tert-butyl protecting group (PG 1) or the tert-butyloxycarbonyl protecting group (PG 2), treatment with trifluoroacetic acid in a solvent such as dichloromethane also provides the compound of formula (2-2). After coupling or coupling followed by removal of the protecting group, a compound of formula (2-2) is obtained, wherein R 2-b is a group consisting of -C 1-4 alkyl, C 14 alkyl-C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, C 15 alkyl OP(O)(OH) 2, -C 1-5 alkyl-P(O)(OH) 2, -C 1-5 alkyl-phenyl-OP(O)(OH) 2, and -heteroaryl; wherein the -C 1-4 alkyl group is substituted with one or two substituents, each of which is independently selected from the group consisting of -NHR a and -CO 2H; and wherein the -C 1-4 alkyl, C 1-4 alkyl-C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, C 15 alkyl OP(O)(OH) 2, -C The 1-5-alkyl-P(O)(OH)₂, -C 1-5-alkyl-phenyl-OP(O)(OH)₂, and –heteroaryl groups may be substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of: halogens, -CO₂H, C 1-2 alkyl groups (substituted with one, two, or three fluorine groups, depending on the case), and aryl groups. Compounds of formula (2-2) are representative of compounds of formula (I). Procedure 3: Representative procedure for the exemplary compounds used in the cost disclosure.

[0105] As shown in process 3, the compound of formula (3-2) can be prepared from the compound of formula (1-1). The compound of formula (1-1) can be coupled with the chloride or chloroformate of the carboxylic acid of formula (31) and subsequently deprotected, if necessary, to remove the protecting group, thereby obtaining the compound of formula (3-2). These chlorides of carboxylic acids can be obtained from commercial sources or prepared from the corresponding carboxylic acid by treatment with oxalic acid and a catalytic amount of N,N-dimethylformamide, thionyl chloride, cyanochloroamine, PCl3, or PCl5. Examples of conditions known for producing esters or carbonates from a mixture of the chloride or chloroformate of the carboxylic acid of formula (3-1) and an alcohol of formula (1-1) include, but are not limited to, the addition of a base such as triethylamine or N,N-diisopropylethylamine, and optional auxiliary coupling agents such as, but not limited to, (dimethylamino)pyridine (DMAP). The coupling reaction can be carried out in solvents, such as, but not limited to, N,N-dimethylformamide, N,N-dimethylacetamide and dichloromethane. R 3a is selected from the group consisting of: -C 1-4 alkyl, -OC 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, C 14 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, -C 1-5 alkyl-OP(O)(OH) 2, C 15 alkyl-OP(O)(OPG 1) 2, -OC 1-5 alkyl-OP(O)(OPG 1) 2, -C 1-5 alkyl-P(O)(OPG 1) 2, C 15 alkyl-Phenylphenyl-OP(O)(OPG 1) 2, and -heteroaryl, wherein the -C 1-4 alkyl is substituted with one or two substituents, each of which is independently selected from the group consisting of -NR aPG 2 and CO 2H; and wherein the -OC 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, C The 14-alkyl group (OC), 14-alkyl C14alkoxy group, -C1-5-alkyl-OP(O)(OH)2 group, C15-alkyl-OP(O)(OPG1)2 group, -OC1-5-alkyl-OP(O)(OPG1)2 group, -C1-5-alkyl-P(O)(OPG1)2 group, C15-alkyl-phenyl-OP(O)(OPG1)2 group, and heteroaryl groups may be substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of halogens, CO2H, -NR aRb, C1-2 alkyl groups (substituted with one, two, or three fluorine groups, depending on the case), and aryl groups. Protecting group PG1 is as defined in process 1, and protecting group PG2 is as defined in process 2. Protecting groups PG1 and PG2 may be removed as described in the previous process, using conditions known to those skilled in the art and according to the specific protecting group.Following coupling or coupling followed by removal of the protecting group, compounds of formula (3-2) are obtained, wherein R 3-b is a -C 1-4 alkyl, -OC 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, C 1-4 alkyl-OC 1-4 alkyl-C 1-4 alkoxy, -C 1-5 alkyl-OP(O)(OH) 2, OC 15 alkyl-OP(O)(OH) 2, -C 1-5 alkyl-P(O)(OH) 2, -C 1-5 alkyl-phenyl-OP(O)(OH) 2, and -heteroaryl; each of which is substituted as described above, depending on the circumstances. In some cases, the esters or carbonates resulting from coupling may be further modified using methods known to those skilled in the art. Compounds of formula (3-2) are representative of compounds of formula (I). Procedure 4. Representative procedure for the exemplary compounds used in this cost disclosure.

[0106] As shown in process 4, the compound of formula (4-2) can be prepared from the compound of formula (1-1). The compound of formula (1-1) can be reacted with triphosgene or N,N'-disuccinimidyl carbonate in pyridine or a mixture of pyridine and dichloromethane, as appropriate, to obtain the compound of formula (4-1). The compound of formula (4-1) can be reacted with a nucleophile R4-bX1-H (where X1 is O or NRa and R4-b is -C1-4 alkyl, C15 alkyl OP(O)(OPG1)2, ​​-anearyl-C1-2 alkyl-OP(O)(OPG1)2, ​​wherein the -C1-4 alkyl is substituted by one or two substituents, each of which is independently selected from the group consisting of bromine and CO2H) in a base such as triethylamine or N,N-diisopropylethylamine or sodium bicarbonate and an auxiliary coupling agent such as, but not limited to, (dimethylamino)pyridine (DMAP) in a solvent such as tetrahydrofuran or ethyl acetate. The protecting group PG1, when present, can be removed as described in procedure 1, using conditions known to those skilled in the art and according to the specific protecting group. In some cases, carbonates or carbamates formed by coupling can be further modified using methods known to those skilled in the art. For example, when R4-b is an alkyl bromide, bromine can be substituted in a nucleophilic substitution reaction. Compounds of formula (4-2) are representative of compounds of formula (I), wherein R4-c is a -C1-4 alkyl, C15 alkyl-OP(O)(OH)2, or -hexaaryl-C1-2 alkyl-OP(O)(OH)2, wherein the -C1-4 alkyl is substituted with one or two CO2H. Compounds of formula (4-2) are representative of compounds of formula (I). Procedure 5. Representative procedure for the exemplary compounds used in the cost disclosure.

[0107] As shown in process 5, compounds of formula (5-2) and (5-3) can be prepared from compounds of formula (1-1). Compound (1-1) can be reacted with chloromethyl methyl sulfide in the presence of iodine and a base such as sodium hydride in a solvent such as tetrahydrofuran to obtain compound (5-1). Compound (51) can be treated first with solid H₃PO₄ and an active 5Å molecular sieve, followed by treatment with N-iodosuccinimide to obtain compound (5-2). Alternatively, compound (51) can be treated first with solid H₃PO₄ and an active 5Å molecular sieve, followed by treatment with N-iodosuccinimide, and then with a C₁-5 alcohol to obtain compound (5-3). Compounds of formula (5-2) and (5-3) are representative of compounds of formula (I). [Pharmaceutical Compositions] []

[0108] The present invention is characterized by a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, 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, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer system thereof is provided in the pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventatively effective amount.

[0109] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include the following steps: combining a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer ("active ingredient") with a carrier and / or one or more other auxiliary components, and then, if necessary and / or required, shaping and / or packaging the product into desired single-dose or multi-dose units. Pharmaceutical compositions can be prepared, packaged, and / or marketed as a whole, in a single unit dose, and / or in multiple single unit doses. As used herein, a "unit dose" refers to an individual amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and / or a convenient portion of such dose, such as half or one-third of such dose.

[0110] Depending on the characteristics, physical condition, and / or status of the subject being treated, and also depending on the route of administration of the composition, the relative amounts of the compound of formula (I) or its pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides or stereoisomers, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical composition of the present invention will vary. For example, the composition may contain between 0.1% and 100% (w / w) of the compound of formula (I) or its pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides or stereoisomers.

[0111] The term "pharmaceutical-acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or mediator that does not impair the pharmacological activity of the compound it is formulated with. Pharmaceutically acceptable excipients that can be used in the manufacture of the pharmaceutical compositions of this invention are any of such excipients well known in the pharmaceutical formulation field and include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients that can be used in the manufacture of the compositions of this invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances, such as phosphates, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin.

[0112] The components of this invention can be administered orally, non-enterically (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, surface, rectum, nose, cheek, vagina, or via an implanted reservoir. In some embodiments, the provided compounds or components can be administered intravenously and / orally.

[0113] As used herein, the term "non-enteric" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, these compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oil suspension. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in this art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-enteric acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are typically used as solvents or suspension media.

[0114] The pharmaceutically acceptable composition of this invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets intended for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For capsules intended for oral administration, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added if necessary. In some embodiments, the provided oral formulation is formulated for immediate release or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges, and soft lozenges. Compounds of formula (I) or pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof may also be in microencapsulated form.

[0115] The components of this invention can be formulated as plasters, solutions, suspensions, emulsions, gels, creams, ointments, pastes, colloids, lotions, powders, and aerosols for transdermal or surface delivery. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, capsules, gels, syrups, slurries, suspensions, etc., suitable for patient ingestion. Solid formulations include powders, tablets, pills, capsules, capsules, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The components of this invention may additionally include components that provide sustained release and / or comfort. Such components include high molecular weight, anionic mucosal mimic polymers, gelling polysaccharides, and finely dispersed drug carrier matrices. These components are described in more detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The components of this invention can also be delivered in the form of microspheres for slow release in vivo. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for slow subcutaneous release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995); or orally (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the components of the present invention can be delivered using liposomes that fuse with the cell membrane or undergo endocytosis, i.e., by employing receptor ligands attached to the liposomes, which bind to cell surface membrane protein receptors, inducing endocytosis. By using liposomes, particularly when the liposomes are loaded with target cell-specific receptor ligands on their surface, or otherwise preferentially directed to specific organs, in vivo delivery of the components of the present invention can be concentrated in target cells. (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 components of the present invention can also be delivered in nanoparticle form.

[0116] Alternatively, the pharmaceutically acceptable composition of the present invention can be administered rectally as a suppository. The pharmaceutically acceptable composition of the present invention can also be administered topically, particularly when the therapeutic target includes areas or organs easily accessible by top administration, including eye, skin, or lower bowel diseases. Suitable top formulations are readily prepared for each of these areas or organs.

[0117] In some embodiments, to prolong the action of a drug, it is often necessary to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved using liquid suspensions of crystalline or amorphous materials with weak water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of drugs administered non-enterically is achieved by dissolving or suspending the drug in an oil-based carrier.

[0118] Although the descriptions of pharmaceutical compositions provided herein are primarily directed at those suitable for human administration, those skilled in the art will understand that such compositions are generally suitable for administration to all species of animals. It should be fully understood that pharmaceutical compositions suitable for human administration can be modified to make them suitable for administration to a variety of animals, and that such modifications can be designed and / or implemented by a generally skilled veterinary pharmacologist with only routine experiments.

[0119] To facilitate administration and dosage uniformity, the compounds provided herein, such as compounds of formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers, are typically formulated in unit dosage forms, such as single unit dosage forms. However, it should be understood that the total daily dosage of the pharmaceutical composition of this invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose for any particular subject or organism will depend on a variety of factors, including the severity of the disease and condition being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health status, sex, and diet; the time of administration; the route of administration; and the excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in the medical field.

[0120] The exact amount of compound required to achieve an effective dose will depend on factors such as species, age and general condition of the subject, severity of side effects or illness, properties of the specific compound, administration pattern, and similar factors that vary with the subject. The required dose may be delivered three times a day, twice a day, once a day, every other day, every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the required dose may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0121] In some embodiments, the effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof for administration once or more daily may comprise about 0.0001 mg to about 5000 mg per unit dosage form, for example, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg.

[0122] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be a compound that is delivered once or more daily in doses sufficient to deliver about 0.001 mg to about 1000 mg per kilogram of the subject's body weight per day, for example, about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 40 mg, about 0.1 mg to about 25 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, or about 1 mg to about 50 mg, to achieve the desired therapeutic effect.

[0123] It should be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical ingredients to adults. The dosage intended for, for example, children or adolescents, may be determined by a medical professional or someone skilled in the art and may be lower than or the same as the adult dosage.

[0124] It should also be understood that compounds or compositions described herein, such as compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers, may be administered in combination with one or more other pharmaceutical agents. These compounds or compositions may be administered in combination with other pharmaceutical agents that improve their bioavailability, reduce and / or regulate their metabolic activity, inhibit their excretion, and / or alter their distribution in the body. It should also be understood that the treatments used may achieve the desired effect for the same condition and / or may achieve different effects.

[0125] The compound or composition may be administered simultaneously, before, or after one or more other pharmaceutical agents, and may be used as, for example, a combination therapy. The pharmaceutical agents include therapeutic agents. The pharmaceutical agents also include prophylactic agents. Each additional pharmaceutical agent may be administered at a determined dose and / or timing. These additional pharmaceutical agents may also be administered, either individually or separately, together with each other and / or with the compound or composition described herein, in a single dose. Specific combinations used in a regimen will take into account the compatibility of the compound with the additional pharmaceutical agents and / or the desired therapeutic and / or preventative effects. Generally, the additional pharmaceutical agents intended for combined use are to be used in amounts not exceeding their individual uses. In some embodiments, the combined amount will be less than the individual amount used.

[0126] Other illustrative pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and pain relievers. Pharmaceutical agents include small organic molecules such as pharmaceutical compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Federal Regulation Code (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, 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.

[0127] The pharmaceutical compositions provided by this invention include compositions containing a therapeutically effective amount, i.e., an amount of active ingredient (e.g., the compounds described herein, including examples or instances) that effectively achieves its intended purpose. The actual amount effective for a particular application will depend particularly on the condition being treated. When administered in a method of treating a disease, such compositions will contain an amount of active ingredient that effectively achieves the desired outcome, such as modulating the activity of target molecules (e.g., components of the eIF2B, eIF2, or eIF2α signaling pathway, or components of the phosphorylated eIF2α pathway or ISR pathway), and / or reducing, eliminating, or slowing disease symptoms (e.g., symptoms of cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with reduced function of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway). The determination of the therapeutically effective amount of the compounds of this invention is within the capabilities of those skilled in the art, and particularly based on the detailed disclosure herein.

[0128] The dosage and frequency (single or multiple doses) administered to mammals can vary depending on a variety of factors, such as whether the mammal has another disease and the route of administration; the recipient's physique, age, sex, health status, weight, body mass index, and diet; the nature and severity of the symptoms of the disease being treated (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or symptoms of diseases or conditions related to reduced function of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway); the type of co-treatment; complications of the disease being treated or other health-related problems. Other treatment regimens or agents may be used in conjunction with the applicant's method and compounds. The adjustment and operation of the determined dosage (e.g., frequency and duration) are within the capabilities of a person skilled in the art.

[0129] For any of the compounds described herein, the therapeutically effective amount may initially be determined by cell culture assay. The target concentration will be the concentration of the active compound capable of achieving the methods described herein, and may be measured using methods described herein or known in this art.

[0130] As is well known in this technique, therapeutically effective doses for humans can also be determined using animal models. For example, human doses can be formulated to achieve concentrations effective for animals. Human doses can be adjusted, as described above, by monitoring the effectiveness of the compound and increasing or decreasing the dose. Adjusting the dose according to the above and other methods to achieve maximum efficacy in humans is well within the capabilities of someone generally skilled in this technique.

[0131] Dosage may vary depending on patient requirements and the compound used. In the context of this invention, the dose administered to the patient should be sufficient to elicit a beneficial therapeutic response in the patient over time. The dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular condition is within the skill level of the practitioner. Generally, treatment is initiated with a lower dose than the optimal dose of the compound. The dose is then increased in small increments until optimal efficacy is achieved under certain conditions. Dosage and time intervals can be adjusted independently to provide an effective amount of the compound administered for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0132] Using the teachings provided herein, effective preventative or therapeutic treatment regimens can be developed that do not produce significant toxicity and effectively treat the clinical symptoms presented by a particular patient. This development should involve careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, presence and severity of adverse side effects, optimal administration modality, and the toxicity profile of the chosen agent.

[0133] This invention also covers kits (e.g., pharmaceutical packaging). Kits of this invention can be used for the prevention and / or treatment of diseases (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or other diseases or conditions described herein).

[0134] The provided kit may contain the pharmaceutical composition or compound of the present invention and a container (e.g., vial, ampoule, bottle, syringe and / or dispenser pack, or other suitable container). In some embodiments, the provided kit may 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 first and second containers are combined to form a unit dosage form.

[0135] Therefore, in one embodiment, a kit is provided comprising a first container containing a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, or a pharmaceutical composition thereof. In some embodiments, such kits may be used to prevent and / or treat a proliferative disease in a subject. In some embodiments, such kits further comprise instructions for administering a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject for the prevention and / or treatment of the disease described herein. [Treatment methods] []

[0136] The present invention is characterized by compounds, compositions, and methods comprising a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, such compounds, compositions, and methods are used to prevent or treat diseases, symptoms, or conditions. Examples of diseases, symptoms, or conditions include, but are not limited to, neurodegenerative diseases, leukodystrophy, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobinopathies, kidney diseases, hearing loss conditions, eye diseases, diseases with UPR-induced mutations, malaria infection, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases.

[0137] In some embodiments, the disease, symptom, or condition is associated with (or caused by) the regulation of eIF2B activity or levels, eIF2α activity or levels, or components of the eIF2 pathway or ISR pathway. In some embodiments, the disease, symptom, or condition is associated with the regulation of signal transduction pathways (e.g., phosphorylation of components of the eIF2 pathway or ISR pathway) related to components of the eIF2 pathway or ISR pathway. In some embodiments, the disease, symptom, or condition is associated with (e.g., caused by) neurodegeneration. In some embodiments, the disease, symptom, or condition is associated with (e.g., caused by) neuronal cell death or dysfunction. In some embodiments, the disease, symptom, or condition is associated with (e.g., caused by) glial cell death or dysfunction. In some embodiments, the disease, symptom, or condition is associated with (or caused by) an increase in the levels or activity of eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway. In some embodiments, the disease, symptom, or condition is associated with (or caused by) a decrease in the levels or activity of eIF2B, eIF2α, or components of the eIF2 pathway or ISR pathway.

[0138] In some embodiments, the disease may be caused by mutations in gene or protein sequences associated with members of the eIF2 pathway (eIF2B, eIF2α, or other components). Exemplary mutations include amino acid mutations in the subunits eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. In some embodiments, amino acid mutations in a particular protein (e.g., amino acid substitution, addition, or deletion) may result in structural changes, such as conformational or spatial variations, that affect protein function. For example, in some embodiments, amino acids in and around or adjacent to binding sites (e.g., phosphorylation sites, small molecule binding sites, or protein binding sites) at the active site may be mutated to affect protein activity. In some cases, amino acid mutations (e.g., amino acid substitution, addition, or deletion) may be conserved mutations and may not substantially affect the structure or function of the protein. For example, in some cases, replacing a serine residue with a threonine residue may not significantly affect protein function. In other cases, amino acid mutations may be of greater concern, such as the substitution of charged amino acids (e.g., aspartic acid or lysine) with larger, nonpolar amino acids (e.g., phenylalanine or tryptophan), and thus can have a significant impact on protein function. The nature of mutations affecting the structure or function of genes or proteins can be readily identified using standard sequencing techniques well known in this field, such as deep sequencing. In some embodiments, mutations in members of the eIF2 pathway can affect the binding or activity of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers, and thereby modulate the treatment of a particular disease, condition, or symptom.

[0139] In some embodiments, the eIF2 protein may contain amino acid mutations (e.g., amino acid substitutions, additions, or deletions) at residues of alanine, arginine, aspartamine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some embodiments, the eIF2 protein may contain amino acid substitutions at residues of alanine, arginine, aspartamine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some embodiments, the eIF2 protein may contain an amino acid addition at alanine, arginine, aspartamine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues. In some embodiments, the eIF2 protein may contain an amino acid deletion at alanine, arginine, aspartamine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues.

[0140] In some embodiments, the eIF2 protein may contain amino acid mutations (e.g., amino acid substitution, addition, or deletion) at alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues in the subunits eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. In some embodiments, the eIF2 protein may contain amino acid substitutions at the alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues in the subunits eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. In some embodiments, the eIF2 protein may include an amino acid addition at the alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residues in the subunits eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. In some embodiments, the eIF2 protein may contain an amino acid deletion at a residue of alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine in 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).

[0141] In some embodiments, amino acid mutations (e.g., amino acid substitution, addition, or deletion) in eIF2 pathway members (e.g., eIF2B protein subunits) can affect the binding or activity of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers and thereby modulate the treatment of a particular disease, condition, or symptom. Neurodegenerative diseases

[0142] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat neurodegenerative diseases. As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the subject's nervous system is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, cortical basal degeneration, Creutzfeldt-Jakob disease, dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy's disease, and Krabby's disease. Diseases including: kuru, Lewy body dementia, Marjorie's disease (type 3 spinocerebellar ataxia), multiple system atrophy, multiple system proteinosis, narcolepsy, spirochete disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prions, Refsum's disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with different characteristics, such as type 2 or type 8 spinocerebellar ataxia), spinal muscular atrophy, and Steele-Richardson-Olszewski disease. Diseases, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pey-Med's disease, Clyber's disease, leukodystrophy caused by DARS2 gene mutation (sometimes called leukodystrophy involving the brainstem and spinal cord with elevated lactate (LBSL)), DARS2-related autism or tabes dorsalis.

[0143] In some embodiments, neurodegenerative diseases include leukoablative encephalopathy, childhood ataxia with CNS myelination insufficiency, leukodystrophy, leukoencephalopathy, myelination dysplasia or demyelinating diseases, intellectual disability syndromes (e.g., Fragile X syndrome), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, frontotemporal dementia (FTD), Gerstmann-Schwarzman syndrome, Huntington's disease, dementia (e.g., HIV-associated dementia or Lewy body dementia), kuru, multiple sclerosis, Parkinson's disease, or prions.

[0144] In some embodiments, neurodegenerative diseases include leukoablative encephalopathy, childhood ataxia with CNS myelination insufficiency, leukodystrophy, leukoencephalopathy, myelination dysplasia or demyelinating diseases, or intellectual disability syndromes (e.g., Fragile X syndrome).

[0145] In some embodiments, neurodegenerative disorders include psychosis, such as agoraphobia, Alzheimer's disease, anorexia nervosa, health disorders, anxiety disorders, attention deficit disorder, bipolar disorder, body image disorder, bulimia, claustrophobia, depression, delusions, Diogenes syndrome, abelian disorders, insomnia, Munchausen's syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, mental disorders, phobias, schizophrenia, seasonal affective disorder, schizophrenia, somnambulism, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania.

[0146] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat leukoablative encephalopathy. Exemplary methods of treating leukoablative encephalopathy include, but are not limited to, reducing or eliminating symptoms of leukoablative encephalopathy; reducing white matter loss; reducing myelin loss; increasing myelin levels; or increasing white matter levels in the subject.

[0147] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat pediatric ataxia with CNS myelination insufficiency. Exemplary methods of treating pediatric ataxia with CNS myelination insufficiency include, but are not limited to, reducing or eliminating symptoms of pediatric ataxia with CNS myelination insufficiency; increasing myelin content; or reducing myelin loss in the subject.

[0148] In some embodiments, intellectual disability syndromes (e.g., Fragile X syndrome) are treated with compounds of formula (I) or pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof. Exemplary methods of treating intellectual disability syndromes include, but are not limited to, reducing or eliminating the symptoms of intellectual disability syndromes.

[0149] In some embodiments, neurodegeneration is treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. Exemplary methods of treating neurodegeneration include, but are not limited to, improving mental state; increasing mental function; slowing the decline of mental function; reducing dementia; reducing dementia episodes; improving cognitive skills; reducing cognitive skill loss; improving memory; reducing memory decline; or prolonging survival.

[0150] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat leukoencephalopathy or demyelinating diseases. Exemplary leukoencephalopathy includes, but is not limited to, progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with white matter ablation, axonoglobulin-like leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, hypertensive leukoencephalopathy, megalencephalopathy with subcortical cysts, Charcot-Marie-Tooth disorder, and Devick's disease. Leukoencephalopathy may include hereditary or acquired demyelinating diseases. In some embodiments, acquired demyelinating diseases can be demyelinating diseases (e.g., infectious or non-infectious inflammatory demyelinating diseases), toxic demyelinating diseases, metabolic demyelinating diseases, hypoxic demyelinating diseases, traumatic demyelinating diseases, or ischemic demyelinating diseases (e.g., Binswanger's disease). Exemplary methods for treating white matter lesions or demyelinating diseases include, but are not limited to, reducing or eliminating symptoms of white matter lesions or demyelinating diseases; reducing myelin loss; increasing myelin levels; reducing white matter loss in the subject; or increasing white matter levels in the subject.

[0151] In some embodiments, compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers are used to treat traumatic or toxin-induced injuries to the nervous system (e.g., the brain). Exemplary traumatic brain injuries include, but are not limited to, brain abscesses, concussions, cerebral ischemia, cerebral hemorrhage, skull fractures, diffuse axonal injury, locked-in syndrome, or damage to organs or tissues related to traumatic force or beatings to the nervous system or brain. Examples of brain injury induced by toxic toxins include, but are not limited to, toxic encephalopathy, meningitis (e.g., bacterial or viral meningitis), meningoencephalitis (e.g., Japanese encephalitis, Eastern equine encephalitis, West Nile encephalitis), Guillain-Barre syndrome, Sydenham's chorea, rabies, leprosy, neurosyphilis, prions, or exposure to chemical agents (e.g., arsenic, lead, toluene, ethanol, manganese, fluorides, dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), tetrachloroethylene, polybrominated diphenyl ethers, pesticides, sodium channel inhibitors, potassium channel inhibitors, chloride channel inhibitors, calcium channel inhibitors, or blood-brain barrier inhibitors).

[0152] In other embodiments, the use of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers improves memory in subjects. Increased, decreased, and reduced eIF2α phosphorylation has been shown to help induce memory. Translation modulators, such as compounds disclosed herein (e.g., compounds of formula (I)), can be used as therapeutic agents to improve memory in human conditions associated with memory loss, such as Alzheimer's disease, and other neurological conditions that activate UPR or ISR in neurons and thus negatively impact memory consolidation, such as Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), and prion diseases. Furthermore, mutations in eIF2γ that disrupt the integrity of the complex are associated with intellectual disability (Intellectual Disability Syndrome or ID) and impaired translation initiation in humans. Therefore, the two diseases with diminished eIF2 function, ID and VWM, exhibit different phenotypes, but both primarily affect the brain and impair learning ability. In some embodiments, the disease or condition is an unpleasant memory (e.g., working memory, long-term memory, short-term memory, or memory consolidation).

[0153] In other embodiments, a method of using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof to improve a subject's memory (e.g., working memory, long-term memory, short-term memory, or memory consolidation). 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 an embodiment, the patient is a cow. In some embodiments, the subject is a primate. cancer

[0154] In some embodiments, compounds disclosed herein, such as those of formula (I), (II), or (III), are used to treat cancer. As used herein, “cancer” means human cancers and tumors, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphomas, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including hepatocellular carcinoma), lymphomas (including B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's small cell lymphoma and large cell lymphoma), Hodgkin's lymphoma), leukemias (including AML, ALL, and CML) and / or multiple myeloma. In some other contexts, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or tumor.

[0155] As used in this article, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods described herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach 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 of the breast, lobular carcinoma, primary cancer, metastatic cancer), 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, sarcoma), glioblastoma multiforme, glioma, or melanoma. Other examples include thyroid cancer, endocrine system cancers, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer or medulloblastoma (e.g., WNT-dependent childhood medulloblastoma), Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, and essential thrombocythemia. Primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic lesions, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the Nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[0156] The term "leukemia" broadly refers to a progressive, malignant disease of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Clinically, leukemia is generally classified based on the following: (1) the duration and nature of the acute or chronic disease; (2) the cells involved; the type of bone marrow (myelopathic), lymphoid (lymphoid), or mononuclear leukemia; and (3) whether the number of abnormal cells in the blood is increased or not in leukemic or non-leukemic (subleukemic) leukemia. Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, and Gross' disease. Leukemia, hairy cell leukemia, hematopoietic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, medulloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia. Leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0157] The term "sarcoma" generally refers to a tumor formed from substances such as embryonic connective tissue and is typically composed of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods described in this article include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose tissue sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, green myeloma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, and Kaposi's sarcoma. Sarcoma, Kupffer cell sarcoma, angiosarcoma, white sarcoma, malignant mesenchymal tumor, periosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous sarcoma, synovial sarcoma, or capillary dilatational sarcoma.

[0158] The term "melanoma" refers to a tumor caused by the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods described herein include, for example, acral melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

[0159] The term "cancer" refers to malignant new growth caused by epithelial cells tending to infiltrate surrounding tissues and cause metastasis. Examples of cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar tumor, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, follicular carcinoma, follicular cell carcinoma, basal cell carcinoma, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, medullary carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine endometrial cancer, cribriform carcinoma, armored carcinoma, carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, sclerosing carcinoma, embryonal carcinoma, brain-like carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative gastric cancer, fibrous carcinoma, and colloid carcinoma. Carcinoma, glial carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulocytic carcinoma, hair-matrix carcinoma, hemangioma, hepatocellular carcinoma, Hurthle cell carcinoma, clear carcinoma, adrenal carcinoma, naive embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipoma-like carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, melanoma molle, mucinous carcinoma Carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, invasive carcinoma, acanthosis nigra, brain-like carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma.Carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tubular carcinoma, nodular carcinoma, verrucous carcinoma, or villous carcinoma.

[0160] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof are used to treat pancreatic cancer, breast cancer, multiple myeloma, and secretory cell carcinoma. For example, some methods described herein treat cancer by reducing 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, compounds of formula (I) or pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof may 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, secretory cell carcinoma).

[0161] In some embodiments, these compounds (compounds described herein, such as compounds of formula (I)) and compositions (such as compositions comprising compounds described herein, such as compounds of formula (I)) are used in conjunction with immunotherapy (such as checkpoint blocking antibodies) to treat a subject (e.g., a human subject) suffering from a disease or condition described herein (e.g., abnormal cell growth, such as cancer (e.g., cancer described herein)). The methods described herein involve administering a compound described herein, such as a compound of formula (I), and immunotherapy to a subject with abnormal cell growth such as cancer. Exemplary immunotherapies include, but are not limited to, the following.

[0162] In some embodiments, immunotherapeutic agents are compounds that inhibit immune checkpoint blockade pathways (e.g., ligands, antibodies). In some embodiments, immunotherapeutic agents are compounds that inhibit the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, immunotherapeutic agents are compounds that antagonize the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three groups of immunotherapies for treating cancer include cell-based therapies, antibody-based therapies, and intercellular substance therapies. All groups utilize slightly different structures (e.g., molecular structures; antigens, proteins, molecules, carbohydrates) that cancer cells display on their surface that can be detected by the immune system. Cancer immunotherapy (i.e., antitumor immunotherapy or antitumor immunotherapeutic agents) includes, but is not limited to, immune checkpoint antibodies (e.g., PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (i.e., antitumor vaccines or neoantigen-based vaccines, such as peptide or RNA vaccines).

[0163] Cell-based therapies (such as cancer vaccines) typically involve obtaining immune cells from a subject with cancer, either from the blood or from the tumor. Tumor-specific immune cells are activated, grown, and reinfused into the subject, where they provide an immune response against the cancer. Cell types that can be used in this manner include natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapy (i.e., chimeric antigen receptor T cells, which are engineered to target specific antigens), TIL therapy (i.e., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An illustrative cell-based therapy is Provenge. In some embodiments, the cell-based therapy is CAR-T therapy.

[0164] Examples of interleukin-2 and interferon-α lineage interleukins, which are proteins that regulate and coordinate the behavior of the immune system. Cancer vaccines using neoantigens

[0165] Neoantigens are antigens encoded by tumor-specific mutated genes. Technological innovations have made it possible to analyze immune responses to patient-specific neoantigens generated by tumor-specific mutations, and emerging data indicate that identifying these neoantigens is a key factor in clinical immunotherapy activities. These observations suggest that neoantigen load can form a biomarker for cancer immunotherapy. Many novel therapies are being developed to selectively enhance T-cell responsiveness to these antigens. One method for targeting neoantigens is... [,via Cancer vaccines have been developed. These vaccines can be developed using peptides or RNA, such as synthetic peptides or synthetic RNA.

[0166] Antibody therapy involves antibody proteins produced by the immune system and bound to target antigens on the cell surface. Antibodies are typically encoded by one or more immunoglobulin genes, or fragments thereof. In normal physiological function, the immune system uses antibodies to fight pathogens. Each antibody is specific to one or more proteins, and antibodies bound to cancer antigens are used, for example, to treat cancer. Antibodies are capable of specifically binding to antigens or antigenic determinants. (Fundamental Immunology, 3rd ed., WE, Paul, Raven Press, NY (1993). Specific binding occurs at the corresponding antigen or antigenic determinant, even in the presence of heterogeneous groups of proteins and other biological agents. Specific binding of an antibody indicates that it binds to its target antigen or antigenic determinant with substantially higher affinity than binding to unrelated antigens. The relative difference in affinity is typically at least 25%, more often at least 50%, and most often at least 100%. 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 50-fold, at least 100-fold, or at least 1000-fold.)

[0167] Exemplary antibody types include, but are not limited to, human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, single-chain antibodies, antibody-binding fragments, and bifunctional antibodies. Upon binding to cancer antigens, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent receptor-ligand interactions, or deliver chemotherapy or radiation loads, all of which can lead to cell death. Exemplary antibodies used to treat cancer include, but are not limited to, alemtuzumab, bevacizumab, bretuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, offatumumab, panitumumab, rituximab, tositumomab, trastuzumab, nivolumab, pembrolizumab, avelumab, durvalumab, and pidilizumab. Checkpoint blocking antibodies

[0168] In some embodiments, the methods described herein include treating a human subject suffering from the disease or condition described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits immune checkpoint blocking pathways. Immune checkpoint proteins maintain self-tolerance (e.g., preventing autoimmunity) under normal physiological conditions and protect tissues from damage in response to the immune system, for example, pathogen infection. Immune checkpoint proteins can be dysregulated in the presence of tumors as an important mechanism of immune resistance (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Energists of co-stimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins) provide an increase in antigen-specific T-cell responses. Antibodies that block immune checkpoints do not directly target tumor cells, but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0169] Exemplary checkpoint blocking antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (i.e., antibodies against lymphocyte activation gene 3), and anti-TIM3 (i.e., antibodies against T cell membrane protein 3). Exemplary anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Exemplary anti-PD-1 ligands include, but are not limited to, PD-L1 (i.e., B7-H1 and CD274) and PD-L2 (i.e., B7-DC and CD273). Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab (i.e., MDX-1106, BMS-936558, or ONO-4538), CT-011, AMP-224, pembrolizumab (trade name Keytruda), and MK-3475. Exemplary PD-L1 specific antibodies include, but are not limited to, BMS936559 (i.e., MDX-1105), MEDI4736, and MPDL-3280A. Exemplary checkpoint blocking antibodies also include, but are not limited to, IMP321 and MGA271.

[0170] Regulatory T cells (such as CD4+, CD25+, or T-reg cells) are also involved in refining the distinction between autoantigens and non-autoantigens (such as foreign antigens) and may represent an important mechanism for suppressing immune responses in many cancers. T-reg cells can originate from the thymus (i.e., "natural T-regs") or differentiate from mature T cells under conditions of peripheral tolerance induction (i.e., "inducible T-regs"). Therefore, strategies to minimize the role of T-reg cells are expected to contribute to immune responses against tumors (Sutmuller, van Duivernvoorde et al., 2001). IDO pathway inhibitors

[0171] The IDO pathway regulates the immune response by inhibiting T cell function and enabling local tumor immune evasion. IDO expression in antigen-presenting cells (APCs) leads to tryptophan depletion and consequently, antigen-specific T cell energy and regulatory T cell recruitment. Some tumors even express IDO to protect themselves from the immune system. Compounds that inhibit IDO or the IDO pathway thereby activate the immune system to attack cancer (e.g., the subject's cancer). Exemplary IDO pathway inhibitors include indoximod, epacadostat, and EOS200271. STING pathway enhancer

[0172] STING (Synthetic Interferon Gene Stimulator) is an adaptor protein that plays an important role in the activation of cytoplasmic nucleic acid ligands in the response of type I interferon. Evidence suggests that the STING pathway is involved in inducing anti-tumor immune responses. It has been shown that activation of the STING-dependent pathway in cancer cells can lead to tumor infiltration by immune cells and regulation of anti-cancer immune responses. STING agonists are being developed as a class of cancer therapeutic agents. Exemplary STING agonists include MK-1454 and ADU-S100. [, , ] Co-stimulatory antibodies

[0173] In some embodiments, the methods described herein include treating a human subject suffering from one of the diseases or conditions described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a co-stimulatory inhibitor or an 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.

[0174] The inventive method of this invention covers single and multiple administrations of therapeutically effective amounts of the compounds described herein. Depending on the nature, severity, and extent of the subject's condition, the compounds, such as those described herein, may be administered at regular time intervals. In some embodiments, the compounds described herein are administered in a single dose. In some embodiments, the compounds described herein are administered in multiple doses. Inflammatory diseases

[0175] In some embodiments, inflammatory diseases are treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., an increased degree of inflammation compared to a control group, such as a healthy person without the disease). Examples of inflammatory diseases include postoperative cognitive impairment, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetic relapse, type 1 diabetes, Graeme-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Schuglin'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, leukoplakia, 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 manifestations are symptoms, causes, or markers of the disease) include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), TNF-α (tumor necrosis factor-α), and C-reactive protein (CRP).

[0176] In some embodiments, inflammatory diseases include postoperative cognitive impairment, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile epoch-related diabetes or type 1 diabetes), Graeme-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Schuglin'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.

[0177] In some embodiments, inflammatory diseases include postoperative cognitive impairment, meaning a decline in cognitive function (e.g., memory or executive function (e.g., working memory, reasoning, task flexibility, processing speed, or problem-solving ability)) after surgery.

[0178] In other embodiments, the treatment method is a preventive method. For example, a method for treating postoperative cognitive impairment may include preventing postoperative cognitive impairment or symptoms of postoperative cognitive impairment by administering the compound described herein before surgery, or reducing the severity of symptoms of postoperative cognitive impairment.

[0179] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat inflammatory diseases (e.g., those described herein) by reducing or eliminating symptoms of the disease. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat inflammatory diseases (e.g., those described herein). Musculoskeletal diseases

[0180] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat musculoskeletal disorders. As used herein, the term "musculoskeletal disorder" refers to a disease or condition in which the function of the subject's musculoskeletal system (e.g., muscles, ligaments, tendons, cartilage, or bone) is impaired. Exemplary musculoskeletal disorders treatable with compounds of formula (I) or their medically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers include muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Edwin-Deutschneider muscular dystrophy, facial-scapular-humeral muscular dystrophy, myotonic dystrophy type I, or myotonic dystrophy type II), limb-girdle muscular dystrophy, multisystem proteinopathy, proximal limb punctate chondrodystrophy, X-linked occult punctate chondrodystrophy, and Conradi-Hünermann syndrome. Syndrome, autosomal dominant punctate chondrodysplasia, 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, spinal-bulbar progressive muscular atrophy, spinal cord rigidity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Mayo C. II disease, Paget's osteopathy, spastic fasciculations, Friedrich's ataxia, wasting disorders (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease or paralysis.

[0181] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat musculoskeletal disorders (e.g., musculoskeletal disorders as described herein) by reducing or eliminating symptoms of the disease. In some embodiments, the treatment method includes treating muscle pain or muscle stiffness associated with musculoskeletal disorders. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat musculoskeletal disorders (e.g., musculoskeletal disorders as described herein). Metabolic diseases

[0182] In some embodiments, a metabolic disorder may be treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "metabolic disorder" refers to a disease or condition that affects the metabolic processes of a subject. Exemplary metabolic disorders for which a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystacidosis, diabetes (e.g., type I diabetes, type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kronoblastic leukemia.

[0183] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat metabolic diseases (e.g., metabolic diseases described herein) by reducing or eliminating symptoms of the disease. In some embodiments, the treatment includes reducing or eliminating symptoms, including elevated blood pressure, elevated blood glucose levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and similar symptoms. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat metabolic diseases (e.g., metabolic diseases described herein). Mitochondrial diseases

[0184] In some embodiments, mitochondrial diseases are treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "mitochondrial disease" refers to a disease or condition affecting the mitochondria of a subject. In some embodiments, a mitochondrial disease is associated with, or is a result of, or is caused by, abnormal mitochondrial function, mutations in one or more mitochondrial proteins, or mutations in one or more mitochondrial DNA. In some embodiments, a mitochondrial disease is a mitochondrial myopathy. In some embodiments, mitochondrial diseases, such as mitochondrial myopathy, can be treated with compounds of formula (I) or their medically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers, including, for example, Bass syndrome, chronic progressive extraocular muscle palsy (cPEO), K-Sachs syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpert syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like seizures (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with fragmented red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leigh hereditary optic neuropathy (LHON), and Pearson syndrome.

[0185] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat mitochondrial diseases (e.g., mitochondrial diseases described herein) by reducing or eliminating symptoms of the disease. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat mitochondrial diseases described herein. Hearing loss

[0186] In some embodiments, hearing loss is treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term “hearing loss” or “hearing loss condition” may broadly encompass any damage to the auditory system, organs, and cells, or any impairment of the ability of an animal subject to hear sounds, which may be measured by standard methods and assessments known in this art, such as auditory emission testing, pure-tone testing, and auditory brainstem response testing. Exemplary hearing loss conditions that may be treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, 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 due to ototoxic exposure, hearing loss due to disease, and hearing loss due to trauma. In some embodiments, mitochondrial asymptomatic hearing loss and deafness are MT-RNR1-related hearing loss. In some embodiments, MT-RNR1-related hearing loss is caused by aminoglycoside ototoxicity. In some embodiments, mitochondrial asymptomatic hearing loss and deafness are MT-TS1-related hearing loss. In some embodiments, mitochondrial asymptomatic hearing loss and deafness are characterized by sensorineural hearing loss.

[0187] In some embodiments, the hearing loss condition described herein is treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the hearing loss condition described herein. Eye diseases

[0188] In some embodiments, an eye disease may be treated with a compound of formula (I) or a pharmaceutically acceptable salt, co-lens, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term “eye disease” refers to a disease or condition in which the function of the subject’s eye is impaired. Exemplary eye diseases and conditions that may be treated with a compound of formula (I) or a pharmaceutically acceptable salt, co-lens, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof include cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0189] In some embodiments, the ocular diseases or conditions described herein are treated by reducing or eliminating symptoms of a disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the ocular diseases or conditions described herein. Kidney disease

[0190] In some embodiments, nephropathy is treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "nephropathy" refers to a disease or condition in which the kidneys of a subject are impaired. Exemplary nephropathy treatable with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof includes Abderhalden-Kaufmann-Lignac syndrome (nephrotic cystacidosis), compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephritis, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, and Allport syndrome. Syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa and nephropathy, angiotensin antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-related glomerulonephritis, APOL1 mutation, epigenetic mineralocorticoid hypersteroid syndrome, aristolochic acid nephropathy, herbal medicine nephropathy, Balkan endemic nephropathy, urinary tract arteriovenous malformations and fistulas, autosomal dominant hypocalcemia, Bardet-Biedl syndrome, Bartter syndrome Syndrome, bath salts and acute kidney injury, excessive beer consumption, beet urine, beta-thalassemia nephropathy, bile duct nephropathy, pre-existing BK polyomavirus nephropathy, bladder rupture, bladder sphincter dyssynergia, bladder tamponade, Border-Crossers' nephropathy, Bourbon virus and acute kidney injury, burning sugarcane harvest and acute renal dysfunction, Byetta and kidney failure, C1q nephropathy, C3 glomerulonephropathy, C3 glomerulonephropathy with monosporinemia, C4 glomerulonephropathy, nephrotoxicity of calcineurin inhibitors, callilepsis laureola poisoning, cannabinoid hyperemesis and acute kidney failure, cardiorenal syndrome, carfilzomib-induced kidney injury. Injury), CFHR5 nephropathy, Charcot-Marie-Tooth diseaseDiseases associated with glomerulonephropathy, herbal remedies and nephrotoxicity, cherry concentrate and acute kidney injury, cholesterol thrombosis, Churg-Strauss syndrome, chyluria, ciliosis, cocaine and kidney injury, cold diuresis, polymyxin nephrotoxicity, collagen fibrosis glomerulonephropathy, collapsed glomerulonephropathy, CMV-associated collapsed glomerulonephropathy, combined antiretroviral (cART)-associated nephropathy, congenital kidney and urinary tract malformations (CAKUT), congenital nephrotic syndrome, congestive renal failure, coronary artery nephropathy (Mainzer-Saldino Syndrome or Saldino-Mainzer disease). Diseases including contrast-induced nephropathy, copper sulfate poisoning, cortical necrosis, crizotinib-associated acute kidney injury, cryoglobulinemia, cryoglobulinemia, crystalline globulin-induced nephropathy, crystal-induced acute kidney injury, crystal reserve cell polycythemia, acquired cystic kidney disease, cystineuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (type 2 MPGN), and Dent disease. Diseases (X-linked occult kidney stones), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes and diabetic nephropathy, diabetes insipidus, dietary supplements and renal failure, diffuse mesangial sclerosis, polyuria, stigmata poisoning, Down syndrome and nephropathy, drug abuse and nephropathy, double ureters, EAST syndrome, Ebola and nephropathy, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry's disease, familial hypocalcemia and hypercalcemia, Fanconi syndrome, Fraser syndrome, fibrinogen glomerulonephropathy, fibroid glomerulonephritis and immune tentacle-like glomerulonephropathy, Fraley syndrome Symptoms include: fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway Mowat syndrome, giant cell (temporal) arteritis with kidney damage, pregnancy-induced hypertension, Gitelman syndrome, glomerular diseases, glomerular-tubular reflux, diabetes, Cubaste syndrome, green juice enzyme detoxification nephropathy, HANAC syndrome, and Harvoni.Kidney injury induced by (Ledipasvir and Sofosbuvir), hair dye intake and acute kidney injury, and Hantavirus infection (podocyte disease). Podocytopathy, heat stress nephropathy, hematuria (blood in urine), uremic hemolytic syndrome (HUS), atypical uremic hemolytic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus nephropathy, Korean hemorrhagic fever, epidemic hemorrhagic fever, epidemic nephropathy), hemosiderosis, hemosiderosis associated with paroxysmal nocturnal hemoglobinuria and hemolytic anemia, hepatic glomerulonephropathy, hepatic venous occlusive disease, hepatic sinusoidal obstruction syndrome, hepatitis C-related nephropathy, hepatocyte nuclear factor 1β-related nephropathy, hepatorenal syndrome, herbal supplements and nephropathy, high-altitude nephropathy, hypertension and nephropathy, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-associated autosomal dominant tubulointerstitial nephropathy, horseshoe kidney (kidney fusion), Huntner's ulcer. Ulcer), hydroxychloroquine-induced renal phospholipid deposition, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemia-induced urticarial angiopathy, hypokalemia, hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in cannabis users, hypertension, monogenic hereditary hypertension, iced tea-related nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, immersion in urine infection, immune checkpoint therapy-related interstitial nephritis, infliximab-related nephropathy, interstitial cystitis, bladder pain syndrome (questionnaire), interstitial nephritis, megakaryocytic interstitial nephritis, Ivemark's syndrome JC virus nephropathy, Joubert syndrome, ketamine-associated bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acetyltransferase deficiency (LCAT deficiency), leptospirosis nephropathy, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubular disease, Liddle syndrome, Lightwood-Albright syndrome.Syndrome, lipoprotein glomerulonephropathy, lithium nephropathy, hereditary FSGS caused by LMX1B mutation, back pain and hematuria, lupus, systemic lupus erythematosus, lupus nephropathy, lupus nephritis, lupus nephritis with positive anti-neutrophil cytoplasmic antibody serum, lupus podocyte disease, Lyme disease-related glomerulonephritis, lysine-proteinuria intolerance, lysozyme nephropathy, malaria nephropathy, malignant tumor-related nephropathy, malignant hypertension, sclerosis, McCittrick-Wheelock syndrome, MDMA (Ecstasy; 3,4-methylenedioxanone) and kidney failure, urethral stricture, medullary cystic nephropathy, urinary regulatory protein-related nephropathy, type 1 juvenile hyperuricemic nephropathy, medullary sponge kidney, megaureterosis, melamine toxicity and kidney damage, MELAS syndrome, membranoproliferative glomerulonephritis, membranous nephropathy, membranous glomerulonephropathy with occult IgGκ deposition, Central American nephropathy, metabolic acidosis, metabolic alkalosis, methotrexate-related renal failure. Failure), microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammaglobulinosis affecting the kidneys, abnormal blood protein, mouthwash intoxication, MUC1 nephropathy, polycystic kidney dysplasia, multiple myeloma, myeloproliferative neoplasms and glomerulonephropathy, nail-patella syndrome, NARP syndrome, nephrocalcinosis, renal systemic fibrosis, ectopic kidney (wandering kidney, nephroptosis), nephrotic syndrome, neurogenic bladder, 9 / 11 and nephropathy, tuberous glomerulosclerosis, non-gonococcal urethritis, Nutcracker syndrome, rare giant nephrons, orofacial-digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephropathy, ovarian hyperstimulation syndrome, oxalate nephropathy, Paget's kidney Kidney syndrome, renal papillary necrosis, bilateral optic disc nephropathy (renal defect syndrome, solitary kidney dysplasia), PARN mutation and nephropathy, parvovirus B19 and nephropathy, peritoneal-renal syndrome, POEMS syndrome, posterior urethral valves, podocyte folding glomerulonephritis, post-infectious glomerulonephritis, 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 polyuria, preeclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nassr disease).Diseases including propolis-related kidney failure, proteinuria (protein in urine), pseudoaldosteronism, pseudohypocarbonylemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), purulent nephropathy, pyidonia and kidney failure, radiation nephropathy, and ranolazine-induced kidney injury. Kidney syndrome, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perirenal abscess, renal agenesis, acute kidney injury related to microthrombosis of the renal arcuate vein, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation and autosomal dominant tubulointerstitial nephropathy, reninoma (adjacent glomerular cell tumor), restoration of osmotic homeostasis, retrovena cava ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis related to bariatric surgery, rheumatoid arthritis-related nephropathy, sarcoidosis-related kidney disease, renal and cerebral salt wasting, schistosomiasis and glomerular diseases, Schimke's immuno-osseous dysplasia. dysplasia, scleroderma renal crisis, serpentine fibular polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silicon dioxide exposure and chronic kidney disease, Sri Lankan farmer's nephropathy, Schulgen syndrome and nephropathy, synthetic cannabinoid use and acute kidney injury, hematopoietic cell transplantation nephropathy, stem cell transplantation-related nephropathy, TAFRO syndrome, tea and toast hyponatremia, tenofovir-induced nephrotoxicity. Nephrotoxicity, thin basement membrane nephropathy, benign familial hematuria, thrombotic microangiopathy associated with monoclonal gammaglobulinosis, trench nephritis, trigoneitis, urinary tract tuberculosis, tuberous sclerosis, renal 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 cyst, urethral caruncle, urethral stricture, urinary incontinence, urethral infection, urethral obstruction, urogenital fistula, urinary regulatory protein-associated nephropathy, vancomycin-associated cystic nephropathy, vasomotor nephropathy, vesicogut fistula, vesicoureteral reflux, VGEF inhibition and renal thrombotic microangiopathy, volatile anesthetics and acute kidney injury, Von Hippel-Lindau disease, Waldenstrom's macroglobulinemia glomerulonephritis. Macroglobulinemic Glomerulonephritis, warfarin-associated nephropathy, wasp stings and acute kidney injury, Wegener's granulomatosisGranulomatosis, granulomatous polyangiitis, West Nile virus and chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or brain-hepatorenal syndrome. Infectious diseases

[0191] In some embodiments, compounds disclosed herein, such as compounds of formula (I), are used to treat infectious diseases. Exemplary infectious diseases that can be treated with compounds disclosed herein, such as compounds of formula (I), include bacterial infections, viral infections (e.g., herpes, shingles, influenza, cold, encephalitis), and parasitic infections.

[0192] In some embodiments, compounds disclosed herein, such as compounds of formula (I), are used to treat infectious diseases (such as those described herein) by reducing or eliminating symptoms of the disease. In some embodiments, compounds disclosed herein, such as compounds of formula (I), may be used as a single agent in a composition or in combination with another agent in a composition to treat infectious diseases. parasitic infection

[0193] In some embodiments, compounds disclosed herein, such as compounds of formula (I), are used to treat parasitic infections.

[0194] In some embodiments, the compounds disclosed herein, such as compounds of formula (I), are used to treat parasitic infections by reducing or eliminating symptoms of the disease. In some embodiments, the compounds disclosed herein, such as compounds of formula (I), may be used as a single agent in a composition or in combination with another agent in a composition to treat parasitic infections. Immunosuppressive diseases

[0195] In some embodiments, compounds disclosed herein, such as compounds of formula (I), are used to treat immunosuppressive diseases.

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

[0197] In some embodiments, the kidney disease described herein is treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the kidney disease described herein. skin disease

[0198] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat skin diseases. As used herein, the term "dermatology" can refer to a disease or condition affecting the skin. Exemplary skin conditions treatable with compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers include acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extra-mammary Paget's disease, simple epidermolysis bullosa, erythropoietic protoporphyria, nail fungal infections, and Hailey-Hailey disease. Diseases, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melanoma, mucosal pemphigoid, pemphigoid, pemphigus vulgaris, lichenoid pityriasis, pityriasis rubra follicularis, plantar warts (warts), polymorphic light eruption, psoriasis, polymorphic light eruption, pyoderma gangrenosa, acne erythematosus, scabies, scleroderma, herpes zoster, squamous cell carcinoma, Sweet's syndrome, rubella and angioedema, and vitiligo.

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

[0200] In some embodiments, fibrotic diseases are treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "fibrotic disease" can refer to a disease or condition defined by the accumulation of excessive extracellular matrix components. Exemplary fibrotic diseases treatable with compounds of formula (I) or their medically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers include adhesion bursitis, arteriosclerosis, joint fibrosis, atrial fibrosis, myocardial fibrosis, sclerosis, congenital liver fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endocardial myocardial fibrosis, glial scars, hepatitis C, hypertrophic cardiomyopathy, allergic pneumonia, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloids, mediastinal fibrosis, myelofibrosis, renal systemic fibrosis, non-alcoholic fatty liver disease, old myocardial infarction, and Peyronie's disease. Diseases including pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

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

[0202] In some embodiments, hemoglobin disorders are treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the terms "hemoglobin disorder" or "hemoglobin syndrome" may refer to a disease or condition characterized by abnormal production or structure of hemoglobin. Exemplary hemoglobinic disorders treatable with compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers include "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 (phenotype of α0 thalassemia), hydrops fetalis with Hb Bart's, sickle cell anemia / disease, sickle cell phenotype, sickle-type β-thalassemia disease, α+ thalassemia, α Thalassemia type 0, alpha thalassemia associated with myelodysplastic syndrome, alpha thalassemia with intellectual disability syndrome (ATR), β-0 thalassemia, β+ thalassemia, delta thalassemia, gamma thalassemia, severe β thalassemia, intermediate β thalassemia, delta β thalassemia, and εγδβ thalassemia.

[0203] In some embodiments, the hemoglobinic disorders described herein are treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the hemoglobinic disorders described herein. Autoimmune diseases

[0204] In some embodiments, an autoimmune disease is treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "autoimmune disease" can refer to a disease or condition in which the subject's immune system attacks and damages the subject's tissues. Examples of autoimmune diseases treatable with compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers 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 dysfunction, 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), and Balo's disease. Diseases including: Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, 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's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome. Eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, idiopathic mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatous polyangiitis, Graves' disease, Graves-Bartholin's syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS).(Atypical acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoblastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease. Multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars plana cyclitis (peripheral uveitis), Parsonnage-Turner syndrome. Polymyalgia, 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, simple erythropoiesis (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's syndrome syndromes including scleritis, scleroderma, Schuyllenhaal syndrome, sperm and testicular autoimmune diseases, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), and Takayasu's arteritis.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, leukoplakia, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatous polyangiitis (GPA)).

[0205] In some embodiments, the autoimmune diseases described herein are treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the autoimmune diseases described herein. Viral infection

[0206] In some embodiments, viral infections are treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. Exemplary viral infections that can be treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof include influenza, human immunodeficiency virus (HIV), and herpes.

[0207] In some embodiments, the viral infection described herein is treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the viral infection described herein. Malaria infection

[0208] In some embodiments, malaria is treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. As used herein, the term "malaria" may refer to a parasitic disease of a protozoan of the genus Plasmodium that causes infection of red blood cells (RBCs). Exemplary forms of malaria infection that can be treated with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof include those caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum. In some embodiments, malaria infections treated with compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers are drug-resistant / recurrent malaria.

[0209] In some embodiments, the malaria infection described herein is treated by reducing or eliminating symptoms of the disease using a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the malaria infection described herein. Diseases involving mutations that induce the unfolded protein response (UPR).

[0210] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat a disease having a mutation that induces UPR. Exemplary diseases having a mutation that induces UPR include Marinesco-Sjogren syndrome, neuropathic pain, diabetic neuropathic pain, noise-induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier White disease, Usher syndrome, collagenopathy, thin basement membrane nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid, and pseudochondrodysplasia.

[0211] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is used to treat a disease having a mutation that causes UPR-inducing mutations by reducing or eliminating the symptoms of the disease. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used as a single agent in a composition or in combination with another agent in a composition to treat the disease having a mutation that causes UPR-inducing mutations as described herein. Methods for regulating protein production

[0212] In another embodiment, this paper discloses a method for modulating the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, comprising contacting the cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, thereby modulating the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells. In some embodiments, contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof results in an increase in the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells. In some embodiments, contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cell.

[0213] In another embodiment, this article discloses a method for preventing or treating the condition, disease, or symptom described herein in a patient in need, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof modulates the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells, thereby treating the condition, disease, or symptom. In some embodiments, the condition, disease, or symptom is characterized by abnormal expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells of a patient, thereby treating the condition, disease, or symptom. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof decreases the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells of a patient, thereby treating the condition, disease, or symptom.

[0214] In another embodiment, this paper discloses a method for modulating the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, comprising contacting the cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, thereby modulating the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells. In some embodiments, contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof results in an increase in the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells. In some embodiments, contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cell.

[0215] In another embodiment, this article discloses a method for preventing or treating the condition, disease, or symptom described herein in a patient in need, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof modulates the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells, thereby treating the condition, disease, or symptom. In some embodiments, the condition, disease, or symptom is characterized by abnormal activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells of a patient, thereby treating the condition, disease, or symptom. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof decreases the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells of a patient, thereby treating the condition, disease, or symptom.

[0216] In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is administered, wherein the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof modulates the expression and activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in patient cells, thereby treating the condition, disease, or symptom.

[0217] In some embodiments, the compound of formula (I) undergoes chemical modification before (in vitro) or after (in vivo) contact with cells to form a bioactive compound that modulates the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells. In some embodiments, the compound of formula (I) is metabolized by a patient to form a bioactive compound that modulates the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells, thereby treating the condition, disease, or symptom disclosed herein. In some embodiments, the bioactive compound is a compound of formula (II).

[0218] In one embodiment, this document discloses a method for treating a patient in need of a disease related to 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 ISR pathway, the method comprising administering to the patient an effective amount of a compound of formula (I). In some embodiments, the modulation comprises increasing the activity or level of eIF2B, increasing the activity or level of eIF2α, or increasing the activity or level of a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease may be caused by mutations in gene or protein sequences associated with members of the eIF2 pathway (e.g., the eIF2α signaling pathway). Methods to increase protein activity and yield

[0219] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used in applications requiring increased yield output of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in a live, cell-free system for producing proteins.

[0220] In some embodiments, the present invention is characterized by a method for increasing the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in a cellular or in vitro expression system, the method comprising contacting the cellular or in vitro expression system with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, the method is a method for increasing the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, the method comprising contacting the cells with an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof). In other embodiments, the method is a way to increase the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in an in vitro protein expression system, the method comprising contacting the in vitro expression system with a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof). In some embodiments, contacting a cell or in vitro expression system with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cell or in vitro expression system 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, contacting a cell or in vitro expression system with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, Contact with N-oxides or stereoisomers increases the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cellular or in vitro expression systems by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 80, 900, 1000, 10000, 100000, or 1,000,000 times.

[0221] In some embodiments, the present invention is characterized by a method for increasing the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in patient cells, the method comprising administering to the patient an effective amount of a compound of formula (I) or a medically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, condition, or symptom disclosed herein, and wherein the disease, condition, or symptom is characterized by abnormal expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof (e.g., leukodystrophy, leukoencephalopathy, myelodysplasia or demyelinating disease, wasting disease, or sarcopenia). In some embodiments, administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer to a patient in need results in an increase of 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 the patient's cells, thereby treating the disease, condition, or illness. In some embodiments, administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, ... N-oxides or stereoisomers increase the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in patient cells by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 10000, 100000, or 1,000000 times, thereby treating the disease, condition, or ailment.

[0222] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used in applications requiring increased activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof.

[0223] In some embodiments, the present invention is characterized by a method for increasing the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, the method comprising contacting the cells with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells 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, contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof increases the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 10000, about 100000, or about 1000000.

[0224] In some embodiments, the present invention is characterized by a method for increasing the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in a patient in need, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with a disease, condition, or symptom disclosed herein and wherein the disease, condition, or symptom is characterized by a reduced level of protein activity. In some embodiments, administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer to a patient in need increases the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, 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 about 100% to treat the disease, condition, or illness. In some embodiments, administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, ... N-oxides or stereoisomers increase the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 10000, 100000, or 1,000000 times, thereby treating the disease, condition, or ailment.

[0225] In some embodiments, the compound of formula (I) undergoes chemical modification before (in vitro) or after (in vivo) contact with cells or an in vitro representation system to form a bioactive compound that increases the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells and / or in vitro representation systems. In some embodiments, the compound of formula (I) is metabolized by a patient to form a bioactive compound that increases the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells, thereby treating the condition, disease, or symptom disclosed herein. In some embodiments, the bioactive compound is a compound of formula (II). Methods to reduce protein activity and yield

[0226] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used in applications requiring reduced yield output of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof.

[0227] In some embodiments, the present invention is characterized by a method for reducing the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, the method comprising contacting the cells with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells 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%.

[0228] In some embodiments, the present invention is characterized by a method for reducing the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in a patient in need, the method comprising administering to the patient an effective amount of a compound of formula (I), or a medically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with the disease, condition, or symptom described herein and wherein the disease, condition, or symptom is characterized by increased protein production. In some embodiments, administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof to a patient in need reduces the expression of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, 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 about 100% to the patient, thereby treating the disease, condition, or illness.

[0229] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof may be used in applications requiring reduction of the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof.

[0230] In some embodiments, the present invention is characterized by a method for reducing the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells, the method comprising contacting the cells with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. In some embodiments, contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof reduces the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the cells 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%, thereby treating the disease, condition, or illness.

[0231] In some embodiments, the present invention is characterized by a method for reducing the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in a patient in need, the method comprising administering to the patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, wherein the patient has been diagnosed with the disease, condition, or ailment described herein and wherein the disease, condition, or ailment 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, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof to a patient in need reduces the activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, 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 about 100% to the patient, thereby treating the disease, condition, or illness.

[0232] In some embodiments, the compound of formula (I) undergoes chemical modification before (in vitro) or after (in vivo) contact with cells to form a bioactive compound that reduces the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in cells. In some embodiments, the compound of formula (I) is metabolized by a patient to form a bioactive compound that reduces the expression and / or activity of eIF2B, eIF2α, eIF2 pathway components, ISR pathway components, or any combination thereof in the patient's cells, thereby treating the condition, disease, or symptom disclosed herein. In some embodiments, the bioactive compound is a compound of formula (I). [Combination therapy] []

[0233] In one embodiment, the present invention is characterized by a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof, and another agent (e.g., another therapeutic agent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the other agent (e.g., another therapeutic agent). In some embodiments, the other agent is an agent for treating cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with impaired function of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway.

[0234] The compounds described herein can be used in combination with each other, with active agents known to be used to treat cancer, neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with impaired function of components in the eIF2B, eIF2α, or eIF2 pathway or ISR pathway, or with adjuvants that cannot be used effectively alone but can enhance the efficacy of the active agent.

[0235] In some embodiments, co-doping includes dosing an active agent at intervals of 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours with another active agent. Co-doping includes dosing two active agents simultaneously, nearly simultaneously (e.g., at intervals of about 1, 5, 10, 15, 20, or 30 minutes), or sequentially in any order. In some embodiments, co-doping can be achieved by co-regulation, i.e., preparing a single pharmaceutical composition comprising two active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active agents and / or adjuvants may be used in combination or conjugated with each other. In some embodiments, the compounds described herein may be used in combination with treatments for cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with impaired function of components of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway.

[0236] In one embodiment, the other agent is an anticancer agent. In another embodiment, the other agent is a chemotherapeutic agent. In another embodiment, the other agent is an agent for improving memory. In another embodiment, the other agent is an agent for treating neurodegenerative diseases. In another embodiment, the other agent is an agent for treating leukodystrophy. In another embodiment, the other agent is an agent for treating leukoablative encephalopathy. In another embodiment, the other agent is an agent for treating childhood ataxia with CNS myelination insufficiency. In another embodiment, the other agent is an agent for treating intellectual disability syndromes (e.g., Fragile X syndrome). In another embodiment, the other agent is an agent for treating pancreatic cancer. In another embodiment, the other agent is an agent for treating breast cancer. In another embodiment, the other agent is an agent for treating multiple myeloma. In another embodiment, the other agent is an agent for treating myeloma. In another embodiment, the other agent is an agent for treating secretory cell carcinoma. In one embodiment, the other agent is an agent for reducing eIF2α phosphorylation. In another embodiment, the other agent is an agent for inhibiting pathways activated by eIF2α phosphorylation. In another embodiment, the other agent is an agent for inhibiting pathways activated by eIF2α. In another embodiment, the other agent is an agent for inhibiting integrated stress responses. In another embodiment, the other agent is an anti-inflammatory agent. In another embodiment, the other agent is an agent for treating postoperative cognitive impairment. In another embodiment, the other agent is an agent for treating traumatic brain injury. In another embodiment, the other agent is an agent for treating musculoskeletal disorders. In another embodiment, the other agent is an agent for treating metabolic diseases. In another embodiment, the other agent is an antidiabetic agent. anticancer agents

[0237] "Anticancer agent" is used in its common sense and refers to a component (e.g., compound, drug, antagonist, inhibitor, regulator) that has anti-proliferative properties or can inhibit cell growth or proliferation. In some embodiments, an anticancer agent is a chemotherapeutic agent. In some embodiments, an anticancer agent is a pharmaceutical agent used in methods of treating cancer as identified herein. In some embodiments, an anticancer agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country other than the USA for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY). 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards).(e.g., nitrogen mustard, cyclophosphamide, chlorambucil, mephalan), ethyleneimine and methyl melamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazine (decarbazine), antimetabolites (e.g., 5-thiazolinone, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed), folic acid analogs (e.g., methotrexate). Xate or pyrimidine analogs (e.g., fluorouracil, fluxouridine, cytarabine), purine analogs (e.g., mecaptopurine, thioguanine, pentostatin, etc.), alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide, etc.). 16) Etoposide phosphate, teniposide, etc.; antitumor antibiotics (such as doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone).Plastic mycin, platinum compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-aspartate aminotransferase), mitogen-activated protein kinase signaling inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY) 43-9006, wortmannin (or LY294002), Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxana), gossyphol, genasense, polyphenol E, chlorhexidine, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.)), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 1 1-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; aifostine; aminolevulinic acidacid); amrubicin; acridine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen (pancreatic cancer); antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene regulator; apoptosis modulator; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; arsenic trioxide; asulacrine; atamestane; atrimustine; axinastatin 1); Azasetron; Azasetron; Azatoxin; Azatyramine; Baccatin III derivatives; Balanol; Batimastat; BCR / ABL antagonists; Benzochlorins; Benzoylstaurosporine; β-lactam derivatives; β-alethine; Beta-clarithromycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bistratene A A); bizelesin; breflate; bropirimine; budotitane; bushionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox virusIL-2; capecitabine; methylamine triazole; carboxyamine triazole; CaRest M3; CARN 700; chondroitin inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cisporine; cladribine; clomifene analogues; clotrimazole; colismycin A; clomifene B; compretastatin A4; compretastatin analogues; conagenin; crambescidin 816 816); cristato; cryptophycin 8; cyclophycin A derivative; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diziquone; didemnin B B); didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolastron; doxifluridine; droloxifene; dronabinol; pyruvic acid SA(duocarmycin SA); ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonist; etanidazole; etoposide phosphate Phosphate); exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium Tetraphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acidacid); idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukin; iobenguane; iododoxorubicin; ipomeanol; iroplact; irsogladine; isobengazole; ishomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7); Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Luttium texaphyrin; Lysofylline; Lylytic peptides; Maitansine; Mannostatin A; Marimastat; Masoprocol; Maspin; MatrixlysinInhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactone; mitoxacin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophospholipid A+ mycobacterial cell wall SK; mopidamol; multidrug resistance gene inhibitors; multiple tumor inhibitor-based therapy (multiple Tumor suppressor 1-based therapy); nitrogen mustard anticancer agents; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzylamine; nafarelin; nagrestip; naloxone + pentazocine; napavin; napterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitroxide antioxidantantioxidant); nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral interferon inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazeliptine; pegaspargase; peldesine; pentosan polysulfate sodium); pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgal protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugates.hemoglobin polyoxyethylerie conjugate); RAF antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribonuclease; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1. Analog; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; single-chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; growth factor-binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist. antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen iodide.methiodide); tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimic; thymalfasin; thymosin receptor agonist; thymotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrphostins; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B B); Vector systems, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer; adriamycin; actinomycin D(Dactinomycin), bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; interleukin; hexamethylenetetramine; ambomycin; ametantrone acetate; amylmethionine; acridine; anastrozole; antramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin C; calusterone; caracemide; carbetimer; carplatin; carmustine; carrubicin hydrochloride; carzefenoxuron; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionatepropionate); dazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esoubicin hydrochloride; estradiol; estradiol sodium phosphate; estradiol; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenivel A; fluxuridine; fludarabine phosphate; fluorouracil; flucitabine; fosquidone; fostriecin sodium Sodium); Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Imofosine; Interleukin II (including recombinant interleukin II) or RL2); Interferon α-2a; Interferon α-2b; Interferon α-nl; Interferon α-n3; Interferon β-la; Interferon γ-lb; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate acetate); melengestrol acetateacetate); mefarin; menogaril; mercaptopurine; methylparaben; methylparaben sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitosper; mitotane; mitoxetine hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; peliomycin; pentamustine; peplomycin sulfate sulfate); perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloridehydrochloride); temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimethotraxane; trimethotraxane glucuronide; triptorelin; tobulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate sulfate); vindesine; vindesine sulfate; vinpidine sulfate; vinpyric acid phosphate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; agents that cause G2-M phase cell arrest and / or regulate microtubule formation or stability (e.g., Taxol, paclitaxel, Taxotere, compounds containing a taxane skeleton, Erbulozole (R-55104), Dolasatin 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), Altorhyrtins(e.g., Atorhestatin A and Atorhestatin C), Spongistatins (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cemadotin hydrochloride (i.e., LU-103793 and SC-D-669356), Epothilones (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-hydroxyepsilon D (i.e., deoxyepsilon F and dEpoF), 26-fluoroepsilon, Auristatin PE (i.e., NSC-654663), Soblidotin (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, also known as 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 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700(Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilelevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A 1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute) The following are listed: Institute, Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadoxene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine. (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), Eleutherobins(such as desmethylarilin, desacetylatedarilin, isoarilin A and Z-arilin), Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, Phenylahistin (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B B), D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110), Wyeth trifluoroacetate, D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-25041 1 Sanofi, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticotropic hormones (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate).Propionate, fluoxymesterone, anti-androgens (e.g., flutamide), immunostimulants (e.g., BCG, levamisole, interleukin-2, alpha-interferon), 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), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody with 111In), (Conjugates of 90Y or 131I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin avastatin, irinotecan, clofazimine, 5-nonoxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib.(Caprelsa™), Afatinib / BIBW2992, CI-1033 / Canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, Dacomitinib / PF299804, OSI-420 / Methylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or similar substances.

[0238] "Chemotherapy" or "chemotherapeutic agents" is used in its common sense and refers to chemical components or compounds that have anti-hypertrophic properties or can inhibit cell growth or proliferation.

[0239] In addition, the compounds described herein can be co-administered with known immunotherapeutic agents, including but not limited to immunostimulants (such as BCG, levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR and anti-VEGF monoclonal antibodies), immunotoxins (such as anti-CD33 monoclonal antibody-cucurbitacin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (such as anti-CD20 monoclonal antibody conjugates with 111In, 90Y or 131I, etc.).

[0240] In another embodiment, the compounds described herein may be co-administered with conventional radiotherapy agents, including but not limited to radionuclides such as 47Sc, 64Cu, 67Cu, 89Sr, 86Y, 87Y, 90Y, 105Rh, mAg, mIn, 117mSn, 149Pm, 153Sm, 166Ho, 177Lu, 186Re, 188Re, 211At, and 212Bi, and conjugated, as appropriate, with antibodies against tumor antigens. Other medicines

[0241] In some embodiments, another agent used in combination with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof) or a composition thereof is an agent for the treatment of neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. In some embodiments, another agent used in combination with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof) or a composition thereof is an agent approved by the FDA or a similar regulatory agency in a country other than the USA for the treatment of the diseases, conditions, or illnesses described herein.

[0242] In some embodiments, another agent used to treat neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, or metabolic diseases includes, but is not limited to, antipsychotics, antidepressants, anxiolytics, analgesics, stimulants, sedatives, pain relievers, anti-inflammatory agents, benzodiazepines, cholinesterase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, MAO inhibitors, beta-blockers, calcium channel blockers, antacids, or other agents. Other illustrative agents may include donepezil, galantamine, rivastigmine, memantine, levodopa, dopamine, pramipexole, ropinirole, rotigotine, doxapram, oxazepam, quetiapine, selegiline, rasagiline, entacapone, benztropine, trihexyphenidyl, and riluzole. luzole, diazepam, chlorodiazepoxide, lorazepam, alprazolam, buspirone, gepirone, ispapillone, hydroxyzine, propranolol, midazolam, trifluoperazine, methylphenidate, atoxetine, pemoline, perphenazine, divalproex, valproic acidacid), sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, trazodone, desvenlafaxine, duloxetine, venlafaxine, amitriptyline, amoxapine, clomipramine, desipramine, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, bupivacaine Nefazodone, vortioxetine, lithium, clozapine, fluphenazine, haloperidol, paliperidone, loxapine, thiothixene, pimozide, thioridazine, risperidone, aspirin, ibuprofen, naproxen, acetaminophen, azathioprine, methotrexate, mycofenac, leflunomide, dibenzoylmethane, cilostazol, pentoxifylline, duloxetine, and cannabinoids. (e.g., nabilone), simethicone, magnesium plus aluminum, aluminum salts, calcium salts, sodium salts, magnesium salts, alginate, acarbose, albiglutide, alogliptin, metformin, insulin, lisinopril, atenolol, atorvastatin, fluvastatin, lovastatin, pitavastatin, simvastatin, rosuvastatin, and analogues.)

[0243] Naturally derived medicines or supplements may also be used in combination with compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, solvates, hydrates, tautomers, esters, N-oxides or stereoisomers, or components thereof, to treat neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. Exemplary naturally derived medicines or supplements include omega-3 fatty acids, carnitine, citicoline, curcumin, gingko, vitamin E, vitamin B (e.g., vitamin B5, vitamin B6, or vitamin B12), huperzine A, phosphatidylserine, rosemary, caffeine, melatonin, chamomile, St. John's wort, tryptophan, and the like. [Example] []

[0244] To provide a more complete understanding of the invention described herein, the following examples are presented. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way. [Synthesis Scheme] []

[0245] The compounds provided herein can be prepared from readily available starting materials using modifications of specific synthetic schemes well known to those skilled in the art, as described below. It should be understood that, given typical or preferred method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other method conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by those skilled in the art using conventional optimal procedures. General methods relating to the preparation of exemplary compounds of the present invention are further described in the section entitled "Methods for Preparing Compounds".

[0246] Furthermore, those skilled in this art will readily recognize that preventing certain functional groups from undergoing undesirable reactions may require knowledge of protecting groups. Protecting groups suitable for specific functional groups, and the conditions suitable for protecting and removing protecting groups, are well known in this art. For example, various protecting groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, 2nd ed., Wiley, New York, 1991, and the references cited therein. abbreviation

[0247] APCI stands for Atmospheric Pressure Chemical Ionization; Boc stands for Tertiary Butoxycarbonyl; t-Bu stands for Tertiary Butyl; DCI stands for Desorption Chemical Ionization; DMOS stands for Dimethyl Ionium; ESI stands for Electrospray Ionization; HATU stands for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC stands for High Performance Liquid Chromatography; LC stands for Liquid Chromatography; LC / MS stands for Liquid Chromatography / Mass Spectrometry; MS stands for Mass Spectrometry; NMR stands for Nuclear Magnetic Resonance; psi stands for pounds per square inch; SFC stands for Supercritical Fluid Chromatography; and UV stands for Ultraviolet Light. [Example] [1] Acetic acid [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [100)] Example 1A: Ethyl 1,4-dioxane[4.5]nonane-8-carboxylate

[0248] A mixture of ethyl 4-sideoxycyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethylene-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 min. The reaction mixture was neutralized with N-ethyl-N-isopropylpropyl-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. 1H NMR (400 MHz, DMSO- d 6) δppm 4.01 (q, J =7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J =10.4, 3.8 Hz, 1H), 1.83 – 1.71 (m, 2H), 1.66 – 1.57 (m, 1H), 1.62 – 1.38 (m, 5H), 1.13 (t, J =7.1 Hz, 3H). Example 1B: Ethyl 8-acetylated-1,4-dioxane[4.5]nonane-8-carboxylate

[0249] At 0 °C, n-butyllithium was slowly added to a solution of diisopropylamine (5.19 mL, 36.4 mmol) in tetrahydrofuran (25 mL), 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, while stirring the resulting mixture at the same temperature for 30 minutes. Next, acetyl chloride (2.59 mL, 36.4 mmol) was slowly added to maintain the temperature below -60 °C, and the mixture was stirred at -70 °C for 2 hours. The reaction was quenched with a saturated aqueous solution of NH₄Cl, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with 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. 1H NMR (500 MHz, DMSO- d 6) δppm 4.19 – 4.11 (m, 2H), 3.85 (s, 4H), 2.13 (s, 3H), 2.10 – 2.01 (m, 2H), 1.90 (ddd, J =13.9, 9.6, 4.6 Hz, 2H), 1.54 (th, J =13.6, 4.7 Hz, 4H), 1.18 (dd, J =7.6, 6.5 Hz, 3H). Example 1C: Ethyl 1-acetyl-4-sideoxycyclohexane-1-carboxylate

[0250] At ambient temperature, 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. Volatile substances were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with 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. ¹H NMR (400 MHz, DMSO-d₆) δppm 4.16 (q, J = 7.1 Hz, 2H), 2.35 2.07 (m, 8H), 2.17 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). Example 1D: 4-(benzylamino)-2-side-oxybicyclo[2.2.2]octane-1-carboxylic acid ethyl ester

[0251] In the presence of a Dean-Stark separator, 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 under reflux. The mixture was concentrated under reduced pressure, and the residue was stirred for 30 minutes with a mixture of ethyl acetate (50 mL) and 3 N HCl (100 mL). The precipitate was collected by filtration, washed with an ethyl acetate / heptane mixture, and air-dried to give 11.3 g of the title compound in hydrochloride form. The filtrate was neutralized with 6 N NaOH and extracted with ethyl acetate (100 mL × 2). The organic layer was washed with 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 0.77 g of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO- d 6) δppm 9.73 (t, J =6.2 Hz, 2H), 7.87 – 7.12 (m, 5H), 4.09 (m, 4H), 2.88 (s, 2H), 2.08 (dt, J =20.7, 13.4 Hz, 6H), 1.16 (t, J =7.1 Hz, 3H); MS (ESI +) m / z302.1 (M+H) +. Example 1E: 4-amino-2-side-oxybicyclo[2.2.2] octane-1-carboxylic acid ethyl ester

[0252] In a 50 mL pressure vessel, moist 20% Pd(OH)₂ / C (2.2 g, 1.6 mmol) was added to a mixture of Example 1D (11.2 g, 33.2 mmol) in tetrahydrofuran (110 mL), and the reaction was carried out under 50 psi hydrogen atmosphere and shaken at 50 °C for 22 h. The reaction mixture was cooled to ambient temperature, and the solid was then removed by filtration and washed with methanol (1 L). The filtrate and washings were concentrated under reduced pressure to give 7.9 g of the title compound in hydrochloride form. 1H NMR (400 MHz, DMSO- d 6) δppm 8.46 (s, 3H), 4.07 (q, J =7.1 Hz, 2H), 2.62 (s, 2H), 2.17 – 2.05 (m, 2H), 2.04 – 1.78 (m, 6H), 1.14 (t, J =7.1 Hz, 3H). Example 1F: 4-[2-(4-chloro-3-fluorophenoxy)acetamino]-2-side-oxybicyclo[2.2.2]octane-1-carboxylic acid ethyl ester

[0253] A suspension of Example 1E (7.8 g, 31.5 mmol), N-ethyl-N-isopropylpropyl-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 mixed with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea-6-fluorophosphate (V) (14.97 g, 39.4 mmol) and stirred at ambient temperature for 16 hours to obtain a brown solution. Water was added and the mixture was stirred for 15 minutes. The precipitate was collected by filtration, washed with water, and air-dried to give 12.1 g of the title compound as a grayish-white solid. 1H NMR (400 MHz, DMSO- d 6) δppm 7.87 (s, 1H), 7.45 (t, J =8.9 Hz, 1H), 7.00 (dd, J =11.4, 2.9 Hz, 1H), 6.79 (ddd, J =8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 4.06 (q, J =7.1 Hz, 2H), 2.73 (s, 2H), 2.07 (m, 1H), 2.01 – 1.84 (m, 6H), 1.14 (t, J =7.1 Hz, 3H);MS (ESI +) m / z398.0 (M+H) +. Example 1G: 4-[2-(4-chloro-3-fluorophenoxy)acetamino]-2-side-oxybicyclo[2.2.2]octane-1-carboxylic acid

[0254] At ambient temperature, 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 for 16 hours. Volatile substances 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. 1H NMR (400 MHz, DMSO- d 6) δppm 12.49 (s, 1H), 7.86 (s, 1H), 7.45 (t, J =8.9 Hz, 1H), 7.00 (dd, J =11.4, 2.9 Hz, 1H), 6.83 – 6.74 (m, 1H), 4.45 (s, 2H), 2.71 (s, 2H), 2.01 – 1.81 (m, 7H); MS (ESI -) m / z368.1 (MH) -. Example 1H: N-(4-amino-3-sideoxybicyclo[2.2.2]octyl)-2-(4-chloro-3-fluorophenoxy)acetamide

[0255] A mixture of Example 1G (3.24 g, 8.76 mmol), diphenyl azidophosphate (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 3 N 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 a white solid in the form of the title compound in hydrochloride form (1.63 g). The filtrate was then alkalized with solid sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with 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 in the form of a free base (0.6 g). 1H NMR (400 MHz, DMSO- d 6) δppm 8.49 (s, 3H), 8.08 (s, 1H), 7.45 (t, J =8.9 Hz, 1H), 7.01 (dd, J =11.4, 2.8 Hz, 1H), 6.79 (ddd, J =9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.90 (s, 2H), 2.12 – 1.79 (m, 8H). Example 1I: N-(4-amino-3-hydroxybicyclo[2.2.2]octyl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride

[0256] The 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 and dichloromethane (50 mL) was stirred for 24 hours. Volatile substances were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic fraction was separated, dried (MgSO4), and concentrated. The residue was then treated with a solution of 4 N HCl in dioxane. The suspension was treated with sonication and concentrated. The residue was dried under vacuum to give 2.82 g of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO- d 6) δppm 7.97 (s, 3H), 7.72 (s, 1H), 7.40 (t, J =8.9 Hz, 1H), 6.95 (dd, J =11.4, 2.8 Hz, 1H), 6.74 (ddd, J =9.0, MS (ESI +) m / z343.0 (M+H) +. Example 1J: N,N'-(2-side-oxybicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide]

[0257] 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-isopropylpropyl-2-amine (1.157 mL, 6.63 mmol) in N,N-dimethylformamide (20 mL) were treated with 2-(3 H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (0.756 g, 1.988 mmol) and treated with 2-(3 H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)acetic acid (0.339 g, 1.657 mmol) and N-ethyl-N-isopropylpropyl-2-amine (1.157 mL, 6.63 mmol) at ambient temperature for 30 minutes, and complete conversion was observed. 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. 1H NMR (400 MHz, DMSO- d 6) δppm 7.88 (s, 1H), 7.67 (s, 1H), 7.45 (td, J =8.9, 2.4 Hz, 2H), 7.03 (ddd, J =15.0, 11.4, 2.8 Hz, 2H), 6.80 (dddd, J =10.3, 8.9, 2.9, 1.2 Hz, 2H), 4.53 (s, 2H), 4.45 (s, 2H), 2.83 (s, 2H), 2.45 – 2.33 (m, 2H), 2.10 – 1.90 (m, 4H), 1.81 (td, J =11.6, 6.3 Hz, 2H);MS (ESI +) m / z527.0 (M+H) +. Example 1K: N,N'-(2-hydroxybicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide]

[0258] Sodium borohydride (0.226 g, 5.97 mmol) was added fractionally 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. Volatile substances were removed, and the residue was wet-milled 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. 1H NMR (400 MHz, DMSO- d 6) δppm 7.49 – 7.39 (m, 3H), 7.22 (s, 1H), 7.00 (ddd, J =12.4, 11.4, 2.8 Hz, 2H), 6.78 (tdd, J =9.1, 2.9, 1.2 Hz, 2H), 5.04 (s, 1H), 4.41 (d, J =13.3 Hz, 4H), 4.00 (dd, J =9.6, 3.1 Hz, 1H), 2.23 (ddd, J =12.1, 9.4, 2.2 Hz, 1H), 2.09 – 1.97 (m, 1H), 1.93 – 1.80 (m, 2H), 1.84 – 1.68 (m, 6H); MS (ESI +) m / z529.1 (M+H) +. Example 1L: N,N'-[(2S)-2-hydroxybicyclo[2.2.2]octane-1,4-diyl]bis[2-(4-chloro-3-fluorophenoxy)acetamide]

[0259] The title compound was separated as a second peak from column dissociation by preparative SFC (supercritical fluid chromatography) of Example 1K. The preparative SFC was performed on a THAR / Waters SFC 80 system, controlled by SuperChrom™ software. The preparative SFC system was equipped with an 8-way preparative column converter, a CO2 pump, a modifier pump, an automatic back pressure regulator (ABPR), a UV detector, and a 6-position dissociation collector. The mobile phase consisted of supercritical CO2 supplied from Dewar oven-dry unidentified CO2 pressurized to 350 psi, containing a methanol modifier, at a flow rate of 70 g / min. The column was at ambient temperature, and the back pressure regulator was set to maintain 100 bar. The sample was dissolved in a methanol / dichloromethane mixture (1:1) at a concentration of 10 mg / mL. The sample was loaded into the modifier stream as 1 mL (10 mg) of injection solution. The mobile phase was maintained at an isoconcentration at 30% methanol:CO2. The collection of dissolved fractions is time-triggered. The instrument is equipped with a Chiralpak® AD-H column, which measures 21 mm id × 250 mm in length and contains 5 µm particles. 1H NMR (400 MHz, DMSO- d 6) δppm 7.49 – 7.39 (m, 3H), 7.23 (s, 1H), 7.00 (dddd, J =12.4, 11.4, 2.9 Hz, 2H), 6.78 (dddd, J =9.0, 8.0, 2.9, 1.2 Hz, 2H), 5.05 (s, 1H), 4.41 (d, J =13.5 Hz, 4H), 4.00 (dd, J =9.4, 3.0 Hz, 1H), 2.23 (ddd, J =12.3, 9.4, 2.3 Hz, 1H), 2.03 (ddd, J =12.3, 10.5, 4.7 Hz, 1H), 1.89 (d, J =10.7 Hz, 2H), 1.87 – 1.76 (m, 1H), 1.74 (ddd, J =12.6, 6.7, 2.4 Hz, 5H); MS (ESI +) m / z529.1 (M+H) +. Example 1M: Acetic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0260] At 0 °C, acetyl chloride (1.35 mL, 19 mmol) was added 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 CH₂Cl₂ (80 mL). The ice-water bath was removed, and the mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was diluted with ethyl acetate. The mixture was washed with 1 N HCl (40 mL), water (25 mL), a saturated aqueous solution of NaHCO₃ (25 mL), and brine (25 mL). The organic fraction was dried over anhydrous Na₂SO₄, adsorbed onto silica gel, and purified on silica gel (25-30% ethyl acetate / dichloromethane) to give 7.78 g of a white solid racemic substance. Enantiomers were separated by preparative SFC (supercritical fluid chromatography). The preparative SFC was performed on a THAR / Waters SFC 80 system, controlled by SuperChrom™ software. The preparative SFC system was equipped with an 8-way preparative column converter, a CO2 pump, a modifier pump, an automatic back pressure regulator (ABPR), a UV detector, and a 6-position dissociation collector. The mobile phase consisted of supercritical CO2 supplied from Dewar oven-dry unidentified CO2 pressurized to 350 psi, containing a methanol modifier, at a flow rate of 80 mL / min. The column was at ambient temperature, and the back pressure regulator was set to maintain 100 bar. The sample was dissolved in a methanol / dichloromethane mixture (1:1) at a concentration of 10 mg / mL. The sample was loaded into the modifier stream as 1 mL (10 mg) of injection solution. The mobile phase was maintained at isoconcentration at 40% methanol:CO2. Dissociation collection was time-triggered. The instrument is equipped with a Chiralpak® AD-H column, which measures 21 mm id × 250 mm in length and contains 5 µm particles.

[0261] The second soluble compound obtained by this palmar separation is the title compound (2.97 g, 5.19 mmol, 35% yield). 1H NMR (501 MHz, DMSO-d 6) δppm 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (td, J =8.9, 2.0 Hz, 2H), 7.00 (ddd, J =16.6, 11.4, 2.9 Hz, 2H), 6.79 (dddd, J =8.6, 7.1, 2.9, 1.1 Hz, 2H), 5.28 (dd, J =9.5, 2.4 Hz, 1H), 4.48 – 4.39 (m, 4H), 2.39 (ddd, J =14.1, 9.4, 2.9 Hz, 1H), 2.21 (dd, J =11.6, 7.6 Hz, 1H), 2.02 (td, J =8.4, 2.8 Hz, 1H), 1.98 (s, 3H), 1.93 (dd, J =9.1, 6.9 Hz, 2H), 1.89 – 1.76 (m, 5H); MS (ESI +) m / z570.7 (M+H) +. [Example] [2] [:dihydrogen phosphate] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [101)] Example 2A: Phosphate (S)-1,4-bis(2-(4-chloro-3-fluorophenoxy)acetaminopheno)bicyclo[2.2.2]octyl 2-ester ditert-butyl ester

[0262] To a solution of the product (0.200 g, 0.378 mmol) from Example 1L in N,N-dimethylformamide (1.1 mL), a solution of 0.45 M 1 H-tetrazole in acetonitrile (2.1 mL, 0.945 mmol) was added, followed by the addition of diethylaminophosphate ditert-butyl (0.21 mL, 0.76 mmol). The mixture was stirred at 50 °C for 1 hour and then cooled to room temperature. Hydrogen peroxide (0.39 mL, 3.82 mmol) was added to the reaction mixture at room temperature, followed by stirring for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel (3% ethanol / dichloromethane). The still impure substance was further purified on silica gel (40% ethyl acetate / dichloromethane) to give the title compound (0.124 g, 0.172 mmol, 46% yield), which was used without further purification. LC / MS (APCI +) m / z 721 (M+H) +. Example 2B: (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl ester of dihydrogen phosphate

[0263] Example 2A (0.1244 g, 0.172 mmol) was stirred in CH₂Cl₂ (0.60 mL) and 2,2,2-trifluoroacetic acid (0.20 mL, 2.61 mmol) for 16 hours, followed by concentration under reduced pressure. The residue was purified by reversed-phase chromatography (Phenomenex® Luna® 250 × 30 mm 10 μm C18 column, 60 mL / min, 15-95% acetonitrile / 0.1% trifluoroacetic acid aqueous gradient) to give the title compound (0.035 g, 0.058 mmol, 34% yield). 1H NMR (400 MHz, DMSO- d 6) δppm7.76 (s, 1H), 7.62 (s, 1H), 7.47 (td, J =8.9, 4.2 Hz, 2H), 7.07 (ddd, J =33.3, 11.4, 2.9 Hz, 2H), 6.85 (dddd, J =31.0, 9.0, 2.9, 1.2 Hz, 2H), 4.59 (t, J =9.0 Hz, 1H), 4.44 (s, 2H), 4.41 (dd, J =3.3 Hz, 2H), 2.45 – 2.28 (m, 2H), 2.18 (td, J =12.8, 12.3, 5.7 Hz, 1H), 2.11 – 1.97 (m, 2H), 1.79 (dt, J =14.5, 9.6 Hz, 5H); MS (ESI -) m / z607 (MH) -. [Example] [3] [:] [(2, S , )-2- ] [Amine] [-4-({(2 , S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [base] [}] [Oxygen group] [)-4-] [Side-oxybutyric acid] [(] [Compound] [102)]

[0264] 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-triazolo[4,5-b]pyridinium 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 hours 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, 0-60% gradient acetonitrile / buffer (0.1% trifluoroacetic acid / water)) to give the title compound in trifluoroacetate form (24 mg, 0.03 mmol, 53% yield). 1H NMR (500 MHz, DMSO- d 6) δppm8.32 (d, J =22.4 Hz, 3H), 7.66 (d, J =14.0 Hz, 1H), 7.55 – 7.41 (m, 3H), 7.07 – 6.95 (m, 2H), 6.84 – 6.74 (m, 2H), 5.55 – 5.34 (m, 1H), 4.50 – 4.38 (m, 4H), 4.38 – 4.21 (m, 1H), 2.96 – 2.83 (m, 2H), 2.48 – 2.40 (m, 1H), 2.27 (d, J =12.5 Hz, 1H), 2.13 – 1.68 (m, 8H);MS (ESI +) m / z645 (M+H) +. [Example] [4] [:] [(2-)] [Methoxyethoxy] [)] [Acetic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [103)]

[0265] The product of Example 1L (30 mg, 0.057 mmol) in a suspension of 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-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (24 mg, 0.062 mmol) and 2-(2-methoxyethoxy)acetic acid (11 mg, 0.082 mmol). The reaction mixture was stirred at 25 °C for 20 hours and then concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column 250 mm × 21.2 mm, flow rate 25 mL / min, 10-80% gradient acetonitrile / buffer (0.1% trifluoroacetic acid / water)) to give the title compound (18 mg, 0.027 mmol, 49% yield). 1H NMR (500 MHz, DMSO- d 6) δppm7.61 (s, 1H), 7.55 (s, 1H), 7.47 (td, J =8.8, 2.2 Hz, 2H), 7.01 (ddd, J =11.0, 7.8, 2.9 Hz, 2H), 6.79 (td, J =9.4, 3.0 Hz, 2H), 5.43 – 5.36 (m, 1H), 4.48 – 4.37 (m, 4H), 4.09 (d, J =3.2 Hz, 2H), 3.64 – 3.54 (m, 2H), 3.44 (t, J =4.7 Hz, 2H), 3.23 (s, 3H), 2.43 (dt, MS (ESI +) m / z646 (M+H) +. [Example] [5] Methoxyacetic acid [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [104)]

[0266] The product of Example 1L (30 mg, 0.057 mmol) in a suspension of 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-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (24 mg, 0.062 mmol) and 2-methoxyacetic acid (8 mg, 0.089 mmol). The reaction mixture was stirred at 25 °C for 20 hours and then concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column 250 mm × 21.2 mm, flow rate 25 mL / min, 10-80% gradient acetonitrile / buffer (0.1% trifluoroacetic acid / water)) to give the title compound (17 mg, 0.028 mmol, 50% yield). 1H NMR (501 MHz, DMSO- d 6) δppm7.62 (s, 1H), 7.58 (s, 1H), 7.47 (td, J =8.9, 3.8 Hz, 2H), 7.01 (td, J =11.2, 2.9 Hz, 2H), 6.79 (tdd, J =10.0, 2.8, 1.2 Hz, 2H), 5.40 (dd, J =9.6, 2.2 Hz, 1H), 4.48 – 4.37 (m, 4H), 4.06 – 3.95 (m, 2H), 3.31 (s, 3H), 2.47 – 2.38 (m, 1H), 2.23 (d, J =13.3 Hz, 1H), 2.04 – 1.96 (m, 1H), 1.96 – 1.90 (m, 2H), 1.85 (ddd, J =24.9, 11.7, 5.7 Hz, 5H); MS (ESI +) m / z602 (M+H) +. [Example] [6] Ethoxyacetic acid [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [105)]

[0267] The product of Example 1L (30 mg, 0.057 mmol) in a suspension of 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-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (24 mg, 0.062 mmol) and 2-ethoxyacetic acid (9 mg, 0.086 mmol). The reaction mixture was stirred at 25 °C for 20 hours and then concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column 250 mm × 21.2 mm, flow rate 25 mL / min, 10-80% gradient acetonitrile / buffer (0.1% trifluoroacetic acid / water)) to give the title compound (16 mg, 0.026 mmol, 46% yield). 1H NMR (501 MHz, DMSO- d 6) δppm7.62 (s, 1H), 7.57 (s, 1H), 7.47 (td, J =8.9, 3.0 Hz, 2H), 7.01 (ddd, J =11.5, 8.7, 2.8 Hz, 2H), 6.83 – 6.75 (m, 2H), 5.39 (dd, J =9.7, 2.1 Hz, 1H), 4.48 – 4.37 (m, 4H), 4.10 – 3.98 (m, 2H), 3.53 – 3.45 (m, 2H), 2.42 (ddd, J =14.1, 9.4, 3.0 Hz, 1H), 2.22 (d, J =12.6 Hz, 1H), 2.05 – 1.96 (m, 1H), 1.96 – 1.90 (m, 2H), 1.90 – 1.75 (m, 5H), 1.11 (t, J =7.0 Hz, 3H); MS (ESI +) m / z616 (M+H) +. [Example] [7] [:] [4-({(2 , S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [base] [}] [Oxygen group] [)-4-] [Side-oxybutyric acid] [(] [Compound] [106)]

[0268] The product of Example 1L (14 mg, 0.026 mmol) and the suspension of N,N-dimethylpyridin-4-amine (3.23 mg, 0.026 mmol) in N,N-dimethylformamide (0.5 mL) were cooled to 0 °C and treated with dihydrofuran-2,5-dione (5.29 mg, 0.053 mmol). The reaction mixture was stirred at 25 °C for 20 h, then the temperature was raised to 40 °C and stirred for 72 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column 250 mm × 21.2 mm, flow rate 25 mL / min, 10-80% gradient acetonitrile / buffer (0.1% trifluoroacetic acid / water)) to give the title compound (13 mg, 0.021 mmol, 78% yield). 1H NMR (400 MHz, DMSO- d 6) δppm12.21 (s, 1H), 7.60 (s, 1H), 7.52 – 7.41 (m, 3H), 7.00 (ddd, J =14.7, 11.4, 2.9 Hz, 2H), 6.79 (tdd, J =9.0, 2.8, 1.2 Hz, 2H), 5.31 (d, J =8.3 Hz, 1H), 4.43 (d, J =2.9 Hz, 4H), 2.51 – 2.37 (m, 3H), 2.24 (t, J =10.3 Hz, 1H), 1.99 – 1.73 (m, 8H);MS (ESI +) m / z630 (M+H) +. [Example] [8] Carbonated [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Ethyl ester] [(] [Compound] [107)]

[0269] At room temperature, ethyl chloroformate (10 µL, 0.105 mmol) was added to a suspension of product (0.0500 g, 0.094 mmol) in pyridine (0.10 mL, 1.24 mmol), and the mixture was stirred for 16 hours, followed by heating to 50 °C and maintaining the temperature for 8 hours. An equal aliquot of ethyl chloroformate (10 µL, 0.105 mmol) was then added. The mixture was stirred at 50 °C for 5 hours, and ethyl chloroformate (10 µL, 0.105 mmol) was added again. The mixture was stirred for 4 hours, diluted with ethyl acetate, washed with water and brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified on silica gel (10% ethyl acetate / dichloromethane) to give the title compound (0.026 g, 0.044 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d 6) δppm7.66 (s, 1H), 7.63 (s, 1H), 7.46 (dt, J =9.9, 8.8 Hz, 2H), 6.99 (ddd, J =17.9, 11.4, 2.9 Hz, 2H), 6.84 – 6.75 (m, 2H), 5.26 (dd, J =9.2, 2.0 Hz, 1H), 4.51 – 4.37 (m, 4H), 4.16 – 3.99 (m, 2H), 2.40 (ddd, J =14.3, 9.3, 2.7 Hz, 1H), 2.34 – 2.22 (m, 1H), 2.00 (d, J =9.2 Hz, 1H), 1.97 – 1.70 (m, 7H), 1.21 (t, J =7.1 Hz, 3H); MS (ESI -) m / z598 (MH) -. [Example] [9] [Diethylaminoformic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [108)] Example 9A: N,N'-[(2S)-2-({[(2,5-dioxypyrrolidin-1-yl)oxy]carbonyl}oxy)bicyclo[2.2.2]octane-1,4-diyl]bis[2-(4-chloro-3-fluorophenoxy)acetamide]

[0270] A mixture of the product of Example 1L (0.40 g, 0.756 mmol) and N,N'-disuccinimidyl carbonate (0.58 g, 2.27 mmol) in pyridine (1 mL) was heated to 50 °C and maintained for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was treated with brine and an aqueous solution of NaHCO3 and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on a 40 g silicon dioxide column using a Biotage Isolera™ One flash system, and dissociated with heptane / ethyl acetate (4:6 to 3:7) to give the title compound (0.292 g, 58%). MS (ESI+) m / z 670.2 (M+H)+. Example 9B: Diethylaminoformic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0271] At room temperature, the product of Example 9A (0.061 g, 0.091 mmol) and diethylamine (38 µL, 0.367 mmol) were stirred in a solution of tetrahydrofuran (0.30 mL) for 1 hour. The mixture was then diluted with ethyl acetate, washed with 1 N NaOH and brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified on silica gel (20–25% ethyl acetate / dichloromethane) to give the title compound (0.024 g, 0.038 mmol, 42% yield). 1H NMR (400 MHz, DMSO- d 6) δppm7.69 (s, 1H), 7.60 (s, 1H), 7.46 (q, J =8.9 Hz, 2H), 7.00 (ddd, J =13.1, 11.4, 2.9 Hz, 2H), 6.79 (tdd, J =8.6, 2.9, 1.2 Hz, 2H), 5.15 – 5.08 (m, 1H), 4.42 (m, 4H), 3.19 (p, J =7.4 Hz, 4H), 2.36 (ddd, J =14.2, 9.2, 2.8 Hz, 1H), 2.17 – 1.69 (m, 9H), 1.04 (d, J =8.6 Hz, 6H); MS (ESI +) m / z628.0 (M+H) +. [Example]

[10] [:] [(] [phosphonoyl] [)] [Acetic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [109)] Example 10A: [(di-tert-butoxyphosphatyl)oxy]benzyl acetate

[0272] Di(3-hydroxyacetic acid) ditert-butyl phosphate (0.80 mL, 2.87 mmol) was added to a solution of methyl 2-hydroxyacetate (0.276 mL, 1.942 mmol) and 0.45 M 1 H-tetrazole in acetonitrile (12.5 mL, 5.63 mmol). The mixture was stirred at room temperature for 2 hours, followed by cooling to 0 °C. Hydrogen peroxide (1.0 mL, 9.79 mmol) was added, and the reaction was stirred for 90 minutes. The mixture was diluted with ethyl acetate (15 mL), washed with saturated Na₂SO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified on silica gel (10% ethyl acetate / dichloromethane) to give the title compound (0.718 g, 2.0 mmol, quantitative). 1H NMR (400 MHz, DMSO- d 6) δppm7.42 – 7.31 (m, 5H), 5.19 (s, 2H), 4.54 (d, J =9.7 Hz, 2H), 1.39 (s, 18H). Example 10B: [(di-tert-butoxyphosphatyl)oxy]acetic acid

[0273] The product of Example 10A (0.2376 g, 0.663 mmol) and a solution of 1 M sodium hydroxide (0.73 mL, 0.730 mmol) in methanol (0.75 mL) and tetrahydrofuran (0.75 mL) were stirred for 10 minutes, diluted with water (8 mL), and extracted with ethyl acetate (8 mL). The aqueous fraction was neutralized with 1 N HCl (0.8 mL), extracted with CH₂Cl₂ (3 × 6 mL), dried (Na₂SO₄), and concentrated to give the title compound (0.145 g, 0.54 mmol, 81% yield) as a clear oil. ¹H NMR (501 MHz, DMSO-d₆) δppm 4.36 (d, J = 9.0 Hz, 2H), 1.41 (d, J = 0.5 Hz, 18H). Example 10C: [(di-tert-butoxyphosphatyl)oxy]acetic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl ester

[0274] At room temperature, a solution of the product of Example 10B (0.0277 g, 0.103 mmol), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (0.0473 g, 0.124 mmol), and triethylamine (0.020 mL, 0.143 mmol) in N,N-dimethylformamide (0.30 mL) was stirred for 15 minutes, followed by the addition of the product of Example 1L (0.050 g, 0.095 mmol). The mixture was stirred overnight, diluted with ethyl acetate, washed with water, 1 N NaOH, and brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified on silica gel (25-50% ethyl acetate / dichloromethane) to give an approximately 1:1 mixture of the product of Example 1L and the title compound (39.2 mg mixture, approximately 31% product yield). This mixture was used without purification. LC / MS (APCI+) m / z 667 (M-2(t-Bu)+H)+. Example 10D: (phosphatoxy)acetic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl ester

[0275] At room temperature, a mixture from Example 10C (approximately 0.025 mmol) and a solution of 2,2,2-trifluoroacetic acid (40 µL, 0.523 mmol) in CH₂Cl₂ (0.20 mL) were stirred for 1 hour. The mixture was concentrated and purified by preparative HPLC (Phenomenex® Luna® 250 × 30 mm 10 μm C18 column, 60 mL / min, 15-95% gradient of acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to give a product containing residual dimethyl sulfoxide. This substance was diluted with ethyl acetate, washed with water, concentrated and dried under vacuum to give the title compound (0.014 g, 0.021 mmol, 41.7% yield). 1H NMR (501 MHz, DMSO- d 6) δppm7.63 (s, 1H), 7.58 (s, 1H), 7.46 (td, J =8.9, 6.3 Hz, 2H), 7.00 (ddd, J =14.0, 11.4, 2.9 Hz, 2H), 6.79 (ddd, J =12.8, 9.0, 2.9 Hz, 2H), 5.36 (d, J =9.1 Hz, 1H), 4.46 – 4.35 (m, 6H), 2.48 – 2.38 (m, 1H), 2.30 – 2.15 (m, 1H), 2.06 – 1.72 (m, 8H);MS (ESI -) m / z664.8 (MH) -. [Example]

[11] Carbonated [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [phosphonoyl] [)] [Methyl acetate] [(] [Compound] [110)] Example 11A: O-(chloromethyl)S-propylthiocarbonate

[0276] In a 1 L round-bottom flask, N,N-diisopropylethylamine (33.1 mL, 189 mmol) and propane-1-thiol (16 mL, 172 mmol) were dissolved in methyl tributyl ether (345 mL), and the flask was cooled to <5 °C. Then, methyl chloroformate (16.08 mL, 181 mmol) was added dropwise via syringe. The reaction was stirred overnight while simultaneously warming to room temperature. The resulting white suspension was treated with 100 mL of 1 M HCl (aqueous solution), and the layers were separated. The organic layer was washed with 1 M HCl (2 × 50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum to give 29 g of the title compound as a colorless oil, which was used without further purification. 1H NMR (400 MHz, CDCl 3) δppm5.77 (s, 2H), 2.90 (dd, J= 7.6, 6.9 Hz, 2H), 1.71 (dt, J= 14.5, 7.3 Hz, 2H), 1.01 (t, J= 7.4 Hz, 3H). Example 11B: O-(iodomethyl)S-propylthiocarbonate

[0277] Example 11A (29.5 g, 175 mmol) was dissolved in acetone (200 mL) and sodium iodide (52.4 g, 350 mmol) was added. The reaction mixture was heated to 40 °C after covering the flask with foil. After 90 minutes, the flask was cooled to room temperature, and the solid material was removed via a sintered funnel. The filtrate was then concentrated under reduced pressure to approximately 30 mL. The solution was diluted with methyl tributyl ether (300 mL) and washed with water (3 × 50 mL), saturated sodium thiosulfate aqueous solution (2 × 25 mL), water (50 mL), and brine (50 mL), followed by drying over anhydrous sodium sulfate. The mixture was concentrated under vacuum to give a crude oil (44.8 g) which was used without further purification. 1H NMR (400 MHz, CDCl 3) δppm5.99 (s, 2H), 2.95 – 2.85 (m, 2H), 1.70 (h, J= 7.3 Hz, 2H), 1.01 (t, J= 7.3 Hz, 3H). Example 11C: Silver (1+) diphenyl phosphate salt

[0278] 26.7 g (96 mmol) of diphenyl phosphate was suspended in 300 mL of deionized water, and sodium hydroxide solution (1 M aqueous solution, 96 mL, 96 mmol) was added. The resulting suspension was stirred at room temperature for 30 minutes, at which point complete dissolution and a pH of approximately 6–7 were achieved. A solution of silver nitrate (I) (17.12 g, 101 mmol) in 150 mL of water was added dropwise through a feeding funnel while stirring vigorously. The resulting white solid was separated by filtration through a 600 mL sintered funnel. The separated solid was washed with acetone (2 × 200 mL) and methyl tributyl ether (200 mL), and then dried to constant weight in a vacuum oven at 70 °C to give 34.1 g of the title compound as a white solid, which was used without further purification or characterization. Example 11D: O-({[bis(benzyloxy)phosphatidyl]oxy}methyl)S-propylthiocarbonate

[0279] Example 11B (44.8 g, 172 mmol) was dissolved in acetonitrile (344 mL), and Example 11C (66.3 g, 172 mmol) was added in whole. The resulting pale yellow suspension was stirred at room temperature under N2 for 3 hours. The solid material was removed via a sintered funnel, and the filtrate was diluted with 100 mL of ethyl acetate and then filtered again. The filtrate was concentrated under vacuum to give the title compound as a pale yellow oil, which was used directly without further purification (63.8 g). 1H NMR (400 MHz, CDCl 3) δppm7.34 (d, J= 2.3 Hz, 10H), 5.65 (d, J= 13.9 Hz, 2H), 5.07 (d, J= 7.9 Hz, 4H), 2.92 – 2.69 (m, 2H), 1.66 (hept, J= 7.5 Hz, 2H), 0.97 (t, J= 7.4 Hz, 3H); MS (ESI) m / z411.1 (M+H) +. Example 11E: Chloroformic acid {[bis(benzylmethyloxy)phosphatidyl]oxy}methyl ester

[0280] Example 11D (25.5 g, 62.1 mmol) and a stir bar were loaded into a 25 mL round-bottom flask. After cooling to <5 °C in an ice-water bath, sulfonyl chloride (6.06 mL, 74.6 mmol) was added dropwise. The solution was stirred at the same temperature for 30 min, and then heated to room temperature and held for 1 h, at which point 1H NMR analysis showed complete conversion. Volatile substances were removed under vacuum at 35 °C. The resulting crude oil was loaded onto a 330 g silicone column and purified by rapid chromatography, dissociating with 0:100 to 50:50 ethyl acetate:heptane for 15 min, followed by dissociation with an equal concentration of 50:50 ethyl acetate:heptane for 5 min, to give 12.5 g of the title compound as a pale yellow oil. 1H NMR (500 MHz, CDCl 3) δppm7.41 – 7.30 (m, 10H), 5.62 (d, J= 14.5 Hz, 2H), 5.08 (d, J= 8.4 Hz, 4H). Example 11F: Carbonic acid {[bis(benzylmethyloxy)phosphatyl]oxy}methyl(2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0281] A suspension of Example 11E (2.0670 g, 5.58 mmol) and N,N-dimethylpyridin-4-amine (0.69 g, 5.67 mmol) in CH₂Cl₂ (15 mL) was stirred for 2 minutes, and the product of Example 1L (1.5 g, 2.83 mmol) was added, followed by the addition of triethylamine (1.0 mL, 7.17 mmol). The mixture was stirred for 1 hour, then quenched with water and concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with 1 N HCl (aqueous solution), water, and brine. The organic fraction was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified on silica gel (50-90% ethyl acetate / heptane, 40 g Teledyne IscoRediSep Rf Gold®) to give a white solid, which was crystallized from ethyl acetate (about 0.5 v / L) and tributyl methyl ether (about 4 v / L) to give the title compound (1.42 g, 1.64 mmol, 58% yield). 1H NMR (501 MHz, DMSO- d 6) δppm7.68 (s, 1H), 7.65 (s, 1H), 7.49 – 7.44 (m, 1H), 7.42 (d, J= 8.9 Hz, 1H), 7.39 – 7.30 (m, 10H), 7.02 (dd, J= 11.4, 2.8 Hz, 1H), 6.94 (dd, J= 11.4, 2.9 Hz, 1H), 6.80 (ddd, J= 8.9, 2.9, 1.1 Hz, 1H), 6.74 (ddd, J= 9.0, 2.9, 1.1 Hz, 1H), 5.65 (dd, J= 14.3, 5.7 Hz, 1H), 5.58 (dd, J= 12.9, 5.7 Hz, 1H), 5.39 (dd, J= 9.4, 2.2 Hz, 1H), 5.05 (dd, J= 8.2, 1.8 Hz, 4H), 4.50 – 4.33 (m, 4H), 2.49 – 2.43 (m, 1H), 2.29 (m, 8.1 Hz, 1H), 2.03 – 1.92 (m, 2H), 1.92 – 1.73 (m, 6H); LC / MS (APCI +) m / z863 (M+H) +. Example 11G: Carbonic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester (phosphatoxy) methyl ester

[0282] In a 20 mL Barnstead Hast C reactor, 5% Pd / C (wet, JM#9) (5.91 mg, 0.025 mmol) was added to a solution of Example 11F (0.030 g, 0.035 mmol) in tetrahydrofuran (1.0 mL) and a dioxane solution of 4 N HCl (0.019 mL, 0.077 mmol). The reactor was purged with argon, and the mixture was stirred at 1200 RPM at 25 °C under 50 psi hydrogen. After 1 hour, the mixture was vented and filtered. The filtrate was concentrated under reduced pressure and azeotropically reacted with toluene. The resulting material was slurried with 1:1 methyl tributyl ether:heptane, and the solid was separated by filtration. The solid was dissolved in acetone and concentrated to remove the solvent. The material was then dissolved in acetonitrile (5 mL) and water (1 mL) and lyophilized to give the title compound (1.02 g, 1.49 mmol, 92% yield). 1H NMR (400 MHz, DMSO- d 6) δppm7.66 (d, J= 6.6 Hz, 2H), 7.47 (td, J= 8.9, 5.9 Hz, 2H), 7.01 (ddd, J= 15.7, 11.4, 2.9 Hz, 2H), 6.79 (td, J= 9.5, 2.8 Hz, 2H), 5.47 (ddd, J= 24.8, 13.2, 5.5 Hz, 2H), 5.35 (dd, J= 9.3, 2.2 Hz, 1H), 4.51 – 4.37 (m, 4H), 2.49 – 2.40 (m, 1H), 2.32 (m, 1H), 2.06 – 1.69 (m, 8H); MS (ESI -) m / z680.6 (MH) -. [Example]

[12] [:] [[4-({(2 , S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [base] [}] [Oxygen group] [)-4-] [Side-oxybutyl] []] [phosphonic acid] [(] [Compound] [111)]

[0283] At room temperature, oxalic acid (0.030 mL, 0.344 mmol) was added to a suspension of 4-phosphatidylbutyric acid (0.0509 g, 0.303 mmol) in CH₂Cl₂ (0.60 mL) and N,N-dimethylformamide (1 drop) for catalysis, and the mixture was stirred for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (0.60 mL). The product from Example 1L (0.158 g, 0.30 mmol) was added, followed by N,N-dimethylpyridin-4-amine (0.037 g, 0.30 mmol) and triethylamine (0.060 mL, 0.430 mmol). The reaction was stirred for 2 hours, then heated to 70°C and stirred for 4 days. The mixture was partitioned between ethyl acetate and 1 N HCl (1 mL, aqueous solution). The organic fraction was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative LC (YMCTriArt™ C18 Hybrid 5 μm column, 50 × 100 mm, 140 mL / min, 3-100% gradient of acetonitrile / 25 mM ammonium bicarbonate buffer, adjusted to pH 10 with concentrated NH₄OH aqueous solution) to give the title compound (0.025 g, 0.037 mmol, 12% yield). 1H NMR (400 MHz, DMSO- d 6) δppm7.95 (s, 1H), 7.65 (s, 1H), 7.44 (dt, J= 13.6, 8.9 Hz, 2H), 6.99 (ddd, J= 14.6, 11.4, 2.9 Hz, 2H), 6.79 (ddd, J= 9.1, 6.1, 2.8 Hz, 2H), 5.32 (dd, J= 9.3, 2.2 Hz, 1H), 4.46 (d, J= 2.6 Hz, 2H), 4.43 (s, 2H), 2.48 – 2.18 (m, 5H), 2.05 – 1.64 (m, 9H), 1.44 (m, 2H);MS (ESI -) m / z677.0 (MH) -. [Example]

[13] [:] [(] [Benzylmethyloxy] [)] [Acetic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [112)]

[0284] To a suspension of the product of Example 1L (0.3 g, 0.567 mmol), 2-(benzylmethyloxy)acetic acid (0.141 g, 0.850 mmol), and N,N-diisopropylethylamine (0.30 mL, 1.70 mmol) in N,N-dimethylformamide (5 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.648 g, 1.71 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. Water was added, and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by HPLC (Phenomenex® Luna® C18(2) 10 µm 100ÅAXIA™ column (250 mm × 50 mm). The residue was purified over 25 minutes using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid / water (B) at a flow rate of 50 mL / min) to give 380 mg of the title compound. 1H NMR (400 MHz, DMSO- d 6) δppm7.66 (d, J =19.7 Hz, 1H), 7.52 – 7.33 (m, 2H), 7.37 – 7.25 (m, 4H), 6.99 (ddd, J =17.3, 11.4, 2.9 Hz, 2H), 6.79 (dddd, J =18.7, 8.9, 2.8, 1.2 Hz, 2H), 5.46 (dd, J =9.6, 2.1 Hz, 1H), 4.59 – 4.50 (m, 2H), 4.52 – 4.34 (m, 4H), 4.14 (d, J =1.4 Hz, 2H), 2.44 (td, J =10.6, 9.1, 5.4 Hz, 1H), 2.26 (d, J =12.3 Hz, 1H), 2.02 (t, J =9.2 Hz, 1H), 1.98 – 1.84 (m, 4H), 1.84 (d, J =11.9 Hz, 3H);MS (ESI+) m / z694.0 (M+H) +. [Example]

[14] [:] [[3-(] [phosphonoyl] [)] [Phenyl] []] [Acetic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [113)] Example 14A: methyl 3-[(di-tert-butoxyphosphatyl)oxy]phenyl}acetate

[0285] At 0 °C, diisopropylaminophosphate ditert-butyl ester (7.1 mL, 23 mmol) was added to a solution of methyl 2-(3-hydroxyphenyl)acetate (2.5 g, 15 mmol) and 1 H-tetrazole (67 mL, 30 mmol, 0.45 M acetonitrile solution) in anhydrous CH₂Cl₂ (20 mL). The resulting solution was heated to ambient temperature and stirred for 4.5 h. The reaction mixture was cooled to 0 °C, and tributyl peroxide (70% aqueous solution, 6.2 mL, 45 mmol) was added. The resulting mixture was heated to ambient temperature and stirred for 1 h, followed by washing with saturated Na₂S₂O₃ solution (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 0–50% ethyl acetate / heptane) to give the title compound as a colorless oil (4.77 g, 13.3 mmol, 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 7.32 (t, J = 7.8 Hz, 1H), 7.15–7.04 (m, 3H), 3.70 (s, 2H), 3.61 (s, 3H), 1.44 (d, J = 0.7 Hz, 18H). Example 14B: {3-[(di-tert-butoxyphosphatyl)oxy]phenyl}acetic acid

[0286] Lithium hydroxide (0.96 g, 40 mmol) was added to a cold (0°C ice bath) solution of the product of Example 14A (4.77 g, 13.3 mmol) in tetrahydrofuran (15 mL) and water (5 mL). The mixture was stirred at ambient temperature for 2 hours, followed by the addition of 1.0 M HCl to acidify the reaction mixture to pH 3.0. The reaction mixture was extracted with ethyl acetate (50 mL). The organic fraction was washed with water (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title intermediate (3 g, 8.7 mmol, 65% yield) as a yellow oil, which was used directly without purification. 1H NMR (500 MHz, DMSO- d 6) δppm 9.32 (s, 1H), 7.34 – 7.28 (m, 1H), 7.11 (dq, J =4.0, 2.6, 1.9 Hz, 1H), 7.09 – 7.04 (m, 2H), 3.57 (s, 2H), 1.46 – 1.43 (m, 18H). Example 14C: {3-[(di-tert-butoxyphosphatyl)oxy]phenyl}acetic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0287] Triethylamine (1.1 mL, 7.6 mmol) was added to a mixture of the product of Example 1L (1 g, 2 mmol) and the product of Example 14B (0.68 g, 2.0 mmol) in N,N-dimethylformamide (10.73 mL), followed by the addition of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.79 g, 2.1 mmol). The mixture was stirred at ambient temperature for 20 hours, and then the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified directly by preparative HPLC [Waters XBridge™ C18 5 μm OBD column, 30 × 100 mm, flow rate 40 mL / min, 5-100% gradient acetonitrile / buffer (0.1% trifluoroacetic acid)] to give the title intermediate (0.49 g, 0.58 mmol, 31% yield). 1H NMR (501 MHz, DMSO- d 6) δppm 7.56 (s, 1H), 7.49 (s, 1H), 7.43 (dt, J =18.7, 8.9 Hz, 2H), 7.27 (t, J =7.9 Hz, 1H), 7.10 – 7.02 (m, 3H), 6.96 (ddd, J =26.8, 11.4, 2.9 Hz, 2H), 6.77 (ddd, J =8.8, 2.8, 1.1 Hz, 1H), 6.71 (ddd, J =9.0, 2.9, 1.1 Hz, 1H), 5.32 (dd, J =9.6, 2.3 Hz, 1H), 4.40 (s, 2H), 4.37 (d, J =15.0 Hz, 1H), 4.29 (d, J =14.6 Hz, 1H), 3.64 (d, J =3.0 Hz, 2H), 2.40 (ddd, J =13.9, 9.0, 2.6 Hz, 1H), 2.25 – 2.16 (m, 1H), 1.89 – 1.69 (m, 8H), 1.40 (d, J =2.5 Hz, 18H). Example 14D: [3-(phosphatoxy)phenyl]acetic acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0288] Trifluoroacetic acid (2 mL) was added to a solution of the product of Example 14C (0.49 g, 0.58 mmol) in CH₂Cl₂ (9.6 mL). The reaction mixture was stirred for 1 hour, followed by concentration under reduced pressure. The solid was dried under vacuum for 2 days to give the title compound (0.43 g, 0.58 mmol, quantitative yield). 1H NMR (400 MHz, DMSO- d 6) δppm 7.61 (d, J =8.0 Hz, 2H), 7.45 (dt, J =15.4, 8.9 Hz, 2H), 7.26 (t, J =7.9 Hz, 1H), 7.14 (d, J =1.9 Hz, 1H), 7.08 – 7.02 (m, 3H), 7.02 – 6.91 (m, 2H), 6.76 (ddt, J =35.0, 9.1, 1.8 Hz, 3H), 5.38 (dd, J =9.5, 2.3 Hz, 1H), 4.43 (s, 2H), 4.40 (d, J =14.5 Hz, 1H), 4.24 (d, J =14.5 Hz, 1H), 3.65 (s, 2H), 2.41 (dd, J =14.1, 9.5 Hz, 1H), 2.29 (td, J =11.9, 5.7 Hz, 1H), 1.96 – 1.72 (m, 8H);MS (ESI +) m / z744 (M+H) +. [Example]

[15] [:] [3-[2,4-] [Dimethyl] [-6-(] [phosphonoyl] [)] [Phenyl] []-3-] [Methylbutyric acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3-] [Fluorophylate] [)] [Acetamino] []] [Double Ring] [[2.2.2]] [pungent] [2-] [Base ester] [(] [Compound] [114)] Example 15A: 3-(2-{[bis(benzyloxy)phosphatidyl]oxy}-4,6-dimethylphenyl)-3-methylbutyric acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl 2-ester

[0289] To a solution of the product of Example 1L (0.150 g, 0.283 mmol), 4-dimethylaminopyridine (0.042 g, 0.340 mmol), and 3-(2-((bis(benzyloxy)phosphatidyl)oxy)-4,6-dimethylphenyl)-3-methylbutyric acid (0.178 g, 0.368 mmol, CAS # 153910-62-4, Bioorganic & Medicinal Chemistry Letters, 1993, 3(8), 1761-1766) in N,N-dimethylformamide (4 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.087 g, 0.45 mmol) was added, and the mixture was stirred overnight. The reaction mixture was then quenched with brine and saturated NaHCO3 aqueous solution and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified on a 40 g silicon dioxide column using a Biotage Isolera™ One flash system, and dissociated with heptane / ethyl acetate (4:6 to 3:7) to give 0.101 g of the title compound (36%). MS (ESI+) m / z 993.4 (M+H)+. Example 15B: 3-[2,4-dimethyl-6-(phosphatoxy)phenyl]-3-methylbutyric acid (2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamino]bicyclo[2.2.2]octyl ester

[0290] The mixture of Example 15A (97.0 mg, 0.098 mmol) and trifluoroacetic acid (0.15 mL, 1.95 mmol) in CH₂Cl₂ (0.4 mL) was stirred for 3 days. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase HPLC on a Phenomenex® Luna® C18 column (250 × 30 mm, 10 µm particle size) using acetonitrile:0.1% trifluoroacetic acid aqueous solution in a 20% to 100% gradient for 26 minutes at a flow rate of 50 mL / min to give the title compound (57.5 mg, 58%). 1H NMR (400 MHz, CD 3OD) δppm 7.35 (dt, J =19.5, 8.7 Hz, 2H), 7.08 (s, 1H), 6.91 (dd, J =11.0, 2.8 Hz, 1H), 6.87 – 6.77 (m, 2H), 6.72 (ddd, J =8.9, 2.8, 1.2 Hz, 1H), 6.63 – 6.53 (m, 1H), 5.33 (dd, J =9.5, 1.9 Hz, 1H), 4.41 (s, 2H), 4.32 (a of ab, J =14.8 Hz, 1H), 4.14 (b of ab, J =14.8 Hz, 1H), 3.04 (s, 2H), 2.49-2.38 (m, 4H), 2.26 (td, J =11.5, 11.0, 5.8 Hz, 1H), 2.05 – 1.69 (m, 8H), 1.63 (s, 3H), 1.58 (s, 3H);MS (ESI +) m / z813.1 (M+H) +. [Example]

[16] [:] [[2-(] [phosphonoyl] [)] [Phenyl] []] [Acetic acid] [(2, S , )-1,4- ] [pair] [[2-(4-] [chlorine] [-3...

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of leukoablative encephalopathy (VWMD) or amyotrophic lateral sclerosis (ALS), wherein the compound is represented by formula (I): (I); or a pharmaceutically acceptable salt or hydrate thereof, wherein: R1 series is selected from the following groups of compositions: -C(O)-C1-4 alkyl, -C(O)-O-C1-4 alkyl, -C(O)-N(Ra)-C1-4 alkyl, -C(O)-C1-4 alkyl-C1-4 alkoxy, -C(O)-C1-4 alkyl-O-C1-4 alkyl-C1-4 alkoxy, -C(O)-C1-5 alkyl-OP(O)(OH)2, -C(O)-O-C1-5 alkyl-OP(O)(OH)2, -C(O)-N(Ra)-C1-5 alkyl-OP(O)(OH)2, -C(O)-C1-5 alkyl-P(O)(OH)2, -C(O)-C1-5 alkyl-phenyl-OP(O)(OH)2, -C(O)-C1-5 alkyl-phenyl-(OP(O)(OH)2) 2. -C(O)-C1-5 alkyl-phenyl-(OP(O)(OH)2)(O-C1-5 alkyl-P(O)(OH)2), -methylene-OC(O)C1-5 alkyl-phenyl-OP(O)(OH)2, -methylene-OC(O)C1-5 alkyl-phenyl-(OP(O)(OH)2)2, -C(O)-O-C1-5 alkyl-OC(O)C1-5 alkyl-phenyl-OP(O)(OH)2, -C(O)-N(Ra)-heteroaryl-C1-2 alkyl-OP(O)(OH)2, -P(O)(OH)2, -SO3H, -SO2NRaRb, -C(O)-heteroaryl, -C(O)-C1-5 alkyl-O-C1-5 alkyl-phenyl and methylene-C1-5 alkoxide; The -C(O)-C1-4 alkyl group is substituted by one or two substituents, each of which is independently selected from the group consisting of -NRaRb and -CO2H.And among them -C(O)-O-C1-4 alkyl, -C(O)-N(Ra)-C1-4 alkyl, -C(O)-C1-4 alkyl-C1-4 alkoxy, -C(O)-C1-4 alkyl-O-C1-4 alkyl-C1-4 alkoxy, -C(O)-C1-5 alkyl-OP(O)(OH)2, -C(O)-O-C1-5 alkyl-OP(O)(OH)2, -C(O)-N(R a) -C1-5-alkyl-OP(O)(OH)2, -C(O)-C1-5-alkyl-P(O)(OH)2, -C(O)-C1-5-alkyl-phenyl-OP(O)(OH)2, -C(O)-C1-5-alkyl-phenyl-(OP(O)(OH)2)2, -C(O)-C1-5-alkyl-phenyl-(OP(O)(OH)2)(O-C1-5-alkyl-P(O)( OH)2), -methylene-OC(O)C1-5 alkyl-phenyl-OP(O)(OH)2, -methylene-OC(O)C1-5 alkyl-phenyl-(OP(O)(OH)2)2, -C(O)-O-C1-5 alkyl-OC(O)C1-5 alkyl-phenyl-OP(O)(OH)2, -C(O)-heteroaryl, -C(O)-C1-5 alkyl-O-C1-5 alkyl- The phenyl group and -C(O)-N(Ra)-endoaryl-C1-2 alkyl-OP(O)(OH)2 may be substituted with one, two, three, or four substituents, each independently selected from the group consisting of halogens, -CO2H, -NRaRb, and C1-2 alkyl groups (substituted with one, two, or three fluorine groups, depending on the case) and aryl groups; and Ra and Rb, each time appearing, are independently selected from the group consisting of hydrogen and C1-3 alkyl groups.

2. As claimed in claim 1, wherein R1 is a -C(O)-C1-4 alkyl group, wherein the -C(O)-C1-4 alkyl group is substituted by one or two substituents, each of which is independently selected from the group consisting of -NRaRb and -CO2H.

3. As used in Request 1 or Request 2, wherein R1 is selected from the group consisting of: , , , and.

4. As claimed in claim 1, wherein R1 is a -C(O)-O-C1-4 alkyl group.

5. As requested in item 4, where R1 is selected as a group of free and composed members.

6. As claimed in claim 1, wherein R1 is a -C(O)-N(Ra)-C1-4 alkyl group, wherein the -C(O)-N(Ra)-C1-4 alkyl group may be substituted with one or two –CO2H groups as appropriate.

7. As used in request item 6, where R1 is represented by, or.

8. As claimed in claim 1, wherein R1 is a C(O)-C1-4 alkyl-C1-4 alkoxy group.

9. As requested in item 8, where R1 is selected as a group of free and composed entities.

10. As claimed in claim 1, wherein R1 is a C(O)-C1-4 alkyl-O-C1-4 alkyl-C1-4 alkoxy.

11. As used in request item 10, where R1 is represented by [representation].

12. As claimed in claim 1, wherein R1 is a -C(O)-C1-5 alkyl-OP(O)(OH)2.

13. As requested in item 12, wherein R1 is selected from the group consisting of: , , and.

14. As claimed in claim 1, wherein R1 is a -C(O)-O-C1-5 alkyl-OP(O)(OH)2.

15. As requested in Item 14, wherein R1 is selected from the group consisting of: , and .

16. As claimed in claim 1, wherein R1 is a -C(O)-N(Ra)-C1-5 alkyl-OP(O)(OH)2.

17. As used in claim 16, where R1 is selected as a group of free and composed members.

18. As claimed in claim 1, wherein R1 is a -C(O)-C1-5 alkyl-P(O)(OH)2.

19. As used in request item 18, where R1 is represented by [representation].

20. As claimed in claim 1, wherein R1 is -C(O)-C1-5-alkyl-phenyl-OP(O)(OH)2, -C(O)-C1-5-alkyl-phenyl-(OP(O)(OH)2)2 or -C(O)-C1-5-alkyl-phenyl-(OP(O)(OH)2)(O-C1-5-alkyl-P(O)(OH)2).

21. As requested in item 20, wherein R1 is selected from the group consisting of: , , , and.

22. As claimed in claim 1, wherein R1 is a C(O)-N(Ra)-aryl-C1-2-aryl-OP(O)(OH)2.

23. As used in request item 22, where R1 is represented by [representation].

24. As requested in item 1, wherein R1 is a -C(O)-heteroaryl group.

25. As requested in item 24, wherein R1 is selected as a group of free and composed members.

26. As claimed in claim 1, wherein R1 is a C(O)-C1-5-alkyl-O-C1-5-alkyl-phenyl.

27. As used in request item 26, where R1 is represented by [representation].

28. As claimed in claim 1, wherein R1 is a methylene-C1-5 alkoxide.

29. As used in request item 28, where R1 is represented by [representation].

30. As claimed in claim 1, wherein R1 is -C(O)-O-C1-5-alkyl-OC(O)C1-5-alkyl-phenyl-OP(O)(OH)2, -methylene-OC(O)C1-5-alkyl-phenyl-OP(O)(OH)2 or -methylene-OC(O)C1-5-alkyl-phenyl-(OP(O)(OH)2)2.

31. As used in request item 30, where R1 is represented by, or.

32. As requested in claim 1, wherein R1 is selected from the group consisting of -P(O)(OH)2, -SO3H and -SO2NH2.

33. Use of a compound or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of leukoablative encephalopathy (VWMD) or amyotrophic lateral sclerosis (ALS), wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt thereof.